ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
Kaletra 133.3 mg/33.3 mg soft capsules
Each Kaletra soft capsule contains 133.3 mg of lopinavir co-formulated with 33.3 mg of ritonavir as a
pharmacokinetic enhancer.
Excipients:
Each capsule contains 64.1 mg of propylene glycol, 21.4 mg of castor oil polyoxyl 35, 132.2 mg of
anhydrised liquid sorbitol (glycerol blend) and 0.8 mg of sunset yellow (E110, see section 4.4).
For a full list of excipients, see section 6.1.
Soft capsule
The capsules are orange with a black ink imprint of [Abbott logo] and “PK”.
4.
Kaletra is indicated for the treatment of HIV-1 infected adults and children above the age of 2 years, in
combination with other antiretroviral agents.
The choice of Kaletra to treat protease inhibitor experienced HIV-1 infected patients should be based
on individual viral resistance testing and treatment history of patients (see sections 4.4 and 5.1).
Kaletra should be prescribed by physicians who are experienced in the treatment of HIV infection.
Posology
Adult and adolescent use:
the recommended dosage of Kaletra is three capsules twice daily taken with
food. Oral solution is available to patients who have difficulty swallowing.
Paediatric use (2 years of age and above):
the oral solution is the recommended option for the most
accurate dosing in children based on body surface area* (please refer to the Kaletra oral solution
Summary of Product Characteristics). However, if it is judged necessary to resort to soft capsules in
children, they should be used with particular caution since they are associated with less precise dosing
capabilities. Therefore, children receiving soft capsules might have higher exposure (with the risk of
increased toxicity) or sub optimal exposure (with the risk of insufficient efficacy). Consequently
when dosing children with soft capsules, therapeutic drug monitoring may be a useful tool to ensure
appropriate lopinavir exposure in an individual patient.
2
Paediatric dosing guidelines with soft capsules
Body Surface Area* (m
2
)
Twice daily dose
(dose in mg)
0.40 – 0.75
1 soft capsule (133.3/33.3 mg)
0.80 – 1.3
2 soft capsules (266.6/66.6 mg)
1.4 – 1.75
3 soft capsules (400/100 mg)
*
Body surface area can be calculated with the following equation
BSA (m
2
) = √ (Height (cm) X Weight (kg) / 3600)
Children less than 2 years of age
: the safety and efficacy of Kaletra in children aged less than 2 years
have not yet been established. Currently available data are described in section 5.2 but no
recommendation on a posology can be made.
Hepatic impairment
: In HIV-infected patients with mild to moderate hepatic impairment, an increase
of approximately 30% in lopinavir exposure has been observed but is not expected to be of clinical
relevance (see section 5.2). No data are available in patients with severe hepatic impairment. Kaletra
must not be given to these patients (see section 4.3).
Renal impairment
: since the renal clearance of lopinavir and ritonavir is negligible, increased plasma
concentrations are not expected in patients with renal impairment. Because lopinavir and ritonavir are
highly protein bound, it is unlikely that they will be significantly removed by haemodialysis or
peritoneal dialysis.
Method of administration
Kaletra is administered orally and should always be taken with food (see section 5.2).
Hypersensitivity to the active substances or to any of the excipients.
Severe hepatic insufficiency.
Kaletra contains lopinavir and ritonavir, both of which are inhibitors of the P450 isoform CYP3A.
Kaletra should not be co-administered with medicinal products that are highly dependent on CYP3A
for clearance and for which elevated plasma concentrations are associated with serious and/or life
threatening events. These medicinal products include astemizole, terfenadine, oral midazolam (for
caution on parenterally administered midazolam, see section 4.5), triazolam, cisapride, pimozide,
amiodarone, ergot alkaloids (e.g. ergotamine, dihydroergotamine, ergonovine and methylergonovine),
lovastatin, simvastatin, sildenafil used for the treatment of pulmonary arterial hypertension (for the use
of sildenafil in patients with erectile dysfunction, see section 4.5) and vardenafil.
Herbal preparations containing St John’s wort (
Hypericum perforatum)
must not be used while taking
lopinavir and ritonavir due to the risk of decreased plasma concentrations and reduced clinical effects
of lopinavir and ritonavir (see section 4.5).
3
Patients with coexisting conditions
Hepatic impairment
: the safety and efficacy of Kaletra has not been established in patients with
significant underlying liver disorders. Kaletra is contraindicated in patients with severe liver
impairment (see section 4.3). 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 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 should be considered.
Elevated transaminases with or without elevated bilirubin levels have been reported in HIV-1
mono-infected and in individuals treated for post-exposure prophylaxis as early as 7 days after the
initiation of lopinavir/ritonavir in conjunction with other antiretroviral agents. In some cases the
hepatic dysfunction was serious.
Appropriate laboratory testing should be conducted prior to initiating therapy with lopinavir/ritonavir
and close monitoring should be performed during treatment.
Renal impairment
: since the renal clearance of lopinavir and ritonavir is negligible, increased plasma
concentrations are not expected in patients with renal impairment. Because lopinavir and ritonavir are
highly protein bound, it is unlikely that they will be significantly removed by haemodialysis or
peritoneal dialysis.
Haemophilia:
there have been reports of increased bleeding, including spontaneous skin haematomas
and haemarthrosis in patients with haemophilia type A and B treated with protease inhibitors. In some
patients additional factor VIII was given. In more than half of the reported cases, treatment with
protease inhibitors was continued or reintroduced if treatment had been discontinued. A causal
relationship had been evoked, although the mechanism of action had not been elucidated.
Haemophiliac patients should therefore be made aware of the possibility of increased bleeding.
Lipid elevations
Treatment with Kaletra has resulted in increases, sometimes marked, in the concentration of total
cholesterol and triglycerides. Triglyceride and cholesterol testing is to be performed prior to initiating
Kaletra therapy and at periodic intervals during therapy. Particular caution should be paid to patients
with high values at baseline and with history of lipid disorders. Lipid disorders are to be managed as
clinically appropriate (see also section 4.5 for additional information on potential interactions with
HMG-CoA reductase inhibitors).
Pancreatitis
Cases of pancreatitis have been reported in patients receiving Kaletra, including those who developed
hypertriglyceridaemia. In most of these cases patients have had a prior history of pancreatitis and/or
concurrent therapy with other medicinal products associated with pancreatitis. Marked triglyceride
elevation is a risk factor for development of pancreatitis. Patients with advanced HIV disease may be
at risk of elevated triglycerides and pancreatitis
4
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 evaluated and
Kaletra therapy should be suspended if a diagnosis of pancreatitis is made (see section 4.8).
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.
Fat redistribution & metabolic disorders
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 protease
inhibitors (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 drug 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).
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.
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 particularly in patients with advanced HIV-disease and/or long-term exposure to combination
antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience
joint aches and pain, joint stiffness or difficulty in movement.
PR interval prolongation
Lopinavir/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 atroventricular block in patients with
underlying structural heart disease and pre-existing conduction system abnormalities or in patients
receiving drugs known to prolong the PR interval (such as verapamil or atazanavir) have been reported
in patients receiving lopinavir/ritonavir. Kaletra should be used with caution in such patients (see
section 5.1).
5
Interactions with medicinal products
Kaletra contains lopinavir and ritonavir, both of which are inhibitors of the P450 isoform CYP3A.
Kaletra is likely to increase plasma concentrations of medicinal products that are primarily
metabolised by CYP3A. These increases of plasma concentrations of co-administered medicinal
products could increase or prolong their therapeutic effect and adverse events (see sections 4.3 and
4.5).
The combination of Kaletra with atorvastatin is not recommended. If the use of atorvastatin is
considered strictly necessary, the lowest possible dose of atorvastatin should be administered with
careful safety monitoring. Caution must also be exercised and reduced doses should be considered if
Kaletra is used concurrently with rosuvastatin. If treatment with a HMG-CoA reductase inhibitor is
indicated, pravastatin or fluvastatin is recommended (see section 4.5).
PDE5 inhibitors
: particular caution should be used when prescribing sildenafil or tadalafil for the
treatment of erectile dysfunction in patients receiving Kaletra. Co-administration of Kaletra with these
medicinal products is expected to substantially increase their concentrations and may result in
associated adverse events such as hypotension, syncope, visual changes and prolonged erection (see
section 4.5). Concomitant use of vardenafil and lopinavir/ritonavir is contraindicated (see section 4.3).
Concomitant use of sildenafil prescribed for the treatment of pulmonary arterial hypertension with
Kaletra is contraindicated (see section 4.3).
Particular caution must be used when prescribing Kaletra and medicinal products known to induce QT
interval prolongation such as: chlorpheniramine, quinidine, erythromycin, clarithromycin. Indeed,
Kaletra could increase concentrations of the co-administered medicinal products and this may result in
an increase of their associated cardiac adverse reactions. Cardiac events have been reported with
Kaletra in preclinical studies; therefore, the potential cardiac effects of Kaletra cannot be currently
ruled out (see sections 4.8 and 5.3).
Co-administration of Kaletra with rifampicin is not recommended. Rifampicin in combination with
Kaletra causes large decreases in lopinavir concentrations which may in turn significantly decrease the
lopinavir therapeutic effect. Adequate exposure to lopinavir/ritonavir may be achieved when a higher
dose of Kaletra is used but this is associated with a higher risk of liver and gastrointestinal toxicity.
Therefore, this co-administration should be avoided unless judged strictly necessary (see section 4.5).
Concomitant use of Kaletra 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).
Paediatric population
Kaletra is not recommended for use in children less than 2 years of age because of limited efficacy and
safety data.
Other
Kaletra is not a cure for HIV infection or AIDS. There is still a risk of passing HIV to others through
sexual contact or contamination with blood when taking Kaletra. Appropriate precautions should be
taken. People taking Kaletra may still develop infections or other illnesses associated with HIV
disease and AIDS.
Kaletra soft capsules contain sunset yellow [E110] as an excipient, which can cause allergic-type
reaction. Allergy is more common in those people who are allergic to aspirin.
6
Kaletra contains lopinavir and ritonavir, both of which are inhibitors of the P450 isoform CYP3A
in vitro
. Co-administration of Kaletra 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 reactions. Kaletra does not inhibit CYP2D6, CYP2C9, CYP2C19,
CYP2E1, CYP2B6 or CYP1A2 at clinically relevant concentrations (see section 4.3).
Kaletra has been shown
in vivo
to induce its own metabolism and to increase the biotransformation of
some medicinal products metabolised by cytochrome P450 enzymes (including CYP2C9 and
CYP2C19) and by glucuronidation. This may result in lowered plasma concentrations and potential
decrease of efficacy of co-administered medicinal products.
Medicinal products that are contraindicated specifically due to the expected magnitude of interaction
and potential for serious adverse events are listed in section 4.3.
Known and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal
products are listed in the table below.
Interaction table
Interactions between Kaletra and co-administered medicinal products are listed in the table below
(increase is indicated as “↑”, decrease as “↓”, no change as “↔”,once daily as “QD”, twice daily as
“BID” and three times daily as "TID").
Unless otherwise stated, studies detailed below have been performed with the recommended dosage of
lopinavir/ritonavir (i.e. 400/100 mg twice daily).
Co-administered drug
by therapeutic area
Effects on drug levels
Clinical recommendation
concerning co-administration
with Kaletra
Geometric Mean Change (%) in
AUC, C
max
, C
min
Mechanism of interaction
Antiretroviral Agents
Nucleoside/Nucleotide reverse transcriptase inhibitors (NRTIs)
Stavudine, Lamivudine Lopinavir: ↔
No dose adjustment necessary.
Abacavir, Zidovudine
Abacavir, Zidovudine:
Concentrations may be reduced
due to increased glucuronidation
by Kaletra.
The clinical significance of
reduced abacavir and zidovudine
concentrations is unknown.
Tenofovir, 300 mg QD
Tenofovir:
AUC: ↑ 32%
C
max
: ↔
C
min
: ↑ 51%
No dose adjustment necessary.
Higher tenofovir concentrations
could potentiate tenofovir
associated adverse events,
including renal disorders.
Lopinavir: ↔
7
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Efavirenz, 600 mg QD
Lopinavir:
AUC: ↓ 20%
C
max
: ↓ 13%
C
min
: ↓ 42%
The Kaletra tablets dosage should
be increased to 500/125 mg twice
daily when co-administered with
efavirenz.
Efavirenz, 600 mg QD
Lopinavir: ↔
(Relative to 400/100 mg BID
administered alone)
(Lopinavir/ritonavir
500/125 mg BID)
Nevirapine, 200 mg
BID
Lopinavir:
AUC: ↓ 27%
C
max
: ↓ 19%
C
min
: ↓ 51%
The Kaletra tablets dosage should
be increased to 500/125 mg twice
daily when co-administered with
nevirapine.
Co-administration with other HIV protease inhibitors (PIs)
According to current treatment guidelines, dual therapy with protease inhibitors is generally not
recommended.
Fosamprenavir/
ritonavir (700/100 mg
BID)
Fosamprenavir:
Amprenavir concentrations are
significantly reduced.
Co-administration of increased
doses of fosamprenavir (1400 mg
BID) with lopinavir/ritonavir
(533/133 mg BID) to protease
inhibitor-experienced patients
resulted in a higher incidence of
gastrointestinal adverse events
and elevations in triglycerides
with the combination regimen
without increases in virological
efficacy, when compared with
standard doses of
fosamprenavir/ritonavir.
Concomitant administration of
these medicinal products is not
recommended.
(Lopinavir/ritonavir
400/100 mg BID)
or
Fosamprenavir (1400
mg BID)
(Lopinavir/ritonavir
533/133 mg BID)
Indinavir, 600 mg BID
Indinavir:
AUC: ↔
C
min
: ↑ 3.5-fold
C
max
: ↓
(relative to indinavir 800 mg TID
alone)
Lopinavir: ↔
(relative to historical comparison)
The appropriate doses for this
combination, with respect to
efficacy and safety, have not been
established.
Nelfinavir
Lopinavir:
Concentrations ↓
The appropriate doses for this
combination, with respect to
efficacy and safety, have not been
established.
Saquinavir
1000 mg BID
Saquinavir: ↔
No dose adjustment necessary.
Tipranavir/ritonavir
(500/100 mg BID)
Lopinavir:
AUC: ↓ 55%
C
min
: ↓ 47%
C
max
: ↓ 70%
Concomitant administration of
these medicinal products is not
recommended.
8
Acid reducing agents
Omeprazole (40 mg
QD)
Omeprazole: ↔
No dose adjustment necessary
Lopinavir: ↔
Ranitidine (150 mg
single dose)
Ranitidine: ↔
No dose adjustment necessary
Analgesics
Fentanyl
Fentanyl:
Increased risk of side-effects
(respiratory depression, sedation)
due to higher plasma
concentrations because of
CYP3A4 inhibition by Kaletra
Careful monitoring of adverse
effects (notably respiratory
depression but also sedation) is
recommended when fentanyl is
concomitantly administered with
Kaletra.
Antiarrhythmics
Digoxin
Digoxin:
Plasma concentrations may be
increased due to P-glycoprotein
inhibition by Kaletra. The
increased digoxin level may
lessen over time as Pgp induction
develops.
Caution is warranted and
therapeutic drug monitoring of
digoxin concentrations, if
available, is recommended in case
of co-administration of Kaletra
and digoxin. Particular caution
should be used when prescribing
Kaletra in patients taking digoxin
as the acute inhibitory effect of
ritonavir on Pgp is expected to
significantly increase digoxin
levels. Initiation of digoxin in
patients already taking Kaletra is
likely to result in lower than
expected increases of digoxin
concentrations.
Bepridil, Systemic
Lidocaine, and
Quinidine
Bepridil, Systemic Lidocaine,
Quinidine:
Concentrations may be increased
when co-administered with
Kaletra.
Caution is warranted and
therapeutic drug concentration
monitoring is recommended when
available.
Antibiotics
Clarithromycin
Clarithromycin:
Moderate increases in
clarithromycin AUC are expected
due to CYP3A inhibition by
Kaletra.
For patients with renal
impairment (CrCL <30 ml/min)
dose reduction of clarithromycin
should be considered (see section
4.4). Caution should be exercised
in administering clarithromycin
with Kaletra to patients with
impaired hepatic or renal
function.
Anticancer agents
Most tyrosine kinase
inhibitors such as
dasatinib and nilotinib,
Vincristine, Vinblastine
Most tyrosine kinase inhibitors
such as dasatinib and nilotinib,
also vincristine and vinblastine:
Risk of increased adverse events
due to higher serum
concentrations because of
CYP3A4 inhibition by Kaletra.
Careful monitoring of the
tolerance of these anticancer
agents.
9
Anticoagulants
Warfarin
Warfarin:
Concentrations may be affected
when co-administered with
Kaletra due to CYP2C9
induction.
It is recommended that INR
(international normalised ratio) be
monitored.
Anticonvulsants
Phenytoin
Phenytoin:
Steady-state concentrations were
moderately decreased due to
CYP2C9 and CYP2C19 induction
by Kaletra.
Caution should be exercised in
administering phenytoin with
Kaletra.
Phenytoin levels should be
monitored when co-administering
with lopinavir/ritonavir.
Lopinavir:
Concentrations are decreased due
to CYP3A induction by
phenytoin.
When co-administered with
phenytoin, an increase of Kaletra
dosage may be envisaged. Dose
adjustment has not been evaluated
in clinical practice.
Carbamazepine and
Phenobarbital
Carbamazepine:
Serum concentrations may be
increased due to CYP3A
inhibition by Kaletra.
Caution should be exercised in
administering carbamazepine or
phenobarbital with Kaletra.
Carbamazepine and phenobarbital
levels should be monitored when
co-administering with
lopinavir/ritonavir.
Lopinavir:
Concentrations may be decreased
due to CYP3A induction by
carbamazepine and phenobarbital.
When co-administered with
carbamazepine or phenobarbital,
an increase of Kaletra dosage may
be envisaged. Dose adjustment
has not been evaluated in clinical
practice
Antidepressants and Anxiolytics
Trazodone single dose
Trazodone:
AUC: ↑ 2.4-fold
It is unknown whether the
combination of lopinavir/ritonavir
causes a similar increase in
trazodone exposure. The
combination should be used with
caution and a lower dose of
trazodone should be considered.
(Ritonavir, 200 mg
BID)
Adverse events of nausea,
dizziness, hypotension and
syncope were observed following
co-administration of trazodone
and ritonavir.
10
Antifungals
Ketoconazole and
Itraconazole
Ketoconazole, Itraconazole:
Serum concentrations may be
increased due to CYP3A
inhibition by Kaletra.
High doses of ketoconazole and
itraconazole (> 200 mg/day) are
not recommended.
Voriconazole
Voriconazole:
Concentrations may be decreased.
Co-administration of
voriconazole and low dose
ritonavir (100 mg BID) as
contained in Kaletra should be
avoided unless an assessment of
the benefit/risk to patient justifies
the use of voriconazole.
Antimycobacterials
Rifabutin, 150 mg QD
Rifabutin (parent drug and active
25-O-desacetyl metabolite):
AUC: ↑ 5.7-fold
C
max
: ↑ 3.5-fold
On the basis of these data, a
rifabutin dose reduction of 75%
(i.e. 150 mg every other day or 3
times per week) is recommended
when administered with Kaletra.
Further reduction may be
necessary.
Rifampicin
Lopinavir:
Large decreases in lopinavir
concentrations may be observed
due to CYP3A induction by
rifampicin.
Co-administration of Kaletra with
rifampicin is not recommended as
the decrease in lopinavir
concentrations may in turn
significantly decrease the
lopinavir therapeutic effect A
dose adjustment of Kaletra
400 mg/400 mg (i.e. Kaletra
400/100 mg + ritonavir 300 mg)
twice daily has allowed
compensating for the CYP 3A4
inducer effect of rifampicin.
However, such a dose adjustment
might be associated with
ALT/AST elevations and with
increase in gastrointestinal
disorders. Therefore, this
co-administration should be
avoided unless judged strictly
necessary. If this
co-administration is judged
unavoidable, increased dose of
Kaletra at 400 mg/400 mg twice
daily may be administered with
rifampicin under close safety and
therapeutic drug monitoring. The
Kaletra dose should be titrated
upward only after rifampicin has
been initiated (see section 4.4).
11
Benzodiazepines
Midazolam
Oral Midazolam:
AUC: ↑ 13-fold
Parenteral Midazolam:
AUC: ↑ 4-fold
Due to CYP3A inhibition by
Kaletra
Kaletra must not be
co-administered with oral
midazolam (see section 4.3),
whereas caution should be used
with co-administration of Kaletra
and parenteral midazolam. If
Kaletra 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.
Calcium channel blockers
Felodipine, Nifedipine,
and Nicardipine
Felodipine, Nifedipine,
Nicardipine:
Concentrations may be increased
due to CYP3A inhibition by
Kaletra.
Clinical monitoring of therapeutic
and adverse effects is
recommended when these
medicines are concomitantly
administered with Kaletra.
12
Corticosteroids
Dexamethasone
Lopinavir:
Concentrations may be decreased
due to CYP3A induction by
dexamethasone.
Clinical monitoring of antiviral
efficacy is recommended when
these medicines are
concomitantly administered with
Kaletra.
Fluticasone propionate,
50 μg intranasal 4 times
daily
Fluticasone propionate:
Plasma concentrations ↑
Cortisol levels ↓ 86%
Greater effects may be expected
when fluticasone propionate is
inhaled. Systemic corticosteroid
effects including Cushing's
syndrome and adrenal
suppression have been reported in
patients receiving ritonavir and
inhaled or intranasally
administered fluticasone
propionate; this could also occur
with other corticosteroids
metabolised via the P450 3A
pathway eg budesonide.
Consequently, concomitant
administration of Kaletra 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 have to be
performed over a longer period.
(100 mg ritonavir BID)
13
Erectile Dysfunction, Phosphodiesterase(PDE5) inhibitors
Tadalafil
Tadalafil:
AUC: ↑ 2-fold
Due to CYP3A inhibition by
Kaletra.
Particular caution must be used
when prescribing sildenafil or
tadalafil in patients receiving
Kaletra with increased monitoring
for adverse events including
hypotension, syncope, visual
changes and prolonged erection
(see section 4.4).
When co-administered with
Kaletra, sildenafil doses must not
exceed 25 mg in 48 hours and
tadalafil doses must not exceed
10 mg every 72 hours.
Co-administration of Kaletra with
sildenafil used for the treatment
of pulmonary arterial
hypertension is contra-indicated
(see section 4.3).
Sildenafil
Sildenafil:
AUC: ↑ 11-fold
Due to CYP3A inhibition by
Kaletra.
Vardenafil
Vardenafil:
AUC: ↑ 49-fold
Due to CYP3A inhibition by
Kaletra.
The use of vardenafil with Kaletra
is contraindicated (see section
4.3).
Herbal products
St John’s wort
(
Hypericum perforatum)
Lopinavir:
Concentrations may be reduced
due to induction of CYP3A by the
herbal preparation St John’s wort.
Herbal preparations containing St
John’s wort must not be
combined with lopinavir and
ritonavir. If a patient is already
taking St John’s wort, stop
St John’s wort and if possible
check viral levels. Lopinavir and
ritonavir levels may increase on
stopping St John’s wort. The
dose of Kaletra 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).
Therefore, Kaletra can be started
safely 2 weeks after cessation of
St. John's wort.
Immunosuppressants
Cyclosporin, Sirolimus
(rapamycin), and
Tacrolimus
Cyclosporin, Sirolimus
(rapamycin), Tacrolimus:
Concentrations may be increased
due to CYP3A inhibition by
Kaletra.
More frequent therapeutic
concentration monitoring is
recommended until plasma levels
of these products have been
stabilised.
14
Lipid lowering agents
Lovastatin and
Simvastatin
Lovastatin, Simvastatin:
Markedly increased plasma
concentrations due to CYP3A
inhibition by Kaletra.
Since increased concentrations of
HMG-CoA reductase inhibitors
may cause myopathy, including
rhabdomyolysis, the combination
of these agents with Kaletra is
contraindicated (see section 4.3).
Atorvastatin
Atorvastatin:
AUC: ↑ 5.9-fold
C
max
:
↑ 4.7-fold
Due to CYP3A inhibition by
Kaletra.
The combination of Kaletra with
atorvastatin is not recommended.
If the use of atorvastatin is
considered strictly necessary, the
lowest possible dose of
atorvastatin should be
administered with careful safety
monitoring (see section 4.4).
Rosuvastatin, 20 mg QD
Rosuvastatin:
AUC: ↑ 2-fold
C
max
:
↑ 5-fold
While rosuvastatin is poorly
metabolised by CYP3A4, an
increase of its plasma
concentrations was observed. The
mechanism of this interaction
may result from inhibition of
transport proteins.
Caution should be exercised and
reduced doses should be
considered when Kaletra is
co-administered with rosuvastatin
(see section 4.4).
Fluvastatin or
Pravastatin
Fluvastatin, Pravastatin:
No clinical relevant interaction
expected.
Pravastatin is not metabolised by
CYP450.
Fluvastatin is partially
metabolised by CYP2C9.
If treatment with an HMG-CoA
reductase inhibitor is indicated,
fluvastatin or pravastatin is
recommended.
Opioids
Buprenorphine, 16 mg
QD
Buprenorphine: ↔
No dose adjustment necessary.
Methadone
Methadone:
↓
Monitoring plasma concentrations
of methadone is recommended.
Oral Contraceptives
Ethinyl Oestradiol
Ethinyl Oestradiol: ↓
In case of co-administration of
Kaletra with contraceptives
containing ethinyl oestradiol
(whatever the contraceptive
formulation e.g. oral or patch),
additional methods of
contraception must be used.
Smoking cessation aids
Bupropion
Buproprion and its active
metabolite, hydroxybupropion:
AUC and C
max
↓ ~50%
If the co-administration of
lopinavir/ritonavir with bupropion
is judged unavoidable, this should
be done under close clinical
monitoring for bupropion
efficacy, without exceeding the
recommended dosage, despite the
observed induction.
This effect may be due to
induction of bupropion
metabolism.
15
Other medicinal products
Based on known metabolic profiles, clinically significant interactions are not expected between
Kaletra and dapsone, trimethoprim/sulfamethoxazole, azithromycin or fluconazole.
Pregnancy
There are no data from the use of Kaletra in pregnant women. Studies in animals have shown
reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Kaletra should not
be used during pregnancy unless clearly necessary.
Breastfeeding
Studies in rats revealed that lopinavir is excreted in the milk. It is not known whether this medicinal
product is excreted in human milk. HIV infected women must 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. Patients
should be informed that nausea has been reported during treatment with Kaletra (see section 4.8).
a. Summary of the safety profile
The safety of Kaletra has been investigated in over 2,600 patients in Phase II-IV clinical trials, of
which over 700 have received a dose of 800/200 mg (6 capsules or 4 tablets) once daily. Along with
nucleoside reverse transcriptase inhibitors (NRTIs), in some studies, Kaletra was used in combination
with efavirenz or nevirapine.
The most common adverse reactions related to Kaletra therapy during clinical trials were diarrhoea,
nausea, vomiting, hypertriglyceridaemia and hypercholesterolemia. Diarrhoea, nausea and vomiting
may occur at the beginning of the treatment while hypertriglyceridaemia and hypercholesterolemia
may occur later. Treatment emergent adverse events led to premature study discontinuation for 7% of
subjects from Phase II-IV studies.
It is important to note that cases of pancreatitis have been reported in patients receiving Kaletra,
including those who developed hypertriglyceridaemia. Furthermore, rare increases in PR interval have
been reported during Kaletra therapy (see section 4.4).
b. Tabulated list of adverse reactions
Adverse reactions from clinical trials and post-marketing experience in adult and paediatric patients:
The following events have been identified as adverse reactions. The frequency category includes all
reported events of moderate to severe intensity, regardless of the individual causality assessment. The
adverse reactions are displayed by system organ class. 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) and not known (cannot be estimated from the available
data).
Events noted as having frequency “Not known” were identified via post-marketing surveillance.
16
System organ class
Frequency Adverse reaction
Very Common Upper respiratory tract infection
Infections and infestations
Common
Lower respiratory tract infection, skin infections
including cellulitis, folliculitis and furuncle
Blood and lymphatic system
disorders
Common
Anaemia, leucopenia, neutropenia,
lymphadenopathy
Immune system disorders
Common
Hypersensitivity including urticaria and
angioedema
Uncommon
Immune reconstitution syndrome
Endocrine disorders
Uncommon
Hypogonadism
Metabolism and nutrition
disorders
Common
Blood glucose disorders including diabetes
mellitus, hypertriglyceridaemia,
hypercholesterolemia, weight decreased,
decreased appetite
Uncommon
Weight increased, increased appetite
Psychiatric disorders
Common
Anxiety
Uncommon
Abnormal dreams, libido decreased
Nervous system disorders
Common
Headache (including migraine), neuropathy
(including peripheral neuropathy), dizziness,
insomnia
Uncommon
Cerebrovascular accident, convulsion,
dysgeusia, ageusia, tremor
Eye disorders
Uncommon
Visual impairment
Ear and labyrinth disorders
Uncommon
Tinnitus, vertigo
Cardiac disorders
Uncommon
Atherosclerosis such as myocardial infarction ,
atrioventricular block, tricuspid valve
incompetence
Vascular disorders
Common
Hypertension
Uncommon
Deep vein thrombosis
Gastrointestinal disorders
Very common
Diarrhoea, nausea
Common
Pancreatitis
1
, vomiting, gastrooesophageal
reflux disease, gastroenteritis and colitis,
abdominal pain (upper and lower), abdominal
distension, dyspepsia, haemorrhoids, flatulence
Uncommon
Gastrointestinal haemorrhage including
gastrointestinal ulcer, duodenitis, gastritis and
rectal haemorrhage, stomatitis and oral ulcers,
faecal incontinence, constipation, dry mouth
17
Hepatobiliary disorders
Common
Hepatitis including AST, ALT and GGT
increases
Uncommon
Hepatic steatosis, hepatomegaly, cholangitis,
hyperbilirubinemia
Not known
Jaundice
Skin and subcutaneous tissue
disorders
Common
Lipodystrophy acquired, including facial
wasting, rash including maculopapular rash,
dermatitis/rash including eczema and seborrheic
dermatitis, night sweats, pruritis
Uncommon
Alopecia, capillaritis, vasculitis
Not known
Stevens-Johnson syndrome, erythema
multiforme
Musculoskeletal and connective
tissue disorders
Common
Myalgia, musculoskeletal pain including
arthralgia and back pain, muscle disorders such
as weakness and spasms
Uncommon
Rhabdomyolysis, osteonecrosis
Renal and urinary disorders
Uncommon
Creatinine clearance decreased, nephritis,
haematuria
Reproductive system and breast
disorders
Common
Erectile dysfunction, menstrual disorders -
amenorrhoea, menorrhagia
General disorders and
administration site conditions
Common
Fatigue including asthenia
1
See Section 4.4 pancreatitis and lipids
c. Description of selected adverse reactions
Cushing’s syndrome has been reported in patients receiving ritonavir and inhaled or intranasally
administered fluticasone propionate; this could also occur with other corticosteroids metabolised via
the P450 3A pathway e.g. budesonide (see section 4.4 and 4.5).
Increased creatine phosphokinase (CPK), myalgia, myositis, and rarely, rhabdomyolysis have been
reported with protease inhibitors, particularly in combination with nucleoside reverse transcriptase
inhibitors.
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).
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).
18
d. Paediatric populations
In children 2 years of age and older, the nature of the safety profile is similar to that seen in adults (see
Table in section b).
To date, there is limited human experience of acute overdose with Kaletra.
The adverse clinical signs observed in dogs included salivation, emesis and diarrhoea/abnormal stool.
The signs of toxicity observed in mice, rats or dogs included decreased activity, ataxia, emaciation,
dehydration and tremors.
There is no specific antidote for overdose with Kaletra. Treatment of overdose with Kaletra is to
consist of general supportive measures including monitoring of vital signs and observation of the
clinical status of the patient. If indicated, elimination of unabsorbed active substance is to be achieved
by emesis or gastric lavage. Administration of activated charcoal may also be used to aid in removal
of unabsorbed active substance. Since Kaletra is highly protein bound, dialysis is unlikely to be
beneficial in significant removal of the active substance.
5.1 Pharmacodynamic properties
Pharmaco-therapeutic group: antivirals for systemic use, protease inhibitors, ATC code: J05AE06
Mechanism of action
: Lopinavir provides the antiviral activity of Kaletra. Lopinavir is an inhibitor of
the HIV-1 and HIV-2 proteases. Inhibition of HIV protease prevents cleavage of the
gag-pol
polyprotein resulting in the production of immature, non-infectious virus.
Effects on the electrocardiogram
:
QTcF interval was evaluated in a randomised, placebo and active
(moxifloxacin 400 mg once daily) controlled crossover study in 39 healthy adults, with 10
measurements over 12 hours on Day 3. The maximum mean (95% upper confidence bound)
differences in QTcF from placebo were 3.6 (6.3) and 13.1(15.8) for 400/100 mg twice daily and
supratherapeutic 800/200 mg twice daily LPV/r, respectively. The induced QRS interval prolongation
from 6 ms to 9.5 ms with high dose lopinavir/ritonavir (800/200 mg twice daily) contributes to QT
prolongation. The two regimens resulted in exposures on Day 3 which were approximately 1.5 and
3-fold higher than those observed with recommended once daily or twice daily LPV/r doses 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 lopinavir/ritonavir in the
same study on Day 3. The mean changes from baseline in PR interval ranged from 11.6 ms to 24.4 ms
in the 12 hour interval post dose.
Maximum PR interval was 286 msec and no second or third degree
heart block was observed (see section 4.4).
Antiviral activity in vitro
: the
in vitro
antiviral activity of lopinavir against laboratory and clinical HIV
strains was evaluated in acutely infected lymphoblastic cell lines and peripheral blood lymphocytes,
respectively. In the absence of human serum, the mean IC
50
of lopinavir against five different HIV-1
laboratory strains was 19 nM. In the absence and presence of 50% human serum, the mean IC
50
of
lopinavir against HIV-1
IIIB
in MT4 cells was 17 nM and 102 nM, respectively. In the absence of
human serum, the mean IC
50
of lopinavir was 6.5 nM against several HIV-1 clinical isolates.
19
Resistance
In vitro selection of resistance:
HIV-1 isolates with reduced susceptibility to lopinavir have been selected
in vitro
. HIV-1 has been
passaged
in vitro
with lopinavir alone and with lopinavir plus ritonavir at concentration ratios
representing the range of plasma concentration ratios observed during Kaletra therapy. Genotypic and
phenotypic analysis of viruses selected in these passages suggest that the presence of ritonavir, at these
concentration ratios, does not measurably influence the selection of lopinavir-resistant viruses.
Overall, the
in vitro
characterisation of phenotypic cross-resistance between lopinavir and other
protease inhibitors suggest that decreased susceptibility to lopinavir correlated closely with decreased
susceptibility to ritonavir and indinavir, but did not correlate closely with decreased susceptibility to
amprenavir, saquinavir, and nelfinavir.
Analysis of resistance in ARV-naïve patients:
In clinical studies with a limited number of isolates analysed, the selection of resistance to lopinavir
has not been observed in naïve patients without significant protease inhibitor resistance at baseline.
See further the detailed description of the clinical studies.
Analysis of resistance in PI-experienced patients:
The selection of resistance to lopinavir in patients having failed prior protease inhibitor therapy was
characterised by analysing the longitudinal isolates from 19 protease inhibitor-experienced subjects in
2 Phase II and one Phase III studies who either experienced incomplete virologic suppression or viral
rebound subsequent to initial response to Kaletra and who demonstrated incremental
in vitro
resistance
between baseline and rebound (defined as emergence of new mutations or 2-fold change in phenotypic
susceptibility to lopinavir). Incremental resistance was most common in subjects whose baseline
isolates had several protease inhibitor-associated mutations, but < 40-fold reduced susceptibility to
lopinavir at baseline. Mutations V82A, I54V and M46I emerged most frequently. Mutations L33F,
I50V and V32I combined with I47V/A were also observed. The 19 isolates demonstrated a 4.3-fold
increase in IC
50
compared to baseline isolates (from 6.2- to 43-fold, compared to wild-type virus).
Genotypic correlates of reduced phenotypic susceptibility to lopinavir in viruses selected by other
protease inhibitors. The
in vitro
antiviral activity of lopinavir against 112 clinical isolates taken from
patients failing therapy with one or more protease inhibitors was assessed. Within this panel, the
following mutations in HIV protease were associated with reduced
in vitro
susceptibility to lopinavir:
L10F/I/R/V, K20M/R, L24I, M46I/L, F53L, I54L/T/V, L63P, A71I/L/T/V, V82A/F/T, I84V and
L90M. The median EC
50
of lopinavir against isolates with 0 − 3, 4 − 5, 6 − 7 and 8 − 10 mutations at
the above amino acid positions was 0.8, 2.7 13.5 and 44.0-fold higher than the EC
50
against wild type
HIV, respectively. The 16 viruses that displayed > 20-fold change in susceptibility all contained
mutations at positions 10, 54, 63 plus 82 and/or 84. In addition, they contained a median of 3
mutations at amino acid positions 20, 24, 46, 53, 71 and 90. In addition to the mutations described
above, mutations V32I and I47A have been observed in rebound isolates with reduced lopinavir
susceptibility from protease inhibitor experienced patients receiving Kaletra therapy, and mutations
I47A and L76V have been observed in rebound isolates with reduced lopinavir susceptibility from
patients receiving Kaletra therapy.
Conclusions regarding the relevance of particular mutations or mutational patterns are subject to
change with additional data, and it is recommended to always consult current interpretation systems
for analysing resistance test results.
Antiviral activity of Kaletra in patients failing protease inhibitor therapy:
the clinical relevance of
reduced
in vitro
susceptibility to lopinavir has been examined by assessing the virologic response to
Kaletra therapy, with respect to baseline viral genotype and phenotype, in 56 patients previous failing
therapy with multiple protease inhibitors. The EC
50
of lopinavir against the 56 baseline viral isolates
ranged from 0.6 to 96-fold higher than the EC
50
against wild type HIV. After 48 weeks of treatment
with Kaletra, efavirenz and nucleoside reverse transcriptase inhibitors, plasma HIV RNA
20
≤ 400 copies/ml was observed in 93% (25/27), 73% (11/15), and 25% (2/8) of patients with < 10-fold,
10 to 40-fold, and > 40-fold reduced susceptibility to lopinavir at baseline, respectively. In addition,
virologic response was observed in 91% (21/23), 71% (15/21) and 33% (2/6) patients with 0 − 5,
6 − 7, and 8 − 10 mutations of the above mutations in HIV protease associated with reduced
in vitro
susceptibility to lopinavir. Since these patients had not previously been exposed to either Kaletra or
efavirenz, part of the response may be attributed to the antiviral activity of efavirenz, particularly in
patients harbouring highly lopinavir resistant virus. The study did not contain a control arm of
patients not receiving Kaletra.
Cross-resistance
: Activity of other protease inhibitors against isolates that developed incremental
resistance to lopinavir after Kaletra therapy in protease inhibitor experienced patients: The presence of
cross resistance to other protease inhibitors was analysed in 18 rebound isolates that had demonstrated
evolution of resistance to lopinavir during 3 Phase II and one Phase III studies of Kaletra in protease
inhibitor-experienced patients. The median fold IC
50
of lopinavir for these 18 isolates at baseline and
rebound was 6.9- and 63-fold, respectively, compared to wild type virus. In general, rebound isolates
either retained (if cross-resistant at baseline) or developed significant cross-resistance to indinavir,
saquinavir and atazanavir. Modest decreases in amprenavir activity were noted with a median
increase of IC
50
from 3.7- to 8-fold in the baseline and rebound isolates, respectively. Isolates retained
susceptibility to tipranavir with a median increase of IC
50
in baseline and rebound isolates of 1.9- and
1.8–fold, respectively, compared to wild type virus. Please refer to the Aptivus Summary of Product
Characteristics for additional information on the use of tipranavir, including genotypic predictors of
response, in treatment of lopinavir-resistant HIV-1 infection.
Clinical results
The effects of Kaletra (in combination with other antiretroviral agents) on biological markers (plasma
HIV RNA levels and CD4+ T-cell counts) have been investigated in controlled studies of Kaletra of
48 to 360 weeks duration.
Adult Use
Patients without prior antiretroviral therapy
Study M98-863 was a randomised, double-blind trial of 653 antiretroviral treatment naïve patients
investigating Kaletra (400/100 mg twice daily) compared to nelfinavir (750 mg three times daily) plus
stavudine and lamivudine. Mean baseline CD4+ T-cell count was 259 cells/mm
3
(range: 2 to 949 cells/
mm
3
) and mean baseline plasma HIV-1 RNA was 4.9 log
10
copies/ml (range: 2.6 to
6.8 log
10
copies/ml).
Table 1
Outcomes at Week 48: Study M98-863
Kaletra (N=326)
Nelfinavir (N=327)
HIV RNA < 400 copies/ml*
75%
63%
HIV RNA < 50 copies/ml*†
67%
52%
Mean increase from baseline in
CD4+
T-cell count (cells/mm
3
)
207
195
* intent to treat analysis where patients with missing values are considered virologic failures
† p<0.001
One-hundred thirteen nelfinavir-treated patients and 74 lopinavir/ritonavir-treated patients had an HIV
RNA above 400 copies/ml while on treatment from Week 24 through Week 96. Of these, isolates
from 96 nelfinavir-treated patients and 51 lopinavir/ritonavir-treated patients could be amplified for
resistance testing. Resistance to nelfinavir, defined as the presence of the D30N or L90M mutation in
protease, was observed in 41/96 (43%) patients. Resistance to lopinavir, defined as the presence of
21
any primary or active site mutations in protease (see above), was observed in 0/51 (0%) patients. Lack
of resistance to lopinavir was confirmed by phenotypic analysis.
Sustained virological response to Kaletra (in combination with nucleoside/nucleotide reverse
transcriptase inhibitors) has been also observed in a small Phase II study (M97-720) through 360
weeks of treatment. One hundred patients were originally treated with Kaletra in the study (including
51 patients receiving 400/100 mg twice daily and 49 patients at either 200/100 mg twice daily or
400/200 mg twice daily). All patients converted to open-label Kaletra at the 400/100 mg twice daily
dose between week 48 and week 72. Thirty-nine patients (39%) discontinued the study, including 16
(16%) discontinuations due to adverse events, one of which was associated with a death. Sixty-one
patients completed the study (35 patients received the recommended 400/100 mg twice daily dose
throughout the study).
Table 2
Outcomes at Week 360: Study M97-720
Kaletra (N=100)
HIV RNA < 400 copies/ml
61%
HIV RNA < 50 copies/ml
59%
Mean increase from baseline in CD4+ T-cell count (cells/mm
3
)
501
Through 360 weeks of treatment, genotypic analysis of viral isolates was successfully conducted in 19
of 28 patients with confirmed HIV RNA above 400 copies/ml revealed no primary or active site
mutations in protease (amino acids at positions 8, 30, 32, 46, 47, 48, 50, 82, 84 and 90) or protease
inhibitor phenotypic resistance.
Patients with prior antiretroviral therapy
M97-765 is a randomised, double-blind trial evaluating Kaletra at two dose levels (400/100 mg and
400/200 mg, both twice daily) plus nevirapine (200 mg twice daily) and two nucleoside reverse
transcriptase inhibitors in 70 single protease inhibitor experienced, non-nucleoside reverse
transcriptase inhibitor naïve patients. Median baseline CD
4
cell count was 349 cells/mm
3
(range
72 to 807 cells/mm
3
) and median baseline plasma HIV-1 RNA was 4.0 log
10
copies/ml (range
2.9 to 5.8 log
10
copies/ml).
Table 3
Outcomes at Week 24: Study M97-765
Kaletra 400/100 mg
(N=36)
HIV RNA < 400 copies/ml (ITT)*
75%
HIV RNA < 50 copies/ml (ITT)*
58%
Mean increase from baseline in CD4+ T-cell count (cells/mm
3
)
174
* intent to treat analysis where patients with missing values are considered virologic failures
M98-957 is a randomised, open-label study evaluating Kaletra treatment at two dose levels
(400/100 mg and 533/133 mg, both twice daily) plus efavirenz (600 mg once daily) and nucleoside
reverse transcriptase inhibitors in 57 multiple protease inhibitor experienced, non-nucleoside reverse
transcriptase inhibitor naïve patients. Between week 24 and 48, patients randomised to a dose of
400/100 mg were converted to a dose of 533/133 mg. Median baseline CD
4
cell count was
220 cells/mm
3
(range 13 to 1030 cells/mm
3
).
22
Table 4
Outcomes at Week 48: Study M98-957
Kaletra 400/100 mg
(N=57)
HIV RNA < 400 copies/ml*
65%
Mean increase from baseline in CD4+ T-cell count (cells/mm
3
)
94
* intent to treat analysis where patients with missing values are considered virologic failures
Paediatric Use
M98-940 was an open-label study of a liquid formulation of Kaletra in 100 antiretroviral naïve (44%)
and experienced (56%) paediatric patients. All patients were non-nucleoside reverse transcriptase
inhibitor naïve. Patients were randomised to either 230 mg lopinavir/57.5 mg ritonavir per m
2
or
300 mg lopinavir/75 mg ritonavir per m
2
. Naïve patients also received nucleoside reverse transcriptase
inhibitors. Experienced patients received nevirapine plus up to two nucleoside reverse transcriptase
inhibitors. Safety, efficacy and pharmacokinetic profiles of the two dose regimens were assessed after
3 weeks of therapy in each patient. Subsequently, all patients were continued on the 300/75 mg per m
2
dose. Patients had a mean age of 5 years (range 6 months to 12 years) with 14 patients less than 2
years old and 6 patients one year or less. Mean baseline CD4+ T-cell count was 838 cells/mm
3
and
mean baseline plasma HIV-1 RNA was 4.7 log
10
copies/ml.
Table 5
Outcomes at Week 48: Study M98-940
Antiretroviral Naïve
(N=44)
Antiretroviral
Experienced (N=56)
HIV RNA < 400 copies/ml
84%
75%
Mean increase from baseline in
CD4+ T-cell count (cells/mm
3
)
404
284
5.2 Pharmacokinetic properties
The pharmacokinetic properties of lopinavir co-administered with ritonavir have been evaluated in
healthy adult volunteers and in HIV-infected patients; no substantial differences were observed
between the two groups. Lopinavir is essentially completely metabolised by CYP3A. Ritonavir
inhibits the metabolism of lopinavir, thereby increasing the plasma levels of lopinavir. Across studies,
administration of Kaletra 400/100 mg twice daily yields mean steady-state lopinavir plasma
concentrations 15 to 20-fold higher than those of ritonavir in HIV-infected patients. The plasma levels
of ritonavir are less than 7% of those obtained after the ritonavir dose of 600 mg twice daily. The
in vitro
antiviral EC
50
of lopinavir is approximately 10-fold lower than that of ritonavir. Therefore, the
antiviral activity of Kaletra is due to lopinavir.
Absorption
: multiple dosing with 400/100 mg Kaletra twice daily for 2 weeks and without meal
restriction produced a mean ± SD lopinavir peak plasma concentration (C
max
) of 12.3 ± 5.4 μg/ml,
occurring approximately 4 hours after administration. The mean steady-state trough concentration
prior to the morning dose was 8.1 ± 5.7 μg/ml. Lopinavir AUC over a 12 hour dosing interval
averaged 113.2 ± 60.5 μg•h/ml. The absolute bioavailability of lopinavir co-formulated with ritonavir
in humans has not been established.
Effects of food on oral absorption
:
Kaletra soft capsules and liquid have been shown to be
bioequivalent under nonfasting conditions (moderate fat meal). Administration of a single
400/100 mg dose of Kaletra soft capsules with a moderate fat meal (500 – 682 kcal, 22.7 –25.1% from
fat) was associated with a mean increase of 48% and 23% in lopinavir AUC and C
max
, respectively,
relative to fasting. For Kaletra oral solution, the corresponding increases in lopinavir AUC and C
max
23
were 80% and 54%, respectively. Administration of Kaletra with a high fat meal (872 kcal, 55.8%
from fat) increased lopinavir AUC and C
max
by 96% and 43%, respectively, for soft capsules, and
130% and 56%, respectively, for oral solution. To enhance bioavailability and minimise variability
Kaletra is to be taken with food.
Distribution
: at steady state, lopinavir is approximately 98 − 99% bound to serum proteins.
Lopinavir binds to both alpha-1-acid glycoprotein (AAG) and albumin, however, it has a higher
affinity for AAG. At steady state, lopinavir protein binding remains constant over the range of
observed concentrations after 400/100 mg Kaletra twice daily, and is similar between healthy
volunteers and HIV-positive patients.
Biotransformation
:
in vitro
experiments with human hepatic microsomes indicate that lopinavir
primarily undergoes oxidative metabolism. Lopinavir is extensively metabolised by the hepatic
cytochrome P450 system, almost exclusively by isozyme CYP3A. Ritonavir is a potent CYP3A
inhibitor which inhibits the metabolism of lopinavir and therefore, increases plasma levels of
lopinavir. A
14
C-lopinavir study in humans showed that 89% of the plasma radioactivity after a single
400/100 mg Kaletra dose was due to parent active substance. At least 13 lopinavir oxidative
metabolites have been identified in man. The 4-oxo and 4-hydroxymetabolite epimeric pair are the
major metabolites with antiviral activity, but comprise only minute amounts of total plasma
radioactivity. Ritonavir has been shown to induce metabolic enzymes, resulting in the induction of its
own metabolism, and likely the induction of lopinavir metabolism. Pre-dose lopinavir concentrations
decline with time during multiple dosing, stabilising after approximately 10 days to 2 weeks.
Elimination
: after a 400/100 mg
14
C-lopinavir/ritonavir dose, approximately 10.4 ± 2.3% and
82.6 ± 2.5% of an administered dose of
14
C-lopinavir can be accounted for in urine and faeces,
respectively. Unchanged lopinavir accounted for approximately 2.2% and 19.8% of the administered
dose in urine and faeces, respectively. After multiple dosing, less than 3% of the lopinavir dose is
excreted unchanged in the urine. The effective (peak to trough) half-life of lopinavir over a 12 hour
dosing interval averaged 5 − 6 hours, and the apparent oral clearance (CL/F) of lopinavir is 6 to 7 l/h.
Special Populations
Paediatrics:
There are limited pharmacokinetic data in children below 2 years of age. The pharmacokinetics of
Kaletra 300/75 mg/m
2
twice daily and 230/57.5 mg/m
2
twice daily have been studied in a total of 53
paediatric patients, ranging in age from 6 months to 12 years. The lopinavir mean steady-state AUC,
C
max
, and C
min
were 72.6 ± 31.1 μg•h/ml, 8.2 ± 2.9 μg/ml and 3.4 ± 2.1 μg/ml, respectively after
Kaletra 230/57.5 mg/m
2
twice daily without nevirapine (n=12), and were 85.8 ± 36.9 μg•h/ml,
10.0 ± 3.3 μg/ml and 3.6 ± 3.5 μg/ml, respectively after 300/75 mg/m
2
twice daily with nevirapine
(n=12). The 230/57.5 mg/m
2
twice daily regimen without nevirapine and the 300/75 mg/m
2
twice
daily regimen with nevirapine provided lopinavir plasma concentrations similar to those obtained in
adult patients receiving the 400/100 mg twice daily regimen without nevirapine. Kaletra soft capsules
and Kaletra oral solution are bioequivalent under nonfasting conditions.
Gender, Race and Age:
Kaletra pharmacokinetics have not been studied in the elderly. No age or gender related
pharmacokinetic differences have been observed in adult patients. Pharmacokinetic differences due to
race have not been identified.
Renal Insufficiency:
Kaletra pharmacokinetics have not been studied in patients with renal insufficiency; however, since
the renal clearance of lopinavir is negligible, a decrease in total body clearance is not expected in
patients with renal insufficiency.
24
Hepatic Insufficiency:
The steady state pharmacokinetic parameters of lopinavir in HIV-infected patients with mild to
moderate hepatic impairment were compared with those of HIV-infected patients with normal hepatic
function in a multiple dose study with lopinavir/ritonavir 400/100 mg twice daily. A limited increase
in total lopinavir concentrations of approximately 30% has been observed which is not expected to be
of clinical relevance (see section 4.2).
5.3 Preclinical safety data
Repeat-dose toxicity studies in rodents and dogs identified major target organs as the liver, kidney,
thyroid, spleen and circulating red blood cells. Hepatic changes indicated cellular swelling with focal
degeneration. While exposure eliciting these changes were comparable to or below human clinical
exposure, dosages in animals were over 6-fold the recommended clinical dose. Mild renal tubular
degeneration was confined to mice exposed with at least twice the recommended human exposure; the
kidney was unaffected in rats and dogs. Reduced serum thyroxin led to an increased release of TSH
with resultant follicular cell hypertrophy in the thyroid glands of rats. These changes were reversible
with withdrawal of the active substance and were absent in mice and dogs. Coombs-negative
anisocytosis and poikilocytosis were observed in rats, but not in mice or dogs. Enlarged spleens with
histiocytosis were seen in rats but not other species. Serum cholesterol was elevated in rodents but not
dogs, while triglycerides were elevated only in mice.
During
in vitro
studies, cloned human cardiac potassium channels (HERG) were inhibited by 30% at
the highest concentrations of lopinavir/ritonavir tested, corresponding to a lopinavir exposure 7-fold
total and 15-fold free peak plasma levels achieved in humans at the maximum recommended
therapeutic dose. In contrast, similar concentrations of lopinavir/ritonavir demonstrated no
repolarisation delay in the canine cardiac Purkinje fibres. Lower concentrations of lopinavir/ritonavir
did not produce significant potassium (HERG) current blockade. Tissue distribution studies
conducted in the rat did not suggest significant cardiac retention of the active substance; 72-hour AUC
in heart was approximately 50% of measured plasma AUC. Therefore, it is reasonable to expect that
cardiac lopinavir levels would not be significantly higher than plasma levels.
In dogs, prominent U waves on the electrocardiogram have been observed associated with prolonged
PR interval and bradycardia. These effects have been assumed to be caused by electrolyte disturbance
The clinical relevance of these preclinical data is unknown, however, the potential cardiac effects of
this product in humans cannot be ruled out (see also sections 4.4 and 4.8).
In rats, embryofoetotoxicity (pregnancy loss, decreased foetal viability, decreased foetal body weights,
increased frequency of skeletal variations) and postnatal developmental toxicity (decreased survival of
pups) was observed at maternally toxic dosages. The systemic exposure to lopinavir/ritonavir at the
maternal and developmental toxic dosages was lower than the intended therapeutic exposure in
humans.
Long-term carcinogenicity studies of lopinavir/ritonavir in mice revealed a nongenotoxic, mitogenic
induction of liver tumours, generally considered to have little relevance to human risk.
Carcinogenicity studies in rats revealed no tumourigenic findings. Lopinavir/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, the mouse lymphoma assay, the mouse micronucleus test and chromosomal
aberration assays in human lymphocytes.
25
6.
6.1 List of excipients
Capsule contents
:
oleic acid,
propylene glycol,
polyoxyl 35 castor oil,
purified water
Capsule shell
:
gelatine,
anhydrized liquid sorbitol (mixture of sorbitol, sorbitol anhydrides and mannitol),
glycerol,
titanium dioxide (E171),
sunset yellow (E110)
medium-chain triglycerides,
lecithin
Black ink containing:
propylene glycol,
black iron oxide (E172),
polyvinyl acetate phthalate,
polyethylene glycol 400,
ammonium hydroxide
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years
6.4 Special precautions for storage
Store in a refrigerator (2°C - 8°C).
In use storage: If kept outside of the refrigerator, do not store above 25°C and discard any unused
contents after 42 days (6 weeks). It is advised to write the date of removal from the refrigerator on the
package.
Avoid exposure to excessive heat.
6.5 Nature and content of container
High density polyethylene (HDPE) bottles closed with polypropylene caps. Each bottle contains 90
capsules. Each pack contains 2 bottles (180 capsules).
Polyvinyl chloride (PVC) blisters with fluoropolymer foil backing in a carton containing 36 capsules.
Each pack contains 5 cartons (180 capsules).
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
26
7.
Abbott Laboratories Limited
Abbott House
Vanwall Business Park
Vanwall Road
Maidenhead
Berkshire SL6 4XE
United Kingdom
8.
EU/1/01/172/001
EU/1/01/172/002
Date of first authorisation: 20 March 2001
Date of latest renewal: 20 March 2006
{MM/YYYY}
Detailed information on this product is available on the website of the European Medicines Agency
27
Kaletra (80 mg + 20 mg) / ml oral solution
Each 5 ml of Kaletra oral solution contains 400 mg of lopinavir co-formulated with 100 mg of
ritonavir as a pharmacokinetic enhancer.
Excipients:
Each 5 ml contains 356.3 mg of alcohol (42% v/v), 168.6 mg of high fructose corn syrup, 152.7 mg of
propylene glycol (see section 4.3), 10.2 mg of polyoxyl 40 hydrogenated castor oil and 4.1 mg of
acesulfame potassium (see section 4.4).
For a full list of excipients, see section 6.1.
Oral solution
The solution is light yellow to golden.
4.
Kaletra is indicated for the treatment of HIV-1 infected adults and children above the age of 2 years, in
combination with other antiretroviral agents.
The choice of Kaletra to treat protease inhibitor experienced HIV-1 infected patients should be based
on individual viral resistance testing and treatment history of patients (see sections 4.4 and 5.1).
Kaletra should be prescribed by physicians who are experienced in the treatment of HIV infection.
Posology
Adult and adolescent use:
the recommended dosage of Kaletra is 5 ml of oral solution (400/100 mg)
twice daily taken with food.
Paediatric use (2 years of age and above):
the recommended dosage of Kaletra is 230/57.5 mg/m
2
twice daily taken with food, up to a maximum dose of 400/100 mg twice daily. The 230/57.5 mg/m
2
dosage might be insufficient in some children when co-administered with nevirapine or efavirenz. An
increase of the dose of Kaletra to 300/75 mg/m
2
should be considered in these patients. Dose should
be administered using a calibrated oral dosing syringe.
The oral solution is the recommended option for the most accurate dosing in children based on body
surface area. However, if it is judged necessary to resort to soft capsules in children, they should be
used with particular caution since they are associated with less precise dosing capabilities. Therefore,
children receiving soft capsules might have higher exposure (with the risk of increased toxicity) or
suboptinal exposure (with the risk of insufficient efficacy). Consequently when dosing children with
soft capsules, therapeutic drug monitoring may be a useful tool to ensure appropriate lopinavir
exposure in an individual patient.
28
Paediatric dosing guidelines for the dose 230/57.5 mg/m
2
Body Surface Area* (m
2
)
Twice daily oral solution dose
(dose in mg)
Twice daily soft capsule dose
(dose in mg)
0.25
0.7 ml (57.5/14.4 mg)
NA
0.40
1.2 ml (96/24 mg)
1 soft capsule (133.3/33.3 mg)
0.50
1.4 ml (115/28.8 mg)
1 soft capsule (133.3/33.3 mg)
0.75
2.2 ml (172.5/43.1 mg)
1 soft capsule (133.3/33.3 mg)
0.80
2.3 ml (184/46 mg)
2 soft capsules (266.6/66/6 mg)
1.00
2.9 ml (230/57.5 mg)
2 soft capsules (266.6/66/6 mg)
1.25
3.6 ml (287.5/71.9 mg)
2 soft capsules (266.6/66/6 mg)
1.3
3.7 ml (299/74.8 mg)
2 soft capsules (266.6/66/6 mg)
1.4
4.0 ml (322/80.5 mg)
3 soft capsules (400/100 mg)
1.5
4.3 ml (345/86.3 mg)
3 soft capsules (400/100 mg)
1.7
5 ml (402.5/100.6 mg)
3 soft capsules (400/100 mg)
*
Body surface area can be calculated with the following equation
BSA (m
2
) = √ (Height (cm) X Weight (kg) / 3600)
Children less than 2 years of age
: the safety and efficacy of Kaletra in children aged less than 2 years
have not yet been established. Currently available data are described in section 5.2 but no
recommendation on the posology can be made.
Hepatic impairment
: In HIV-infected patients with mild to moderate hepatic impairment, an increase
of approximately 30% in lopinavir exposure has been observed but is not expected to be of clinical
relevance (see section 5.2). No data are available in patients with severe hepatic impairment. Kaletra
must not be given to these patients (see section 4.3).
Renal impairment
: since the renal clearance of lopinavir and ritonavir is negligible, increased plasma
concentrations are not expected in patients with renal impairment. Because lopinavir and ritonavir are
highly protein bound, it is unlikely that they will be significantly removed by haemodialysis or
peritoneal dialysis.
Method of administration
Kaletra is administered orally and should always be taken with food (see section 5.2)
Hypersensitivity to the active substances or to any of the excipients.
Severe hepatic insufficiency.
Kaletra contains lopinavir and ritonavir, both of which are inhibitors of the P450 isoform CYP3A.
Kaletra should not be co-administered with medicinal products that are highly dependent on CYP3A
for clearance and for which elevated plasma concentrations are associated with serious and/or life
threatening events. These medicinal products include astemizole, terfenadine, oral midazolam (for
caution on parenterally administered midazolam, see section 4.5), triazolam, cisapride, pimozide,
amiodarone, ergot alkaloids (e.g. ergotamine, dihydroergotamine, ergonovine and methylergonovine)
lovastatin, simvastatin, sildenafil used for the treatment of pulmonary arterial hypertension (for the use
of sildenafil in patients with erectile dysfunction, see section 4.5) and vardenafil.
Herbal preparations containing St John’s wort (
Hypericum perforatum)
must not be used while taking
lopinavir and ritonavir due to the risk of decreased plasma concentrations and reduced clinical effects
of lopinavir and ritonavir (see section 4.5).
29
Kaletra oral solution is contraindicated in children below the age of 2 years, pregnant women, patients
with hepatic or renal failure and patients treated with disulfiram or metronidazole due to the potential
risk of toxicity from the excipient propylene glycol (see section 4.4).
Patients with coexisting conditions
Hepatic impairment
: the safety and efficacy of Kaletra has not been established in patients with
significant underlying liver disorders. Kaletra is contraindicated in patients with severe liver
impairment (see section 4.3). 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 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 should be considered.
Elevated transaminases with or without elevated bilirubin levels have been reported in HIV-1
mono-infected and in individuals treated for post-exposure prophylaxis as early as 7 days after the
initiation of lopinavir/ritonavir in conjunction with other antiretroviral agents. In some cases the
hepatic dysfunction was serious.
Appropriate laboratory testing should be conducted prior to initiating therapy with lopinavir/ritonavir
and close monitoring should be performed during treatment.
Renal impairment:
since the renal clearance of lopinavir and ritonavir is negligible, increased plasma
concentrations are not expected in patients with renal impairment. Because lopinavir and ritonavir are
highly protein bound, it is unlikely that they will be significantly removed by haemodialysis or
peritoneal dialysis.
Haemophilia:
there have been reports of increased bleeding, including spontaneous skin haematomas
and haemarthrosis in patients with haemophilia type A and B treated with protease inhibitors. In some
patients additional factor VIII was given. In more than half of the reported cases, treatment with
protease inhibitors was continued or reintroduced if treatment had been discontinued. A causal
relationship had been evoked, although the mechanism of action had not been elucidated.
Haemophiliac patients should therefore be made aware of the possibility of increased bleeding.
Lipid elevations
Treatment with Kaletra has resulted in increases, sometimes marked, in the concentration of total
cholesterol and triglycerides. Triglyceride and cholesterol testing is to be performed prior to initiating
Kaletra therapy and at periodic intervals during therapy. Particular caution should be paid to patients
with high values at baseline and with history of lipid disorders. Lipid disorders are to be managed as
clinically appropriate (see also section 4.5 for additional information on potential interactions with
HMG-CoA reductase inhibitors).
Pancreatitis
Cases of pancreatitis have been reported in patients receiving Kaletra, including those who developed
hypertriglyceridaemia. In most of these cases patients have had a prior history of pancreatitis and/or
concurrent therapy with other medicinal products associated with pancreatitis. Marked triglyceride
elevation is a risk factor for development of pancreatitis. Patients with advanced HIV disease may be
at risk of elevated triglycerides and pancreatitis.
30
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 evaluated and
Kaletra therapy should be suspended if a diagnosis of pancreatitis is made (see section 4.8).
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.
Fat redistribution & metabolic disorders
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 protease
inhibitors (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 drug 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).
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.
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 particularly in patients with advanced HIV-disease and/or long-term exposure to combination
antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience
joint aches and pain, joint stiffness or difficulty in movement.
PR interval prolongation
Lopinavir/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 atroventricular block in patients with
underlying structural heart disease and pre-existing conduction system abnormalities or in patients
receiving drugs known to prolong the PR interval (such as verapamil or atazanavir) have been reported
in patients receiving lopinavir/ritonavir. Kaletra should be used with caution in such patients (see
section 5.1).
Interactions with medicinal products
Kaletra contains lopinavir and ritonavir, both of which are inhibitors of the P450 isoform CYP3A.
Kaletra is likely to increase plasma concentrations of medicinal products that are primarily
metabolised by CYP3A. These increases of plasma concentrations of co-administered medicinal
31
products could increase or prolong their therapeutic effect and adverse events (see sections 4.3 and
4.5).
The combination of Kaletra with atorvastatin is not recommended. If the use of atorvastatin is
considered strictly necessary, the lowest possible dose of atorvastatin should be administered with
careful safety monitoring. Caution must also be exercised and reduced doses should be considered if
Kaletra is used concurrently with rosuvastatin. If treatment with an HMG-CoA reductase inhibitor is
indicated, pravastatin or fluvastatin is recommended (see section 4.5).
PDE5 inhibitors
: particular caution should be used when prescribing sildenafil or tadalafil for the
treatment of erectile dysfunction in patients receiving Kaletra. Co-administration of Kaletra with these
medicinal products is expected to substantially increase their concentrations and may result in
associated adverse events such as hypotension, syncope, visual changes and prolonged erection (see
section 4.5). Concomitant use of vardenafil and lopinavir/ritonavir is contraindicated (see section 4.3).
Concomitant use of sildenafil prescribed for the treatment of pulmonary arterial hypertension with
Kaletra is contraindicated (see section 4.3).
Particular caution must be used when prescribing Kaletra and medicinal products known to induce QT
interval prolongation such as: chlorpheniramine, quinidine, erythromycin, clarithromycin. Indeed,
Kaletra could increase concentrations of the co-administered medicinal products and this may result in
an increase of their associated cardiac adverse reactions. Cardiac events have been reported with
Kaletra in preclinical studies; therefore, the potential cardiac effects of Kaletra cannot be currently
ruled out (see sections 4.8 and 5.3).
Co-administration of Kaletra with rifampicin is not recommended. Rifampicin in combination with
Kaletra causes large decreases in lopinavir concentrations which may in turn significantly decrease the
lopinavir therapeutic effect. Adequate exposure to lopinavir/ritonavir may be achieved when a higher
dose of Kaletra is used but this is associated with a higher risk of liver and gastrointestinal toxicity.
Therefore, this co-administration should be avoided unless judged strictly necessary (see section 4.5).
Concomitant use of Kaletra 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).
Other
Patients taking the oral solution, particularly those with renal impairment or with decreased ability to
metabolise propylene glycol (e.g. those of Asian origin), should be monitored for adverse reactions
potentially related to propylene glycol toxicity (i.e. seizures, stupor, tachycardia, hyperosmolarity,
lactic acidosis, renal toxicity, haemolysis) (see section 4.3).
Kaletra is not a cure for HIV infection or AIDS. There is still a risk of passing HIV to others through
sexual contact or contamination with blood when taking Kaletra. Appropriate precautions should be
taken. People taking Kaletra may still develop infections or other illnesses associated with HIV
disease and AIDS.
Besides propylene glycol as described above, Kaletra oral solution contains alcohol (42% v/v) which
is potentially harmful for those suffering from liver disease, alcoholism, epilepsy, brain injury or
disease as well as for pregnant women and children. It may modify or increase the effects of other
medicines. Kaletra oral solution contains up to 0.8 g of fructose per dose when taken according to the
dosage recommendations. This may be unsuitable in hereditary fructose intolerance. Kaletra oral
solution contains up to 0.3 g of glycerol per dose. Only at high inadvertent doses, it can cause
headache and gastrointestinal upset. Furthermore, polyoxol 40 hydrogenated castor oil and potassium
present in Kaletra oral solution may cause only at high inadvertent doses gastrointestinal upset.
Patients on a low potassium diet should be cautioned.
32
Kaletra contains lopinavir and ritonavir, both of which are inhibitors of the P450 isoform CYP3A
in vitro
. Co-administration of Kaletra 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 reactions. Kaletra does not inhibit CYP2D6, CYP2C9, CYP2C19,
CYP2E1, CYP2B6 or CYP1A2 at clinically relevant concentrations (see section 4.3).
Kaletra has been shown
in vivo
to induce its own metabolism and to increase the biotransformation of
some medicinal products metabolised by cytochrome P450 enzymes (including CYP2C9 and
CYP2C19) and by glucuronidation. This may result in lowered plasma concentrations and potential
decrease of efficacy of co-administered medicinal products.
Medicinal products that are contraindicated specifically due to the expected magnitude of interaction
and potential for serious adverse events are listed in section 4.3.
Known and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal
products are listed in the table below.
Interaction table
Interactions between Kaletra and co-administered medicinal products are listed in the table below
(increase is indicated as “↑”, decrease as “↓”, no change as “↔”,once daily as “QD”, twice daily as
“BID” and three times daily as "TID").
Unless otherwise stated, studies detailed below have been performed with the recommended dosage of
lopinavir/ritonavir (i.e. 400/100 mg twice daily).
Co-administered drug
by therapeutic area
Effects on drug levels
Clinical recommendation
concerning co-administration
with Kaletra
Geometric Mean Change (%) in
AUC, C
max
, C
min
Mechanism of interaction
Antiretroviral Agents
Nucleoside/Nucleotide reverse transcriptase inhibitors (NRTIs)
Stavudine, Lamivudine Lopinavir: ↔
No dose adjustment necessary.
Abacavir, Zidovudine
Abacavir, Zidovudine:
Concentrations may be reduced
due to increased glucuronidation
by Kaletra.
The clinical significance of
reduced abacavir and zidovudine
concentrations is unknown.
Tenofovir, 300 mg QD
Tenofovir:
AUC: ↑ 32%
C
max
: ↔
C
min
: ↑ 51%
No dose adjustment necessary.
Higher tenofovir concentrations
could potentiate tenofovir
associated adverse events,
including renal disorders.
Lopinavir: ↔
33
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Efavirenz, 600 mg QD
Lopinavir:
AUC: ↓ 20%
C
max
: ↓ 13%
C
min
: ↓ 42%
The Kaletra tablets dosage should
be increased to 500/125 mg twice
daily when co-administered with
efavirenz.
Efavirenz, 600 mg QD
Lopinavir: ↔
(Relative to 400/100 mg BID
administered alone)
(Lopinavir/ritonavir
500/125 mg BID)
Nevirapine, 200 mg
BID
Lopinavir:
AUC: ↓ 27%
C
max
: ↓ 19%
C
min
: ↓ 51%
The Kaletra tablets dosage should
be increased to 500/125 mg twice
daily when co-administered with
nevirapine.
Co-administration with other HIV protease inhibitors (PIs)
According to current treatment guidelines, dual therapy with protease inhibitors is generally not
recommended.
Fosamprenavir/
ritonavir (700/100 mg
BID)
Fosamprenavir:
Amprenavir concentrations are
significantly reduced.
Co-administration of increased
doses of fosamprenavir (1400 mg
BID) with lopinavir/ritonavir
(533/133 mg BID) to protease
inhibitor-experienced patients
resulted in a higher incidence of
gastrointestinal adverse events
and elevations in triglycerides
with the combination regimen
without increases in virological
efficacy, when compared with
standard doses of
fosamprenavir/ritonavir.
Concomitant administration of
these medicinal products is not
recommended.
(Lopinavir/ritonavir
400/100 mg BID)
or
Fosamprenavir (1400
mg BID)
(Lopinavir/ritonavir
533/133 mg BID)
Indinavir, 600 mg BID
Indinavir:
AUC: ↔
C
min
: ↑ 3.5-fold
C
max
: ↓
(relative to indinavir 800 mg TID
alone)
Lopinavir: ↔
(relative to historical comparison)
The appropriate doses for this
combination, with respect to
efficacy and safety, have not been
established.
Nelfinavir
Lopinavir:
Concentrations ↓
The appropriate doses for this
combination, with respect to
efficacy and safety, have not been
established.
Saquinavir
1000 mg BID
Saquinavir: ↔
No dose adjustment necessary.
Tipranavir/ritonavir
(500/100 mg BID)
Lopinavir:
AUC: ↓ 55%
C
min
: ↓ 47%
C
max
: ↓ 70%
Concomitant administration of
these medicinal products is not
recommended.
34
Acid reducing agents
Omeprazole (40 mg
QD)
Omeprazole: ↔
No dose adjustment necessary
Lopinavir: ↔
Ranitidine (150 mg
single dose)
Ranitidine: ↔
No dose adjustment necessary
Analgesics
Fentanyl
Fentanyl:
Increased risk of side-effects
(respiratory depression, sedation)
due to higher plasma
concentrations because of
CYP3A4 inhibition by Kaletra
Careful monitoring of adverse
effects (notably respiratory
depression but also sedation) is
recommended when fentanyl is
concomitantly administered with
Kaletra.
Antiarrhythmics
Digoxin
Digoxin:
Plasma concentrations may be
increased due to P-glycoprotein
inhibition by Kaletra. The
increased digoxin level may
lessen over time as Pgp induction
develops.
Caution is warranted and
therapeutic drug monitoring of
digoxin concentrations, if
available, is recommended in case
of co-administration of Kaletra
and digoxin. Particular caution
should be used when prescribing
Kaletra in patients taking digoxin
as the acute inhibitory effect of
ritonavir on Pgp is expected to
significantly increase digoxin
levels. Initiation of digoxin in
patients already taking Kaletra is
likely to result in lower than
expected increases of digoxin
concentrations.
Bepridil, Systemic
Lidocaine, and
Quinidine
Bepridil, Systemic Lidocaine,
Quinidine:
Concentrations may be increased
when co-administered with
Kaletra.
Caution is warranted and
therapeutic drug concentration
monitoring is recommended when
available.
Antibiotics
Clarithromycin
Clarithromycin:
Moderate increases in
clarithromycin AUC are expected
due to CYP3A inhibition by
Kaletra.
For patients with renal
impairment (CrCL <30 ml/min)
dose reduction of clarithromycin
should be considered (see section
4.4). Caution should be exercised
in administering clarithromycin
with Kaletra to patients with
impaired hepatic or renal
function.
Anticancer agents
Most tyrosine kinase
inhibitors such as
dasatinib and nilotinib,
Vincristine, Vinblastine
Most tyrosine kinase inhibitors
such as dasatinib and nilotinib,
also vincristine and vinblastine:
Risk of increased adverse events
due to higher serum
concentrations because of
CYP3A4 inhibition by Kaletra.
Careful monitoring of the
tolerance of these anticancer
agents.
35
Anticoagulants
Warfarin
Warfarin:
Concentrations may be affected
when co-administered with
Kaletra due to CYP2C9
induction.
It is recommended that INR
(international normalised ratio) be
monitored.
Anticonvulsants
Phenytoin
Phenytoin:
Steady-state concentrations were
moderately decreased due to
CYP2C9 and CYP2C19 induction
by Kaletra.
Caution should be exercised in
administering phenytoin with
Kaletra.
Phenytoin levels should be
monitored when co-administering
with lopinavir/ritonavir.
Lopinavir:
Concentrations are decreased due
to CYP3A induction by
phenytoin.
When co-administered with
phenytoin, an increase of Kaletra
dosage may be envisaged. Dose
adjustment has not been evaluated
in clinical practice.
Carbamazepine and
Phenobarbital
Carbamazepine:
Serum concentrations may be
increased due to CYP3A
inhibition by Kaletra.
Caution should be exercised in
administering carbamazepine or
phenobarbital with Kaletra.
Carbamazepine and phenobarbital
levels should be monitored when
co-administering with
lopinavir/ritonavir.
Lopinavir:
Concentrations may be decreased
due to CYP3A induction by
carbamazepine and phenobarbital.
When co-administered with
carbamazepine or phenobarbital,
an increase of Kaletra dosage may
be envisaged. Dose adjustment
has not been evaluated in clinical
practice
Antidepressants and Anxiolytics
Trazodone single dose
Trazodone:
AUC: ↑ 2.4-fold
It is unknown whether the
combination of lopinavir/ritonavir
causes a similar increase in
trazodone exposure. The
combination should be used with
caution and a lower dose of
trazodone should be considered.
(Ritonavir, 200 mg
BID)
Adverse events of nausea,
dizziness, hypotension and
syncope were observed following
co-administration of trazodone
and ritonavir.
36
Antifungals
Ketoconazole and
Itraconazole
Ketoconazole, Itraconazole:
Serum concentrations may be
increased due to CYP3A
inhibition by Kaletra.
High doses of ketoconazole and
itraconazole (> 200 mg/day) are
not recommended.
Voriconazole
Voriconazole:
Concentrations may be decreased.
Co-administration of
voriconazole and low dose
ritonavir (100 mg BID) as
contained in Kaletra should be
avoided unless an assessment of
the benefit/risk to patient justifies
the use of voriconazole.
Antimycobacterials
Rifabutin, 150 mg QD
Rifabutin (parent drug and active
25-O-desacetyl metabolite):
AUC: ↑ 5.7-fold
C
max
: ↑ 3.5-fold
On the basis of these data, a
rifabutin dose reduction of 75%
(i.e. 150 mg every other day or 3
times per week) is recommended
when administered with Kaletra.
Further reduction may be
necessary.
Rifampicin
Lopinavir:
Large decreases in lopinavir
concentrations may be observed
due to CYP3A induction by
rifampicin.
Co-administration of Kaletra with
rifampicin is not recommended as
the decrease in lopinavir
concentrations may in turn
significantly decrease the
lopinavir therapeutic effect A
dose adjustment of Kaletra
400 mg/400 mg (i.e. Kaletra
400/100 mg + ritonavir 300 mg)
twice daily has allowed
compensating for the CYP 3A4
inducer effect of rifampicin.
However, such a dose adjustment
might be associated with
ALT/AST elevations and with
increase in gastrointestinal
disorders. Therefore, this
co-administration should be
avoided unless judged strictly
necessary. If this
co-administration is judged
unavoidable, increased dose of
Kaletra at 400 mg/400 mg twice
daily may be administered with
rifampicin under close safety and
therapeutic drug monitoring. The
Kaletra dose should be titrated
upward only after rifampicin has
been initiated (see section 4.4).
37
Benzodiazepines
Midazolam
Oral Midazolam:
AUC: ↑ 13-fold
Parenteral Midazolam:
AUC: ↑ 4-fold
Due to CYP3A inhibition by
Kaletra
Kaletra must not be
co-administered with oral
midazolam (see section 4.3),
whereas caution should be used
with co-administration of Kaletra
and parenteral midazolam. If
Kaletra 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.
Calcium channel blockers
Felodipine, Nifedipine,
and Nicardipine
Felodipine, Nifedipine,
Nicardipine:
Concentrations may be increased
due to CYP3A inhibition by
Kaletra.
Clinical monitoring of therapeutic
and adverse effects is
recommended when these
medicines are concomitantly
administered with Kaletra.
38
Corticosteroids
Dexamethasone
Lopinavir:
Concentrations may be decreased
due to CYP3A induction by
dexamethasone.
Clinical monitoring of antiviral
efficacy is recommended when
these medicines are
concomitantly administered with
Kaletra.
Fluticasone propionate,
50 μg intranasal 4 times
daily
Fluticasone propionate:
Plasma concentrations ↑
Cortisol levels ↓ 86%
Greater effects may be expected
when fluticasone propionate is
inhaled. Systemic corticosteroid
effects including Cushing's
syndrome and adrenal
suppression have been reported in
patients receiving ritonavir and
inhaled or intranasally
administered fluticasone
propionate; this could also occur
with other corticosteroids
metabolised via the P450 3A
pathway eg budesonide.
Consequently, concomitant
administration of Kaletra 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 have to be
performed over a longer period.
(100 mg ritonavir BID)
39
Erectile Dysfunction, Phosphodiesterase(PDE5) inhibitors
Tadalafil
Tadalafil:
AUC: ↑ 2-fold
Due to CYP3A inhibition by
Kaletra.
Particular caution must be used
when prescribing sildenafil or
tadalafil in patients receiving
Kaletra with increased monitoring
for adverse events including
hypotension, syncope, visual
changes and prolonged erection
(see section 4.4).
When co-administered with
Kaletra, sildenafil doses must not
exceed 25 mg in 48 hours and
tadalafil doses must not exceed
10 mg every 72 hours.
Co-administration of Kaletra with
sildenafil used for the treatment
of pulmonary arterial
hypertension is contra-indicated
(see section 4.3).
Sildenafil
Sildenafil:
AUC: ↑ 11-fold
Due to CYP3A inhibition by
Kaletra.
Vardenafil
Vardenafil:
AUC: ↑ 49-fold
Due to CYP3A inhibition by
Kaletra.
The use of vardenafil with Kaletra
is contraindicated (see section
4.3).
Herbal products
St John’s wort
(
Hypericum perforatum)
Lopinavir:
Concentrations may be reduced
due to induction of CYP3A by the
herbal preparation St John’s wort.
Herbal preparations containing St
John’s wort must not be
combined with lopinavir and
ritonavir. If a patient is already
taking St John’s wort, stop
St John’s wort and if possible
check viral levels. Lopinavir and
ritonavir levels may increase on
stopping St John’s wort. The
dose of Kaletra 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).
Therefore, Kaletra can be started
safely 2 weeks after cessation of
St. John's wort.
Immunosuppressants
Cyclosporin, Sirolimus
(rapamycin), and
Tacrolimus
Cyclosporin, Sirolimus
(rapamycin), Tacrolimus:
Concentrations may be increased
due to CYP3A inhibition by
Kaletra.
More frequent therapeutic
concentration monitoring is
recommended until plasma levels
of these products have been
stabilised.
40
Lipid lowering agents
Lovastatin and
Simvastatin
Lovastatin, Simvastatin:
Markedly increased plasma
concentrations due to CYP3A
inhibition by Kaletra.
Since increased concentrations of
HMG-CoA reductase inhibitors
may cause myopathy, including
rhabdomyolysis, the combination
of these agents with Kaletra is
contraindicated (see section 4.3).
Atorvastatin
Atorvastatin:
AUC: ↑ 5.9-fold
C
max
:
↑ 4.7-fold
Due to CYP3A inhibition by
Kaletra.
The combination of Kaletra with
atorvastatin is not recommended.
If the use of atorvastatin is
considered strictly necessary, the
lowest possible dose of
atorvastatin should be
administered with careful safety
monitoring (see section 4.4).
Rosuvastatin, 20 mg QD
Rosuvastatin:
AUC: ↑ 2-fold
C
max
:
↑ 5-fold
While rosuvastatin is poorly
metabolised by CYP3A4, an
increase of its plasma
concentrations was observed. The
mechanism of this interaction
may result from inhibition of
transport proteins.
Caution should be exercised and
reduced doses should be
considered when Kaletra is
co-administered with rosuvastatin
(see section 4.4).
Fluvastatin or
Pravastatin
Fluvastatin, Pravastatin:
No clinical relevant interaction
expected.
Pravastatin is not metabolised by
CYP450.
Fluvastatin is partially
metabolised by CYP2C9.
If treatment with an HMG-CoA
reductase inhibitor is indicated,
fluvastatin or pravastatin is
recommended.
Opioids
Buprenorphine, 16 mg
QD
Buprenorphine: ↔
No dose adjustment necessary.
Methadone
Methadone:
↓
Monitoring plasma concentrations
of methadone is recommended.
Oral Contraceptives
Ethinyl Oestradiol
Ethinyl Oestradiol: ↓
In case of co-administration of
Kaletra with contraceptives
containing ethinyl oestradiol
(whatever the contraceptive
formulation e.g. oral or patch),
additional methods of
contraception must be used.
Smoking cessation aids
Bupropion
Buproprion and its active
metabolite, hydroxybupropion:
AUC and C
max
↓ ~50%
If the co-administration of
lopinavir/ritonavir with bupropion
is judged unavoidable, this should
be done under close clinical
monitoring for bupropion
efficacy, without exceeding the
recommended dosage, despite the
observed induction.
This effect may be due to
induction of bupropion
metabolism.
41
Other medicinal products
Based on known metabolic profiles, clinically significant interactions are not expected between
Kaletra and dapsone, trimethoprim/sulfamethoxazole, azithromycin or fluconazole.
Pregnancy
There are no data from the use of Kaletra in pregnant women. Studies in animals have shown
reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Kaletra should not
be used during pregnancy unless clearly necessary.
Breastfeeding
Studies in rats revealed that lopinavir is excreted in the milk. It is not known whether this medicinal
product is excreted in human milk. HIV-infected women must 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. Patients
should be informed that nausea has been reported during treatment with Kaletra (see section 4.8).
Kaletra oral solution contains approximately 42% v/v alcohol.
a. Summary of the safety profile
The safety of Kaletra has been investigated in over 2600 patients in Phase II-IV clinical trials, of
which over 700 have received a dose of 800/200 mg (6 capsules or 4 tablets) once daily. Along with
nucleoside reverse transcriptase inhibitors (NRTIs), in some studies, Kaletra was used in combination
with efavirenz or nevirapine.
The most common adverse reactions related to Kaletra therapy during clinical trials were diarrhoea,
nausea, vomiting, hypertriglyceridaemia and hypercholesterolemia. Diarrhoea, nausea and vomiting
may occur at the beginning of the treatment while hypertriglyceridaemia and hypercholesterolemia
may occur later. Treatment emergent adverse events led to premature study discontinuation for 7% of
subjects from Phase II-IV studies.
It is important to note that cases of pancreatitis have been reported in patients receiving Kaletra,
including those who developed hypertriglyceridaemia. Furthermore, rare increases in PR interval have
been reported during Kaletra therapy (see section 4.4).
b. Tabulated list of adverse reactions
Adverse reactions from clinical trials and post-marketing experience in adult and paediatric patients:
The following events have been identified as adverse reactions. The frequency category includes all
reported events of moderate to severe intensity, regardless of the individual causality assessment. The
adverse reactions are displayed by system organ class. 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) and not known (cannot be estimated from the available
data).
Events noted as having frequency “Not known” were identified via post-marketing surveillance.
42
System organ class
Frequency
Adverse reaction
Infections and infestations
Very common
Upper respiratory tract infection
Common
Lower respiratory tract infection, skin infections
including cellulitis, folliculitis and furuncle
Blood and lymphatic system
disorders
Common
Anaemia, leucopenia, neutropenia,
lymphadenopathy
Immune system disorders
Common
Hypersensitivity including urticaria and
angioedema
Uncommon
Immune reconstitution syndrome
Endocrine disorders
Uncommon
Hypogonadism
Metabolism and nutrition
disorders
Common
Blood glucose disorders including diabetes
mellitus, hypertriglyceridaemia,
hypercholesterolemia, weight decreased,
decreased appetite
Uncommon
Weight increased, increased appetite
Psychiatric disorders
Common
Anxiety
Uncommon
Abnormal dreams, libido decreased
Nervous system disorders
Common
Headache (including migraine), neuropathy
(including peripheral neuropathy), dizziness,
insomnia
Uncommon
Cerebrovascular accident, convulsion,
dysgeusia, ageusia, tremor
Eye disorders
Uncommon
Visual impairment
Ear and labyrinth disorders
Uncommon
Tinnitus, vertigo
Cardiac disorders
Uncommon
Atherosclerosis such as myocardial infarction
1
,
atrioventricular block, tricuspid valve
incompetence
Vascular disorders
Common
Hypertension
Uncommon
Deep vein thrombosis
Gastrointestinal disorders
Very common
Diarrhoea, nausea
Common
Pancreatitis
1
, vomiting, gastrooesophageal
reflux disease, gastroenteritis and colitis,
abdominal pain (upper and lower), abdominal
distension, dyspepsia, haemorrhoids, flatulence
Uncommon
Gastrointestinal haemorrhage including
gastrointestinal ulcer, duodenitis, gastritis and
rectal haemorrhage, stomatitis and oral ulcers,
faecal incontinence, constipation, dry mouth
43
Hepatobiliary disorders
Common
Hepatitis including AST, ALT and GGT
increases
Uncommon
Hepatic steatosis, hepatomegaly, cholangitis,
hyperbilirubinemia
Not known
Jaundice
Skin and subcutaneous tissue
disorders
Common
Lipodystrophy acquired including facial
wasting, rash including maculopapular rash,
dermatitis/rash including eczema and seborrheic
dermatitis, night sweats, pruritis
Uncommon
Alopecia, capillaritis, vasculitis
Not known
Steven-Johnson syndrome, erythema
multiforme
Musculoskeletal and connective
tissue disorders
Common
Myalgia, musculoskeletal pain including
arthralgia and back pain, muscle disorders such
as weakness and spasms
Uncommon
Rhabdomyolysis, osteonecrosis
Renal and urinary disorders
Uncommon
Creatinine clearance decreased, nephritis,
haematuria
Reproductive system and breast
disorders
Common
Erectile dysfunction, menstrual disorders -
amenorrhoea, menorrhagia
General disorders and
administration site conditions
Common
Fatigue including asthenia
1
See section 4.4: pancreatitis and lipids
c. Description of selected adverse reactions
Cushing’s syndrome has been reported in patients receiving ritonavir and inhaled or intranasally
administered fluticasone propionate; this could also occur with other corticosteroids metabolised via
the P450 3A pathway e.g. budesonide (see section 4.4 and 4.5).
Increased creatine phosphokinase (CPK), myalgia, myositis, and rarely, rhabdomyolysis have been
reported with protease inhibitors, particularly in combination with nucleoside reverse transcriptase
inhibitors.
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).
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).
44
d. Paediatric populations
In children 2 years of age and older, the nature of the safety profile is similar to that seen in adults (see
Table in section b).
To date, there is limited human experience of acute overdose with Kaletra.
The adverse clinical signs observed in dogs included salivation, emesis and diarrhoea/abnormal stool.
The signs of toxicity observed in mice, rats or dogs included decreased activity, ataxia, emaciation,
dehydration and tremors.
There is no specific antidote for overdose with Kaletra. Treatment of overdose with Kaletra is to
consist of general supportive measures including monitoring of vital signs and observation of the
clinical status of the patient. If indicated, elimination of unabsorbed active substance is to be achieved
by emesis or gastric lavage. Administration of activated charcoal may also be used to aid in removal
of unabsorbed active substance. Since Kaletra is highly protein bound, dialysis is unlikely to be
beneficial in significant removal of the active substance.
5.1 Pharmacodynamic properties
Pharmaco-therapeutic group: antivirals for systemic use, protease inhibitors, ATC code: J05AE06
Mechanism of action
:
Lopinavir provides the antiviral activity of Kaletra. Lopinavir is an inhibitor of
the HIV-1 and HIV-2 proteases. Inhibition of HIV protease prevents cleavage of the
gag-pol
polyprotein resulting in the production of immature, non-infectious virus.
Effects on the electrocardiogram
:
QTcF interval was evaluated in a randomised, placebo and active
(moxifloxacin 400 mg once daily) controlled crossover study in 39 healthy adults, with 10
measurements over 12 hours on Day 3. The maximum mean (95% upper confidence bound)
differences in QTcF from placebo were 3.6 (6.3) and 13.1(15.8) for 400/100 mg twice daily and
supratherapeutic 800/200 mg twice daily LPV/r, respectively. The induced QRS interval prolongation
from 6 ms to 9.5 ms with high dose lopinavir/ritonavir (800/200 mg twice daily) contributes to QT
prolongation. The two regimens resulted in exposures on Day 3 which were approximately 1.5 and 3-
fold higher than those observed with recommended once daily or twice daily LPV/r doses 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 lopinavir/ritonavir in the
same study on Day 3. The mean changes from baseline in PR interval ranged from 11.6 ms to 24.4 ms
in the 12 hour interval post dose.
Maximum PR interval was 286 msec and no second or third degree
heart block was observed (see section 4.4).
Antiviral activity in vitro
:
the
in vitro
antiviral activity of lopinavir against laboratory and clinical HIV
strains was evaluated in acutely infected lymphoblastic cell lines and peripheral blood lymphocytes,
respectively. In the absence of human serum, the mean IC
50
of lopinavir against five different HIV-1
laboratory strains was 19 nM. In the absence and presence of 50% human serum, the mean IC
50
of
lopinavir against HIV-1
IIIB
in MT4 cells was 17 nM and 102 nM, respectively. In the absence of
human serum, the mean IC
50
of lopinavir was 6.5 nM against several HIV-1 clinical isolates.
45
Resistance
In vitro selection of resistance:
HIV-1 isolates with reduced susceptibility to lopinavir have been selected
in vitro
. HIV-1 has been
passaged
in vitro
with lopinavir alone and with lopinavir plus ritonavir at concentration ratios
representing the range of plasma concentration ratios observed during Kaletra therapy. Genotypic and
phenotypic analysis of viruses selected in these passages suggest that the presence of ritonavir, at these
concentration ratios, does not measurably influence the selection of lopinavir-resistant viruses.
Overall, the
in vitro
characterisation of phenotypic cross-resistance between lopinavir and other
protease inhibitors suggest that decreased susceptibility to lopinavir correlated closely with decreased
susceptibility to ritonavir and indinavir, but did not correlate closely with decreased susceptibility to
amprenavir, saquinavir, and nelfinavir.
Analysis of resistance in ARV-naïve patients:
In clinical studies with a limited number of isolates analysed, the selection of resistance to lopinavir
has not been observed in naïve patients without significant protease inhibitor resistance at baseline.
See further the detailed description of the clinical studies.
Analysis of resistance in PI-experienced patients:
The selection of resistance to lopinavir in patients having failed prior protease inhibitor therapy was
characterised by analysing the longitudinal isolates from 19 protease inhibitor-experienced subjects in
2 Phase II and one Phase III studies who either experienced incomplete virologic suppression or viral
rebound subsequent to initial response to Kaletra and who demonstrated incremental
in vitro
resistance
between baseline and rebound (defined as emergence of new mutations or 2-fold change in phenotypic
susceptibility to lopinavir). Incremental resistance was most common in subjects whose baseline
isolates had several protease inhibitor-associated mutations, but < 40-fold reduced susceptibility to
lopinavir at baseline. Mutations V82A, I54V and M46I emerged most frequently. Mutations L33F,
I50V and V32I combined with I47V/A were also observed. The 19 isolates demonstrated a 4.3-fold
increase in IC
50
compared to baseline isolates (from 6.2- to 43-fold, compared to wild-type virus).
Genotypic correlates of reduced phenotypic susceptibility to lopinavir in viruses selected by other
protease inhibitors. The
in vitro
antiviral activity of lopinavir against 112 clinical isolates taken from
patients failing therapy with one or more protease inhibitors was assessed. Within this panel, the
following mutations in HIV protease were associated with reduced
in vitro
susceptibility to lopinavir:
L10F/I/R/V, K20M/R, L24I, M46I/L, F53L, I54L/T/V, L63P, A71I/L/T/V, V82A/F/T, I84V and
L90M. The median EC
50
of lopinavir against isolates with 0 − 3, 4 − 5, 6 − 7 and 8 − 10 mutations at
the above amino acid positions was 0.8, 2.7 13.5 and 44.0-fold higher than the EC
50
against wild type
HIV, respectively. The 16 viruses that displayed > 20-fold change in susceptibility all contained
mutations at positions 10, 54, 63 plus 82 and/or 84. In addition, they contained a median of
3 mutations at amino acid positions 20, 24, 46, 53, 71 and 90. In addition to the mutations described
above, mutations V32I and I47A have been observed in rebound isolates with reduced lopinavir
susceptibility from protease inhibitor experienced patients receiving Kaletra therapy, and mutations
I47A and L76V have been observed in rebound isolates with reduced lopinavir susceptibility from
patients receiving Kaletra therapy.
Conclusions regarding the relevance of particular mutations or mutational patterns are subject to
change with additional data, and it is recommended to always consult current interpretation systems
for analysing resistance test results.
Antiviral activity of Kaletra in patients failing protease inhibitor therapy:
the clinical relevance of
reduced
in vitro
susceptibility to lopinavir has been examined by assessing the virologic response to
Kaletra therapy, with respect to baseline viral genotype and phenotype, in 56 patients previous failing
therapy with multiple protease inhibitors. The EC
50
of lopinavir against the 56 baseline viral isolates
ranged from 0.6 to 96-fold higher than the EC
50
against wild type HIV. After 48 weeks of treatment
46
with Kaletra, efavirenz and nucleoside reverse transcriptase inhibitors, plasma HIV RNA
≤ 400 copies/ml was observed in 93% (25/27), 73% (11/15), and 25% (2/8) of patients with < 10-fold,
10 to 40-fold, and > 40-fold reduced susceptibility to lopinavir at baseline, respectively. In addition,
virologic response was observed in 91% (21/23), 71% (15/21) and 33% (2/6) patients with 0 − 5,
6 − 7, and 8 − 10 mutations of the above mutations in HIV protease associated with reduced
in vitro
susceptibility to lopinavir. Since these patients had not previously been exposed to either Kaletra or
efavirenz, part of the response may be attributed to the antiviral activity of efavirenz, particularly in
patients harbouring highly lopinavir resistant virus. The study did not contain a control arm of
patients not receiving Kaletra.
Cross-resistance:
Activity of other protease inhibitors against isolates that developed incremental
resistance to lopinavir after Kaletra therapy in protease inhibitor experienced patients: The presence of
cross resistance to other protease inhibitors was analysed in 18 rebound isolates that had demonstrated
evolution of resistance to lopinavir during 3 Phase II and one Phase III studies of Kaletra in protease
inhibitor-experienced patients. The median fold IC
50
of lopinavir for these 18 isolates at baseline and
rebound was 6.9- and 63-fold, respectively, compared to wild type virus. In general, rebound isolates
either retained (if cross-resistant at baseline) or developed significant cross-resistance to indinavir,
saquinavir and atazanavir. Modest decreases in amprenavir activity were noted with a median
increase of IC
50
from 3.7- to 8-fold in the baseline and rebound isolates, respectively. Isolates retained
susceptibility to tipranavir with a median increase of IC
50
in baseline and rebound isolates of 1.9- and
1.8–fold, respectively, compared to wild type virus. Please refer to the Aptivus Summary of Product
Characteristics for additional information on the use of tipranavir, including genotypic predictors of
response, in treatment of lopinavir-resistant HIV-1 infection.
Clinical results
The effects of Kaletra (in combination with other antiretroviral agents) on biological markers (plasma
HIV RNA levels and CD4+ T-cell counts) have been investigated in controlled studies of Kaletra of
48 to 360 weeks duration.
Adult Use
Patients without prior antiretroviral therapy
Study M98-863 was a randomised, double-blind trial of 653 antiretroviral treatment naïve patients
investigating Kaletra (400/100 mg twice daily) compared to nelfinavir (750 mg three times daily) plus
stavudine and lamivudine. Mean baseline CD4+ T-cell count was 259 cells/mm
3
(range: 2 to 949 cells/
mm
3
) and mean baseline plasma HIV-1 RNA was 4.9 log
10
copies/ml (range: 2.6 to
6.8 log
10
copies/ml).
Table 1
Outcomes at Week 48: Study M98-863
Kaletra (N=326)
Nelfinavir (N=327)
HIV RNA < 400 copies/ml*
75%
63%
HIV RNA < 50 copies/ml*†
67%
52%
Mean increase from baseline in
CD4+
T-cell count (cells/mm
3
)
207
195
* intent to treat analysis where patients with missing values are considered virologic failures
† p<0.001
One-hundred thirteen nelfinavir-treated patients and 74 lopinavir/ritonavir-treated patients had an HIV
RNA above 400 copies/ml while on treatment from Week 24 through Week 96. Of these, isolates
from 96 nelfinavir-treated patients and 51 lopinavir/ritonavir-treated patients could be amplified for
resistance testing. Resistance to nelfinavir, defined as the presence of the D30N or L90M mutation in
protease, was observed in 41/96 (43%) patients. Resistance to lopinavir, defined as the presence of
47
any primary or active site mutations in protease (see above), was observed in 0/51 (0%) patients. Lack
of resistance to lopinavir was confirmed by phenotypic analysis.
Sustained virological response to Kaletra (in combination with nucleoside/nucleotide reverse
transcriptase inhibitors) has been also observed in a small Phase II study (M97-720) through 360
weeks of treatment. One hundred patients were originally treated with Kaletra in the study (including
51 patients receiving 400/100 mg twice daily and 49 patients at either 200/100 mg twice daily or
400/200 mg twice daily). All patients converted to open-label Kaletra at the 400/100 mg twice daily
dose between week 48 and week 72. Thirty-nine patients (39%) discontinued the study, including 16
(16%) discontinuations due to adverse events, one of which was associated with a death. Sixty-one
patients completed the study (35 patients received the recommended 400/100 mg twice daily dose
throughout the study).
Table 2
Outcomes at Week 360: Study M97-720
Kaletra (N=100)
HIV RNA < 400 copies/ml
61%
HIV RNA < 50 copies/ml
59%
Mean increase from baseline in CD4+ T-cell count (cells/mm
3
)
501
Through 360 weeks of treatment, genotypic analysis of viral isolates was successfully conducted in 19
of 28 patients with confirmed HIV RNA above 400 copies/ml revealed no primary or active site
mutations in protease (amino acids at positions 8, 30, 32, 46, 47, 48, 50, 82, 84 and 90) or protease
inhibitor phenotypic resistance.
Patients with prior antiretroviral therapy
M97-765 is a randomised, double-blind trial evaluating Kaletra at two dose levels (400/100 mg and
400/200 mg, both twice daily) plus nevirapine (200 mg twice daily) and two nucleoside reverse
transcriptase inhibitors in 70 single protease inhibitor experienced, non-nucleoside reverse
transcriptase inhibitor naïve patients. Median baseline CD
4
cell count was 349 cells/mm
3
(range
72 to 807 cells/mm
3
) and median baseline plasma HIV-1 RNA was 4.0 log
10
copies/ml (range
2.9 to 5.8 log
10
copies/ml).
Table 3
Outcomes at Week 24: Study M97-765
Kaletra 400/100 mg
(N=36)
HIV RNA < 400 copies/ml (ITT)*
75%
HIV RNA < 50 copies/ml (ITT)*
58%
Mean increase from baseline in CD4+ T-cell count (cells/mm
3
)
174
* intent to treat analysis where patients with missing values are considered virologic failures
M98-957 is a randomised, open-label study evaluating Kaletra treatment at two dose levels
(400/100 mg and 533/133 mg, both twice daily) plus efavirenz (600 mg once daily) and nucleoside
reverse transcriptase inhibitors in 57 multiple protease inhibitor experienced, non-nucleoside reverse
transcriptase inhibitor naïve patients. Between week 24 and 48, patients randomised to a dose of
400/100 mg were converted to a dose of 533/133 mg. Median baseline CD
4
cell count was
220 cells/mm
3
(range13 to 1030 cells/mm
3
).
48
Table 4
Outcomes at Week 48: Study M98-957
Kaletra 400/100 mg
(N=57)
HIV RNA < 400 copies/ml*
65%
Mean increase from baseline in CD4+ T-cell count (cells/mm
3
)
94
* intent to treat analysis where patients with missing values are considered virologic failures
Paediatric Use
M98-940 was an open-label study of a liquid formulation of Kaletra in 100 antiretroviral naïve (44%)
and experienced (56%) paediatric patients. All patients were non-nucleoside reverse transcriptase
inhibitor naïve. Patients were randomised to either 230 mg lopinavir/57.5 mg ritonavir per m
2
or
300 mg lopinavir/75 mg ritonavir per m
2
. Naïve patients also received nucleoside reverse transcriptase
inhibitors. Experienced patients received nevirapine plus up to two nucleoside reverse transcriptase
inhibitors. Safety, efficacy and pharmacokinetic profiles of the two dose regimens were assessed after
3 weeks of therapy in each patient. Subsequently, all patients were continued on the 300/75 mg per m
2
dose. Patients had a mean age of 5 years (range 6 months to 12 years) with 14 patients less than 2
years old and 6 patients one year or less. Mean baseline CD4+ T-cell count was 838 cells/mm
3
and
mean baseline plasma HIV-1 RNA was 4.7 log
10
copies/ml.
Table 5
Outcomes at Week 48: Study M98-940
Antiretroviral Naïve
(N=44)
Antiretroviral
Experienced (N=56)
HIV RNA < 400 copies/ml
84%
75%
Mean increase from baseline in
CD4+ T-cell count (cells/mm
3
)
404
284
5.2 Pharmacokinetic properties
The pharmacokinetic properties of lopinavir co-administered with ritonavir have been evaluated in
healthy adult volunteers and in HIV-infected patients; no substantial differences were observed
between the two groups. Lopinavir is essentially completely metabolised by CYP3A. Ritonavir
inhibits the metabolism of lopinavir, thereby increasing the plasma levels of lopinavir. Across studies,
administration of Kaletra 400/100 mg twice daily yields mean steady-state lopinavir plasma
concentrations 15 to 20-fold higher than those of ritonavir in HIV-infected patients. The plasma levels
of ritonavir are less than 7% of those obtained after the ritonavir dose of 600 mg twice daily. The
in vitro
antiviral EC
50
of lopinavir is approximately 10-fold lower than that of ritonavir. Therefore, the
antiviral activity of Kaletra is due to lopinavir.
Absorption
: multiple dosing with 400/100 mg Kaletra twice daily for 2 weeks and without meal
restriction produced a mean ± SD lopinavir peak plasma concentration (C
max
) of 12.3 ± 5.4 μg/ml,
occurring approximately 4 hours after administration. The mean steady-state trough concentration
prior to the morning dose was 8.1 ± 5.7 μg/ml. Lopinavir AUC over a 12 hour dosing interval
averaged 113.2 ± 60.5 μg•h/ml. The absolute bioavailability of lopinavir co-formulated with ritonavir
in humans has not been established.
Effects of food on oral absorption
: Kaletra soft capsules and liquid have been shown to be
bioequivalent under nonfasting conditions (moderate fat meal). Administration of a single
400/100 mg dose of Kaletra soft capsules with a moderate fat meal (500 – 682 kcal, 22.7 –25.1% from
fat) was associated with a mean increase of 48% and 23% in lopinavir AUC and C
max
, respectively,
relative to fasting. For Kaletra oral solution, the corresponding increases in lopinavir AUC and C
max
49
were 80% and 54%, respectively. Administration of Kaletra with a high fat meal (872 kcal, 55.8%
from fat) increased lopinavir AUC and C
max
by 96% and 43%, respectively, for soft capsules, and
130% and 56%, respectively, for oral solution. To enhance bioavailability and minimise variability
Kaletra is to be taken with food.
Distribution
: at steady state, lopinavir is approximately 98 − 99% bound to serum proteins.
Lopinavir binds to both alpha-1-acid glycoprotein (AAG) and albumin, however, it has a higher
affinity for AAG. At steady state, lopinavir protein binding remains constant over the range of
observed concentrations after 400/100 mg Kaletra twice daily, and is similar between healthy
volunteers and HIV-positive patients.
Biotransformation
:
in vitro
experiments with human hepatic microsomes indicate that lopinavir
primarily undergoes oxidative metabolism. Lopinavir is extensively metabolised by the hepatic
cytochrome P450 system, almost exclusively by isozyme CYP3A. Ritonavir is a potent CYP3A
inhibitor which inhibits the metabolism of lopinavir and therefore, increases plasma levels of
lopinavir. A
14
C-lopinavir study in humans showed that 89% of the plasma radioactivity after a single
400/100 mg Kaletra dose was due to parent active substance. At least 13 lopinavir oxidative
metabolites have been identified in man. The 4-oxo and 4-hydroxymetabolite epimeric pair are the
major metabolites with antiviral activity, but comprise only minute amounts of total plasma
radioactivity. Ritonavir has been shown to induce metabolic enzymes, resulting in the induction of its
own metabolism, and likely the induction of lopinavir metabolism. Pre-dose lopinavir concentrations
decline with time during multiple dosing, stabilising after approximately 10 days to 2 weeks.
Elimination
:
after a 400/100 mg
14
C-lopinavir/ritonavir dose, approximately 10.4 ± 2.3% and
82.6 ± 2.5% of an administered dose of
14
C-lopinavir can be accounted for in urine and faeces,
respectively. Unchanged lopinavir accounted for approximately 2.2% and 19.8% of the administered
dose in urine and faeces, respectively. After multiple dosing, less than 3% of the lopinavir dose is
excreted unchanged in the urine. The effective (peak to trough) half-life of lopinavir over a 12 hour
dosing interval averaged 5 − 6 hours, and the apparent oral clearance (CL/F) of lopinavir is 6 to 7 l/h.
Special Populations
Paediatrics:
There are limited pharmacokinetic data in children below 2 years of age. The pharmacokinetics of
Kaletra 300/75 mg/m
2
twice daily and 230/57.5 mg/m
2
twice daily have been studied in a total of 53
paediatric patients, ranging in age from 6 months to 12 years. The lopinavir mean steady-state AUC,
C
max
, and C
min
were 72.6 ± 31.1 μg•h/ml, 8.2 ± 2.9 μg/ml and 3.4 ± 2.1 μg/ml, respectively after
Kaletra 230/57.5 mg/m
2
twice daily without nevirapine (n=12), and were 85.8 ± 36.9 μg•h/ml,
10.0 ± 3.3 μg/ml and 3.6 ± 3.5 μg/ml, respectively after 300/75 mg/m
2
twice daily with nevirapine
(n=12). The 230/57.5 mg/m
2
twice daily regimen without nevirapine and the 300/75 mg/m
2
twice
daily regimen with nevirapine provided lopinavir plasma concentrations similar to those obtained in
adult patients receiving the 400/100 mg twice daily regimen without nevirapine. Kaletra soft capsules
and Kaletra oral solution are bioequivalent under nonfasting conditions.
Gender, Race and Age:
Kaletra pharmacokinetics have not been studied in the elderly. No age or gender related
pharmacokinetic differences have been observed in adult patients. Pharmacokinetic differences due to
race have not been identified.
Renal Insufficiency:
Kaletra pharmacokinetics have not been studied in patients with renal insufficiency; however, since
the renal clearance of lopinavir is negligible, a decrease in total body clearance is not expected in
patients with renal insufficiency.
50
Hepatic Insufficiency:
The steady state pharmacokinetic parameters of lopinavir in HIV-infected patients with mild to
moderate hepatic impairment were compared with those of HIV-infected patients with normal hepatic
function in a multiple dose study with lopinavir/ritonavir 400/100 mg twice daily. A limited increase
in total lopinavir concentrations of approximately 30% has been observed which is not expected to be
of clinical relevance (see section 4.2).
5.3 Preclinical safety data
Repeat-dose toxicity studies in rodents and dogs identified major target organs as the liver, kidney,
thyroid, spleen and circulating red blood cells. Hepatic changes indicated cellular swelling with focal
degeneration. While exposure eliciting these changes were comparable to or below human clinical
exposure, dosages in animals were over 6-fold the recommended clinical dose. Mild renal tubular
degeneration was confined to mice exposed with at least twice the recommended human exposure; the
kidney was unaffected in rats and dogs. Reduced serum thyroxin led to an increased release of TSH
with resultant follicular cell hypertrophy in the thyroid glands of rats. These changes were reversible
with withdrawal of the active substance and were absent in mice and dogs. Coombs-negative
anisocytosis and poikilocytosis were observed in rats, but not in mice or dogs. Enlarged spleens with
histiocytosis were seen in rats but not other species. Serum cholesterol was elevated in rodents but not
dogs, while triglycerides were elevated only in mice.
During
in vitro
studies, cloned human cardiac potassium channels (HERG) were inhibited by 30% at
the highest concentrations of lopinavir/ritonavir tested, corresponding to a lopinavir exposure 7-fold
total and 15-fold free peak plasma levels achieved in humans at the maximum recommended
therapeutic dose. In contrast, similar concentrations of lopinavir/ritonavir demonstrated no
repolarisation delay in the canine cardiac Purkinje fibres. Lower concentrations of lopinavir/ritonavir
did not produce significant potassium (HERG) current blockade. Tissue distribution studies
conducted in the rat did not suggest significant cardiac retention of the active substance; 72-hour AUC
in heart was approximately 50% of measured plasma AUC. Therefore, it is reasonable to expect that
cardiac lopinavir levels would not be significantly higher than plasma levels.
In dogs, prominent U waves on the electrocardiogram have been observed associated with prolonged
PR interval and bradycardia. These effects have been assumed to be caused by electrolyte
disturbance.
The clinical relevance of these preclinical data is unknown, however, the potential cardiac effects of
this product in humans cannot be ruled out (see also sections 4.4 and 4.8).
In rats, embryofoetotoxicity (pregnancy loss, decreased foetal viability, decreased foetal body weights,
increased frequency of skeletal variations) and postnatal developmental toxicity (decreased survival of
pups) was observed at maternally toxic dosages. The systemic exposure to lopinavir/ritonavir at the
maternal and developmental toxic dosages was lower than the intended therapeutic exposure in
humans.
Long-term carcinogenicity studies of lopinavir/ritonavir in mice revealed a nongenotoxic, mitogenic
induction of liver tumours, generally considered to have little relevance to human risk.
Carcinogenicity studies in rats revealed no tumourigenic findings. Lopinavir/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, the mouse lymphoma assay, the mouse micronucleus test and chromosomal
aberration assays in human lymphocytes.
51
6.
6.1 List of excipients
Oral solution contains:
alcohol (42% v/v),
high fructose corn syrup,
propylene glycol,
purified water,
glycerol,
povidone,
magnasweet-110 flavour (mixture of monoammonium glycyrrhizinate and glycerol),
vanilla flavour (containing p-hydroxybenzoic acid, p-hydroxybenzaldehyde, vanillic acid, vanillin,
heliotrope, ethyl vanillin),
polyoxyl 40 hydrogenated castor oil,
cotton candy flavour (containing ethyl maltol, ethyl vanillin, acetoin, dihydrocoumarin, propylene
glycol),
acesulfame potassium,
saccharin sodium,
sodium chloride,
peppermint oil,
sodium citrate,
citric acid,
menthol.
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years
6.4 Special precautions for storage
Store in a refrigerator (2°C - 8°C).
In use storage: If kept outside of the refrigerator, do not store above 25°C and discard any unused
contents after 42 days (6 weeks). It is advised to write the date of removal from the refrigerator on the
package.
Avoid exposure to excessive heat.
6.5 Nature and content of container
Amber coloured multiple-dose polyethylene terephthalate (PET) bottles in a 60 ml size. Each pack
contains 5 bottles of 60 ml (300 ml). The pack also contains 5 x 5 ml syringes with 0.1 ml graduations
from 0 to 5 ml (400/100 mg).
6.6 Special precautions for disposal
No special requirements.
52
7.
Abbott Laboratories Limited
Abbott House
Vanwall Business Park
Vanwall Road
Maidenhead
Berkshire SL6 4XE
United Kingdom
8.
EU/1/01/172/003
Date of first authorisation: 20 March 2001
Date of latest renewal: 20 March 2006
{MM/YYYY}
Detailed information on this product is available on the website of the European Medicines Agency
53
Abbott Laboratories Limited
Abbott House
Vanwall Business Park
Vanwall Road
Maidenhead
Berkshire SL6 4XE
United Kingdom
8.
EU/1/01/172/004
EU/1/01/172/005
EU/1/01/172/007
EU/1/01/172/008
Date of first authorisation: 20 March 2001
Date of latest renewal: 20 March 2006
{MM/YYYY}
Detailed information on this product is available on the website of the European Medicines Agency
80
