ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
APTIVUS 250 mg soft capsules
2.
Each soft capsule contains 250 mg tipranavir.
Excipients (per capsule): 100.0 mg ethanol, 455.0 mg macrogolglycerol ricinoleate and 12.6 mg
sorbitol (constituent in « Sorbitol Special-Glycerin Blend »)
For a full list of excipients, see section 6.1.
3.
Soft capsule.
Each capsule is pink and is imprinted with “TPV 250”.
4.
APTIVUS, co-administered with low dose ritonavir, is indicated for combination antiretroviral
treatment of HIV-1 infection in highly pre-treated adults and adolescents 12 years of age or older with
virus resistant to multiple protease inhibitors. APTIVUS should only be used as part of an active
combination antiretroviral regimen in patients with no other therapeutic options.
This indication is based on the results of two phase III studies, performed in highly pre-treated adult
patients (median number of 12 prior antiretroviral agents) with virus resistant to protease inhibitors
and of one phase II study investigating pharmacokinetics, safety and efficacy of APTIVUS in mostly
treatment-experienced adolescent patients aged 12 to 18 years (see section 5.1).
In deciding to initiate treatment with APTIVUS, co-administered with low dose ritonavir, careful
consideration should be given to the treatment history of the individual patient and the patterns of
mutations associated with different agents. Genotypic or phenotypic testing (when available) and
treatment history should guide the use of APTIVUS. Initiation of treatment should take into account
the combinations of mutations which may negatively impact the virological response to APTIVUS,
co-administered with low dose ritonavir (see section 5.1).
APTIVUS must always be given with low dose ritonavir as a pharmacokinetic enhancer, and in
combination with other antiretroviral medicinal products. The Summary of Product Characteristics of
ritonavir must therefore be consulted prior to initiation of therapy with APTIVUS (especially as
regards the contraindications, warnings and undesirable effects sections).
APTIVUS should be prescribed by physicians who are experienced in the treatment of HIV-1
infection.
APTIVUSwith ritonavir should not be used in treatment-naïve patients.
Posology
2
Patients should be advised of the need to take APTIVUS and ritonavir every day as prescribed. If a
dose is missed by more than 5 hours, the patient should be instructed to wait and then to take the next
dose of APTIVUS and ritonavir at the regularly scheduled time. If a dose is missed by less than 5
hours, the patient should be instructed to take the missed dose immediately, and then to take the next
dose of APTIVUS and ritonavir at the regularly scheduled time.
Adults
The recommended dose of APTIVUS is 500 mg, co-administered with 200 mg ritonavir (low dose
ritonavir), twice daily.
Doses of ritonavir lower than 200 mg twice daily should not be used as they might alter the efficacy
profile of the combination.
Paediatric population
Adolescents from 12 years of age
The recommended dose of APTIVUS is 500 mg, co-administered with 200 mg ritonavir (low dose
ritonavir), twice daily (see section 4.4 for precautionary measures in adolescents).
Doses of ritonavir lower than 200 mg twice daily should not be used as they might alter the efficacy
profile of the combination.
Since currently only limited efficacy and safety data are available for adolescents (see section 5.1)
close monitoring of virologic response and tolerance is particularly warranted in this patient group.
Children under 12 years of age:
The safety and efficacy of APTIVUS capsules in children aged 2 to 12 years has not been established.
Currently available data are described in section 5.1 and 5.2 but no recommendation on a posology can
be made.
Also, appropriate dose adjustments for children under 12 years cannot be achieved with APTIVUS
capsules. APTIVUS oral solution is available for children between 2 and 12 years of age (please refer
to the respective SPC for further details).
The safety and efficacy of APTIVUS in children under 2 years of age has not been established. No
data are available.
Elderly
Clinical studies of APTIVUS did not include sufficient numbers of subjects aged 65 and over to
determine whether they respond differently from younger subjects (see section 5.2).
In general, caution should be exercised in the administration and monitoring of APTIVUS in elderly
patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of
concomitant disease or other therapy. (see section 4.4)
Liver impairment
Tipranavir is metabolised by the hepatic system. Liver impairment could therefore result in an increase
of tipranavir exposure and a worsening of its safety profile. Therefore, APTIVUS should be used with
caution, and with increased monitoring frequency, in patients with mild hepatic impairment (Child-
Pugh Class A). APTIVUS is contraindicated in patients with moderate or severe (Child-Pugh Class B
or C) hepatic impairment (see sections 4.3, 4.4 and 5.2).
Renal impairment
No dosage adjustment is required in patients with renal impairment (see sections 4.4 and 5.2).
Method of administration
APTIVUS soft capsules co-administered with low dose ritonavir should be taken with food (see
section 5.2).
3
Hypersensitivity to the active substance or to any of the excipients.
Patients with moderate or severe (Child-Pugh B or C) hepatic impairment.
Combination of rifampicin with APTIVUS with concomitant low dose ritonavir is contraindicated (see
section 4.5).
Herbal preparations containing St John’s wort (
Hypericum perforatum
) must not be used while taking
APTIVUS due to the risk of decreased plasma concentrations and reduced clinical effects of tipranavir
(see section 4.5).
Co-administration of APTIVUS with low dose ritonavir, with active substances that are highly
dependent on CYP3A for clearance, and for which elevated plasma concentrations are associated with
serious and/or life-threatening events, is contraindicated. These active substances include
antiarrhythmics (amiodarone, bepridil, quinidine), antihistamines (astemizole, terfenadine), ergot
derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine), gastrointestinal motility
agents (cisapride), neuroleptics (pimozide, sertindole), sedatives/hypnotics (orally administered
midazolam and triazolam. For caution on parenterally administered midazolam see section 4.5) and
HMG-CoA reductase inhibitors (simvastatin and lovastatin). In addition, co-administration of
APTIVUS with low dose ritonavir, and medicinal products that are highly dependent on CYP2D6 for
clearance, such as the antiarrhythmics flecainide, propafenone and metoprolol given in heart failure, is
contraindicated (see section 4.5).
APTIVUS must be administered with low dose ritonavir to ensure its therapeutic effect (see section
4.2). Failure to correctly co-administer tipranavir with ritonavir will result in reduced plasma levels of
tipranavir that may be insufficient to achieve the desired antiviral effect. Patients should be instructed
accordingly.
APTIVUS is not a cure for HIV-1 infection or AIDS. Patients receiving APTIVUS
or any other
antiretroviral therapy may continue to develop opportunistic infections and other complications of
HIV-1 infection.
Patients should be advised that current antiretroviral therapy has not been proven to prevent the risk of
transmission of HIV to others through blood or sexual contact. Appropriate precautions should
continue to be employed.
Switching from APTIVUS capsules to the oral solution:
APTIVUS capsules are not interchangeable
with the oral solution. Compared to the capsules, tipranavir exposure is higher when administering the
same dose as oral solution. Also, the composition of the oral solution is different from that of the
capsules, with the high vitamin E content being especially noteworthy. Both of these factors may
contribute to an increased risk of adverse reactions (type, frequency and/or severity). Therefore
patients should not be switched from APTIVUS capsules to APTIVUS oral solution (see sections 5.1
and 5.2).
Switching from APTIVUS oral solution to the capsules:
APTIVUS oral solution is not interchangeable
with the capsules. Compared to the oral solution, tipranavir exposure is lower when administering the
same dose as capsules. However, children previously treated with APTIVUS oral solution and
becoming 12 years of age should be switched to capsules, particularly because of the more favourable
safety profile of the capsules. It has to be noted that the switch from the oral solution to the capsule
formulation of APTIVUS could be associated with decreased exposure. Therefore, it is recommended
that patients switching from APTIVUS oral solution to capsules at the age of 12 years are closely
monitored for the virologic response of their antiretroviral regimen (see sections 5.1 and 5.2).
4
Elderly:
Clinical studies of APTIVUS did not include sufficient numbers of subjects aged 65 and over
to determine whether they respond differently from younger subjects (see section 5.2).
In general, caution should be exercised in the administration and monitoring of APTIVUS in elderly
patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of
concomitant disease or other therapy (see section 4.2).
Liver disease:
APTIVUS is contraindicated in patients with moderate or severe (Child-Pugh Class B
or C) hepatic insufficiency. Limited data are currently available for the use of APTIVUS, co-
administered with low dose ritonavir, in patients co-infected with hepatitis B or C. Patients with
chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for
severe and potentially fatal hepatic adverse reaction. APTIVUS should be used in this patient
population only if the potential benefit outweighs the potential risk, and with increased clinical and
laboratory monitoring. In the case of concomitant antiviral therapy for hepatitis B or C, please refer
also to the relevant Summary of Product Characteristics for these medicinal products.
Patients with mild hepatic impairment (Child-Pugh Class A) should be closely monitored.
Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased
frequency of liver function abnormalities during combination therapy and should be monitored
according to standard practice. APTIVUS with ritonavir should be discontinued once signs of
worsening liver function occur in patients with pre-existing liver disease.
APTIVUS co-administered with low dose ritonavir, has been associated with reports of clinical
hepatitis and hepatic decompensation, including some fatalities. These have generally occurred in
patients with advanced HIV disease taking multiple concomitant medicinal products. Caution should
be exercised when administering APTIVUS to patients with liver enzyme abnormalities or with a
history of hepatitis. Increased ALAT/ASAT monitoring should be considered in these patients.
APTIVUS therapy should not be initiated in patients with pre-treatment ASAT or ALAT greater than
5 times the Upper Limit Normal (ULN) until baseline ASAT/ALAT is stabilised at less than 5X ULN,
unless the potential benefit justifies the potential risk.
APTIVUS therapy should be discontinued in patients experiencing ASAT or ALAT elevations greater
than 10X ULN, or developing signs or symptoms of clinical hepatitis during therapy. If another cause
is identified (eg acute hepatitis A, B or C virus, gallbladder disease, other medicinal products), then
rechallenge with APTIVUS may be considered when ASAT/ALAT have returned to the patient’s
baseline levels.
Liver monitoring
Monitoring of hepatic tests should be done prior to initiation of therapy, after two, four and then every
four weeks until 24 weeks, and then every eight to twelve weeks thereafter. Increased monitoring (i.e.
prior to initiation of therapy, every two weeks during the first three months of treatment, then monthly
until 48 weeks, and then every eight to twelve weeks thereafter) is warranted when APTIVUS and low
dose ritonavir are administered to patients with elevated ASAT and ALAT levels, mild hepatic
impairment, chronic hepatitis B or C, or other underlying liver disease.
Treatment-naïve patients
In a study performed in antiretroviral naïve adult patients, tipranavir 500°mg with ritonavir 200 mg
twice daily, as compared to lopinavir/ritonavir, was associated with an excess in the occurrence of
significant (grade 3 and 4) transaminase elevations without any advantage in terms of efficacy (trend
towards a lower efficacy). The study was prematurely stopped after 60 weeks.
Therefore, tipranavir with ritonavir should not be used in treatment-naïve patients. (see section 4.2)
Renal impairment
Since the renal clearance of tipranavir is negligible, increased plasma concentrations are not expected
in patients with renal impairment.
5
Haemophilia
There have been reports of increased bleeding, including spontaneous skin haematomas and
haemarthrosis in patients with haemophilia type A and B treated with protease inhibitors. In some
patients additional Factor VIII was given. In more than half of the reported cases, treatment with
protease inhibitors was continued or reintroduced if treatment had been discontinued. A causal
relationship has been evoked, although the mechanism of action had not been elucidated.
Haemophiliac patients should therefore be made aware of the possibility of increased bleeding.
Bleeding
RESIST participants receiving APTIVUS withritonavir tended to have an increased risk of bleeding;
at 24 weeks the relative risk was 1.98 (95% CI=1.03, 3.80). At 48-weeks the relative risk decreased to
1.27 (95% CI=0.76, 2.12). There was no pattern for the bleeding events and no difference between
treatment groups in coagulation parameters. The significance of this finding is being further studied.
Fatal and non-fatal intracranial haemorrhages (ICH) have been reported in patients receiving
APTIVUS, many of whom had other medical conditions or were receiving concomitant medicinal
products that may have caused or contributed to these events. However, in some cases the role of
APTIVUS cannot be excluded. No pattern of abnormal haematological or coagulation parameters has
been observed in patients in general, or preceding the development of ICH. Therefore, routine
measurement of coagulation parameters is not currently indicated in the management of patients on
APTIVUS.
An increased risk of ICH has previously been observed in patients with advanced HIV disease/AIDS
such as those treated in the APTIVUS clinical trials.
In
in vitro
experiments, tipranavir was observed to inhibit human platelet aggregation at levels
consistent with exposures observed in patients receiving APTIVUS with ritonavir.
In rats, co-administration with vitamin E increased the bleeding effects of tipranavir (see section 5.3
Preclinical safety data).
APTIVUS, co-administered with low dose ritonavir, should be used with caution in patients who may
be at risk of increased bleeding from trauma, surgery or other medical conditions, or who are receiving
medicinal products known to increase the risk of bleeding such as antiplatelet agents and
anticoagulants or who are taking supplemental vitamin E. Based on the limits of exposure available
from observation in clinical trials, it is recommended not to co-administer to patients more than
1,200 IU vitamin E per day.
Diabetes mellitus/hyperglycaemia
New onset of diabetes mellitus, hyperglycaemia or exacerbations of existing diabetes mellitus has
been reported in patients receiving antiretroviral therapy, including protease inhibitors. In some of
these the hyperglycaemia was severe and in some cases also associated with ketoacidosis. Many of the
patients had confounding medical conditions, some of which required therapy with agents that have
been associated with the development of diabetes mellitus or hyperglycaemia.
Lipid elevations
Treatment with APTIVUS co-administered with low dose ritonavir and other antiretroviral agents has
resulted in increased plasma total triglycerides and cholesterol. Triglyceride and cholesterol testing
should be performed prior to initiating tipranavir therapy and during therapy. Treatment-related lipid
elevations should be managed as clinically appropriate.
Fat redistribution
Combination antiretroviral therapy has been associated with the redistribution of body fat
(lipodystrophy) in HIV infected patients. The long-term consequences of these events are currently
unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis
and protease inhibitors, and lipoatrophy and nucleoside reverse transcriptase inhibitors, has been
6
hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older
age, and with factors related to the active substance such as longer duration of antiretroviral treatment
and associated metabolic disturbances. Clinical examination should include evaluation for physical
signs of fat redistribution. Consideration should be given to the measurement of fasting serum lipids
and blood glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8).
Immune reactivation syndrome
In HIV-infected patients with severe immune deficiency at the time of institution of combination
antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic
pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically,
such reactions have been observed within the first few weeks or months of initiation of CART.
Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and
Pneumocystis pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted
when necessary. In addition, reactivation of herpes simplex and herpes zoster has been observed in
clinical studies with APTIVUS, co-administered with low dose ritonavir.
Rash
Mild to moderate rashes including urticarial rash, maculopapular rash, and photosensitivity have been
reported in subjects receiving APTIVUS, co-administered with low dose ritonavir. At 48-weeks in
Phase III trials, rash of various types was observed in 15.5% males and 20.5% females receiving
APTIVUS co-administered with low dose ritonavir. Additionally, in one interaction trial, in healthy
female volunteers administered a single dose of ethinyl oestradiol followed by APTIVUS co-
administered with low dose ritonavir, 33% of subjects developed a rash. Rash accompanied by joint
pain or stiffness, throat tightness, or generalized pruritus has been reported in both men and women
receiving APTIVUS co-administered with low dose ritonavir. In the paediatric clinical trial, the
frequency of rash (all grades, all causality) through 48 weeks of treatment was higher than in adult
patients.
Osteonecrosis
Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol
consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been
reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination
antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience
joint aches and pain, joint stiffness or difficulty in movement.
Interactions
The interaction profile of tipranavir, co-administered with low dose ritonavir, is complex. For a
description of the mechanisms and potential mechanisms contributing to the interaction profile of
tipranavir, see section 4.5.
Abacavir and zidovudine:
The concomitant use of APTIVUS, co-administered with low dose ritonavir,
with zidovudine or abacavir, results in a significant decrease in plasma concentration of these
nucleoside reverse transcriptase inhibitors (NRTIs). Therefore, the concomitant use of zidovudine or
abacavir with APTIVUS, co-administered with low dose ritonavir, is not-recommended unless there
are no other available NRTIs suitable for patient management (see section 4.5).
Protease inhibitors:
Concomitant use of APTIVUS, co-administered with low dose ritonavir, with the
protease inhibitors amprenavir, lopinavir or saquinavir (each co-administered with low dose ritonavir)
in a dual-boosted regimen, results in significant decreases in plasma concentrations of these protease
inhibitors. A significant decrease in plasma concentrations of atazanavir and a marked increase of
tipranavir and ritonavir concentrations was observed when APTIVUS, associated with low dose
ritonavir, was co-administered with atazanavir (see section 4.5). No data are currently available on
interactions of tipranavir, co-administered with low dose ritonavir, with protease inhibitors other than
those listed above. Therefore, the co-administration of tipranavir, co-administered with low dose
ritonavir, with protease inhibitors is not recommended.
7
Oral contraceptives and oestrogens:
Since levels of ethinyl oestradiol are decreased, the co-
administration of APTIVUS co-administered with low dose ritonavir is not recommended. Alternative
or additional contraceptive measures are to be used when oestrogen based oral contraceptives are co-
administered with APTIVUS co-administered with low dose ritonavir (see section 4.5). Patients using
oestrogens as hormone replacement therapy should be clinically monitored for signs of oestrogen
deficiency. Women using oestrogens may have an increased risk of non serious rash.
Anticonvulsants
: Caution should be used when prescribing carbamazepine, phenobarbital, and
phenytoin. APTIVUS may be less effective due to decreased tipranavir plasma concentrations in
patients taking these agents concomitantly.
Halofantrine, lumefantrine:
Due to their metabolic profile and inherent risk of inducing torsades de
pointes, administration of halofantrine and lumefantrine with APTIVUS co-administered with low
dose ritonavir, is not recommended.
Disulfiram/metronidazole:
APTIVUS soft capsules contain alcohol (7% ethanol, ie 100 mg per
capsule or up to 200 mg per dose) which can produce disulfiram-like reactions when co-administered
with disulfiram or other medicinal products which produce this reaction (eg metronidazole).
Fluticasone
: Concomitant use of tipranavir, co-administered with low dose ritonavir, and fluticasone
or other glucocorticoids that are metabolised by CYP3A4 is not recommended unless the potential
benefit of treatment outweighs the risk of systemic corticosteroid effects, including Cushing's
syndrome and adrenal suppression (see section 4.5).
Atorvastatin
: tipranavir, co-administered with low dose ritonavir, increases the plasma concentrations
of atorvastatin (see section 4.5). The combination is not recommended. Other HMG-CoA reductase
inhibitors should be considered such as pravastatin, fluvastatin or rosuvastatin (see section 4.5).
However, if atorvastatin is specifically required for patient management, it should be started with the
lowest dose and careful monitoring is necessary.
Omeprazole and other proton pump inhibitors:
The combined use of APTIVUS with ritonavir with
either omeprazole, esomeprazole or with other proton pump inhibitors is not recommended (see
section 4.5).
Warnings related to certain excipients:
Due to APTIVUS containing small amounts of sorbitol, patients with rare hereditary problems of
fructose intolerance should not take this medicine.
APTIVUS contains macrogolglycerol ricinoleate which may cause stomach upset and diarrhoea.
This medicinal product contains 7 vol % ethanol (alcohol), i.e. up to 400 mg per daily dose, equivalent
to 8 ml of beer, or less than 4 ml of wine.
Harmful for those suffering from alcoholism.
To be taken into account in pregnant or breast-feeding women, children and high-risk groups such as
patients with liver disease, or epilepsy.
The interaction profile of APTIVUS, co-administered with low dose ritonavir, is complex and requires
special attention in particular in combination with other antiretroviral agents.
Interaction studies have only been performed in adults.
Metabolic profile of tipranavir:
Tipranavir is a substrate, an inducer and an inhibitor of cytochrome P450 CYP3A. When co-
administered with ritonavir at the
recommended dosage (see section 4.2) there is a net inhibition of
P450 CYP3A. Co-administration of APTIVUS and low dose ritonavir with agents primarily
8
metabolised by CYP3A may result in changed plasma concentrations of tipranavir or the other agents,
which could alter their therapeutic and undesirable effects (see list and details of considered agents,
below). Agents that are contraindicated specifically due to the expected magnitude of interaction and
potential for serious adverse reactions are detailed in this section, and listed in section 4.3.
A cocktail study was conducted in 16 healthy volunteers with twice-daily 500 mg tipranavir with
200 mg ritonavir capsule administration for 10 days to assess the net effect on the activity of hepatic
CYP 1A2 (caffeine), 2C9 (warfarin), 2D6 (dextromethorphan), both intestinal/hepatic CYP 3A4
(midazolam) and P-glycoprotein (Pgp) (digoxin). At steady state, there was a significant induction of
CYP 1A2 and a slight induction on CYP 2C9. Potent inhibition of CYP 2D6 and both hepatic and
intestinal CYP 3A4 activities were observed. Pgp activity is significantly inhibited after the first dose,
but there was a slight induction at steady state. Practical recommendations deriving from this study are
displayed below.
Studies in human liver microsomes indicated tipranavir is an inhibitor of CYP 1A2, CYP 2C9, CYP
2C19 and CYP 2D6. The potential net effect of tipranavir with ritonavir on CYP 2D6 is inhibition,
because ritonavir is also a CYP 2D6 inhibitor. The
in vivo
net effect of tipranavir with ritonavir on
CYP 1A2, CYP 2C9 and CYP 2C19, indicates, through a preliminary study, an inducing potential of
tipranavir withritonavir on CYP1A2 and, to a lesser extent, on CYP2C9 and P-gp after several days of
treatment.
Data are not available to indicate whether tipranavir inhibits or induces glucuronosyl
transferases.
In vitro
studies show that tipranavir is a substrate and also an inhibitor of Pgp.
It is difficult to predict the net effect of APTIVUS co-administered with low dose ritonavir on oral
bioavailability and plasma concentrations of agents that are dual substrates of CYP3A and Pgp. The
net effect will vary depending on the relative affinity of the co-administered substance for CYP3A and
Pgp, and the extent of intestinal first-pass metabolism/efflux.
Co-administration of APTIVUS and agents that induce CYP3A and/or Pgp may decrease tipranavir
concentrations and reduce its therapeutic effect (see list and details of considered agents, below). Co-
administration of APTIVUS and medicinal products that inhibit Pgp may increase tipranavir plasma
concentrations.
Known and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal
products are listed in the table below.
Interaction table
Interactions between APTIVUS and co-administered medicinal products are listed in the table below
(increase is indicated as “↑”, decrease as “↓”, no change as “↔”,once daily as “QD”, twice daily as
“BID”).
Unless otherwise stated, studies detailed below have been performed with the recommended dosage of
APTIVUS/r (i.e. 500/200 mg BID). However, some PK interaction studies were not performed with
this recommended dosage. Nevertheless, the results of many of these interaction studies can be
extrapolated to the recommended dosage since the doses used (eg. TPV/r 500/100 mg, TPV/r
750/200 mg) represented extremes of hepatic enzyme induction and inhibition and bracketed the
recommended dosage of APTIVUS/r.
Drugs by therapeutic area
Interaction
Geometric mean change (%)
Recommendations concerning
co-administration
Anti-infectives
Antiretrovirals
Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs)
Since there is no significant impact of nucleoside and nucleotide analogues on the P450 enzyme system no
dosage adjustment of APTIVUS is required when co-administered with these agents.
9
Abacavir
300 mg BID
(TPV/r 750/100 mg BID)
Abacavir Cmax ↓ 46%
Abacavir AUC ↓ 36%
The concomitant use of APTIVUS,
co-administered with low dose
ritonavir, with abacavir is not
recommended unless there are no
other available NRTIs suitable for
patient management. In such cases
no dosage adjustment of abacavir
can be recommended (see section
4.4).
The clinical relevance of this
reduction has not been
established, but may decrease the
efficacy of abacavir.
Mechanism unknown.
Didanosine
200 mg BID, ≥
60 kg - 125 mg BID, < 60 kg
(TPV/r 250/200 mg BID)
Didanosine Cmax ↓ 43%
Didanosine AUC ↓ 33%
Dosing of enteric-coated didanosine
and APTIVUS soft capsules, co-
administered with low dose
ritonavir, should be separated by at
least 2 hours to avoid formulation
incompatibility.
(TPV/r 750/100 mg BID)
Didanosine Cmax ↓ 24%
Didanosine AUC ↔
The clinical relevance of this
reduction in didanosine
concentrations has not been
established.
Mechanism unknown.
Lamivudine
150 mg BID
(TPV/r 750/100 mg BID)
No clinically significant
interaction is observed.
No dosage adjustment necessary.
Stavudine
40 mg BID
>
60 kg
30 mg BID < 60 kg
(TPV/r 750/100 mg BID)
No clinically significant
interaction is observed.
No dosage adjustment necessary.
Zidovudine
300 mg BID
(TPV/r 750/100 mg BID)
Zidovudine Cmax ↓ 49%
Zidovudine AUC ↓ 36%
The concomitant use of APTIVUS,
co-administered with low dose
ritonavir with zidovudine is not
recommended unless there are no
other available NRTIs suitable for
patient management. In such cases
no dosage adjustment of zidovudine
can be recommended (see section
4.4).
The clinical relevance of this
reduction has not been
established, but may decrease the
efficacy of zidovudine.
Mechanism unknown.
Tenofovir
300 mg QD
(TPV/r 750/200 mg BID)
No clinically significant
interaction is observed.
No dosage adjustment necessary.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Efavirenz
600 mg QD
No clinically significant interaction
is observed.
No dosage adjustment necessary.
Nevirapine
No interaction study
performed
The limited data available from a
phase IIa study in HIV-infected
patients suggest that no significant
interaction is expected between
nevirapine and TPV/r. Moreover a
study with TPV/r and another
NNRTI (efavirenz) did not show
any clinically relevant interaction
(see above).
No dosage adjustment necessary.
Protease inhibitors (PIs)
According to current treatment guidelines, dual therapy with protease inhibitors is generally not
recommended
Amprenavir/ritonavir
600/100 mg BID
Amprenavir Cmax ↓ 39%
Amprenavir AUC ↓ 44%
Amprenavir Cmin ↓ 55%
The concomitant use of APTIVUS,
co-administered with low dose
ritonavir, with amprenavir/ritonavir
10
The clinical relevance of this
reduction in amprenavir
concentrations has not been
established.
is not recommended.
If the combination is nevertheless
considered necessary, a monitoring
of the plasma levels of amprenavir
is strongly encouraged (see section
4.4).
Mechanism unknown.
Atazanavir/ritonavir
300/100 mg QD
(TPV/r 500/100 mg BID)
Atazanavir Cmax ↓ 57%
Atazanavir AUC ↓ 68%
Atazanavir Cmin ↓ 81%
The concomitant use of APTIVUS,
co-administered with low dose
ritonavir, with atazanavir/ritonavir
is not recommended.
If the co-administration is
nevertheless considered necessary, a
close monitoring of the safety of
tipranavir and a monitoring of
plasma concentrations of atazanavir
are strongly encouraged (see section
4.4).
Mechanism unknown.
Tipranavir Cmax
↑
8%
Tipranavir AUC
↑
20%
Tipranavir Cmin
↑
75%
Inhibition of CYP 3A4 by
atazanavir/ritonavir and induction
by tipranavir/r.
Lopinavir/ritonavir
400/100 mg BID
Lopinavir Cmax ↓ 47%
Lopinavir AUC ↓ 55%
Lopinavir Cmin ↓ 70%
The concomitant use of APTIVUS,
co-administered with low dose
ritonavir, with lopinavir/ritonavir is
not recommended.
If the combination is nevertheless
considered necessary, a monitoring
of the plasma levels of lopinavir is
strongly encouraged (see section
4.4).
The clinical relevance of this
reduction in lopinavir
concentrations has not been
established.
Mechanism unknown.
Saquinavir/ritonavir
600/100 mg QD
Saquinavir Cmax ↓ 70%
Saquinavir AUC ↓ 76%
Saquinavir Cmin ↓ 82%
The concomitant use of APTIVUS,
co-administered with low dose
ritonavir, with saquinavir/ritonavir
is not recommended.
If the combination is nevertheless
considered necessary, a monitoring
of the plasma levels of saquinavir is
strongly encouraged (see section
4.4).
The clinical relevance of this
reduction in saquinavir
concentrations has not been
established.
Mechanism unknown.
Protease inhibitors other
than those listed above
No data are currently available on
interactions of tipranavir, co-
administered with low dose
ritonavir, with protease inhibitors
other than those listed above.
Combination with APTIVUS, co-
administered with low dose
ritonavir, is not recommended (see
section 4.4)
Fusion inhibitors
Enfuvirtide
No interaction study
performed
In studies where tipranavir co-
administered with low-dose
ritonavir was used with or without
enfuvirtide, it has been observed
that the steady-state plasma
tipranavir trough concentration of
patients receiving enfuvirtide were
45% higher as compared to patients
not receiving enfuvirtide. No
information is available for the
parameters AUC and C
max
.
The clinical impact of the observed
data, especially regarding the
tipranavir with ritonavir safety
profile, remains unknown.
Nevertheless, the clinical data
available from the RESIST trials did
not suggest any significant
alteration of the tipranavir with
ritonavir safety profile when
combined with enfuvirtide as
compared to patients treated with
11
A pharmacokinetic interaction is
mechanistically unexpected and the
interaction has not been confirmed
in a controlled interaction study.
tipranavir with ritonavir without
enfuvirtide.
Antifungals
Fluconazole
200 mg QD
(Day 1) then 100 mg QD
Fluconazole ↔
No dosage adjustments are
recommended. Fluconazole doses
>
Tipranavir Cmax ↑ 32%
Tipranavir AUC ↑ 50%
Tipranavir Cmin ↑ 69%
200 mg/day are not recommended.
Mechanism unknown
Itraconazole
Ketoconazole
No interaction study
performed
Based on theoretical considerations
tipranavir, co-administered with
low dose ritonavir, is expected to
increase itraconazole or
ketoconazole concentrations.
Itraconazole or ketoconazole should
be used with caution (doses
>
Based on theoretical considerations,
tipranavir or ritonavir
concentrations might increase upon
co-administration with itraconazole
or ketoconazole.
Voriconazole
No interaction study
performed
Due to multiple CYP isoenzyme
systems involved in voriconazole
metabolism, it is difficult to predict
the interaction with tipranavir, co-
administered with low-dose
ritonavir.
Based on the known interaction of
voriconazole with low dose
ritonavir (see voriconazole SPC) the
co-administration of tipranavir/r
and voriconazole should be
avoided, unless an assessment of
the benefit/risk to the patient
justifies the use of voriconazole.
Antibiotics
Clarithromycin
500 mg
BID
Clarithromycin Cmax ↔
Clarithromycin AUC ↑ 19%
Clarithromycin Cmin ↑ 68%
Whilst the changes in
clarithromycin parameters are not
considered clinically relevant, the
reduction in the 14-OH metabolite
AUC should be considered for the
treatment of infections caused by
Haemophilus influenzae
in which
the 14-OH metabolite is most
active. The increase of tipranavir
Cmin may be clinically relevant.
Patients using clarithromycin at
doses higher than 500 mg twice
daily should be carefully monitored
for signs of toxicity of
clarithromycin and tipranavir. For
patients with renal impairment dose
reduction of clarithromycin should
be considered (see clarithromycin
and ritonavir product information).
14-OH-clarithromycin Cmax ↓ 97%
14-OH-clarithromycin AUC ↓ 97%
14-OH-clarithromycin Cmin ↓ 95%
Tipranavir Cmax ↑ 40%
Tipranavir AUC ↑ 66%
Tipranavir Cmin ↑ 100%
CYP 3A4 inhibition by tipranavir/r
and P-gp (an intestinal efflux
transporter) inhibition by
clarithromycin.
Rifabutin
150 mg QD
Rifabutin Cmax ↑ 70%
Rifabutin AUC ↑ 190%
Rifabutin Cmin ↑ 114%
Dosage reductions of rifabutin by at
least 75% of the usual 300 mg/day
are recommended (ie 150 mg on
alternate days, or three times per
week). Patients receiving rifabutin
with APTIVUS, co-administered
25-O-desacetylrifabutin Cmax ↑ 3.2
fold
12
200 mg/day are not
recommended).
25-O-desacetylrifabutin AUC ↑ 21
fold
25-O-desacetylrifabutin Cmin ↑ 7.8
fold
with low dose ritonavir, should be
closely monitored for emergence of
adverse events associated with
rifabutin therapy. Further dosage
reduction may be necessary.
Inhibition of CYP 3A4 by
tipranavir/r
No clinically significant change is
observed in tipranavir PK
parameters.
Rifampicin
Co-administration of protease
inhibitors with rifampicin
substantially decreases protease
inhibitor concentrations. In the case
of tipranavir co-administered with
low dose ritonavir, concomitant use
with rifampicin is expected to result
in sub-optimal levels of tipranavir
which may lead to loss of virologic
response and possible resistance to
tipranavir.
Concomitant use of APTIVUS, co-
administered with low dose
ritonavir, and rifampicin is
contraindicated (see section 4.3).
Alternate antimycobacterial agents
such as rifabutin should be
considered.
Antimalarial
Halofantrine
Lumefantrine
No interaction study
performed
Based on theoretical
considerations, tipranavir, co-
administered with low dose
ritonavir, is expected to increase
halofantrine and lumefantrine
concentrations.
Due to their metabolic profile and
inherent risk of inducing torsades
de pointes, administration of
halofantrine and lumefantrine with
APTIVUS, co-administered with
low dose ritonavir, is not
recommended (see section 4.4).
Inhibition of CYP 3A4 by
tipranavir/r
Anticonvulsants
Carbamazepine
200 mg
BID
Carbamazepine total* Cmax ↑ 13%
Carbamazepine total* AUC ↑ 16%
Carbamazepine total* Cmin ↑ 23%
Carbamazepine should be used with
caution in combination with
APTIVUS, co-administered with
low dose ritonavir. Higher doses of
carbamazepine (> 200 mg) may
result in even larger decreases in
tipranavir plasma concentrations
(see section 4.4).
*Carbamazepine total = total of
carbamazepine and epoxy-
carbamazepine (both are
pharmacologically active moieties).
The increase in carbamazepine total
PK parameters is not expected to
have clinical consequences.
Tipranavir Cmin ↓ 61% (compared
to historical data)
The decrease in tipranavir
concentrations may result in
decreased effectiveness.
Carbamazepine induces CYP3A4.
Phenobarbital
Phenytoin
No interaction study
Phenobarbital and phenytoin induce
CYP3A4.
Phenobarbital and phenytoin should
be used with caution in combination
with APTIVUS, co-administered
13
performed
with low dose ritonavir (see section
4.4).
Antispasmodic
Tolterodine
No interaction study
performed
Based on theoretical
considerations, tipranavir, co-
administered with low dose
ritonavir, is expected to increase
tolterodine concentrations.
Co-administration is not
recommended.
Inhibition of CYP 3A4 and CYP
2D6 by tipranavir/r
HMG CoA reductase inhibitors
Atorvastatin
10 mg QD
Atorvastatin Cmax ↑ 8.6 fold
Atorvastatin AUC ↑ 9.4 fold
Atorvastatin Cmin ↑ 5.2 fold
Co-administration of atorvastatin
and APTIVUS, co-administered
with low dose ritonavir, is not
recommended. Other HMG-CoA
reductase inhibitors should be
considered such as pravastatin,
fluvastatin or rosuvastatin (See also
section 4.4 and rosuvastatin and
pravastatin recommendations).
However, if atorvastatin is
specifically required for patient
management, it should be started
with the lowest dose and careful
monitoring is necessary (see section
4.4).
Tipranavir ↔
Inhibition of CYP 3A4 by
tipranavir/r
Rosuvastatin
10 mg QD
Rosuvastatin Cmax ↑ 123%
Rosuvastatin AUC ↑ 37%
Rosuvastatin Cmin ↑ 6%
Co-administration of APTIVUS,
co-administered with low dose
ritonavir, and rosuvastatin should
be initiated with the lowest dose
(5 mg/day) of rosuvastatin, titrated
to treatment response, and
accompanied with careful clinical
monitoring for rosuvastatin
associated symptoms as described
in the label of rosuvastatin.
Tipranavir ↔
Mechanism unknown.
Pravastatin
No interaction study
performed
Based on similarities in the
elimination between pravastatin and
rosuvastatin, TPV/r could increase
the plasma levels of pravastatin.
Co-administration of APTIVUS,
co-administered with low dose
ritonavir, and pravastatin should be
initiated with the lowest dose
(10 mg/day) of pravastatin, titrated
to treatment response, and
accompanied with careful clinical
monitoring for pravastatin
associated symptoms as described
in the label of pravastatin.
Mechanism unknown.
Simvastatin
Lovastatin
No interaction study
performed
The HMG-CoA reductase inhibitors
simvastatin and lovastatin are
highly dependent on CYP3A for
metabolism.
The concomitant use of APTIVUS,
co-administered with low dose
ritonavir, with simvastatin or
lovastatin are contra-indicated due
to an increased risk of myopathy,
including rhabdomyolysis (see
section 4.3).
HERBAL PRODUCTS
St. John’s wort (
Hypericum
Plasma concentrations of tipranavir Herbal preparations containing St.
14
perforatum
)
No interaction study
performed
can be reduced by concomitant use
of the herbal preparation St John’s
wort (
Hypericum perforatum
). This
is due to induction of drug
metabolising enzymes by St John’s
wort.
John’s wort must not be combined
with APTIVUS, co-administered
with low dose ritonavir. Co-
administration of APTIVUS with
ritonavir, with St. John’s wort is
expected to substantially decrease
tipranavir and ritonavir
concentrations and may result in
sub-optimal levels of tipranavir and
lead to loss of virologic response
and possible resistance to
tipranavir.
Oral contraceptives / Oestrogens
Ethinyl oestradiol
0.035 mg
/
Norethindrone
1.0 mg QD
(TPV/r 750/200 mg BID)
Ethinyl oestradiol Cmax ↓ 52%
Ethinyl oestradiol AUC ↓ 43%
The concomitant administration
with APTIVUS, co-administered
with low dose ritonavir, is not
recommended. Alternative or
additional contraceptive measures
are to be used when oestrogen
based oral contraceptives are co-
administered with APTIVUS and
low dose ritonavir. Patients using
oestrogens as hormone replacement
therapy should be clinically
monitored for signs of oestrogen
deficiency (see section 4.4 and
section 4.6).
Mechanism unkown
Norethindrone Cmax ↔
Norethindrone AUC ↑ 27%
Tipranavir ↔
Phosphodiesterase 5 (PDE5) inhibitors
Sildenafil
Vardenafil
No interaction study
performed
Co-administration of tipranavir and
low dose ritonavir with PDE5
inhibitors is expected to
substantially increase PDE5
concentrations and may result in an
increase in PDE5 inhibitor-
associated adverse events including
hypotension, visual changes and
priapism.
Particular caution should be used
when prescribing the
phosphodiesterase (PDE5)
inhibitors sildenafil or vardenafil in
patients receiving APTIVUS, co-
administered with low dose
ritonavir.
Tadalafil
10 mg QD
Tadalafil first-dose Cmax ↓ 22%
Tadalafil first-dose AUC ↑ 133%
It is recommended to prescribe
tadalafil after at least 7 days of
APTIVUS with ritonavir dosing.
CYP 3A4 inhibition and induction
by tipranavir/r
Tadalafil steady-state Cmax ↓ 30%
Tadalafil steady-state AUC ↔
No clinically significant change is
observed in tipranavir PK
parameters.
Narcotic analgesics
Methadone
5 mg QD
Methadone Cmax ↓ 55%
Methadone AUC ↓ 53%
Methadone Cmin ↓ 50%
Patients should be monitored for
opiate withdrawal syndrome.
Dosage of methadone may need to
be increased.
R-methadone Cmax ↓ 46%
R-methadone AUC ↓ 48%
15
S-methadone Cmax ↓ 62%
S-methadone AUC ↓ 63%
Mechanism unknown
Meperidine
No interaction study
performed
Tipranavir, co-administered with
low dose ritonavir, is expected to
decrease meperidine concentrations
and increase normeperidine
metabolite concentrations.
Dosage increase and long-term use
of meperidine with APTIVUS, co-
administered with low dose
ritonavir, are not recommended due
to the increased concentrations of
the metabolite normeperidine which
has both analgesic activity and CNS
stimulant activity (eg seizures).
Buprenorphine/Naloxone
Buprenorphine ↔
Due to reduction in the levels of the
active metabolite norbuprenorphine,
co-administration of APTIVUS, co-
administered with low dose
ritonavir, and buprenorphine/
naloxone may result in decreased
clinical efficacy of buprenorphine.
Therefore, patients should be
monitored for opiate withdrawal
syndrome.
Norbuprenorphine AUC
↓
79%
Norbuprenorphine Cmax
↓
80%
Norbuprenorphine Cmin
↓
80%
Immunosupressants
Cyclosporin
Tacrolimus
Sirolimus
No interaction study
performed
Concentrations of cyclosporin,
tacrolimus, or sirolimus cannot be
predicted when co-administered
with tipranavir co-administered
with low dose ritonavir, due to
conflicting effect of tipranavir, co-
administered with low dose
ritonavir, on CYP 3A and Pgp.
More frequent concentration
monitoring of these medicinal
products is recommended until
blood levels have been stabilised.
Antithrombotics
Warfarin
10 mg QD
First-dose tipranavir/r:
S-warfarin Cmax ↔
S-warfarin AUC ↑ 18%
APTIVUS, co-administered with
low dose ritonavir, when combined
with warfarin may be associated
with changes in INR (International
Normalised Ratio) values, and may
affect anticoagulation
(thrombogenic effect) or increase
the risk of bleeding. Close clinical
and biological (INR measurement)
monitoring is recommended when
warfarin and tipranavir are
combined.
Steady-state tipranavir/r:
S-warfarin Cmax ↓ 17%
S-warfarin AUC ↓ 12%
Inhibition of CYP 2C9 with first-
dose tipranavir/r, then induction of
CYP 2C9 with steady-state
tipranavir/r
Antacids
aluminium- and magnesium-
based liquid antacid 20 ml
QD
Tipranavir Cmax ↓ 25%
Tipranavir AUC ↓ 27%
Dosing of APTIVUS, co-
administered with low dose
ritonavir, with antacids should be
separated by at least a two hours
time interval.
Mechanism unknown
Proton pump inhibitors (PPIs)
Omeprazole
40 mg QD
Omeprazole Cmax ↓ 73%
Omeprazole AUC ↓ 70%
The combined use of APTIVUS,
co-administered with low dose
ritonavir, with either omeprazole or
esomeprazole is not recommended
(see section 4.4). If unavoidable,
Similar effects were observed for
the S-enantiomer, esomeprazole.
16
Induction of CYP 2C19 by
tipranavir/r
upward dose adjustments for either
omeprazole or esomeprazole may
be considered based on clinical
response to therapy. There are no
data available indicating that
omeprazole or esomeprazole dose
adjustments will overcome the
observed pharmacokinetic
interaction. Recommendations for
maximal doses of omeprazole or
esomeprazole are found in the
corresponding product information.
No tipranavir with ritonavir dose
adjustment is required.
Tipranavir ↔
Lansoprazole
Pantoprazole
Rabeprazole
No interaction study
performed
Based on the metabolic profiles of
tipranavir/r and the proton pump
inhibitors, an interaction can be
expected. As a result of CYP3A4
inhibition and CYP2C19 induction
by tipranavir/r, lansoprazole and
pantoprazole plasma concentrations
are difficult to predict. Rabeprazole
plasma concentrations might
decrease as a result of induction of
CYP2C19 by tipranavir/r.
The combined use of APTIVUS,
co-administered with low dose
ritonavir, with proton pump
inhibitors is not recommended (see
section 4.4). If the co-
administration is judged
unavoidable, this should be done
under close clinical monitoring.
H2-receptor antagonists
No interaction study
performed
No data are available for H2-
receptor antagonists in combination
with tipranavir and low dose
ritonavir.
An increase in gastric pH that may
result from H2-receptor antagonist
therapy is not expected to have an
impact on tipranavir plasma
concentrations.
Antiarrhythmics
Amiodarone
Bepridil
Quinidine
No interaction study
performed
Based on theoretical considerations,
tipranavir, co-administered with
low dose ritonavir, is expected to
increase amiodarone, bepridil and
quinidine concentrations.
The concomitant use of APTIVUS,
co-administered with low dose
ritonavir, with amiodarone, bepridil
or quinidine is contraindicated due
to potential serious and/or
lifethreatening events (see section
4.3)
Inhibition of CYP 3A4 by
tipranavir/r
Flecainide
Propafenone
Metoprolol
(given in heart
failure)
No interaction study
performed
Based on theoretical considerations,
tipranavir, co-administered with
low dose ritonavir, is expected to
increase flecainide, propafenone
and metoprolol concentrations.
The concomitant use of APTIVUS,
co-administered with low dose
ritonavir, with flecainide,
propafenone or metoprolol is
contraindicated (see section 4.3)
Inhibition of CYP 2D6
by tipranavir/r
Antihistamines
Astemizole
Terfenadine
No interaction study
performed
Based on theoretical considerations,
tipranavir, co-administered with
low dose ritonavir, is expected to
increase astemizole and terfenadine
concentrations.
The concomitant use of APTIVUS,
co-administered with low dose
ritonavir, with astemizole or
terfenadine is contraindicated due to
potential serious and/or
lifethreatening events (see section
4.3)
Inhibition of CYP 3A4 by
17
tipranavir/r
Ergot derivatives
Dihydroergotamine
Ergonovine
Ergotamine
Methylergonovine
No interaction study
performed
Based on theoretical considerations,
tipranavir, co-administered with
low dose ritonavir, is expected to
increase dihydroergotamine,
ergonovine, ergotamine and
methylergonovine concentrations.
The concomitant use of APTIVUS,
co-administered with low dose
ritonavir, with dihydroergotamine,
ergonovine, ergotamine or
methylergonovine is
contraindicated due to potential
serious and/or lifethreatening events
(see section 4.3)
Inhibition of CYP 3A4 by
tipranavir/r
Gastrointestinal motility agents
Cisapride
No interaction study
performed
Based on theoretical considerations,
tipranavir, co-administered with
low dose ritonavir, is expected to
increase cisapride concentrations.
The concomitant use of APTIVUS,
co-administered with low dose
ritonavir, with cisapride is
contraindicated due to potential
serious and/or lifethreatening events
(see section 4.3)
Inhibition of CYP 3A4 by
tipranavir/r
Neuroleptics
Pimozide
Sertindole
No interaction study
performed
Based on theoretical considerations,
tipranavir, co-administered with
low dose ritonavir, is expected to
increase pimozide and sertindole
concentrations.
The concomitant use of APTIVUS,
co-administered with low dose
ritonavir, with pimozide or
sertindole is contraindicated due to
potential serious and/or
lifethreatening events (see section
4.3)
Inhibition of CYP 3A4 by
tipranavir/r
Sedatives/hypnotics
Midazolam
2 mg QD (iv)
First-dose tipranavir/r:
Midazolam Cmax ↔
Midazolam AUC ↑ 5.1 fold
Concomitant use of APTIVUS, co-
administered with low dose
ritonavir, and oral midazolam is
contra-indicated (see section 4.3). If
APTIVUS with ritonavir is
administered with parenteral
midazolam, close clinical
monitoring for respiratory
depression and/or prolonged
sedation should be instituted and
dosage adjustment should be
considered.
Steady-state tipranavir/r:
Midazolam Cmax ↓ 13%
Midazolam AUC ↑ 181%
Midazolam
5 mg QD (po)
First-dose tipranavir/r
Midazolam Cmax ↑ 5.0 fold
Midazolam AUC ↑ 27 fold
Steady-state tipranavir/r
Midazolam Cmax ↑ 3.7 fold
Midazolam AUC ↑ 9.8 fold
Ritonavir is a potent inhibitor of
CYP3A4 and therefore affect drugs
metabolised by this enzyme.
Triazolam
No interaction study
performed
Based on theoretical considerations,
tipranavir, co-administered with
low dose ritonavir, is expected to
increase triazolam concentrations.
The concomitant use of APTIVUS,
co-administered with low dose
ritonavir, with triazolam is
contraindicated due to potential
serious and/or lifethreatening events
(see section 4.3)
Inhibition of CYP 3A4 by
tipranavir/r
Others
18
Theophylline
No interaction study
performed
Based on data from the cocktail
study where caffeine (CYP1A2
substrate) AUC was reduced by
43%, tipranavir with ritonavir is
expected to decrease theophylline
concentrations.
Theophylline plasma concentrations
should be monitored during the first
two weeks of co-administration
with APTIVUS, co-administered
with low dose ritonavir, and the
theophylline dose should be
increased as needed.
Induction of CYP 1A2 by
tipranavir/r
Desipramine
No interaction study
performed
tipranavir, co-administered with
low dose ritonavir, is expected to
increase desipramine concentrations
Dosage reduction and concentration
monitoring of desipramine is
recommended.
Inhibition of CYP 2D6 by
tipranavir/r
Digoxin
0.25 mg QD iv
First-dose tipranavir/r
Digoxin Cmax ↔
Digoxin AUC ↔
Monitoring of digoxin serum
concentrations is recommended
until steady state has been obtained.
Steady-state tipranavir/r
Digoxin Cmax ↓ 20%
Digoxin AUC ↔
Digoxin
0.25 mg QD po
First-dose tipranavir/r
Digoxin Cmax ↑ 93%
Digoxin AUC ↑ 91%
Transient inhibition of P-gp by
tipranavir/r, followed by induction
of P-gp by tipranavir/r at steady-
state
Steady-state tipranavir/r
Digoxin Cmax ↓ 38%
Digoxin AUC ↔
Trazodone
Interaction study performed
only with ritonavir
In a pharmacokinetic study
performed in healthy volunteers,
concomitant use of low dose
ritonavir (200 mg twice daily) with
a single dose of trazodone led to an
increased plasma concentration of
trazodone (AUC increased by
2.4 fold). Adverse events of nausea,
dizziness, hypotension and syncope
have been observed following co-
administration of trazodone and
ritonavir in this study. However, it
is unknown whether the
combination of tipranavir with
ritonavir might cause a larger
increase in trazodone exposure.
The combination should be used
with caution and a lower dose of
trazodone should be considered.
Bupropion
150 mg BID
Bupropion Cmax ↓ 51%
Bupropion AUC ↓ 56%
If the co-administration with
bupropion is judged unavoidable,
this should be done under close
clinical monitoring for bupropion
efficacy, without exceeding the
recommended dosage, despite the
Tipranavir ↔
The reduction of bupropion plasma
19
levels is likely due to induction of
CYP2B6 and UGT activity by RTV
observed induction.
Loperamide
16 mg QD
Loperamide Cmax ↓ 61%
Loperamide AUC ↓ 51%
A pharmacodynamic interaction
study in healthy volunteers
demonstrated that administration of
loperamide and APTIVUS, co-
administered with low dose
ritonavir, does not cause any
clinically relevant change in the
respiratory response to carbon
dioxide. The clinical relevance of
the reduced loperamide plasma
concentration is unknown.
Mechanism unknown
Tipranavir Cmax ↔
Tipranavir AUC ↔
Tipranavir Cmin ↓ 26%
Fluticasone propionate
Interaction study performed
only with ritonavir
In a clinical study where ritonavir
100 mg capsules bid were co-
administered with 50 µg intranasal
fluticasone propionate (4 times
daily) for 7 days in healthy subjects,
the fluticasone propionate plasma
levels increased significantly,
whereas the intrinsic cortisol levels
decreased by approximately 86%
(90% confidence interval 82-89%).
Greater effects may be expected
when fluticasone propionate is
inhaled. Systemic corticosteroid
effects including Cushing's
syndrome and adrenal suppression
have been reported in patients
receiving ritonavir and inhaled or
intranasally administered
fluticasone propionate; this could
also occur with other corticosteroids
metabolised via the P450 3A
pathway eg budesonide.
It is unknown whether the
combination of tipranavir with
ritonavir might cause a larger
increase in fluticasone exposure.
Concomitant administration of
APTIVUS, co-administered with
low dose ritonavir, and these
glucocorticoids is not recommended
unless the potential benefit of
treatment outweighs the risk of
systemic corticosteroid effects (see
section 4.4). A dose reduction of the
glucocorticoid should be considered
with close monitoring of local and
systemic effects or a switch to a
glucocorticoid, which is not a
substrate for CYP3A4 (e.g.
beclomethasone). Moreover, in case
of withdrawal of glucocorticoids
progressive dose reduction may
have to be performed over a longer
period. The effects of high
fluticasone systemic exposure on
ritonavir plasma levels are as yet
unknown.
Pregnancy
There are no adequate data from the use of tipranavir in pregnant women. Studies in animals have
shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Tipranavir
should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Contraception in males and females
Tipranavir adversely interacts with oral contraceptives. Therefore, an alternative, effective, safe
method of contraception should be used during treatment (see section 4.5).
Breastfeeding
Consistent with the recommendation that HIV-infected mothers should not breast-feed their infants
under any circumstances to avoid risking postnatal transmission of HIV, mothers should discontinue
breast-feeding if they are receiving APTIVUS.
Fertility
20
Clinical data on fertility are not available for tipranavir. Preclinical studies performed with tipranavir
showed no adverse effect on fertility (see section 5.3).
No studies on the effects on the ability to drive and use machines have been performed.
APTIVUS co-administered with low dose ritonavir, has been associated with reports of significant
liver toxicity. In Phase III RESIST trials, the frequency of transaminase elevations was significantly
increased in the tipranavir with ritonavir arm compared to the comparator arm. Close monitoring is
therefore needed in patients treated with APTIVUS, co-administered with low dose ritonavir (see
section 4.4).
Limited data are currently available for the use of APTIVUS, co-administered with low dose ritonavir,
in patients co-infected with hepatitis B or C. APTIVUS should therefore be used with caution in
patients co-infected with hepatitis B or C. APTIVUS should be used in this patient population only if
the potential benefit outweighs the potential risk, and with increased clinical and laboratory
monitoring.
Adults
Tipranavir (as soft capsules), co-administered with low dose ritonavir has been studied in a total of
6,308 HIV-positive adults as combination therapy in clinical studies, including compassionate use
studies. Of these 5,219 patients received the dose of 500 mg/200 mg twice daily. 909 adults in clinical
trials, including 541 in the RESIST-1 and RESIST-2 Phase III pivotal trials, have been treated with
500 mg/200 mg twice daily for at least 48 weeks.
Clinically meaningful adverse reactions of any intensity (Grades 1-4) of adult patients in all Phase II
and III trials treated with the 500 mg tipranavir with 200 mg ritonavir dose twice daily (n=1397) are
listed below by system organ class and frequency according to the following categories:
Very common (≥ 1/10), common (≥ 1/100 to
<
1/10), uncommon (≥1/1,000 to
<
1/100),
rare (≥1/10,000 to
<
1/1,000)
Blood and lymphatic system disorders
:
Uncommon: neutropenia, anaemia, thrombocytopenia.
Immune system disorders
:
Uncommon: hypersensitivity.
Metabolism and nutrition disorders
:
Common: hypertriglyceridaemia, hyperlipidaemia.
Uncommon: anorexia, decreased appetite, weight decreased, hyperamylasaemia,
hypercholesterolaemia, diabetes mellitus, hyperglycaemia.
Rare: dehydration, facial wasting.
Psychiatric disorders
:
Uncommon: insomnia, sleep disorder.
Nervous system disorders
:
Common: headache.
Uncommon: intracranial haemorrhage*, dizziness, neuropathy peripheral, somnolence.
Respiratory, thoracic and mediastinal disorders
:
Uncommon: dyspnoea.
21
Gastrointestinal disorders
:
Very common: diarrhoea, nausea.
Common: vomiting, flatulence, abdominal pain, abdominal distension, loose stools, dyspepsia.
Uncommon: gastrooesophageal reflux disease, pancreatitis.
Rare: lipase increased.
Hepatobiliary disorders
:
Uncommon: hepatic enzymes increased (ALAT, ASAT), cytolytic hepatitis, liver function test
abnormal (ALAT, ASAT), toxic hepatitis.
Rare: hepatic failure (including fatal outcome), hepatitis, hepatic steatosis, hyperbilirubinaemia.
Skin and subcutaneous tissue disorders
:
Common: rash.
Uncommon: pruritus, lipohypertrophy, exanthem, lipoatrophy, lipodystrophy acquired.
Musculoskeletal and connective tissue disorders
:
Uncommon: myalgia, muscle cramp.
Renal and urinary disorders
:
Uncommon: renal insufficiency.
General disorders and administration site conditions
:
Common: fatigue.
Uncommon: pyrexia, influenza like illness, malaise.
*
This undesirable effect was not observed as an at least possibly related adverse event in the
respective studies. The frequency estimate is based on the upper limit of its 95% confidence interval,
calculated from the totality of treated patients in accordance with the EU SPC guideline (3/1397 which
relates to “uncommon”).
Description of selected adverse reactions
The following clinical safety features (hepatotoxicity, hyperlipidaemia, bleeding events, rash) were
seen at higher frequency among tipranavirwithritonavir treated patients when compared with the
comparator arm treated patients in the RESIST trials, or have been observed with tipranavir with
ritonavir administration. The clinical significance of these observations has not been fully explored.
Hepatotoxicity:
After 48 weeks of follow-up, the frequency of Grade 3 or 4 ALAT and/or ASAT
abnormalities was higher in tipranavir with ritonavir patients compared with comparator arm patients
(10% and 3.4%, respectively). Multivariate analyses showed that baseline ALAT or ASAT above
DAIDS Grade 1 and co-infection with hepatitis B or C were risk factors for these elevations. Most
patients were able to continue treatment with tipranavir with ritonavir.
Hyperlipidaemia:
Grade 3 or 4 elevations of triglycerides occurred more frequently in the tipranavir
with ritonavir arm compared with the comparator arm. At 48 weeks these rates were 25.2% of
patients in the tipranavir withritonavir arm and 15.6% in the comparator arm.
Bleeding:
RESIST participants receiving tipranavir with ritonavir tended to have an increased risk of
bleeding; at 24 weeks the relative risk was 1.98 (95% CI=1.03, 3.80). At 48-weeks the relative risk
decreased to 1.27 (95% CI=0.76, 2.12). There was no pattern for the bleeding events and no difference
between treatment groups in coagulation parameters. The significance of this finding is being further
studied.
Fatal and non-fatal intracranial haemorrhage (ICH) have been reported in patients receiving tipranavir,
many of whom had other medical conditions or were receiving concomitant medicinal products that
may have caused or contributed to these events. However, in some cases the role of tipranavir cannot
be excluded. No pattern of abnormal haematological or coagulation parameters has been observed in
patients in general, or preceding the development of ICH. Therefore, routine measurement of
coagulation parameters is not currently indicated in the management of patients on APTIVUS.
22
An increased risk of ICH has previously been observed in patients with advanced HIV disease/AIDS
such as those treated in the APTIVUS clinical trials.
Rash:
An interaction study in women between tipranavir, co-administered with low dose ritonavir, and
ethinyl oestradiol/norethindrone demonstrated a high frequency of non-serious rash. In the RESIST
trials, the risk of rash was similar between tipranavir with ritonavir and comparator arms (16.3% vs.
12.5%, respectively; see section 4.4). No cases of Stevens-Johnson Syndrome or Toxic Epidermal
Necrolysis have been reported in the clinical development programme of tipranavir.
Laboratory abnormalities
Frequencies of marked clinical laboratory abnormalities (Grade 3 or 4) reported in at least 2% of
patients in the tipranavir withritonavir arms in the phase III clinical studies (RESIST-1 and RESIST-2)
after 48-weeks were increased ASAT (6.1%), increased ALAT (9.7%), increased amylase (6.0%),
increased cholesterol (4.2%), increased triglycerides (24.9%), and decreased white blood cell count
(5.7%).
Combination antiretroviral therapy, including regimens containing a protease inhibitor, is associated
with redistribution of body fat in some patients, including loss of peripheral subcutaneous fat,
increased intra-abdominal fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump).
Protease inhibitors are also associated with metabolic abnormalities such as hypertriglyceridaemia,
hypercholesterolaemia, insulin resistance and hyperglycaemia.
Increased CPK, myalgia, myositis and, rarely, rhabdomyolysis, have been reported with protease
inhibitors, particularly in combination with nucleoside reverse transcriptase inhibitors.
In HIV-infected patients with severe immune deficiency at the time of initiation of combination
antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic
infections may arise (see section 4.4). Reactivation of herpes simplex and herpes zoster virus
infections were observed in the RESIST trials.
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk
factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART).
The frequency of this is unknown (see section 4.4).
Paediatric population
In an open-label, dose-finding study of tipranavir plus ritonavir (Trial 1182.14), 28 children who were
12 years of age or above received APTIVUS capsules. In general, adverse reactions were similar to
those seen in adults, with the exception of vomiting, rash and pyrexia, which were reported more
frequently in children than in adults. The most frequently reported moderate or severe adverse
reactions in the 48 week analyses are noted below.
Most frequently reported moderate or severe adverse reactions in paediatric patients aged 12 to
18 years who took Aptivus capsules (reported in 2 or more children, Trial 1182.14, week 48
analyses, Full Analysis Set).
Total patients treated (N) 28
Events [N(%)]
Vomiting/ retching 3 (10.7)
Nausea 2 (7.1)
Abdominal pain
1
2 (7.1)
Rash
2
3 (10.7)
Insomnia 2 (7.1)
ALAT increased 4 (14.3)
1. Includes abdominal pain (N=1) and dyspepsia (N=1).
2. Rash consists of one or more of the preferred terms of rash, drug eruption, rash macular, rash papular, erythema, rash
maculo-papular, rash pruritic, and urticaria
23
Human experience with tipranavir overdose is very limited. No specific signs and symptoms of
overdose are known. Generally, an increased frequency and higher severity of undesirable effects may
result from overdose.
There is no known antidote for tipranavir overdose. Treatment of overdose should consist of general
supportive measures, including monitoring of vital signs and observation of the patient’s clinical
status. If indicated, elimination of unabsorbed tipranavir should be achieved by emesis or gastric
lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed
substance. Since tipranavir is highly protein bound, dialysis is unlikely to be beneficial in significant
removal of this medicine.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: antivirals for systemic use, protease inhibitors, ATC code: J05AE09
Mechanism of action
The human immunodeficiency virus (HIV-1) encodes an aspartyl protease that is essential for the
cleavage and maturation of viral protein precursors. Tipranavir is a non-peptidic inhibitor of the HIV-1
protease that inhibits viral replication by preventing the maturation of viral particles.
Antiviral activity
in vitro
Tipranavir inhibits the replication of laboratory strains of HIV-1 and clinical isolates in acute models
of T-cell infection, with 50% and 90% effective concentrations (EC
50
and EC
90
) ranging from 0.03 to
0.07 µM (18-42 ng/ml) and 0.07 to 0.18 µM (42-108 ng/ml), respectively. Tipranavir demonstrates
antiviral activity
in vitro
against a broad panel of HIV-1 group M non-clade B isolates (A, C, D, F, G,
H, CRF01 AE, CRF02 AG, CRF12 BF). Group O and HIV-2 isolates have reduced susceptibility
in
vitro
to tipranavir with EC
50
values ranging from 0.164-1 µM and 0.233-0.522 µM, respectively.
Protein binding studies have shown that the antiviral activity of tipranavir decreases on average 3.75-
fold in conditions where human serum is present.
Resistance
The development of resistance to tipranavir
in vitro
is slow and complex. In one particular
in vitro
resistance experiment, an HIV-1 isolate that was 87-fold resistant to tipranavir was selected after 9
months, and contained 10 mutations in the protease: L10F, I13V, V32I, L33F, M36I, K45I, I54V/T,
A71V, V82L, I84V as well as a mutation in the gag polyprotein CA/P2 cleavage site. Reverse genetic
experiments showed that the presence of 6 mutations in the protease (I13V, V32I, L33F, K45I, V82L,
I84V) was required to confer > 10-fold resistance to tipranavir while the full 10-mutation genotype
conferred 69-fold resistance to tipranavir.
In vitro
, there is an inverse correlation between the degree
of resistance to tipranavir and the capacity of viruses to replicate. Recombinant viruses showing ≥ 3-
fold resistance to tipranavir grow at less than 1% of the rate detected for wild type HIV-1 in the same
conditions. Tipranavir resistant viruses which emerge
in vitro
from wild-type HIV-1 show decreased
susceptibility to the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir and
ritonavir but remain sensitive to saquinavir.
Through a series of multiple stepwise regression analyses of baseline and on-treatment genotypes from
all clinical studies, 16 amino acids have been associated with reduced tipranavir susceptibility and/or
reduced 48-week viral load response: 10V, 13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/M/V,
58E, 69K, 74P, 82L/T, 83D and 84V. Clinical isolates that exhibited a
≥
24
10-fold decrease in tipranavir
susceptibility harboured 8 or more tipranavir-associated mutations. In Phase II and III clinical trials,
276 patients with on-treatment genotypes have demonstrated that the predominant emerging mutations
with tipranavir treatment are L33F/I/V, V82T/L and I84V. Combination of all three of these is usually
required for reduced susceptibility. Mutations at position 82 occur via two pathways: one from pre-
existing mutation 82A selecting to 82T, the other from wild type 82V selecting to 82L.
Cross-resistance
Tipranavir maintains significant antiviral activity (< 4-fold resistance) against the majority of HIV-1
clinical isolates showing post-treatment decreased susceptibility to the currently approved protease
inhibitors: amprenavir, atazanavir, indinavir, lopinavir, ritonavir, nelfinavir and saquinavir. Greater
than 10-fold resistance to tipranavir is uncommon (< 2.5% of tested isolates) in viruses obtained from
highly treatment experienced patients who have received multiple peptidic protease inhibitors.
Clinical pharmacodynamic data
The following clinical data is derived from analyses of 48-week data from ongoing studies (RESIST-1
and RESIST-2) measuring effects on plasma HIV RNA levels and CD4 cell counts. RESIST-1 and
RESIST-2 are ongoing, randomised, open-label, multicentre studies in HIV-positive, triple-class
experienced patients, evaluating treatment with 500 mg tipranavir co-administered with low dose
ritonavir (200 mg; twice daily) plus an optimised background regimen (OBR) individually defined for
each patient based on genotypic resistance testing and patient history. The comparator regimen
included a ritonavir-boosted PI (also individually defined) plus an OBR. The ritonavir-boosted PI was
chosen from among saquinavir, amprenavir, indinavir or lopinavir/ritonavir.
All patients had received at least two PI-based antiretroviral regimens and were failing a PI-based
regimen at the time of study entry. At least one primary protease gene mutation from among 30N, 46I,
46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V or 90M had to be present at baseline, with not more than
two mutations on codons 33, 82, 84 or 90.
After Week 8, patients in the comparator arm who met the protocol defined criteria of initial lack of
virologic response had the option of discontinuing treatment and switching over to tipranavir with
ritonavir in a separate roll-over study
.
The 1483 patients included in the primary analysis had a median age of 43 years (range 17-80), were
86% male, 75% white, 13% black and 1% Asian. In the tipranavir and comparator arms median
baseline CD4 cell counts were 158 and 166 cells/mm
3
, respectively, (ranges 1-1893 and 1-
1184 cells/mm
3
); median baseline plasma HIV-1 RNA was 4.79 and 4.80 log
10
copies/ml, respectively
(ranges 2.34-6.52 and 2.01-6.76 log
10
copies/ml).
Patients had prior exposure to a median of 6 NRTIs, 1 NNRTI, and 4 PIs. In both studies, a total of
67% patient viruses were resistant and 22% were possibly resistant to the pre-selected comparator PIs.
A total of 10% of patients had previously used enfuvirtide. Patients had baseline HIV-1 isolates with a
median of 16 HIV-1 protease gene mutations, including a median of 3 primary protease gene
mutations D30N, L33F/I, V46I/L, G48V, I50V, V82A/F/T/L, I84V, and L90M. With respect to
mutations on codons 33, 82, 84 and 90 approximately 4% had no mutations, 24% had mutations at
codons 82 (less than 1% of patients had the mutation V82L) and 90, 18% had mutations at codons 84
and 90 and 53% had at least one key mutation at codon 90. One patient in the tipranavir arm had four
mutations. In addition the majority of participants had mutations associated with both NRTI and
NNRTI resistance. Baseline phenotypic susceptibility was evaluated in 454 baseline patient samples.
There was an average decrease in susceptibility of 2-fold wild type (WT) for tipranavir, 12-fold WT
for amprenavir, 55-fold WT for atazanavir, 41-fold WT for indinavir, 87-fold WT for lopinavir, 41-
fold WT for nelfinavir, 195-fold WT for ritonavir, and 20-fold WT for saquinavir.
1 log RNA drop from baseline and without evidence of treatment failure) for both studies was 34%
in the tipranavir with ritonavir arm and 15% in the comparator arm. Treatment response is presented
for the overall population (displayed by enfuvirtide use), and detailed by PI strata for the subgroup of
patients with genotypically resistant strains in the Table below.
25
Combined 48-week treatment response (composite endpoint defined as patients with a confirmed
≥
Treatment response* at week 48 (pooled studies RESIST-1 and RESIST-2 in treatment-
experienced patients)
RESIST study
Tipranavir
/RTV
CPI/RTV**
p-value
n (%)
N
n (%)
N
Overall population
FAS
PP
255 (34.2)
171 (37.7)
746
454
114 (15.5)
74 (17.1)
737
432
<
0.0001
<
0.0001
- with ENF
(FAS)
85 (50.0)
170
28 (20.7)
135
<
0.0001
- without ENF
(FAS)
170 (29.5)
576
86 (14.3)
602
<
0.0001
Genotypically Resistant
LPV/rtv
FAS
PP
66 (28.9)
47 (32.2)
228
146
23 (9.5)
13 (9.1)
242
143
<
0.0001
<
0.0001
APV/rtv
FAS
PP
50 (33.3)
38 (39.2)
150
97
22 (14.9)
17 (18.3)
148
93
0.0001
0.0010
SQV/rtv
FAS
PP
22 (30.6)
11 (28.2)
72
39
5 (7.0)
2 (5.7)
71
35
0.0001
0.0650
0.0026
0.0650
* Composite endpoint defined as patients with a confirmed 1 log RNA drop from baseline and without
evidence of treatment failure
** Comparator PI/RTV: LPV/r 400 mg/100 mg twice daily (n=358), IDV/r 800 mg/100 mg twice
daily (n=23), SQV/r 1000 mg/100 mg twice daily or 800 mg/200 mg twice daily (n=162), APV/r
600 mg/100 mg twice daily (n=194)
ENF Enfuvirtide; FAS Full Analysis Set; PP Per Protocol; APV/rtv Amprenavir/ritonavir; IDV/rtv
Indinavir/ritonavir; LPV/rtv Lopinavir/ritonavir; SQV/rtv Saquinavir/ritonavir
6 (46.2)
3 (50.0)
13
6
1 (5.3)
1 (7.1)
19
14
Combined 48-week median time to treatment failure for both studies was 115 days in the tipranavir
withritonavir arm and 0 days in the comparator arm (no treatment response was imputed to day 0).
Through 48 weeks of treatment, the proportion of patients in the tipranavir with ritonavir arm
compared to the comparator PI/ritonavir arm with HIV-1 RNA < 400 copies/ml was 30% and 14%
respectively, and with HIV-1 RNA < 50 copies/ml was 23% and 10% respectively. Among all
randomised and treated patients, the median change from baseline in HIV-1 RNA at the last
measurement up to Week 48 was -0.64 log
10
copies/ml in patients receiving tipranavir with ritonavir
versus -0.22 log
10
copies/ml in the comparator PI/ritonavir arm.
Among all randomised and treated patients, the median change from baseline in CD4+ cell count at
the last measurement up to Week 48 was +23 cells/mm
3
in patients receiving tipranavir with ritonavir
(N=740) versus +4 cells/mm
3
in the comparator PI/ritonavir (N=727) arm.
The superiority of tipranavir co-administered with low dose ritonavir over the comparator protease
inhibitor/ritonavir arm was observed for all efficacy parameters at week 48. It has not been shown that
tipranavir is superior to these boosted comparator protease inhibitors in patients harbouring strains
susceptible to these protease inhibitors. RESIST data also demonstrate that tipranavir co-administered
with low dose ritonavir exhibits a better treatment response at 48 weeks when the OBR contains
genotypically available antiretroviral agents (eg enfuvirtide).
At present there are no results from controlled trials evaluating the effect of tipranavir on clinical
progression of HIV.
Paediatric population
26
<
<
IDV/rtv
FAS
PP
HIV-positive, paediatric patients, aged 2 through 18 years, were studied in a randomized, open-label,
multicenter study (trial 1182.14). Patients were required to have a baseline HIV-1 RNA concentration
of at least 1500 copies/ml, were stratified by age (2 to < 6 years, 6 to < 12 years and 12 to 18 years)
and randomized to receive one of two tipranavir with ritonavir dose regimens: 375 mg/m
2
/150 mg/m
2
dose, compared to the 290 mg/m
2
/115 mg/m
2
dose, plus background therapy of at least two non-
protease inhibitor antiretroviral medicinal products, optimized using baseline genotypic resistance
testing. All patients initially received APTIVUS oral solution. Paediatric patients who were 12 years
or older and received the maximum dose of 500 mg/200 mg twice daily could change to APTIVUS
capsules from study day 28. The trial evaluated pharmacokinetics, safety and tolerability, as well as
virologic and immunologic responses through 48 weeks.
No data are available on the efficacy and safety of APTIVUS capsules in children less than 12 years of
age. Since APTIVUS capsules and oral solution are not bioequivalent, results obtained with the oral
solution cannot be extrapolated to the capsules (see also section 5.2). In patients with a body surface
area of less than 1.33 m
2
appropriate dose adjustments cannot be achieved with the capsule
formulation.
The baseline characteristics and the key efficacy results at 48 weeks for the paediatric patients
receiving APTIVUS capsules are displayed in the tables below. Data on the 29 patients who switched
to capsules during the first 48 weeks are presented. Due to limitations in the study design (e.g. non-
randomized switch allowed according to patient/clinician decision), any comparisons between patients
taking capsules and oral solution are not meaningful.
Baseline characteristics
for patients 12 – 18 years of age who took capsule
Variable
Value
Number of Patients
29
Age-Median (years)
15.1
Gender
% Male
48.3%
Race
% White
69.0%
% Black
31.0%
% Asian
0.0%
Baseline HIV-1 RNA
(log
10
copies/ml)
Median
(Min – Max)
4.6 (3.0 – 6.8)
% with VL >
100,000 copies/ml
27.6%
Baseline CD4+
(cells/mm
3
)
Median
(Min – Max)
330 (12 – 593)
% ≤ 200
27.6%
Baseline % CD4+ cells Median
(Min – Max)
18.5% (3.1% –
37.4%)
Previous ADI*
% with Category C
29.2%
Treatment history
% with any ARV
96.6%
Median # previous
NRTIs
5
Median # previous
NNRTIs
1
Median # previous
PIs
3
* AIDS defining illness
27
Key efficacy results at 48 weeks for patients 12 – 18 years of age who took capsule
Endpoint
Result
Number of patients
29
Primary efficacy endpoint:
% with VL < 400
31.0%
Median change from baseline
in log10 HIV-1 RNA (copies/ml)
-0.79
Median change from baseline
in CD4+ cell count (cells/mm3)
39
Median change from baseline
in % CD4+ cells
3%
Analyses of tipranavir resistance in treatment experienced patients
tipranavir with ritonavir response rates in the RESIST studies were assessed by baseline tipranavir
genotype and phenotype. Relationships between baseline phenotypic susceptibility to tipranavir,
primary PI mutations, protease mutations at codons 33, 82, 84 and 90, tipranavir resistance-associated
mutations, and response to tipranavir with ritonavir therapy were assessed.
Of note, patients in the RESIST studies had a specific mutational pattern at baseline of at least one
primary protease gene mutation among codons 30N, 46I, 46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V or
90M, and no more than two mutations on codons 33, 82, 84 or 90.
The following observations were made:
Primary PI mutations:
Analyses were conducted to assess virological outcome by the number of primary PI mutations (any
change at protease codons 30, 32, 36, 46, 47, 48, 50, 53, 54, 82, 84, 88 and 90) present at baseline.
Response rates were higher in tipranavir with ritonavir patients than comparator PI boosted with
ritonavir in new enfuvirtide patients, or patients without new enfuvirtide. However, without new
enfuvirtide some patients began to lose antiviral activity between weeks 4 and 8.
Mutations at protease codons 33, 82, 84 and 90:
A reduced virological response was observed in patients with viral strains harbouring two or more
mutations at HIV protease codons 33, 82, 84 or 90, and not receiving new enfuvirtide.
Tipranavir resistance-associated mutations:
Virological response to tipranavir with ritonavir therapy has been evaluated using a tipranavir-
associated mutation score based on baseline genotype in RESIST-1 and RESIST-2 patients. This score
(counting the 16 amino acids that have been associated with reduced tipranavir susceptibility and/or
reduced viral load response: 10V, 13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/M/V, 58E,
69K, 74P, 82L/T, 83D and 84V) was applied to baseline viral protease sequences. A correlation
between the tipranavir mutation score and response to tipranavir with ritonavir therapy at week 48 has
been established.
This score has been determined from the selected RESIST patient population having specific mutation
inclusion criteria and therefore extrapolation to a wider population mandates caution.
At 48-weeks, a higher proportion of patients receiving tipranavir with ritonavir achieved a treatment
response in comparison to the comparator protease inhibitor/ritonavir for nearly all of the possible
combinations of genotypic resistance mutations (see table below).
28
−
−
−
Proportion of patients achieving treatment response at Week 48 (confirmed ≥1 log
10
copies/ml
decrease in viral load compared to baseline), according to tipranavir baseline mutation score
and enfuvirtide use in RESIST patients
New ENF
No New
ENF*
Number of
TPV Score
Mutations**
TPV/r
TPV/r
0,1 73% 53%
2 61% 33%
3 75% 27%
4 59% 23%
≥ 5 47% 13%
All patients 61% 29%
* Includes patients who did not receive ENF and those who were previously treated with and
continued ENF
**Mutations in HIV protease at positions L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, M46L,
I47V, I54A/M/V, 58E, H69K, T74P, V82L/T, N83D or I84V
ENF Enfuvirtide; TPV/r Tipranavir with ritonavir
Sustained HIV-1 RNA decreases up to week 48 were mainly observed in patients who received
tipranavir with ritonavir and new enfuvirtide. If patients did not receive tipranavir with ritonavir with
new enfuvirtide, diminished treatment responses at week 48 were observed, relative to new enfuvirtide
use (see Table below).
Mean decrease in viral load from baseline to week 48, according to tipranavir baseline mutation
score and enfuvirtide use in RESIST patients
New ENF
No New
ENF*
Number of
TPV Score
Mutations**
TPV/r
TPV/r
0, 1 -2.3 -1.6
2 -2.1 -1.1
3 -2.4 -0.9
4 -1.7 -0.8
≥ 5 -1.9 -0.6
All patients -2.0 -1.0
* Includes patients who did not receive ENF and those who were previously treated with and
continued ENF
** Mutations in HIV protease at positions L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T,
M46L, I47V, I54A/M/V, 58E, H69K, T74P, V82L/T, N83D or I84V
ENF Enfuvirtide; TPV/r Tipranavir with ritonavir
Tipranavir phenotypic resistance:
Increasing baseline phenotypic fold change to tipranavir in isolates is correlated to decreasing
virological response. Isolates with baseline fold change of >0 to 3 are considered susceptible; isolates
with >3 to 10 fold changes have decreased susceptibility; isolates with >10 fold changes are resistant.
Conclusions regarding the relevance of particular mutations or mutational patterns are subject to
change with additional data, and it is recommended to always consult current interpretation systems
for analysing resistance test results.
29
−
5.2 Pharmacokinetic properties
In order to achieve effective tipranavir plasma concentrations and a twice daily dosing regimen,
coadministration of tipranavir with low dose ritonavir twice daily is essential (see section 4.2).
Ritonavir acts by inhibiting hepatic cytochrome P450 CYP3A, the intestinal P-glycoprotein (Pgp)
efflux pump and possibly intestinal cytochrome P450 CYP3A as well. As demonstrated in a dose-
ranging evaluation in 113 HIV-negative healthy male and female volunteers, ritonavir increases AUC
0-
12h
, C
max
and C
min
and decreases the clearance of tipranavir. 500 mg Tipranavir co-administered with
low dose ritonavir (200 mg; twice daily) was associated with a 29-fold increase in the geometric mean
morning steady-state trough plasma concentrations compared to tipranavir 500 mg twice daily without
ritonavir.
Absorption
Absorption of tipranavir in humans is limited, though no absolute quantification of absorption is
available. Tipranavir is a Pgp substrate, a weak Pgp inhibitor and appears to be a potent Pgp inducer as
well. Data suggest that, although ritonavir is a Pgp inhibitor, the net effect of APTIVUS, co-
administered with low dose ritonavir, at the proposed dose regimen at steady-state, is Pgp induction.
Peak plasma concentrations are reached within 1 to 5 hours after dose administration depending upon
the dosage used. With repeated dosing, tipranavir plasma concentrations are lower than predicted from
single dose data, presumably due to hepatic enzyme induction. Steady-state is attained in most subjects
after 7 days of dosing. Tipranavir, co-administered with low dose ritonavir, exhibits linear
pharmacokinetics at steady state.
Dosing with APTIVUS capsules 500 mg twice daily concomitant with 200 mg ritonavir twice daily
for 2 to 4 weeks and without meal restriction produced a mean tipranavir peak plasma concentration
(C
max
) of 94.8 ± 22.8 µM for female patients (n=14) and 77.6 ± 16.6 µM for male patients (n=106),
occurring approximately 3 hours after administration. The mean steady-state trough concentration
prior to the morning dose was 41.6 ± 24.3 µM for female patients and 35.6 ± 16.7 µM for male
patients. Tipranavir AUC over a 12 hour dosing interval averaged 851 ± 309 µM•h (CL=1.15 l/h) for
female patients and 710 ± 207 µM•h (CL=1.27 l/h) for male patients. The mean half-life was
5.5 (females) or 6.0 hours (males).
Effects of food on oral absorption
Food improves the tolerability of tipranavir with ritonavir. Therefore APTIVUS, co-administered with
low dose ritonavir, should be given with food.
Absorption of tipranavir, co-administered with low dose ritonavir, is reduced in the presence of
antacids (see section 4.5).
Distribution
Tipranavir is extensively bound to plasma proteins (>99.9%). From clinical samples of healthy
volunteers and HIV-1 positive subjects who received tipranavir without ritonavir the mean fraction of
tipranavir unbound in plasma was similar in both populations (healthy volunteers 0.015%
±
0.006%;
HIV-positive subjects 0.019%
±
0.076%). Total plasma tipranavir concentrations for these samples
M. The unbound fraction of tipranavir appeared to be independent of total
concentration over this concentration range.
µ
No studies have been conducted to determine the distribution of tipranavir into human cerebrospinal
fluid or semen.
Biotransformation
In vitro
metabolism studies with human liver microsomes indicated that CYP3A4 is the predominant
CYP isoform involved in tipranavir metabolism.
The oral clearance of tipranavir decreased after the addition of ritonavir which may represent
diminished first-pass clearance of the substance at the gastrointestinal tract as well as the liver.
30
ranged from 9 to 82
The metabolism of tipranavir in the presence of low dose ritonavir is minimal. In a
14
C-tipranavir
human study (500 mg
14
C-tipranavir with 200 mg ritonavir, twice daily), unchanged tipranavir was
predominant and accounted for 98.4% or greater of the total plasma radioactivity circulating at 3, 8, or
12 hours after dosing. Only a few metabolites were found in plasma, and all were at trace levels (0.2%
or less of the plasma radioactivity). In faeces, unchanged tipranavir represented the majority of faecal
radioactivity (79.9% of faecal radioactivity). The most abundant faecal metabolite, at 4.9% of faecal
radioactivity (3.2% of dose), was a hydroxyl metabolite of tipranavir. In urine, unchanged tipranavir
was found in trace amounts (0.5% of urine radioactivity). The most abundant urinary metabolite, at
11.0% of urine radioactivity (0.5% of dose) was a glucuronide conjugate of tipranavir.
Elimination
Administration of
14
C-tipranavir to subjects (n = 8) that received 500 mg tipranavir with 200 mg
ritonavir; twice daily dosed to steady-state demonstrated that most radioactivity (median 82.3%) was
excreted in faeces, while only a median of 4.4% of the radioactive dose administered was recovered in
urine. In addition, most radioactivity (56%) was excreted between 24 and 96 hours after dosing. The
effective mean elimination half-life of tipranavir with ritonavir in healthy volunteers (n = 67) and
HIV-infected adult patients (n = 120) was approximately 4.8 and 6.0 hours, respectively, at steady
state following a dose of 500 mg/200 mg twice daily with a light meal.
Special populations
Although data available at this stage are currently limited to allow a definitive analysis, they suggest
that the pharmacokinetic profile is unchanged in elderly and comparable between races. By contrast,
evaluation of the steady-state plasma tipranavir trough concentrations at 10-14 h after dosing from the
RESIST-1 and RESIST-2 studies demonstrate that females generally had higher tipranavir
concentrations than males. After four weeks of APTIVUS 500 mg with 200 mg ritonavir (twice daily)
the median plasma trough concentration of tipranavir was 43.9 µM for females and 31.1 µM for males.
This difference in concentrations does not warrant a dose adjustment.
Renal dysfunction
: Tipranavir pharmacokinetics have not been studied in patients with renal
impairment. However, since the renal clearance of tipranavir is negligible, a decrease in total body
clearance is not expected in patients with renal impairment.
Hepatic dysfunction
: In a study comparing 9 patients with mild (Child-Pugh A) hepatic impairment to
9 controls, the single and multiple dose exposure of tipranavir and ritonavir were increased in patients
with hepatic impairment but still within the range observed in clinical studies. No dosing adjustment
is required in patients with mild hepatic impairment but patients should be closely monitored (see
sections 4.2 and 4.4).
The influence of moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment on the
multiple dose pharmacokinetics of either tipranavir or ritonavir has so far not been investigated.
tipranavir is contraindicated in moderate or severe hepatic impairment (see sections 4.2 and 4.3).
Paediatric population
:
The oral solution has been shown to have greater bioavailability than the soft capsule formulation.
5.3 Preclinical safety data
Animal toxicology studies have been conducted with tipranavir alone, in mice, rats and dogs, and co-
administered with ritonavir (3.75:1 w/w ratio) in rats and dogs. Studies with co-administration of
tipranavir and ritonavir did not reveal any additional toxicological effects when compared to those
seen in the tipranavir single agent toxicological studies.
The predominant effects of repeated administration of tipranavir across all species toxicologically
tested were on the gastrointestinal tract (emesis, soft stool, diarrhoea) and the liver (hypertrophy). The
effects were reversible with termination of treatment. Additional changes included bleeding in rats at
high doses (rodents specific). Bleeding observed in rats was associated with prolonged prothrombin
time (PT), activated partial thromboplastin time (APTT) and a decrease in some vitamin K dependent
31
factors. The co-administration of tipranavir with vitamin E in the form of TPGS (d-alphatocopherol
polyethylene glycol 1000 succinate) from 2,322 IU/m² upwards in rats resulted in a significant
increase in effects on coagulation parameters, bleeding events and death. In preclinical studies of
tipranavir in dogs, an effect on coagulation parameters was not seen. Co-administration of tipranavir
and vitamin E has not been studied in dogs.
The majority of the effects in repeat-dose toxicity studies appeared at systemic exposure levels which
are equivalent to or even below the human exposure levels at the recommended clinical dose.
In in-vitro studies, tipranavir was found to inhibit platelet aggregation when using human platelets (see
section 4.4) and thromboxane A2 binding in an in vitro cell model at levels consistent with exposure
observed in patients receiving APTIVUS with ritonavir. The clinical implications of these findings
are not known.
In a study conducted in rats with tipranavir at systemic exposure levels (AUC) equivalent to human
exposure at the recommended clinical dose, no adverse effects on mating or fertility were observed. At
maternal doses producing systemic exposure levels similar to or below those at the recommended
clinical dose, tipranavir did not produce teratogenic effects. At tipranavir exposures in rats at 0.8-fold
human exposure at the clinical dose, foetal toxicity (decreased sternebrae ossification and body
weights) was observed. In pre- and post-natal development studies with tipranavir in rats, growth
inhibition of pups was observed at maternally toxic doses approximating 0.8-fold human exposure.
Carcinogenicity studies of tipranavir in mice and rats revealed tumourigenic potential specific for
these species, which are regarded as of no clinical relevance. Tipranavir showed no evidence of
genetic toxicity in a battery of
in vitro
and
in vivo
tests.
6.
6.1 List of excipients
Capsule contents:
Macrogolglycerol ricinoleate
Ethanol
Mono/diglycerides of caprylic/capric acid
Propylene glycol
Purified water
Trometamol
Propyl gallate.
Capsule shell:
Gelatin
Red iron oxide (E172)
Propylene glycol
Purified water
‘Sorbitol special-glycerin blend’ (d-sorbitol, 1,4 sorbitan, mannitol and glycerin)
Titanium dioxide (E171).
Black printing ink:
Propylene glycol
Black iron oxide (E172)
Polyvinyl acetate phthalate
Macrogol
Ammonium hydroxide.
6.2 Incompatibilities
32
Not applicable.
6.3 Shelf life
3 years.
In use storage: 60 days (below 25°C), after first opening of the bottle. It is advisable that the patient
writes the date of opening the bottle on the label and/or carton.
6.4 Special precautions for storage
Store in a refrigerator (2 - 8°C).
6.5 Nature and contents of container
High density polyethylene (HDPE) bottle with two-piece child-resistant closure (outer shell HDPE,
inner shell polypropylene, with a pulpboard/aluminium liner). Each bottle contains 120 soft capsules.
6.6 Special precautions for disposal
No special requirements.
7.
Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany
8.
EU/1/05/315/001
9.
Date of first authorisation:
25 October 2005
Date of latest renewal:
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu/
33
1.
APTIVUS 100 mg/ml oral solution
2.
Each ml of oral solution contains 100 mg tipranavir.
For a full list of excipients, see section 6.1.
3.
Oral solution.
Clear yellow viscous liquid.
4.
APTIVUS 100 mg/ml oral solution, co-administered with low dose ritonavir, is indicated for
combination antiretroviral treatment of HIV-1 infection in highly pre-treated children from 2 to
12 years of age with virus resistant to multiple protease inhibitors. APTIVUS should only be used as
part of an active combination antiretroviral regimen in patients with no other therapeutic options (see
sections 4.4 and 5.1).
This indication is based on the results of one phase II study investigating pharmacokinetics, safety and
efficacy of APTIVUS oral solution in mostly treatment-experienced children aged 2 to 12 years (see
section 5.1).
In deciding to initiate treatment with APTIVUS, co-administered with low dose ritonavir, careful
consideration should be given to the treatment history of the individual patient and the patterns of
mutations associated with different agents. Genotypic or phenotypic testing (when available) and
treatment history should guide the use of APTIVUS. Initiation of treatment should take into account
the combinations of mutations which may negatively impact the virological response to APTIVUS,
co-administered with low dose ritonavir (see section 5.1).
APTIVUS must always be given with low dose ritonavir as a pharmacokinetic enhancer, and in
combination with other antiretroviral medicinal products. The Summary of Product Characteristics of
ritonavir must therefore be consulted prior to initiation of therapy with APTIVUS (especially as
regards the contraindications, warnings and undesirable effects sections).
APTIVUS should be prescribed by physicians who are experienced in the treatment of HIV-1
infection.
APTIVUS with ritonavir should not be used in treatment-naïve patients.
Posology
Patients should be advised of the need to take APTIVUS and ritonavir every day as prescribed. If a
dose is missed by more than 5 hours, the patient should be instructed to wait and then to take the next
dose of tipranavir and ritonavir at the regularly scheduled time. If a dose is missed by less than
34
5 hours, the patient should be instructed to take the missed dose immediately, and then to take the next
dose of tipranavir and ritonavir at the regularly scheduled time.
Paediatric population
The recommended dose for children (age 2 to 12 years) is 375 mg/m
2
APTIVUS co-administered with
150 mg/m
2
ritonavir, twice daily. The paediatric dose should not exceed the 500 mg/200 mg dose.
APTIVUS/ritonavir dose (375 mg/m
2
APTIVUS + 150 mg/m
2
ritonavir)
BSA Range
(m
2
)
Dose
APTIVUS
(mg)
Volume
APTIVUS (ml)
Dose
ritonavir
(mg)
Volume
ritonavir
(ml)
0.37 – 0.42
140
1.4
56
0.7
0.43 – 0.47
160
1.6
63
0.8
0.48 – 0.52
180
1.8
71
0.9
0.53 – 0.58
200
2
79
1
0.59 – 0.63
220
2.2
87
1.1
0.64 – 0.68
240
2.4
95
1.2
0.69 - 0.74
260
2.6
103
1.3
0.75 – 0.79
280
2.8
111
1.4
0.80 – 0.84
300
3
119
1.5
0.85 – 0.90
320
3.2
127
1.6
0.91 – 0.95
340
3.4
135
1.7
0.96 – 1.00
360
3.6
143
1.8
1.01 - 1.06
380
3.8
151
1.9
1.07 – 1.11
400
4
159
2
1.12 – 1.16
420
4.2
167
2.1
1.17 – 1.22
440
4.4
174
2.2
1.23 – 1.27
460
4.6
182
2.3
1.28 – 1.32
480
4.8
190
2.4
> 1.33
500
5
200
2.5
Doses of ritonavir lower than 150 mg/m
2
twice daily, should not be used as they might alter the
efficacy profile of the combination.
The safety and efficacy of APTIVUS in children under 2 years of age has not been established. No
data are available.
APTIVUS is available as soft capsules for adults and adolescents from 12 years of age (please refer to
the respective SPC for further details). Patients treated with APTIVUS and reaching the age of
12 years should be switched to the capsule formulation (see sections 4.4 and 5.1).
Liver impairment
Tipranavir is metabolised by the hepatic system. Liver impairment could therefore result in an increase
of tipranavir exposure and a worsening of its safety profile. Therefore, APTIVUS should be used with
caution, and with increased monitoring frequency, in patients with mild hepatic impairment (Child-
Pugh Class A). APTIVUS is contraindicated in patients with moderate or severe (Child-Pugh Class B
or C) hepatic impairment (see sections 4.3, 4.4 and 5.2).
Renal impairment
No dosage adjustment is required in patients with renal impairment (see sections 4.4 and 5.2).
Method of administration
APTIVUS oral solution co-administered with low dose oral solution ritonavir should be taken with
food (see section 5.2).
35
Hypersensitivity to the active substance or to any of the excipients.
Patients with moderate or severe (Child-Pugh B or C) hepatic impairment.
Combination of rifampicin with APTIVUS with concomitant low dose ritonavir is contraindicated (see
section 4.5).
Herbal preparations containing St John’s wort (
Hypericum perforatum
) must not be used while taking
APTIVUS due to the risk of decreased plasma concentrations and reduced clinical effects of tipranavir
(see section 4.5).
Co-administration of APTIVUS with low dose ritonavir, with active substances that are highly
dependent on CYP3A for clearance, and for which elevated plasma concentrations are associated with
serious and/or life-threatening events, is contraindicated. These active substances include
antiarrhythmics (amiodarone, bepridil, quinidine), antihistamines (astemizole, terfenadine), ergot
derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine), gastrointestinal motility
agents (cisapride), neuroleptics (pimozide, sertindole), sedatives/hypnotics (orally administered
midazolam and triazolam. For caution on parenterally administered midazolam see section 4.5) and
HMG-CoA reductase inhibitors (simvastatin and lovastatin). In addition, co-administration of
APTIVUS with low dose ritonavir, and medicinal products that are highly dependent on CYP2D6 for
clearance, such as the antiarrhythmics flecainide, propafenone and metoprolol given in heart failure, is
contraindicated (see section 4.5).
APTIVUS must be administered with low dose ritonavir to ensure its therapeutic effect (see section
4.2). Failure to correctly co-administer tipranavir with ritonavir will result in reduced plasma levels of
tipranavir that may be insufficient to achieve the desired antiviral effect. Patients should be instructed
accordingly.
APTIVUS is not a cure for HIV-1 infection or AIDS. Patients receiving APTIVUS
or any other
antiretroviral therapy may continue to develop opportunistic infections and other complications of
HIV-1 infection.
Patients should be advised that current antiretroviral therapy has not been proven to prevent the risk of
transmission of HIV to others through blood or sexual contact. Appropriate precautions should
continue to be employed.
Switching from APTIVUS capsules to the oral solution:
APTIVUS capsules are not interchangeable
with the oral solution. Compared to the capsules, tipranavir exposure is higher when administering the
same dose as oral solution. Also, the composition of the oral solution is different from that of the
capsules, with the high vitamin E content being especially noteworthy. Both of these factors may
contribute to an increased risk of adverse reactions (type, frequency and/or severity). Therefore
patients should not be switched from APTIVUS capsules to APTIVUS oral solution (see sections 5.1
and 5.2).
Switching from APTIVUS oral solution to the capsules:
APTIVUS oral solution is not interchangeable
with the capsules. Compared to the oral solution, tipranavir exposure is lower when administering the
same dose as capsules. However, children previously treated with APTIVUS oral solution and
becoming 12 years of age should be switched to capsules, particularly because of the more favourable
safety profile of the capsules. It has to be noted that the switch from the oral solution to the capsule
formulation of APTIVUS could be associated with decreased exposure. Therefore, it is recommended
that patients switching from APTIVUS oral solution to capsules at the age of 12 years are closely
monitored for the virologic response of their antiretroviral regimen (see sections 5.1 and 5.2).
36
Liver disease:
APTIVUS is contraindicated in patients with moderate or severe (Child-Pugh Class B
or C) hepatic insufficiency. Limited data are currently available for the use of APTIVUS, co-
administered with low dose ritonavir, in patients co-infected with hepatitis B or C. Patients with
chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for
severe and potentially fatal hepatic adverse reaction. APTIVUS should be used in this patient
population only if the potential benefit outweighs the potential risk, and with increased clinical and
laboratory monitoring. In the case of concomitant antiviral therapy for hepatitis B or C, please refer
also to the relevant Summary of Product Characteristics for these medicinal products.
Patients with mild hepatic impairment (Child-Pugh Class A) should be closely monitored.
Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased
frequency of liver function abnormalities during combination therapy and should be monitored
according to standard practice. APTIVUS with ritonavir should be discontinued once signs of
worsening liver function occur in patients with pre-existing liver disease.
APTIVUS co-administered with low dose ritonavir, has been associated with reports of clinical
hepatitis and hepatic decompensation, including some fatalities. These have generally occurred in
patients with advanced HIV disease taking multiple concomitant medicinal products. Caution should
be exercised when administering APTIVUS to patients with liver enzyme abnormalities or with a
history of hepatitis. Increased ALAT/ASAT monitoring should be considered in these patients.
APTIVUS therapy should not be initiated in patients with pre-treatment ASAT or ALAT greater than
5 times the Upper Limit Normal (ULN) until baseline ASAT/ALAT is stabilised at less than 5X ULN,
unless the potential benefit justifies the potential risk.
APTIVUS therapy should be discontinued in patients experiencing ASAT or ALAT elevations greater
than 10X ULN, or developing signs or symptoms of clinical hepatitis during therapy. If another cause
is identified (eg acute hepatitis A, B or C virus, gallbladder disease, other medicinal products), then
rechallenge with APTIVUS may be considered when ASAT/ALAT have returned to the patient’s
baseline levels.
Liver monitoring
Monitoring of hepatic tests should be done prior to initiation of therapy, after two, four and then every
four weeks until 24 weeks, and then every eight to twelve weeks thereafter. Increased monitoring (i.e.
prior to initiation of therapy, every two weeks during the first three months of treatment, then monthly
until 48 weeks, and then every eight to twelve weeks thereafter) is warranted when APTIVUS and low
dose ritonavir are administered to patients with elevated ASAT and ALAT levels, mild hepatic
impairment, chronic hepatitis B or C, or other underlying liver disease.
Treatment-naïve patients
In a study performed in antiretroviral naïve adult patients, tipranavir 500 mg with ritonavir 200 mg
twice daily, as compared to lopinavir/ritonavir, was associated with an excess in the occurrence of
significant (grade 3 and 4) transaminase elevations without any advantage in terms of efficacy (trend
towards a lower efficacy). The study was prematurely stopped after 60 weeks.
Therefore, tipranavir with ritonavir should not be used in treatment-naïve patients.
Renal impairment
Since the renal clearance of tipranavir is negligible, increased plasma concentrations are not expected
in patients with renal impairment.
Haemophilia
There have been reports of increased bleeding, including spontaneous skin haematomas and
haemarthrosis in patients with haemophilia type A and B treated with protease inhibitors. In some
patients additional Factor VIII was given. In more than half of the reported cases, treatment with
protease inhibitors was continued or reintroduced if treatment had been discontinued. A causal
37
relationship has been evoked, although the mechanism of action had not been elucidated.
Haemophiliac patients should therefore be made aware of the possibility of increased bleeding.
Bleeding
RESIST participants receiving APTIVUS with ritonavir tended to have an increased risk of bleeding;
at 24 weeks the relative risk was 1.98 (95% CI=1.03, 3.80). At 48-weeks the relative risk decreased to
1.27 (95% CI=0.76, 2.12). There was no pattern for the bleeding events and no difference between
treatment groups in coagulation parameters. The significance of this finding is being further studied.
Fatal and non-fatal intracranial haemorrhages (ICH) have been reported in patients receiving
APTIVUS, many of whom had other medical conditions or were receiving concomitant medicinal
products that may have caused or contributed to these events. However, in some cases the role of
APTIVUS cannot be excluded. No pattern of abnormal haematological or coagulation parameters has
been observed in patients in general, or preceding the development of ICH. Therefore, routine
measurement of coagulation parameters is not currently indicated in the management of patients on
APTIVUS.
An increased risk of ICH has previously been observed in patients with advanced HIV disease/AIDS
such as those treated in the APTIVUS clinical trials.
In
in vitro
experiments, tipranavir was observed to inhibit human platelet aggregation at levels
consistent with exposures observed in patients receiving APTIVUS with ritonavir.
In rats, co-administration with vitamin E increased the bleeding effects of tipranavir (see section 5.3
Preclinical safety data).
APTIVUS, co-administered with low dose ritonavir, should be used with caution in patients who may
be at risk of increased bleeding from trauma, surgery or other medical conditions, or who are receiving
medicinal products known to increase the risk of bleeding such as antiplatelet agents and
anticoagulants or who are taking supplemental vitamin E. Patients taking APTIVUS oral solution
should be advised not to take any supplemental vitamin E.
Diabetes mellitus/hyperglycaemia
New onset of diabetes mellitus, hyperglycaemia or exacerbations of existing diabetes mellitus has
been reported in patients receiving antiretroviral therapy, including protease inhibitors. In some of
these the hyperglycaemia was severe and in some cases also associated with ketoacidosis. Many of the
patients had confounding medical conditions, some of which required therapy with agents that have
been associated with the development of diabetes mellitus or hyperglycaemia.
Lipid elevations
Treatment with APTIVUS co-administered with low dose ritonavir and other antiretroviral agents has
resulted in increased plasma total triglycerides and cholesterol. Triglyceride and cholesterol testing
should be performed prior to initiating tipranavir therapy and during therapy. Treatment-related lipid
elevations should be managed as clinically appropriate.
Fat redistribution
Combination antiretroviral therapy has been associated with the redistribution of body fat
(lipodystrophy) in HIV infected patients. The long-term consequences of these events are currently
unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis
and protease inhibitors, and lipoatrophy and nucleoside reverse transcriptase inhibitors, has been
hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older
age, and with factors related to the active substance such as longer duration of antiretroviral treatment
and associated metabolic disturbances. Clinical examination should include evaluation for physical
signs of fat redistribution. Consideration should be given to the measurement of fasting serum lipids
and blood glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8).
Immune reactivation syndrome
38
In HIV-infected patients with severe immune deficiency at the time of institution of combination
antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic
pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically,
such reactions have been observed within the first few weeks or months of initiation of CART.
Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections and
Pneumocystis pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted
when necessary. In addition, reactivation of herpes simplex and herpes zoster has been observed in
clinical studies with APTIVUS, co-administered with low dose ritonavir.
Rash
Mild to moderate rashes including urticarial rash, maculopapular rash, and photosensitivity have been
reported in subjects receiving APTIVUS, co-administered with low dose ritonavir. At 48-weeks in
Phase III trials, rash of various types was observed in 15.5% males and 20.5% females receiving
APTIVUS co-administered with low dose ritonavir. Additionally, in one interaction trial, in healthy
female volunteers administered a single dose of ethinyl oestradiol followed by APTIVUS co-
administered with low dose ritonavir, 33% of subjects developed a rash. Rash accompanied by joint
pain or stiffness, throat tightness, or generalized pruritus has been reported in both men and women
receiving APTIVUS co-administered with low dose ritonavir.
In the paediatric clinical trial, the
frequency of rash (all grades, all causality) through 48 weeks of treatment was higher than in adult
patients.
Osteonecrosis
Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol
consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been
reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination
antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience
joint aches and pain, joint stiffness or difficulty in movement.
Interactions
The interaction profile of tipranavir, co-administered with low dose ritonavir, is complex. For a
description of the mechanisms and potential mechanisms contributing to the interaction profile of
tipranavir, see section 4.5.
Abacavir and zidovudine:
The concomitant use of APTIVUS, co-administered with low dose ritonavir,
with zidovudine or abacavir, results in a significant decrease in plasma concentration of these
nucleoside reverse transcriptase inhibitors (NRTIs). Therefore, the concomitant use of zidovudine or
abacavir with APTIVUS, co-administered with low dose ritonavir, is not-recommended unless there
are no other available NRTIs suitable for patient management (see section 4.5).
Protease inhibitors:
Concomitant use of APTIVUS, co-administered with low dose ritonavir, with the
protease inhibitors amprenavir, lopinavir or saquinavir (each co-administered with low dose ritonavir)
in a dual-boosted regimen, results in significant decreases in plasma concentrations of these protease
inhibitors. A significant decrease in plasma concentrations of atazanavir and a marked increase of
tipranavir and ritonavir concentrations was observed when APTIVUS, associated with low dose
ritonavir, was co-administered with atazanavir (see section 4.5). No data are currently available on
interactions of tipranavir, co-administered with low dose ritonavir, with protease inhibitors other than
those listed above. Therefore, the co-administration of tipranavir, co-administered with low dose
ritonavir, with protease inhibitors is not recommended.
Oral contraceptives and oestrogens:
Since levels of ethinyl oestradiol are decreased, the co-
administration of APTIVUS co-administered with low dose ritonavir is not recommended. Alternative
or additional contraceptive measures are to be used when oestrogen based oral contraceptives are co-
administered with APTIVUS co-administered with low dose ritonavir (see section 4.5). Patients using
oestrogens as hormone replacement therapy should be clinically monitored for signs of oestrogen
deficiency. Women using oestrogens may have an increased risk of non serious rash.
39
Anticonvulsants
: Caution should be used when prescribing carbamazepine, phenobarbital, and
phenytoin. APTIVUS may be less effective due to decreased tipranavir plasma concentrations in
patients taking these agents concomitantly.
Halofantrine, lumefantrine:
Due to their metabolic profile and inherent risk of inducing torsades de
pointes, administration of halofantrine and lumefantrine with APTIVUS co-administered with low
dose ritonavir, is not recommended.
Fluticasone
: Concomitant use of tipranavir, co-administered with low dose ritonavir, and fluticasone
or other glucocorticoids that are metabolised by CYP3A4 is not recommended unless the potential
benefit of treatment outweighs the risk of systemic corticosteroid effects, including Cushing's
syndrome and adrenal suppression (see section 4.5).
Atorvastatin
: Tipranavir, co-administered with low dose ritonavir, increases the plasma concentrations
of atorvastatin (see section 4.5). The combination is not recommended. Other HMG-CoA reductase
inhibitors should be considered such as pravastatin, fluvastatin or rosuvastatin (see section 4.5).
However, if atorvastatin is specifically required for patient management, it should be started with the
lowest dose and careful monitoring is necessary.
Omeprazole and other proton pump inhibitors:
The combined use of APTIVUS with ritonavir with
either omeprazole, esomeprazole or with other proton pump inhibitors is not recommended (see
section 4.5).
The interaction profile of APTIVUS, co-administered with low dose ritonavir, is complex and requires
special attention in particular in combination with other antiretroviral agents.
Interaction studies have only been performed in adults.
Metabolic profile of tipranavir:
Tipranavir is a substrate, an inducer and an inhibitor of cytochrome P450 CYP3A. When co-
administered with ritonavir at the
recommended dosage (see section 4.2) there is a net inhibition of
P450 CYP3A. Co-administration of APTIVUS and low dose ritonavir with agents primarily
metabolised by CYP3A may result in changed plasma concentrations of tipranavir or the other agents,
which could alter their therapeutic and undesirable effects (see list and details of considered agents,
below). Agents that are contraindicated specifically due to the expected magnitude of interaction and
potential for serious adverse reactions are detailed in this section, and listed in section 4.3.
A cocktail study was conducted in 16 healthy volunteers with twice-daily tipranavir 500 mg with
ritonavir 200 mg capsule administration for 10 days to assess the net effect on the activity of hepatic
CYP 1A2 (caffeine), 2C9 (warfarin), 2D6 (dextromethorphan), both intestinal/hepatic CYP 3A4
(midazolam) and P-glycoprotein (Pgp) (digoxin). At steady state, there was a significant induction of
CYP 1A2 and a slight induction on CYP 2C9. Potent inhibition of CYP 2D6 and both hepatic and
intestinal CYP 3A4 activities were observed. Pgp activity is significantly inhibited after the first dose,
but there was a slight induction at steady state. Practical recommendations deriving from this study are
displayed below. This study was also conducted with APTIVUS oral solution 500 mg with ritonavir
200 mg and showed the same CYP P450 and Pgp interactions as the APTIVUS capsule 500 mg with
ritonavir 200 mg. Based on the results from this study, APTIVUS oral solution might be expected to
have a similar interaction profile as the capsules.
Studies in human liver microsomes indicated tipranavir is an inhibitor of CYP 1A2, CYP 2C9, CYP
2C19 and CYP 2D6. The potential net effect of tipranavir with ritonavir on CYP 2D6 is inhibition,
because ritonavir is also a CYP 2D6 inhibitor. The
in vivo
net effect of tipranavir with ritonavir on
CYP 1A2, CYP 2C9 and CYP 2C19, indicates, through a preliminary study, an inducing potential of
tipranavir withritonavir on CYP1A2 and, to a lesser extent, on CYP2C9 and P-gp after several days of
40
treatment.
Data are not available to indicate whether tipranavir inhibits or induces glucuronosyl
transferases.
In vitro studies show that tipranavir is a substrate and also an inhibitor of Pgp.
It is difficult to predict the net effect of APTIVUS co-administered with low dose ritonavir on oral
bioavailability and plasma concentrations of agents that are dual substrates of CYP3A and Pgp. The
net effect will vary depending on the relative affinity of the co-administered substance for CYP3A and
Pgp, and the extent of intestinal first-pass metabolism/efflux.
Co-administration of APTIVUS and agents that induce CYP3A and/or Pgp may decrease tipranavir
concentrations and reduce its therapeutic effect (see list and details of considered agents, below). Co-
administration of APTIVUS and medicinal products that inhibit Pgp may increase tipranavir plasma
concentrations.
Known and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal
products are listed in the table below.
Interaction table
Interactions between APTIVUS and co-administered medicinal products are listed in the table below
(increase is indicated as “↑”, decrease as “↓”, no change as “↔”,once daily as “QD”, twice daily as
“BID”).
Unless otherwise stated, studies detailed below have been performed with the recommended dosage of
APTIVUS/r (i.e. 500/200 mg BID). However, some PK interaction studies were not performed with
this recommended dosage. Nevertheless, the results of many of these interaction studies can be
extrapolated to the recommended dosage since the doses used (eg. TPV/r 500/100 mg, TPV/r
750/200 mg) represented extremes of hepatic enzyme induction and inhibition and bracketed the
recommended dosage of APTIVUS/r.
Drugs by Therapeutic Area
Interaction
Geometric mean change (%)
Recommendations concerning
co-administration
Anti-infectives
Antiretrovirals
Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs)
Since there is no significant impact of nucleoside and nucleotide analogues on the P450 enzyme system no
dosage adjustment of APTIVUS is required when co-administered with these agents.
Abacavir
300 mg BID
(TPV/r 750/100 mg BID)
Abacavir Cmax ↓ 46%
Abacavir AUC ↓ 36%
The concomitant use of APTIVUS,
co-administered with low dose
ritonavir, with abacavir is not
recommended unless there are no
other available NRTIs suitable for
patient management. In such cases
no dosage adjustment of abacavir
can be recommended (see section
4.4).
The clinical relevance of this
reduction has not been
established, but may decrease the
efficacy of abacavir.
Mechanism unknown.
Didanosine
200 mg BID, ≥
60 kg - 125 mg BID, < 60 kg
(TPV/r 250/200 mg BID)
Didanosine Cmax ↓ 43%
Didanosine AUC ↓ 33%
Dosing of enteric-coated didanosine
and APTIVUS soft capsules, co-
administered with low dose
ritonavir, should be separated by at
least 2 hours to avoid formulation
incompatibility.
(TPV/r 750/100 mg BID)
Didanosine Cmax ↓ 24%
Didanosine AUC ↔
The clinical relevance of this
reduction in didanosine
concentrations has not been
41
established.
Mechanism unknown.
Lamivudine
150 mg BID
(TPV/r 750/100 mg BID)
No clinically significant
interaction is observed.
No dosage adjustment necessary.
Stavudine
40 mg BID
>
60 kg
30 mg BID < 60 kg
(TPV/r 750/100 mg BID)
No clinically significant
interaction is observed.
No dosage adjustment necessary.
Zidovudine
300 mg BID
(TPV/r 750/100 mg BID)
Zidovudine Cmax ↓ 49%
Zidovudine AUC ↓ 36%
The concomitant use of APTIVUS,
co-administered with low dose
ritonavir with zidovudine is not
recommended unless there are no
other available NRTIs suitable for
patient management. In such cases
no dosage adjustment of zidovudine
can be recommended (see section
4.4).
The clinical relevance of this
reduction has not been
established, but may decrease the
efficacy of zidovudine.
Mechanism unknown.
Tenofovir
300 mg QD
(TPV/r 750/200 mg BID)
No clinically significant
interaction is observed.
No dosage adjustment necessary.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Efavirenz
600 mg QD
No clinically significant interaction
is observed.
No dosage adjustment necessary.
Nevirapine
No interaction study
performed
The limited data available from a
phase IIa study in HIV-infected
patients suggest that no significant
interaction is expected between
nevirapine and TPV/r. Moreover a
study with TPV/r and another
NNRTI (efavirenz) did not show
any clinically relevant interaction
(see above).
No dosage adjustment necessary.
Protease inhibitors (PIs)
According to current treatment guidelines, dual therapy with protease inhibitors is generally not
recommended
Amprenavir/ritonavir
600/100 mg BID
Amprenavir Cmax ↓ 39%
Amprenavir AUC ↓ 44%
Amprenavir Cmin ↓ 55%
The concomitant use of APTIVUS,
co-administered with low dose
ritonavir, with amprenavir/ritonavir
is not recommended.
If the combination is nevertheless
considered necessary, a monitoring
of the plasma levels of amprenavir
is strongly encouraged (see section
4.4).
The clinical relevance of this
reduction in amprenavir
concentrations has not been
established.
Mechanism unknown.
Atazanavir/ritonavir
300/100 mg QD
(TPV/r 500/100 mg BID)
Atazanavir Cmax ↓ 57%
Atazanavir AUC ↓ 68%
Atazanavir Cmin ↓ 81%
The concomitant use of APTIVUS,
co-administered with low dose
ritonavir, with atazanavir/ritonavir
is not recommended.
If the co-administration is
nevertheless considered necessary, a
close monitoring of the safety of
tipranavir and a monitoring of
plasma concentrations of atazanavir
are strongly encouraged (see section
4.4).
Mechanism unknown.
Tipranavir Cmax
↑
8%
Tipranavir AUC
↑
20%
Tipranavir Cmin
↑
75%
Inhibition of CYP 3A4 by
42
atazanavir/ritonavir and induction
by tipranavir/r.
Lopinavir/ritonavir
400/100 mg BID
Lopinavir Cmax ↓ 47%
Lopinavir AUC ↓ 55%
Lopinavir Cmin ↓ 70%
The concomitant use of APTIVUS,
co-administered with low dose
ritonavir, with lopinavir/ritonavir is
not recommended.
If the combination is nevertheless
considered necessary, a monitoring
of the plasma levels of lopinavir is
strongly encouraged (see section
4.4).
The clinical relevance of this
reduction in lopinavir
concentrations has not been
established.
Mechanism unknown.
Saquinavir/ritonavir
600/100 mg QD
Saquinavir Cmax ↓ 70%
Saquinavir AUC ↓ 76%
Saquinavir Cmin ↓ 82%
The concomitant use of APTIVUS,
co-administered with low dose
ritonavir, with saquinavir/ritonavir
is not recommended.
If the combination is nevertheless
considered necessary, a monitoring
of the plasma levels of saquinavir is
strongly encouraged (see section
4.4).
The clinical relevance of this
reduction in saquinavir
concentrations has not been
established.
Mechanism unknown.
Protease inhibitors other
than those listed above
No data are currently available on
interactions of tipranavir, co-
administered with low dose
ritonavir, with protease inhibitors
other than those listed above.
Combination with APTIVUS, co-
administered with low dose
ritonavir, is not recommended (see
section 4.4)
Fusion inhibitors
Enfuvirtide
No interaction study
performed
In studies where tipranavir co-
administered with low-dose
ritonavir was used with or without
enfuvirtide, it has been observed
that the steady-state plasma
tipranavir trough concentration of
patients receiving enfuvirtide were
45% higher as compared to patients
not receiving enfuvirtide. No
information is available for the
parameters AUC and C
max
.
A pharmacokinetic interaction is
mechanistically unexpected and the
interaction has not been confirmed
in a controlled interaction study.
The clinical impact of the observed
data, especially regarding the
tipranavir with ritonavir safety
profile, remains unknown.
Nevertheless, the clinical data
available from the RESIST trials did
not suggest any significant
alteration of the tipranavir with
ritonavir safety profile when
combined with enfuvirtide as
compared to patients treated with
tipranavir with ritonavir without
enfuvirtide.
Antifungals
Fluconazole
200 mg QD
(Day 1) then 100 mg QD
Fluconazole ↔
No dosage adjustments are
recommended. Fluconazole doses
>
Tipranavir Cmax ↑ 32%
Tipranavir AUC ↑ 50%
Tipranavir Cmin ↑ 69%
200 mg/day are not recommended.
Mechanism unknown
Itraconazole
Ketoconazole
No interaction study
performed
Based on theoretical considerations
tipranavir, co-administered with
low dose ritonavir, is expected to
increase itraconazole or
ketoconazole concentrations.
Itraconazole or ketoconazole should
be used with caution (doses
>
43
200 mg/day are not
recommended).
Based on theoretical considerations,
tipranavir or ritonavir
concentrations might increase upon
co-administration with itraconazole
or ketoconazole.
Voriconazole
No interaction study
performed
Due to multiple CYP isoenzyme
systems involved in voriconazole
metabolism, it is difficult to predict
the interaction with tipranavir, co-
administered with low-dose
ritonavir.
Based on the known interaction of
voriconazole with low dose
ritonavir (see voriconazole SPC) the
co-administration of tipranavir/r
and voriconazole should be
avoided, unless an assessment of
the benefit/risk to the patient
justifies the use of voriconazole.
Antibiotics
Clarithromycin
500 mg
BID
Clarithromycin Cmax ↔
Clarithromycin AUC ↑ 19%
Clarithromycin Cmin ↑ 68%
Whilst the changes in
clarithromycin parameters are not
considered clinically relevant, the
reduction in the 14-OH metabolite
AUC should be considered for the
treatment of infections caused by
Haemophilus influenzae
in which
the 14-OH metabolite is most
active. The increase of tipranavir
Cmin may be clinically relevant.
Patients using clarithromycin at
doses higher than 500 mg twice
daily should be carefully monitored
for signs of toxicity of
clarithromycin and tipranavir. For
patients with renal impairment dose
reduction of clarithromycin should
be considered (see clarithromycin
and ritonavir product information).
14-OH-clarithromycin Cmax ↓ 97%
14-OH-clarithromycin AUC ↓ 97%
14-OH-clarithromycin Cmin ↓ 95%
Tipranavir Cmax ↑ 40%
Tipranavir AUC ↑ 66%
Tipranavir Cmin ↑ 100%
CYP 3A4 inhibition by tipranavir/r
and P-gp (an intestinal efflux
transporter) inhibition by
clarithromycin.
Rifabutin
150 mg QD
Rifabutin Cmax ↑ 70%
Rifabutin AUC ↑ 190%
Rifabutin Cmin ↑ 114%
Dosage reductions of rifabutin by at
least 75% of the usual 300 mg/day
are recommended (ie 150 mg on
alternate days, or three times per
week). Patients receiving rifabutin
with APTIVUS, co-administered
with low dose ritonavir, should be
closely monitored for emergence of
adverse events associated with
rifabutin therapy. Further dosage
reduction may be necessary.
25-O-desacetylrifabutin Cmax ↑ 3.2
fold
25-O-desacetylrifabutin AUC ↑ 21
fold
25-O-desacetylrifabutin Cmin ↑ 7.8
fold
Inhibition of CYP 3A4 by
tipranavir/r
No clinically significant change is
observed in tipranavir PK
parameters.
Rifampicin
Co-administration of protease
inhibitors with rifampicin
substantially decreases protease
inhibitor concentrations. In the case
of tipranavir co-administered with
low dose ritonavir, concomitant use
with rifampicin is expected to result
Concomitant use of APTIVUS, co-
administered with low dose
ritonavir, and rifampicin is
contraindicated (see section 4.3).
Alternate antimycobacterial agents
such as rifabutin should be
considered.
44
in sub-optimal levels of tipranavir
which may lead to loss of virologic
response and possible resistance to
tipranavir.
Antimalarial
Halofantrine
Lumefantrine
No interaction study
performed
Based on theoretical
considerations, tipranavir, co-
administered with low dose
ritonavir, is expected to increase
halofantrine and lumefantrine
concentrations.
Due to their metabolic profile and
inherent risk of inducing torsades
de pointes, administration of
halofantrine and lumefantrine with
APTIVUS, co-administered with
low dose ritonavir, is not
recommended (see section 4.4).
Inhibition of CYP 3A4 by
tipranavir/r
Anticonvulsants
Carbamazepine
200 mg
BID
Carbamazepine total* Cmax ↑ 13%
Carbamazepine total* AUC ↑ 16%
Carbamazepine total* Cmin ↑ 23%
Carbamazepine should be used with
caution in combination with
APTIVUS, co-administered with
low dose ritonavir. Higher doses of
carbamazepine (> 200 mg) may
result in even larger decreases in
tipranavir plasma concentrations
(see section 4.4).
*Carbamazepine total = total of
carbamazepine and epoxy-
carbamazepine (both are
pharmacologically active moieties).
The increase in carbamazepine total
PK parameters is not expected to
have clinical consequences.
Tipranavir Cmin ↓ 61% (compared
to historical data)
The decrease in tipranavir
concentrations may result in
decreased effectiveness.
Carbamazepine induces CYP3A4.
Phenobarbital
Phenytoin
No interaction study
performed
Phenobarbital and phenytoin induce
CYP3A4.
Phenobarbital and phenytoin should
be used with caution in combination
with APTIVUS, co-administered
with low dose ritonavir (see section
4.4).
Antispasmodic
Tolterodine
No interaction study
performed
Based on theoretical considerations,
tipranavir, co-administered with
low dose ritonavir, is expected to
increase tolterodine concentrations.
Co-administration is not
recommended.
Inhibition of CYP 3A4 and CYP
2D6 by tipranavir/r
HMG CoA reductase inhibitors
Atorvastatin
10 mg QD
Atorvastatin Cmax ↑ 8.6 fold
Atorvastatin AUC ↑ 9.4 fold
Atorvastatin Cmin ↑ 5.2 fold
Co-administration of atorvastatin
and APTIVUS, co-administered
with low dose ritonavir, is not
recommended. Other HMG-CoA
reductase inhibitors should be
considered such as pravastatin,
fluvastatin or rosuvastatin (See also
Tipranavir ↔
Inhibition of CYP 3A4 by
45
tipranavir/r
section 4.4 and rosuvastatin and
pravastatin recommendations).
However, if atorvastatin is
specifically required for patient
management, it should be started
with the lowest dose and careful
monitoring is necessary (see section
4.4).
Rosuvastatin
10 mg QD
Rosuvastatin Cmax ↑ 123%
Rosuvastatin AUC ↑ 37%
Rosuvastatin Cmin ↑ 6%
Co-administration of APTIVUS,
co-administered with low dose
ritonavir, and rosuvastatin should
be initiated with the lowest dose
(5 mg/day) of rosuvastatin, titrated
to treatment response, and
accompanied with careful clinical
monitoring for rosuvastatin
associated symptoms as described
in the label of rosuvastatin.
Tipranavir ↔
Mechanism unknown.
Pravastatin
No interaction study
performed
Based on similarities in the
elimination between pravastatin and
rosuvastatin, TPV/r could increase
the plasma levels of pravastatin.
Co-administration of APTIVUS,
co-administered with low dose
ritonavir, and pravastatin should be
initiated with the lowest dose
(10 mg/day) of pravastatin, titrated
to treatment response, and
accompanied with careful clinical
monitoring for pravastatin
associated symptoms as described
in the label of pravastatin.
Mechanism unknown.
Simvastatin
Lovastatin
No interaction study
performed
The HMG-CoA reductase inhibitors
simvastatin and lovastatin are
highly dependent on CYP3A for
metabolism.
The concomitant use of APTIVUS,
co-administered with low dose
ritonavir, with simvastatin or
lovastatin are contra-indicated due
to an increased risk of myopathy,
including rhabdomyolysis (see
section 4.3).
HERBAL PRODUCTS
St. John’s wort (
Hypericum
perforatum
)
No interaction study
performed
Plasma concentrations of tipranavir
can be reduced by concomitant use
of the herbal preparation St John’s
wort (
Hypericum perforatum
). This
is due to induction of drug
metabolising enzymes by St John’s
wort.
Herbal preparations containing St.
John’s wort must not be combined
with APTIVUS, co-administered
with low dose ritonavir. Co-
administration of APTIVUS with
ritonavir, with St. John’s wort is
expected to substantially decrease
tipranavir and ritonavir
concentrations and may result in
sub-optimal levels of tipranavir and
lead to loss of virologic response
and possible resistance to
tipranavir.
Oral contraceptives / Oestrogens
Ethinyl oestradiol
0.035 mg
/
Norethindrone
1.0 mg QD
(TPV/r 750/200 mg BID)
Ethinyl oestradiol Cmax ↓ 52%
Ethinyl oestradiol AUC ↓ 43%
The concomitant administration
with APTIVUS, co-administered
with low dose ritonavir, is not
recommended. Alternative or
additional contraceptive measures
are to be used when oestrogen
Mechanism unkown
Norethindrone Cmax ↔
46
Norethindrone AUC ↑ 27%
based oral contraceptives are co-
administered with APTIVUS and
low dose ritonavir. Patients using
oestrogens as hormone replacement
therapy should be clinically
monitored for signs of oestrogen
deficiency (see section 4.4 and
section 4.6).
Tipranavir ↔
Phosphodiesterase 5 (PDE5) inhibitors
Sildenafil
Vardenafil
No interaction study
performed
Co-administration of tipranavir and
low dose ritonavir with PDE5
inhibitors is expected to
substantially increase PDE5
concentrations and may result in an
increase in PDE5 inhibitor-
associated adverse events including
hypotension, visual changes and
priapism.
Particular caution should be used
when prescribing the
phosphodiesterase (PDE5)
inhibitors sildenafil or vardenafil in
patients receiving APTIVUS, co-
administered with low dose
ritonavir.
Tadalafil
10 mg QD
Tadalafil first-dose Cmax ↓ 22%
Tadalafil first-dose AUC ↑ 133%
It is recommended to prescribe
tadalafil after at least 7 days of
APTIVUS with ritonavir dosing.
CYP 3A4 inhibition and induction
by tipranavir/r
Tadalafil steady-state Cmax ↓ 30%
Tadalafil steady-state AUC ↔
No clinically significant change is
observed in tipranavir PK
parameters.
Narcotic analgesics
Methadone
5 mg QD
Methadone Cmax ↓ 55%
Methadone AUC ↓ 53%
Methadone Cmin ↓ 50%
Patients should be monitored for
opiate withdrawal syndrome.
Dosage of methadone may need to
be increased.
R-methadone Cmax ↓ 46%
R-methadone AUC ↓ 48%
S-methadone Cmax ↓ 62%
S-methadone AUC ↓ 63%
Mechanism unknown
Meperidine
No interaction study
performed
Tipranavir, co-administered with
low dose ritonavir, is expected to
decrease meperidine concentrations
and increase normeperidine
metabolite concentrations.
Dosage increase and long-term use
of meperidine with APTIVUS, co-
administered with low dose
ritonavir, are not recommended due
to the increased concentrations of
the metabolite normeperidine which
has both analgesic activity and CNS
stimulant activity (eg seizures).
Buprenorphine/Naloxone
Buprenorphine ↔
Due to reduction in the levels of the
active metabolite norbuprenorphine,
co-administration of APTIVUS, co-
administered with low dose
ritonavir, and buprenorphine/
naloxone may result in decreased
clinical efficacy of buprenorphine.
Norbuprenorphine AUC
↓
79%
Norbuprenorphine Cmax
↓
80%
Norbuprenorphine Cmin
↓
80%
47
Therefore, patients should be
monitored for opiate withdrawal
syndrome.
Immunosupressants
Cyclosporin
Tacrolimus
Sirolimus
No interaction study
performed
Concentrations of cyclosporin,
tacrolimus, or sirolimus cannot be
predicted when co-administered
with tipranavir co-administered
with low dose ritonavir, due to
conflicting effect of tipranavir, co-
administered with low dose
ritonavir, on CYP 3A and Pgp.
More frequent concentration
monitoring of these medicinal
products is recommended until
blood levels have been stabilised.
Antithrombotics
Warfarin
10 mg QD
First-dose tipranavir /r:
S-warfarin Cmax ↔
S-warfarin AUC ↑ 18%
APTIVUS, co-administered with
low dose ritonavir, when combined
with warfarin may be associated
with changes in INR (International
Normalised Ratio) values, and may
affect anticoagulation
(thrombogenic effect) or increase
the risk of bleeding. Close clinical
and biological (INR measurement)
monitoring is recommended when
warfarin and tipranavir are
combined.
Steady-state tipranavir/r:
S-warfarin Cmax ↓ 17%
S-warfarin AUC ↓ 12%
Inhibition of CYP 2C9 with first-
dose tipranavir /r, then induction of
CYP 2C9 with steady-state
tipranavir/r
Antacids
aluminium- and magnesium-
based liquid antacid 20 ml
QD
Tipranavir Cmax ↓ 25%
Tipranavir AUC ↓ 27%
Dosing of APTIVUS, co-
administered with low dose
ritonavir, with antacids should be
separated by at least a two hours
time interval.
Mechanism unknown
Proton pump inhibitors (PPIs)
Omeprazole
40 mg QD
Omeprazole Cmax ↓ 73%
Omeprazole AUC ↓ 70%
The combined use of APTIVUS,
co-administered with low dose
ritonavir, with either omeprazole or
esomeprazole is not recommended
(see section 4.4). If unavoidable,
upward dose adjustments for either
omeprazole or esomeprazole may
be considered based on clinical
response to therapy. There are no
data available indicating that
omeprazole or esomeprazole dose
adjustments will overcome the
observed pharmacokinetic
interaction. Recommendations for
maximal doses of omeprazole or
esomeprazole are found in the
corresponding product information.
No tipranavir with ritonavir dose
adjustment is required.
Similar effects were observed for
the S-enantiomer, esomeprazole.
Induction of CYP 2C19 by
tipranavir/r
Tipranavir ↔
Lansoprazole
Pantoprazole
Rabeprazole
No interaction study
performed
Based on the metabolic profiles of
tipranavir/r and the proton pump
inhibitors, an interaction can be
expected. As a result of CYP3A4
inhibition and CYP2C19 induction
The combined use of APTIVUS,
co-administered with low dose
ritonavir, with proton pump
inhibitors is not recommended (see
section 4.4). If the co-
48
by tipranavir/r, lansoprazole and
pantoprazole plasma concentrations
are difficult to predict. Rabeprazole
plasma concentrations might
decrease as a result of induction of
CYP2C19 by tipranavir/r.
administration is judged
unavoidable, this should be done
under close clinical monitoring.
H2-receptor antagonists
No interaction study
performed
No data are available for H2-
receptor antagonists in combination
with tipranavir and low dose
ritonavir.
An increase in gastric pH that may
result from H2-receptor antagonist
therapy is not expected to have an
impact on tipranavir plasma
concentrations.
Antiarrhythmics
Amiodarone
Bepridil
Quinidine
No interaction study
performed
Based on theoretical considerations,
tipranavir, co-administered with
low dose ritonavir, is expected to
increase amiodarone, bepridil and
quinidine concentrations.
The concomitant use of APTIVUS,
co-administered with low dose
ritonavir, with amiodarone, bepridil
or quinidine is contraindicated due
to potential serious and/or
lifethreatening events (see section
4.3)
Inhibition of CYP 3A4 by
tipranavir/r
Flecainide
Propafenone
Metoprolol
(given in heart
failure)
No interaction study
performed
Based on theoretical considerations,
tipranavir, co-administered with
low dose ritonavir, is expected to
increase flecainide, propafenone
and metoprolol concentrations.
The concomitant use of APTIVUS,
co-administered with low dose
ritonavir, with flecainide,
propafenone or metoprolol is
contraindicated (see section 4.3)
Inhibition of CYP 2D6
by tipranavir/r
Antihistamines
Astemizole
Terfenadine
No interaction study
performed
Based on theoretical considerations,
tipranavir, co-administered with
low dose ritonavir, is expected to
increase astemizole and terfenadine
concentrations.
The concomitant use of APTIVUS,
co-administered with low dose
ritonavir, with astemizole or
terfenadine is contraindicated due to
potential serious and/or
lifethreatening events (see section
4.3)
Inhibition of CYP 3A4 by
tipranavir/r
Ergot derivatives
Dihydroergotamine
Ergonovine
Ergotamine
Methylergonovine
No interaction study
performed
Based on theoretical considerations,
tipranavir, co-administered with
low dose ritonavir, is expected to
increase dihydroergotamine,
ergonovine, ergotamine and
methylergonovine concentrations.
The concomitant use of APTIVUS,
co-administered with low dose
ritonavir, with dihydroergotamine,
ergonovine, ergotamine or
methylergonovine is
contraindicated due to potential
serious and/or lifethreatening events
(see section 4.3)
Inhibition of CYP 3A4 by
tipranavir/r
Gastrointestinal motility agents
Cisapride
No interaction study
performed
Based on theoretical considerations,
tipranavir, co-administered with
low dose ritonavir, is expected to
increase cisapride concentrations.
The concomitant use of APTIVUS,
co-administered with low dose
ritonavir, with cisapride is
contraindicated due to potential
serious and/or lifethreatening events
(see section 4.3)
Inhibition of CYP 3A4 by
49
tipranavir/r
Neuroleptics
Pimozide
Sertindole
No interaction study
performed
Based on theoretical considerations,
tipranavir, co-administered with
low dose ritonavir, is expected to
increase pimozide and sertindole
concentrations.
The concomitant use of APTIVUS,
co-administered with low dose
ritonavir, with pimozide or
sertindole is contraindicated due to
potential serious and/or
lifethreatening events (see section
4.3)
Inhibition of CYP 3A4 by
tipranavir/r
Sedatives/hypnotics
Midazolam
2 mg QD (iv)
First-dose tipranavir/r:
Midazolam Cmax ↔
Midazolam AUC ↑ 5.1 fold
Concomitant use of APTIVUS, co-
administered with low dose
ritonavir, and oral midazolam is
contra-indicated (see section 4.3). If
APTIVUS with ritonavir is
administered with parenteral
midazolam, close clinical
monitoring for respiratory
depression and/or prolonged
sedation should be instituted and
dosage adjustment should be
considered.
Steady-state tipranavir/r:
Midazolam Cmax ↓ 13%
Midazolam AUC ↑ 181%
Midazolam
5 mg QD (po)
First-dose tipranavir/r
Midazolam Cmax ↑ 5.0 fold
Midazolam AUC ↑ 27 fold
Steady-state tipranavir/r
Midazolam Cmax ↑ 3.7 fold
Midazolam AUC ↑ 9.8 fold
Ritonavir is a potent inhibitor of
CYP3A4 and therefore affect drugs
metabolised by this enzyme.
Triazolam
No interaction study
performed
Based on theoretical considerations,
tipranavir, co-administered with
low dose ritonavir, is expected to
increase triazolam concentrations.
The concomitant use of APTIVUS,
co-administered with low dose
ritonavir, with triazolam is
contraindicated due to potential
serious and/or lifethreatening events
(see section 4.3)
Inhibition of CYP 3A4 by
tipranavir/r
Others
Theophylline
No interaction study
performed
Based on data from the cocktail
study where caffeine (CYP1A2
substrate) AUC was reduced by
43%, tipranavir with ritonavir is
expected to decrease theophylline
concentrations.
Theophylline plasma concentrations
should be monitored during the first
two weeks of co-administration
with APTIVUS, co-administered
with low dose ritonavir, and the
theophylline dose should be
increased as needed.
Induction of CYP 1A2 by
tipranavir/r
Desipramine
No interaction study
performed
Tipranavir, co-administered with
low dose ritonavir, is expected to
increase desipramine concentrations
Dosage reduction and concentration
monitoring of desipramine is
recommended.
Inhibition of CYP 2D6 by
tipranavir/r
Digoxin
0.25 mg QD iv
First-dose tipranavir/r
Digoxin Cmax ↔
Digoxin AUC ↔
Monitoring of digoxin serum
concentrations is recommended
until steady state has been obtained.
50
Steady-state tipranavir/r
Digoxin Cmax ↓ 20%
Digoxin AUC ↔
Digoxin
0.25 mg QD po
First-dose tipranavir/r
Digoxin Cmax ↑ 93%
Digoxin AUC ↑ 91%
Transient inhibition of P-gp by
tipranavir/r, followed by induction
of P-gp by tipranavir/r at steady-
state
Steady-state tipranavir/r
Digoxin Cmax ↓ 38%
Digoxin AUC ↔
Trazodone
Interaction study performed
only with ritonavir
In a pharmacokinetic study
performed in healthy volunteers,
concomitant use of low dose
ritonavir (200 mg twice daily) with
a single dose of trazodone led to an
increased plasma concentration of
trazodone (AUC increased by
2.4 fold). Adverse events of nausea,
dizziness, hypotension and syncope
have been observed following co-
administration of trazodone and
ritonavir in this study. However, it
is unknown whether the
combination of tipranavir with
ritonavir might cause a larger
increase in trazodone exposure.
The combination should be used
with caution and a lower dose of
trazodone should be considered.
Bupropion
150 mg BID
Bupropion Cmax ↓ 51%
Bupropion AUC ↓ 56%
If the co-administration with
bupropion is judged unavoidable,
this should be done under close
clinical monitoring for bupropion
efficacy, without exceeding the
recommended dosage, despite the
observed induction.
Tipranavir ↔
The reduction of bupropion plasma
levels is likely due to induction of
CYP2B6 and UGT activity by RTV
Loperamide
16 mg QD
Loperamide Cmax ↓ 61%
Loperamide AUC ↓ 51%
A pharmacodynamic interaction
study in healthy volunteers
demonstrated that administration of
loperamide and APTIVUS, co-
administered with low dose
ritonavir, does not cause any
clinically relevant change in the
respiratory response to carbon
dioxide. The clinical relevance of
the reduced loperamide plasma
concentration is unknown.
Mechanism unknown
Tipranavir Cmax ↔
Tipranavir AUC ↔
Tipranavir Cmin ↓ 26%
Fluticasone propionate
Interaction study performed
only with ritonavir
In a clinical study where ritonavir
100 mg capsules bid were co-
administered with 50 µg intranasal
fluticasone propionate (4 times
daily) for 7 days in healthy subjects,
the fluticasone propionate plasma
Concomitant administration of
APTIVUS, co-administered with
low dose ritonavir, and these
glucocorticoids is not recommended
unless the potential benefit of
treatment outweighs the risk of
51
levels increased significantly,
whereas the intrinsic cortisol levels
decreased by approximately 86%
(90% confidence interval 82-89%).
Greater effects may be expected
when fluticasone propionate is
inhaled. Systemic corticosteroid
effects including Cushing's
syndrome and adrenal suppression
have been reported in patients
receiving ritonavir and inhaled or
intranasally administered
fluticasone propionate; this could
also occur with other corticosteroids
metabolised via the P450 3A
pathway eg budesonide.
It is unknown whether the
combination of tipranavir with
ritonavir might cause a larger
increase in fluticasone exposure.
systemic corticosteroid effects (see
section 4.4). A dose reduction of the
glucocorticoid should be considered
with close monitoring of local and
systemic effects or a switch to a
glucocorticoid, which is not a
substrate for CYP3A4 (e.g.
beclomethasone). Moreover, in case
of withdrawal of glucocorticoids
progressive dose reduction may
have to be performed over a longer
period. The effects of high
fluticasone systemic exposure on
ritonavir plasma levels are as yet
unknown.
Pregnancy
There are no adequate data from the use of tipranavir in pregnant women. Studies in animals have
shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Tipranavir
should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Contraception in males and females
Tipranavir adversely interacts with oral contraceptives. Therefore, an alternative, effective, safe
method of contraception should be used during treatment (see section 4.5).
Breastfeeding
Consistent with the recommendation that HIV-infected mothers should not breast-feed their infants
under any circumstances to avoid risking postnatal transmission of HIV, mothers should discontinue
breast-feeding if they are receiving APTIVUS.
Fertility
Clinical data on fertility are not available for tipranavir. Preclinical studies performed with tipranavir
showed no adverse effect on fertility (see section 5.3).
No studies on the effects on the ability to drive and use machines have been performed.
52
APTIVUS co-administered with low dose ritonavir, has been associated with reports of significant
liver toxicity. In Phase III RESIST trials, the frequency of transaminase elevations was significantly
increased in the tipranavir with ritonavir arm compared to the comparator arm. Close monitoring is
therefore needed in patients treated with APTIVUS, co-administered with low dose ritonavir (see
section 4.4).
Limited data are currently available for the use of APTIVUS, co-administered with low dose ritonavir,
in patients co-infected with hepatitis B or C. APTIVUS should therefore be used with caution in
patients co-infected with hepatitis B or C. APTIVUS should be used in this patient population only if
the potential benefit outweighs the potential risk, and with increased clinical and laboratory
monitoring.
Adults:
Tipranavir (as soft capsules), co-administered with low dose ritonavir has been studied in a total of
6,308 HIV-positive adults as combination therapy in clinical studies, including compassionate use
studies. Of these 5,219 patients received the dose of 500 mg/200 mg twice daily. 909 adults in clinical
trials, including 541 in the RESIST-1 and RESIST-2 Phase III pivotal trials, have been treated with
500 mg/200 mg twice daily for at least 48 weeks.
Clinically meaningful adverse reactions of any intensity (Grades 1-4) of adult patients in all Phase II
and III trials treated with the 500 mg tipranavir with 200 mg ritonavir dose (n=1397) are listed below
by system organ class and frequency according to the following categories:
Very common (≥ 1/10), common (≥ 1/100 to
<
1/10), uncommon (≥1/1,000 to
<
1/100),
rare (≥1/10,000 to
<
1/1,000)
Blood and lymphatic system disorders
:
Uncommon: neutropenia, anaemia, thrombocytopenia.
Immune system disorders
:
Uncommon: hypersensitivity.
Metabolism and nutrition disorders
:
Common: hypertriglyceridaemia, hyperlipidaemia.
Uncommon: anorexia, decreased appetite, weight decreased, hyperamylasaemia,
hypercholesterolaemia, diabetes mellitus, hyperglycaemia.
Rare: dehydration, facial wasting.
Psychiatric disorders
:
Uncommon: insomnia, sleep disorder.
Nervous system disorders
:
Common: headache.
Uncommon: intracranial haemorrhage*, dizziness, neuropathy peripheral, somnolence.
Respiratory, thoracic and mediastinal disorders
:
Uncommon: dyspnoea.
Gastrointestinal disorders
:
Very common: diarrhoea, nausea.
Common: vomiting, flatulence, abdominal pain, abdominal distension, loose stools, dyspepsia.
Uncommon: gastrooesophageal reflux disease, pancreatitis.
Rare: lipase increased.
Hepatobiliary disorders
:
53
Uncommon: hepatic enzymes increased (ALAT, ASAT), cytolytic hepatitis, liver function test
abnormal (ALAT, ASAT), toxic hepatitis.
Rare: hepatic failure (including fatal outcome), hepatitis, hepatic steatosis, hyperbilirubinaemia.
Skin and subcutaneous tissue disorders
:
Common: rash.
Uncommon: pruritus, lipohypertrophy, exanthem, lipoatrophy, lipodystrophy acquired.
Musculoskeletal and connective tissue disorders
:
Uncommon: myalgia, muscle cramp.
Renal and urinary disorders
:
Uncommon: renal insufficiency.
General disorders and administration site conditions
:
Common: fatigue.
Uncommon: pyrexia, influenza like illness, malaise.
* This undesirable effect was not observed as an at least possibly related adverse event in the
respective studies. The frequency estimate is based on the upper limit of its 95% confidence interval,
calculated from the totality of treated patients in accordance with the EU SPC guideline (3/1397 which
relates to “uncommon”).
Description of selected adverse reactions
The following clinical safety features (hepatotoxicity, hyperlipidaemia, bleeding events, rash) were
seen at higher frequency among tipranavir with ritonavir treated patients when compared with the
comparator arm treated patients in the RESIST trials, or have been observed with tipranavir with
ritonavir administration. The clinical significance of these observations has not been fully explored.
Hepatotoxicity:
After 48 weeks of follow-up, the frequency of Grade 3 or 4 ALAT and/or ASAT
abnormalities was higher in tipranavir with ritonavir patients compared with comparator arm patients
(10% and 3.4%, respectively). Multivariate analyses showed that baseline ALAT or ASAT above
DAIDS Grade 1 and co-infection with hepatitis B or C were risk factors for these elevations. Most
patients were able to continue treatment with tipranavir with ritonavir.
Hyperlipidaemia:
Grade 3 or 4 elevations of triglycerides occurred more frequently in the tipranavir
with ritonavir arm compared with the comparator arm. At 48 weeks these rates were 25.2% of
patients in the tipranavir with ritonavir arm and 15.6% in the comparator arm.
Bleeding:
RESIST participants receiving tipranavir with ritonavir tended to have an increased risk of
bleeding; at 24 weeks the relative risk was 1.98 (95% CI=1.03, 3.80). At 48-weeks the relative risk
decreased to 1.27 (95% CI=0.76, 2.12). There was no pattern for the bleeding events and no difference
between treatment groups in coagulation parameters. The significance of this finding is being further
studied.
Fatal and non-fatal intracranial haemorrhage (ICH) have been reported in patients receiving tipranavir,
many of whom had other medical conditions or were receiving concomitant medicinal products that
may have caused or contributed to these events. However, in some cases the role of tipranavir cannot
be excluded. No pattern of abnormal haematological or coagulation parameters has been observed in
patients in general, or preceding the development of ICH. Therefore, routine measurement of
coagulation parameters is not currently indicated in the management of patients on APTIVUS.
An increased risk of ICH has previously been observed in patients with advanced HIV disease/AIDS
such as those treated in the APTIVUS clinical trials.
Rash:
An interaction study in women between tipranavir, co-administered with low dose ritonavir, and
ethinyl oestradiol/norethindrone demonstrated a high frequency of non-serious rash. In the RESIST
trials, the risk of rash was similar between tipranavir with ritonavir and comparator arms (16.3% vs.
54
12.5%, respectively; see section 4.4). No cases of Stevens-Johnson Syndrome or Toxic Epidermal
Necrolysis have been reported in the clinical development programme of tipranavir.
Laboratory abnormalities
Frequencies of marked clinical laboratory abnormalities (Grade 3 or 4) reported in at least 2% of
patients in the tipranavir with ritonavir arms in the phase III clinical studies (RESIST-1 and RESIST-
2) after 48-weeks were increased ASAT (6.1%), increased ALAT (9.7%), increased amylase (6.0%),
increased cholesterol (4.2%), increased triglycerides (24.9%), and decreased white blood cell count
(5.7%).
Combination antiretroviral therapy, including regimens containing a protease inhibitor, is associated
with redistribution of body fat in some patients, including loss of peripheral subcutaneous fat,
increased intra-abdominal fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump).
Protease inhibitors are also associated with metabolic abnormalities such as hypertriglyceridaemia,
hypercholesterolaemia, insulin resistance and hyperglycaemia.
Increased CPK, myalgia, myositis and, rarely, rhabdomyolysis, have been reported with protease
inhibitors, particularly in combination with nucleoside reverse transcriptase inhibitors.
In HIV-infected patients with severe immune deficiency at the time of initiation of combination
antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic
infections may arise (see section 4.4). Reactivation of herpes simplex and herpes zoster virus
infections were observed in the RESIST trials.
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk
factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART).
The frequency of this is unknown (see section 4.4).
Paediatric population
In an open-label, dose-finding study of tipranavir plus ritonavir (Trial 1182.14), 62 children aged 2 to
12 years received APTIVUS oral solution. In general, adverse reactions were similar to those seen in
adults, with the exception of vomiting, rash and pyrexia which were reported more frequently in
children than in adults. The most frequently reported moderate or severe adverse reactions in the
48 week analyses are noted below.
Most frequently reported moderate or severe adverse reactions in paediatric patients age 2 to <
12 years (reported in 2 or more children, Trial 1182.14, 48 weeks analyses, Full Analysis Set).
Total patients treated (N) 62
Events [N(%)]
Diarrhoea 4 (6.5)
Vomiting 3 (4.8)
Nausea 3 (4.8)
Abdominal pain
1
3 (4.8)
Pyrexia 4 (6.5)
Rash
2
4 (6.5)
gamma GT increased 4 (6.5)
ALAT increased 2 (3.2)
Anaemia 2 (3.2)
1
Includes abdominal pain (N=1), dysphagia (N=1) and epigastric discomfort (N=1).
2
Rash consists of one or more of the preferred terms of rash, drug eruption, rash macular, rash
papular, erythema, rash maculo-papular, rash pruritic, and urticaria.
55
Human experience with tipranavir overdose is very limited. No specific signs and symptoms of
overdose are known. Generally, an increased frequency and higher severity of undesirable effects may
result from overdose.
There is no known antidote for tipranavir overdose. Treatment of overdose should consist of general
supportive measures, including monitoring of vital signs and observation of the patient’s clinical
status. If indicated, elimination of unabsorbed tipranavir should be achieved by emesis or gastric
lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed
substance. Since tipranavir is highly protein bound, dialysis is unlikely to be beneficial in significant
removal of this medicine.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: antivirals for systemic use, protease inhibitors, ATC code: J05AE09
Mechanism of action
The human immunodeficiency virus (HIV-1) encodes an aspartyl protease that is essential for the
cleavage and maturation of viral protein precursors. Tipranavir is a non-peptidic inhibitor of the HIV-1
protease that inhibits viral replication by preventing the maturation of viral particles.
Antiviral activity
in vitro
Tipranavir inhibits the replication of laboratory strains of HIV-1 and clinical isolates in acute models
of T-cell infection, with 50% and 90% effective concentrations (EC
50
and EC
90
) ranging from 0.03 to
0.07 µM (18-42 ng/ml) and 0.07 to 0.18 µM (42-108 ng/ml), respectively. Tipranavir demonstrates
antiviral activity
in vitro
against a broad panel of HIV-1 group M non-clade B isolates (A, C, D, F, G,
H, CRF01 AE, CRF02 AG, CRF12 BF). Group O and HIV-2 isolates have reduced susceptibility
in
vitro
to tipranavir with EC
50
values ranging from 0.164-1 µM and 0.233-0.522 µM, respectively.
Protein binding studies have shown that the antiviral activity of tipranavir decreases on average 3.75-
fold in conditions where human serum is present.
Resistance
The development of resistance to tipranavir
in vitro
is slow and complex. In one particular
in vitro
resistance experiment, an HIV-1 isolate that was 87-fold resistant to tipranavir was selected after 9
months, and contained 10 mutations in the protease: L10F, I13V, V32I, L33F, M36I, K45I, I54V/T,
A71V, V82L, I84V as well as a mutation in the gag polyprotein CA/P2 cleavage site. Reverse genetic
experiments showed that the presence of 6 mutations in the protease (I13V, V32I, L33F, K45I, V82L,
I84V) was required to confer > 10-fold resistance to tipranavir while the full 10-mutation genotype
conferred 69-fold resistance to tipranavir.
In vitro
, there is an inverse correlation between the degree
of resistance to tipranavir and the capacity of viruses to replicate. Recombinant viruses showing ≥ 3-
fold resistance to tipranavir grow at less than 1% of the rate detected for wild type HIV-1 in the same
conditions. Tipranavir resistant viruses which emerge
in vitro
from wild-type HIV-1 show decreased
susceptibility to the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir and
ritonavir but remain sensitive to saquinavir.
Through a series of multiple stepwise regression analyses of baseline and on-treatment genotypes from
all clinical studies, 16 amino acids have been associated with reduced tipranavir susceptibility and/or
reduced 48-week viral load response: 10V, 13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/M/V,
58E, 69K, 74P, 82L/T, 83D and 84V. Clinical isolates that exhibited a
≥
56
10-fold decrease in tipranavir
susceptibility harboured 8 or more tipranavir-associated mutations. In Phase II and III clinical trials,
276 patients with on-treatment genotypes have demonstrated that the predominant emerging mutations
with tipranavir treatment are L33F/I/V, V82T/L and I84V. Combination of all three of these is usually
required for reduced susceptibility. Mutations at position 82 occur via two pathways: one from pre-
existing mutation 82A selecting to 82T, the other from wild type 82V selecting to 82L.
Cross-resistance
Tipranavir maintains significant antiviral activity (< 4-fold resistance) against the majority of HIV-1
clinical isolates showing post-treatment decreased susceptibility to the currently approved protease
inhibitors: amprenavir, atazanavir, indinavir, lopinavir, ritonavir, nelfinavir and saquinavir. Greater
than 10-fold resistance to tipranavir is uncommon (< 2.5% of tested isolates) in viruses obtained from
highly treatment experienced patients who have received multiple peptidic protease inhibitors.
Clinical pharmacodynamic data
The following clinical data is derived from analyses of 48-week data from ongoing studies (RESIST-1
and RESIST-2) measuring effects on plasma HIV RNA levels and CD4 cell counts. RESIST-1 and
RESIST-2 are ongoing, randomised, open-label, multicentre studies in HIV-positive, triple-class
experienced patients, evaluating treatment with tipranavir 500 mg co-administered with low dose
ritonavir 200 mg (twice daily) plus an optimised background regimen (OBR) individually defined for
each patient based on genotypic resistance testing and patient history. The comparator regimen
included a ritonavir-boosted PI (also individually defined) plus an OBR. The ritonavir-boosted PI was
chosen from among saquinavir, amprenavir, indinavir or lopinavir/ritonavir.
All patients had received at least two PI-based antiretroviral regimens and were failing a PI-based
regimen at the time of study entry. At least one primary protease gene mutation from among 30N, 46I,
46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V or 90M had to be present at baseline, with not more than
two mutations on codons 33, 82, 84 or 90.
After Week 8, patients in the comparator arm who met the protocol defined criteria of initial lack of
virologic response had the option of discontinuing treatment and switching over to tipranavir with
ritonavir in a separate roll-over study
.
The 1483 patients included in the primary analysis had a median age of 43 years (range 17-80), were
86% male, 75% white, 13% black and 1% Asian. In the tipranavir and comparator arms median
baseline CD4 cell counts were 158 and 166 cells/mm
3
, respectively, (ranges 1-1893 and 1-
1184 cells/mm
3
); median baseline plasma HIV-1 RNA was 4.79 and 4.80 log
10
copies/ml, respectively
(ranges 2.34-6.52 and 2.01-6.76 log
10
copies/ml).
Patients had prior exposure to a median of 6 NRTIs, 1 NNRTI, and 4 PIs. In both studies, a total of
67% patient viruses were resistant and 22% were possibly resistant to the pre-selected comparator PIs.
A total of 10% of patients had previously used enfuvirtide. Patients had baseline HIV-1 isolates with a
median of 16 HIV-1 protease gene mutations, including a median of 3 primary protease gene
mutations D30N, L33F/I, V46I/L, G48V, I50V, V82A/F/T/L, I84V, and L90M. With respect to
mutations on codons 33, 82, 84 and 90 approximately 4% had no mutations, 24% had mutations at
codons 82 (less than 1% of patients had the mutation V82L) and 90, 18% had mutations at codons 84
and 90 and 53% had at least one key mutation at codon 90. One patient in the tipranavir arm had four
mutations. In addition the majority of participants had mutations associated with both NRTI and
NNRTI resistance. Baseline phenotypic susceptibility was evaluated in 454 baseline patient samples.
There was an average decrease in susceptibility of 2-fold wild type (WT) for tipranavir, 12-fold WT
for amprenavir, 55-fold WT for atazanavir, 41-fold WT for indinavir, 87-fold WT for lopinavir, 41-
fold WT for nelfinavir, 195-fold WT for ritonavir, and 20-fold WT for saquinavir.
1 log RNA drop from baseline and without evidence of treatment failure) for both studies was 34%
in the tipranavir with ritonavir arm and 15% in the comparator arm. Treatment response is presented
for the overall population (displayed by enfuvirtide use), and detailed by PI strata for the subgroup of
patients with genotypically resistant strains in the Table below.
57
Combined 48-week treatment response (composite endpoint defined as patients with a confirmed
≥
Treatment response* at week 48 (pooled studies RESIST-1 and RESIST-2 in treatment-
experienced patients)
RESIST study
Tipranavir
/RTV
CPI/RTV**
p-value
n (%)
N
n (%)
N
Overall population
FAS
PP
255 (34.2)
171 (37.7)
746
454
114 (15.5)
74 (17.1)
737
432
<
0.0001
<
0.0001
- with ENF
(FAS)
85 (50.0)
170
28 (20.7)
135
<
0.0001
- without ENF
(FAS)
170 (29.5)
576
86 (14.3)
602
<
0.0001
Genotypically Resistant
LPV/rtv
FAS
PP
66 (28.9)
47 (32.2)
228
146
23 (9.5)
13 (9.1)
242
143
<
0.0001
<
0.0001
APV/rtv
FAS
PP
50 (33.3)
38 (39.2)
150
97
22 (14.9)
17 (18.3)
148
93
0.0001
0.0010
SQV/rtv
FAS
PP
22 (30.6)
11 (28.2)
72
39
5 (7.0)
2 (5.7)
71
35
0.0001
0.0650
0.0026
0.0650
* Composite endpoint defined as patients with a confirmed 1 log RNA drop from baseline and without
evidence of treatment failure
** Comparator PI/RTV: LPV/r 400 mg/100 mg twice daily (n=358), IDV/r 800 mg/100 mg twice
daily (n=23), SQV/r 1000 mg/100 mg twice daily or 800 mg/200 mg twice daily (n=162), APV/r
600 mg/100 mg twice daily (n=194)
ENF Enfuvirtide; FAS Full Analysis Set; PP Per Protocol; APV/rtv Amprenavir/ritonavir; IDV/rtv
Indinavir/ritonavir; LPV/rtv Lopinavir/ritonavir; SQV/rtv Saquinavir/ritonavir
6 (46.2)
3 (50.0)
13
6
1 (5.3)
1 (7.1)
19
14
Combined 48-week median time to treatment failure for both studies was 115 days in the tipranavir
with ritonavir arm and 0 days in the comparator arm (no treatment response was imputed to day 0).
Through 48 weeks of treatment, the proportion of patients in the tipranavir with ritonavir arm
compared to the comparator PI/ritonavir arm with HIV-1 RNA < 400 copies/ml was 30% and 14%
respectively, and with HIV-1 RNA < 50 copies/ml was 23% and 10% respectively. Among all
randomised and treated patients, the median change from baseline in HIV-1 RNA at the last
measurement up to Week 48 was -0.64 log
10
copies/ml in patients receiving tipranavir with ritonavir
versus -0.22 log
10
copies/ml in the comparator PI/ritonavir arm.
Among all randomised and treated patients, the median change from baseline in CD4+ cell count at
the last measurement up to Week 48 was +23 cells/mm
3
in patients receiving tipranavir with ritonavir
(N=740) versus +4 cells/mm
3
in the comparator PI/ritonavir (N=727) arm.
The superiority of tipranavir co-administered with low dose ritonavir over the comparator protease
inhibitor/ritonavir arm was observed for all efficacy parameters at week 48. It has not been shown that
tipranavir is superior to these boosted comparator protease inhibitors in patients harbouring strains
susceptible to these protease inhibitors. RESIST data also demonstrate that tipranavir co-administered
with low dose ritonavir exhibits a better treatment response at 48 weeks when the OBR contains
genotypically available antiretroviral agents (eg enfuvirtide).
At present there are no results from controlled trials evaluating the effect of tipranavir on clinical
progression of HIV.
Paediatric population
58
<
<
IDV/rtv
FAS
PP
HIV-positive, paediatric patients, aged 2 through 18 years, were studied in a randomized, open-label,
multicenter study (trial 1182.14). Patients were required to have a baseline HIV-1 RNA concentration
of at least 1500 copies/ml, were stratified by age (2 to < 6 years, 6 to < 12 years and 12 to 18 years)
and randomized to receive one of two tipranavir with ritonavir dose regimens: 375 mg/m
2
/150 mg/m
2
dose, compared to the 290 mg/m
2
/115 mg/m
2
dose, plus background therapy of at least two non-
protease inhibitor antiretroviral medicinal products, optimized using baseline genotypic resistance
testing. All patients initially received APTIVUS oral solution. Paediatric patients who were 12 years
or older and received the maximum dose of 500 mg/200 mg twice daily could change to APTIVUS
capsules from study day 28. The trial evaluated pharmacokinetics, safety and tolerability, as well as
virologic and immunologic responses through 48 weeks.
The available clinical data do not support the use of APTIVUS oral solution in adolescents or adults.
Compared to the capsules, tipranavir exposure is higher when administering the same dose as oral
solution (see section 5.2). Due to this and to the high vitamin E content of the oral solution, the risk of
adverse reactions (type, frequency and/or severity) may be higher than with the capsule formulation.
In patients less than 12 years of age, however, the oral solution is the only available option for
treatment with tipranavir, as no data are available on the efficacy and safety of APTIVUS capsules in
children less than 12 years of age. Since APTIVUS capsules and oral solution are not bioequivalent,
results obtained with the oral solution cannot be extrapolated to the capsules (see also section 5.2).
Moreover, in patients with a body surface area of less than 1.33 m² appropriate dose adjustments
cannot be achieved with the capsule formulation. These factors lead to the conclusion that the benefits
outweigh the risks of APTIVUS oral solution only in children between 2 and 12 years of age without
any other therapeutic option (see section 4.1).
The baseline characteristics and the key efficacy results at 48 weeks for the paediatric patients
receiving APTIVUS oral solution are displayed in the tables below.
Baseline characteristics
for patients 2 - <12 years treated with APTIVUS oral solution
Variable
Value
Number of Patients
62
Age-Median (years)
8.1
Gender
% Male
59.7%
Race
% White
71.0%
% Black
25.8%
% Asian
3.2%
Baseline HIV-1 RNA
(log
10
copies/ml)
Median
(Min – Max)
4.8 (3.3 – 6.0)
% with VL >
100,000 copies/ml
37.1%
Baseline CD4+
(cells/mm
3
)
Median
(Min – Max)
600 (24 – 2578)
% ≤ 200
15.5%
Baseline % CD4+ cells Median
(Min – Max)
21.9% (1.5% –
44.0%)
Previous ADI*
% with Category C
48.4%
Treatment history
% with any ARV
96.8%
Median # previous
NRTIs
4
Median # previous
NNRTIs
1
Median # previous
PIs
1
* AIDS defining illness
59
Key efficacy results at 48 weeks for patients 2 - <12 years treated with APTIVUS oral solution
Endpoint
Result
Number of patients
62
Primary efficacy endpoint:
% with VL < 400
50.0%
Median change from baseline
in log10 HIV-1 RNA (copies/ml)
-2.06
Median change from baseline
in CD4+ cell count (cells/mm3)
167
Median change from baseline
in % CD4+ cells
5%
Analyses of tipranavir resistance in treatment experienced patients
Tipranavir with ritonavir response rates in the RESIST studies were assessed by baseline tipranavir
genotype and phenotype. Relationships between baseline phenotypic susceptibility to tipranavir,
primary PI mutations, protease mutations at codons 33, 82, 84 and 90, tipranavir resistance-associated
mutations, and response to tipranavir with ritonavir therapy were assessed.
Of note, patients in the RESIST studies had a specific mutational pattern at baseline of at least one
primary protease gene mutation among codons 30N, 46I, 46L, 48V, 50V, 82A, 82F, 82L, 82T, 84V or
90M, and no more than two mutations on codons 33, 82, 84 or 90.
The following observations were made:
Primary PI mutations:
Analyses were conducted to assess virological outcome by the number of primary PI mutations (any
change at protease codons 30, 32, 36, 46, 47, 48, 50, 53, 54, 82, 84, 88 and 90) present at baseline.
Response rates were higher in tipranavir with ritonavir patients than comparator PI boosted with
ritonavir in new enfuvirtide patients, or patients without new enfuvirtide. However, without new
enfuvirtide some patients began to lose antiviral activity between weeks 4 and 8.
Mutations at protease codons 33, 82, 84 and 90:
A reduced virological response was observed in patients with viral strains harbouring two or more
mutations at HIV protease codons 33, 82, 84 or 90, and not receiving new enfuvirtide.
Tipranavir resistance-associated mutations:
Virological response to tipranavir with ritonavir therapy has been evaluated using a tipranavir-
associated mutation score based on baseline genotype in RESIST-1 and RESIST-2 patients. This score
(counting the 16 amino acids that have been associated with reduced tipranavir susceptibility and/or
reduced viral load response: 10V, 13V, 20M/R/V, 33F, 35G, 36I, 43T, 46L, 47V, 54A/M/V, 58E,
69K, 74P, 82L/T, 83D and 84V) was applied to baseline viral protease sequences. A correlation
between the tipranavir mutation score and response to tipranavir with ritonavir therapy at week 48 has
been established.
This score has been determined from the selected RESIST patient population having specific mutation
inclusion criteria and therefore extrapolation to a wider population mandates caution.
At 48-weeks, a higher proportion of patients receiving tipranavir with ritonavir achieved a treatment
response in comparison to the comparator protease inhibitor/ritonavir for nearly all of the possible
combinations of genotypic resistance mutations (see table below).
60
−
−
−
Proportion of patients achieving treatment response at Week 48 (confirmed ≥1 log
10
copies/ml
decrease in viral load compared to baseline), according to tipranavir baseline mutation score
and enfuvirtide use in RESIST patients
New ENF
No New
ENF*
Number of
TPV Score
Mutations**
TPV/r
TPV/r
0,1 73% 53%
2 61% 33%
3 75% 27%
4 59% 23%
≥ 5 47% 13%
All patients 61% 29%
* Includes patients who did not receive ENF and those who were previously treated with and
continued ENF
**Mutations in HIV protease at positions L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, M46L,
I47V, I54A/M/V, 58E, H69K, T74P, V82L/T, N83D or I84V
ENF Enfuvirtide; TPV/r Tipranavir with ritonavir
Sustained HIV-1 RNA decreases up to week 48 were mainly observed in patients who received
tipranavir with ritonavir and new enfuvirtide. If patients did not receive tipranavir with ritonavir with
new enfuvirtide, diminished treatment responses at week 48 were observed, relative to new enfuvirtide
use (see Table below).
Mean decrease in viral load from baseline to week 48, according to tipranavir baseline mutation
score and enfuvirtide use in RESIST patients
New ENF
No New
ENF*
Number of
TPV Score
Mutations**
TPV/r
TPV/r
0, 1 -2.3 -1.6
2 -2.1 -1.1
3 -2.4 -0.9
4 -1.7 -0.8
≥ 5 -1.9 -0.6
All patients -2.0 -1.0
* Includes patients who did not receive ENF and those who were previously treated with and
continued ENF
** Mutations in HIV protease at positions L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T,
M46L, I47V, I54A/M/V, 58E, H69K, T74P, V82L/T, N83D or I84V
ENF Enfuvirtide; TPV/r Tipranavir with ritonavir
Tipranavir phenotypic resistance:
Increasing baseline phenotypic fold change to tipranavir in isolates is correlated to decreasing
virological response. Isolates with baseline fold change of >0 to 3 are considered susceptible; isolates
with >3 to 10 fold changes have decreased susceptibility; isolates with >10 fold changes are resistant.
Conclusions regarding the relevance of particular mutations or mutational patterns are subject to
change with additional data, and it is recommended to always consult current interpretation systems
for analysing resistance test results.
61
−
5.2 Pharmacokinetic properties
In order to achieve effective tipranavir plasma concentrations and a twice daily dosing regimen,
coadministration of tipranavir with low dose ritonavir twice daily is essential (see section 4.2).
Ritonavir acts by inhibiting hepatic cytochrome P450 CYP3A, the intestinal P-glycoprotein (Pgp)
efflux pump and possibly intestinal cytochrome P450 CYP3A as well. As demonstrated in a dose-
ranging evaluation in 113 HIV-negative healthy male and female volunteers, ritonavir increases AUC
0-
12h
, C
max
and C
min
and decreases the clearance of tipranavir. 500 mg tipranavir co-administered with
low dose ritonavir (200 mg; twice daily) was associated with a 29-fold increase in the geometric mean
morning steady-state trough plasma concentrations compared to tipranavir 500 mg twice daily without
ritonavir.
Absorption
Absorption of tipranavir in humans is limited, though no absolute quantification of absorption is
available. Tipranavir is a Pgp substrate, a weak Pgp inhibitor and appears to be a potent Pgp inducer as
well. Data suggest that, although ritonavir is a Pgp inhibitor, the net effect of APTIVUS, co-
administered with low dose ritonavir, at the proposed dose regimen at steady-state, is Pgp induction.
Peak plasma concentrations are reached within 1 to 5 hours after dose administration depending upon
the dosage used. With repeated dosing, tipranavir plasma concentrations are lower than predicted from
single dose data, presumably due to hepatic enzyme induction. Steady-state is attained in most subjects
after 7 days of dosing. Tipranavir, co-administered with low dose ritonavir, exhibits linear
pharmacokinetics at steady state.
Dosing with APTIVUS capsules 500 mg twice daily concomitant with 200 mg ritonavir twice daily
for 2 to 4 weeks and without meal restriction produced a mean tipranavir peak plasma concentration
(C
max
) of 94.8 ± 22.8 µM for female patients (n=14) and 77.6 ± 16.6 µM for male patients (n=106),
occurring approximately 3 hours after administration. The mean steady-state trough concentration
prior to the morning dose was 41.6 ± 24.3 µM for female patients and 35.6 ± 16.7 µM for male
patients. Tipranavir AUC over a 12 hour dosing interval averaged 851 ± 309 µM•h (CL=1.15 l/h) for
female patients and 710 ± 207 µM•h (CL=1.27 l/h) for male patients. The mean half-life was
5.5 (females) or 6.0 hours (males).
Effects of food on oral absorption
Food improves the tolerability of tipranavir with ritonavir. Therefore APTIVUS, co-administered with
low dose ritonavir, should be given with food.
Absorption of tipranavir, co-administered with low dose ritonavir, is reduced in the presence of
antacids (see section 4.5).
Distribution
Tipranavir is extensively bound to plasma proteins (>99.9%). From clinical samples of healthy
volunteers and HIV-1 positive subjects who received tipranavir without ritonavir the mean fraction of
tipranavir unbound in plasma was similar in both populations (healthy volunteers 0.015%
±
0.006%;
HIV-positive subjects 0.019%
±
0.076%). Total plasma tipranavir concentrations for these samples
M. The unbound fraction of tipranavir appeared to be independent of total
concentration over this concentration range.
µ
No studies have been conducted to determine the distribution of tipranavir into human cerebrospinal
fluid or semen.
Biotransformation
In vitro
metabolism studies with human liver microsomes indicated that CYP3A4 is the predominant
CYP isoform involved in tipranavir metabolism.
The oral clearance of tipranavir decreased after the addition of ritonavir which may represent
diminished first-pass clearance of the substance at the gastrointestinal tract as well as the liver.
62
ranged from 9 to 82
The metabolism of tipranavir in the presence of low dose ritonavir is minimal. In a
14
C-tipranavir
human study (500 mg
14
C-tipranavir with 200 mg ritonavir, twice daily), unchanged tipranavir was
predominant and accounted for 98.4% or greater of the total plasma radioactivity circulating at 3, 8, or
12 hours after dosing. Only a few metabolites were found in plasma, and all were at trace levels (0.2%
or less of the plasma radioactivity). In faeces, unchanged tipranavir represented the majority of faecal
radioactivity (79.9% of faecal radioactivity). The most abundant faecal metabolite, at 4.9% of faecal
radioactivity (3.2% of dose), was a hydroxyl metabolite of tipranavir. In urine, unchanged tipranavir
was found in trace amounts (0.5% of urine radioactivity). The most abundant urinary metabolite, at
11.0% of urine radioactivity (0.5% of dose) was a glucuronide conjugate of tipranavir.
Elimination
Administration of
14
C-tipranavir to subjects (n = 8) that received 500 mg tipranavir with 200 mg
ritonavir twice daily dosed to steady-state demonstrated that most radioactivity (median 82.3%) was
excreted in faeces, while only a median of 4.4% of the radioactive dose administered was recovered in
urine. In addition, most radioactivity (56%) was excreted between 24 and 96 hours after dosing. The
effective mean elimination half-life of tipranavir with ritonavir in healthy volunteers (n = 67) and
HIV-infected adult patients (n = 120) was approximately 4.8 and 6.0 hours, respectively, at steady
state following a dose of 500 mg/200 mg twice daily with a light meal.
Special populations
Although data available at this stage are currently limited to allow a definitive analysis, they suggest
that the pharmacokinetic profile is unchanged in elderly and comparable between races. By contrast,
evaluation of the steady-state plasma tipranavir trough concentrations at 10-14 h after dosing from the
RESIST-1 and RESIST-2 studies demonstrate that females generally had higher tipranavir
concentrations than males. After four weeks of APTIVUS 500 mg with 200 mg ritonavir (twice daily)
the median plasma trough concentration of tipranavir was 43.9 µM for females and 31.1 µM for males.
This difference in concentrations does not warrant a dose adjustment.
Renal dysfunction
: Tipranavir pharmacokinetics have not been studied in patients with renal
impairment. However, since the renal clearance of tipranavir is negligible, a decrease in total body
clearance is not expected in patients with renal impairment.
Hepatic dysfunction
: In a study comparing 9 patients with mild (Child-Pugh A) hepatic impairment to
9 controls, the single and multiple dose exposure of tipranavir and ritonavir were increased in patients
with hepatic impairment but still within the range observed in clinical studies. No dosing adjustment
is required in patients with mild hepatic impairment but patients should be closely monitored (see
sections 4.2 and 4.4).
The influence of moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment on the
multiple dose pharmacokinetics of either tipranavir or ritonavir has so far not been investigated.
Tipranavir is contraindicated in moderate or severe hepatic impairment (see sections 4.2 and 4.3).
Paediatric population
:
The oral solution has been shown to have greater bioavailability than the soft capsule formulation.
5.3 Preclinical safety data
Animal toxicology studies have been conducted with tipranavir alone, in mice, rats and dogs, and co-
administered with ritonavir (3.75:1 w/w ratio) in rats and dogs. Studies with co-administration of
tipranavir and ritonavir did not reveal any additional toxicological effects when compared to those
seen in the tipranavir single agent toxicological studies.
The predominant effects of repeated administration of tipranavir across all species toxicologically
tested were on the gastrointestinal tract (emesis, soft stool, diarrhoea) and the liver (hypertrophy). The
effects were reversible with termination of treatment. Additional changes included bleeding in rats at
high doses (rodents specific). Bleeding observed in rats was associated with prolonged prothrombin
time (PT), activated partial thromboplastin time (APTT) and a decrease in some vitamin K dependent
63
factors. The co-administration of tipranavir with vitamin E in the form of TPGS (d-alphatocopherol
polyethylene glycol 1000 succinate) from 2,322 IU/m² upwards in rats resulted in a significant
increase in effects on coagulation parameters, bleeding events and death. In preclinical studies of
tipranavir in dogs, an effect on coagulation parameters was not seen. Co-administration of tipranavir
and vitamin E has not been studied in dogs.
The majority of the effects in repeat-dose toxicity studies appeared at systemic exposure levels which
are equivalent to or even below the human exposure levels at the recommended clinical dose.
In in-vitro studies, tipranavir was found to inhibit platelet aggregation when using human platelets (see
section 4.4) and thromboxane A2 binding in an in vitro cell model at levels consistent with exposure
observed in patients receiving APTIVUSwith ritonavir. The clinical implications of these findings are
not known.
In a study conducted in rats with tipranavir at systemic exposure levels (AUC) equivalent to human
exposure at the recommended clinical dose, no adverse effects on mating or fertility were observed. At
maternal doses producing systemic exposure levels similar to or below those at the recommended
clinical dose, tipranavir did not produce teratogenic effects. At tipranavir exposures in rats at 0.8-fold
human exposure at the clinical dose, foetal toxicity (decreased sternebrae ossification and body
weights) was observed. In pre- and post-natal development studies with tipranavir in rats, growth
inhibition of pups was observed at maternally toxic doses approximating 0.8-fold human exposure.
Carcinogenicity studies of tipranavir in mice and rats revealed tumourigenic potential specific for
these species, which are regarded as of no clinical relevance. Tipranavir showed no evidence of
genetic toxicity in a battery of
in vitro
and
in vivo
tests.
6.
6.1 List of excipients
Macrogol
Vitamin E polyethylene glycol succinate
Purified water
Propylene glycol
Mono/diglycerides of caprylic/capric acid
Sucralose
Butter mint (flavouring)
Butter toffee (flavouring)
Ascorbic acid
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
30 months.
In use storage: 60 days, after first opening of the bottle. It is advisable that the patient writes the date
of opening the bottle on the label and/or carton.
6.4 Special precautions for storage
Do not store below 15°C. Do not refrigerate or freeze.
64
6.5
Nature and contents of container
Amber glass bottle, with two-piece child-resistant closure (outer shell high density polyethylene
(HDPE), inner shell polypropylene with a foamed low density polyethylene (LDPE)/HDPE liner).
Each pack contains 1 bottle of 95 ml oral solution and is supplied with a clear polypropylene 5 ml
dispensing syringe, polypropylene syringe cap and clear LDPE bottle-syringe adapter.
6.6 Special precautions for disposal and other handling
Before taking APTIVUS it should be checked that the oral solution is clear and whether there are
crystals or other particles at the bottom of the bottle. A small amount of crystals may be observed in
the bottle, which does not affect the potency or safety of the product. If observed, crystals are
typically seen as a paper-thin layer on the bottom when the bottle is stored upright. Dosing by means
of the measuring device remains accurate even when crystals are observed. If there is more than a thin
layer of crystals at the bottom of the bottle or uncertainty about the amount of crystals observed, the
bottle should be returned for a replacement as soon as possible. Until the bottle is exchanged the
patient should continue to take the usual doses of the oral solution. Patients should be instructed to
observe closely for crystals.
The exact dose should be measured using the supplied measuring syringe and adapter, as follows:
1.
Open the bottle by pressing down on the cap and turning in an anti-clockwise direction.
2.
Remove the syringe cap covering the tip of the syringe (the cap will not be attached if this is the
first time the syringe has been used) and insert the syringe into the adapter located in the neck of
the bottle. Make sure the syringe is tightly inserted.
3.
Turn the bottle upside down and gently withdraw the required amount of APTIVUS oral
solution.
4.
Administer APTIVUS oral solution immediately. The maximum volume which can be
withdrawn at one time is 5 ml (equivalent to 500 mg tipranavir), which is the maximum single
dose for a child with BSA > 1.33 m
2
.
5.
After use of the syringe, reapply the syringe cap.
No special requirements for disposal.
7.
Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany
8.
EU/1/05/315/002
9.
Date of first authorisation:
25 October 2005
Date of latest renewal:
10.
65
Detailed information on this product is available on the website of the European Medicines Agency
(EMA) http://www.ema.europa.eu/
66
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
67
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Boehringer Ingelheim Pharma GmbH & Co. KG, Binger Strasse 173, D-55216 Ingelheim am Rhein,
Germany.
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 5.2 presented in
Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning before and
whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 4.2 of the Risk Management Plan (RMP) presented
in Module 1.8.2. of the Marketing Authorisation Dossier and any subsequent updates of the RMP
agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the EMEA
PSURs
PSURs will have to be submitted yearly, until otherwise specified by the CHMP.
68
ANNEX III
LABELLING AND PACKAGE LEAFLET
69
A. LABELLING
70
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
FOLDING BOX/OUTER PACKAGING
1.
APTIVUS 250 mg soft capsules
Tipranavir
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each soft capsule contains 250 mg tipranavir
3.
LIST OF EXCIPIENTS
Contains macrogolglycerol ricinoleate, sorbitol and ethanol (see package leaflet for further
information)
4.
120 soft capsules (one bottle)
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP {MM/YYYY}
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator.
In use storage: 60 days (below 25°C) after first opening of the bottle.
Date of first opening of the bottle:
71
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany
EU/1/05/315/001
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
APTIVUS 250 mg
72
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
BOTTLE/IMMEDIATE PACKAGING
1.
APTIVUS 250 mg soft capsules
Tipranavir
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each soft capsule contains 250 mg tipranavir
3.
LIST OF EXCIPIENTS
Contains macrogolglycerol ricinoleate, sorbitol and ethanol (see package leaflet for further
information)
4.
120 soft capsules
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP {MM/YYYY}
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator.
In use storage: 60 days (below 25°C) after first opening of the bottle.
Date of first opening of the bottle:
73
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany
EU/1/05/315/001
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
74
PARTICULARS TO APPEAR ON THE OUTER
FOLDING BOX/OUTER PACKAGING
1.
APTIVUS 100 mg/ml oral solution
Tipranavir
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each ml contains 100 mg tipranavir
3.
LIST OF EXCIPIENTS
4.
95 ml oral solution (1 bottle)
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use
The bottle has a child-resistant closure
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP {MM/YYYY}
9.
SPECIAL STORAGE CONDITIONS
Do not store below 15°C. Do not refrigerate or freeze
After first opening of the bottle, the product can be used for 60 days.
Date of first opening of the bottle:
75
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany
EU/1/05/315/002
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
APTIVUS 100 mg/ml
76
PARTICULARS TO APPEAR ON THE THE IMMEDIATE PACKAGING
BOTTLE/IMMEDIATE PACKAGING
1.
APTIVUS 100 mg/ml oral solution
Tipranavir
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each ml contains 100 mg tipranavir
3.
LIST OF EXCIPIENTS
4.
95 ml
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use
The bottle has a child-resistant closure
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP {MM/YYYY}
9.
SPECIAL STORAGE CONDITIONS
Do not store below 15°C. Do not refrigerate or freeze
After first opening of the bottle, the product can be used for 60 days.
Date of first opening of the bottle:
77
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany
EU/1/05/315/002
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
78
B. PACKAGE LEAFLET
79
PACKAGE LEAFLET: INFORMATION FOR THE USER
APTIVUS 250 mg soft capsules
Tipranavir
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, please ask your doctor or your pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1.
What APTIVUS is and what it is used for
2.
Before you take APTIVUS
3.
How to take APTIVUS
5
How to store APTIVUS
6.
Further information
If APTIVUS has been prescribed for your child, please note that all information in this leaflet is
addressed to your child (in this case please read “your child” instead of “you”).
1.
WHAT APTIVUS IS AND WHAT IT IS USED FOR
APTIVUS belongs to a group of medicines called protease inhibitors and is used in the treatment of
Human Immunodeficiency Virus (HIV) infection. APTIVUS is an inhibitor of the HIV protease
enzyme which the HIV needs to multiply. By inhibiting the protease enzyme APTIVUS helps control
HIV infection. You must take APTIVUS together with:
−
low dose ritonavir (this helps APTIVUS to reach a high enough level in your blood)
−
other HIV medicines. Your doctor will decide which other medicines you should take. This will
depend on, for example:
−
which other medicines you have already taken for HIV
−
which medicines your HIV is resistant to. If your HIV is resistant to some HIV
medicines, this means that the medicine will not work so well.
APTIVUS is specifically used for the treatment of HIV which is resistant to most other protease
inhibitors. Before starting treatment, your doctor will have taken blood samples to test the resistance
of your HIV. These tests will have confirmed that the HIV in your blood is resistant to most other
protease inhibitors. APTIVUS treatment is therefore appropriate for you. You should not use
APTIVUS if you have never received antiretroviral therapy or have other antiretroviral options
available.
APTIVUS capsules are indicated for:
−
adolescents 12 years of age or older
−
adults
80
4.
Possible side effects
2.
BEFORE YOU TAKE APTIVUS
You must take APTIVUS in combination with low dose ritonavir and other antiretroviral
medicines. It is therefore important that you know about these medicines too. You should
therefore carefully read the Package Leaflets of ritonavir and your other antiretroviral
medicines. If you have any further questions about ritonavir or the other medicines you are
prescribed, please ask your doctor or pharmacist.
Do NOT take APTIVUS
-
if you are allergic (hypersensitive) to any of the other ingredients of APTIVUS. See Section 6
for a list of other ingredients
-
if you have moderate to severe liver problems. Your doctor will take a blood sample to test how
well your liver is working (your liver function). Depending on your liver function you may have
to delay or stop APTIVUS treatment
-
if you are currently taking products containing:
-
rifampicin (used to treat tuberculosis)
-
cisapride (used to treat stomach problems)
-
pimozide or sertindole (used to treat schizophrenia)
-
triazolam or oral midazolam (taken by mouth). These medicines are used to treat
anxiety or sleep disorders
-
ergot derivatives (used to treat headaches)
-
astemizole or terfenadine (used to treat allergies or hay fever)
-
simvastatin or lovastatin (used to lower blood cholesterol)
-
amiodarone, bepridil, flecainide, propafenone or quinidine (used to treat heart
disorders)
-
metoprolol (used to treat heart failure)
Do not take products containing St John’s wort (a herbal remedy for depression). This may stop
APTIVUS from working properly.
Take special care with APTIVUS
Tell your doctor if you have:
-
type A or B haemophilia
-
diabetes
-
liver disease.
If you have:
- high liver function test results
- hepatitis B or C infection
you are at increased risk of severe and potentially fatal liver damage while taking antiretroviral
therapy in general, including APTIVUS. Your doctor will monitor your liver function by blood tests
before and during APTIVUS treatment. If you have liver disease or hepatitis, your doctor will decide
if you need additional testing. You should inform your doctor as soon as possible if you notice the
signs or symptoms of hepatitis:
-
fever
-
malaise (feeling generally unwell)
-
vomiting
-
abdominal pain
-
tiredness
-
jaundice (yellowing of the skin or the eyeballs)
APTIVUS is not a cure for HIV infection:
You should know that you may continue to develop infections and other illnesses associated with HIV
disease. You should therefore remain in regular contact with your doctor. In addition, APTIVUS does
not prevent the risk of passing on HIV to others through blood or sexual contact. You should therefore
81
-
if you are allergic (hypersensitive) to tipranavir
-
nausea (feeling sick)
continue to use appropriate precautions to prevent HIV transmission. For example you should use a
condom and you should not breast-feed or donate blood.
Rash
:
Mild to moderate rash, including:
-
hives
-
rash with flat or raised small red spots
-
sensitivity to the sun
have been reported in approximately 1 in 10 patients receiving APTIVUS. Some patients who
developed rash also had:
-
joint pain or stiffness
-
throat tightness
-
generalized itching
Redistribution, accumulation or loss of body fat may occur in patients receiving combination
antiretroviral therapy. Contact your doctor if you notice changes in body fat.
Your doctor may decide to monitor your levels of blood lipids (fats) before and during APTIVUS
treatment.
In some patients with advanced HIV infection (AIDS) and a history of opportunistic infection, signs
and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is
started. It is believed that these symptoms are due to an improvement in the body’s immune response,
enabling the body to fight infections that may have been present with no obvious symptoms. If you
notice any symptoms of infection, please inform your doctor immediately.
Bone problems:
Some patients taking combination antiretroviral therapy may develop a bone disease
called osteonecrosis (death of bone tissue caused by loss of blood supply to the bone). The length of
combination antiretroviral therapy, corticosteroid use, alcohol consumption, severe
immunosuppression, higher body mass index, among others, may be some of the many risk factors for
developing this disease. Signs of osteonecrosis are joint stiffness, aches and pains (especially of the
hip, knee and shoulder) and difficulty in movement. If you notice any of these symptoms please
inform your doctor.
Children:
APTIVUS soft capsules should not be used by children under 12 years of age.
Elderly:
If you are older than 65 years your doctor will exercise caution when prescribing APTIVUS soft
capsules to you and will closely monitor your therapy.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
This is
very important
. If you take other medicines at the same time as APTIVUS and ritonavir, this
can strengthen or weaken the effect of the medicines. These effects are called interactions, and can
lead to serious side effects, or prevent proper control of other conditions you may have.
Interactions with other HIV medicines:
-
Abacavir and zidovudine. These belong to a class of HIV medicines called nucleoside reverse
transcriptase inhibitors (NRTIs). Your doctor will only prescribe you abacavir and zidovudine if
you are unable to take other NRTIs. Otherwise, you can take APTIVUS, together with ritonavir,
with HIV reverse transcriptase inhibitors including:
-
stavudine
-
lamivudine
-
tenofovir
82
-
didanosine:
If you are taking didanosine enteric coated tablets, you should take them
at least two hours before or after APTIVUS
.
-
Protease Inhibitors (PIs): Taking APTIVUS may cause large decreases in the blood levels of
other HIV protease inhibitors. For example the protease inhibitors amprenavir, atazanavir,
lopinavir and saquinavir will be decreased.
Taking APTIVUS, with atazanavir, may cause the blood levels of APTIVUS and ritonavir to
increase a lot.
Your doctor will carefully consider whether to treat you with combinations of APTIVUS and
these protease inhibitors.
Other medicines with which APTIVUS may interact include:
-
oral contraceptives/hormone replacement therapy (HRT): If you are taking the contraceptive pill
to prevent pregnancy you should use an additional or different type of contraception (e.g. barrier
contraception like condoms). Generally, it is not recommended to take APTIVUS, with
ritonavir, together with oral contraceptives or hormone replacement therapy (HRT). You should
check with your doctor if you do wish to continue taking oral contraceptives or HRT. If you use
oral contraceptives or HRT you have an increased chance of developing a skin rash while taking
APTIVUS. If a rash occurs, it is usually mild to moderate. You should talk to your doctor as you
may need to temporarily stop taking either APTIVUS or your oral contraceptives or HRT
-
carbamazepine, phenobarbital and phenytoin (used to treat epilepsy). These may decrease the
effectiveness of APTIVUS.
-
sildenafil, vardenafil, tadalafil (medicines used to produce and maintain an erection). The effects
of sildenafil and vardenafil are likely to be increased if you take them with APTIVUS. You
should not be prescribed tadalafil until you have been taking APTIVUS for 7 days or more.
-
omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole
(proton pump inhibitors
used to reduce the gastric acid production)
-
metronidazole (used to treat infections)
-
disulfiram (used to treat alcohol dependence)
The following medications are not recommended:
-
fluticasone (used to treat asthma)
-
atorvastatin (used to lower blood cholesterol).
APTIVUS may lead to a loss of effectiveness of some medicines including:
-
methadone, meperidine (pethidine), used as morphine substitutes
Your doctor may have to increase or decrease the dose of other medicines which you take together
with APTIVUS. Examples include:
-
rifabutin and clarithromycin (antibiotics)
-
desipramine, trazodone and bupropion (used to treat depression; bupropion is also used for
smoking cessation)
-
midazolam (when given by injection); midazolam is a sedative used to treat anxiety and to help
you sleep.
Tell your doctor if you receive medication such as antiplatelet agents and anticoagulants, or if you are
taking vitamin E. Your doctor may wish to consider certain precautionary measures in such
circumstances.
Pregnancy and breast-feeding
Tell your doctor if you are pregnant or planning to become pregnant. If you are pregnant you should
only take APTIVUS after careful discussion with your doctor. It is not known whether APTIVUS may
be used safely during pregnancy. See also Section 2, under “Oral contraceptives/hormone replacement
therapy (HRT)”.
83
-
theophylline (used to treat asthma)
APTIVUS contains very small amounts of alcohol (see
Important information about some of the
ingredients of APTIVUS
).
Make sure you tell your doctor if you are breast-feeding. You must not breast-feed your baby because
it is possible that the baby can become HIV-infected through the breast milk.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
Some of the side effects of APTIVUS may affect your ability to drive or operate machinery (e.g.
dizziness and sleepiness). If affected, you should not drive or operate machinery.
Important information about some of the ingredients of APTIVUS capsules
APTIVUS contains 7 % ethanol (alcohol), i.e. up to 400 mg per daily dose, equivalent to 8 ml of beer,
or less than 4 ml of wine. Harmful for those suffering from alcoholism. To be taken into account in
pregnant or breast-feeding women, children and high-risk groups such as patients with liver disease, or
epilepsy.
APTIVUS also contains macrogolglycerol ricinoleate which may cause stomach upset and diarrhoea.
This medicine contains small amounts of sorbitol. If you have been told by your doctor that you have
an intolerance to some sugars, contact your doctor before taking this medicine.
3.
HOW TO TAKE APTIVUS
Always take APTIVUS exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure. You must take APTIVUS together with ritonavir.
APTIVUS capsules should be taken with food.
The usual dose for an adult or an adolescent 12 years and above is:
- 500 mg (two 250 mg capsules) APTIVUS together with
- 200 mg (two 100 mg capsules) ritonavir
twice per day with food.
You will always have to take APTIVUS in combination with other antiretroviral medicines. You
should follow the instructions for these medicines within the supplied Package Leaflets.
You should continue to take APTIVUS for as long as your doctor tells you.
If you take more APTIVUS than you should
Inform your doctor as soon as possible if you take more than the prescribed dose of APTIVUS.
If you forget to take APTIVUS
If you miss a dose of APTIVUS or ritonavir by more than 5 hours, wait and then take the next dose of
APTIVUS and ritonavir at the regularly scheduled time. If you miss a dose of APTIVUS and/or
ritonavir by less than 5 hours, take your missed dose immediately. Then take your next dose of
APTIVUS and ritonavir at the regularly scheduled time.
If you stop taking APTIVUS
It has been shown that taking all doses at the appropriate times:
-
greatly increases the effectiveness of your combination antiretroviral medicines
-
reduces the chances of your HIV becoming resistant to your antiretroviral medicines
Therefore, it is important that you continue taking APTIVUS correctly, as described above. Do NOT
stop taking APTIVUS unless your doctor instructs you to do so.
84
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, APTIVUS can cause side effects, although not everybody gets them. It may be
difficult to tell the difference between:
-
side effects caused by APTIVUS
-
side effects caused by the other medicines you are also taking
-
complications of HIV infection.
For this reason it is very important that you tell your doctor about any changes in your health.
Important side effects associated with Aptivus:
-
Abnormal liver function
- Hepatitis and fatty liver (affects 1 to 10 users in 1,000)
- Liver failure (affects 1 to 10 users in 10,000). This can lead to death
- Increased blood levels of bilirubin (a breakdown product of haemoglobin)
You should inform your doctor if you experience:
- Loss of appetite
- Nausea (feeling sick)
- Vomiting and/or jaundice
which may be symptoms of abnormal liver function
-
Bleeding
-
Bleeding in the brain. This can lead to permanent disability or death, and has occurred
in some patients treated with APTIVUS in clinical trials. In the majority of these
patients the bleeding may have had other causes. For example they had other medical
conditions or were receiving other medicine that may have caused the bleeding.
Possible side effects:
The frequency of possible side effects listed below is defined using the following convention:
-
very common (affects more than 1 user in 10)
-
common (affects 1 to 10 users in 100)
-
uncommon (affects 1 to 10 users in 1,000)
-
rare (affects 1 to 10 users in 10,000)
-
very rare (affects less than 1 user in 10,000)
Adults
Very common
-
Nausea (feeling sick)
-
Increases in blood lipid (fat) levels
Common
-
Vomiting
-
Flatulence (when you break wind more often)
-
Tiredness
-
Headache
-
Mild rashes e.g. with hives or with flat or raised small red spots
-
Increases in liver enzyme activity.
Uncommon
-
Reduction in red and white blood cells
-
Reduction in blood platelets
85
-
Diarrhoea
-
Abdominal pain (tummy pain)
-
Allergic (hypersensitivity) reactions
-
Diabetes
-
Increased blood sugar
-
Increased blood levels of cholesterol:
-
Sleeplessness and other sleep disorders (including sleepiness)
-
Numbness and/or tingling and/or pain in the feet or hands
-
Breathing difficulties
-
Heartburn
-
Inflammation of the pancreas
-
Skin inflammation
-
Itching
-
Loss or gain of body fat and other changes in fat distribution (see below)
-
Muscle cramp
-
Muscle pain
-
Kidney disease
-
Flu like symptoms (feeling unwell with fever)
-
Weight loss.
Rare
-
Dehydration (when your body does not have enough water)
-
Thinning of the face
-
Increased blood levels of the pancreas enzymes amylase and lipase
Further information on possible side effects related to combination antiretroviral treatment:
-
Blood
Combination antiretroviral therapy may also cause:
-
-
Raised sugar in the blood. The effect of insulin (used to treat diabetics to reduce blood
sugar) may be reduced.
-
Hypertriglyceridaemia (increased triglycerides (fats) in the blood)
-
Bleeding
-
Increased bleeding. If you have haemophilia type A and B, you may experience
increased bleeding. This may be in the skin or joints. If you suffer increased bleeding
you should see your doctor immediately.
Combination antiretroviral therapy may cause changes in body shape due to changes in fat distribution.
These may include loss of fat from legs, arms and face, increased fat in the abdomen (belly) and other
internal organs, breast enlargement and fatty lumps on the back of the neck (‘buffalo hump’). The
cause and long-term health effects of these conditions are not known at this time.
Muscle disorders
There have been reports of muscle pain, tenderness or weakness. These occur particularly when
APTIVUS or other protease inhibitors are taken together with nucleoside analogues. Rarely these
muscle disorders have been serious, involving breakdown of muscle tissue (rhabdomyolysis).
Children
The most common side effects were generally similar to those described in adults. Vomiting, rash and
fever were observed more frequently in children than in adults.
If any of the side effects gets serious, or if you notice any side effects not mentioned in this leaflet,
please tell your doctor or pharmacist.
86
-
Decreased appetite
-
Dizziness
-
Raised lactic acid in the blood.
-
Hypercholesterolaemia (increased cholesterol in the blood)
5.
HOW TO STORE APTIVUS
Keep out of the reach and sight of children.
Do not use APTIVUS after the expiry date which is stated on the bottle after EXP. The expiry date
refers to the last day of that month.
Store in a refrigerator (2°C to 8°C). Once the bottle is opened the contents must be used within 60
days (stored below 25°C). You should write the date of opening the bottle on the label and/or outer
carton.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What APTIVUS contains
-
The active substance is tipranavir. Each capsule contains 250 mg tipranavir.
-
The other ingredients are macrogolglycerol ricinoleate, ethanol (alcohol), mono/diglycerides of
caprylic/capric acid, propylene glycol, purified water, trometamol and propyl gallate. The
capsule shell contains gelatin, red iron oxide, propylene glycol, purified water, ‘sorbitol special-
glycerin blend’ (d-sorbitol, 1,4 sorbitan, mannitol and glycerin) and titanium dioxide. The black
printing ink contains propylene glycol, black iron oxide, polyvinyl acetate phthalate, macrogol
and ammonium hydroxide.
What APTIVUS looks like and contents of the pack
APTIVUS soft capsules are pink coloured, with a black print imprint of ‘TPV 250’. Each APTIVUS
capsule contains 250 mg of the active substance tipranavir. APTIVUS is supplied in bottles containing
120 capsules.
APTIVUS is also available as an oral solution containing 100 mg tipranavir per ml. Not all
presentations may be marketed in your country.
Marketing Authorisation Holder
Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany
Manufacturer
Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
S.C.S. Boehringer Ingelheim Comm.V.
Tél/Tel: +32 2 773 33 11
Luxembourg/Luxemburg
S.C.S. Boehringer Ingelheim Comm.V.
Tél/Tel: +32 2 773 33 11
87
България
Бьорингер Ингелхайм РЦВ ГмбХ и Ко КГ -
клон България
Тел: +359 2 958 79 98
Magyarország
Boehringer Ingelheim RCV GmbH & Co KG
Magyarországi Fióktelepe
Tel: +36 1 299 8900
Česká republika
Boehringer Ingelheim spol. s r.o.
Tel: +420 234 655 111
Malta
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600
Danmark
Boehringer Ingelheim Danmark A/S
Tlf: +45 39 15 88 49
Nederland
Boehringer Ingelheim b.v.
Tel: +31 (0) 800 22 55 889
Deutschland
Boehringer Ingelheim Pharma GmbH & Co. KG
Tel: +49 1805 / 77 90 90
Norge
Boehringer Ingelheim Norway KS
Tlf: +47 66 76 13 00
Eesti
Boehringer Ingelheim RCV GmbH & Co KG
Eesti filiaal
Tel: +372 60 80 940
Österreich
Boehringer Ingelheim RCV GmbH & Co KG
Tel: +43 1 80 105-0
Ελλάδα
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300
Polska
Boehringer Ingelheim Sp.zo.o.
Tel: +48 22 699 0 699
España
Boehringer Ingelheim España S.A.
Tel: +34 93 404 58 00
Portugal
Boehringer Ingelheim, Lda.
Tel: +351 21 313 53 00
France
Boehringer Ingelheim France S.A.S.
Tél: +33 3 26 50 45 33
România
Boehringer Ingelheim RCV GmbH & Co KG
Viena - Sucursala Bucuresti
Tel: +40 21 330 99 63
Ireland
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620
Slovenija
Boehringer Ingelheim RCV GmbH & Co KG
Podružnica Ljubljana
Tel: +386 1 586 40 00
Ísland
Vistor hf.
Sími: +354 535 7000
Slovenská republika
Boehringer Ingelheim RCV GmbH & Co KG
organizačná zložka
Tel: +421 2 5810 1211
88
Italia
Boehringer Ingelheim Italia S.p.A.
Tel: +39 02 5355 1
Suomi/Finland
Boehringer Ingelheim Finland Ky
Puh/Tel: +358 10 3102 800
Κύπρος
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300
Sverige
Boehringer Ingelheim AB
Tel: +46 8 721 21 00
Latvija
Boehringer Ingelheim Pharma GmbH
Pārstāvniecība Latvijā
Tel: +371 7 240 068
United Kingdom
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600
Lietuva
Boehringer Ingelheim RCV GmbH & Co KG
Lietuvos filialas
Tel: +370 37 473922
This leaflet was last approved in {MM/YYYY}
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu.
89
PACKAGE LEAFLET: INFORMATION FOR THE USER
APTIVUS 100 mg/ml oral solution
Tipranavir
Read all of this leaflet carefully before your child starts taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, please ask your child’s doctor or pharmacist.
-
This medicine has been prescribed for your child. Do not pass it on to others. It may harm them,
even if their symptoms are the same as your child’s.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your child’s doctor or pharmacist.
In this leaflet
:
1.
What APTIVUS is and what it is used for
2.
Before your child takes APTIVUS
3.
How to take APTIVUS
5
How to store APTIVUS
6.
Further information
1.
WHAT APTIVUS IS AND WHAT IT IS USED FOR
APTIVUS belongs to a group of medicines called protease inhibitors and is used in the treatment of
Human Immunodeficiency Virus (HIV) infection. APTIVUS is an inhibitor of the HIV protease
enzyme which the HIV needs to multiply. By inhibiting the protease enzyme APTIVUS helps control
HIV infection. Your child must take APTIVUS together with:
−
low dose ritonavir (this helps APTIVUS to reach a high enough level in your child’s blood)
−
other HIV medicines. Your child’s doctor will decide which other medicines they should take.
This will depend on, for example:
−
which other medicines your child has already taken for HIV
−
which medicines your child’s HIV is resistant to. If your child’s HIV is resistant to
some HIV medicines, this means that the medicine will not work so well.
APTIVUS is specifically used for the treatment of HIV which is resistant to most other protease
inhibitors. Before starting treatment, your child’s doctor will have taken blood samples to test the
resistance of your child’s HIV. These tests will have confirmed that the HIV in your child’s blood is
resistant to most other protease inhibitors. APTIVUS treatment is therefore appropriate for your child.
Your child should not use APTIVUS if they have never received antiretroviral therapy or have other
antiretroviral options available.
APTIVUS oral solution is indicated for:
−
children from 2 to 12 years of age
2.
BEFORE YOUR CHILD TAKES APTIVUS
Your child must take APTIVUS in combination with low dose ritonavir and other antiretroviral
medicines. It is therefore important that you know about these medicines too. You should
therefore carefully read the Package Leaflets of ritonavir and your child’s other antiretroviral
medicines. If you have any further questions about ritonavir or the other medicines your child is
prescribed, please ask your child’s doctor or pharmacist.
90
4.
Possible side effects
Do NOT give APTIVUS
-
if your child is allergic (hypersensitive) to tipranavir
-
if your child is allergic (hypersensitive) to any of the other ingredients of APTIVUS. See
Section 6 for a list of other ingredients
-
if your child has moderate to severe liver problems. Your child’s doctor will take a blood
sample to test how well your child’s liver is working (your child’s liver function). Depending on
your child’s liver function they may have to delay or stop APTIVUS treatment
-
if your child is currently taking products containing:
-
rifampicin (used to treat tuberculosis)
-
cisapride (used to treat stomach problems)
-
pimozide or sertindole (used to treat schizophrenia)
-
triazolam or oral midazolam (taken by mouth). These medicines are used to treat
anxiety or sleep disorders
-
ergot derivatives (used to treat headaches)
-
astemizole or terfenadine (used to treat allergies or hay fever)
-
simvastatin or lovastatin (used to lower blood cholesterol)
-
amiodarone, bepridil, flecainide, propafenone or quinidine (used to treat heart
disorders)
-
metoprolol (used to treat heart failure)
Your child must not take products containing St John’s wort (a herbal remedy for depression). This
may stop APTIVUS from working properly.
Take special care with APTIVUS
Tell your child’s doctor if they have:
-
type A or B haemophilia
-
liver disease.
If your child has:
-
high liver function tests results
-
hepatitis B or C infection
your child is at increased risk of severe and potentially fatal liver damage while taking antiretroviral
therapy in general, including APTIVUS. Your child’s doctor will monitor their liver function by blood
tests before and during APTIVUS treatment. If your child has liver disease or hepatitis, their doctor
will decide if they need additional testing. You should inform your child’s doctor as soon as possible if
you notice your child has the signs or symptoms of hepatitis:
-
malaise (feeling generally unwell)
-
nausea (feeling sick)
-
vomiting
-
abdominal pain
-
tiredness
-
jaundice (yellowing of the skin or the eyeballs)
APTIVUS is not a cure for HIV infection:
You should know that your child may continue to develop infections and other illnesses associated
with HIV disease. You should therefore remain in regular contact with your child’s doctor. In addition,
APTIVUS does not prevent the risk of passing on HIV to others through blood or sexual contact. Your
child should therefore continue to use appropriate precautions to prevent HIV transmission. For
example your child should use a condom and your child should not breast-feed or donate blood.
Rash
:
Mild to moderate rash, including:
-
hives
-
rash with flat or raised small red spots
-
sensitivity to the sun
91
-
diabetes
-
fever
have been reported in approximately 1 in 10 patients receiving APTIVUS. Some patients who
developed rash also had:
-
joint pain or stiffness
-
generalized itching
Redistribution, accumulation or loss of body fat may occur in patients receiving combination
antiretroviral therapy. Contact your child’s doctor if you notice changes in body fat.
Your child’s doctor may decide to monitor their levels of blood lipids (fats) before and during
APTIVUS treatment.
In some patients with advanced HIV infection (AIDS) and a history of opportunistic infection, signs
and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is
started. It is believed that these symptoms are due to an improvement in the body’s immune response,
enabling the body to fight infections that may have been present with no obvious symptoms. If you
notice any symptoms of infection, please inform your child’s doctor immediately.
Bone problems:
Some patients taking combination antiretroviral therapy may develop a bone disease
called osteonecrosis (death of bone tissue caused by loss of blood supply to the bone). The length of
combination antiretroviral therapy, corticosteroid use, alcohol consumption, severe
immunosuppression, higher body mass index, among others, may be some of the many risk factors for
developing this disease. Signs of osteonecrosis are joint stiffness, aches and pains (especially of the
hip, knee and shoulder) and difficulty in movement. If you notice any of these symptoms please
inform your child’s doctor.
Children:
APTIVUS should neither be used by children under 2 years of age nor by adolescents 12 years of age
or older.
APTIVUS oral solution contains vitamin E. Your child should not take any additional vitamin E
supplements.
Elderly:
If you are older than 65 years your doctor will exercise caution when prescribing APTIVUS oral
solution to you and will closely monitor your therapy.
Taking other medicines
Please tell your child’s doctor or pharmacist if they are taking or have recently taken any other
medicines, including medicines obtained without a prescription.
This is
very important
. If your child takes other medicines at the same time as APTIVUS and
ritonavir, this can strengthen or weaken the effect of the medicines. These effects are called
interactions, and can lead to serious side effects, or prevent proper control of other conditions your
child may have.
Interactions with other HIV medicines:
-
Abacavir and zidovudine. These belong to a class of HIV medicines called nucleoside reverse
transcriptase inhibitors (NRTIs). Your child’s doctor will only prescribe them abacavir and
zidovudine if they are unable to take other NRTIs. Otherwise, your child can take APTIVUS,
together with ritonavir, with HIV reverse transcriptase inhibitors including:
-
stavudine
-
lamivudine
-
tenofovir
-
didanosine:
If your child is taking didanosine enteric coated tablets, they should take
them at least two hours before or after APTIVUS
.
92
-
throat tightness
-
Protease Inhibitors (PIs): Taking APTIVUS may cause large decreases in the blood levels of
other HIV protease inhibitors. For example the protease inhibitors amprenavir, atazanavir,
lopinavir and saquinavir will be decreased.
Taking APTIVUS, with atazanavir, may cause the blood levels of APTIVUS and ritonavir to
increase a lot.
Your child’s doctor will carefully consider whether to treat them with combinations of
APTIVUS and these protease inhibitors.
Other medicines with which APTIVUS may interact include:
-
oral contraceptives/hormone replacement therapy (HRT): If your child is taking the
contraceptive pill to prevent pregnancy they should use an additional or different type of
contraception (e.g. barrier contraception like condoms). Generally, it is not recommended to
take APTIVUS, with ritonavir, together with oral contraceptives or hormone replacement
therapy (HRT). You should check with your child’s doctor if they do wish to continue taking
oral contraceptives or HRT. If your child uses oral contraceptives or HRT they have an
increased chance of developing a skin rash while taking APTIVUS. If a rash occurs, it is usually
mild to moderate. You should talk to your child’s doctor as they may need to temporarily stop
taking either APTIVUS or their oral contraceptives or HRT
-
carbamazepine, phenobarbital and phenytoin (used to treat epilepsy). These may decrease the
effectiveness of APTIVUS.
-
sildenafil, vardenafil, tadalafil (medicines used to produce and maintain an erection). The effects
of sildenafil and vardenafil are likely to be increased if taken with APTIVUS. Tadalafil should
not be prescribed until APTIVUS has been taken for 7 days or more.
-
omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole (proton pump inhibitors
used to reduce the gastric acid production)
-
metronidazole (used to treat infections)
-
disulfiram (used to treat alcohol dependence)
The following medications are not recommended:
-
fluticasone (used to treat asthma)
-
atorvastatin (used to lower blood cholesterol).
APTIVUS may lead to a loss of effectiveness of some medicines including:
-
methadone, meperidine (pethidine), used as morphine substitutes
Your child’s doctor may have to increase or decrease the dose of other medicines which they take
together with APTIVUS. Examples include:
-
rifabutin and clarithromycin (antibiotics)
-
theophylline (used to treat asthma)
-
desipramine, trazodone and bupropion (used to treat depression; bupropion is also used for
smoking cessation)
-
midazolam (when given by injection); midazolam is a sedative used to treat anxiety and to help
your child sleep.
Tell your child’s doctor if they receive medication such as antiplatelet agents and anticoagulants, or if
they are taking vitamin E. Your child’s doctor may wish to consider certain precautionary measures in
such circumstances.
Pregnancy and breast-feeding
Tell your child’s doctor if they are pregnant or planning to become pregnant. If your child is pregnant
they should only take APTIVUS after careful discussion with their doctor. It is not known whether
APTIVUS may be used safely during pregnancy. See also Section 2, under “Oral
contraceptives/hormone replacement therapy (HRT)”.
Make sure you tell your child’s doctor if they are breast-feeding. Your child must not breast-feed their
baby because it is possible that the baby can become HIV-infected through the breast milk.
93
Ask your child’s doctor or pharmacist for advice before they take any medicine.
Driving and using machines
Some of the side effects of APTIVUS may affect your child’s ability to drive or operate machinery
(e.g. dizziness and sleepiness). If affected, your child should not drive or operate machinery.
3.
HOW TO TAKE APTIVUS
Your child must always take APTIVUS exactly as their doctor has told them. You should check with
your child’s doctor or pharmacist if you are not sure. Your child must take APTIVUS together with
ritonavir.
APTIVUS oral solution should be taken with food.
The dose for children, age 2 to 12 years, will be calculated by the doctor. This will be based on the
child’s body surface area in metres squared. The dose for children should not exceed 5 ml (500 mg)
twice a day. Be sure your child’s doctor clearly informs you what the correct dose for your child
should be. You should measure the exact dose using the supplied measuring syringe and adapter, as
follows:
1.
Check that the oral solution is clear (see below).
2.
Open the bottle by pressing down on the cap and turning it in an anti-clockwise direction.
3.
Remove the syringe cap covering the tip of the syringe (the cap will not be attached if this is the
first time you are using the syringe).
4.
Insert the syringe into the adapter located in the neck of the bottle. Make sure the syringe is
tightly inserted. The maximum volume you can withdraw at one time is 5 ml (equivalent to
500 mg tipranavir), which is the maximum single dose for a child with BSA (Calculated body
surface area) > 1.33 m
2
5.
Turn the bottle upside down and gently withdraw the required amount of APTIVUS oral
solution.
6.
Gently empty APTIVUS oral solution from the syringe into your child’s mouth.
7.
After use of the syringe, replace the syringe cap.
Before giving APTIVUS you should check that the oral solution is clear. Crystals may be seen as a
paper-thin layer at the bottom of the bottle when it is stored upright. There may be other particles at
the bottom of the bottle. A small amount of crystals does not affect the strength or safety of your
child’s medicine.
You should return the bottle to your child’s pharmacist or doctor for a replacement as soon as possible
if:
- there is more than a thin layer of crystals at the bottom of the bottle, or
- you are uncertain about the amount of crystals you see or
- any other particles are visible.
Until you exchange the bottle, please continue to give your child their usual doses of APTIVUS oral
solution.
Your child will always have to take APTIVUS in combination with other antiretroviral medicines.
You should follow the instructions for these medicines within the supplied Package Leaflets.
Your child should continue to take APTIVUS for as long as your child’s doctor tells them. At the age
of 12 years, children treated with APTIVUS should be switched from the oral solution to the capsules.
If your child takes more APTIVUS than they should
Inform your child’s doctor as soon as possible if they take more than the prescribed dose of
APTIVUS.
94
If your child forgets to take APTIVUS
If your child misses a dose of APTIVUS or ritonavir by more than 5 hours, wait and then give the next
dose of APTIVUS and ritonavir at the regularly scheduled time. If your child misses a dose of
APTIVUS and/or ritonavir by less than 5 hours, give the missed dose immediately. Then give the next
dose of APTIVUS and ritonavir at the regularly scheduled time.
If your child stops taking APTIVUS
It has been shown that taking all doses at the appropriate times:
-
greatly increases the effectiveness of your child’s combination antiretroviral medicines
-
reduces the chances of your child’s HIV becoming resistant to their antiretroviral medicines.
Therefore, it is important that your child continues taking APTIVUS correctly, as described above.
Your child must NOT stop taking APTIVUS unless their doctor instructs them to do so.
If you have any further questions on the use of this product, ask your child’s doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, APTIVUS can cause side effects, although not everybody gets them. It may be
difficult to tell the difference between:
-
side effects caused by APTIVUS
-
side effects caused by the other medicines your child is also taking
-
complications of HIV infection.
For this reason it is very important that you tell your child’s doctor about any changes in their health.
Important side effects associated with Aptivus:
-
Abnormal liver function
- Hepatitis and fatty liver (affects 1 to 10 users in 1,000)
- Liver failure (affects 1 to 10 users in 10,000). This can lead to death
- Increased blood levels of bilirubin (a breakdown product of haemoglobin)
You should inform your child’s doctor if they experience:
- Loss of appetite
- Nausea (feeling sick)
- Vomiting and/or jaundice
which may be symptoms of abnormal liver function
-
Bleeding
-
Bleeding in the brain. This can lead to permanent disability or death, and has occurred
in some patients treated with APTIVUS in clinical trials. In the majority of these
patients the bleeding may have had other causes. For example they had other medical
conditions or were receiving other medicine that may have caused the bleeding.
Possible side effects:
The frequency of possible side effects listed below is defined using the following convention:
-
very common (affects more than 1 user in 10)
-
common (affects 1 to 10 users in 100)
-
uncommon (affects 1 to 10 users in 1,000)
-
rare (affects 1 to 10 users in 10,000)
-
very rare (affects less than 1 user in 10,000)
Adults
Very common
-
Diarrhoea
-
Nausea (feeling sick)
95
-
Increases in blood lipid (fat) levels
Common
-
Abdominal pain (tummy pain)
-
Flatulence (breaking wind more often)
-
Tiredness
-
Headache
-
Mild rashes e.g. with hives or with flat or raised small red spots
-
Increases in liver enzyme activity.
Uncommon
-
Reduction in red and white blood cells
-
Allergic (hypersensitivity) reactions
-
Decreased appetite
-
Diabetes
-
Increased blood sugar
-
Increased blood levels of cholesterol
-
Sleeplessness and other sleep disorders (including sleepiness)
-
Numbness and/or tingling and/or pain in the feet or hands
-
Breathing difficulties
-
Heartburn
-
Inflammation of the pancreas
-
Skin inflammation
-
Itching
-
Loss or gain of body fat and other changes in fat distribution (see below)
-
Muscle cramp
-
Muscle pain
-
Kidney disease
-
Flu like symptoms (feeling unwell with fever)
-
Weight loss.
Rare
-
Dehydration (when the body does not have enough water)
-
Thinning of the face
-
Increased blood levels of the pancreas enzymes amylase and lipase.
Further information on possible side effects related to combination antiretroviral treatment:
-
Blood
Combination antiretroviral therapy may also cause:
-
-
Raised sugar in the blood. The effect of insulin (used to treat diabetics to reduce blood
sugar) may be reduced.
-
Hypertriglyceridaemia (increased triglycerides (fats) in the blood)
-
Bleeding
-
Increased bleeding. If your child has haemophilia type A and B, they may experience
increased bleeding. This may be in the skin or joints. If your child suffers increased
bleeding you should see your child’s doctor immediately.
Combination antiretroviral therapy may cause changes in body shape due to changes in fat distribution.
These may include loss of fat from legs, arms and face, increased fat in the abdomen (belly) and other
96
-
Vomiting
-
Reduction in blood platelets
-
Dizziness
-
Raised lactic acid in the blood.
-
Hypercholesterolaemia (increased cholesterol in the blood)
internal organs, breast enlargement and fatty lumps on the back of the neck (‘buffalo hump’). The
cause and long-term health effects of these conditions are not known at this time.
Muscle disorders
There have been reports of muscle pain, tenderness or weakness. These occur particularly when
APTIVUS or other protease inhibitors are taken together with nucleoside analogues. Rarely these
muscle disorders have been serious, involving breakdown of muscle tissue (rhabdomyolysis).
Children
The most common side effects were generally similar to those described in adults. Vomiting, rash and
fever were observed more frequently in children than in adults.
If any of the side effects gets serious, or if you notice any side effects not mentioned in this leaflet,
please tell your child’s doctor or pharmacist.
5.
HOW TO STORE APTIVUS
Keep out of the reach and sight of children.
Do not use APTIVUS after the expiry date which is stated on the bottle after EXP. The expiry date
refers to the last day of that month.
Do not store below 15°C. Do not refrigerate or freeze. Once the bottle is opened your child should use
the medicine within 60 days. You should write the date of opening the bottle on the label and/or outer
carton. Keep the container in the outer carton.
If you notice more than a thin layer of crystals at the bottom of the bottle you should:
-
give the next dose
-
return the bottle to the pharmacist or doctor as soon as possible for a fresh supply.
Medicines should not be disposed of via wastewater or household waste. Ask your child’s pharmacist
how to dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What APTIVUS contains
-
The active substance is tipranavir. Each ml contains 100 mg tipranavir.
-
The other ingredients are macrogol, vitamin E polyethylene glycol succinate, purified water,
propylene glycol, mono/diglycerides of caprylic/capric acid, sucralose, ascorbic acid, Butter
Mint and Butter Toffee flavourings.
What APTIVUS looks like and contents of the pack
APTIVUS oral solution is a clear yellow liquid.
APTIVUS oral solution is supplied in amber glass bottles containing 95 ml of oral solution. A 5 ml
syringe and adapter is supplied for dosing.
APTIVUS is also available as soft capsules.
Not all presentations may be marketed in your country.
Marketing Authorisation Holder
Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
97
Germany
Manufacturer
Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
S.C.S. Boehringer Ingelheim Comm.V.
Tél/Tel: +32 2 773 33 11
Luxembourg/Luxemburg
S.C.S. Boehringer Ingelheim Comm.V.
Tél/Tel: +32 2 773 33 11
България
Бьорингер Ингелхайм РЦВ ГмбХ и Ко КГ -
клон България
Тел: +359 2 958 79 98
Magyarország
Boehringer Ingelheim RCV GmbH & Co KG
Magyarországi Fióktelepe
Tel: +36 1 299 8900
Česká republika
Boehringer Ingelheim spol. s r.o.
Tel: +420 234 655 111
Malta
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600
Danmark
Boehringer Ingelheim Danmark A/S
Tlf: +45 39 15 88 49
Nederland
Boehringer Ingelheim b.v.
Tel: +31 (0) 800 22 55 889
Deutschland
Boehringer Ingelheim Pharma GmbH & Co. KG
Tel: +49 1805 / 77 90 90
Norge
Boehringer Ingelheim Norway KS
Tlf: +47 66 76 13 00
Eesti
Boehringer Ingelheim RCV GmbH & Co KG
Eesti filiaal
Tel: +372 60 80 940
Österreich
Boehringer Ingelheim RCV GmbH & Co KG
Tel: +43 1 80 105-0
Ελλάδα
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300
Polska
Boehringer Ingelheim Sp.zo.o.
Tel: +48 22 699 0 699
España
Boehringer Ingelheim España S.A.
Tel: +34 93 404 58 00
Portugal
Boehringer Ingelheim, Lda.
Tel: +351 21 313 53 00
France
Boehringer Ingelheim France S.A.S.
Tél: +33 3 26 50 45 33
România
Boehringer Ingelheim RCV GmbH & Co KG
Viena - Sucursala Bucuresti
Tel: +40 21 330 99 63
Ireland
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620
Slovenija
Boehringer Ingelheim RCV GmbH & Co KG
Podružnica Ljubljana
Tel: +386 1 586 40 00
Ísland
Slovenská republika
98
Vistor hf.
Sími: +354 535 7000
Boehringer Ingelheim RCV GmbH & Co KG
organizačná zložka
Tel: +421 2 5810 1211
Italia
Boehringer Ingelheim Italia S.p.A.
Tel: +39 02 5355 1
Suomi/Finland
Boehringer Ingelheim Finland Ky
Puh/Tel: +358 10 3102 800
Κύπρος
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300
Sverige
Boehringer Ingelheim AB
Tel: +46 8 721 21 00
Latvija
Boehringer Ingelheim Pharma GmbH
Pārstāvniecība Latvijā
Tel: +371 7 240 068
United Kingdom
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600
Lietuva
Boehringer Ingelheim RCV GmbH & Co KG
Lietuvos filialas
Tel: +370 37 473922
This leaflet was last approved in {MM/YYYY}
Detailed information on this medicine is available on the European Medicines Agency (EMA) web
99
Annex IV
Grounds for one additional renewal
100
Grounds for one additional renewal
Based upon the data that have become available since the granting of the initial Marketing
Authorisation, the CHMP considers that the benefit-risk balance of Aptivus remains positive, but
considers that its safety profile is to be closely monitored for the following reasons:
Given the safety profile of Aptivus regarding the hepatotoxicity events and blood disorders including
blood coagulation parameters and intracranial haemorrhage cases which have to be kept under close
scrutiny, the CHMP decided that the MAH should continue to submit yearly PSURs.
Therefore, based upon the safety profile of Aptivus, which requires the submission of yearly PSURs,
the CHMP concluded that the MAH should submit one additional renewal application in 5 years time.
101
Source: European Medicines Agency
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