ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
Norvir 80 mg/ml oral solution
Each ml of oral solution contains 80 mg of ritonavir.
Excipients:
Alcohol (43% v/v)
Polyoxyl 35 Castor Oil
Sunset Yellow (E110)
For a full list of excipients, see section 6.1.
Oral solution
The solution is a practically clear, orange solution for oral administration.
4.
Ritonavir is indicated in combination with other antiretroviral agents for the treatment of HIV-1
infected patients (adults and children of 2 years of age and older).
Ritonavir should be administered by physicians who are experienced in the treatment of HIV
infection.
Norvir solution is administered orally and should preferably be ingested with food.
Ritonavir dosed as a pharmacokinetic enhancer
When ritonavir is used as a pharmacokinetic enhancer with other protease inhibitors the Summary of
Product Characteristics for the particular protease inhibitor must be consulted.
The following HIV-1 protease inhibitors have been approved for use with ritonavir as a
pharmacokinetic enhancer at the noted doses.
Adult use:
Amprenavir 600 mg twice daily with ritonavir 100 mg twice daily
Atazanavir 300 mg once daily with ritonavir 100 mg once daily
Fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily
Lopinavirco-formulated with ritonavir (lopinavir/ritonavir) 400 mg/100 mg or 800 mg/200mg.
Saquinavir 1000 mg twice daily with ritonavir 100 mg twice daily
Tipranavir 500 mg twice daily with ritonavir 200 mg twice daily
Darunavir 600 mg twice daily with ritonavir 100 mg twice daily in antiretroviral treatment
(ART) experienced patients
Darunavir 800mg once daily with ritonavir 100 mg once daily in ART-naïve patients
2
Paediatric use:
Ritonavir is recommended for children 2 years of age and older. For further dosage
recommendations, refer to the product information of other Protease Inhibitors approved for co-
administration with ritonavir. Norvir is not recommended in children below 2 years of age due to lack
of data on safety and efficacy.
Renal impairment:
As ritonavir is primarily metabolised by the liver, ritonavir may be appropriate for
use with caution as a pharmacokinetic enhancer in patients with renal insufficiency depending on the
specific protease inhibitor with which it is co-administered. However, since the renal clearance of
ritonavir is negligible, the decrease in the total body clearance is not expected in patients with renal
impairment. For specific dosing information in patients with renal impairment, refer to the Summary
of Product Characteristics (SPC) of the co-administered protease inhibitor.
Hepatic impairment:
Ritonavir should not be given as a pharmacokinetic enhancer to patients with
decompensated liver disease (see section 4.3). In the absence of pharmacokinetic studies in patients
with stable severe hepatic impairment (Child Pugh Grade C) without decompensation, caution should
be exercised when ritonavir is used as a pharmacokinetic enhancer as increased levels of the co-
administered PI may occur. Specific recommendations for use of ritonavir as a pharmacokinetic
enhancer in patients with hepatic impairment are dependent on the protease inhibitor with which it is
co-administered. The SPC of the co-administered PI should be reviewed for specific dosing
information in this patient population.
Ritonavir dosed as an antiretroviral agent
Adult use:
The recommended dosage of Norvir solution is 600 mg (7.5 ml) twice daily by mouth.
Gradually increasing the dose of ritonavir when initiating therapy may help to improve tolerance.
Treatment should be initiated at 300 mg (3.75 ml) twice daily for a period of three days and increased
by 100 mg (1.25 ml) twice daily increments up to 600 mg twice daily over a period of no longer than
14 days. Patients should not remain on 300 mg twice daily for more than 3 days.
Paediatric use (2 years of age and above):
the recommended dosage of Norvir solution in children is
350 mg/m
²
by mouth twice daily and should not exceed 600 mg twice daily. Norvir should be started
at 250 mg/m
²
and increased at 2 to 3 day intervals by 50 mg/m
²
twice daily. When possible, dose
should be administered using a calibrated dosing syringe.
Paediatric Dosage Guidelines
Body Surface area*
(m
²
)
Twice daily dose
250 mg/m
²
Twice daily dose
300 mg/m
²
Twice daily dose
350 mg/m
²
0.25
0.8 ml (62.5 mg)
0.9 ml (75 mg)
1.1 ml (87.5 mg)
0.50
1.6 ml (125 mg)
1.9 ml (150 mg)
2.2 ml (175 mg)
1.00
3.1 ml (250 mg)
3.8 ml (300 mg)
4.4 ml (350 mg)
1.25
3.9 ml (312.5 mg)
4.7 ml (375 mg)
5.5 ml (437.5 mg)
1.50
4.7 ml (375 mg)
5.6 ml (450 mg)
6.6 ml (525 mg)
* Body surface area can be calculated with the following equation
BSA (m
²
)
=
√
(Height (cm) X Weight (kg)
/
3600)
Doses for intermediate body surface areas not included in the above table can be calculated using the
following equations:
To calculate the volume to be administered (in ml) the body surface area should be multiplied by a
factor of: 3.1 for a dose of 250 mg/m
²
; 3.8 for one of 300 mg/m
²
; and by 4.4 for 350 mg/m
²
.
Renal impairment
: Currently, there are no data specific to this patient population and therefore specific
dosage recommendations cannot be made. The renal clearance of ritonavir is negligible; therefore, a
decrease in the total body clearance is not expected in patients with renal impairment. Because
3
ritonavir is highly protein bound it is unlikely that it will be significantly removed by haemodialysis or
peritoneal dialysis.
Hepatic impairment:
Ritonavir
is principally metabolised and eliminated by the liver.
Pharmacokinetic data indicate that no dose adjustment is necessary in patients with mild to moderate
hepatic impairment (see section 5.2). Ritonavir should not be given to patients with severe hepatic
impairment (see section 4.3).
Elderly:
Pharmacokinetic data indicated that no dose adjustment is necessary for elderly patients (see
section 5.2).
The bitter taste of Norvir solution may be lessened if mixed with chocolate milk.
Hypersensitivity to the active substance or to any of the excipients.
When ritonavir is used as a pharmacokinetic enhancer of other PIs, consult the Summary of Product
Characteristics of the co-administered protease inhibitor for contraindications.
Ritonavir should not be given as a pharmacokinetic enhancer or as an antiretroviral agent to patients
with decompensated liver disease.
In vitro
and
in vivo
studies have demonstrated that ritonavir is a potent inhibitor of CYP3A- and
CYP2D6- mediated biotransformations. The following medicines are contraindicated when used with
ritonavir and unless otherwise noted, the contraindication is based on the potential for ritonavir to
inhibit metabolism of the co-administered medicinal product, resulting in increased exposure to the
co-administered medicinal product and risk of clinically significant adverse effects.
The enzyme-modulating effect of ritonavir may be dose dependent. For some products,
contraindications may be more relevant when ritonavir is used as an antiretroviral agent than when
ritonavir is used as a pharmacokinetic enhancer (eg rifabutin and voriconazole):
Medicinal Product
Class
Medicinal Products
within Class
Rationale
Concomitant medicinal product levels increased
α
1
-Adrenoreceptor
Antagonist
Alfuzosin
Increased plasma concentrations of alfuzosin
which may lead to severe hypotension (see
section 4.5).
Analgesics
Pethidine, piroxicam,
propoxyphne
Increased plasma concentrations of norpethidine,
piroxicam and propoxyphene. Thereby,
increasing the risk of serious respiratory
depression or haematologic abnormalities, or
other serious adverse effects from these agents.
Antiarrthymics
Amiodarone, bepridil,
encainide, flecanide,
propafenone, quinidine
Increased plasma concentrations of amiodarone,
bepridil, encainide, flecanide, propafenone,
quinidine. Thereby, increasing the risk of
arrhythmias or other serious adverse reactions
from these agents.
Antibiotic
Fusidic Acid
Increased plasma concentrations of fusidic acid
and ritonavir.
4
Antifungal
Voriconazole
Concomitant use of ritonavir (400 mg twice daily
and more) and voriconazole is contraindicated
due to a reduction in voriconazole plasma
concentrations and possible loss of effect (see
section 4.5)
Antihistamines
Astemizole, terfenadine Increased plasma concentrations of astemizole
and terfenadine. Thereby, increasing the risk of
serious arrhythmias from these agents.
Antimycobacterial
Rifabutin
Concomitant use of ritonavir dosed as an
antiretroviral agent (600 mg twice daily) and
rifabutin due to an increase of rifabutin serum
concentrations and risk of adverse events
including uveitis (see section 4.4).
Recommendations regarding use of ritonavir
dosed as a pharmacokinetic enhancer with
rifabutin are noted in section 4.5
Antipsychotics/
Neuroleptics
Clozapine, pimozide
Increased plasma concentrations of clozapine and
pimozide. Thereby, increasing the risk of serious
haematologic abnormalities, or other serious
adverse effects from these agents.
Ergot Derivatives
Dihydroergotamine,
ergonovine,
ergotamine,
methylergonovine
Increased plasma concentrations of ergot
derivatives leading to acute ergot toxicity,
including vasospasm and ischaemia.
GI motility agent
Cisapride
Increased plasma concentrations of cisapride.
Thereby, increasing the risk of serious
arrhythmias from this agent.
HMG Co-A Reductase
Inhibitor
Lovastatin, simvastatin Increased plasma concentrations of lovastatin and
simvastatin; thereby, increasing the risk of
myopathy including rhabdomyolysis (see section
4.5).
PDE5 inhibitor
Sildenafil
Contraindicated when used for the treatment of
pulmonary arterial hypertension (PAH) only.
Increased plasma concentrations of sildenafil.
Thereby, increasing the potential for sildenafil-
associated adverse events (which include
hypotension and syncope). See section 4.4 and
section 4.5 for coadministration of sildenafil in
patients with erectile dysfunction.
Sedatives/hypnotics
Clorazepate, diazepam,
estazolam, flurazepam,
oral midazolam and
triazolam
Increased plasma concentrations of clorazepate,
diazepam, estazolam, flurazepam, oral midazolam
and triazolam. Thereby, increasing the risk of
extreme sedation and respiratory depression from
these agents. (For caution on parenterally
administered midazolam, see section 4.5).
Ritonavir medicinal product level decreased
5
Herbal Preparation
St. John’s Wort
Herbal preparations containing St John’s wort
(
Hypericum perforatum)
due to the risk of
decreased plasma concentrations and reduced
clinical effects of ritonavir (see section 4.5).
Ritonavir is not a cure for HIV-1 infection or AIDS. Patients receiving ritonavir 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 used
.
When ritonavir is used as a pharmacokinetic enhancer with other PIs, full details on the warnings and
precautions relevant to that particular PI should be considered, therefore the Summary of Product
Characteristics for the particular PI must be consulted.
Ritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer
Patients with chronic diarrhoea or malabsorption
: Extra monitoring is recommended when diarrhoea
occurs. The relatively high frequency of diarrhoea during treatment with ritonavir may compromise
the absorption and efficacy (due to decreased compliance) of ritonavir or other concurrent medicinal
products. Serious persistent vomiting and/or diarrhoea associated with ritonavir use might also
compromise renal function. It is advisable to monitor renal function in patients with renal function
impairment.
Haemophilia
: there have been reports of increased bleeding, including spontaneous skin haematomas
and haemarthroses, in haemophiliac patients type A and B treated with protease inhibitors. In some
patients additional factor VIII was given. In more than a 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 has not been elucidated.
Haemophiliac patients should therefore be made aware of the possibility of increased bleeding.
Diabetes mellitus and hyperglycaemia
: New onset diabetes mellitus, hyperglycaemia or exacerbation
of existing diabetes mellitus has been reported in patients receiving protease inhibitors. In some of
these the hyperglycaemia was severe and in some cases also associated with ketoacidosis. Many
patients had confounding medical conditions, some of which required therapy with agents that have
been associated with the development of diabetes mellitus or hyperglycaemia.
Lipodystrophy
: Combination antiretroviral therapy has been associated with redistribution of body fat
(lipodystrophy) in HIV patients. The long-term consequences of these events are currently unknown.
Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and PIs
and lipoatrophy and nucleoside reverse transcriptase inhibitors (NRTIs) has been hypothesised. A
higher risk of lipodystrophy has been associated with individual factors such as older age, and with
medicinal product related factors 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 measurement of fasting serum lipids and blood
glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8).
Pancreatitis
: Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal
pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values)
suggestive of pancreatitis should occur. Patients who exhibit these signs or symptoms should be
6
evaluated and Norvir therapy should be discontinued if a diagnosis of pancreatitis is made (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 asymtomatic
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 jiroveci pneumonia. Any inflammatory symptoms should
be evaluated and treatment instituted when necessary.
Liver disease:
Ritonavir should not be given to patients with decompensated liver disease. For
patients with stable severe hepatic impairment (Child Pugh Grade C) without decompensation see
section 4.2. 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 reactions. In case of
concomitant antiviral therapy for hepatitis B or C, please refer to the relevant product information for
these medicinal products.
Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased
frequency of liver function abnormalities during combination antiretroviral therapy and should be
monitored according to standard practice. If there is evidence of worsening liver disease in such
patients, interruption or discontinuation of treatment must be considered.
Renal disease:
Since the renal clearance of ritonavir is negligible, the decrease in the total body
clearance is not expected in patients with renal impairment. For specific dosing information in
patients with renal impairment, refer to the Summary of Product Characteristics (SPC) of the
co-administered protease inhibitor. See also section 4.2.
Ritonavir oral solution contains castor oil polyoxyl which may cause stomach upset and diarrhoea.
Ritonavir oral solution also contains the azo-colouring agent sunset yellow (E110) which may cause
allergic reactions.
Ritonavir oral solution contains alcohol (43% v/v), ie up to 258 mg per maximum dose of 600 mg,
equivalent to 65 ml beer, 27 ml wine per dose. Each 100 mg dose contains up to 43 mg alcohol and
each 200 mg dose contains 86 mg alcohol. Therefore concomitant administration of Norvir with
disulfiram or medicines with disulfiram-like reactions (eg metronidazole) should be avoided. Also to
be taken into account in pregnant or breast-feeding women, children and high-risk groups such as
patients with liver disease or epilepsy.
Osteonecrosis:
Although the etiology is considered to be multifactorial (including corticosteroid use,
alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis
have been reported 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.
PR interval prolongation
: ritonavir has been shown to cause modest asymptomatic prolongation of the
PR interval in some healthy adult subjects. Rare reports of 2
nd
or 3
rd
degree atrioventricular block in
patients with underlying structural heart disease and pre-existing conduction system abnormalities or
in patients receiving medicinal products known to prolong the PR interval (such as verapamil or
atazanavir) have been reported in patients receiving ritonavir. Norvir should be used with caution in
such patients (see section 5.1).
7
Interactions with other medicinal products
Ritonavir dosed as an antiretroviral agent
The following Warnings and Precautions should be considered when ritonavir is used as an
antiretroviral agent. When ritonavir is used as a pharmacokinetic enhancer at the 100 mg and 200 mg
level it cannot be assumed that the following warnings and precautions will also apply. When
ritonavir is used as a pharmacokinetic enhancer, full details on the warnings and precautions relevant
to that particular PI must be considered, therefore the Summary of Product Characteristics, section 4.4,
for the particular PI must be consulted to determine if the information below is applicable.
PDE5 inhibitors
: Particular caution should be used when prescribing sildenafil, tadalafil or vardenafil
for the treatment of erectile dysfunction in patients receiving ritonavir. Co-administration of ritonavir
with these medicinal products is expected to substantially increase their concentrations and may result
in associated adverse reactions such as hypotension and prolonged erection (see section 4.5).
Concomitant use of sildenafil with ritonavir is contraindicated in pulmonary arterial hypertension
patients (see section 4.3).
HMG-CoA reductase inhibitors:
The HMG-CoA reductase inhibitors simvastatin and lovastatin are
highly dependent on CYP3A for metabolism, thus concomitant use of ritonavir with simvastatin or
lovastatin is not recommended due to an increased risk of myopathy including rhabdomyolysis.
Caution must also be exercised and reduced doses should be considered if ritonavir is used
concurrently with atorvastatin, which is metabolised to a lesser extent by CYP3A. While rosuvastatin
elimination is not dependent on CYP3A, an elevation of rosuvastatin exposure has been reported with
ritonavir co-administration. The mechanism of this interaction is not clear, but may be the result of
transporter inhibition. When used with ritonavir dosed as a pharmacokinetic enhancer or as an
antiretroviral agent, the lowest doses of atorvastatin or rosuvastatin should be administered. The
metabolism of pravastatin and fluvastatin is not dependent of CYP3A, and interactions are not
expected with ritonavir. If treatment with an HMG-CoA reductase inhibitor is indicated, pravastatin
or fluvastatin is recommended (see section 4.5).
Digoxin
: Particular caution should be used when prescribing ritonavir in patients taking digoxin since
co-administration of ritonavir with digoxin is expected to increase digoxin levels. The increased
digoxin levels may lessen over time (see section 4.5).
In patients who are already taking digoxin when ritonavir is introduced, the digoxin dose should be
reduced to one-half of the patients’ normal dose and patient need to be followed more closely than
usual for several weeks after initiating co-administration of ritonavir and digoxin.
In patients who are already taking ritonavir when digoxin is introduced, digoxin should be introduced
more gradually than usual. Digoxin levels should be monitored more intensively than usual during
this period, with dose adjustments made, as necessary, based on clinical, electrocardiographic and
digoxin level findings.
Ethinyl estradiol
: Barrier or other non-hormonal methods of contraception should be considered when
administering ritonavir at therapeutic or low doses as ritonavir is likely to reduce the effect and change
the uterine bleeding profile when co-administered with estradiol-containing contraceptives.
Glucocorticoids
: Concomitant use of 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).
8
Trazodone
: Particular caution should be used when prescribing ritonavir in patients using trazodone.
Trazodone is a CYP3A4 substrate and co-administration of ritonavir is expected to increase trazodone
levels. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed in single
dose interaction studies in healthy volunteers (see section 4.5)
Ritonavir dosed as a pharmacokinetic enhancer
The interaction profiles of HIV-protease inhibitors, co-administered with low dose ritonavir, are
dependant on the specific co-administered protease inhibitor.
For a description of the mechanisms and potential mechanisms contributing to the interaction profile
of the PIs, see section 4.5. Please also review the Summary of Product Characteristics for the
particular boosted PI.
Saquinavir
: Doses of ritonavir higher than 100 mg twice daily should not be used. Higher doses of
ritonavir have been shown to be associated with an increased incidence of adverse reactions.
Co-administration of saquinavir and ritonavir has led to severe adverse reactions, mainly diabetic
ketoacidosis and liver disorders, especially in patients with pre-existing liver disease.
Saquinavir/ritonavir should not be given together with rifampicin, due to the risk of severe
hepatotoxicity (presenting as increased hepatic transaminases) if the three medicines are given together
(see section 4.5).
Tipranavir:
co-administered with 200 mg of ritonavir has been associated with reports of clinical
hepatitis and hepatic decompensation including some fatalities. Extra vigilance is warranted in
patients with chronic hepatitis B or hepatitis C co-infection, as these patients have an increased risk of
hepatotoxicity.
Doses of ritonavir lower than 200 mg twice daily should not be used as they might alter the efficacy
profile of the combination.
Fosamprenavir
: Co-administration of fosamprenavir with ritonavir in doses greater than 100 mg twice
daily has not been clinically evaluated. The use of higher ritonavir doses might alter the safety profile
of the combination and therefore is not recommended.
Atazanavir
: Co-administration of atazanavir with ritonavir at doses greater than 100 mg once daily
has not been clinically evaluated. The use of higher ritonavir doses may alter the safety profile of
atazanavir (cardiac effects, hyperbilirubinemia) and therefore is not recommended. Only when
atazanavir with ritonavir is co-administered with efavirenz, a dose increase of ritonavir to 200mg once
daily could be considered. In this instance, close clinical monitoring is warranted. Refer to the
Reyataz Summary of Product Characteristics for further details.
Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent
Ritonavir has a high affinity for several cytochrome P450 (CYP) isoforms and may inhibit oxidation
with the following ranked order: CYP3A4 > CYP2D6. Co-administration of Norvir and medicinal
products primarily metabolised by CYP3A may result in increased plasma concentrations of the other
medicinal product, which could increase or prolong its therapeutic and adverse effects. For select
medicinal products (eg alprazolam) the inhibitory effects of ritonavir on CYP3A4 may decrease over
time. Ritonavir also has a high affinity for P-glycoprotein and may inhibit this transporter. The
inhibitory effect of ritonavir (with or without other protease inhibitors) on P-gp activity may decrease
over time (eg digoxin and fexofenadine-see table “Ritonavir effects on non-antiretroviral medicinal
products” below). Ritonavir may induce glucuronidation and oxidation by CYP1A2, CYP2C8,
CYP2C9 and CYP2C19 thereby increasing the biotransformation of some medicinal products
9
metabolised by these pathways, and may result in decreased systemic exposure to such medicinal
products, which could decease or shorten their therapeutic effect.
Important information regarding medicinal product interactions when ritonavir is used as a
pharmacokinetic enhancer is also contained in the Summary of Product Characteristics of the
co-administered protease inhibitor.
Medicinal products that affect ritonavir levels
Serum levels of ritonavir can be reduced by concomitant use of herbal preparations containing
St John’s wort (
Hypericum perforatum).
This is due to the induction of medicinal product
metabolising enzymes by St John’s wort. Herbal preparations containing St John’s wort must not be
used in combination with ritonavir. If a patient is already taking St John’s wort, stop St John’s wort
and if possible check viral levels. Ritonavir levels may increase on stopping St John’s wort. The dose
of ritonavir may need adjusting. The inducing effect may persist for at least 2 weeks after cessation of
treatment with St John’s wort (see section 4.3).
Serum levels of ritonavir may be affected by select co-administered medicinal products (eg
delavirdine, efavirenz, phenytoin and rifampicin). These interactions are noted in the medicinal
product interaction tables below.
Medicinal product that are affected by the use of ritonavir
Interactions between ritonavir and protease inhibitors, antiretroviral agents other than protease
inhibitors and other non-antiretroviral medicinal products are listed in the tables below.
Medicinal Product Interactions – Ritonavir with Protease Inhibitors
Co-
administered
Medicinal
Product
Dose of Co-administered
Medicinal Product (mg)
Dose of NORVIR
(mg)
Medicinal
Product
Assessed
AUC
C
min
Amprenavir 600 q12h 100 q12h Amprenavir
2
↑ 64% ↑ 5 fold
Ritonavir increases the serum levels of amprenavir as a result of CYP3A4 inhibition. Clinical
trials confirmed the safety and efficacy of 600 mg amprenavir twice daily with ritonavir 100 mg
twice daily. Norvir oral solution should not be co-administered with amprenavir oral solution to
children due to the risk of toxicity from excipients in the two formulations. For further
information, physicians should refer to the Agenerase Summary of Product Characteristics.
Atazanavir 300 q24h 100 q24h Atazanavir ↑ 86% ↑ 11 fold
Atazanavir
1
↑ 2 fold ↑ 3-7 fold
Ritonavir increases the serum levels of atazanavir as a result of CYP3A4 inhibition. Clinical trials
confirmed the safety and efficacy of 300 mg atazanavir once daily with ritonavir 100 mg once
daily in treatment experienced patients. For further information, physicians should refer to the
Reyataz Summary of Product Characteristics.
Darunavir 600, single 100 q12h Darunavir ↑ 14 fold
Ritonavir increases the serum levels of darunavir as a result of CYP3A inhibition. Darunavir must
be given with ritonavir to ensure its therapeutic effect. Ritonavir doses higher than 100 mg twice
daily have not been studied with darunavir. For further information, refer to the Summary of
Product Characteristics for Prezista.
Fosamprenavir 700 q12h
100 q12h
Amprenavir ↑ 2.4 fold ↑ 11 fold
Ritonavir increases the serum levels of amprenavir (from fosamprenavir) as a result of CYP3A4
inhibition. Fosamprenavir must be given with ritonavir to ensure its therapeutic effect. Clinical
trials confirmed the safety and efficacy of fosamprenavir 700 mg twice daily with ritonavir 100
mg twice daily. Ritonavir doses higher than 100 mg twice daily have not been studied with
fosamprenavir. For further information, physicians should refer to the Telzir Summary of Product
Characteristics.
10
Indinavir
800 q12h
100 q12h
Indinavir
3
↑ 178%
ND
Ritonavir ↑ 72%
ND
400 q12h
400 q12h
Indinavir
3
↔ ↑ 4 fold
Ritonavir ↔ ↔
Ritonavir increases the serum levels of indinavir as a result of CYP3A4 inhibition. Appropriate
doses for this combination, with respect to efficacy and safety, have not been established.
Minimal benefit of ritonavir-mediated pharmacokinetic enhancement is achieved with doses higher
than 100 mg twice daily. In cases of co-administration of ritonavir (100 mg twice daily) and
indinavir (800 mg twice daily) caution is warranted as the risk of nephrolithiasis may be increased.
Nelfinavir
1250 q12h
100 q12h
Nelfinavir ↑ 20to39%
ND
750, single
500 q12h
Nelfinavir ↑ 152%
ND
Ritonavir ↔ ↔
Ritonavir increases the serum levels of nelfinavir as a result of CYP3A4 inhibition. Appropriate
doses for this combination, with respect to efficacy and safety, have not been established.
Minimal benefit of ritonavir-mediated pharmacokinetic enhancement is achieved with doses higher
than 100 mg twice daily.
Saquinavir
1000 q12h
100 q12h
Saquinavir
4
↑ 15-fold ↑ 5-fold
Ritonavir ↔ ↔
400 q12h
400 q12h
Saquinavir
4
↑ 17-fold
ND
Ritonavir ↔ ↔
Ritonavir increases the serum levels of saquinavir as a result of CYP3A4 inhibition. Saquinavir
should only be given in combination with ritonavir. Ritonavir 100 mg twice daily with saquinavir
1000 mg twice daily provides saquinavir systemic exposure over 24 hours similar to or greater
than those achieved with saquinavir 1200 mg three times daily without ritonavir.
In a clinical study investigating the interaction of rifampicin 600 mg once daily and saquinavir
1000 mg with ritonavir 100 mg twice daily in healthy volunteers, severe hepatocellular toxicity
with transaminase elevations up to > 20-fold the upper limit of normal after 1 to 5 days of
co-administration was noted. Due to the risk of severe hepatoxicity, saquinavir/ritonavir should
not be given together with rifampicin.
For further information, physicians should refer to the Invirase or Fortovase Summary of Product
Characteristics.
Tipranavir
500 q12h
200 q12h
Tipranavir ↑ 11 fold ↑ 29 fold
Ritonavir ↓ 40%
ND
Ritonavir increases the serum levels of tipranavir as a result of CYP3A inhibition. Tipranavir
must be given with low dose ritonavir to ensure its therapeutic effect. Doses of ritonavir less than
200 mg twice daily should not be used with tipranavir as they might alter the efficacy of the
combination. For further information, physicians should refer to the Aptivus Summary of Product
Characteristics.
ND: Not determined.
1.
Based on cross-study comparison to 400 mg atazanavir once daily alone.
2.
Based on cross-study comparison to 1200 mg amprenavir twice daily alone.
3.
Based on cross-study comparison to 800 mg indinavir three times daily alone.
4.
Based on cross-stud y comparison to 600 mg saquinavir three times daily alone.
11
Medicinal Product Interactions – Ritonavir with Antiretroviral Agents Other Than Protease
Inhibitors
Co-
administered
Medicinal
Product
Dose of Co-
administered
Medicinal Product
(mg)
Dose of NORVIR (mg)
Medicinal
Product
Assessed
AUC
C
min
Didanosine
200 q12h
600 q12h 2 h later
Didanosine ↓ 13% ↔
As ritonavir is recommended to be taken with food and didanosine should be taken on an empty
stomach, dosing should be separated by 2.5 h. Dose alterations should not be necessary.
Delavirdine
400 q8h
600 q12h
Delavirdine
1
↔
↔
Ritonavir ↑ 50% ↑ 75%
Based on comparison to historical data, the pharmacokinetics of delavirdine did not appear to be
affected by ritonavir. When used in combination with delavirdine, dose reduction of ritonavir may
be considered.
Efavirenz
600 q24h
500 q12h
Efavirenz ↑ 21%
Ritonavir ↑ 17%
A higher frequency of adverse reactions (eg, dizziness, nausea, paraesthesia) and laboratory
abnormalities (elevated liver enzymes) have been observed when efavirenz is co-administered with
ritonavir dosed as an antiretroviral agent.
Maraviroc
100 q12h
100 q12h
Maraviroc ↑161%
↑28%
Ritonavir increases the serum levels of maraviroc as a result of CYP3A inhibition. Maraviroc may
be given with ritonavir to increase the maraviroc exposure. For further information, refer to the
Summary of Product Characteristics for Celsentri.
Nevirapine
200 q12h
600 q12h
Nevirapine ↔
↔
Ritonavir ↔
↔
Co-administration of ritonavir with nevirapine does not lead to clinically relevant changes in the
pharmacokinetics of either nevirapine or ritonavir.
Zidovudine
200 q8h
300 q6h
Zidovudine ↓ 25%
ND
Ritonavir may induce the glucuronidation of zidovudine, resulting in slightly decreased levels of
zidovudine. Dose alterations should not be necessary.
ND: Not determined
1. Based on parallel group comparison.
Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products
Co-administered Medicinal Products
Dose of Co-
administered
Medicinal
Products (mg)
Dose of
NORVIR
(mg)
Effect on Co-
administered
Medicinal
Products AUC
Effect on Co-
administered
Medicinal
Products C
max
Alpha
1
-Adrenoreceptor Antagonist
Alfuzosin
Ritonavir co-administration is likely to result in increased plasma
concentrations of alfuzosin and is therefore
contraindicated
(see
section 4.3).
Amphetamine Derivatives
Amphetamine
Ritonavir dosed as an antiretroviral agent is likely to inhibit CYP2D6
and as a result is expected to increase concentrations of amphetamine
and its derivatives. Careful monitoring of therapeutic and adverse
effects is recommended when these medicines are concomitantly
administered with antiretroviral doses of ritonavir (see section 4.4).
12
Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products
Co-administered Medicinal Products
Dose of Co-
administered
Medicinal
Products (mg)
Dose of
NORVIR
(mg)
Effect on Co-
administered
Medicinal
Products AUC
Effect on Co-
administered
Medicinal
Products C
max
Analgesics
Buprenorphine
16 q24h
100 q12h ↑ 57% ↑ 77%
Norbuprenorphine
↑ 33% ↑ 108%
Glucuronide metabolites
↔ ↔
The increases of plasma levels of buprenorphine and its active
metabolite did not lead to clinically significant pharmacodynamic
changes in a population of opioid tolerant patients. Adjustment to the
dose of buprenorphine or ritonavir may therefore not be necessary
when the two are dosed together. When ritonavir is used in
combination with another protease inhibitor and buprenorphine, the
SPC of the co-administered protease inhibitor should be reviewed for
specific dosing information.
Pethidine, piroxicam, propoxyphene
Ritonavir co-administration is likely to result in increased plasma
concentrations of pethidine, piroxicam, and propoxyphene and is
therefore
contraindicated
(see section 4.3).
Fentanyl
Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral
agent inhibits CYP3A4 and as a result is expected to increase the
plasma concentrations of fentanyl. Careful monitoring of therapeutic
and adverse effects is recommended when fentanyl is concomitantly
administered with ritonavir.
Methadone
1
5, single dose
500 q12h, ↓ 36% ↓ 38%
Increased methadone dose may be necessary when concomitantly
administered with ritonavir dosed as an antiretroviral agent or as a
pharmacokinetic enhancer due to induction of glucuronidation. Dose
adjustment should be considered based on the patient’s clinical
response to methadone therapy.
Morphine
Morphine levels may be decreased due to induction of glucuronidation
by co-administered ritonavir dosed as an antiretroviral agent or as a
pharmacokinetic enhancer.
Antiarrthymics
Amiodarone, bepridil, encainide, flecanide,
propafenone, quinidine
Ritonavir co-administration is likely to result in increased plasma
concentrations of amiodarone, bepridil, encainide, flecanide,
propafenone, and quinidine and is therefore
contraindicated
(see
section 4.3).
Digoxin
0.5 single IV dose
300 q12h, 3 days ↑ 86%
ND
0.4 single oral
dose
200 q12h, 13 days ↑ 22% ↔
This interaction may be due to modification of P-glycoprotein mediated
digoxin efflux by ritonavir dosed as an antriretroviral agent or as a
pharmacokinetic enhancer. Increased digoxin levels observed in
patients receiving ritonavir may lessen over time as induction develops
(see section 4.4).
13
Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products
Co-administered Medicinal Products
Dose of Co-
administered
Medicinal
Products (mg)
Dose of
NORVIR
(mg)
Effect on Co-
administered
Medicinal
Products AUC
Effect on Co-
administered
Medicinal
Products C
max
Antiasthmatic
Theophylline
1
3 mg/kg q8h
500 q12h ↓ 43% ↓ 32%
An increased dose of theophyline may be required when co-
administered with ritonavir, due to induction of CYP1A2.
Anticancer agents
Vincristine, vinblastine
Serum concentrations may be increased when co-administered with
ritonavir resulting in the potential for increased incidence of adverse
events.
Anticoagulant
Warfarin
S-Warfarin
R-Warfarin
5, single dose
400 q12h
↑ 9%
↓ 33%
↓ 9%
↔
Induction of CYP1A2 and CYP2C9 lead to decreased levels of R-
warfarin while little pharmacokinetic effect is noted on S- warfarin
when co-administered with ritonavir. Decreased R-warfarin levels may
lead to reduced anticoagulation, therefore it is recommended that
anticoagulation parameters are monitored when warfarin is co-
administered with ritonavir dosed as an antiretroviral agent or as a
pharmacokinetic enhancer.
Anticonvulsants
Carbamazepine
Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral
agent inhibits CYP3A4 and as a result is expected to increase the
plasma concentrations of carbamazepine. Careful monitoring of
therapeutic and adverse effects is recommended when carbamazepine is
concomitantly administered with ritonavir.
Divalproex, lamotrigine, phenytoin
Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral
agent induces oxidation by CYP2C9 and glucuronidation and as a result
is expected to decrease the plasma concentrations of anticonvulsants.
Careful monitoring of serum levels or therapeutic effects is
recommended when these medicines are concomitantly administered
with ritonavir. Phenytoin may decrease serum levels of ritonavir.
Antidepressants
Amitriptyline, fluoxetine, imipramine,
nortriptyline, paroxetine, sertraline
Ritonavir dosed as an antiretroviral agent is likely to inhibit CYP2D6
and as a result is expected to increase concentrations of desipramine,
imipramine, amitriptyline, nortriptyline, fluoxetine, paroxetine or
sertraline. Careful monitoring of therapeutic and adverse effects is
recommended when these medicines are concomitantly administered
with antiretroviral doses of ritonavir (see section 4.4).
Desipramine
100, single oral dose 500 q12h ↑ 145% ↑ 22%
14
Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products
Co-administered Medicinal Products
Dose of Co-
administered
Medicinal
Products (mg)
Dose of
NORVIR
(mg)
Effect on Co-
administered
Medicinal
Products AUC
Effect on Co-
administered
Medicinal
Products C
max
The AUC and Cmax of the 2-hydroxy metabolite were decreased 15
and 67%, respectively. Dosage reduction of desipramine is
recommended when co-administered with ritonavir dosed as an
antiretroviral agent.
Trazodone
50, single dose
200 q12h ↑ 2.4-fold ↑ 34%
An increase in the incidence in trazodone-related adverse reactions was
noted when co-administered with ritonavir dosed as an antiretroviral
agent or as a pharmacokinetic enhancer. If trazodone is co-
administered with ritonavir, the combination should be used with
caution, initiating trazodone at the lowest dosage and monitoring for
clinical response and tolerability.
Antihistamines
Astemizole, terfenadine
Ritonavir co-administration is likely to result in increased plasma
concentrations of astemizole and terfenadine and is therefore
contraindicated
(see section 4.3).
Fexofenadine
Ritonavir may modify P-glycoprotein mediated fexofenadine efflux
when dosed as an antriretroviral agent or as a pharmacokinetic enhancer
resulting in increased concentrations of fexofenadine. Increased
fexofenadine levels may lessen over time as induction develops.
Loratadine
Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral
agent inhibits CYP3A and as a result is expected to increase the plasma
concentrations of loratadine. Careful monitoring of therapeutic and
adverse effects is recommended when loratidine is concomitantly
administered with ritonavir.
Anti-infectives
Fusidic Acid
Ritonavir co-administration is likely to result in increased plasma
concentrations of both fusidic acid and ritonavir and is therefore
contraindicated
(see section 4.3).
Rifabutin
1
150 daily
500 q12h, ↑ 4-fold
↑ 2.5-fold
25-
O
-desacetyl rifabutin metabolite
↑ 38-fold
↑ 16-fold
Due to the large increase in rifabutin AUC, the concomitant use of
rifabutin with ritonavir dosed as an antiretroviral agent is
contraindicated
(see section 4.3). The reduction of the rifabutin dose
to 150 mg 3 times per week may be indicated for select PIs when
co-administered with ritonavir as a pharmacokinetic enhancer. The
Summary of Product Characteristics of the co-administered protease
inhibitor should be consulted for specific recommendations.
Consideration should be given to official guidance on the appropriate
treatment of tuberculosis in HIV-infected patients.
Rifampicin
Although rifampicin may induce metabolism of ritonavir, limited data
indicate that when high doses of ritonavir (600 mg twice daily) is
co-administered with rifampicin, the additional inducing effect of
rifampicin (next to that of ritonavir itself) is small and may have no
clinical relevant effect on ritonavir levels in high-dose ritonavir
therapy. The effect of ritonavir on rifampicin is not known.
15
Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products
Co-administered Medicinal Products
Dose of Co-
administered
Medicinal
Products (mg)
Dose of
NORVIR
(mg)
Effect on Co-
administered
Medicinal
Products AUC
Effect on Co-
administered
Medicinal
Products C
max
Voriconazole
200 q12h
400 q12h ↓ 82% ↓ 66%
200 q12h
100 q12h ↓ 39% ↓ 24%
Concomitant use of ritonavir dosed as an antiretroviral agent and
voriconazole is
contraindicated
due to reduction in voriconazole
concentrations (see section 4.3). Co-administration of voriconazole and
ritonavir dosed as a pharmacokinetic enhancer should be avoided,
unless an assessment of the benefit/risk to the patient justifies the use of
voriconazole.
Atovaquone
Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral
agent induces glucuronidation and as a result is expected to decrease
the plasma concentrations of atovaquone. Careful monitoring of serum
levels or therapeutic effects is recommended when atovaquone is
concomitantly administered with ritonavir.
Clarithromycin
500 q12h
200 q8h ↑ 77%
↑ 31%
14-OH clarithromycin metabolite
↓ 100%
↓ 99%
Due to the large therapeutic window of clarithromycin no dose
reduction should be necessary in patients with normal renal function.
Clarithromycin doses greater than 1 g per day should not be co-
administered with ritonavir dosed as an antiretroviral agent or as a
pharmacokinetic enhancer. For patients with renal impairment, a
clarithromycin dose reduction should be considered: for patients with
creatinine clearance of 30 to 60 ml/min the dose should be reduced by
50%, for patients with creatinine clearance less than 30 ml/min the dose
should be reduced by 75%.
Erythromycin, itraconazole
Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral
agent inhibits CYP3A4 and as a result is expected to increase the
plasma concentrations of erythromycin and itraconazole. Careful
monitoring of therapeutic and adverse effects is recommended when
erythromycin or itraconazole is used concomitantly administered with
ritonavir.
Ketoconazole
200 daily
500 q12h ↑ 3.4-fold ↑ 55%
Ritonavir inhibits CYP3A-mediated metabolism of ketoconazole. Due
to an increased incidence of gastrointestinal and hepatic adverse
reactions, a dose reduction of ketoconazole should be considered when
co-administered with ritonavir dosed as an antiretroviral agent or as a
pharmacokinetic enhancer.
Sulfamethoxazole/Trimethoprim
2
800/160, single
dose
500 q12h ↓ 20% / ↑ 20% ↔
Dose alteration of sulfamethoxazole/trimethoprim during concomitant
ritonavir therapy should not be necessary.
Antipsychotics/Neuroleptics
Clozapine, pimozide
Ritonavir co-administration is likely to result in increased plasma
concentrations of clozapine or pimozide and is therefore
contraindicated
(see section 4.3).
16
Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products
Co-administered Medicinal Products
Dose of Co-
administered
Medicinal
Products (mg)
Dose of
NORVIR
(mg)
Effect on Co-
administered
Medicinal
Products AUC
Effect on Co-
administered
Medicinal
Products C
max
Haloperidol, risperidone, thioridazine
Ritonavir dosed as an antiretroviral agent is likely to inhibit CYP2D6
and as a result is expected to increase concentrations of haloperidol,
risperidone and thioridazine. Careful monitoring of therapeutic and
adverse effects is recommended when these medicines are
concomitantly administered with antiretroviral doses of ritonavir (see
section 4.3).
β2-agonist (long acting)
Salmetarol
Ritonavir inhibits CYP3A4 and as a result a pronounced increase in the
plasma concentrations of salmetarol is expected. Therefore
concomitant use is not recommended.
Calcium channel antagonists
Amlodipine, diltiazem, nifedipine
Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral
agent inhibits CYP3A4 and as a result is expected to increase the
plasma concentrations of calcium channel antagonists. Careful
monitoring of therapeutic and adverse effects is recommended when
these medicines are concomitantly administered with ritonavir.
Ergot Derivatives
Dihydroergotamine, ergonovine,
ergotamine, methylergonovine
Ritonavir co-administration is likely to result in increased plasma
concentrations of ergot derivatives and is therefore
contraindicated
(see section 4.3).
GI motility agent
Cisapride
Ritonavir co-administration is likely to result in increased plasma
concentrations of cisapride and is therefore
contraindicated
(see
section 4.3).
HMG Co-A Reductase Inhibitors
Atorvastatin, Fluvastatin, Lovastatin,
Pravstatin, Rosuvastatin, Simvastatin
HMG-CoA reductase inhibitors which are highly dependent on CYP3A
metabolism, such as lovastatin and simvastatin, are expected to have
markedly increased plasma concentrations when co-administered with
ritonavir dosed as an antiretroviral agent or as a pharmacokinetic
enhancer. Since increased concentrations of lovastatin and simvastatin
may predispose patients to myopathies, including rhabdomyolysis, the
combination of these medicinal products with ritonavir is
contraindicated
(see section 4.3). Atorvastatin is less dependent on
CYP3A for metabolism. While rosuvastatin elimination is not
dependent on CYP3A, an elevation of rosuvastatin exposure has been
reported with ritonavir co-administration. The mechanism of this
interaction is not clear, but may be the result of transporter inhibition.
When used with ritonavir dosed as a pharmacokinetic enhancer or as an
antiretroviral agent, the lowest possible doses of atorvastatin or
rosuvastatin should be administered. The metabolism of pravastatin
and fluvastatin is not dependent on CYP3A, and interactions are not
expected with ritonavir. If treatment with an HMG-CoA reductase
inhibitor is indicated, pravastatin or fluvastatin is recommended.
Hormonal contraceptive
Ethinyl estradiol
50 µg, single dose 500 q12h ↓ 40% ↓ 32%
17
Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products
Co-administered Medicinal Products
Dose of Co-
administered
Medicinal
Products (mg)
Dose of
NORVIR
(mg)
Effect on Co-
administered
Medicinal
Products AUC
Effect on Co-
administered
Medicinal
Products C
max
Due to reductions in ethinyl estradiol concentrations, barrier or other
non-hormonal methods of contraception should be considered with
concomitant ritonavir use when dosed as an antiretroviral agent or as a
pharmacokinetic enhancer. Ritonavir is likely to change the uterine
bleeding profile and reduce the effectiveness of estradiol-containing
contraceptives (see section 4.4).
Immunosupressants
Cyclosporine, tacrolimus, everolimus
Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral
agent inhibits CYP3A4 and as a result is expected to increase the
plasma concentrations of cyclosporine, tacrolimus or everolimus.
Careful monitoring of therapeutic and adverse effects is recommended
when these medicines are concomitantly administered with ritonavir.
Phosphodiesterase inhibitors
Sildenafil
100, single dose
500 q12h ↑ 11-fold ↑ 4-fold
Concomitant use of sildenafil for the treatment of erectile dysfunction,
with ritonavir dosed as an antiretroviral agent or as a pharmacokinetic
enhancer should be used with caution and in no instance should
sildenafil doses exceed 25 mg in 48 hours (see also section 4.4).
Concomitant use of sildenafil with ritonavir is
contraindicated
in
pulmonary arterial hypertension patients (see section 4.3).
Tadalafil
20, single dose
200 q12h ↑ 124% ↔
The concomitant use of tadalafil with ritonavir dosed as an
antiretroviral agent or as a pharmacokinetic enhancer should be with
caution at reduced doses of no more than 10 mg tadalafil every 72
hours with increased monitoring for adverse reactions (see section 4.4).
Vardenafil
5, single dose
600 q12h ↑ 49-fold ↑ 13-fold
The concomitant use of vardenafil and ritonavir dosed as an
antiretroviral agent or as a pharmacokinetic enhancer should be with
caution at reduced doses of no more than 2.5 mg every 72 hours with
increased monitoring for adverse reactions (see section 4.4).
18
Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products
Co-administered Medicinal Products
Dose of Co-
administered
Medicinal
Products (mg)
Dose of
NORVIR
(mg)
Effect on Co-
administered
Medicinal
Products AUC
Effect on Co-
administered
Medicinal
Products C
max
Sedatives/hynoptics
Clorazepate, diazepam, estazolam,
flurazepam, oral and parenteral midazolam
and triazolam
Ritonavir co-administration is likely to result in increased plasma
concentrations of clorazepate, diazepam, estazolam and flurazepam and
is therefore
contraindicated
(see section 4.3).
Midazolam is extensively metabolised by CYP3A4. Co-administration
with Norvir may cause a large increase in the concentration of this
benzodiazepine. No medicinal product interaction study has been
performed for the co-administration of Norvir with benzodiazepines.
Based on data for other CYP3A4 inhibitors, plasma concentrations of
midazolam are expected to be significantly higher when midazolam is
given orally. Therefore, Norvir should not be co-administered with
orally administered midazolam (see section 4.3), whereas caution
should be used with co-administration of Norvir and parenteral
midazolam. Data from concomitant use of parenteral midazolam with
other protease inhibitors suggest a possible 3 – 4 fold increase in
midazolam plasma levels. If Norvir is co-administered with parenteral
midazolam, it should be done in an intensive care unit (ICU) or similar
setting which ensures close clinical monitoring and appropriate medical
management in case of respiratory depression and/or prolonged
sedation. Dosage adjustment for midazolam should be considered,
especially if more than a single dose of midazolam is administered.
Triazolam
0.125, single dose 200, 4 doses ↑ > 20 fold ↑ 87%
Ritonavir co-administration is likely to result in increased plasma
concentrations of triazolam and is therefore
contraindicated
(see
section 4.3).
Pethidine
50, oral single
dose
500 q12h ↓ 62%
↓ 59%
Norpethidine metabolite
↑ 47%
↑ 87%
The use of pethidine and ritonavir is
contraindicated
due to the
increased concentrations of the metabolite, norpethidine, which has
both analgesic and CNS stimulant activity. Elevated norpethidine
concentrations may increase the risk of CNS effects (eg, seizures), see
section 4.3.
Alprazolam
1, single dose
200 q12h, 2
days
↑2.5 fold ↔
500 q12h,
10
days
↓ 12% ↓ 16%
Alprazolam metabolism was inhibited following the introduction of
ritonavir. After ritonavir use for 10 days, no inhibitory effect of
ritonavir was observed. Caution is warranted during the first several
days when alprazolam is co-administered with ritonavir dosed as an
antiretroviral agent or as a pharmacokinetic enhancer, before induction
of alprazolam metabolism develops.
Buspirone
Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral
agent inhibits CYP3A and as a result is expected to increase the plasma
concentrations of buspirone. Careful monitoring of therapeutic and
adverse effects is recommended when buspirone concomitantly
administered with ritonavir.
19
Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products
Co-administered Medicinal Products
Dose of Co-
administered
Medicinal
Products (mg)
Dose of
NORVIR
(mg)
Effect on Co-
administered
Medicinal
Products AUC
Effect on Co-
administered
Medicinal
Products C
max
Sleeping agent
Zolpidem
5
200, 4 doses ↑ 28% ↑ 22%
Zolpidem and ritonavir may be co-administered with careful monitoring
for excessive sedative effects.
Smoke cessation
Bupropion
150
100 q12h ↓ 22% ↓ 21%
150
600 q12h ↓ 66% ↓ 62%
Bupropion is primarily metabolised by CYP2B6. Concurrent
administration of bupropion with repeated doses of ritonavir is expected
to decrease bupropion levels. These effects are thought to represent
induction of bupropion metabolism. However, because ritonavir has
also been shown to inhibit CYP2B6 in vitro, the recommended dose of
bupropion should not be exceeded. In contrast to long-term
administration of ritonavir, there was no significant interaction with
bupropion after short-term administration of low doses of ritonavir (200
mg twice daily for 2 days), suggesting reductions in bupropion
concentrations may have onset several days after initiation of ritonavir
co-administration.
Steroids
Fluticasone propionate aqueous nasal spray 200 µg qd
100 q12h ↑ ~350-fold ↑ ~ 25-fold
Systemic corticosteroid effects including Cushing's syndrome and
adrenal suppression (plasma cortisol levels were noted to be decreased
86% in the above study) have been reported in patients receiving
ritonavir and inhaled or intranasal fluticasone propionate; similar
effects could also occur with other corticosteroids metabolised by
CYP3A eg, budesonide. Consequently, concomitant administration of
ritonavir dosed as an antiretroviral agent or as a pharmacokinetic
enhancer 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 (eg, beclomethasone). Moreover, in case of withdrawal of
glucocorticoids progressive dose reduction may be required over a
longer period.
Dexamethasone
Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral
agent inhibits CYP3A and as a result is expected to increase the plasma
concentrations of dexamethasone. Careful monitoring of therapeutic
and adverse effects is recommended when dexamethasone is
concomitantly administered with ritonavir.
Prednisolone
20
200 q12h ↑ 28% ↑ 9%
Careful monitoring of therapeutic and adverse effects is recommended
when prednisolone is concomitantly administered with ritonavir. The
AUC of the metabolite prednisolone increased by 37 and 28% after 4
and 14 days ritonavir, respectively.
ND: Not determined
1.
Based on a parallel group comparison
20
Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products
Co-administered Medicinal Products
Dose of Co-
administered
Medicinal
Products (mg)
Effect on Co-
administered
Medicinal
Products C
max
2.
Sulfamethoxazole was co-administered with trimethoprim.
Dose of
NORVIR
(mg)
Effect on Co-
administered
Medicinal
Products AUC
Cardiac and neurologic events have been reported when ritonavir has been co-administered with
disopyramide, mexiletine or nefazadone. The possibility of medicinal product interaction cannot be
excluded.
In addition to the interactions listed above, as ritonavir is highly protein bound, the possibility of
increased therapeutic and toxic effects due to protein binding displacement of concomitant medicinal
products should be considered.
Ritonavir dosed as a pharmacokinetic enhancer
Important information regarding medicinal product interactions when ritonavir is used a
pharmacokinetic enhancer is also contained in the Summary of Product Characteristics of the co-
administered protease inhibitor.
Proton pump inhibitors and H
2
-receptor antagonists
: proton pump inhibitors and H
2
-receptor
antagonists (e.g. omeprazole or ranitidine) may reduce concentrations for co-administered protease
inhibitors. For specific information regarding the impact of co-administration of acid reducing agents,
refer to the SmPC of the co-administered protease inhibitor. Based on interaction studies with the
ritonavir boosted protease inhibitors (lopinavir/ritonavir, atazanavir), concurrent administration of
omeprazole or ranitidine does not significantly modify ritonavir efficacy as a pharmacokinetic
enhancer despite a slight change of exposure (about 6 - 18%).
A limited number (> 800) of pregnant women were exposed to ritonavir during pregnancy; a very
limited number (< 300) were exposed during the first trimester. These data largely refer to exposures
where ritonavir was used in combination therapy and not at therapeutic ritonavir doses but at lower
doses as a pharmacokinetic enhancer for other PIs. These limited data indicate no increase in the rate
of birth defects compared to rates observed in population-based birth defect surveillance systems.
Animal data have shown reproductive toxicity (see 5.3). The use of Norvir may be considered in
pregnancy only when the benefits outweigh the risk to the foetus.
Ritonavir adversely interacts with oral contraceptives (OCs). Therefore, an alternative, effective and
safe method of contraception should be used during treatment.
It is not known whether this medicine is excreted in human milk. Milk excretion has not been
measured in the animal studies, however a study in rats showed some effects on offspring
development during lactation which are compatible with excretion of ritonavir in milk in that species.
HIV infected women should not breast-feed their infants under any circumstances to avoid
transmission of HIV.
No studies on the effects on the ability to drive and use machines have been performed. As
somnolence and dizziness are known undesirable effects, this should be taken into account when
driving or using machinery.
Norvir oral solution contains alcohol (43%).
21
Ritonavir dosed as a pharmacokinetic enhancer
Adverse reactions associated with the use of ritonavir as a pharmacokinetic enhancer are dependent on
the specific co-administered PI. For information on adverse reactions refer to the SPC of the specific
co-administered PI.
Ritonavir dosed as an antiretroviral agent
In the original clinical studies (Phase II/III), adverse reactions with possible, probable or unknown
relationship to ritonavir were reported in ≥ 2% of 1033 patients.
The following adverse reactions of moderate to severe intensity with possible or probable relationship
to ritonavir have been reported. Within each frequency grouping, undesirable effects are presented in
order of decreasing seriousness: very common (> 1/10); common (> 1/100 to < 1/10); uncommon
(> 1/1000 to < 1/100); rare(> 1/10,000 to < 1/1,000): not known (cannot be estimated from the
available data).
Events noted as having a frequency not known were identified via post-marketing surveillance
Decreased WBC, decreased haemoglobin,
decreased neutrophils, increased eosinophils
Uncommon
Increased WBC, increased neutrophils and
increased prothrombin time
Not known
Thrombocytopenia
Immune system disorders
Common
Allergic reactions including urticaria, mild
skin eruptions, bronchospasm and
angioedema
Rare
Anaphylaxis and Stevens Johnson syndrome
Metabolic and nutritional disorders
Uncommon
Dehydration, diabetes mellitus
Rare
Hyperglycaemia
Not known
Hypertriglyceridaemia,
hypercholesterolaemia, hyperuricaemia
22
Blood and lymphatic system
disorders
Nervous system disorders
Very common
Taste perversion, circumoral and peripheral
paresthesia, headache
Common
Dizziness, paraesthesia, hyperaesthesia,
somnolence, insomnia, anxiety
Not known
Seizure, syncope
Vascular disorders
Common
Vasodilation
Not known
Orthostatic hypotension
Respiratory, thoracic and
mediastinal disorders
Common
Pharyngitis, cough increased
Gastrointestinal disorders
Very common
Abdominal pain, nausea, diarrhoea, vomiting
Common
Dyspepsia, anorexia, local throat irritation,
flatulence, dry mouth, eructation, mouth
ulcer
Hepatobiliary disorders
Uncommon
Hepatitis and jaundice
Skin and subcutaneous tissue
disorders
Common
Rash, pruritus, sweating, lipodystrophy
Musculosketal and connective
tissue disorders
Common
Increased CPK, myalgia
Uncommon
Myositis, rhabdomyolysis
Renal and urinary disorders
Not known
Acute renal failure
Reproductive system and breast
disorders
Not known
Menorrhagia
General disorders and
administration site conditions
Very common
Asthenia
Common
Fever, pain weight loss
Investigations
Common
Increased GGT, increased CPK, increased
triglycerides, increased SGPT, increased
SGOT, increased amylase, increased uric
acid, decreased potassium, decreased free
and total thyroxin
Uncommon
Increased glucose, decreased total calcium,
increased magnesium, increased bilirubin,
increased alkaline phosphatase
Hepatic transaminase elevations exceeding five times the upper limit or normal, clinical hepatitis, and
jaundice have occurred in patients receiving ritonavir alone or in combination with other
antiretrovirals.
Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy)
in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal
and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump).
23
Combination antiretroviral therapy has been associated with metabolic abnormalities such as
hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and
hyperlactataemia (see section 4.4).
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).
Pancreatitis has been observed in patients receiving ritonavir therapy, including those who developed
hypertriglyceridemia. In some cases fatalities have been observed. Patients with advanced HIV
disease may be at risk of elevated triglycerides and pancreatitis (see section 4.4).
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).
Human experience of acute overdose with ritonavir is limited. One patient in clinical trials took
ritonavir 1500 mg/day for two days and reported paraesthesia, which resolved after the dose was
decreased. A case of renal failure with eosinophilia has been reported.
The signs of toxicity observed in animals (mice and rats) included decreased activity, ataxia, dyspnoea
and tremors.
There is no specific antidote for overdose with ritonavir. Treatment of overdose with ritonavir should
consist of general supportive measures including monitoring of vital signs and observation of the
clinical status of the patient. Due to the solubility characteristics and possibility of transintestinal
elimination, it is proposed that management of overdose could entail gastric lavage and administration
of activated charcoal. Since ritonavir is extensively metabolised by the liver and is highly protein
bound, dialysis is unlikely to be beneficial in significant removal of the medicine.
5.1 Pharmacodynamic properties
Pharmaco-therapeutic group: antiviral for systemic use, protease inhibitors ATC code: J05AE03
Ritonavir dosed as a pharmacokinetic enhancer
Pharmacokinetic enhancement by ritonavir is based on ritonavir’s activity as a potent inhibitor of
CYP3A- mediated metabolism. The degree of enhancement is related to the metabolic pathway of the
co-administered protease inhibitor and the impact of the co-administered protease inhibitor on the
metabolism of ritonavir. Maximal inhibition of metabolism of the co-administered protease inhibitor
is generally achieved with ritonavir doses of 100 mg daily to 200 mg twice daily, and is dependent on
the co-administered protease inhibitor. For additional information on the effect of ritonavir on
co-administered protease inhibitor metabolism, see section 4.5 and refer to the Summary of Product
Characteristics of the particular co-administered PIs.
24
Ritonavir dosed as an antiretroviral agent
Ritonavir is an orally active peptidomimetic inhibitor of the HIV-1 and HIV-2 aspartyl proteases.
Inhibition of HIV protease renders the enzyme incapable of processing the
gag-pol
polyprotein
precursor which leads to the production of HIV particles with immature morphology that are unable to
initiate new rounds of infection. Ritonavir has selective affinity for the HIV protease and has little
inhibitory activity against human aspartyl proteases.
Ritonavir was the first protease inhibitor
(approved in 1996) for which efficacy was proven in a study
with clinical endpoints. However, due to ritonavir’s metabolic inhibitory properties
its use as a
pharmacokinetic enhancer of other protease inhibitors is the prevalent use of ritonavir in clinical
practice (see section 4.2).
Effects on the Electrocardiogram
QTcF interval was evaluated in a randomised, placebo and active (moxifloxacin 400 mg once daily)
controlled crossover study in 45 healthy adults, with 10 measurements over 12 hours on Day 3. The
maximum mean (95% upper confidence bound) difference in QTcF from placebo was 5.5 (7.6) for 400
mg twice daily ritonavir. The Day 3 ritonavir exposure was approximately 1.5 fold higher than that
observed with the 600 mg twice daily dose at steady state. No subject experienced an increase in
QTcF of ≥ 60 msec from baseline or a QTcF interval exceeding the potentially clinically relevant
threshold of 500 msec.
Modest prolongation of the PR interval was also noted in subjects receiving ritonavir in the same study
on Day 3. The mean changes from baseline in PR interval ranged from 11.0 to 24.0 msec in the 12
hour interval post dose. Maximum PR interval was 252 msec and no second or third degree heart
block was observed (see section 4.4).
Resistance
Ritonavir-resistant isolates of HIV-1 have been selected
in vitro
and isolated from patients treated with
therapeutic doses of ritonavir.
Reduction in the antiretroviral activity of ritonavir is primarily associated with the protease mutations
V82A/F/T/S and I84V. Accumulation of other mutations in the protease gene (including at positions
20, 33, 36, 46, 54, 71, and 90) can also contribute to ritonavir resistance. In general, as mutations
associated with ritonavir resistance accumulate, susceptibility to select other PIs may decrease due to
cross-resistance. The Summary of Product Characteristics of other protease inhibitors or official
continuous updates should be consulted for specific information regarding protease mutations
associated with reduced response to these agents.
Clinical pharmacodynamic data
The effects of ritonavir (alone or combined with other antiretroviral agents) on biological markers of
disease activity such as CD4 cell count and viral RNA were evaluated in several studies involving
HIV-1 infected patients. The following studies are the most important.
Adult Use
A controlled study completed in 1996 with ritonavir as add-on therapy in HIV-1 infected patients
extensively pre-treated with nucleoside analogues and baseline CD4 cell counts ≤ 100 cells/μl showed
a reduction in mortality and AIDS defining events. The mean average change from baseline over 16
weeks for HIV RNA levels was -0.79 log
10
(maximum mean decrease: 1.29 log
10
) in the ritonavir
group versus-0.01 log
10
in the control group. The most frequently used nucleosides in this study were
zidovudine, stavudine, didanosine and zalcitabine.
25
In a study completed in 1996 recruiting less advanced HIV-1 infected patients (CD4 200-500 cells/μl)
without previous antiretroviral therapy, ritonavir in combination with zidovudine or alone reduced
viral load in plasma and increased CD4 count. The mean average change from baseline over 48 weeks
for HIV RNA levels was -0.88 log
10
in the ritonavir group versus -0.66 log
10
in the ritonavir +
zidovudine group versus -0.42 log
10
in the zidovudine group.
The continuation of ritonavir therapy should be evaluated by viral load because of the possibility of
Paediatric Use
In an open label trial completed in 1998 in HIV infected, clinically stable children there was a
significant difference (p = 0.03) in the detectable RNA levels in favour of a triple regimen (ritonavir,
zidovudine and lamivudine) following 48 weeks treatment.
In a study completed in 2003, 50 HIV-1 infected, protease inhibitor and lamivudine naïve children age
4 weeks to 2 years received ritonavir 350 or 450 mg/m
2
every 12 hours co-administered with
zidovudine 160 mg/m
2
every 8 hours and lamivudine 4 mg/kg every 12 hours. In intent to treat
analyses, 72% and 36% of patients achieved reduction in plasma HIV-1 RNA of ≤ 400 copies/ml at
Week 16 and 104, respectively. Response was similar in both dosing regimens and across patient age.
In a study completed in 2000, 76 HIV-1 infected children aged 6 months to 12 years who were
protease inhibitor naive and naive to lamivudine and/or stavudine received ritonavir 350 or 450 mg/m
2
every 12 hours co-administered with lamivudine and stavudine. In intent to treat analyses, 50% and
57% of patients in the 350 and 450 mg/m
2
dose groups, respectively, achieved reduction in plasma
HIV-1 RNA to ≤ 400 copies/ml at Week 48.
5.2 Pharmacokinetic properties
Absorption
:
There is no parenteral formulation of ritonavir, therefore the extent of absorption and absolute
bioavailability have not been determined. The pharmacokinetics of ritonavir during multiple dose
regimens were studied in non-fasting HIV-infected adult volunteers. Upon multiple dosing, ritonavir
accumulation is slightly less than predicted from a single dose due to a time and dose-related increase
in apparent clearance (Cl/F). Trough concentrations of ritonavir decrease over time, possibly due to
enzyme induction, but appeared to stabilise by the end of 2 weeks. The time to maximum
concentration (T
max
) remained constant at approximately 4 hours with increasing dose. Renal
clearance averaged less than 0.1 l/h and was relatively constant throughout the dosage range.
The pharmacokinetic parameters observed with various dosing schemes of ritonavir alone are shown
in the table below.
Ritonavir Dosing Regimen
100 mg once
daily
100 mg twice
daily
1
200 mg once
daily
200 mg twice
daily
600 mg twice
daily
C
max
(µg/ml)
0.84 ± 0.39
0.89
3.4 ± 1.3
4.5 ± 1.3
11.2 ± 3.6
C
trough
(µg/ml)
0.08 ± 0.04
0.22
0.16 ± 0.10
0.6 ± 0.2
3.7 ± 2.6
AUC
12 or 24
(µg•h/ml)
6.6 ± 2.4
6.2
20.0 ± 5.6
21.92 ± 6.48
77.5 ± 31.5
t
½
(h) ~5 ~5 ~4 ~8 ~3 to 5
Cl/F (L/h)
17.2 ± 6.6
16.1
10.8 ± 3.1 10.0 ± 3.2 8.8 ± 3.2
1
Values expressed as geometric means. Note: ritonavir was dosed after a meal for all listed regimens.
26
Effects of food on oral absorption
:
Ingestion of ritonavir with food results in higher ritonavir exposure than ingestion in the fasted state.
Distribution
:
The apparent volume of distribution (V
B
/F) of ritonavir is approximately 20 - 40 l after a single
600 mg dose. The protein binding of ritonavir in human plasma is approximately 98 - 99% and is
constant over the concentration range of 1.0 – 100 μg /ml. Ritonavir binds to both human alpha 1-acid
glycoprotein (AAG) and human serum albumin (HSA) with comparable affinities.
Tissue distribution studies with
14
C-labelled ritonavir in rats showed the liver, adrenals, pancreas,
kidneys and thyroid to have the highest concentrations of ritonavir. Tissue to plasma ratios of
approximately 1 measured in rat lymph nodes suggests that ritonavir distributes into lymphatic tissues.
Ritonavir penetrates minimally into the brain.
Metabolism
:
Ritonavir was noted to be extensively metabolised by the hepatic cytochrome P450 system, primarily
by the CYP3A isozyme family and to a lesser extent by the CYP2D6 isoform. Animal studies as well
as
in vitro
experiments with human hepatic microsomes indicated that ritonavir primarily underwent
oxidative metabolism. Four ritonavir metabolites have been identified in man. The isopropylthiazole
oxidation metabolite (M-2) is the major metabolite and has antiviral activity similar to that of parent
compound. However, the AUC of the M-2 metabolite was approximately 3% of the AUC of parent
compound.
Low doses of ritonavir have shown profound effects on the pharmacokinetics of other protease
inhibitors (and other products metabolised by CYP3A4) and other protease inhibitors may influence
the pharmacokinetics of ritonavir (see section 4.5).
Elimination
:
Human studies with radiolabelled ritonavir demonstrated that the elimination of ritonavir was
primarily via the hepatobiliary system; approximately 86% of radiolabel was recovered from stool,
part of which is expected to be unabsorbed ritonavir. In these studies renal elimination was not found
to be a major route of elimination of ritonavir. This was consistent with the observations in animal
studies.
Special Populations
: No clinically significant differences in AUC or C
max
were noted between males
and females. Ritonavir pharmacokinetic parameters were not statistically significantly associated with
body weight or lean body mass. Ritonavir plasma exposures in patients 50 – 70 years of age when
dosed 100 mg in combination with lopinavir or at higher doses in the absence of other protease
inhibitors is similar to that observed in younger adults.
Patients with impaired liver function
: After multiple dosing of ritonavir to healthy volunteers (500 mg
twice daily) and subjects with mild to moderate hepatic impairment (Child Pugh Class A and B,
400 mg twice daily) exposure to ritonavir after dose normalisation was not significantly different
between the two groups.
Patients with impaired renal function
: Ritonavir pharmacokinetic parameters have not been studied in
patients with renal impairment. However, since the renal clearance of ritonavir is negligible, no
changes in the total body clearance are expected in patients with renal impairment.
Paediatric Patients
: Ritonavir steady-state pharmacokinetic parameters were evaluated in HIV infected
children above 2 years of age receiving doses ranging from 250 mg/m
²
twice daily to 400 mg/m
²
twice
daily. Ritonavir concentrations obtained after 350 to 400 mg/m
²
twice daily in paediatric patients were
comparable to those obtained in adults receiving 600 mg (approximately 330 mg/m
²
) twice daily.
Across dose groups, ritonavir oral clearance (CL/F/m
2
) was approximately 1.5 to 1.7 times faster in
paediatric patients above 2 years of age than in adult subjects.
27
Ritonavir steady-state pharmacokinetic parameters were evaluated in HIV infected children less than
2 years of age receiving doses ranging from 350 to 450 mg/m² twice daily. Ritonavir concentrations
in this study were highly variable and somewhat lower than those obtained in adults receiving 600 mg
(approximately 330 mg/m²) twice daily. Across dose groups, ritonavir oral clearance (CL/F/m
2
)
declined with age with median values of 9.0 L/h/m
2
in children less than 3 months of age, 7.8 L/h/m
2
in children between 3 and 6 months of age and 4.4 L/h/m
2
in children between 6 and 24 months of age.
5.3 Preclinical safety data
Repeated dose toxicity studies in animals identified major target organs as the liver, retina, thyroid
gland and kidney. Hepatic changes involved hepatocellular, biliary and phagocytic elements and were
accompanied by increases in hepatic enzymes. Hyperplasia of the retinal pigment epithelium (RPE)
and retinal degeneration have been seen in all of the rodent studies conducted with ritonavir, but have
not been seen in dogs. Ultrastructural evidence suggests that these retinal changes may be secondary
to phospholipidosis. However, clinical trials revealed no evidence of medicinal product-induced
ocular changes in humans. All thyroid changes were reversible upon discontinuation of ritonavir.
Clinical investigation in humans has revealed no clinically significant alteration in thyroid function
tests. Renal changes including tubular degeneration, chronic inflammation and proteinurea were noted
in rats and are felt to be attributable to species-specific spontaneous disease. Furthermore, no
clinically significant renal abnormalities were noted in clinical trials.
Developmental toxicity observed in rats (embryolethality, decreased foetal body weight and
ossification delays and visceral changes, including delayed testicular descent) occurred mainly at a
maternally toxic dosage. Developmental toxicity in rabbits (embryolethality, decreased litter size and
decreased foetal weights) occurred at a maternally toxic dosage.
Ritonavir was not found to be mutagenic or clastogenic in a battery of
in vitro
and
in vivo
assays
including the Ames bacterial reverse mutation assay using
S. typhimurium
and
E. coli
, the mouse
lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human
lymphocytes.
Long term carcinogenicity studies of ritonavir in mice and rats revealed tumourigenic potential
specific for these species, but are regarded as of no relevance for humans.
6.1 List of excipients
Norvir oral solution contains:
alcohol,
purified water,
polyoxyl 35 castor oil,
propylene glycol,
anhydrous citric acid,
saccharin sodium,
peppermint oil,
creamy caramel flavour,
sunset yellow E110.
6.2 Incompatibilities
Norvir should not be diluted with water.
28
6.3 Shelf life
6 months
6.4 Special precautions for storage
Store below 25°C and use within the expiry date shown on the bottle. Do not refrigerate or freeze.
Avoid exposure to excessive heat. Keep the bottle tightly closed.
6.5 Nature and contents of container
Norvir oral solution is supplied in amber coloured multiple-dose polyethylene terephthalate (PET)
bottles in a 90 ml size.
Two pack sizes are available for Norvir oral solution:
•
1 bottle of 90 ml (90 ml) plus one 7.5 ml dosing syringe. The 7.5 ml dosing syringe has
graduations from 0.8 ml to 7.5 ml.
•
5 bottles of 90 ml (450 ml) plus a dosage cup. The dosage cup has graduations at 3.75 ml (300 mg
dose), 5 ml (400 mg dose), 6.25 ml (500 mg dose) and 7.5 ml (600 mg dose)
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Shake well before each use. If, after shaking, particles or precipitate can be seen in the solution, the
patient should take the next dose and see their doctor about a fresh supply.
The dosage cup or oral syringe should be cleaned immediately with hot water and dish soap after use.
When cleaned immediately, drug residue is removed. The device
must
be dry prior to use
Abbott Laboratories Limited
Abbott House,
Vanwall Business Park,
Vanwall Road,
Maidenhead,
Berkshire,
SL6 4XE
United Kingdom
8.
EU/1/96/016/001
EU/1/96/016/008
Date of first authorisation: 26 August 1996
Date of latest renewal: 26 August 2006
29
Norvir 100 mg soft capsules
Each soft capsule contains 100 mg ritonavir.
Excipients (per soft capsule):
Alcohol (12%w/w)
Castor Oil Polyoxyl 35
For a full list of excipients, see section 6.1.
Soft
capsule.
The capsule is white with “Abbott A” and the code “DS100” imprinted on the shell in black ink.
4.
Ritonavir is indicated in combination with other antiretroviral agents for the treatment of HIV-1
infected patients (adults and children of 2 years of age and older).
Ritonavir should be administered by physicians who are experienced in the treatment of HIV
infection.
Ritonavir soft capsules are administered orally and should preferably be ingested with food.
Ritonavir dosed as a pharmacokinetic enhancer
When ritonavir is used as a pharmacokinetic enhancer with other protease inhibitors the Summary
of Product Characteristics for the particular protease inhibitor must be consulted.
The following HIV-1 protease inhibitors have been approved for use with ritonavir as a
pharmacokinetic enhancer at the noted doses.
Adult use:
Amprenavir 600 mg twice daily with ritonavir 100 mg twice daily
Atazanavir 300 mg once daily with ritonavir 100 mg once daily
Fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily
Lopinavir co-formulated with ritonavir(lopinavir/ritonavir) 400 mg/100 mg or 800 mg/200
mgSaquinavir 1000 mg twice daily with ritonavir 100 mg twice daily
Tipranavir 500 mg twice daily with ritonavir 200 mg twice daily
Darunavir 600 mg twice daily with ritonavir 100 mg twice daily in antiretroviral treatment
(ART) experienced patients
Darunavir 800mg once daily with ritonavir 100 mg once daily in ART-naïve patients
31
Paediatric use:
Ritonavir is recommended for children 2 years of age and older. For further dosage
recommendations, refer to the product information of other Protease Inhibitors approved for
co-administation with ritonavir. Norvir is not recommended in children below 2 years of age due to
lack of data on safety and efficacy.
Renal impairment:
As ritonavir is primarily metabolised by the liver, ritonavir may be appropriate for
use with caution as a pharmacokinetic enhancer in patients with renal insufficiency depending on the
specific protease inhibitor with which it is co-administered. However, since the renal clearance of
ritonavir is negligible, the decrease in the total body clearance is not expected in patients with renal
impairment. For specific dosing information in patients with renal impairment, refer to the Summary
of Product Characteristics (SPC) of the co-administered protease inhibitor.
Hepatic impairment:
Ritonavir should not be given as a pharmacokinetic enhancer to patients with
decompensated liver disease (see section 4.3). In the absence of pharmacokinetic studies in patients
with stable severe hepatic impairment (Child Pugh Grade C) without decompensation, caution should
be exercised when ritonavir is used as a pharmacokinetic enhancer as increased levels of the co-
administered PI may occur.
Specific recommendations for use of ritonavir as a pharmacokinetic
enhancer in patients with hepatic impairment are dependent on the protease inhibitor with which it is
co-administered. The SPC of the co-administered PI should be reviewed for specific dosing
information in this patient population.
Ritonavir dosed as an antiretroviral agent
Adult use:
The recommended dosage of Norvir soft capsules is 600 mg (6 capsules) twice daily by
mouth.
Gradually increasing the dose of ritonavir when initiating therapy may help to improve tolerance.
Treatment should be initiated at 300 mg (3 capsules) twice daily for a period of three days and
increased by 100 mg (1 capsule) twice daily increments up to 600 mg twice daily over a period of no
longer than 14 days. Patients should not remain on 300 mg twice daily for more than 3 days.
Paediatric use (2 years of age and above):
the recommended dosage of Norvir in children is
350 mg/m
²
by mouth twice daily and should not exceed 600 mg twice daily. Norvir should be started
at 250 mg/m
²
and increased at 2 to 3 day intervals by 50 mg/m
²
twice daily (please refer to the Norvir
80 mg/ml oral solution Summary of Product Characteristics)
For older children it may be feasible to substitute soft capsules for the maintenance dose of the oral
solution.
Dosage conversion from oral solution to soft capsules for children
Oral solution dose Capsule dose
175 mg (2.2 ml) twice daily 200 mg in the morning and 200 mg in the evening
350 mg (4.4 ml) twice daily 400 mg in the morning and 300 mg in the evening
437.5 mg (5.5 ml) twice daily 500 mg in the morning and 400 mg in the evening
525 mg (6.6 ml) twice daily
Norvir is not recommended in children below 2 years of age due to lack of data on safety and afficacy.
Renal impairment:
Currently, there are no data specific to this patient population and therefore
specific dosage recommendations cannot be made. The renal clearance of ritonavir is negligible,
therefore, a decrease in the total body clearance is not expected in patients with renal impairment.
Because ritonavir is highly protein bound it is unlikely that it will be significantly removed by
haemodialysis or peritoneal dialysis.
32
500 mg in the morning and 500 mg in the evening
Hepatic impairment:
Ritonavir
is principally metabolised and eliminated by the liver.
Pharmacokinetic data indicate that no dose adjustment is necessary in patients with mild to moderate
hepatic impairment (see section 5.2). Ritonavir should not be given to patients with severe hepatic
impairment (see section 4.3).
Elderly:
Pharmacokinetic data indicated that no dose adjustment is necessary for elderly patients (see
section 5.2).
Hypersensitivity to the active substance or to any of the excipients.
When ritonavir is used as a pharmacokinetic enhancer of other PIs, consult the Summary of Product
Characteristics of the co-administered protease inhibitor for contraindications.
Ritonavir should not be given as a pharmacokinetic enhancer or as an antiretroviral agent to patients
with decompensated liver disease.
In vitro
and
in vivo
studies have demonstrated that ritonavir is a potent inhibitor of CYP3A- and
CYP2D6- mediated biotransformations. The following medicines are contraindicated when used with
ritonavir and unless otherwise noted, the contraindication is based on the potential for ritonavir to
inhibit metabolism of the co-administered medicinal product, resulting in increased exposure to the
co-administered medicinal product and risk of clinically significant adverse effects.
The enzyme-modulating effect of ritonavir may be dose dependent. For some products,
contraindications may be more relevant when ritonavir is used as an antiretroviral agent than when
ritonavir is used as a pharmacokinetic enhancer (eg rifabutin and voriconazole):
Medicinal Product
Class
Medicinal Products
within Class
Rationale
Concomitant medicinal product levels increased
α
1
-Adrenoreceptor
Antagonist
Alfuzosin
Increased plasma concentrations of alfuzosin
which may lead to severe hypotension (see
section 4.5).
Analgesics
Pethidine, piroxicam,
propoxyphne
Increased plasma concentrations of norpethidine,
piroxicam and propoxyphene. Thereby,
increasing the risk of serious respiratory
depression or haematologic abnormalities, or
other serious adverse effects from these agents.
Antiarrthymics
Amiodarone, bepridil,
encainide, flecanide,
propafenone, quinidine
Increased plasma concentrations of amiodarone,
bepridil, encainide, flecanide, propafenone,
quinidine. Thereby, increasing the risk of
arrhythmias or other serious adverse effects from
these agents.
Antibiotic
Fusidic Acid
Increased plasma concentrations of fusidic acid
and ritonavir.
33
Antifungal
Voriconazole
Concomitant use of ritonavir (400 mg twice daily
and more) and voriconazole is contraindicated
due to a reduction in voriconazole plasma
concentrations and possible loss of effect (see
section 4.5)
Antihistamines
Astemizole, terfenadine Increased plasma concentrations of astemizole
and terfenadine. Thereby, increasing the risk of
serious arrhythmias from these agents.
Antimycobacterial
Rifabutin
Concomitant use of ritonavir dosed as an
antiretroviral agent (600 mg twice daily) and
rifabutin due to an increase of rifabutin serum
concentrations and risk of adverse reactions
including uveitis (see section 4.4).
Recommendations regarding use of ritonavir
dosed as a pharmacokinetic enhancer with
rifabutin are noted in section 4.5
Antipsychotics/
Neuroleptics
Clozapine, pimozide
Increased plasma concentrations of clozapine and
pimozide. Thereby, increasing the risk of serious
haematologic abnormalities, or other serious
adverse effects from these agents.
Ergot Derivatives
Dihydroergotamine,
ergonovine,
ergotamine,
methylergonovine
Increased plasma concentrations of ergot
derivatives leading to acute ergot toxicity,
including vasospasm and ischaemia.
GI motility agent
Cisapride
Increased plasma concentrations of cisapride.
Thereby, increasing the risk of serious
arrhythmias from this agent.
HMG Co-A Reductase
Inhibitor
Lovastatin, simvastatin Increased plasma concentrations of lovastatin and
simvastatin; thereby, increasing the risk of
myopathy including rhabdomyolysis (see section
4.5).
PDE5 inhibitor
Sildenafil
Contraindicated when used for the treatment of
pulmonary arterial hypertension (PAH) only.
Increased plasma concentrations of sildenafil.
Thereby, increasing the potential for sildenafil-
associated adverse events (which include
hypotension and syncope). See section 4.4 and
section 4.5 for coadministration of sildenafil in
patients with erectile dysfunction.
Sedatives/hypnotics
Clorazepate, diazepam,
estazolam, flurazepam,
oral midazolam and
triazolam
Increased plasma concentrations of clorazepate,
diazepam, estazolam, flurazepam, oral midazolam
and triazolam. Thereby, increasing the risk of
extreme sedation and respiratory depression from
these agents. (For caution on parenterally
administered midazolam, see section 4.5.)
34
Ritonavir medicinal product level decreased
Herbal Preparation
St. John’s Wort
Herbal preparations containing St John’s wort
(
Hypericum perforatum)
due to the risk of
decreased plasma concentrations and reduced
clinical effects of ritonavir (see section 4.5).
Ritonavir is not a cure for HIV-1 infection or AIDS. Patients receiving Ritonavir 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 used
.
When ritonavir is used as a pharmacokinetic enhancer with other PIs, full details on the warnings and
precautions relevant to that particular PI should be considered, therefore the Summary of Product
Characteristics for the particular PI must be consulted.
Ritonavir dosed as an antiretroviral agent or as a pharmacokinetic enhancer
Patients with chronic diarrhoea or malabsorption
: Extra monitoring is recommended when diarrhoea
occurs. The relatively high frequency of diarrhoea during treatment with ritonavir may compromise
the absorption and efficacy (due to decreased compliance) of ritonavir or other concurrent medicinal
products. Serious persistent vomiting and/or diarrhoea associated with ritonavir use might also
compromise renal function. It is advisable to monitor renal function in patients with renal function
impairment.
Haemophilia
: there have been reports of increased bleeding, including spontaneous skin haematomas
and haemarthroses, in haemophiliac patients type A and B treated with protease inhibitors. In some
patients additional factor VIII was given. In more than a 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 has not been elucidated.
Haemophiliac patients should therefore be made aware of the possibility of increased bleeding.
Diabetes mellitus and hyperglycaemia
: New onset diabetes mellitus, hyperglycaemia or exacerbation
of existing diabetes mellitus has been reported in patients receiving protease inhibitors. In some of
these the hyperglycaemia was severe and in some cases also associated with ketoacidosis. Many
patients had confounding medical conditions, some of which required therapy with agents that have
been associated with the development of diabetes mellitus or hyperglycaemia.
Lipodystrophy
: Combination antiretroviral therapy has been associated with redistribution of body fat
(lipodystrophy) in HIV patients. The long-term consequences of these events are currently unknown.
Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and PIs
and lipoatrophy and nucleoside reverse transcriptase inhibitors (NRTIs) has been hypothesised. A
higher risk of lipodystrophy has been associated with individual factors such as older age, and with
medicinal product related factors 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 measurement of fasting serum lipids and blood
glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8).
Pancreatitis
: Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal
pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values)
35
suggestive of pancreatitis should occur. Patients who exhibit these signs or symptoms should be
evaluated and Norvir therapy should be discontinued if a diagnosis of pancreatitis is made (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 asymtomatic
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 jiroveci pneumonia. Any inflammatory symptoms should
be evaluated and treatment instituted when necessary.
Liver disease:
Ritonavir should not be given to patients with decompensated liver disease. For
patients with stable severe hepatic impairment (Child Pugh Grade C) without decompensation see
section 4.2. 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 reactions. In case of
concomitant antiviral therapy for hepatitis B or C, please refer to the relevant product information for
these medicinal products.
Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased
frequency of liver function abnormalities during combination antiretroviral therapy and should be
monitored according to standard practice. If there is evidence of worsening liver disease in such
patients, interruption or discontinuation of treatment must be considered.
Renal disease:
Since the renal clearance of ritonavir is negligible, the decrease in the total body
clearance is not expected in patients with renal impairment. For specific dosing information in
patients with renal impairment, refer to the Summary of Product Characteristics (SPC) of the
co-administered protease inhibitor. See also section 4.2.
Ritonavir soft capsules contains castor oil polyoxyl which may cause stomach upset and diarrhoea.
Osteonecrosis:
Although the etiology is considered to be multifactorial (including corticosteroid use,
alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis
have been reported 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.
This medicinal product contains small amounts of ethanol (alcohol), less than 100 mg per maximum
dose of 600 mg.
PR interval prolongation:
ritonavir has been shown to cause modest asymptomatic prolongation of the
PR interval in some healthy adult subjects. Rare reports of 2
nd
or 3
rd
degree atrioventricular block in
patients with underlying structural heart disease and pre-existing conduction system abnormalities or
in patients receiving medicinal products known to prolong the PR interval (such as verapamil or
atazanavir) have been reported in patients receiving ritonavir. Norvir should be used with caution in
such patients (see section 5.1).
36
Interactions with other medicinal products
Ritonavir dosed as an antiretroviral agent
The following Warnings and Precautions should be considered when ritonavir is used as a
antiretroviral agent. When ritonavir is used as a pharmacokinetic enhancer at the 100 mg and 200 mg
level it cannot be assumed that the following warnings and precautions will also apply. When
ritonavir is used as a pharmacokinetic enhancer, full details on the warnings and precautions relevant
to that particular PI must be considered, therefore the Summary of Product Characteristics, section 4.4,
for the particular PI must be consulted to determine if the information below is applicable.
PDE5 inhibitors
: Particular caution should be used when prescribing sildenafil, tadalafil or vardenafil
for the treatment of erectile dysfunction in patients receiving ritonavir. Co-administration of ritonavir
with these medicinal products is expected to substantially increase their concentrations and may result
in associated adverse reactions such as hypotension and prolonged erection (see section 4.5).
Concomitant use of sildenafil with ritonavir is contraindicated in pulmonary arterial hypertension
patients (see section 4.3).
HMG-CoA reductase inhibitors:
The HMG-CoA reductase inhibitors simvastatin and lovastatin are
highly dependent on CYP3A for metabolism, thus concomitant use of ritonavir with simvastatin or
lovastatin is not recommended due to an increased risk of myopathy including rhabdomyolysis.
Caution must also be exercised and reduced doses should be considered if ritonavir is used
concurrently with atorvastatin, which is metabolised to a lesser extent by CYP3A. While rosuvastatin
elimination is not dependent on CYP3A, an elevation of rosuvastatin exposure has been reported with
ritonavir co-administration. The mechanism of this interaction is not clear, but may be the result of
transporter inhibition. When used with ritonavir dosed as a pharmacokinetic enhancer or as an
antiretroviral agent, the lowest doses of atorvastatin or rosuvastatin should be administered. The
metabolism of pravastatin and fluvastatin is not dependent of CYP3A, and interactions are not
expected with ritonavir. If treatment with an HMG-CoA reductase inhibitor is indicated, pravastatin
or fluvastatin is recommended (see section 4.5).
Digoxin
: Particular caution should be used when prescribing ritonavir in patients taking digoxin since
co-administration of ritonavir with digoxin is expected to increase digoxin levels. The increased
digoxin levels may lessen over time (see section 4.5).
In patients who are already taking digoxin when ritonavir is introduced, the digoxin dose should be
reduced to one-half of the patients’ normal dose and patients need to be followed more closely than
usual for several weeks after initiating co-administration of ritonavir and digoxin.
In patients who are already taking ritonavir when digoxin is introduced, digoxin should be introduced
more gradually than usual. Digoxin levels should be monitored more intensively than usual during
this period, with dose adjustments made, as necessary, based on clinical, electrocardiographic and
digoxin level findings.
Ethinyl estradiol
: Barrier or other non-hormonal methods of contraception should be considered when
administering ritonavir at therapeutic or low doses as ritonavir is likely to reduce the effect and change
the uterine bleeding profile when co-administered with estradiol-containing contraceptives.
Glucocorticoids
: Concomitant use of 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).
37
Trazodone
: Particular caution should be used when prescribing ritonavir in patients using trazodone.
Trazodone is a CYP3A4 substrate and co-administration of ritonavir is expected to increase trazodone
levels. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed in single
dose interaction studies in healthy volunteers (see section 4.5)
Ritonavir dosed as a pharmacokinetic enhancer
The interaction profiles of HIV-protease inhibitors, co-administered with low dose ritonavir, are
dependant on the specific co-administered protease inhibitor.
For a description of the mechanisms and potential mechanisms contributing to the interaction profile
of the PIs, see section 4.5. Please also review the Summary of Product Characteristics for the
particular boosted PI.
Saquinavir
: Doses of ritonavir higher than 100 mg twice daily should not be used. Higher doses of
ritonavir have been shown to be associated with an increased incidence of adverse reactions.
Co-administration of saquinavir and ritonavir has led to severe adverse reactions, mainly diabetic
ketoacidosis and liver disorders, especially in patients with pre-existing liver disease.
Saquinavir/ritonavir should not be given together with rifampicin, due to the risk of severe
hepatotoxicity (presenting as increased hepatic transaminases) if the three medicines are given together
(see section 4.5).
Tipranavir:
co-administered with 200 mg of ritonavir has been associated with reports of clinical
hepatitis and hepatic decompensation including some fatalities. Extra vigilance is warranted in
patients with chronic hepatitis B or hepatitis C co-infection, as these patients have an increased risk of
hepatotoxicity.
Doses of ritonavir lower than 200 mg twice daily should not be used as they might alter the efficacy
profile of the combination.
Fosamprenavir
: Co-administration of fosamprenavir with ritonavir in doses greater than 100 mg twice
daily has not been clinically evaluated. The use of higher ritonavir doses might alter the safety profile
of the combination and therefore is not recommended.
Atazanavir
: Co-administration of atazanavir with ritonavir at doses greater than 100 mg once daily has
not been clinically evaluated. The use of higher ritonavir doses may alter the safety profile of
atazanavir (cardiac effects, hyperbilirubinemia) and therefore is not recommended. Only when
atazanavir with ritonavir is co-administered with efavirenz, a dose increase of ritonavir to 200mg once
daily could be considered. In this instance, close clinical monitoring is warranted. Refer to the
Reyataz Summary of Product Characteristics for further details.
Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral agent
Ritonavir has a high affinity for several cytochrome P450 (CYP) isoforms and may inhibit oxidation
with the following ranked order: CYP3A4 > CYP2D6. Co-administration of Norvir and medicinal
products primarily metabolised by CYP3A may result in increased plasma concentrations of the other
medicinal product, which could increase or prolong its therapeutic and adverse effects. For select
medicinal products (eg alprazolam) the inhibitory effects of ritonavir on CYP3A4 may decrease over
time. Ritonavir also has a high affinity for P-glycoprotein and may inhibit this transporter. The
inhibitory effect of ritonavir (with or without other protease inhibitors) on P-gp activity may decrease
over time (eg digoxin and fexofenadine-see table “Ritonavir effects on non-antiretroviral medicinal
products” below). Ritonavir may induce glucuronidation and oxidation by CYP1A2, CYP2C8,
CYP2C9 and CYP2C19 thereby increasing the biotransformation of some medicinal products
38
metabolised by these pathways, and may result in decreased systemic exposure to such medicinal
products, which could decease or shorten their therapeutic effect.
Important information regarding medicinal product interactions when ritonavir is used as a
pharmacokinetic enhancer is also contained in the Summary of Product Characteristics of the
co-administered protease inhibitor.
Medicinal products that affect ritonavir levels
Serum levels of ritonavir can be reduced by concomitant use of herbal preparations containing
St John’s wort (
Hypericum perforatum).
This is due to the induction of medicinal product
metabolising enzymes by St John’s wort. Herbal preparations containing St John’s wort must not be
used in combination with ritonavir. If a patient is already taking St John’s wort, stop St John’s wort
and if possible check viral levels. Ritonavir levels may increase on stopping St John’s wort. The dose
of ritonavir may need adjusting. The inducing effect may persist for at least 2 weeks after cessation of
treatment with St John’s wort (see section 4.3).
Serum levels of ritonavir may be affected by select co-administered medicinal products (eg
delavirdine, efavirenz, phenytoin and rifampicin). These interactions are noted in the medicinal
product interaction tables below.
Medicinal products that are affected by the use of ritonavir
Interactions between ritonavir and protease inhibitors, antiretroviral agents other than protease
inhibitors and other non-antiretroviral medicinal products are listed in the tables below.
Medicinal Product Interactions – Ritonavir with Protease Inhibitors
Co-
administered
Medicinal
Product
Dose of Co-administered
Medicinal Product (mg)
Dose of NORVIR
(mg)
Medicinal
product
Assessed
AUC
C
min
Amprenavir 600 q12h 100 q12h Amprenavir
2
↑ 64% ↑ 5 fold
Ritonavir increases the serum levels of amprenavir as a result of CYP3A4 inhibition. Clinical
trials confirmed the safety and efficacy of 600 mg amprenavir twice daily with ritonavir 100 mg
twice daily. Norvir oral solution should not be co-administered with amprenavir oral solution to
children due to the risk of toxicity from excipients in the two formulations. For further
information, physicians should refer to the Agenerase Summary of Product Characteristics.
Atazanavir 300 q24h 100 q24h Atazanavir ↑ 86% ↑ 11 fold
Atazanavir
1
↑ 2 fold ↑ 3-7 fold
Ritonavir increases the serum levels of atazanavir as a result of CYP3A4 inhibition. Clinical trials
confirmed the safety and efficacy of 300 mg atazanavir once daily with ritonavir 100 mg once
daily in treatment experienced patients. For further information, physicians should refer to the
Reyataz Summary of Product Characteristics.
Darunavir 600, single 100 q12h Darunavir ↑ 14 fold
Ritonavir increases the serum levels of darunavir as a result of CYP3A inhibition. Darunavir must
be given with ritonavir to ensure its therapeutic effect. Ritonavir doses higher than 100 mg twice
daily have not been studied with darunavir. For further information, refer to the Summary of
Product Characteristics for Prezista.
Fosamprenavir 700 q12h
100 q12h
Amprenavir ↑ 2.4 fold ↑ 11 fold
Ritonavir increases the serum levels of amprenavir (from fosamprenavir) as a result of CYP3A4
inhibition. Fosamprenavir must be given with ritonavir to ensure its therapeutic effect. Clinical
trials confirmed the safety and efficacy of fosamprenavir 700 mg twice daily with ritonavir 100
mg twice daily. Ritonavir doses higher than 100 mg twice daily have not been studied with
fosamprenavir. For further information, physicians should refer to the Telzir Summary of Product
Characteristics.
39
Indinavir
800 q12h
100 q12h
Indinavir
3
↑ 178%
ND
Ritonavir ↑ 72%
ND
400 q12h
400 q12h
Indinavir
3
↔ ↑ 4 fold
Ritonavir ↔ ↔
Ritonavir increases the serum levels of indinavir as a result of CYP3A4 inhibition. Appropriate
doses for this combination, with respect to efficacy and safety, have not been established.
Minimal benefit of ritonavir-mediated pharmacokinetic enhancement is achieved with doses higher
than 100 mg twice daily. In cases of co-administration of ritonavir (100 mg twice daily) and
indinavir (800 mg twice daily) caution is warranted as the risk of nephrolithiasis may be increased.
Nelfinavir
1250 q12h
100 q12h
Nelfinavir ↑ 20to39%
ND
750, single
500 q12h
Nelfinavir ↑ 152%
ND
Ritonavir ↔ ↔
Ritonavir increases the serum levels of nelfinavir as a result of CYP3A4 inhibition. Appropriate
doses for this combination, with respect to efficacy and safety, have not been established.
Minimal benefit of ritonavir-mediated pharmacokinetic enhancement is achieved with doses higher
than 100 mg twice daily.
Saquinavir
1000 q12h
100 q12h
Saquinavir
4
↑ 15-fold ↑ 5-fold
Ritonavir ↔ ↔
400 q12h
400 q12h
Saquinavir
4
↑ 17-fold
ND
Ritonavir ↔ ↔
Ritonavir increases the serum levels of saquinavir as a result of CYP3A4 inhibition. Saquinavir
should only be given in combination with ritonavir. Ritonavir100 mg twice daily with saquinavir
1000 mg twice daily provides saquinavir systemic exposure over 24 hours similar to or greater
than those achieved with saquinavir 1200 mg three times daily without ritonavir.
In a clinical study investigating the interaction of rifampicin 600 mg once daily and saquinavir
1000 mg with ritonavir 100 mg twice daily in healthy volunteers, severe hepatocellular toxicity
with transaminase elevations up to > 20-fold the upper limit of normal after 1 to 5 days of
co-administration was noted. Due to the risk of severe hepatoxicity, saquinavir/ritonavir should
not be given together with rifampicin.
For further information, physicians should refer to the Invirase or Fortovase Summary of Product
Characteristics.
Tipranavir
500 q12h
200 q12h
Tipranavir ↑ 11 fold ↑ 29 fold
Ritonavir ↓ 40%
ND
Ritonavir increases the serum levels of tipranavir as a result of CYP3A inhibition. Tipranavir
must be given with low dose ritonavir to ensure its therapeutic effect. Doses of ritonavir less than
200 mg twice daily should not be used with tipranavir as they might alter the efficacy of the
combination. For further information, physicians should refer to the Aptivus Summary of Product
Characteristics.
ND: Not determined.
1. Based on cross-study comparison to 400 mg atazanavir once daily alone.
2. Based on cross-study comparison to 1200 mg amprenavir twice daily alone.
3. Based on cross-study comparison to 800 mg indinavir three times daily alone.
4. Based on cross-stud y comparison to 600 mg saquinavir three times daily alone.
40
Medicinal Product Interactions – Ritonavir with Antiretroviral Agents Other Than Protease
Inhibitors
Co-
administered
Medicinal
Product
Dose of Co-
administered
Medicinal Product
(mg)
Dose of NORVIR
(mg)
Medicinal
Product
Assessed
AUC
C
min
Didanosine
200 q12h
600 q12h 2 h later
Didanosine ↓ 13% ↔
As ritonavir is recommended to be taken with food and didanosine should be taken on an empty
stomach, dosing should be separated by 2.5 h. Dose alterations should not be necessary.
Delavirdine
400 q8h
600 q12h
Delavirdine
1
↔
↔
Ritonavir ↑ 50% ↑ 75%
Based on comparison to historical data, the pharmacokinetics of delavirdine did not appear to be
affected by ritonavir. When used in combination with delavirdine, dose reduction of ritonavir may
be considered.
Efavirenz
600 q24h
500 q12h
Efavirenz ↑ 21%
Ritonavir ↑ 17%
A higher frequency of adverse reactions (eg, dizziness, nausea, paraesthesia) and laboratory
abnormalities (elevated liver enzymes) have been observed when efavirenz is co-administered with
ritonavir dosed as an antiretroviral agent.
Maraviroc
100 q12h
100 q12h
Maraviroc ↑ 161% ↑ 28%
Ritonavir increases the serum levels of maraviroc as a result of CYP3A inhibition. Maraviroc may
be given with ritonavir to increase the maraviroc exposure. For further information, refer to the
Summary of Product Characteristics for Celsentri.
Nevirapine
200 q12h
600 q12h
Nevirapine ↔
↔
Ritonavir ↔
↔
Co-administration of ritonavir with nevirapine does not lead to clinically relevant changes in the
pharmacokinetics of either nevirapine or ritonavir.
Zidovudine
200 q8h
300 q6h
Zidovudine ↓ 25%
ND
Ritonavir may induce the glucuronidation of zidovudine, resulting in slightly decreased levels of
zidovudine. Dose alterations should not be necessary.
ND: Not determined
1. Based on parallel group comparison.
Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products
Co-administered Medicinal Products
Dose of Co-
administered
Medicinal
Products (mg)
Dose of
NORVIR
(mg)
Effect on Co-
administered
Medicinal
Products AUC
Effect on Co-
administered
Medicinal
Products C
max
Alpha
1
-Adrenoreceptor Antagonist
Alfuzosin
Ritonavir co-administration is likely to result in increased plasma
concentrations of alfuzosin and is therefore
contraindicated
(see
section 4.3).
Amphetamine Derivatives
Amphetamine
Ritonavir dosed as an antiretroviral agent is likely to inhibit CYP2D6
and as a result is expected to increase concentrations of amphetamine
and its derivatives. Careful monitoring of therapeutic and adverse
effects is recommended when these medicines are concomitantly
administered with antiretroviral doses of ritonavir (see section 4.4).
41
Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products
Co-administered Medicinal Products
Dose of Co-
administered
Medicinal
Products (mg)
Dose of
NORVIR
(mg)
Effect on Co-
administered
Medicinal
Products AUC
Effect on Co-
administered
Medicinal
Products C
max
Analgesics
Buprenorphine
16 q24h
100 q12h ↑ 57% ↑ 77%
Norbuprenorphine
↑ 33% ↑ 108%
Glucuronide metabolites
↔ ↔
The increases of plasma levels of buprenorphine and its active
metabolite did not lead to clinically significant pharmacodynamic
changes in a population of opioid tolerant patients. Adjustment to the
dose of buprenorphine or ritonavir may therefore not be necessary
when the two are dosed together. When ritonavir is used in
combination with another protease inhibitor and buprenorphine, the
SPC of the co-administered protease inhibitor should be reviewed for
specific dosing information.
Pethidine, piroxicam, propoxyphene
Ritonavir co-administration is likely to result in increased plasma
concentrations of pethidine, piroxicam, and propoxyphene and is
therefore
contraindicated
(see section 4.3).
Fentanyl
Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral
agent inhibits CYP3A4 and as a result is expected to increase the
plasma concentrations of fentanyl. Careful monitoring of therapeutic
and adverse effects is recommended when fentanyl is concomitantly
administered with ritonavir.
Methadone
1
5, single dose
500 q12h, ↓ 36% ↓ 38%
Increased methadone dose may be necessary when concomitantly
administered with ritonavir dosed as an antiretroviral agent or as a
pharmacokinetic enhancer due to induction of glucuronidation. Dose
adjustment should be considered based on the patient’s clinical
response to methadone therapy.
Morphine
Morphine levels may be decreased due to induction of glucuronidation
by co-administered ritonavir dosed as an antiretroviral agent or as a
pharmacokinetic enhancer.
Antiarrthymics
Amiodarone, bepridil, encainide, flecanide,
propafenone, quinidine
Ritonavir co-administration is likely to result in increased plasma
concentrations of amiodarone, bepridil, encainide, flecanide,
propafenone, and quinidine and is therefore
contraindicated
(see
section 4.3).
Digoxin
0.5 single IV dose
300 q12h, 3 days ↑ 86%
ND
0.4 single oral
dose
200 q12h, 13 days ↑ 22% ↔
This interaction may be due to modification of P-glycoprotein mediated
digoxin efflux by ritonavir dosed as an antriretroviral agent or as a
pharmacokinetic enhancer. Increased digoxin levels observed in
patients receiving ritonavir may lessen over time as induction develops
(see section 4.4).
42
Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products
Co-administered Medicinal Products
Dose of Co-
administered
Medicinal
Products (mg)
Dose of
NORVIR
(mg)
Effect on Co-
administered
Medicinal
Products AUC
Effect on Co-
administered
Medicinal
Products C
max
Antiasthmatic
Theophylline
1
3 mg/kg q8h
500 q12h ↓ 43% ↓ 32%
An increased dose of theophyline may be required when co-
administered with ritonavir, due to induction of CYP1A2.
Anticancer agents
Vincristine, vinblastine
Serum concentrations may be increased when co-administered with
ritonavir resulting in the potential for increased incidence of adverse
reactions.
Anticoagulant
Warfarin
S-Warfarin
R-Warfarin
5, single dose
400 q12h
↑ 9%
↓ 33%
↓ 9%
↔
Induction of CYP1A2 and CYP2C9 lead to decreased levels of R-
warfarin while little pharmacokinetic effect is noted on S- warfarin
when co-administered with ritonavir. Decreased R-warfarin levels may
lead to reduced anticoagulation, therefore it is recommended that
anticoagulation parameters are monitored when warfarin is co-
administered with ritonavir dosed as an antiretroviral agent or as a
pharmacokinetic enhancer.
Anticonvulsants
Carbamazepine
Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral
agent inhibits CYP3A4 and as a result is expected to increase the
plasma concentrations of carbamazepine. Careful monitoring of
therapeutic and adverse effects is recommended when carbamazepine is
concomitantly administered with ritonavir.
Divalproex, lamotrigine, phenytoin
Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral
agent induces oxidation by CYP2C9 and glucuronidation and as a result
is expected to decrease the plasma concentrations of anticonvulsants.
Careful monitoring of serum levels or therapeutic effects is
recommended when these medicines are concomitantly administered
with ritonavir. Phenytoin may decrease serum levels of ritonavir.
Antidepressants
Amitriptyline, fluoxetine, imipramine,
nortriptyline, paroxetine, sertraline
Ritonavir dosed as an antiretroviral agent is likely to inhibit CYP2D6
and as a result is expected to increase concentrations of desipramine,
imipramine, amitriptyline, nortriptyline, fluoxetine, paroxetine or
sertraline. Careful monitoring of therapeutic and adverse effects is
recommended when these medicines are concomitantly administered
with antiretroviral doses of ritonavir (see section 4.4).
Desipramine
100, single oral dose 500 q12h ↑ 145% ↑ 22%
43
Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products
Co-administered Medicinal Products
Dose of Co-
administered
Medicinal
Products (mg)
Dose of
NORVIR
(mg)
Effect on Co-
administered
Medicinal
Products AUC
Effect on Co-
administered
Medicinal
Products C
max
The AUC and Cmax of the 2-hydroxy metabolite were decreased 15
and 67%, respectively. Dosage reduction of desipramine is
recommended when co-administered with ritonavir dosed as an
antiretroviral agent.
Trazodone
50, single dose
200 q12h ↑ 2.4-fold ↑ 34%
An increase in the incidence in trazodone-related adverse reactions was
noted when co-administered with ritonavir dosed as an antiretroviral
agent or as a pharmacokinetic enhancer. If trazodone is co-
administered with ritonavir, the combination should be used with
caution, initiating trazodone at the lowest dosage and monitoring for
clinical response and tolerability.
Antihistamines
Astemizole, terfenadine
Ritonavir co-administration is likely to result in increased plasma
concentrations of astemizole and terfenadine and is therefore
contraindicated
(see section 4.3).
Fexofenadine
Ritonavir may modify P-glycoprotein mediated fexofenadine efflux
when dosed as an antriretroviral agent or as a pharmacokinetic enhancer
resulting in increased concentrations of fexofenadine. Increased
fexofenadine levels may lessen over time as induction develops.
Loratadine
Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral
agent inhibits CYP3A and as a result is expected to increase the plasma
concentrations of loratadine. Careful monitoring of therapeutic and
adverse effects is recommended when loratidine is concomitantly
administered with ritonavir.
Anti-infectives
Fusidic Acid
Ritonavir co-administration is likely to result in increased plasma
concentrations of both fusidic acid and ritonavir and is therefore
contraindicated
(see section 4.3).
Rifabutin
1
150 daily
500 q12h, ↑ 4-fold
↑ 2.5-fold
25-
O
-desacetyl rifabutin metabolite
↑ 38-fold
↑ 16-fold
Due to the large increase in rifabutin AUC, the concomitant use of
rifabutin with ritonavir dosed as an antiretroviral agent is
contraindicated
(see section 4.3). The reduction of the rifabutin dose
to 150 mg 3 times per week may be indicated for select PIs when
co-administered with ritonavir as a pharmacokinetic enhancer. The
Summary of Product Characteristics of the co-administered protease
inhibitor should be consulted for specific recommendations.
Consideration should be given to official guidance on the appropriate
treatment of tuberculosis in HIV-infected patients.
Rifampicin
Although rifampicin may induce metabolism of ritonavir, limited data
indicate that when high doses of ritonavir (600 mg twice daily) is
co-administered with rifampicin, the additional inducing effect of
rifampicin (next to that of ritonavir itself) is small and may have no
clinical relevant effect on ritonavir levels in high-dose ritonavir
therapy. The effect of ritonavir on rifampicin is not known.
44
Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products
Co-administered Medicinal Products
Dose of Co-
administered
Medicinal
Products (mg)
Dose of
NORVIR
(mg)
Effect on Co-
administered
Medicinal
Products AUC
Effect on Co-
administered
Medicinal
Products C
max
Voriconazole
200 q12h
400 q12h ↓ 82% ↓ 66%
200 q12h
100 q12h ↓ 39% ↓ 24%
Concomitant use of ritonavir dosed as an antiretroviral agent and
voriconazole is
contraindicated
due to reduction in voriconazole
concentrations (see section 4.3). Co-administration of voriconazole and
ritonavir dosed as a pharmacokinetic enhancer should be avoided,
unless an assessment of the benefit/risk to the patient justifies the use of
voriconazole.
Atovaquone
Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral
agent induces glucuronidation and as a result is expected to decrease
the plasma concentrations of atovaquone. Careful monitoring of serum
levels or therapeutic effects is recommended when atovaquone is
concomitantly administered with ritonavir.
Clarithromycin
500 q12h
200 q8h ↑ 77%
↑ 31%
14-OH clarithromycin metabolite
↓ 100%
↓ 99%
Due to the large therapeutic window of clarithromycin no dose
reduction should be necessary in patients with normal renal function.
Clarithromycin doses greater than 1 g per day should not be co-
administered with ritonavir dosed as an antiretroviral agent or as a
pharmacokinetic enhancer. For patients with renal impairment, a
clarithromycin dose reduction should be considered: for patients with
creatinine clearance of 30 to 60 ml/min the dose should be reduced by
50%, for patients with creatinine clearance less than 30 ml/min the dose
should be reduced by 75%.
Erythromycin, itraconazole
Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral
agent inhibits CYP3A4 and as a result is expected to increase the
plasma concentrations of erythromycin and itraconazole. Careful
monitoring of therapeutic and adverse effects is recommended when
erythromycin or itraconazole is used concomitantly administered with
ritonavir.
Ketoconazole
200 daily
500 q12h ↑ 3.4-fold ↑ 55%
Ritonavir inhibits CYP3A-mediated metabolism of ketoconazole. Due
to an increased incidence of gastrointestinal and hepatic adverse
reactions, a dose reduction of ketoconazole should be considered when
co-administered with ritonavir dosed as an antiretroviral agent or as a
pharmacokinetic enhancer.
Sulfamethoxazole/Trimethoprim
2
800/160, single
dose
500 q12h ↓ 20% / ↑ 20% ↔
Dose alteration of sulfamethoxazole/trimethoprim during concomitant
ritonavir therapy should not be necessary.
Antipsychotics/Neuroleptics
Clozapine, pimozide
Ritonavir co-administration is likely to result in increased plasma
concentrations of clozapine or pimozide and is therefore
contraindicated
(see section 4.3).
45
Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products
Co-administered Medicinal Products
Dose of Co-
administered
Medicinal
Products (mg)
Dose of
NORVIR
(mg)
Effect on Co-
administered
Medicinal
Products AUC
Effect on Co-
administered
Medicinal
Products C
max
Haloperidol, risperidone, thioridazine
Ritonavir dosed as an antiretroviral agent is likely to inhibit CYP2D6
and as a result is expected to increase concentrations of haloperidol,
risperidone and thioridazine. Careful monitoring of therapeutic and
adverse effects is recommended when these medicines are
concomitantly administered with antiretroviral doses of ritonavir (see
section 4.3).
β2-agonist (long acting)
Salmetarol
Ritonavir inhibitsCYP3A4 and as a result a pronounced increase in the
plasma concentrations of salmetarol is expected. Therefore
concomitant use is not recommended.
Calcium channel antagonists
Amlodipine, diltiazem, nifedipine
Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral
agent inhibits CYP3A4 and as a result is expected to increase the
plasma concentrations of calcium channel antagonists. Careful
monitoring of therapeutic and adverse effects is recommended when
these medicines are concomitantly administered with ritonavir.
Ergot Derivatives
Dihydroergotamine, ergonovine,
ergotamine, methylergonovine
Ritonavir co-administration is likely to result in increased plasma
concentrations of ergot derivatives and is therefore
contraindicated
(see section 4.3).
GI motility agent
Cisapride
Ritonavir co-administration is likely to result in increased plasma
concentrations of cisapride and is therefore
contraindicated
(see
section 4.3).
HMG Co-A Reductase Inhibitors
Atorvastatin, Fluvastatin, Lovastatin,
Pravstatin, Rosuvastatin, Simvastatin
HMG-CoA reductase inhibitors which are highly dependent on CYP3A
metabolism, such as lovastatin and simvastatin, are expected to have
markedly increased plasma concentrations when co-administered with
ritonavir dosed as an antiretroviral agent or as a pharmacokinetic
enhancer. Since increased concentrations of lovastatin and simvastatin
may predispose patients to myopathies, including rhabdomyolysis, the
combination of these medicinal products with ritonavir is
contraindicated
(see section 4.3). Atorvastatin is less dependent on
CYP3A for metabolism. While rosuvastatin elimination is not
dependent on CYP3A, an elevation of rosuvastatin exposure has been
reported with ritonavir co-administration. The mechanism of this
interaction is not clear, but may be the result of transporter inhibition.
When used with ritonavir dosed as a pharmacokinetic enhancer or as an
antiretroviral agent, the lowest possible doses of atorvastatin or
rosuvastatin should be administered. The metabolism of pravastatin
and fluvastatin is not dependent on CYP3A, and interactions are not
expected with ritonavir. If treatment with an HMG-CoA reductase
inhibitor is indicated, pravastatin or fluvastatin is recommended.
Hormonal contraceptive
Ethinyl estradiol
50 µg, single dose 500 q12h ↓ 40% ↓ 32%
46
Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products
Co-administered Medicinal Products
Dose of Co-
administered
Medicinal
Products (mg)
Dose of
NORVIR
(mg)
Effect on Co-
administered
Medicinal
Products AUC
Effect on Co-
administered
Medicinal
Products C
max
Due to reductions in ethinyl estradiol concentrations, barrier or other
non-hormonal methods of contraception should be considered with
concomitant ritonavir use when dosed as an antiretroviral agent or as a
pharmacokinetic enhancer. Ritonavir is likely to change the uterine
bleeding profile and reduce the effectiveness of estradiol-containing
contraceptives (see section 4.4).
Immunosupressants
Cyclosporine, tacrolimus, everolimus
Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral
agent inhibits CYP3A4 and as a result is expected to increase the
plasma concentrations of cyclosporine, tacrolimus or everolimus.
Careful monitoring of therapeutic and adverse effects is recommended
when these medicines are concomitantly administered with ritonavir.
Phosphodiesterase inhibitors
Sildenafil
100, single dose
500 q12h ↑ 11-fold ↑ 4-fold
Concomitant use of sildenafil for the treatment of erectile dysfunction,
with ritonavir dosed as an antiretroviral agent or as a pharmacokinetic
enhancer should be with caution and in no instance should sildenafil
doses exceed 25 mg in 48 hours (see also section 4.4). Concomitant use
of sildenafil with ritonavir is
contraindicated
in pulmonary arterial
hypertension patients (see section 4.3).
Tadalafil
20, single dose
200 q12h ↑ 124% ↔
The concomitant use of tadalafil with ritonavir dosed as an
antiretroviral agent or as a pharmacokinetic enhancer should be with
caution at reduced doses of no more than 10 mg tadalafil every 72
hours with increased monitoring for adverse reactions (see section 4.4).
Vardenafil
5, single dose
600 q12h ↑ 49-fold ↑ 13-fold
The concomitant use of vardenafil and ritonavir dosed as an
antiretroviral agent or as a pharmacokinetic enhancer should be with
caution at reduced doses of no more than 2.5 mg every 72 hours with
increased monitoring for adverse reactions (see section 4.4).
47
Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products
Co-administered Medicinal Products
Dose of Co-
administered
Medicinal
Products (mg)
Dose of
NORVIR
(mg)
Effect on Co-
administered
Medicinal
Products AUC
Effect on Co-
administered
Medicinal
Products C
max
Sedatives/hynoptics
Clorazepate, diazepam, estazolam,
flurazepam, oral and parenteral midazolam
and triazolam
Ritonavir co-administration is likely to result in increased plasma
concentrations of clorazepate, diazepam, estazolam and flurazepam and
is therefore
contraindicated
(see section 4.3).
Midazolam is extensively metabolised by CYP3A4. Co-administration
with Norvir may cause a large increase in the concentration of this
benzodiazepine. No medicinal product interaction study has been
performed for the co-administration of Norvir with benzodiazepines.
Based on data for other CYP3A4 inhibitors, plasma concentrations of
midazolam are expected to be significantly higher when midazolam is
given orally. Therefore, Norvir should not be co-administered with
orally administered midazolam (see section 4.3), whereas caution
should be used with co-administration of Norvir and parenteral
midazolam. Data from concomitant use of parenteral midazolam with
other protease inhibitors suggest a possible 3 – 4 fold increase in
midazolam plasma levels. If Norvir is co-administered with parenteral
midazolam, it should be done in an intensive care unit (ICU) or similar
setting which ensures close clinical monitoring and appropriate medical
management in case of respiratory depression and/or prolonged
sedation. Dosage adjustment for midazolam should be considered,
especially if more than a single dose of midazolam is administered.
Triazolam
0.125, single dose 200, 4 doses ↑ > 20 fold ↑ 87%
Ritonavir co-administration is likely to result in increased plasma
concentrations of triazolam and is therefore
contraindicated
(see
section 4.3).
Pethidine
50, oral single
dose
500 q12h ↓ 62%
↓ 59%
Norpethidine metabolite
↑ 47%
↑ 87%
The use of pethidine and ritonavir is
contraindicated
due to the
increased concentrations of the metabolite, norpethidine, which has
both analgesic and CNS stimulant activity. Elevated norpethidine
concentrations may increase the risk of CNS effects (eg, seizures), see
section 4.3.
Alprazolam
1, single dose
200 q12h, 2
days
↑2.5 fold ↔
500 q12h,
10
days
↓ 12% ↓ 16%
Alprazolam metabolism was inhibited following the introduction of
ritonavir. After ritonavir use for 10 days, no inhibitory effect of
ritonavir was observed. Caution is warranted during the first several
days when alprazolam is co-administered with ritonavir dosed as an
antiretroviral agent or as a pharmacokinetic enhancer, before induction
of alprazolam metabolism develops.
Buspirone
Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral
agent inhibits CYP3A and as a result is expected to increase the plasma
concentrations of buspirone. Careful monitoring of therapeutic and
adverse effects is recommended when buspirone concomitantly
administered with ritonavir.
48
Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products
Co-administered Medicinal Products
Dose of Co-
administered
Medicinal
Products (mg)
Dose of
NORVIR
(mg)
Effect on Co-
administered
Medicinal
Products AUC
Effect on Co-
administered
Medicinal
Products C
max
Sleeping agent
Zolpidem
5
200, 4 doses ↑ 28% ↑ 22%
Zolpidem and ritonavir may be co-administered with careful monitoring
for excessive sedative effects.
Smoke cessation
Bupropion
150
100 q12h ↓ 22% ↓ 21%
150
600 q12h ↓ 66% ↓ 62%
Bupropion is primarily metabolised by CYP2B6. Concurrent
administration of bupropion with repeated doses of ritonavir is expected
to decrease bupropion levels. These effects are thought to represent
induction of bupropion metabolism. However, because ritonavir has
also been shown to inhibit CYP2B6 in vitro, the recommended dose of
bupropion should not be exceeded. In contrast to long-term
administration of ritonavir, there was no significant interaction with
bupropion after short-term administration of low doses of ritonavir (200
mg twice daily for 2 days), suggesting reductions in bupropion
concentrations may have onset several days after initiation of ritonavir
co-administration.
Steroids
Fluticasone propionate aqueous nasal spray 200 µg qd
100 q12h ↑ ~350-fold ↑ ~ 25-fold
Systemic corticosteroid effects including Cushing's syndrome and
adrenal suppression (plasma cortisol levels were noted to be decreased
86% in the above study) have been reported in patients receiving
ritonavir and inhaled or intranasal fluticasone propionate; similar
effects could also occur with other corticosteroids metabolised by
CYP3A eg, budesonide. Consequently, concomitant administration of
ritonavir dosed as an antiretroviral agent or as a pharmacokinetic
enhancer 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 (eg, beclomethasone). Moreover, in case of withdrawal of
glucocorticoids progressive dose reduction may be required over a
longer period.
Dexamethasone
Ritonavir dosed as a pharmacokinetic enhancer or as an antiretroviral
agent inhibits CYP3A and as a result is expected to increase the plasma
concentrations of dexamethasone. Careful monitoring of therapeutic
and adverse effects is recommended when dexamethasone is
concomitantly administered with ritonavir.
Prednisolone
20
200 q12h ↑ 28% ↑ 9%
Careful monitoring of therapeutic and adverse effects is recommended
when prednisolone is concomitantly administered with ritonavir. The
AUC of the metabolite prednisolone increased by 37 and 28% after 4
and 14 days ritonavir, respectively.
ND: Not determined
3.
Based on a parallel group comparison
49
Ritonavir effects on Non-antiretroviral Co-administered Medicinal Products
Co-administered Medicinal Products
Effect on Co-
administered
Medicinal
Products C
max
4.
Sulfamethoxazole was co-administered with trimethoprim.
Dose of
NORVIR
(mg)
Effect on Co-
administered
Medicinal
Products AUC
Cardiac and neurologic events have been reported when ritonavir has been co-administered with
disopyramide, mexiletine or nefazadone. The possibility of medicinal product interaction cannot be
excluded.
In addition to the interactions listed above, as ritonavir is highly protein bound, the possibility of
increased therapeutic and toxic effects due to protein binding displacement of concomitant medicinal
products should be considered.
Ritonavir dosed as a pharmacokinetic enhancer
Important information regarding medicinal product interactions when ritonavir is used a
pharmacokinetic enhancer is also contained in the Summary of Product Characteristics of the co-
administered protease inhibitor.
Proton pump inhibitors and H
2
-receptor antagonists
: proton pump inhibitors and H
2
-receptor
antagonists (e.g. omeprazole or ranitidine) may reduce concentrations for co-administered protease
inhibitors. For specific information regarding the impact of co-administration of acid reducing agents,
refer to the SmPC of the co-administered protease inhibitor. Based on interaction studies with the
ritonavir boosted protease inhibitors (lopinavir/ritonavir, atazanavir), concurrent administration of
omeprazole or ranitidine does not significantly modify ritonavir efficacy as a pharmacokinetic
enhancer despite a slight change of exposure (about 6 - 18%).
A limited number (> 800) of pregnant women were exposed to ritonavir during pregnancy; a very
limited number (< 300) were exposed during the first trimester. These data largely refer to exposures
where ritonavir was used in combination therapy and not at therapeutic ritonavir doses but at lower
doses as a pharmacokinetic enhancer for other PIs. These limited data indicate no increase in the rate
of birth defects compared to rates observed in population-based birth defect surveillance systems.
Animal data have shown reproductive toxicity (see 5.3). The use of Norvir may be considered in
pregnancy only when the benefits outweigh the risk to the foetus.
Ritonavir adversely interacts with oral contraceptives (OCs). Therefore, an alternative, effective and
safe method of contraception should be used during treatment.
It is not known whether this medicine is excreted in human milk. Milk excretion has not been
measured in the animal studies, however a study in rats showed some effects on offspring
development during lactation which are compatible with excretion of ritonavir in milk in that species.
HIV infected women should not breast-feed their infants under any circumstances to avoid
transmission of HIV.
50
Dose of Co-
administered
Medicinal
Products (mg)
No studies on the effects on the ability to drive and use machines have been performed. As
somnolence and dizziness are known undesirable effects, this should be taken into account when
driving or using machinery.
Ritonavir dosed as a pharmacokinetic enhancer
Adverse reactions associated with the use of ritonavir as a pharmacokinetic enhancer are dependent on
the specific co-administered PI. For information on adverse reactions refer to the SPC of the specific
co-administered PI.
Ritonavir dosed as an antiretroviral agent
In the original clinical studies (Phase II/III), adverse reactions with possible, probable or unknown
relationship to ritonavir were reported in ≥ 2% of 1033 patients.
The following adverse reactions of moderate to severe intensity with possible or probable relationship
to Ritonavir have been reported. Within each frequency grouping, undesirable effects are presented in
order of decreasing seriousness: very common (> 1/10); common (> 1/100 to < 1/10); uncommon
(> 1/1000 to < 1/100); rare (> 1/10,000 to < 1/1,000); not known (cannot be estimated from the
available data).
Events noted as having frequency not known were identified via post-marketing surveillance.
Decreased WBC, decreased haemoglobin,
decreased neutrophils, increased eosinophils
Uncommon
Increased WBC, increased neutrophils and
increased prothrombin time
Not known
Thrombocytopenia
Immune system disorders
Common
Allergic reactions including urticaria, mild
skin eruptions, bronchospasm and
angioedema
Rare
Anaphylaxis and Stevens Johnson syndrome
Metabolic and nutritional disorders
Uncommon
Dehydration, diabetes mellitus
Rare
Hyperglycaemia
Not known
Hypertriglyceridaemia,
hypercholesterolaemia, hyperuricaemia
Nervous system disorders
Very common
Taste perversion, circumoral and peripheral
paresthesia, headache
Common
Dizziness, paraesthesia, hyperaesthesia,
somnolence, insomnia, anxiety
51
Blood and lymphatic system
disorders
Not known
Seizure, syncope
Vascular disorders
Common
Vasodilation
Not known
Orthostatic hypotension
Respiratory, thoracic and
mediastinal disorders
Common
Pharyngitis, cough increased
Gastrointestinal disorders
Very common
Abdominal pain, nausea, diarrhoea, vomiting
Common
Dyspepsia, anorexia, local throat irritation,
flatulence, dry mouth, eructation, mouth
ulcer
Hepatobiliary disorders
Uncommon
Hepatitis and jaundice
Skin and subcutaneous tissue
disorders
Common
Rash, pruritus, sweating, lipodystrophy
Musculosketal and connective
tissue disorders
Common
Increased CPK, myalgia
Uncommon
Myositis, rhabdomyolysis
Renal and urinary disorders
Not known
Acute renal failure
Reproductive system and breast
disorders
Not known
Menorrhagia
General disorders and
administration site conditions
Very common
Asthenia
Common
Fever, pain weight loss
Investigations
Common
Increased GGT, increased CPK, increased
triglycerides, increased SGPT, increased
SGOT, increased amylase, increased uric
acid, decreased potassium, decreased free
and total thyroxin
Uncommon
Increased glucose, decreased total calcium,
increased magnesium, increased bilirubin,
increased alkaline phosphatase
Hepatic transaminase elevations exceeding five times the upper limit or normal, clinical hepatitis, and
jaundice have occurred in patients receiving ritonavir alone or in combination with other
antiretrovirals.
Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy)
in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal
and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump).
Combination antiretroviral therapy has been associated with metabolic abnormalities such as
hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and
hyperlactataemia (see section 4.4).
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).
52
Pancreatitis has been observed in patients receiving ritonavir therapy, including those who developed
hypertriglyceridemia. In some cases fatalities have been observed. Patients with advanced HIV
disease may be at risk of elevated triglycerides and pancreatitis (see section 4.4).
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).
Human experience of acute overdose with ritonavir is limited. One patient in clinical trials took
ritonavir 1500 mg/day for two days and reported paraesthesia, which resolved after the dose was
decreased. A case of renal failure with eosinophilia has been reported.
The signs of toxicity observed in animals (mice and rats) included decreased activity, ataxia, dyspnoea
and tremors.
There is no specific antidote for overdose with ritonavir. Treatment of overdose with ritonavir should
consist of general supportive measures including monitoring of vital signs and observation of the
clinical status of the patient. Due to the solubility characteristics and possibility of transintestinal
elimination, it is proposed that management of overdose could entail gastric lavage and administration
of activated charcoal. Since ritonavir is extensively metabolised by the liver and is highly protein
bound, dialysis is unlikely to be beneficial in significant removal of the medicine.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: antiviral for systemic use protease inhibitors, ATC code: J05AE03
Ritonavir dosed as a pharmacokinetic enhancer
Pharmacokinetic enhancement by ritonavir is based on ritonavir’s activity as a potent inhibitor of
CYP3A- mediated metabolism. The degree of enhancement is related to the metabolic pathway of the
co-administered protease inhibitor and the impact of the co-administered protease inhibitor on the
metabolism of ritonavir. Maximal inhibition of metabolism of the co-administered protease inhibitor
is generally achieved with ritonavir doses of 100 mg daily to 200 mg twice daily, and is dependent on
the co-administered protease inhibitor. For additional information on the effect of ritonavir on
co-administered protease inhibitor metabolism, see Section 4.5 and refer to the Summary of Product
Characteristics of the particular co-administered PIs.
Ritonavir dosed as an antiretroviral agent
Ritonavir is an orally active peptidomimetic inhibitor of the HIV-1 and HIV-2 aspartyl proteases.
Inhibition of HIV protease renders the enzyme incapable of processing the
gag-pol
polyprotein
precursor which leads to the production of HIV particles with immature morphology that are unable to
initiate new rounds of infection. Ritonavir has selective affinity for the HIV protease and has little
inhibitory activity against human aspartyl proteases.
Ritonavir was the first protease inhibitor
(approved in 1996) for which efficacy was proven in a study
with clinical endpoints. However, due to ritonavir’s metabolic inhibitory properties
its use as a
pharmacokinetic enhancer of other protease inhibitors is the prevalent use of ritonavir in clinical
practice (see section 4.2).
Effects on the Electrocardiogram
53
QTcF interval was evaluated in a randomised, placebo and active (moxifloxacin 400 mg once daily)
controlled crossover study in 45 healthy adults, with 10 measurements over 12 hours on Day 3. The
maximum mean (95% upper confidence bound) difference in QTcF from placebo was 5.5 (7.6) for 400
mg twice daily ritonavir. The Day 3 ritonavir exposure was approximately 1.5 fold higher than that
observed with the 600 mg twice daily dose at steady state. No subject experienced an increase in
QTcF of ≥ 60 msec from baseline or a QTcF interval exceeding the potentially clinically relevant
threshold of 500 msec.
Modest prolongation of the PR interval was also noted in subjects receiving ritonavir in the same study
on Day 3. The mean changes from baseline in PR interval ranged from 11.0 to 24.0 msec in the 12
hour interval post dose. Maximum PR interval was 252 msec and no second or third degree heart
block was observed (see section 4.4).
Resistance
Ritonavir-resistant isolates of HIV-1 have been selected
in vitro
and isolated from patients treated
with therapeutic doses of ritonavir
.
Reduction in the antiretroviral activity of ritonavir is primarily associated with the protease mutations
V82A/F/T/S and I84V. Accumulation of other mutations in the protease gene (including at positions
20, 33, 36, 46, 54, 71, and 90) can also contribute to ritonavir resistance. In general, as mutations
associated with ritonavir resistance accumulate, susceptibility to select other PIs may decrease due to
cross-resistance. The Summary of Product Characteristics of other protease inhibitors or official
continuous updates should be consulted for specific information regarding protease mutations
associated with reduced response to these agents.
Clinical pharmacodynamic data
The effects of ritonavir (alone or combined with other antiretroviral agents) on biological markers of
disease activity such as CD4 cell count and viral RNA were evaluated in several studies involving
HIV-1 infected patients. The following studies are the most important.
Adult Use
A controlled study completed in 1996 with ritonavir as add-on therapy in HIV-1 infected patients
extensively pre-treated with nucleoside analogues and baseline CD4 cell counts ≤ 100 cells/μl showed
a reduction in mortality and AIDS defining events. The mean average change from baseline over 16
weeks for HIV RNA levels was -0.79 log
10
(maximum mean decrease: 1.29 log
10
) in the ritonavir
group versus -0.01 log
10
in the control group. The most frequently used nucleosides in this study were
zidovudine, stavudine, didanosine and zalcitabine.
In a study completed in 1996 recruiting less advanced HIV-1 infected patients (CD4 200-500 cells/μl)
without previous antiretroviral therapy, ritonavir in combination with zidovudine or alone reduced
viral load in plasma and increased CD4 count. The mean average change from baseline over 48 weeks
for HIV RNA levels was -0.88 log
10
in the ritonavir group versus -0.66 log
10
in the ritonavir +
zidovudine group versus -0.42 log
10
in the zidovudine group.
The continuation of ritonavir therapy should be evaluated by viral load because of the possibility of
Paediatric Use
In an open label trial completed in 1998 in HIV infected, clinically stable children there was a
significant difference (p = 0.03) in the detectable RNA levels in favour of a triple regimen (ritonavir,
zidovudine and lamivudine) following 48 weeks treatment.
54
In a study completed in 2003, 50 HIV-1 infected, protease inhibitor and lamivudine naïve children age
4 weeks to 2 years received ritonavir 350 or 450 mg/m
2
every 12 hours co-administered with
zidovudine 160 mg/m
2
every 8 hours and lamivudine 4 mg/kg every 12 hours. In intent to treat
analyses, 72% and 36% of patients achieved reduction in plasma HIV-1 RNA of ≤ 400 copies/ml at
Week 16 and 104, respectively. Response was similar in both dosing regimens and across patient age.
In a study completed in 2000, 76 HIV-1 infected children aged 6 months to 12 years who were
protease inhibitor naive and naive to lamivudine and/or stavudine received ritonavir 350 or 450 mg/m
2
every 12 hours co-administered with lamivudine and stavudine. In intent to treat analyses, 50% and
57% of patients in the 350 and 450 mg/m
2
dose groups, respectively, achieved reduction in plasma
HIV-1 RNA to ≤ 400 copies/ml at Week 48.
5.2 Pharmacokinetic properties
Absorption
:
There is no parenteral formulation of ritonavir, therefore the extent of absorption and absolute
bioavailability have not been determined. The pharmacokinetics of ritonavir during multiple dose
regimens were studied in non-fasting HIV-infected adult volunteers. Upon multiple dosing, ritonavir
accumulation is slightly less than predicted from a single dose due to a time and dose-related increase
in apparent clearance (Cl/F). Trough concentrations of ritonavir decrease over time, possibly due to
enzyme induction, but appeared to stabilise by the end of 2 weeks. The time to maximum
concentration (T
max
) remained constant at approximately 4 hours with increasing dose. Renal
clearance averaged less than 0.1 l/h and was relatively constant throughout the dosage range.
The pharmacokinetic parameters observed with various dosing schemes of ritonavir alone are shown
in the table below.
Ritonavir Dosing Regimen
100 mg once
daily
100 mg twice
daily
1
200 mg once
daily
200 mg twice
daily
600 mg twice
daily
C
max
(µg/ml)
0.84 ± 0.39
0.89
3.4 ± 1.3
4.5 ± 1.3
11.2 ± 3.6
C
trough
(µg/ml) 0.08 ± 0.04
0.22
0.16 ± 0.10
0.6 ± 0.2
3.7 ± 2.6
AUC
12 or 24
(µg•h/ml)
6.6 ± 2.4
6.2
20.0 ± 5.6
21.92 ± 6.48
77.5 ± 31.5
t
½
(h) ~5 ~5 ~4 ~8 ~3 to 5
Cl/F (L/h)
17.2 ± 6.6
16.1
10.8 ± 3.1 10.0 ± 3.2 8.8 ± 3.2
1
Values expressed as geometric means. Note: ritonavir was dosed after a meal for all listed regimens.
Effects of food on oral absorption:
Ingestion of ritonavir with food results in higher ritonavir exposure than ingestion in the fasted state.
Distribution:
The apparent volume of distribution (V
B
/F) of ritonavir is approximately 20 - 40 l after a single
600 mg dose. The protein binding of ritonavir in human plasma is approximately 98 - 99% and is
constant over the concentration range of 1.0 – 100 μg /ml. Ritonavir binds to both human alpha 1-acid
glycoprotein (AAG) and human serum albumin (HSA) with comparable affinities.
Tissue distribution studies with
14
C-labelled ritonavir in rats showed the liver, adrenals, pancreas,
kidneys and thyroid to have the highest concentrations of ritonavir. Tissue to plasma ratios of
approximately 1 measured in rat lymph nodes suggests that ritonavir distributes into lymphatic tissues.
Ritonavir penetrates minimally into the brain.
Metabolism:
Ritonavir was noted to be extensively metabolised by the hepatic cytochrome P450 system, primarily
by the CYP3A isozyme family and to a lesser extent by the CYP2D6 isoform. Animal studies as well
55
as
in vitro
experiments with human hepatic microsomes indicated that ritonavir primarily underwent
oxidative metabolism. Four ritonavir metabolites have been identified in man. The isopropylthiazole
oxidation metabolite (M-2) is the major metabolite and has antiviral activity similar to that of parent
compound However, the AUC of the M-2 metabolite was approximately 3% of the AUC of parent
compound.
Low doses of ritonavir have shown profound effects on the pharmacokinetics of other protease
inhibitors (and other products metabolised by CYP3A4) and other protease inhibitors may influence
the pharmacokinetics of ritonavir (see section 4.5).
Elimination:
Human studies with radiolabelled ritonavir demonstrated that the elimination of ritonavir was
primarily via the hepatobiliary system; approximately 86% of radiolabel was recovered from stool,
part of which is expected to be unabsorbed ritonavir. In these studies renal elimination was not found
to be a major route of elimination of ritonavir. This was consistent with the observations in animal
studies.
Special Populations:
No clinically significant differences in AUC or C
max
were noted between males
and females. Ritonavir pharmacokinetic parameters were not statistically significantly associated with
body weight or lean body mass. Ritonavir plasma exposures in patients 50 – 70 years of age when
dosed 100 mg in combination with lopinavir or at higher doses in the absence of other protease
inhibitors is similar to that observed in younger adults.
Patients with impaired liver function:
After multiple dosing of ritonavir to healthy volunteers (500 mg
twice daily) and subjects with mild to moderate hepatic impairment (Child Pugh Class A and B,
400 mg twice daily) exposure to ritonavir after dose normalisation was not significantly different
between the two groups.
Patients with impaired renal function
: Ritonavir pharmacokinetic parameters have not been studied in
patients with renal impairment. However, since the renal clearance of ritonavir is negligible, no
changes in the total body clearance are expected in patients with renal impairment.
Paediatric patients:
Ritonavir steady-state pharmacokinetic parameters were evaluated in HIV infected
children above 2 years of age receiving doses ranging from 250 mg/m
²
twice daily to 400 mg/m
²
twice
daily. Ritonavir concentrations obtained after 350 to 400 mg/m
²
twice daily in paediatric patients were
comparable to those obtained in adults receiving 600 mg (approximately 330 mg/m
²
) twice daily.
Across dose groups, ritonavir oral clearance (CL/F/m
2
) was approximately 1.5 to 1.7 times faster in
paediatric patients above 2 years of age than in adult subjects.
Ritonavir steady-state pharmacokinetic parameters were evaluated in HIV infected children less than
2 years of age receiving doses ranging from 350 to 450 mg/m² twice daily. Ritonavir concentrations
in this study were highly variable and somewhat lower than those obtained in adults receiving 600 mg
(approximately 330 mg/m²) twice daily. Across dose groups, ritonavir oral clearance (CL/F/m
2
)
declined with age with median values of 9.0 L/h/m
2
in children less than 3 months of age, 7.8 L/h/m
2
in children between 3 and 6 months of age and 4.4 L/h/m
2
in children between 6 and 24 months of age.
5.3 Preclinical safety data
Repeated dose toxicity studies in animals identified major target organs as the liver, retina, thyroid
gland and kidney. Hepatic changes involved hepatocellular, biliary and phagocytic elements and were
accompanied by increases in hepatic enzymes. Hyperplasia of the retinal pigment epithelium (RPE)
and retinal degeneration have been seen in all of the rodent studies conducted with ritonavir, but have
not been seen in dogs. Ultrastructural evidence suggests that these retinal changes may be secondary
to phospholipidosis. However, clinical trials revealed no evidence of medicinal product-induced
ocular changes in humans. All thyroid changes were reversible upon discontinuation of ritonavir.
Clinical investigation in humans has revealed no clinically significant alteration in thyroid function
tests. Renal changes including tubular degeneration, chronic inflammation and proteinurea were noted
56
in rats and are felt to be attributable to species-specific spontaneous disease. Furthermore, no
clinically significant renal abnormalities were noted in clinical trials.
Developmental toxicity observed in rats (embryolethality, decreased foetal body weight and
ossification delays and visceral changes, including delayed testicular descent) occurred mainly at a
maternally toxic dosage. Developmental toxicity in rabbits (embryolethality, decreased litter size and
decreased foetal weights) occurred at a maternally toxic dosage.
Ritonavir was not found to be mutagenic or clastogenic in a battery of
in vitro
and
in vivo
assays
including the Ames bacterial reverse mutation assay using
S. typhimurium
and
E. coli
, the mouse
lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human
lymphocytes.
Long term carcinogenicity studies of ritonavir in mice and rats revealed tumourigenic potential
specific for these species, but are regarded as of no relevance for humans.
6.1 List of excipients
Capsule contents
:
alcohol,
butylated hydroxytoluene (E321),
oleic acid,
polyoxyl 35 castor oil.
Capsule shell
:
gelatine,
“sorbitol special” (ie sorbitol sorbitolanhydrides and mannitol),
glycerine,
titanium dioxide (white colour),
medium chain triglycerides,
lecithin,
black ink containing: propylene glycol, black iron oxide, polyvinyl acetate phthalate, polyethylene
glycol 400 and ammonium hydroxide.
6.2 Incompatibilities
Not applicable
57
6.3 Shelf life
2 years
6.4 Special precautions for storage
Store in a refrigerator (2ºC - 8ºC) until they are dispensed to the patient. Refrigeration by the patient
is not required if used within 30 days and stored below 25°C.
Avoid exposure to freezing and excessive heat. Keep the bottle tightly closed.
6.5 Nature and contents of container
Norvir soft
capsules are supplied in white high density polyethylene (HDPE) bottles closed with
polypropylene caps containing 84 capsules.
Two pack sizes are available for Norvir soft capsules:
−
1 bottle of 84 capsules (84 capsules)
−
4 bottles of 84 capsules (336 capsules)
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements.
Abbott Laboratories Limited
Abbott House,
Vanwall Business Park,
Vanwall Road,
Maidenhead,
Berkshire,
SL6 4XE
United Kingdom
8.
EU/1/96/016/003-004
Date of first authorisation: 26 August 1996
Date of latest renewal: 26 August 2006
58
Marketing Authorisation Holder
Abbott Laboratories Limited
Abbott House,
Vanwall Business Park,
Vanwall Road,
Maidenhead,
Berkshire,
SL6 4XE
United Kingdom
Manufacturers
Abbott GmbH & Co. KG
Knollstrasse
67061 Ludwigshafen
Germany
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
Abbott SA
Tél/Tel: + 32 10 475311
Luxembourg/Luxemburg
Abbott SA
Tél/Tel: + 32 10 475311
България
Т.П. Абот Лабораторис С.А.
Teл.: + 359 2 489 1950
Magyarország
Abbott Laboratories (Magyarország) Kft.
Tel.: +36 1 465 2100
Česká republika
Abbott Laboratories s. r. o.
Tel: + 420 267 292 111
Malta
V.J.Salomone Pharma Limited
Tel: + 356 22983201
Danmark
Abbott Laboratories A/S
Tlf: + 45 39 77-00-00
Nederland
Abbott B.V.
Tel: + 31 (0) 88 8222 688
Deutschland
Abbott GmbH & Co. KG
Tel: + 49 (0) 6122 58-0
Norge
Abbott Norge AS
Tlf: + 47 81 55 99 20
Eesti
Abbott Laboratories Baltics
Tel: + 371 67605580
Österreich
Abbott Ges.m.b.H.
Tel: + 43 1 891-22
Ελλάδα
Abbott Laboratories (ΕΛΛΑΣ) Α.Β.Ε.Ε.
Τηλ: +30 21 0 9985-222
Polska
Abbott Laboratories Poland Sp. z o.o.
tel: +48 22 319 12 00
España
Abbott Laboratories, S.A.
Tel: + 34 9 1 337-5200
Portugal
Abbott Laboratórios, Lda.
Tel: + 351 (0) 21 472 7100
143
France
Abbott France
Tél: + 33 (0) 1 45 60 25 00
România
Abbott Laboratories S.A.
Tel: +40 21 529 30 00
Ireland
Abbott Laboratories, Ireland, Ltd
Tel: + 353 (0) 1 469-1500
Slovenija
Abbott Laboratories d.o.o.
Tel: + 386 (1) 23 631 60
Ísland
Vistor hf.
Sími: +354 535 7000
Slovenská republika
Abbott Laboratories Slovakia s.r.o.
Tel: + 421 (0) 2 4445 4176
Italia
Abbott S.r.l.
Tel: + 39 06 928921
Suomi/Finland
Abbott OY
Puh/Tel: + 358 (0) 9 7518 4120
Κύπρος
Lifepharma (ZAM) Ltd
Τηλ: +357 22 347440
Sverige
Abbott Scandinavia AB
Tel: + 46 (0) 8 5465 67 00
Latvija
Abbott Laboratories Baltics
Tel: + 371 67605580
United Kingdom
Abbott Laboratories Ltd
Tel: + 44 (0) 1628 773355
Lietuva
Abbott Laboratories Baltics
Tel: + 371 67605580
This leaflet was last approved in {MM/YYYY}
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web
site: http://www.emea.europa.eu
144
Source: European Medicines Agency
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