Kaletra

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 
 



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1. NAME OF THE MEDICINAL PRODUCT  
 
Kaletra (80 mg + 20 mg) / ml oral solution 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION  
 
Each 1 ml of Kaletra oral solution contains 80 mg of lopinavir co-formulated with 20 mg of ritonavir 
as a pharmacokinetic enhancer. 
 
Excipients with known effect: 
 
Each 1 ml contains 356.3 mg of alcohol (42.4% v/v), 168.6 mg of high fructose corn syrup, 152.7 mg 
of propylene glycol (15.3% w/v) (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 the full list of excipients, see section 6.1.  
 
 
3. PHARMACEUTICAL FORM  
 
Oral solution 
 
The solution is light yellow to orange. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Kaletra is indicated in combination with other antiretroviral medicinal products for the treatment of 
human immunodeficiency virus (HIV-1) infected adults, adolescents and children aged from 14 days 
and older. 
 
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). 
 
4.2 Posology and method of administration 
 
Kaletra should be prescribed by physicians who are experienced in the treatment of HIV infection. 
 
Posology 
 
Adults and adolescents  
The recommended dosage of Kaletra is 5 ml of oral solution (400/100 mg) twice daily taken with 
food. 
 
Paediatric population aged from 14 days and older  
The oral solution formulation is the recommended option for the most accurate dosing in children 
based on body surface area or body weight.  However, if it is judged necessary to resort to solid oral 
dosage form for children weighing less than 40 kg or with a BSA between 0.5 and 1.4 m2 and able to 
swallow tablets, Kaletra 100 mg/25 mg tablets may be used.  The adult dose of Kaletra tablets 
(400/100 mg twice daily) may be used in children 40 kg or greater or with a Body Surface Area 
(BSA)* greater than 1.4 m2.  Kaletra tablets are administered orally and must be swallowed whole and 
not chewed, broken or crushed.  Please refer to the Kaletra 100 mg/25 mg film-coated tablets 
Summary of Product Characteristics. 
 



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Total amounts of alcohol and propylene glycol from all medicines, including Kaletra oral solution, that 
are to be given to infants should be taken into account in order to avoid toxicity from these excipients 
(see section 4.4). 
 
Dosage recommendation for paediatric patients aged from 14 days to 6 months 
 

Paediatric dosing guidelines 
2 weeks to 6 months 

Based on weight 
(mg/kg) 

Based on BSA (mg/m2)* Frequency 

16/4 mg/kg 
(corresponding to 0.2 ml/kg) 

300/75 mg/m2 
(corresponding to 3.75 ml/m2) 

Given twice daily 
with food 

*Body surface area can be calculated with the following equation 
BSA (m2) = √ (Height (cm) X Weight (kg) / 3600) 

 
It is recommended that Kaletra not be administered in combination with efavirenz or nevirapine in 
patients less than 6 months of age. 
 
Dosage recommendation for paediatric patients older than 6 months to less than 18 years 
 
Without Concomitant Efavirenz or Nevirapine 
 
The following tables contain dosing guidelines for Kaletra oral solution based on body weight and 
BSA. 
 

Paediatric dosing guidelines based on body weight* 
> 6 months to 18 years 

Body weight (kg) Twice daily oral solution dose  
(dose in mg/kg) 

Volume of oral solution 
twice daily taken with food 

(80 mg lopinavir/20 mg 
ritonavir per ml)** 

7 to < 15 kg 
7 to 10 kg 

> 10 to < 15 kg 

12/3 mg/kg  
1.25 ml 
1.75 ml 

≥ 15 to 40 kg 
15 to 20 kg 

> 20 to 25 kg 
> 25 to 30 kg 
> 30 to 35 kg 
> 35 to 40 kg 

10/2.5 mg/kg  
2.25 ml 
2.75 ml 
3.50 ml 
4.00 ml 
4.75 ml 

≥ 40 kg See adult dosage recommendation 
 *weight based dosing recommendations are based on limited data  
 ** the volume (ml) of oral solution represents the average dose for the weight range 
 



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Paediatric dosing guidelines for the dose 230/57.5 mg/m2 
> 6 months to < 18 years 

Body Surface Area* (m2) Twice daily oral solution dose (dose in mg) 

0.25 0.7 ml (57.5/14.4 mg) 
0.40 1.2 ml (96/24 mg) 
0.50 1.4 ml (115/28.8 mg) 
0.75 2.2 ml (172.5/43.1 mg) 
0.80 2.3 ml (184/46 mg) 
1.00 2.9 ml (230/57.5 mg) 
1.25 3.6 ml (287.5/71.9 mg) 
1.3 3.7 ml (299/74.8 mg) 
1.4 4.0 ml (322/80.5 mg) 
1.5 4.3 ml (345/86.3 mg) 
1.7 5 ml (402.5/100.6 mg) 

 *Body surface area can be calculated with the following equation 
 BSA (m2) = √ (Height (cm) X Weight (kg) / 3600) 
 
Concomitant Therapy: Efavirenz or Nevirapine 
 
The 230/57.5 mg/m2 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/m2 is needed in these 
patients.  The recommended dose of 533/133 mg or 6.5 ml twice daily should not be exceeded. 
 
Children less than 14 days of age and premature neonates  
Kaletra oral solution should not be administered to neonates before a postmenstrual age (first day of 
the mother’s last menstrual period to birth plus the time elapsed after birth) of 42 weeks and a 
postnatal age of at least 14 days has been reached (see section 4.4). 
 
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).  The dose 
should be administered using a calibrated 2 ml or 5 ml oral dosing syringe best corresponding to the 
volume prescribed. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.  
 
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: 



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Medicinal product 
class 

Medicinal products within 
class 

Rationale 

Concomitant medicinal product levels increased 

Alpha1-adrenoreceptor 
antagonist 

Alfuzosin Increased plasma concentrations of 
alfuzosin which may lead to severe 
hypotension.  The concomitant 
administration with alfuzosin is 
contraindicated (see section 4.5). 

Antianginal Ranolazine Increased plasma concentrations of 
ranolazine which may increase the 
potential for serious and/or life-
threatening reactions (see section 4.5). 

Antiarrhythmics Amiodarone, dronedarone Increased plasma concentrations of 
amiodarone and dronedarone.  Thereby, 
increasing the risk of arrhythmias or 
other serious adverse reactions (see 
section 4.5). 

Antibiotic Fusidic Acid Increased plasma concentrations of 
fusidic acid. The concomitant 
administration with fusidic acid is 
contraindicated in dermatological 
infections (see section 4.5). 

Anticancer Neratinib Increased plasma concentrations of 
neratinib which may increase the 
potential for serious and/or 
life-threatening reactions (see section 
4.5). 

Venetoclax Increased plasma concentrations of 
venetoclax.  Increased risk of tumor lysis 
syndrome at the dose initiation and 
during the ramp-up phase (see section 
4.5). 

Anti-gout Colchicine Increased plasma concentrations of 
colchicine.  Potential for serious and/or 
life-threatening reactions in patients with 
renal and/or hepatic impairment (see 
sections 4.4 and 4.5). 

Antihistamines Astemizole, terfenadine Increased plasma concentrations of 
astemizole and terfenadine.  Thereby, 
increasing the risk of serious 
arrhythmias from these agents (see 
section 4.5). 

Antipsychotics/ 
Neuroleptics 

Lurasidone Increased plasma concentrations of 
lurasidone which may increase the 
potential for serious and/or life-
threatening reactions (see section 4.5). 

Pimozide Increased plasma concentrations of 
pimozide.  Thereby, increasing the risk 
of serious haematologic abnormalities, 
or other serious adverse effects from this 
agent (see section 4.5). 



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Quetiapine Increased plasma concentrations of 
quetiapine which may lead to coma.  The 
concomitant administration with 
quetiapine is contraindicated (see section 
4.5). 

Ergot alkaloids 
 

Dihydroergotamine, ergonovine, 
ergotamine, methylergonovine 

Increased plasma concentrations of ergot 
derivatives leading to acute ergot 
toxicity, including vasospasm and 
ischaemia (see section 4.5). 

GI motility agent Cisapride Increased plasma concentrations of 
cisapride.  Thereby, increasing the risk 
of serious arrhythmias from this agent 
(see section 4.5). 

Hepatitis C virus 
direct acting antivirals 

Elbasvir/grazoprevir Increased risk of alanine transaminase 
(ALT) elevations (see section 4.5). 

Ombitasvir/paritaprevir/ritonavir 
with or without dasabuvir 

Increased plasma concentrations of 
paritaprevir; thereby, increasing the risk 
of alanine transaminase (ALT) 
elevations (see section 4.5). 

Lipid-modifying agents 
 

 

HMG Co-A Reductase 
Inhibitors 

Lovastatin, simvastatin Increased plasma concentrations of 
lovastatin and simvastatin; thereby, 
increasing the risk of myopathy 
including rhabdomyolysis (see section 
4.5). 

Microsomal 
triglyceride transfer 
protein (MTTP) 
inhibitor 

Lomitapide Increased plasma concentrations of 
lomitapide (see section 4.5). 

Phosphodiesterase 
(PDE5) inhibitors 

Avanafil Increased plasma concentrations of 
avanafil (see sections 4.4 and 4.5). 

Sildenafil 
 

Contraindicated when used for the 
treatment of pulmonary arterial 
hypertension (PAH) only.  Increased 
plasma concentrations of sildenafil.  
Thereby, increasing the potential for 
sildenafil-associated adverse events 
(which include hypotension and 
syncope).  See section 4.4 and section 
4.5 for co-administration of sildenafil in 
patients with erectile dysfunction. 

Vardenafil Increased plasma concentrations of 
vardenafil (see sections 4.4 and 4.5) 

Sedatives/hypnotics Oral midazolam, triazolam Increased plasma concentrations of oral 
midazolam and triazolam.  Thereby, 
increasing the risk of extreme sedation 
and respiratory depression from these 
agents.   
For caution on parenterally administered 
midazolam, see section 4.5. 



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Lopinavir/ritonavir medicinal product level decreased 

Herbal products St. John’s wort Herbal preparations containing St John’s 
wort (Hypericum perforatum) due to the 
risk of decreased plasma concentrations 
and reduced clinical effects of lopinavir 
and ritonavir (see section 4.5). 

 
Kaletra oral solution is contraindicated in children below the age of 14 days, 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). 
 
4.4 Special warnings and precautions for use  
 
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. 
 
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. 
 



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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). 
 
Immune Reconstitution Inflammatory 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. 
 
Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to 
occur in the setting of immune reconstitution; however, the reported time to onset is more variable and 
can occur many months after initiation of treatment. 
 
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 2nd or 3rd 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). 
 
Weight and metabolic parameters 
An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral 
therapy.  Such changes may in part be linked to disease control and life style.  For lipids, there is in 
some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating 
this to any particular treatment.  For monitoring of blood lipids and glucose, reference is made to 
established HIV treatment guidelines.  Lipid disorders should be managed as clinically appropriate. 
 
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).  
 
Strong CYP3A4 inhibitors such as protease inhibitors may increase bedaquiline exposure which could 
potentially increase the risk of bedaquiline-related adverse reactions.  Therefore, combination of 
bedaquiline with lopinavir/ritonavir should be avoided.  However, if the benefit outweighs the risk, 
co-administration of bedaquiline with lopinavir/ritonavir must be done with caution.  More frequent 
electrocardiogram monitoring and monitoring of transaminases is recommended (see section 4.5 and 
refer to the bedaquiline SmPC). 
 
Co-administration of delamanid with a strong inhibitor of CYP3A (as lopinavir/ritonavir) may 
increase exposure to delamanid metabolite, which has been associated with QTc prolongation.  



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Therefore, if co-administration of delamanid with lopinavir/ritonavir is considered necessary, very 
frequent ECG monitoring throughout the full delamanid treatment period is recommended (see section 
4.5 and refer to the delamanid SmPC). 
 
Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and 
strong inhibitors of CYP3A like ritonavir.  Concomitant administration with colchicine is 
contraindicated in patients with renal and/or hepatic impairment (see sections 4.3 and 4.5). 
 
The combination of Kaletra with:  
- tadalafil, indicated for the treatment of pulmonary arterial hypertension, is not recommended 

(see section 4.5); 
- riociguat is not recommended (see section 4.5); 
- vorapaxar is not recommended (see section 4.5); 
- fusidic acid in osteo-articular infections is not recommended (see section 4.5); 
- salmeterol is not recommended (see section 4.5); 
- rivaroxaban is not recommended (see section 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 avanafil or 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, 
such as budesonide and triamcinolone, 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). 
 



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Kaletra is not a cure for HIV infection or AIDS.  While effective viral suppression with antiretroviral 
therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot 
be excluded.  Precautions to prevent transmission should be taken in accordance with national 
guidelines.  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. 
 
Particular risk of toxicity in relation to the amount of alcohol and propylene glycol contained in 
Kaletra oral solution 
 
Healthcare professionals should be aware that Kaletra oral solution is highly concentrated and contains 
42.4% alcohol (v/v) and 15.3% propylene glycol (w/v).   Each 1 ml of Kaletra oral solution contains 
356.3 mg of alcohol and 152.7 mg of propylene glycol.    
 
Special attention should be given to accurate calculation of the dose of Kaletra, transcription of the 
medication order, dispensing information and dosing instructions to minimize the risk for medication 
errors and overdose.  This is especially important for infants and young children.   
 
Total amounts of alcohol and propylene glycol from all medicines that are to be given to infants 
should be taken into account in order to avoid toxicity from these excipients.  Infants should be 
monitored closely for toxicity related to Kaletra oral solution including: hyperosmolality, with or 
without lactic acidosis, renal toxicity, central nervous system (CNS) depression (including stupor, 
coma, and apnea), seizures, hypotonia, cardiac arrhythmias and ECG changes, and hemolysis.  
Postmarketing life-threatening cases of cardiac toxicity (including complete atrioventricular (AV) 
block, bradycardia, and cardiomyopathy), lactic acidosis, acute renal failure, CNS depression and 
respiratory complications leading to death have been reported, predominantly in preterm neonates 
receiving Kaletra oral solution (see sections 4.3 and 4.9).  
 
Based on the findings in a paediatric study (observed exposures were approximately 35% AUC12 and 
75% lower Cmin than in adults), young children from 14 days to 3 months could have sub-optimal 
exposure with a potential risk of inadequate virologic suppression and emergence of resistance (see 
section 5.2). 
 
Because Kaletra oral solution contains alcohol, it is not recommended for use with polyurethane 
feeding tubes due to potential incompatibility. 
 
4.5  Interaction with other medicinal products and other forms of interaction  
 
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. 



 11 

 
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.  This list is not intended to be inclusive or comprehensive.  
Individual SmPCs should be consulted. 
 
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 
 
Geometric Mean Change (%) in 
AUC, Cmax, Cmin 
 
Mechanism of interaction 

Clinical recommendation 
concerning co-administration 
with Kaletra 

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 lopinavir/ritonavir. 

The clinical significance of 
reduced abacavir and zidovudine 
concentrations is unknown. 

Tenofovir disoproxil 
fumarate (DF), 300 mg QD 
  
(equivalent to 245 mg 
tenofovir disoproxil) 

Tenofovir: 
AUC: ↑ 32% 
Cmax: ↔ 
Cmin: ↑ 51% 
 
Lopinavir: ↔ 

No dose adjustment necessary.   
Higher tenofovir concentrations 
could potentiate tenofovir 
associated adverse events, 
including renal disorders. 

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)  
Efavirenz, 600 mg QD 
 
 

Lopinavir: 
AUC: ↓ 20% 
Cmax: ↓ 13% 
Cmin: ↓ 42% 

The Kaletra tablets dosage should 
be increased to 500/125 mg twice 
daily when co-administered with 
efavirenz.   

Efavirenz, 600 mg QD 
 
(Lopinavir/ritonavir 
500/125 mg BID) 

 
Lopinavir: ↔ 
(Relative to 400/100 mg BID 
administered alone)  

Nevirapine, 200 mg BID 
 
 

Lopinavir: 
AUC: ↓ 27% 
Cmax: ↓ 19% 
Cmin: ↓ 51% 

The Kaletra tablets dosage should 
be increased to 500/125 mg twice 
daily when co-administered with 
nevirapine.   

Etravirine 
 
(Lopinavir/ritonavir tablet 
400/100 mg BID) 

Etravirine: 
AUC: ↓ 35% 
Cmin: ↓ 45%  
Cmax: ↓ 30% 
 
Lopinavir: 
AUC: ↔  

No dose adjustment necessary 



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Cmin: ↓ 20% 
Cmax: ↔  

Rilpivirine 
 
(Lopinavir/ritonavir 
capsule 400/100 mg BID) 

Rilpivirine: 
AUC: ↑ 52%  
Cmin: ↑ 74%  
Cmax: ↑ 29% 
 
Lopinavir: 
AUC: ↔ 
Cmin: ↓ 11%  
Cmax: ↔  
 
(inhibition of CYP3A enzymes) 

Concomitant use of Kaletra with 
rilpivirine causes an increase in 
the plasma concentrations of 
rilpivirine, but no dose adjustment 
is required. 

HIV CCR5 – antagonist 
Maraviroc 
 

Maraviroc: 
AUC: ↑ 295%  
Cmax: ↑ 97%  
Due to CYP3A inhibition by 
lopinavir/ritonavir. 

The dose of maraviroc should be 
decreased to 150 mg twice daily 
during co-administration with 
Kaletra 400/100 mg twice daily.   

Integrase inhibitor 
Raltegravir Raltegravir:  

AUC: ↔ 
Cmax: ↔ 
C12: ↓ 30% 
Lopinavir: ↔ 

No dose adjustment necessary 

 

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)  
 
(Lopinavir/ritonavir 
400/100 mg BID) 
 
or  
 
Fosamprenavir (1400 mg 
BID) 
 
(Lopinavir/ritonavir 
533/133 mg BID) 
 
 

Fosamprenavir: 
Amprenavir concentrations are 
significantly reduced.  
 
 

 

Co-administration of increased 
doses of fosamprenavir (1400 mg 
BID) with Kaletra (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. 

Indinavir, 600 mg BID 
 
 

Indinavir:  
AUC: ↔ 
Cmin: ↑ 3.5-fold 
Cmax: ↓ 
(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. 

Saquinavir  
1000 mg BID 

Saquinavir:  ↔  No dose adjustment necessary. 

Tipranavir/ritonavir 
(500/100 mg BID) 

Lopinavir: 
AUC: ↓ 55% 
Cmin: ↓ 70% 

Concomitant administration of 
these medicinal products is not 
recommended. 



 13 

Cmax: ↓ 47% 
Acid reducing agents 
Omeprazole (40 mg QD)  
  

Omeprazole: ↔ 
 
Lopinavir: ↔ 

No dose adjustment necessary 

Ranitidine (150 mg single 
dose) 

Ranitidine: ↔ No dose adjustment necessary 

Alpha1 adrenoreceptor antagonist 
Alfuzosin  Alfuzosin: 

Due to CYP3A inhibition by 
lopinavir/ritonavir, concentrations 
of alfuzosin are expected to 
increase. 

Concomitant administration of 
Kaletra and alfuzosin is contra-
indicated (see section 4.3) as 
alfuzosin-related toxicity, 
including hypotension, may be 
increased. 

Analgesics 
Fentanyl 
  

Fentanyl: 
Increased risk of side-effects 
(respiratory depression, sedation) 
due to higher plasma 
concentrations because of 
CYP3A4 inhibition by 
lopinavir/ritonavir. 

Careful monitoring of adverse 
effects (notably respiratory 
depression but also sedation) is 
recommended when fentanyl is 
concomitantly administered with 
Kaletra. 

Antianginal 
Ranolazine Due to CYP3A inhibition by 

lopinavir/ritonavir, concentrations 
of ranolazine are expected to 
increase. 

The concomitant administration of 
Kaletra and ranolazine is 
contraindicated (see section 4.3). 

Antiarrhythmics 
Amiodarone, Dronedarone Amiodarone, Dronedarone: 

Concentrations may be increased 
due to CYP3A4 inhibition by 
lopinavir/ritonavir. 

Concomitant administration of 
Kaletra and amiodarone or 
dronedarone is contraindicated 
(see section 4.3) as the risk of 
arrhythmias or other serious 
adverse reactions may be 
increased. 

Digoxin 
 
 

Digoxin: 
Plasma concentrations may be 
increased due to P-glycoprotein 
inhibition by lopinavir/ritonavir.  
The increased digoxin level may 
lessen over time as P-gp 
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 P-gp 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 
lopinavir/ritonavir.  

Caution is warranted and 
therapeutic drug concentration 
monitoring is recommended when 
available. 



 14 

Antibiotics 
Clarithromycin Clarithromycin:  

Moderate increases in 
clarithromycin AUC are expected 
due to CYP3A inhibition by 
lopinavir/ritonavir.  
 

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 and kinase inhibitors 
Abemaciclib  Serum concentrations may be 

increased due to CYP3A 
inhibition by ritonavir. 

Co-administration of abemaciclib 
and Kaletra should be avoided.  If 
this co-administration is judged 
unavoidable, refer to the 
abemaciclib SmPC for dosage 
adjustment recommendations.  
Monitor for ADRs related to 
abemaciclib. 

Apalutamide Apalutamide is a moderate to 
strong CYP3A4 inducer and this 
may lead to a decreased exposure 
of lopinavir/ritonavir. 
 
Serum concentrations of 
apalutamide may be increased 
due to CYP3A inhibition by 
lopinavir/ritonavir. 

Decreased exposure of Kaletra 
may result in potential loss of 
virological response.   
In addition, co-administration of 
apalutamide and Kaletra may lead 
to serious adverse events 
including seizure due to higher 
apalutamide levels.  Concomitant 
use of Kaletra with apalutamide is 
not recommended. 

Afatinib 
 
(Ritonavir 200 mg twice 
daily) 

Afatinib: 
AUC: ↑  
Cmax: ↑ 
 
The extent of increase depends on 
the timing of ritonavir 
administration. 
 
Due to BCRP (breast cancer 
resistance protein/ABCG2) and 
acute P-gp inhibition by 
lopinavir/ritonavir. 

Caution should be exercised in 
administering afatinib with 
Kaletra.  Refer to the afatinib 
SmPC for dosage adjustment 
recommendations.  Monitor for 
ADRs related to afatinib. 

Ceritinib Serum concentrations may be 
increased due to CYP3A and 
P-gp inhibition by 
lopinavir/ritonavir. 

Caution should be exercised in 
administering ceritinib with 
Kaletra.  Refer to the ceritinib 
SmPC for dosage adjustment 
recommendations.  Monitor for 
ADRs related to ceritinib. 

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 
lopinavir/ritonavir. 

Careful monitoring of the 
tolerance of these anticancer 
agents. 
 



 15 

Encorafenib Serum concentrations may be 
increased due to CYP3A 
inhibition by lopinavir/ritonavir. 

Co-administration of encorafenib 
with Kaletra may increase 
encorafenib exposure which may 
increase the risk of toxicity, 
including the risk of serious 
adverse events such as QT interval 
prolongation.  Co-administration 
of encorafenib and Kaletra should 
be avoided.  If the benefit is 
considered to outweigh the risk 
and Kaletra must be used, patients 
should be carefully monitored for 
safety. 

Fostamatinib Increase in fostamatinib 
metabolite R406 exposure. 

Co-administration of fostamatinib 
with Kaletra may increase 
fostamatinib metabolite R406 
exposure resulting in dose-related 
adverse events such as 
hepatotoxicity, neutropenia, 
hypertension, or diarrhoea.  Refer 
to the fostamatinib SmPC for dose 
reduction recommendations if 
such events occur. 

Ibrutinib Serum concentrations may be 
increased due to CYP3A 
inhibition by lopinavir/ritonavir. 

Co-administration of ibrutinib and 
Kaletra may increase ibrutinib 
exposure which may increase the 
risk of toxicity including risk of 
tumor lysis syndrome. 
Co-administration of ibrutinib and 
Kaletra should be avoided.  If the 
benefit is considered to outweigh 
the risk and Kaletra must be used, 
reduce the ibrutinib dose to 
140 mg and monitor patient 
closely for toxicity. 

Neratinib Serum concentrations may be 
increased due to CYP3A 
inhibition by ritonavir. 

Concomitant use of neratinib with 
Kaletra is contraindicated due to 
serious and/or life-threatening 
potential reactions including 
hepatotoxicity (see section 4.3). 

Venetoclax Due to CYP3A inhibition by 
lopinavir/ritonavir. 

Serum concentrations may be 
increased due to CYP3A 
inhibition by lopinavir/ritonavir, 
resulting in increased risk of 
tumor lysis syndrome at the dose 
initiation and during the ramp-up 
phase (see section 4.3 and refer to 
the venetoclax SmPC). 
 
For patients who have completed 
the ramp-up phase and are on a 
steady daily dose of venetoclax, 
reduce the venetoclax dose by at 
least 75% when used with strong 
CYP3A inhibitors (refer to the 
venetoclax SmPC for dosing 
instructions).  Patients should be 



 16 

closely monitored for signs related 
to venetoclax toxicities. 

Anticoagulants 
Warfarin 
 
 
 

Warfarin: 
Concentrations may be affected 
when co-administered with 
lopinavir/ritonavir due to 
CYP2C9 induction.   

It is recommended that INR 
(international normalised ratio) be 
monitored. 
 

Rivaroxaban 
 
(Ritonavir 600 mg twice 
daily) 

Rivaroxaban:   
AUC: ↑ 153%  
Cmax: ↑ 55% 
Due to CYP3A and P-gp 
inhibition by lopinavir/ritonavir. 

Co-administration of rivaroxaban 
and Kaletra may increase 
rivaroxaban exposure which may 
increase the risk of bleeding. 
The use of rivaroxaban is not 
recommended in patients 
receiving concomitant treatment 
with Kaletra (see section 4.4). 

Vorapaxar Serum concentrations may be 
increased due to CYP3A 
inhibition by lopinavir/ritonavir. 

The co-administration of 
vorapaxar with Kaletra is not 
recommended (see section 4.4 and 
refer to the vorapaxar SmPC). 

Anticonvulsants 
Phenytoin 
 

Phenytoin: 
Steady-state concentrations was 
moderately decreased due to 
CYP2C9 and CYP2C19 induction 
by lopinavir/ritonavir. 
 
Lopinavir:   
Concentrations are decreased due 
to CYP3A induction by 
phenytoin.   
 

Caution should be exercised in 
administering phenytoin with 
Kaletra. 
 
Phenytoin levels should be 
monitored when co-administering 
with Kaletra. 
 
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 lopinavir/ritonavir. 
 
Lopinavir: 
Concentrations may be decreased 
due to CYP3A induction by 
carbamazepine and phenobarbital.   
 

Caution should be exercised in 
administering carbamazepine or 
phenobarbital with Kaletra. 
 
Carbamazepine and phenobarbital 
levels should be monitored when 
co-administering with Kaletra. 
 
When co-administered with 
carbamazepine or phenobarbital, 
an increase of Kaletra dosage may 
be envisaged.  Dose adjustment 
has not been evaluated in clinical 
practice 



 17 

Lamotrigine and Valproate Lamotrigine:  
AUC: ↓ 50% 
Cmax: ↓ 46% 
Cmin: ↓ 56% 
 
Due to induction of lamotrigine 
glucuronidation 
 
Valproate: ↓ 

Patients should be monitored 
closely for a decreased VPA effect 
when Kaletra and valproic acid or 
valproate are given concomitantly. 
 
In patients starting or stopping 
Kaletra while currently taking 
maintenance dose of lamotrigine: 
lamotrigine dose may need to be 
increased if Kaletra is added, or 
decreased if Kaletra is 
discontinued; therefore plasma 
lamotrigine monitoring should be 
conducted, particularly before and 
during 2 weeks after starting or 
stopping Kaletra, in order to see if 
lamotrigine dose adjustment is 
needed. 
In patients currently taking 
Kaletra and starting lamotrigine: 
no dose adjustments to the 
recommended dose escalation of 
lamotrigine should be necessary. 

Antidepressants and Anxiolytics 
Trazodone single dose 
 
(Ritonavir, 200 mg BID) 
 

Trazodone: 
AUC: ↑ 2.4-fold 
 
Adverse events of nausea, 
dizziness, hypotension and 
syncope were observed following 
co-administration of trazodone 
and ritonavir.   

It is unknown whether the 
combination of Kaletra causes a 
similar increase in trazodone 
exposure.  The combination 
should be used with caution and a 
lower dose of trazodone should be 
considered. 
 

Antifungals 
Ketoconazole and 
Itraconazole 

Ketoconazole, Itraconazole: 
Serum concentrations may be 
increased due to CYP3A 
inhibition by lopinavir/ritonavir.  

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. 



 18 

Anti-gout agents 
Colchicine single dose 
 
(Ritonavir 200 mg twice 
daily) 

Colchicine: 
AUC: ↑ 3-fold 
Cmax: ↑ 1.8-fold 
Due to P-gp and/or CYP3A4 
inhibition by ritonavir. 
 

Concomitant administration of 
Kaletra with colchicine in patients 
with renal and/or hepatic 
impairment is contraindicated due 
to a potential increase of 
colchicine-related serious and/or 
life-threatening reactions such as 
neuromuscular toxicity (including 
rhabdomyolysis) (see sections 4.3 
and 4.4).  A reduction in 
colchicine dosage or an 
interruption of colchicine 
treatment is recommended in 
patients with normal renal or 
hepatic function if treatment with 
Kaletra is required.  Refer to 
colchicine prescribing 
information. 

Antihistamines 
Astemizole 
Terfenadine 

Serum concentrations may be 
increased due to CYP3A 
inhibition by lopinavir/ritonavir. 

Concomitant administration of 
Kaletra and astemizole and 
terfenadine is contraindicated as it 
may increase the risk of serious 
arrhythmias from these agents 
(see section 4.3). 

Anti-infectives 
Fusidic acid Fusidic acid: 

Concentrations may be increased 
due to CYP3A inhibition by 
lopinavir/ritonavir. 

Concomitant administration of 
Kaletra with fusidic acid is contra-
indicated in dermatological 
indications due to the increased 
risk of adverse events related to 
fusidic acid, notably 
rhabdomyolysis (see section 4.3).  
When used for osteo-articular 
infections, where the co-
administration is unavoidable, 
close clinical monitoring for 
muscular adverse events is 
strongly recommended (see section 
4.4).  

Antimycobacterials 
Bedaquiline 
(single dose) 
 
(Lopinavir/ritonavir 
400/100 mg BID, multiple 
dose) 

Bedaquiline: 
AUC: ↑ 22% 
Cmax: ↔ 
 
A more pronounced effect on 
bedaquiline plasma exposures 
may be observed during 
prolonged co-administration with 
lopinavir/ritonavir. 
 
CYP3A4 inhibition likely due to 
lopinavir/ritonavir. 
 

Due to the risk of bedaquiline 
related adverse events, the 
combination of bedaquiline and 
Kaletra should be avoided.  If the 
benefit outweighs the risk, 
co-administration of bedaquiline 
with Kaletra must be done with 
caution.  More frequent 
electrocardiogram monitoring and 
monitoring of transaminases is 
recommended (see section 4.4 and 
refer to the bedaquiline SmPC). 



 19 

Delamanid (100 mg BID) 
 
(Lopinavir/ritonavir 
400/100 mg BID) 

Delamanid: 
AUC: ↑ 22% 
 
DM-6705 (delamanid active 
metabolite): 
AUC: ↑ 30% 
 
A more pronounced effect on 
DM-6705 exposure may be 
observed during prolonged co-
administration with 
lopinavir/ritonavir. 

Due to the risk of QTc prolongation 
associated with DM-6705, if 
co-administration of delamanid 
with Kaletra is considered 
necessary, very frequent ECG 
monitoring throughout the full 
delamanid treatment period is 
recommended (see section 4.4 and 
refer to the delamanid SmPC). 

Rifabutin, 150 mg QD 
 

Rifabutin (parent drug and active 
25-O-desacetyl metabolite):  
AUC: ↑ 5.7-fold 
Cmax: ↑ 3.5-fold  
 
 

When given with Kaletra the 
recommended dose of rifabutin is 
150 mg 3 times per week on set 
days (for example Monday-
Wednesday-Friday).  Increased 
monitoring for rifabutin-associated 
adverse reactions including 
neutropenia and uveitis is 
warranted due to an expected 
increase in exposure to rifabutin.  
Further dosage reduction of 
rifabutin to 150 mg twice weekly 
on set days is recommended for 
patients in whom the 150 mg dose 3 
times per week is not tolerated.  It 
should be kept in mind that the 
twice weekly dosage of 150 mg 
may not provide an optimal 
exposure to rifabutin thus leading to 
a risk of rifamycin resistance and a 
treatment failure.  No dose 
adjustment is needed for Kaletra.  



 20 

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). 

Antipsychotics 
Lurasidone Due to CYP3A inhibition by 

lopinavir/ritonavir, 
concentrations of lurasidone are 
expected to increase. 

The concomitant administration 
with lurasidone is contraindicated 
(see section 4.3). 

Pimozide Due to CYP3A inhibition by 
lopinavir/ritonavir, 
concentrations of pimozide are 
expected to increase. 

Concomitant administration of 
Kaletra and pimozide is 
contraindicated as it may increase 
the risk of serious haematologic 
abnormalities or other serious 
adverse effects from this agent (see 
section 4.3) 

Quetiapine Due to CYP3A inhibition by 
lopinavir/ritonavir, 
concentrations of quetiapine are 
expected to increase. 

Concomitant administration of 
Kaletra and quetiapine is 
contraindicated as it may increase 
quetiapine-related toxicity. 



 21 

Benzodiazepines 
Midazolam 
 

Oral Midazolam:  
AUC: ↑ 13-fold  
Parenteral Midazolam: 
AUC: ↑ 4-fold 
Due to CYP3A inhibition by 
lopinavir/ritonavir 
 
 

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. 

Beta2-adrenoceptor agonist (long acting) 
Salmeterol Salmeterol: 

Concentrations are expected to 
increase due to CYP3A inhibition 
by lopinavir/ritonavir. 

The combination may result in 
increased risk of cardiovascular 
adverse events associated with 
salmeterol, including QT 
prolongation, palpitations and 
sinus tachycardia. 
Therefore, concomitant 
administration of Kaletra with 
salmeterol is not recommended 
(see section 4.4). 

Calcium channel blockers 
Felodipine, Nifedipine, and 
Nicardipine 

Felodipine, Nifedipine, 
Nicardipine: 
Concentrations may be increased 
due to CYP3A inhibition by 
lopinavir/ritonavir. 

Clinical monitoring of therapeutic 
and adverse effects is 
recommended when these 
medicines are concomitantly 
administered with Kaletra. 

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. 



 22 

Inhaled, injectable or 
intranasal fluticasone 
propionate, budesonide, 
triamcinolone 

Fluticasone propionate, 50 µg 
intranasal 4 times daily: 
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 e.g. budesonide 
and triamcinolone.  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 (e.g. 
beclomethasone).  Moreover, in 
case of withdrawal of 
glucocorticoids progressive dose 
reduction may have to be 
performed over a longer period.   

Phosphodiesterase(PDE5) inhibitors 
Avanafil 
(ritonavir 600 mg BID)  

Avanafil: 
AUC: ↑ 13-fold 
Due to CYP3A inhibition by 
lopinavir/ritonavir. 
 

The use of avanafil with Kaletra is 
contraindicated (see section 4.3). 



 23 

Tadalafil  
 
 

Tadalafil: 
AUC: ↑ 2-fold 
Due to CYP3A4 inhibition by 
lopinavir/ritonavir. 
 

For the treatment of pulmonary 
arterial hypertension: 
Co-administration of Kaletra with 
sildenafil is contraindicated (see 
section 4.3).  Co-administration of 
Kaletra with tadalafil is not 
recommended. 
 
For erectile dysfunction: 
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 
 

Sildenafil 
 
 

Sildenafil:  
AUC: ↑ 11-fold 
Due to CYP3A inhibition by 
lopinavir/ritonavir. 
 

Vardenafil  
 
 

Vardenafil: 
AUC: ↑ 49-fold  
Due to CYP3A inhibition by 
lopinavir/ritonavir. 

The use of vardenafil with Kaletra 
is contraindicated (see section 4.3).   
 

Ergot alkaloids 
Dihydroergotamine, 
ergonovine, ergotamine, 
methylergonovine 

Serum concentrations may be 
increased due to CYP3A 
inhibition by lopinavir/ritonavir. 

Concomitant administration of 
Kaletra and ergot alkaloids are 
contraindicated as it may lead to 
acute ergot toxicity, including 
vasospasm and ischaemia (see 
section 4.3). 

GI motility agent 
Cisapride Serum concentrations may be 

increased due to CYP3A 
inhibition by lopinavir/ritonavir. 

Concomitant administration of 
Kaletra and cisapride is 
contraindicated as it may increase 
the risk of serious arrhythmias 
from this agent (see section 4.3). 

HCV direct acting antivirals 
Elbasvir/grazoprevir 
(50/200 mg QD) 

 Elbasvir: 
AUC: ↑ 2.71-fold 
Cmax: ↑ 1.87-fold 
C24: ↑ 3.58-fold 
 
Grazoprevir: 
AUC: ↑ 11.86-fold 
Cmax: ↑ 6.31-fold 
C24: ↑ 20.70-fold 
 
(combinations of mechanisms 
including CYP3A inhibition) 
 
Lopinavir: ↔ 

Concomitant administration of 
elbasvir/grazoprevir with Kaletra 
is contraindicated (see section 
4.3). 



 24 

Glecaprevir/pibrentasvir Serum concentrations may be 
increased due to P-glycoprotein, 
BCRP and OATP1B inhibition by 
lopinavir/ritonavir. 

Concomitant administration of 
glecaprevir/pibrentasvir and 
Kaletra is not recommended due 
to an increased risk of ALT 
elevations associated with 
increased glecaprevir exposure. 

Ombitasvir/paritaprevir/rito
navir + dasabuvir 
 
(25/150/100 mg QD + 
400 mg BID) 
 
Lopinavir/ritonavir  
400/100 mg BID 

Ombitasvir: ↔  
 
Paritaprevir: 
AUC: ↑ 2.17-fold 
Cmax: ↑ 2.04-fold 
Ctrough: ↑ 2.36-fold 
 
(inhibition of CYP3A/efflux 
transporters) 
 
Dasabuvir: ↔ 
 
Lopinavir: ↔ 

Co-administration is 
contraindicated. 
 
Lopinavir/ritonavir 800/200 mg 
QD was administered with 
ombitasvir/paritaprevir/ritonavir 
with or without dasabuvir.  The 
effect on DAAs and lopinavir was 
similar to that observed when 
lopinavir/ritonavir 400/100 mg 
BID was administered (see 
section 4.3). 

Ombitasvir/paritaprevir/ 
ritonavir 
 
(25/150/100 mg QD) 
 
Lopinavir/ritonavir 
400/100 mg BID 

Ombitasvir: ↔ 
 
Paritaprevir: 
AUC: ↑ 6.10-fold 
Cmax: ↑ 4.76-fold 
Ctrough: ↑ 12.33-fold 
 
(inhibition of CYP3A/efflux 
transporters) 
 
Lopinavir: ↔ 

Sofosbuvir/velpatasvir/ 
voxilaprevir 

Serum concentrations of 
sofosbuvir, velpatasvir and 
voxilaprevir may be increased due 
to P-glycoprotein, BCRP and 
OATP1B1/3 inhibition by 
lopinavir/ritonavir.  However, 
only the increase in voxilaprevir 
exposure is considered clinically 
relevant. 

It is not recommended to 
co-administer Kaletra and 
sofosbuvir/velpatasvir/ 
voxilaprevir. 

HCV protease inhibitors 
Simeprevir 200 mg daily 
(ritonavir 100 mg BID) 
 

Simeprevir: 
AUC: ↑ 7.2-fold 
Cmax: ↑ 4.7-fold 
Cmin: ↑ 14.4-fold 

It is not recommended to 
co-administer Kaletra and 
simeprevir. 



 25 

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 
lopinavir/ritonavir. 

More frequent therapeutic 
concentration monitoring is 
recommended until plasma levels 
of these products have been 
stabilised. 

Lipid lowering agents 
Lovastatin and Simvastatin Lovastatin, Simvastatin: 

Markedly increased plasma 
concentrations due to CYP3A 
inhibition by lopinavir/ritonavir. 

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). 

Lipid-modifying agents 
Lomitapide CYP3A4 inhibitors increase the 

exposure of lomitapide, with 
strong inhibitors increasing 
exposure approximately 27-fold.  
Due to CYP3A inhibition by 
lopinavir/ritonavir, concentrations 
of lomitapide are expected to 
increase. 

Concomitant use of Kaletra with 
lomitapide is contraindicated (see 
prescribing information for 
lomitapide) (see section 4.3). 

Atorvastatin Atorvastatin: 
AUC: ↑ 5.9-fold  
Cmax: ↑ 4.7-fold 
Due to CYP3A inhibition by 
lopinavir/ritonavir. 

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  
Cmax: ↑ 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). 



 26 

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 Cmax ↓ ~50%  
 
This effect may be due to 
induction of bupropion 
metabolism. 
 

If the co-administration of Kaletra 
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. 

Thyroid hormone replacement therapy 
Levothyroxine Post-marketing cases have been 

reported indicating a potential 
interaction between ritonavir 
containing products and 
levothyroxine. 

Thyroid-stimulating hormone 
(TSH) should be monitored in 
patients treated with levothyroxine 
at least the first month after 
starting and/or ending 
lopinavir/ritonavir treatment. 

Vasodilating agents 
Bosentan Lopinavir - ritonavir: 

Lopinavir/ritonavir plasma 
concentrations may decrease due 
to CYP3A4 induction by 
bosentan. 
 
Bosentan: 
AUC: ↑ 5-fold  
Cmax: ↑ 6-fold 
Initially, bosentan Cmin: ↑ by 
approximately 48-fold.  
Due to CYP3A4 inhibition by 
lopinavir/ritonavir. 

Caution should be exercised in 
administering Kaletra with 
bosentan. 
When Kaletra is administered 
concomitantly with bosentan, the 
efficacy of the HIV therapy should 
be monitored and patients should 
be closely observed for bosentan 
toxicity, especially during the first 
week of co-administration.   

Riociguat Serum concentrations may be 
increased due to CYP3A and 
P-gp inhibition by 
lopinavir/ritonavir. 

The co-administration of riociguat 
with Kaletra is not recommended 
(see section 4.4 and refer to 
riociguat SmPC). 



 27 

Other medicinal products 
Based on known metabolic profiles, clinically significant interactions are not expected between 
Kaletra and dapsone, trimethoprim/sulfamethoxazole, azithromycin or fluconazole. 

 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in 
pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, 
the animal data as well as the clinical experience in pregnant women should be taken into account in 
order to characterise the safety for the foetus. 
 
Lopinavir/ritonavir has been evaluated in over 3000 women during pregnancy, including over 1000 
during the first trimester. 
 
In post-marketing surveillance through the Antiretroviral Pregnancy Registry, established since 
January 1989, an increased risk of birth defects exposures with Kaletra has not been reported among 
over 1000 women exposed during the first trimester.  The prevalence of birth defects after any 
trimester exposure to lopinavir is comparable to the prevalence observed in the general population.  
No pattern of birth defects suggestive of a common etiology was seen.  Studies in animals have shown 
reproductive toxicity (see section 5.3).  Based on the data mentioned, the malformative risk is unlikely 
in humans.  Lopinavir can be used during pregnancy if clinically needed. 
 
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.  As a general rule, it is recommended that mothers infected by HIV 
do not breastfeed their babies under any circumstances in order to avoid transmission of HIV.  
 
Fertility 
Animal studies have shown no effects on fertility.  No human data on the effect of lopinavir/ritonavir 
on fertility are available. 
 
4.7 Effects on ability to drive and use machines 
 
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.  
 
4.8 Undesirable effects  
 
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).  



 28 

 
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), rare (≥1/10,000 to <1/1000) and not known (cannot be 
estimated from the available data). 
 

Undesirable effects in clinical studies and post-marketing in adult patients 

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 inflammatory 
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 infarction1, 

atrioventricular block, tricuspid valve 
incompetence 

Vascular disorders Common Hypertension 
 

Uncommon Deep vein thrombosis 
Gastrointestinal disorders Very common Diarrhoea, nausea 

 



 29 

Common Pancreatitis1, 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 

Hepatobiliary disorders Common Hepatitis including AST, ALT and GGT 
increases 
 

Uncommon Jaundice, hepatic steatosis, hepatomegaly, 
cholangitis, hyperbilirubinemia 

Skin and subcutaneous tissue 
disorders 

Common Rash including maculopapular rash, 
dermatitis/rash including eczema and 
seborrheic dermatitis, night sweats, pruritus 
 

Uncommon Alopecia, capillaritis, vasculitis  
 

Rare 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 

 
 
Not known 

Creatinine clearance decreased, nephritis, 
haematuria  
 
Nephrolithiasis 

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. 
 
Metabolic parameters 
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (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.  Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have 



 30 

also been reported; however, the reported time to onset is more variable and can occur many months 
after initiation of treatment (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). 
 
d. Paediatric populations 
 
In children 14 days of age and older, the nature of the safety profile is similar to that seen in adults 
(see Table in section b).  
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important.  It 
allows continued monitoring of the benefit/risk balance of the medicinal product.  Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
To date, there is limited human experience of acute overdose with Kaletra. 
 
Overdoses with Kaletra oral solution have been reported (including fatal outcome).  The following 
events have been reported in association with unintended overdoses in preterm neonates: complete 
atrioventricular block, cardiomyopathy, lactic acidosis, and acute renal failure.   
 
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. 
 
However, dialysis can remove both alcohol and propylene glycol in the case of overdose with Kaletra 
oral solution. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmaco-therapeutic group: antivirals for systemic use, antivirals for treatment of HIV infections, 
combinations, ATC code: J05AR10  
 
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 

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 31 

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 ms from baseline or a QTcF interval exceeding the potentially clinically 
relevant threshold of 500 ms. 
 
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 ms 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 IC50 of lopinavir against five different HIV-1 laboratory strains 
was 19 nM.  In the absence and presence of 50% human serum, the mean IC50 of lopinavir against 
HIV-1IIIB in MT4 cells was 17 nM and 102 nM, respectively.  In the absence of human serum, the 
mean IC50 of lopinavir was 6.5 nM against several HIV-1 clinical isolates. 
 
Resistance 
 
In vitro selection of resistanceHIV-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 IC50 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 EC50 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 EC50 against wild type 



 32 

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 EC50 of lopinavir against the 
56 baseline viral isolates ranged from 0.6 to 96-fold higher than the EC50 against wild type HIV.  After 
48 weeks of treatment 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 IC50 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 IC50 from 3.7- to 8-fold in the baseline and rebound isolates, respectively.  Isolates retained 
susceptibility to tipranavir with a median increase of IC50 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/mm3 (range: 2 to 
949 cells/ mm3) and mean baseline plasma HIV-1 RNA was 4.9 log10 copies/ml (range: 2.6 to 
6.8 log10 copies/ml).   
 



 33 

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/mm3) 

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 
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/mm3) 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 CD4 cell count was 349 cells/mm3 (range 
72 to 807 cells/mm3) and median baseline plasma HIV-1 RNA was 4.0 log10 copies/ml (range 
2.9 to 5.8 log10 copies/ml).   
 



 34 

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/mm3) 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 CD4 cell count was 
220 cells/mm3 (range13 to 1030 cells/mm3).   
 
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/mm3) 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 m2 or 
300 mg lopinavir/75 mg ritonavir per m2.  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 m2 
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/mm3 and 
mean baseline plasma HIV-1 RNA was 4.7 log10 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/mm3) 

404 284 

 * intent to treat analysis where patients with missing values are considered virologic failures 
 
Study P1030 was an open-label, dose-finding trial evaluating the pharmacokinetic profile, tolerability, 
safety and efficacy of Kaletra oral solution at a dose of 300 mg lopinavir/75 mg ritonavir per m2 twice 
daily plus 2 NRTIs in HIV-1 infected infants ≥ 14 days and < 6 months of age.  At entry, median 
(range) HIV-1 RNA was 6.0 (4.7-7.2) log10 copies/ml and median (range) CD4+T-cell percentage was 
41 (16-59).   



 35 

 
Table 6 
 

Outcomes at Week 24: Study P1030 

 Age: ≥ 14 days and 
 < 6 weeks  

(N=10) 

Age: ≥ 6 weeks and  
< 6 months  

(N=21) 
HIV RNA < 400 copies/ml* 70% 48% 
Median change from baseline 
in CD4+ T-cell count 
(cells/mm3) 

- 1% (95% CI: -10, 18) 
(n=6) 

+ 4% (95% CI: -1, 9) 
(n=19) 

 *Proportion of subjects who had HIV-1 < 400 copies/ml and had remained on study treatment 
 
Study P1060 was a randomised controlled trial of nevirapine versus lopinavir/ritonavir-based therapy 
in subjects 2 to 36 months of age infected with HIV-1 who had (Cohort I) and had not (Cohort II) been 
exposed to nevirapine during pregnancy for prevention of mother-to-child transmission.  
Lopinavir/ritonavir was administered twice daily at 16/4 mg/kg for subjects 2 months to < 6 months, 
12/3 mg/kg for subjects ≥ 6 months and < 15 kg, 10/2.5 mg/kg for subjects ≥ 6 months and ≥ 15 kg to 
< 40 kg, or 400/100 mg for subjects ≥ 40 kg.  The nevirapine-based regimen was 160-200 mg/m2 once 
daily for 14 days, then 160-200 mg/m2 every 12 hours.  Both treatment arms included zidovudine 
180 mg/m2 every 12 hours and lamivudine 4 mg/kg every 12 hours.  The median follow-up was 
48 weeks in Cohort I and 72 weeks in Cohort II.  At entry, median age was 0.7 years, median CD4 
T-cell count was 1147 cells/mm3, median CD4 T-cell was 19%, and median HIV-1 RNA was 
> 750,000 copies/ml.  Among 13 subjects with viral failure in the lopinavir/ritonavir group with 
resistance data available no resistance to lopinavir/ritonavir was found. 
 
Table 7 
 

Outcomes at Week 24: Study P1060 

 Cohort I Cohort II  
 lopinavir/ritonavir 

(N=82) 
nevirapine 

(N=82) 
lopinavir/ritonavir 

(N=140) 
nevirapine 
(N=147) 

Virologic 
failure* 

21.7% 39.6% 19.3% 40.8% 

*Defined as confirmed plasma HIV-1 RNA level > 400 copies/ml at 24 weeks or viral rebound 
> 4000 copies/ml after Week 24.  Overall failure rate combining the treatment differences 
across age strata, weighted by the precision of the estimate within each age stratum 
p=0.015 (Cohort I); p< 0.001 (Cohort II) 

 
The CHER study was a randomized, open-label study comparing 3 treatment strategies (deferred 
treatment, early treatment for 40 weeks, or early treatment for 96 weeks) in children with perinatally 
acquired HIV-1 infection.  The treatment regimen was zidovudine plus lamivudine plus 300 mg 
lopinavir/75 mg ritonavir per m2 twice daily until 6 months of age, then 230 mg lopinavir/57.5 mg 
ritonavir per m2 twice daily.  There were no reported events of failure attributed to therapy limiting 
toxicity. 
 



 36 

Table 8 
 

Hazard Ratio for Death or Failure of First-line Therapy Relative 
 to ART Deferred Treatment: CHER Study 

 40 week arm (N=13) 96 week arm (N=13) 
Hazard ratio for 
death or failure 
of therapy*  

 
0.319 

 
0.332 

* Failure defined as clinical, immunological disease progression, virological failure or regimen 
limiting ART toxicity 
p=0.0005 (40 week arm); p< 0.0008 (96 week arm) 

 
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 EC50 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 (Cmax) 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 Cmax, respectively, relative to fasting.  For Kaletra oral solution, the 
corresponding increases in lopinavir AUC and Cmax were 80% and 54%, respectively.  Administration 
of Kaletra with a high fat meal (872 kcal, 55.8% from fat) increased lopinavir AUC and Cmax 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 14C-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 



 37 

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 14C-lopinavir/ritonavir dose, approximately 10.4 ± 2.3% and 82.6 ± 2.5% of an 
administered dose of 14C-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  
Data from clinical trials in children below 2 years of age include the pharmacokinetics of Kaletra 
300/75 mg/m2 twice daily studied in a total of 31 paediatric patients, ranging in age from 14 days to 
6 months.  The pharmacokinetics of Kaletra 300/75 mg/m2 twice daily with nevirapine and 
230/57.5 mg/ m2 twice daily alone have been studied in 53 paediatric patients ranging in age from 
6 months to 12 years.  The mean (SD) for the studies are reported in the table below.  The 
230/57.5 mg/m2 twice daily regimen without nevirapine and the 300/75 mg/m2 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.   
 

Cmax (µg/ml) Cmin (µg/ml) AUC12 (µg•h/ml) 
Age ≥ 14 days to < 6 weeks cohort (N = 9): 

5.17 (1.84) 1.40 (0.48) 43.39 (14.80) 
Age ≥ 6 weeks to < 6 months cohort (N = 18): 

9.39 (4.91) 1.95 (1.80) 74.50 (37.87) 
Age ≥ 6 months to < 12 years cohort (N = 53): 

8.2 (2.9)a 3.4 (2.1)a 72.6 (31.1)a 
10.0 (3.3)b 3.6 (3.5)b 85.8 (36.9)b 

Adultc 
12.3 (5.4) 8.1 (5.7) 113.2 (60.5) 

a. Kaletra oral solution 230/57.5 mg/m2 twice daily regimen without nevirapine 
b. Kaletra oral solution 300/75 mg/m2 twice daily regimen with nevirapine 
c. Kaletra film-coated tablets 400/100 mg twice daily at steady state 

 
Gender, Race and Age   
Kaletra pharmacokinetics have not been studied in older people.  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. 
 
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). 
 



 38 

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. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Oral solution contains:  
alcohol (42.4% v/v),  
high fructose corn syrup,  
propylene glycol (15.3% w/v),  
purified water,  
glycerol,  
povidone,  
magnasweet-110 flavour (mixture of monoammonium glycyrrhizinate and glycerol),  



 39 

vanilla flavour (containing p-hydroxybenzoic acid, p-hydroxybenzaldehyde, vanillic acid, vanillin, 
heliotropin, 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,  
levomenthol. 
 
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.  
 
6.5 Nature and contents of container 
 
Kaletra oral solution is supplied in amber coloured multiple-dose polyethylene terephthalate (PET) 
bottles in a 60 ml size. 
 
Two pack sizes are available for Kaletra oral solution: 
- 120 ml (2 bottles x 60 ml) with 2 x 2 ml syringes with 0.1 ml graduations 

For volumes up to 2 ml.  For larger volumes an alternative pack is available.  
- 300 ml (5 bottles x 60 ml) with 5 x 5 ml syringes with 0.1 ml graduations  

For volumes greater than 2 ml.  For smaller volumes an alternative pack is available. 
 
6.6 Special precautions for disposal 
 
No special requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
AbbVie Deutschland GmbH & Co. KG 
Knollstrasse 
67061 Ludwigshafen 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER 
 
EU/1/01/172/003 
EU/1/01/172/009 
 



 40 

 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 20 March 2001 
Date of latest renewal: 20 March 2011 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this product is available on the website of the European Medicines Agency 
http://www.ema.europa.eu 

http://www.ema.europa.eu/


 41 

1. NAME OF THE MEDICINAL PRODUCT  
 
Kaletra 200 mg/50 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION  
 
Each film-coated tablet contains 200 mg of lopinavir co-formulated with 50 mg of ritonavir as a 
pharmacokinetic enhancer. 
 
For the full list of excipients, see section 6.1.  
 
 
3. PHARMACEUTICAL FORM  
 
Film-coated tablet 
 
Yellow debossed with [Abbott logo] and “KA”. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Kaletra is indicated in combination with other antiretroviral medicinal products for the treatment of 
human immunodeficiency virus (HIV-1) infected adults, adolescents and children above the age of 
2 years.  
 
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). 
 
4.2 Posology and method of administration 
 
Kaletra should be prescribed by physicians who are experienced in the treatment of HIV infection. 
 
Kaletra tablets must be swallowed whole and not chewed, broken or crushed. 
 
Posology 
 
Adults and adolescents  
The standard recommended dosage of Kaletra tablets is 400/100 mg (two 200/50 mg) tablets twice 
daily taken with or without food.  In adult patients, in cases where once-daily dosing is considered 
necessary for the management of the patient, Kaletra tablets may be administered as 800/200 mg (four 
200/50 mg tablets) once daily with or without food.  The use of a once-daily dosing should be limited 
to those adult patients having only very few protease inhibitor (PI) associated mutations (i.e. less than 
3 PI mutations in line with clinical trial results, see section 5.1 for the full description of the 
population) and should take into account the risk of a lesser sustainability of the virologic suppression 
(see section 5.1) and higher risk of diarrhoea (see section 4.8) compared to the recommended standard 
twice-daily dosing.  An oral solution is available to patients who have difficulty swallowing.  Refer to 
the Summary of Product Characteristics for Kaletra oral solution for dosing instructions. 
 



 42 

Paediatric population (2 years of age and above)  
The adult dose of Kaletra tablets (400/100 mg twice daily) may be used in children 40 kg or greater or 
with a Body Surface Area (BSA)* greater than 1.4 m2.  For children weighing less than 40 kg or with 
a BSA between 0.5 and 1.4 m2 and able to swallow tablets, please refer to the Kaletra 100 mg/25 mg 
tablets Summary of Product Characteristics.  For children unable to swallow tablets, please refer to the 
Kaletra oral solution Summary of Product Characteristics.  Based on the current data available, Kaletra 
should not be administered once daily in paediatric patients (see section 5.1). 
 
* Body surface area can be calculated with the following equation: 
 

BSA (m2) = √ (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.  
 
Concomitant Therapy: Efavirenz or nevirapine 
The following table contains dosing guidelines for Kaletra tablets based on BSA when used in 
combination with efavirenz or nevirapine in children. 
 

Paediatric dosing guidelines with  
concomitant efavirenz or nevirapine 

Body Surface Area (m2) Recommended lopinavir/ritonavir dosing 
(mg) twice daily.   

The adequate dosing may be achieved with 
the two available strengths of Kaletra 
tablets: 100/25 mg and 200/50 mg.* 

≥ 0.5 to < 0.8 200/50 mg 
≥ 0.8 to < 1.2 300/75 mg 
≥ 1.2 to < 1.4 400/100 mg 

≥ 1.4 500/125 mg 
* Kaletra tablets must not be chewed, broken or crushed. 

 
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.   
 
Pregnancy and postpartum 
• No dose adjustment is required for lopinavir/ritonavir during pregnancy and postpartum. 
• Once-daily administration of lopinavir/ritonavir is not recommended for pregnant women due to 

the lack of pharmacokinetic and clinical data. 
 
Method of administration 
 
Kaletra tablets are administered orally and must be swallowed whole and not chewed, broken or 
crushed.  Kaletra tablets can be taken with or without food. 



 43 

 
4.3 Contraindications 
 
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. 
 
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:  
 

Medicinal product 
class 

Medicinal products within 
class 

Rationale 

Concomitant medicinal product levels increased 

Alpha1-
adrenoreceptor 
antagonist 

Alfuzosin Increased plasma concentrations of 
alfuzosin which may lead to severe 
hypotension.  The concomitant 
administration with alfuzosin is 
contraindicated (see section 4.5). 

Antianginal Ranolazine Increased plasma concentrations of 
ranolazine which may increase the 
potential for serious and/or life-
threatening reactions (see section 4.5). 

Antiarrhythmics Amiodarone, dronedarone Increased plasma concentrations of 
amiodarone and dronedarone.  Thereby, 
increasing the risk of arrhythmias or 
other serious adverse reactions (see 
section 4.5). 

Antibiotic Fusidic Acid Increased plasma concentrations of 
fusidic acid. The concomitant 
administration with fusidic acid is 
contraindicated in dermatological 
infections (see section 4.5). 

Anticancer Neratinib Increased plasma concentrations of 
neratinib which may increase the 
potential for serious and/or 
life-threatening reactions (see section 
4.5). 

Venetoclax Increased plasma concentrations of 
venetoclax.  Increased risk of tumor 
lysis syndrome at the dose initiation 
and during the ramp-up phase (see 
section 4.5). 

Anti-gout Colchicine Increased plasma concentrations of 
colchicine.  Potential for serious and/or 
life-threatening reactions in patients 
with renal and/or hepatic impairment 
(see sections 4.4 and 4.5). 

Antihistamines Astemizole, terfenadine Increased plasma concentrations of 
astemizole and terfenadine.  Thereby, 
increasing the risk of serious 
arrhythmias from these agents (see 
section 4.5). 



 44 

Antipsychotics/ 
Neuroleptics 

Lurasidone Increased plasma concentrations of 
lurasidone which may increase the 
potential for serious and/or life-
threatening reactions (see section 4.5). 

Pimozide Increased plasma concentrations of 
pimozide.  Thereby, increasing the risk 
of serious haematologic abnormalities, 
or other serious adverse effects from 
this agent (see section 4.5). 

Quetiapine Increased plasma concentrations of 
quetiapine which may lead to coma.  
The concomitant administration with 
quetiapine is contraindicated (see 
section 4.5). 

Ergot alkaloids Dihydroergotamine, ergonovine, 
ergotamine, methylergonovine 

Increased plasma concentrations of 
ergot derivatives leading to acute ergot 
toxicity, including vasospasm and 
ischaemia (see section 4.5). 

GI motility agent Cisapride Increased plasma concentrations of 
cisapride.  Thereby, increasing the risk 
of serious arrhythmias from this agent 
(see section 4.5). 

Hepatitis C virus 
direct acting antivirals 

Elbasvir/grazoprevir Increased risk of alanine transaminase 
(ALT) elevations (see section 4.5). 

Ombitasvir/paritaprevir/ritonavir 
with or without dasabuvir 

Increased plasma concentrations of 
paritaprevir; thereby, increasing the 
risk of alanine transaminase (ALT) 
elevations (see section 4.5). 

Lipid-modifying agents 
 

 

HMG Co-A 
Reductase Inhibitors 

Lovastatin, simvastatin Increased plasma concentrations of 
lovastatin and simvastatin; thereby, 
increasing the risk of myopathy 
including rhabdomyolysis (see section 
4.5). 

Microsomal 
triglyceride transfer 
protein (MTTP) 
inhibitor 

Lomitapide Increased plasma concentrations of 
lomitapide (see section 4.5). 

Phosphodiesterase 
(PDE5) inhibitors 

Avanafil Increased plasma concentrations of 
avanafil (see sections 4.4 and 4.5) 

Sildenafil 
 

Contraindicated when used for the 
treatment of pulmonary arterial 
hypertension (PAH) only.  Increased 
plasma concentrations of sildenafil.  
Thereby, increasing the potential for 
sildenafil-associated adverse events 
(which include hypotension and 
syncope).  See section 4.4 and section 
4.5 for co-administration of sildenafil 
in patients with erectile dysfunction. 

Vardenafil Increased plasma concentrations of 
vardenafil (see sections 4.4 and 4.5) 



 45 

Sedatives/hypnotics Oral midazolam, triazolam Increased plasma concentrations of oral 
midazolam and triazolam.  Thereby, 
increasing the risk of extreme sedation 
and respiratory depression from these 
agents.   
For caution on parenterally 
administered midazolam, see section 
4.5. 

Lopinavir/ritonavir medicinal product level decreased 

Herbal products St. John’s wort Herbal preparations containing St 
John’s wort (Hypericum perforatum) 
due to the risk of decreased plasma 
concentrations and reduced clinical 
effects of lopinavir and ritonavir (see 
section 4.5). 

 
4.4 Special warnings and precautions for use  
 
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. 
 



 46 

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 
 
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).  
 
Immune Reconstitution Inflammatory 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. 
 
Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to 
occur in the setting of immune reconstitution; however, the reported time to onset is more variable and 
can occur many months after initiation of treatment. 
 
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 2nd or 3rd 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). 
 
Weight and metabolic parameters 
An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral 
therapy.  Such changes may in part be linked to disease control and life style.  For lipids, there is in 
some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating 
this to any particular treatment.  For monitoring of blood lipids and glucose, reference is made to 
established HIV treatment guidelines.  Lipid disorders should be managed as clinically appropriate. 
 
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). 
 
Strong CYP3A4 inhibitors such as protease inhibitors may increase bedaquiline exposure which could 
potentially increase the risk of bedaquiline-related adverse reactions.  Therefore, combination of 



 47 

bedaquiline with lopinavir/ritonavir should be avoided.  However, if the benefit outweighs the risk, 
co-administration of bedaquiline with lopinavir/ritonavir must be done with caution.  More frequent 
electrocardiogram monitoring and monitoring of transaminases is recommended (see section 4.5 and 
refer to the bedaquiline SmPC). 
 
Co-administration of delamanid with a strong inhibitor of CYP3A (as lopinavir/ritonavir) may 
increase exposure to delamanid metabolite, which has been associated with QTc prolongation.  
Therefore, if co-administration of delamanid with lopinavir/ritonavir is considered necessary, very 
frequent ECG monitoring throughout the full delamanid treatment period is recommended (see section 
4.5 and refer to the delamanid SmPC). 
 
Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and 
strong inhibitors of CYP3A like ritonavir.  Concomitant administration with colchicine is 
contraindicated in patients with renal and/or hepatic impairment (see sections 4.3 and 4.5). 
 
The combination of Kaletra with:  
- tadalafil, indicated for the treatment of pulmonary arterial hypertension, is not recommended 

(see section 4.5);  
- riociguat is not recommended (see section 4.5); 
- vorapaxar is not recommended (see section 4.5); 
- fusidic acid in osteo-articular infections is not recommended (see section 4.5); 
- salmeterol is not recommended (see section 4.5); 
-  rivaroxaban is not recommended (see section 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 avanafil or 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, 
such as budesonide and triamcinolone, 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). 
 



 48 

Other 
Kaletra is not a cure for HIV infection or AIDS.  While effective viral suppression with antiretroviral 
therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot 
be excluded.  Precautions to prevent transmission should be taken in accordance with national 
guidelines.   People taking Kaletra may still develop infections or other illnesses associated with HIV 
disease and AIDS. 
 
4.5 Interaction with other medicinal products and other forms of interaction  
 
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. 
 
All interaction studies, when otherwise not stated, were performed using Kaletra capsules, which gives 
an approximately 20% lower exposure of lopinavir than the 200/50 mg tablets. 
 
Known and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal 
products are listed in the table below.  This list is not intended to be inclusive or comprehensive.  
Individual SmPCs should be consulted. 
 
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 
 
Geometric Mean Change (%) in 
AUC, Cmax, Cmin 
 
Mechanism of interaction 

Clinical recommendation 
concerning co-administration with 
Kaletra 

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 lopinavir/ritonavir. 

The clinical significance of reduced 
abacavir and zidovudine 
concentrations is unknown. 

Tenofovir disoproxil 
fumarate (DF), 300 mg 
QD 

Tenofovir: 
AUC: ↑ 32% 
Cmax: ↔ 

No dose adjustment necessary. 
Higher tenofovir concentrations could 
potentiate tenofovir associated 



 49 

 
(equivalent to 245 mg 
tenofovir disoproxil) 

Cmin: ↑ 51% 
 
Lopinavir: ↔ 

adverse events, including renal 
disorders. 

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)  
Efavirenz, 600 mg QD 
 
 

Lopinavir: 
AUC: ↓ 20% 
Cmax: ↓ 13% 
Cmin: ↓ 42% 

The Kaletra tablets dosage should be 
increased to 500/125 mg twice daily 
when co-administered with efavirenz.   
Kaletra must not be administered 
once daily in combination with 
efavirenz. 

Efavirenz, 600 mg QD 
 
(Lopinavir/ritonavir 
500/125 mg BID) 

 
Lopinavir: ↔ 
(Relative to 400/100 mg BID 
administered alone)  

Nevirapine, 200 mg 
BID 
 
 

Lopinavir: 
AUC: ↓ 27% 
Cmax: ↓ 19% 
Cmin: ↓ 51% 

The Kaletra tablets dosage should be 
increased to 500/125 mg twice daily 
when co-administered with 
nevirapine.   
Kaletra must not be administered 
once daily in combination with 
nevirapine. 

Etravirine 
 
(Lopinavir/ritonavir 
tablet 400/100 mg BID) 

Etravirine: 
AUC: ↓ 35% 
Cmin: ↓ 45%  
Cmax: ↓ 30% 
 
Lopinavir: 
AUC: ↔  
Cmin: ↓ 20% 
Cmax: ↔  

No dose adjustment necessary 

Rilpivirine 
 
(Lopinavir/ritonavir 
capsule 400/100 mg 
BID) 

Rilpivirine: 
AUC: ↑ 52%  
Cmin: ↑ 74%  
Cmax: ↑ 29% 
 
Lopinavir: 
AUC: ↔ 
Cmin: ↓ 11%  
Cmax: ↔  
 
(inhibition of CYP3A enzymes) 

Concomitant use of Kaletra with 
rilpivirine causes an increase in the 
plasma concentrations of rilpivirine, 
but no dose adjustment is required. 

HIV CCR5 – antagonist 
Maraviroc 
 

Maraviroc: 
AUC: ↑ 295%  
Cmax: ↑ 97%  
Due to CYP3A inhibition by 
lopinavir/ritonavir. 

The dose of maraviroc should be 
decreased to 150 mg twice daily 
during co-administration with Kaletra 
400/100 mg twice daily.   

Integrase inhibitor 
Raltegravir Raltegravir:  

AUC: ↔ 
Cmax: ↔ 
C12: ↓ 30% 
Lopinavir: ↔ 

No dose adjustment necessary 

 

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 Kaletra (533/133 mg BID) to 



 50 

 
(Lopinavir/ritonavir 
400/100 mg BID) 
 
or  
 
Fosamprenavir 
(1400 mg BID) 
 
(Lopinavir/ritonavir 
533/133 mg BID) 
 

 
 

 

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.  
Kaletra must not be administered 
once daily in combination with 
amprenavir. 

Indinavir, 600 mg BID 
 
 

Indinavir:  
AUC: ↔ 
Cmin: ↑ 3.5-fold 
Cmax: ↓ 
(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. 

Saquinavir  
1000 mg BID 

Saquinavir:  ↔  No dose adjustment necessary. 

Tipranavir/ritonavir 
(500/100 mg BID) 

Lopinavir: 
AUC: ↓ 55% 
Cmin: ↓ 70% 
Cmax: ↓ 47% 

Concomitant administration of these 
medicinal products is not 
recommended. 

Acid reducing agents 
Omeprazole (40 mg 
QD)  
  

Omeprazole: ↔ 
 
Lopinavir: ↔ 

No dose adjustment necessary 

Ranitidine (150 mg 
single dose) 

Ranitidine: ↔ No dose adjustment necessary 

Alpha1 adrenoreceptor antagonist 
Alfuzosin  Alfuzosin: 

Due to CYP3A inhibition by 
lopinavir/ritonavir, concentrations 
of alfuzosin are expected to 
increase. 

Concomitant administration of 
Kaletra and alfuzosin is contra-
indicated (see section 4.3) as 
alfuzosin-related toxicity, including 
hypotension, may be increased. 

Analgesics 
Fentanyl 
  

Fentanyl: 
Increased risk of side-effects 
(respiratory depression, sedation) 
due to higher plasma 
concentrations because of 
CYP3A4 inhibition by 
lopinavir/ritonavir. 

Careful monitoring of adverse effects 
(notably respiratory depression but 
also sedation) is recommended when 
fentanyl is concomitantly 
administered with Kaletra. 

Antianginal 
Ranolazine Due to CYP3A inhibition by 

lopinavir/ritonavir, concentrations 
of ranolazine are expected to 
increase. 

The concomitant administration of 
Kaletra and ranolazine is 
contraindicated (see section 4.3). 



 51 

Antiarrhythmics 
Amiodarone, 
Dronedarone 

Amiodarone, Dronedarone: 
Concentrations may be increased 
due to CYP3A4 inhibition by 
lopinavir/ritonavir. 

Concomitant administration of 
Kaletra and amiodarone or 
dronedarone is contraindicated (see 
section 4.3) as the risk of arrhythmias 
or other serious adverse reactions 
may be increased. 

Digoxin 
 
 

Digoxin: 
Plasma concentrations may be 
increased due to P-glycoprotein 
inhibition by lopinavir/ritonavir.  
The increased digoxin level may 
lessen over time as P-gp 
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 P-gp 
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 
lopinavir/ritonavir.  

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 
lopinavir/ritonavir.  
 

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 and kinase inhibitors 
Abemaciclib Serum concentrations may be 

increased due to CYP3A 
inhibition by ritonavir. 

Co-administration of abemaciclib 
and Kaletra should be avoided.  If 
this co-administration is judged 
unavoidable, refer to the abemaciclib 
SmPC for dosage adjustment 
recommendations.  Monitor for 
ADRs related to abemaciclib. 

Apalutamide Apalutamide is a moderate to 
strong CYP3A4 inducer and this 
may lead to a decreased exposure 
of lopinavir/ritonavir. 
 
Serum concentrations of 
apalutamide may be increased due 
to CYP3A inhibition by 
lopinavir/ritonavir. 

Decreased exposure of Kaletra may 
result in potential loss of virological 
response.   
In addition, co-administration of 
apalutamide and Kaletra may lead to 
serious adverse events including 
seizure due to higher apalutamide 
levels.  Concomitant use of Kaletra 
with apalutamide is not 
recommended. 

Afatinib 
 
(Ritonavir 200 mg twice 
daily) 

Afatinib: 
AUC: ↑  
Cmax: ↑ 
 

Caution should be exercised in 
administering afatinib with Kaletra.  
Refer to the afatinib SmPC for 



 52 

The extent of increase depends on 
the timing of ritonavir 
administration. 
 
Due to BCRP (breast cancer 
resistance protein/ABCG2) and 
acute P-gp inhibition by 
lopinavir/ritonavir. 

dosage adjustment recommendations.  
Monitor for ADRs related to afatinib. 

Ceritinib Serum concentrations may be 
increased due to CYP3A and P-gp 
inhibition by lopinavir/ritonavir. 

Caution should be exercised in 
administering ceritinib with Kaletra.  
Refer to the ceritinib SmPC for 
dosage adjustment recommendations.  
Monitor for ADRs related to 
ceritinib. 

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 
lopinavir/ritonavir. 

Careful monitoring of the tolerance 
of these anticancer agents. 
 

Encorafenib Serum concentrations may be 
increased due to CYP3A 
inhibition by lopinavir/ritonavir. 

Co-administration of encorafenib 
with Kaletra may increase 
encorafenib exposure which may 
increase the risk of toxicity, 
including the risk of serious adverse 
events such as QT interval 
prolongation.  Co-administration of 
encorafenib and Kaletra should be 
avoided.  If the benefit is considered 
to outweigh the risk and Kaletra must 
be used, patients should be carefully 
monitored for safety. 

Fostamatinib Increase in fostamatinib 
metabolite R406 exposure. 

Co-administration of fostamatinib 
with Kaletra may increase 
fostamatinib metabolite R406 
exposure resulting in dose-related 
adverse events such as 
hepatotoxicity, neutropenia, 
hypertension, or diarrhoea.  Refer to 
the fostamatinib SmPC for dose 
reduction recommendations if such 
events occur. 

Ibrutinib Serum concentrations may be 
increased due to CYP3A 
inhibition by lopinavir/ritonavir. 

Co-administration of ibrutinib and 
Kaletra may increase ibrutinib 
exposure which may increase the risk 
of toxicity including risk of tumor 
lysis syndrome. Co-administration of 
ibrutinib and Kaletra should be 
avoided.  If the benefit is considered 
to outweigh the risk and Kaletra must 
be used, reduce the ibrutinib dose to 
140 mg and monitor patient closely 
for toxicity. 



 53 

Neratinib Serum concentrations may be 
increased due to CYP3A 
inhibition by ritonavir. 

Concomitant use of neratinib with 
Kaletra is contraindicated due to 
serious and/or life-threatening 
potential reactions including 
hepatotoxicity (see section 4.3). 

Venetoclax Due to CYP3A inhibition by 
lopinavir/ritonavir. 

Serum concentrations may be 
increased due to CYP3A inhibition 
by lopinavir/ritonavir, resulting in 
increased risk of tumor lysis 
syndrome at the dose initiation and 
during the ramp-up phase (see 
section 4.3 and refer to the 
venetoclax SmPC). 
 
For patients who have completed the 
ramp-up phase and are on a steady 
daily dose of venetoclax, reduce the 
venetoclax dose by at least 75% 
when used with strong CYP3A 
inhibitors (refer to the venetoclax 
SmPC for dosing instructions).  
Patients should be closely monitored 
for signs related to venetoclax 
toxicities. 

Anticoagulants 
Warfarin 
 
 
 

Warfarin: 
Concentrations may be affected 
when co-administered with 
lopinavir/ritonavir due to 
CYP2C9 induction.   

It is recommended that INR 
(international normalised ratio) be 
monitored. 
 

Rivaroxaban 
 
(Ritonavir 600 mg twice 
daily) 

Rivaroxaban:   
AUC: ↑ 153%  
Cmax: ↑ 55% 
Due to CYP3A and P-gp 
inhibition by lopinavir/ritonavir. 

Co-administration of rivaroxaban and 
Kaletra may increase rivaroxaban 
exposure which may increase the risk 
of bleeding. 
The use of rivaroxaban is not 
recommended in patients receiving 
concomitant treatment with Kaletra 
(see section 4.4). 

Vorapaxar Serum concentrations may be 
increased due to CYP3A 
inhibition by lopinavir/ritonavir. 

The co-administration of vorapaxar 
with Kaletra is not recommended (see 
section 4.4 and refer to the vorapaxar 
SmPC). 

Anticonvulsants 
Phenytoin 
 

Phenytoin: 
Steady-state concentrations was 
moderately decreased due to 
CYP2C9 and CYP2C19 induction 
by lopinavir/ritonavir. 
 
Lopinavir:   
Concentrations are decreased due 
to CYP3A induction by 
phenytoin.   
 

Caution should be exercised in 
administering phenytoin with Kaletra. 
Phenytoin levels should be monitored 
when co-administering with Kaletra. 
When co-administered with 
phenytoin, an increase of Kaletra 
dosage may be envisaged.  Dose 
adjustment has not been evaluated in 
clinical practice. 
Kaletra must not be administered 
once daily in combination with 
phenytoin. 



 54 

Carbamazepine and 
Phenobarbital  

Carbamazepine: 
Serum concentrations may be 
increased due to CYP3A 
inhibition by lopinavir/ritonavir. 
 
Lopinavir: 
Concentrations may be decreased 
due to CYP3A induction by 
carbamazepine and phenobarbital.   
 

Caution should be exercised in 
administering carbamazepine or 
phenobarbital with Kaletra. 
Carbamazepine and phenobarbital 
levels should be monitored when 
co-administering with Kaletra. 
When co-administered with 
carbamazepine or phenobarbital, an 
increase of Kaletra dosage may be 
envisaged.  Dose adjustment has not 
been evaluated in clinical practice. 
Kaletra must not be administered 
once daily in combination with 
carbamazepine and phenobarbital. 

Lamotrigine and 
Valproate 

Lamotrigine:  
AUC: ↓ 50% 
Cmax: ↓ 46% 
Cmin: ↓ 56% 
 
Due to induction of lamotrigine 
glucuronidation 
 
Valproate: ↓ 

Patients should be monitored closely 
for a decreased VPA effect when 
Kaletra and valproic acid or valproate 
are given concomitantly. 
 
In patients starting or stopping 
Kaletra while currently taking 
maintenance dose of lamotrigine:  
lamotrigine dose may need to be 
increased if Kaletra is added, or 
decreased if Kaletra is discontinued; 
therefore plasma lamotrigine 
monitoring should be conducted, 
particularly before and during 2 
weeks after starting or stopping 
Kaletra, in order to see if lamotrigine 
dose adjustment is needed. 
In patients currently taking Kaletra 
and starting lamotrigine: no dose 
adjustments to the recommended 
dose escalation of lamotrigine should 
be necessary.  

Antidepressants and Anxiolytics 
Trazodone single dose 
 
(Ritonavir, 200 mg 
BID) 
 

Trazodone: 
AUC: ↑ 2.4-fold 
 
Adverse events of nausea, 
dizziness, hypotension and 
syncope were observed following 
co-administration of trazodone 
and ritonavir.   

It is unknown whether the 
combination of Kaletra causes a 
similar increase in trazodone 
exposure.  The combination should 
be used with caution and a lower dose 
of trazodone should be considered. 
 

Antifungals 
Ketoconazole and 
Itraconazole 

Ketoconazole, Itraconazole: 
Serum concentrations may be 
increased due to CYP3A 
inhibition by lopinavir/ritonavir.  

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. 



 55 

Anti-gout agents 
Colchicine single dose 
 
(Ritonavir 200 mg 
twice-daily) 

Colchicine: 
AUC: ↑ 3-fold 
Cmax: ↑ 1.8-fold 
Due to P-gp and/or CYP3A4 
inhibition by ritonavir. 
 

Concomitant administration of 
Kaletra with colchicine in patients 
with renal and/or hepatic impairment 
is contraindicated due to a potential 
increase of colchicine-related serious 
and/or life-threatening reactions such 
as neuromuscular toxicity (including 
rhabdomyolysis) (see sections 4.3 and 
4.4).  A reduction in colchicine 
dosage or an interruption of 
colchicine treatment is recommended 
in patients with normal renal or 
hepatic function if treatment with 
Kaletra is required.  Refer to 
colchicine prescribing information. 

Antihistamines 
Astemizole 
Terfenadine 

Serum concentrations may be 
increased due to CYP3A 
inhibition by lopinavir/ritonavir. 

Concomitant administration of 
Kaletra and astemizole and 
terfenadine is contraindicated as it 
may increase the risk of serious 
arrhythmias from these agents (see 
section 4.3). 

Anti-infectives 
Fusidic acid Fusidic acid: 

Concentrations may be increased 
due to CYP3A inhibition by 
lopinavir/ritonavir. 

Concomitant administration of 
Kaletra with fusidic acid is contra-
indicated in dermatological 
indications due to the increased risk 
of adverse events related to fusidic 
acid, notably rhabdomyolysis (see 
section 4.3).  When used for osteo-
articular infections, where the co-
administration is unavoidable, close 
clinical monitoring for muscular 
adverse events is strongly 
recommended (see section 4.4).  

Antimycobacterials 
Bedaquiline 
(single dose) 
 
(Lopinavir/ritonavir 
400/100 mg BID, 
multiple dose) 

Bedaquiline: 
AUC: ↑ 22% 
Cmax: ↔ 
 
A more pronounced effect on 
bedaquiline plasma exposures 
may be observed during 
prolonged co-administration with 
lopinavir/ritonavir. 
 
CYP3A4 inhibition likely due to 
lopinavir/ritonavir. 
 

Due to the risk of bedaquiline related 
adverse events, the combination of 
bedaquiline and Kaletra should be 
avoided.  If the benefit outweighs the 
risk, co-administration of bedaquiline 
with Kaletra must be done with 
caution.  More frequent 
electrocardiogram monitoring and 
monitoring of transaminases is 
recommended (see section 4.4 and 
refer to the bedaquiline SmPC). 



 56 

Delamanid (100 mg 
BID) 
 
(Lopinavir/ritonavir 
400/100 mg BID) 

Delamanid: 
AUC: ↑ 22% 
 
DM-6705 (delamanid active 
metabolite): 
AUC: ↑ 30% 
 
A more pronounced effect on 
DM-6705 exposure may be 
observed during prolonged co-
administration with 
lopinavir/ritonavir. 

Due to the risk of QTc prolongation 
associated with DM-6705, if 
co-administration of delamanid with 
Kaletra is considered necessary, very 
frequent ECG monitoring throughout 
the full delamanid treatment period is 
recommended (see section 4.4 and 
refer to the delamanid SmPC). 

Rifabutin, 150 mg QD 
 

Rifabutin (parent drug and active 
25-O-desacetyl metabolite):  
AUC: ↑ 5.7-fold 
Cmax: ↑ 3.5-fold  
 
 

When given with Kaletra the 
recommended dose of rifabutin is 
150 mg 3 times per week on set days 
(for example Monday-Wednesday-
Friday).  Increased monitoring for 
rifabutin-associated adverse reactions 
including neutropenia and uveitis is 
warranted due to an expected increase 
in exposure to rifabutin.  Further 
dosage reduction of rifabutin to 
150 mg twice weekly on set days is 
recommended for patients in whom 
the 150 mg dose 3 times per week is 
not tolerated.  It should be kept in 
mind that the twice weekly dosage of 
150 mg may not provide an optimal 
exposure to rifabutin thus leading to a 
risk of rifamycin resistance and a 
treatment failure.  No dose 
adjustment is needed for Kaletra.  



 57 

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). 

Antipsychotics 
Lurasidone Due to CYP3A inhibition by 

lopinavir/ritonavir, concentrations 
of lurasidone are expected to 
increase. 

The concomitant administration with 
lurasidone is contraindicated (see 
section 4.3). 

Pimozide Due to CYP3A inhibition by 
lopinavir/ritonavir, concentrations 
of pimozide are expected to 
increase. 

Concomitant administration of 
Kaletra and pimozide is 
contraindicated as it may increase the 
risk of serious haematologic 
abnormalities or other serious 
adverse effects from this agent (see 
section 4.3) 

Quetiapine Due to CYP3A inhibition by 
lopinavir/ritonavir, concentrations 
of quetiapine are expected to 
increase. 

Concomitant administration of 
Kaletra and quetiapine is 
contraindicated as it may increase 
quetiapine-related toxicity. 



 58 

Benzodiazepines 
Midazolam 
 

Oral Midazolam:  
AUC: ↑ 13-fold  
Parenteral Midazolam: 
AUC: ↑ 4-fold 
Due to CYP3A inhibition by 
lopinavir/ritonavir 
 

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. 

Beta2-adrenoceptor agonist (long acting) 
Salmeterol Salmeterol: 

Concentrations are expected to 
increase due to CYP3A inhibition 
by lopinavir/ritonavir. 

The combination may result in 
increased risk of cardiovascular 
adverse events associated with 
salmeterol, including QT 
prolongation, palpitations and sinus 
tachycardia. 
Therefore, concomitant 
administration of Kaletra with 
salmeterol is not recommended (see 
section 4.4). 

Calcium channel blockers 
Felodipine, Nifedipine, 
and Nicardipine 

Felodipine, Nifedipine, 
Nicardipine: 
Concentrations may be increased 
due to CYP3A inhibition by 
lopinavir/ritonavir. 

Clinical monitoring of therapeutic 
and adverse effects is recommended 
when these medicines are 
concomitantly administered with 
Kaletra. 

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. 



 59 

Inhaled, injectable or 
intranasal fluticasone 
propionate, budesonide, 
triamcinolone 

Fluticasone propionate, 50 µg 
intranasal 4 times daily: 
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 e.g. budesonide 
and triamcinolone.  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 (e.g. 
beclomethasone).  Moreover, in case 
of withdrawal of glucocorticoids 
progressive dose reduction may have 
to be performed over a longer period.   

Phosphodiesterase(PDE5) inhibitors 
Avanafil  
(ritonavir 600 mg BID)  

Avanafil: 
AUC: ↑ 13-fold  
Due to CYP3A inhibition by 
lopinavir/ritonavir. 

The use of avanafil with Kaletra is 
contraindicated (see section 4.3).   
 

Tadalafil  
 
 

Tadalafil: 
AUC: ↑ 2-fold 
Due to CYP3A4 inhibition by 
lopinavir/ritonavir. 

For the treatment of pulmonary 
arterial hypertension: 
Co-administration of Kaletra with 
sildenafil is contraindicated (see 
section 4.3).  Co-administration of 
Kaletra with tadalafil is not 
recommended. 
 
For erectile dysfunction: 
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.   

Sildenafil 
 
 

Sildenafil:  
AUC: ↑ 11-fold 
Due to CYP3A inhibition by 
lopinavir/ritonavir. 
 

Vardenafil  
 
 

Vardenafil: 
AUC: ↑ 49-fold  
Due to CYP3A inhibition by 
lopinavir/ritonavir. 

The use of vardenafil with Kaletra is 
contraindicated (see section 4.3).   
 



 60 

Ergot alkaloids 
Dihydroergotamine, 
ergonovine, ergotamine, 
methylergonovine 

Serum concentrations may be 
increased due to CYP3A 
inhibition by lopinavir/ritonavir. 

Concomitant administration of 
Kaletra and ergot alkaloids are 
contraindicated as it may lead to 
acute ergot toxicity, including 
vasospasm and ischaemia (see 
section 4.3). 

GI motility agent 
Cisapride Serum concentrations may be 

increased due to CYP3A 
inhibition by lopinavir/ritonavir. 

Concomitant administration of 
Kaletra and cisapride is 
contraindicated as it may increase the 
risk of serious arrhythmias from this 
agent (see section 4.3). 

HCV direct acting antivirals 
Elbasvir/grazoprevir 
(50/200 mg QD) 

 
Elbasvir: 
AUC: ↑ 2.71-fold 
Cmax: ↑ 1.87-fold 
C24: ↑ 3.58-fold 
 
Grazoprevir: 
AUC: ↑ 11.86-fold 
Cmax: ↑ 6.31-fold 
C24: ↑ 20.70-fold 
 
(combinations of mechanisms 
including CYP3A inhibition) 
 
Lopinavir: ↔ 

Concomitant administration of 
elbasvir/grazoprevir with Kaletra is 
contraindicated (see section 4.3). 

Glecaprevir/pibrentasvir Serum concentrations may be 
increased due to P-glycoprotein, 
BCRP and OATP1B inhibition by 
lopinavir/ritonavir. 

Concomitant administration of 
glecaprevir/pibrentasvir and Kaletra 
is not recommended due to an 
increased risk of ALT elevations 
associated with increased glecaprevir 
exposure. 



 61 

Ombitasvir/paritaprevir/
ritonavir + dasabuvir 
 
(25/150/100 mg QD + 
400 mg BID) 
 
Lopinavir/ritonavir  
400/100 mg BID 

Ombitasvir: ↔  
 
Paritaprevir: 
AUC: ↑ 2.17-fold 
Cmax: ↑ 2.04-fold 
Ctrough: ↑ 2.36-fold 
 
(inhibition of CYP3A/efflux 
transporters) 
 
Dasabuvir: ↔ 
 
Lopinavir: ↔ 

Co-administration is contraindicated. 
 
Lopinavir/ritonavir 800/200 mg QD 
was administered with 
ombitasvir/paritaprevir/ritonavir with 
or without dasabuvir.  The effect on 
DAAs and lopinavir was similar to 
that observed when 
lopinavir/ritonavir 400/100 mg BID 
was administered (see section 4.3). 

Ombitasvir/paritaprevir/ 
ritonavir 
 
(25/150/100 mg QD) 
 
Lopinavir/ritonavir 
400/100 mg BID 

Ombitasvir: ↔ 
 
Paritaprevir: 
AUC: ↑ 6.10-fold 
Cmax: ↑ 4.76-fold 
Ctrough: ↑ 12.33-fold 
 
(inhibition of CYP3A/efflux 
transporters) 
 
Lopinavir: ↔ 

Sofosbuvir/velpatasvir/ 
voxilaprevir 

Serum concentrations of 
sofosbuvir, velpatasvir and 
voxilaprevir may be increased due 
to P-glycoprotein, BCRP and 
OATP1B1/3 inhibition by 
lopinavir/ritonavir. However, only 
the increase in voxilaprevir 
exposure is considered clinically 
relevant. 

It is not recommended to 
co-administer Kaletra and 
sofosbuvir/velpatasvir/ voxilaprevir. 

HCV protease inhibitors 
Simeprevir 200 mg 
daily (ritonavir 100 mg 
BID) 
 

Simeprevir: 
AUC: ↑ 7.2-fold 
Cmax: ↑ 4.7-fold 
Cmin: ↑ 14.4-fold 

It is not recommended to 
co-administer Kaletra and simeprevir. 



 62 

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 
lopinavir/ritonavir. 

More frequent therapeutic 
concentration monitoring is 
recommended until plasma levels of 
these products have been stabilised. 

Lipid lowering agents 
Lovastatin and 
Simvastatin 

Lovastatin, Simvastatin: 
Markedly increased plasma 
concentrations due to CYP3A 
inhibition by lopinavir/ritonavir. 

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). 

Lipid-modifying agents 
Lomitapide CYP3A4 inhibitors increase the 

exposure of lomitapide, with 
strong inhibitors increasing 
exposure approximately 27-fold.  
Due to CYP3A inhibition by 
lopinavir/ritonavir, concentrations 
of lomitapide are expected to 
increase. 

Concomitant use of Kaletra with 
lomitapide is contraindicated (see 
prescribing information for 
lomitapide) (see section 4.3). 

Atorvastatin Atorvastatin: 
AUC: ↑ 5.9-fold  
Cmax: ↑ 4.7-fold 
Due to CYP3A inhibition by 
lopinavir/ritonavir. 

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  
Cmax:  ↑ 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:  If treatment with an HMG-CoA 
reductase inhibitor is indicated, 



 63 

No clinical relevant interaction 
expected. 
Pravastatin is not metabolised by 
CYP450. 
Fluvastatin is partially 
metabolised by CYP2C9. 

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 Cmax ↓ ~50%  
 
This effect may be due to 
induction of bupropion 
metabolism. 
 

If the co-administration of Kaletra 
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. 

Thyroid hormone replacement therapy 
Levothyroxine Post-marketing cases have been 

reported indicating a potential 
interaction between ritonavir 
containing products and 
levothyroxine. 

Thyroid-stimulating hormone (TSH) 
should be monitored in patients 
treated with levothyroxine at least the 
first month after starting and/or 
ending lopinavir/ritonavir treatment. 

Vasodilating agents 
Bosentan Lopinavir - ritonavir: 

Lopinavir/ritonavir plasma 
concentrations may decrease due 
to CYP3A4 induction by 
bosentan. 
 
Bosentan: 
AUC: ↑ 5-fold  
Cmax:  ↑ 6-fold 
Initially, bosentan Cmin: ↑ by 
approximately 48-fold.  
Due to CYP3A4 inhibition by 
lopinavir/ritonavir. 

Caution should be exercised in 
administering Kaletra with bosentan. 
When Kaletra is administered 
concomitantly with bosentan, the 
efficacy of the HIV therapy should 
be monitored and patients should be 
closely observed for bosentan 
toxicity, especially during the first 
week of co-administration.   

Riociguat Serum concentrations may be 
increased due to CYP3A and P-gp 
inhibition by lopinavir/ritonavir. 

The co-administration of riociguat 
with Kaletra is not recommended 
(see section 4.4 and refer to riociguat 
SmPC). 

Other medicinal products 
Based on known metabolic profiles, clinically significant interactions are not expected between 
Kaletra and dapsone, trimethoprim/sulfamethoxazole, azithromycin or fluconazole. 

 



 64 

4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in 
pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, 
the animal data as well as the clinical experience in pregnant women should be taken into account in 
order to characterise the safety for the foetus. 
 
Lopinavir/ritonavir has been evaluated in over 3000 women during pregnancy, including over 1000 
during the first trimester. 
 
In post-marketing surveillance through the Antiretroviral Pregnancy Registry, established since 
January 1989, an increased risk of birth defects exposures with Kaletra has not been reported among 
over 1000 women exposed during the first trimester.  The prevalence of birth defects after any 
trimester exposure to lopinavir is comparable to the prevalence observed in the general population.  
No pattern of birth defects suggestive of a common etiology was seen.  Studies in animals have shown 
reproductive toxicity (see section 5.3).  Based on the data mentioned, the malformative risk is unlikely 
in humans.  Lopinavir can be used during pregnancy if clinically needed. 
 
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.  As a general rule, it is recommended that mothers infected by HIV 
do not breastfeed their babies under any circumstances in order to avoid transmission of HIV.  
 
Fertility 
Animal studies have shown no effects on fertility.  No human data on the effect of lopinavir/ritonavir 
on fertility are available. 
 
4.7 Effects on ability to drive and use machines 
 
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). 
 
4.8 Undesirable effects  
 
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.  The risk of diarrhoea may be 
greater with once-daily dosing of Kaletra.  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: 
 



 65 

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), rare (≥1/10,000 to <1/1000) and not known (cannot be 
estimated from the available data). 
 

Undesirable effects in clinical studies and post-marketing in adult patients 

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 inflammatory 
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 Pancreatitis1, vomiting, gastrooesophageal 
reflux disease, gastroenteritis and colitis, 
abdominal pain (upper and lower), abdominal 
distension, dyspepsia, haemorrhoids, 
flatulence 
 



 66 

Uncommon Gastrointestinal haemorrhage including 
gastrointestinal ulcer, duodenitis, gastritis and 
rectal haemorrhage, stomatitis and oral ulcers, 
faecal incontinence, constipation, dry mouth 

Hepatobiliary disorders Common Hepatitis including AST, ALT and GGT 
increases 
 

Uncommon Jaundice, hepatic steatosis, hepatomegaly, 
cholangitis, hyperbilirubinemia 

Skin and subcutaneous tissue 
disorders 

Common 
 

Rash including maculopapular rash, 
dermatitis/rash including eczema and 
seborrheic dermatitis, night sweats, pruritus 
 

Uncommon Alopecia, capillaritis, vasculitis  
 

Rare 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 

 
 
Not known 

Creatinine clearance decreased, nephritis, 
haematuria 
 
Nephrolithiasis 

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. 
 
Metabolic parameters 
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (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.  Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have 
also been reported; however, the reported time to onset is more variable and can occur many months 
after initiation of treatment (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). 



 67 

 
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).  
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important.  It 
allows continued monitoring of the benefit/risk balance of the medicinal product.  Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
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.  PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmaco-therapeutic group: antivirals for systemic use, antivirals for treatment of HIV infections, 
combinations, ATC code: J05AR10  
 
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 ms from baseline or a QTcF interval exceeding the potentially clinically 
relevant threshold of 500 ms. 
 
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 ms and no second or third degree 
heart block was observed (see section 4.4). 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 68 

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 IC50 of lopinavir against five different HIV-1 laboratory strains 
was 19 nM.  In the absence and presence of 50% human serum, the mean IC50 of lopinavir against 
HIV-1IIIB in MT4 cells was 17 nM and 102 nM, respectively.  In the absence of human serum, the 
mean IC50 of lopinavir was 6.5 nM against several HIV-1 clinical isolates. 
 
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 IC50 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 EC50 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 EC50 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. 
 



 69 

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 EC50 of lopinavir against the 
56 baseline viral isolates ranged from 0.6 to 96-fold higher than the EC50 against wild type HIV.  After 
48 weeks of treatment 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 IC50 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 IC50 from 3.7- to 8-fold in the baseline and rebound isolates, respectively.  Isolates retained 
susceptibility to tipranavir with a median increase of IC50 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/mm3 (range: 2 to 
949 cells/ mm3) and mean baseline plasma HIV-1 RNA was 4.9 log10 copies/ml (range: 2.6 to 
6.8 log10 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/mm3) 

207 195 

* intent to treat analysis where patients with missing values are considered virologic failures  
† p < 0.001 

 



 70 

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 
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. 
 
Study M05-730 was a randomised, open-label, multicentre trial comparing treatment with Kaletra 
800/200 mg once daily plus tenofovir DF and emtricitabine versus Kaletra 400/100 mg twice daily 
plus tenofovir DF and emtricitabine in 664 antiretroviral treatment-naïve patients.  Given the 
pharmacokinetic interaction between Kaletra and tenofovir (see section 4.5), the results of this study 
might not be strictly extrapolable when other backbone regimens are used with Kaletra.  Patients were 
randomised in a 1:1 ratio to receive either Kaletra 800/200 mg once daily (n = 333) or Kaletra 
400/100 mg twice daily (n = 331).  Further stratification within each group was 1:1 (tablet versus soft 
capsule).  Patients were administered either the tablet or the soft capsule formulation for 8 weeks, after 
which all patients were administered the tablet formulation once daily or twice daily for the remainder 
of the study.  Patients were administered emtricitabine 200 mg once daily and tenofovir DF 300 mg 
once daily (equivalent to 245 mg tenofovir disoproxil).  Protocol defined non-inferiority of once-daily 
dosing compared with twice-daily dosing was demonstrated if the lower bound of the 95% confidence 
interval for the difference in proportion of subjects responding (once daily minus twice daily) 
excluded -12% at Week 48.  Mean age of patients enrolled was 39 years (range: 19 to 71); 75% were 
Caucasian, and 78% were male.  Mean baseline CD4+ T-cell count was 216 cells/mm3 (range: 20 to 
775 cells/mm3) and mean baseline plasma HIV-1 RNA was 5.0 log10 copies/ml (range: 1.7 to 
7.0 log10 copies/ml).   
 
Table 2 
 

Virologic Response of Study Subjects at Week 48 and Week 96 

 Week 48 Week 96 
 QD BID  Difference 

[95% CI] 
QD BID  Difference 

[95% CI] 
NC= Failure 257/333 

(77.2%) 
251/331 
(75.8%) 

1.3 % 
[-5.1, 7.8] 

216/333 
(64.9%) 

229/331 
(69.2%) 

-4.3% 
[-11.5, 2.8] 

Observed data 257/295 
(87.1%) 

250/280 
(89.3%) 

-2.2% 
[-7.4, 3.1] 

216/247 
(87.4%) 

229/248 
(92.3%) 

-4.9% 
[-10.2, 0.4] 

Mean increase from 
baseline in CD4+ T-cell 
count (cells/mm3) 

186 198  238 254  

 
Through Week 96, genotypic resistance testing results were available from 25 patients in the QD 
group and 26 patients in the BID group who had incomplete virologic response.  In the QD group, no 
patient demonstrated lopinavir resistance, and in the BID group, 1 patient who had significant protease 
inhibitor resistance at baseline demonstrated additional lopinavir resistance on study. 
 
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).   
 



 71 

Table 3 
 

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/mm3) 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 
 
M06-802 was a randomised open-label study comparing the safety, tolerability and antiviral activity of 
once-daily and twice-daily dosing of lopinavir/ritonavir tablets in 599 subjects with detectable viral 
loads while receiving their current antiviral therapy.  Patients had not been on prior lopinavir/ritonavir 
therapy.  They were randomised in a 1:1 ratio to receive either lopinavir/ritonavir 800/200 mg once 
daily (n = 300) or lopinavir/ritonavir 400/100 mg twice daily (n = 299).  Patients were administered at 
least two nucleoside/nucleotide reverse transcriptase inhibitors selected by the investigator.  The 
enrolled population was moderately PI-experienced with more than half of patients having never 
received prior PI and around 80% of patients presenting a viral strain with less than 3 PI mutations.  
Mean age of patients enrolled was 41 years (range: 21 to 73); 51% were Caucasian and 66% were 
male.  Mean baseline CD4+ T-cell count was 254 cells/mm3 (range: 4 to 952 cells/mm3) and mean 
baseline plasma HIV-1 RNA was 4.3 log10 copies/ml (range: 1.7 to 6.6 log10 copies/ml).  Around 85% 
of patients had a viral load of < 100,000 copies/ml. 
 
Table 4 
 

Virologic Response of Study Subjects at Week 48 Study 802 

 QD BID Difference 
[95% CI] 

NC= Failure 171/300 
(57%) 

161/299 
(53.8%) 

3.2% 
[-4.8%, 11.1%] 

Observed data 171/225 
(76.0%) 

161/223 
(72.2%) 

3.8% 
[-4.3%, 11.9%] 

Mean increase from baseline in 
CD4+ T-cell count (cells/mm3) 

135 122  

 
Through Week 48, genotypic resistance testing results were available from 75 patients in the QD 
group and 75 patients in the BID group who had incomplete virologic response.  In the QD group, 
6/75 (8%) patients demonstrated new primary protease inhibitor mutations (codons 30, 32, 48, 50, 82, 
84, 90), as did 12/77 (16%) patients in the BID group. 
 
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 m2 or 
300 mg lopinavir/75 mg ritonavir per m2.  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 m2 



 72 

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/mm3 and 
mean baseline plasma HIV-1 RNA was 4.7 log10 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/mm3) 

404 284 

 
KONCERT/PENTA 18 is a prospective multicentre, randomised, open-label study that evaluated the 
pharmacokinetic profile, efficacy and safety of twice-daily versus once-daily dosing of 
lopinavir/ritonavir 100 mg/25 mg tablets dosed by weight as part of combination antiretroviral therapy 
(cART) in virologically suppressed HIV-1 infected children (n=173).  Children were eligible when 
they were aged <18 years, ≥15 kg in weight, receiving cART that included lopinavir/ritonavir, HIV-1 
ribonucleic acid (RNA) <50 copies/ml for at least 24 weeks and able to swallow tablets.  At week 48, 
the efficacy and safety with twice-daily dosing (n=87) in the paediatric population given 
lopinavir/ritonavir 100 mg/25 mg tablets was consistent with the efficacy and safety findings in 
previous adult and paediatric studies using lopinavir/ritonavir twice daily.  The percentage of patients 
with confirmed viral rebound >50 copies/ml during 48 weeks of follow-up was higher in the paediatric 
patients receiving lopinavir/ritonavir tablets once daily (12%) than in patients receiving the twice-daily 
dosing (8%, p = 0.19), mainly due to lower adherence in the once-daily group.  The efficacy data 
favouring the twice-daily regimen are reinforced by a differential in pharmacokinetic parameters 
significantly favouring the twice-daily regimen (see section 5.2). 
 
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 EC50 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 (Cmax) 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 
Administration of a single 400/100 mg dose of Kaletra tablets under fed conditions (high fat, 872 kcal, 
56% from fat) compared to fasted state was associated with no significant changes in Cmax and AUCinf.  
Therefore, Kaletra tablets may be taken with or without food.  Kaletra tablets have also shown less 
pharmacokinetic variability under all meal conditions compared to Kaletra soft capsules. 
 



 73 

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 14C-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 14C-lopinavir/ritonavir dose, approximately 10.4 ± 2.3% and 82.6 ± 2.5% of an 
administered dose of 14C-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. 
 
Once-daily dosing: the pharmacokinetics of once daily Kaletra have been evaluated in HIV-infected 
subjects naïve to antiretroviral treatment.  Kaletra 800/200 mg was administered in combination with 
emtricitabine 200 mg and tenofovir DF 300 mg as part of a once-daily regimen.  Multiple dosing of 
800/200 mg Kaletra once daily for 2 weeks without meal restriction (n=16) produced a mean ± SD 
lopinavir peak plasma concentration (Cmax) of 14.8 ± 3.5 µg/ml, occurring approximately 6 hours after 
administration.  The mean steady-state trough concentration prior to the morning dose was 
5.5 ± 5.4 µg/ml.  Lopinavir AUC over a 24 hour dosing interval averaged 206.5 ± 89.7 µg•h/ml. 
 
As compared to the BID regimen, the once-daily dosing is associated with a reduction in the 
Cmin/Ctrough values of approximately 50%.   
 
Special Populations 
 
Paediatrics 
There are limited pharmacokinetic data in children below 2 years of age.  The pharmacokinetics of 
Kaletra oral solution 300/75 mg/m2 twice daily and 230/57.5 mg/m2 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, Cmax, and Cmin were 72.6 ± 31.1 µg•h/ml, 8.2 ± 2.9 µg/ml and 3.4 ± 2.1 µg/ml, respectively 
after Kaletra oral solution 230/57.5 mg/m2 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/m2 twice 
daily with nevirapine (n=12).  The 230/57.5 mg/m2 twice-daily regimen without nevirapine and the 
300/75 mg/m2 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.   
 
Gender, Race and Age   
Kaletra pharmacokinetics have not been studied in older people.  No age or gender related 
pharmacokinetic differences have been observed in adult patients.  Pharmacokinetic differences due to 
race have not been identified. 
 



 74 

Pregnancy and postpartum 
In an open-label pharmacokinetic study, 12 HIV-infected pregnant women who were less than 20 
weeks of gestation and on combination antiretroviral therapy initially received lopinavir/ritonavir 400 
mg/100 mg (two 200/50 mg tablets) twice daily up to a gestational age of 30 weeks. At 30 weeks age 
of gestation, the dose was increased to 500/125 mg (two 200/50 mg tablets plus one 100/25 mg tablet) 
twice daily until subjects were 2 weeks postpartum. Plasma concentrations of lopinavir were measured 
over four 12-hour periods during second trimester (20-24 weeks gestation), third trimester before dose 
increase (30 weeks gestation), third trimester after dose increase (32 weeks gestation), and at 8 weeks 
post-partum. The dose increase did not result in a significant increase in the plasma lopinavir 
concentration.  
 
In another open-label pharmacokinetic study, 19 HIV-infected pregnant women received 
lopinavir/ritonavir 400/100 mg twice daily as part of combination antiretroviral therapy during 
pregnancy from before conception. A series of blood samples were collected pre-dose and at intervals 
over the course of 12 hours in trimester 2 and trimester 3, at birth, and 4–6 weeks postpartum (in 
women who continued treatment post-delivery) for pharmacokinetic analysis of total and unbound 
levels of plasma lopinavir concentrations. 
 
The pharmacokinetic data from HIV-1 infected pregnant women receiving lopinavir/ritonavir tablets 
400/100 mg twice daily are presented in Table 6 (see section 4.2). 
 
Table 6 
 

Mean (%CV) Steady-State Pharmacokinetic Parameters of Lopinavir  
in HIV-Infected Pregnant Women 

Pharmacokinetic 
Parameter 

2nd Trimester 
n = 17* 

3rd Trimester 
n = 23 

Postpartum 
n = 17** 

AUC0-12 μg•hr/mL 68.7 (20.6) 61.3 (22.7) 94.3 (30.3) 
Cmax 7.9 (21.1) 7.5 (18.7) 9.8 (24.3) 

Cpredose μg /mL 4.7 (25.2) 4.3 (39.0) 6.5 (40.4) 
*   n = 18 for Cmax 
** n = 16 for Cpredose 

 
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. 
 
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 



 75 

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. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet contents:  
Copovidone 
Sorbitan laurate 
Colloidal anhydrous silica 
Sodium stearyl fumarate 
 
Film-coating:  
Hypromellose 
Titanium dioxide 
Macrogols type 400 (Polyethylene glycol 400) 
Hydroxypropyl cellulose 
Talc  
Colloidal anhydrous silica 
Macrogols type 3350 (Polyethylene glycol 3350) 
Yellow ferric oxide E172 
Polysorbate 80 
 



 76 

6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
Bottle packs: 4 years. 
Blister packs: 3 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
High density polyethylene (HDPE) bottles closed with propylene caps.  Each bottle contains 120 
tablets.   
Two pack sizes are available: 
- 1 bottle of 120 tablets 
- multipack containing 360 (3 bottles of 120) film-coated tablets 
 
Blisters packs - polyvinyl chloride (PVC) blisters with fluoropolymer foil backing   
Two pack sizes are available: 
-  carton containing 120 film-coated tablets 
- multipack containing 120 (3 cartons of 40) film-coated tablets 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
No special requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
AbbVie Deutschland GmbH & Co. KG 
Knollstrasse 
67061 Ludwigshafen 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/01/172/004 
EU/1/01/172/005 
EU/1/01/172/007 
EU/1/01/172/008 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 20 March 2001 
Date of latest renewal: 20 March 2011 
 
 



 77 

10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this product is available on the website of the European Medicines Agency 
http://www.ema.europa.eu 

http://www.ema.europa.eu/


 78 

1. NAME OF THE MEDICINAL PRODUCT  
 
Kaletra 100 mg/25 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION  
Each film-coated tablet contains 100 mg of lopinavir co-formulated with 25 mg of ritonavir as a 
pharmacokinetic enhancer. 
 
For the full list of excipients, see section 6.1.  
 
 
3. PHARMACEUTICAL FORM  
 
Film-coated tablet 
 
Pale yellow debossed with [Abbott logo] and “KC”. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Kaletra is indicated in combination with other antiretroviral medicinal products for the treatment of 
human immunodeficiency virus (HIV-1) infected children above the age of 2 years, adolescents and 
adults.  
 
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). 
 
4.2 Posology and method of administration 
 
Kaletra should be prescribed by physicians who are experienced in the treatment of HIV infection. 
 
Kaletra tablets must be swallowed whole and not chewed, broken or crushed.  
 
Posology 
 
Adults and adolescents  
The standard recommended dosage of Kaletra tablets is 400/100 mg (two 200/50 mg) tablets twice 
daily taken with or without food.  In adult patients, in cases where once-daily dosing is considered 
necessary for the management of the patient, Kaletra tablets may be administered as 800/200 mg (four 
200/50 mg tablets) once daily with or without food.  The use of a once-daily dosing should be limited 
to those adult patients having only very few protease inhibitor (PI) associated mutations (i.e. less than 
3 PI mutations in line with clinical trial results, see section 5.1 for the full description of the 
population) and should take into account the risk of a lesser sustainability of the virologic suppression 
(see section 5.1) and higher risk of diarrhoea (see section 4.8) compared to the recommended standard 
twice-daily dosing.  An oral solution is available to patients who have difficulty swallowing.  Refer to 
the Summary of Product Characteristics for Kaletra oral solution for dosing instructions. 
 
Paediatric population (2 years of age and above) 
The adult dose of Kaletra tablets (400/100 mg twice daily) may be used in children 40 kg or greater or 
with a Body Surface Area (BSA)* greater than 1.4 m2.  For children weighing less than 40 kg or with 
a BSA between 0.5 and 1.4 m2 and able to swallow tablets, refer to the dosing guideline tables below.  
For children unable to swallow tablets, please refer to the Kaletra oral solution Summary of Product 
Characteristics.  Based on the current data available, Kaletra should not be administered once daily in 
paediatric patients (see section 5.1). 



 79 

 
Before prescribing Kaletra 100/25 mg tablets, infants and young children should be assessed for the 
ability to swallow intact tablets.  If a child is unable to reliably swallow a Kaletra tablet, Kaletra oral 
solution formulation should be prescribed. 
 
The following table contains dosing guidelines for Kaletra 100/25 mg tablets based on body weight 
and BSA.   
 

Paediatric dosing guidelines 
without concomitant efavirenz or nevirapine*  

Weight (kg) Body Surface Area (m2) Recommended number of  
100/25 mg tablets twice-daily 

15 to 25 ≥ 0.5 to < 0.9 2 tablets (200/50 mg) 
> 25 to 35 ≥ 0.9 to < 1.4 3 tablets (300/75 mg) 

> 35 ≥ 1.4 4 tablets (400/100 mg) 
 *weight based dosing recommendations are based on limited data  
 
If more convenient for patients, the Kaletra 200/50 mg tablets may also be considered alone or in 
combination with the Kaletra 100/25 mg tablet to achieve the recommended dose. 
 
* Body surface area can be calculated with the following equation: 
 

BSA (m2) = √ (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 been established.  
Currently available data are described in section 5.2 but no recommendation on the posology can be 
made. 
 
Concomitant Therapy: Efavirenz or nevirapine 
The following table contains dosing guidelines for Kaletra 100/25 mg tablets based on BSA when 
used in combination with efavirenz or nevirapine in children. 
 

Paediatric dosing guidelines with concomitant  
efavirenz or nevirapine  

Body Surface Area (m2) Recommended number of  
100/25 mg tablets twice-daily 

≥ 0.5 to < 0.8 2 tablets (200/50 mg) 
≥ 0.8 to < 1.2 3 tablets (300/75 mg) 
≥ 1.2 to < 1.4 4 tablets (400/100 mg) 

≥ 1.4 5 tablets (500/125 mg) 
 
If more convenient for patients, the Kaletra 200/50 mg tablets may also be considered alone or in 
combination with the Kaletra 100/25 mg tablet to achieve the recommended dose. 
 
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). 
 



 80 

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. 
 
Pregnancy and postpartum 
• No dose adjustment is required for lopinavir/ritonavir during pregnancy and postpartum. 
• Once-daily administration of lopinavir/ritonavir is not recommended for pregnant women due to 

the lack of pharmacokinetic and clinical data. 
 
Method of administration 
 
Kaletra tablets are administered orally and must be swallowed whole and not chewed, broken or 
crushed.  Kaletra tablets can be taken with or without food. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. 
 
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:  
 

Medicinal product 
class 

Medicinal products within 
class 

Rationale 

Concomitant medicinal product levels increased 

Alpha1-adrenoreceptor 
antagonist 

Alfuzosin Increased plasma concentrations of 
alfuzosin which may lead to severe 
hypotension.  The concomitant 
administration with alfuzosin is 
contraindicated (see section 4.5). 

Antianginal Ranolazine Increased plasma concentrations of 
ranolazine which may increase the 
potential for serious and/or life-
threatening reactions (see section 4.5). 

Antiarrhythmics Amiodarone, dronedarone Increased plasma concentrations of 
amiodarone and dronedarone.  Thereby, 
increasing the risk of arrhythmias or other 
serious adverse reactions (see section 4.5). 

Antibiotic Fusidic Acid Increased plasma concentrations of fusidic 
acid. The concomitant administration with 
fusidic acid is contraindicated in 
dermatological infections (see section 
4.5). 

Anticancer Neratinib Increased plasma concentrations of 
neratinib which may increase the potential 
for serious and/or life-threatening 
reactions (see section 4.5). 

Venetoclax Increased plasma concentrations of 
venetoclax.  Increased risk of tumor lysis 
syndrome at the dose initiation and during 
the ramp-up phase (see section 4.5). 



 81 

Anti-gout Colchicine Increased plasma concentrations of 
colchicine.  Potential for serious and/or 
life-threatening reactions in patients with 
renal and/or hepatic impairment (see 
sections 4.4 and 4.5). 

Antihistamines Astemizole, terfenadine Increased plasma concentrations of 
astemizole and terfenadine.  Thereby, 
increasing the risk of serious arrhythmias 
from these agents (see section 4.5). 

Antipsychotics/ 
Neuroleptics 

Lurasidone Increased plasma concentrations of 
lurasidone which may increase the 
potential for serious and/or life-
threatening reactions (see section 4.5). 

Pimozide Increased plasma concentrations of 
pimozide.  Thereby, increasing the risk of 
serious haematologic abnormalities, or 
other serious adverse effects from this 
agent (see section 4.5). 

Quetiapine Increased plasma concentrations of 
quetiapine which may lead to coma.  The 
concomitant administration with 
quetiapine is contraindicated (see section 
4.5). 

Ergot alkaloids Dihydroergotamine, ergonovine, 
ergotamine, methylergonovine 

Increased plasma concentrations of ergot 
derivatives leading to acute ergot toxicity, 
including vasospasm and ischaemia (see 
section 4.5). 

GI motility agent Cisapride Increased plasma concentrations of 
cisapride.  Thereby, increasing the risk of 
serious arrhythmias from this agent (see 
section 4.5). 

Hepatitis C virus direct 
acting antivirals 

Elbasvir/grazoprevir Increased risk of alanine transaminase 
(ALT) elevations (see section 4.5). 

Ombitasvir/paritaprevir/ritonavir 
with or without dasabuvir 

Increased plasma concentrations of 
paritaprevir; thereby, increasing the risk of 
alanine transaminase (ALT) elevations 
(see section 4.5). 

Lipid-modifying agents 
 

 

HMG Co-A Reductase 
Inhibitors 

Lovastatin, simvastatin Increased plasma concentrations of 
lovastatin and simvastatin; thereby, 
increasing the risk of myopathy including 
rhabdomyolysis (see section 4.5). 

Microsomal triglyceride 
transfer protein (MTTP) 
inhibitor 

Lomitapide Increased plasma concentrations of 
lomitapide (see section 4.5). 



 82 

Phosphodiesterase 
(PDE5) inhibitors 

Avanafil Increased plasma concentrations of 
avanafil (see sections 4.4 and 4.5) 

Sildenafil 
 

Contraindicated when used for the 
treatment of pulmonary arterial 
hypertension (PAH) only.  Increased 
plasma concentrations of sildenafil.  
Thereby, increasing the potential for 
sildenafil-associated adverse events 
(which include hypotension and syncope).  
See section 4.4 and section 4.5 for 
co-administration of sildenafil in patients 
with erectile dysfunction. 

Vardenafil Increased plasma concentrations of 
vardenafil (see sections 4.4 and 4.5) 

Sedatives/hypnotics Oral midazolam, triazolam Increased plasma concentrations of oral 
midazolam and triazolam.  Thereby, 
increasing the risk of extreme sedation 
and respiratory depression from these 
agents.   
For caution on parenterally administered 
midazolam, see section 4.5. 

Lopinavir/ritonavir medicinal product level decreased 

Herbal products St. John’s wort Herbal preparations containing St John’s 
wort (Hypericum perforatum) due to the 
risk of decreased plasma concentrations 
and reduced clinical effects of lopinavir 
and ritonavir (see section 4.5). 

 
4.4 Special warnings and precautions for use  
 
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. 
 



 83 

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. 
 
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 
 
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).  
 
Immune Reconstitution Inflammatory 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. 
 
Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported to 
occur in the setting of immune reconstitution; however, the reported time to onset is more variable and 
can occur many months after initiation of treatment. 
 
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 2nd or 3rd 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). 
 
Weight and metabolic parameters 
An increase in weight and in levels of blood lipids and glucose may occur during antiretroviral 
therapy.  Such changes may in part be linked to disease control and life style.  For lipids, there is in 
some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating 



 84 

this to any particular treatment.  For monitoring of blood lipids and glucose, reference is made to 
established HIV treatment guidelines.  Lipid disorders should be managed as clinically appropriate. 
 
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). 
 
Strong CYP3A4 inhibitors such as protease inhibitors may increase bedaquiline exposure which could 
potentially increase the risk of bedaquiline-related adverse reactions.  Therefore, combination of 
bedaquiline with lopinavir/ritonavir should be avoided.  However, if the benefit outweighs the risk, 
co-administration of bedaquiline with lopinavir/ritonavir must be done with caution.  More frequent 
electrocardiogram monitoring and monitoring of transaminases is recommended (see section 4.5 and 
refer to the bedaquiline SmPC). 
 
Co-administration of delamanid with a strong inhibitor of CYP3A (as lopinavir/ritonavir) may 
increase exposure to delamanid metabolite, which has been associated with QTc prolongation.  
Therefore, if co-administration of delamanid with lopinavir/ritonavir is considered necessary, very 
frequent ECG monitoring throughout the full delamanid treatment period is recommended (see section 
4.5 and refer to the delamanid SmPC). 
 
Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and 
strong inhibitors of CYP3A like ritonavir.  Concomitant administration with colchicine is 
contraindicated in patients with renal and/or hepatic impairment (see sections 4.3 and 4.5). 
 
The combination of Kaletra with:  
- tadalafil, indicated for the treatment of pulmonary arterial hypertension, is not recommended 

(see section 4.5);  
- riociguat is not recommended (see section 4.5); 
- vorapaxar is not recommended (see section 4.5); 
- fusidic acid in osteo-articular infections is not recommended (see section 4.5); 
- salmeterol is not recommended (see section 4.5); 
- rivaroxaban is not recommended (see section 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 avanafil or 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). 



 85 

 
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, 
such as budesonide and triamcinolone, 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 
Kaletra is not a cure for HIV infection or AIDS.  While effective viral suppression with antiretroviral 
therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot 
be excluded.  Precautions to prevent transmission should be taken in accordance with national 
guidelines.   People taking Kaletra may still develop infections or other illnesses associated with HIV 
disease and AIDS. 
 
4.5 Interaction with other medicinal products and other forms of interaction  
 
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. 
 
All interaction studies, when otherwise not stated, were performed using Kaletra capsules, which gives 
an approximately 20% lower exposure of lopinavir than the 200/50 mg tablets. 
 
Known and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal 
products are listed in the table below.  This list is not intended to be inclusive or comprehensive.  
Individual SmPCs should be consulted. 
 
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 
 
Geometric Mean Change (%) in 
AUC, Cmax, Cmin 
 
Mechanism of interaction 

Clinical recommendation 
concerning co-administration 
with Kaletra 



 86 

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 lopinavir/ritonavir. 

The clinical significance of reduced 
abacavir and zidovudine 
concentrations is unknown. 

Tenofovir disoproxil 
fumarate (DF), 300 mg 
QD 
 
(equivalent to 245 mg 
tenofovir disoproxil) 

Tenofovir: 
AUC: ↑ 32% 
Cmax: ↔ 
Cmin: ↑ 51% 
 
Lopinavir: ↔ 

No dose adjustment necessary. 
Higher tenofovir concentrations 
could potentiate tenofovir 
associated adverse events, including 
renal disorders. 

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)  
Efavirenz, 600 mg QD 
 
 

Lopinavir: 
AUC: ↓ 20% 
Cmax: ↓ 13% 
Cmin: ↓ 42% 

The Kaletra tablets dosage should 
be increased to 500/125 mg twice 
daily when co-administered with 
efavirenz.   
Kaletra must not be administered 
once daily in combination with 
efavirenz. 

Efavirenz, 600 mg QD 
 
(Lopinavir/ritonavir 
500/125 mg BID) 
 

 
Lopinavir: ↔ 
(Relative to 400/100 mg BID 
administered alone)  

Nevirapine, 200 mg 
BID 
 
 

Lopinavir: 
AUC: ↓ 27% 
Cmax: ↓ 19% 
Cmin: ↓ 51% 

The Kaletra tablets dosage should 
be increased to 500/125 mg twice 
daily when co-administered with 
nevirapine.   
Kaletra must not be administered 
once daily in combination with 
nevirapine. 

Etravirine 
 
(Lopinavir/ritonavir 
tablet 400/100 mg BID) 

Etravirine: 
AUC: ↓ 35% 
Cmin: ↓ 45%  
Cmax: ↓ 30% 
 
Lopinavir: 
AUC: ↔  
Cmin: ↓ 20% 
Cmax: ↔  

No dose adjustment necessary 

Rilpivirine 
 
(Lopinavir/ritonavir 
capsule 400/100 mg 
BID) 

Rilpivirine: 
AUC: ↑ 52%  
Cmin: ↑ 74%  
Cmax: ↑ 29% 
 
Lopinavir: 
AUC: ↔ 
Cmin: ↓ 11%  
Cmax: ↔  
 
(inhibition of CYP3A enzymes) 

Concomitant use of Kaletra with 
rilpivirine causes an increase in the 
plasma concentrations of rilpivirine, 
but no dose adjustment is required. 

HIV CCR5 – antagonist 
Maraviroc 
 

Maraviroc: 
AUC: ↑ 295%  
Cmax: ↑ 97%  

The dose of maraviroc should be 
decreased to 150 mg twice daily 
during co-administration with 
Kaletra 400/100 mg twice daily.   



 87 

Due to CYP3A inhibition by 
lopinavir/ritonavir. 

Integrase inhibitor 
Raltegravir Raltegravir:  

AUC: ↔ 
Cmax: ↔ 
C12: ↓ 30% 
Lopinavir: ↔ 

No dose adjustment necessary 

 

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)  
 
(Lopinavir/ritonavir 
400/100 mg BID) 
 
or  
 
Fosamprenavir 
(1400 mg BID) 
 
(Lopinavir/ritonavir 
533/133 mg BID) 
 
 

Fosamprenavir: 
Amprenavir concentrations are 
significantly reduced.  
 
 

 

Co-administration of increased 
doses of fosamprenavir (1400 mg 
BID) with Kaletra (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. 
Kaletra must not be administered 
once daily in combination with 
amprenavir. 

Indinavir, 600 mg BID 
 
 

Indinavir:  
AUC: ↔ 
Cmin: ↑ 3.5-fold 
Cmax: ↓ 
(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. 

Saquinavir  
1000 mg BID 

Saquinavir: ↔  No dose adjustment necessary. 

Tipranavir/ritonavir 
(500/100 mg BID) 

Lopinavir: 
AUC: ↓ 55% 
Cmin: ↓ 70% 
Cmax: ↓ 47% 

Concomitant administration of these 
medicinal products is not 
recommended. 

Acid reducing agents 
Omeprazole (40 mg 
QD)  
  

Omeprazole: ↔ 
 
Lopinavir: ↔ 

No dose adjustment necessary 

Ranitidine (150 mg 
single dose) 

Ranitidine: ↔ No dose adjustment necessary 

Alpha1 adrenoreceptor antagonist 
Alfuzosin  Alfuzosin: 

Due to CYP3A inhibition by 
lopinavir/ritonavir, concentrations 
of alfuzosin are expected to 
increase. 

Concomitant administration of 
Kaletra and alfuzosin is contra-
indicated (see section 4.3) as 
alfuzosin-related toxicity, including 
hypotension, may be increased. 



 88 

Analgesics 
Fentanyl 
  

Fentanyl: 
Increased risk of side-effects 
(respiratory depression, sedation) 
due to higher plasma 
concentrations because of 
CYP3A4 inhibition by 
lopinavir/ritonavir. 

Careful monitoring of adverse 
effects (notably respiratory 
depression but also sedation) is 
recommended when fentanyl is 
concomitantly administered with 
Kaletra. 

Antianginal 
Ranolazine Due to CYP3A inhibition by 

lopinavir/ritonavir, concentrations 
of ranolazine are expected to 
increase. 

The concomitant administration of 
Kaletra and ranolazine is 
contraindicated (see section 4.3). 

Antiarrhythmics 
Amiodarone, 
Dronedarone 

Amiodarone, Dronedarone: 
Concentrations may be increased 
due to CYP3A4 inhibition by 
lopinavir/ritonavir. 

Concomitant administration of 
Kaletra and amiodarone or 
dronedarone is contraindicated (see 
section 4.3) as the risk of 
arrhythmias or other serious adverse 
reactions may be increased. 

Digoxin 
 
 

Digoxin: 
Plasma concentrations may be 
increased due to P-glycoprotein 
inhibition by lopinavir/ritonavir.  
The increased digoxin level may 
lessen over time as P-gp 
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 
P-gp 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 
lopinavir/ritonavir.  

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 
lopinavir/ritonavir.  
 

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 and kinase inhibitors 
Abemaciclib Serum concentrations may be 

increased due to CYP3A 
inhibition by ritonavir. 

Co-administration of abemaciclib 
and Kaletra should be avoided.  If 
this co-administration is judged 
unavoidable, refer to the 
abemaciclib SmPC for dosage 
adjustment recommendations.  



 89 

Monitor for ADRs related to 
abemaciclib. 

Apalutamide Apalutamide is a moderate to 
strong CYP3A4 inducer and this 
may lead to a decreased exposure 
of lopinavir/ritonavir. 
 
Serum concentrations of 
apalutamide may be increased 
due to CYP3A inhibition by 
lopinavir/ritonavir. 

Decreased exposure of Kaletra may 
result in potential loss of virological 
response.   
In addition, co-administration of 
apalutamide and Kaletra may lead 
to serious adverse events including 
seizure due to higher apalutamide 
levels.  Concomitant use of Kaletra 
with apalutamide is not 
recommended. 

Afatinib 
 
(Ritonavir 200 mg twice 
daily) 

Afatinib: 
AUC: ↑  
Cmax: ↑ 
 
The extent of increase depends on 
the timing of ritonavir 
administration. 
 
Due to BCRP (breast cancer 
resistance protein/ABCG2) and 
acute P-gp inhibition by 
lopinavir/ritonavir. 

Caution should be exercised in 
administering afatinib with Kaletra.  
Refer to the afatinib SmPC for 
dosage adjustment 
recommendations.  Monitor for 
ADRs related to afatinib. 

Ceritinib Serum concentrations may be 
increased due to CYP3A and 
P-gp inhibition by 
lopinavir/ritonavir. 

Caution should be exercised in 
administering ceritinib with Kaletra.  
Refer to the ceritinib SmPC for 
dosage adjustment 
recommendations.  Monitor for 
ADRs related to ceritinib. 

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 
lopinavir/ritonavir. 

Careful monitoring of the tolerance 
of these anticancer agents. 
 

Encorafenib Serum concentrations may be 
increased due to CYP3A 
inhibition by lopinavir/ritonavir. 

Co-administration of encorafenib 
with Kaletra may increase 
encorafenib exposure which may 
increase the risk of toxicity, 
including the risk of serious adverse 
events such as QT interval 
prolongation.  Co-administration of 
encorafenib and Kaletra should be 
avoided.  If the benefit is considered 
to outweigh the risk and Kaletra 
must be used, patients should be 
carefully monitored for safety. 

Fostamatinib Increase in fostamatinib 
metabolite R406 exposure. 

Co-administration of fostamatinib 
with Kaletra may increase 
fostamatinib metabolite R406 
exposure resulting in dose-related 
adverse events such as 
hepatotoxicity, neutropenia, 
hypertension, or diarrhoea.  Refer to 



 90 

the fostamatinib SmPC for dose 
reduction recommendations if such 
events occur. 

Ibrutinib Serum concentrations may be 
increased due to CYP3A 
inhibition by lopinavir/ritonavir. 

Co-administration of ibrutinib and 
Kaletra may increase ibrutinib 
exposure which may increase the 
risk of toxicity including risk of 
tumor lysis syndrome. 
Co-administration of ibrutinib and 
Kaletra should be avoided.  If the 
benefit is considered to outweigh 
the risk and Kaletra must be used, 
reduce the ibrutinib dose to 140 mg 
and monitor patient closely for 
toxicity. 

Neratinib Serum concentrations may be 
increased due to CYP3A 
inhibition by ritonavir. 

Concomitant use of neratinib with 
Kaletra is contraindicated due to 
serious and/or life-threatening 
potential reactions including 
hepatotoxicity (see section 4.3). 

Venetoclax Due to CYP3A inhibition by 
lopinavir/ritonavir. 

Serum concentrations may be 
increased due to CYP3A inhibition 
by lopinavir/ritonavir, resulting in 
increased risk of tumor lysis 
syndrome at the dose initiation and 
during the ramp-up phase (see 
section 4.3 and refer to the 
venetoclax SmPC). 
 
For patients who have completed 
the ramp-up phase and are on a 
steady daily dose of venetoclax, 
reduce the venetoclax dose by at 
least 75% when used with strong 
CYP3A inhibitors (refer to the 
venetoclax SmPC for dosing 
instructions).  Patients should be 
closely monitored for signs related 
to venetoclax toxicities. 

Anticoagulants 
Warfarin 
 
 
 

Warfarin: 
Concentrations may be affected 
when co-administered with 
lopinavir/ritonavir due to 
CYP2C9 induction.   

It is recommended that INR 
(international normalised ratio) be 
monitored. 
 

Rivaroxaban 
 
(Ritonavir 600 mg twice 
daily) 

Rivaroxaban:   
AUC: ↑ 153%  
Cmax: ↑ 55% 
Due to CYP3A and P-gp 
inhibition by lopinavir/ritonavir. 

Co-administration of rivaroxaban 
and Kaletra may increase 
rivaroxaban exposure which may 
increase the risk of bleeding. 
The use of rivaroxaban is not 
recommended in patients receiving 
concomitant treatment with Kaletra 
(see section 4.4). 

Vorapaxar Serum concentrations may be 
increased due to CYP3A 
inhibition by lopinavir/ritonavir. 

The co-administration of vorapaxar 
with Kaletra is not recommended 
(see section 4.4 and refer to the 
vorapaxar SmPC). 



 91 

Anticonvulsants 
Phenytoin 
 

Phenytoin: 
Steady-state concentrations was 
moderately decreased due to 
CYP2C9 and CYP2C19 induction 
by lopinavir/ritonavir. 
 
Lopinavir:   
Concentrations are decreased due 
to CYP3A induction by 
phenytoin.   
 

Caution should be exercised in 
administering phenytoin with 
Kaletra. 
Phenytoin levels should be 
monitored when co-administering 
with Kaletra. 
When co-administered with 
phenytoin, an increase of Kaletra 
dosage may be envisaged.  Dose 
adjustment has not been evaluated 
in clinical practice. 
Kaletra must not be administered 
once daily in combination with 
phenytoin. 

Carbamazepine and 
Phenobarbital  

Carbamazepine: 
Serum concentrations may be 
increased due to CYP3A 
inhibition by lopinavir/ritonavir. 
 
Lopinavir: 
Concentrations may be decreased 
due to CYP3A induction by 
carbamazepine and phenobarbital.   
 

Caution should be exercised in 
administering carbamazepine or 
phenobarbital with Kaletra. 
Carbamazepine and phenobarbital 
levels should be monitored when 
co-administering with Kaletra. 
When co-administered with 
carbamazepine or phenobarbital, an 
increase of Kaletra dosage may be 
envisaged.  Dose adjustment has not 
been evaluated in clinical practice. 
Kaletra must not be administered 
once daily in combination with 
carbamazepine and phenobarbital. 

Lamotrigine and 
Valproate 

Lamotrigine:  
AUC: ↓ 50% 
Cmax: ↓ 46% 
Cmin: ↓ 56% 
 
Due to induction of lamotrigine 
glucuronidation 
 
Valproate: ↓ 

Patients should be monitored 
closely for a decreased VPA effect 
when Kaletra and valproic acid or 
valproate are given concomitantly. 
 
In patients starting or stopping 
Kaletra while currently taking 
maintenance dose of lamotrigine:  
lamotrigine dose may need to be 
increased if Kaletra is added, or 
decreased if Kaletra is discontinued; 
therefore plasma lamotrigine 
monitoring should be conducted, 
particularly before and during 2 
weeks after starting or stopping 
Kaletra, in order to see if 
lamotrigine dose adjustment is 
needed. 
In patients currently taking Kaletra 
and starting lamotrigine: no dose 
adjustments to the recommended 
dose escalation of lamotrigine 
should be necessary. 
 



 92 

Antidepressants and Anxiolytics 
Trazodone single dose 
 
(Ritonavir, 200 mg 
BID) 
 

Trazodone: 
AUC: ↑ 2.4-fold 
 
Adverse events of nausea, 
dizziness, hypotension and 
syncope were observed following 
co-administration of trazodone 
and ritonavir.   

It is unknown whether the 
combination of Kaletra causes a 
similar increase in trazodone 
exposure.  The combination should 
be used with caution and a lower 
dose of trazodone should be 
considered. 
 

Antifungals 
Ketoconazole and 
Itraconazole 

Ketoconazole, Itraconazole: 
Serum concentrations may be 
increased due to CYP3A 
inhibition by lopinavir/ritonavir.  

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. 

Anti-gout agents: 
Colchicine single dose 
 
(Ritonavir 200 mg twice 
daily) 

Colchicine: 
AUC: ↑ 3-fold 
Cmax: ↑ 1.8-fold 
Due to P-gp and/or CYP3A4 
inhibition by ritonavir. 
 

Concomitant administration of 
Kaletra with colchicine in patients 
with renal and/or hepatic 
impairment is contraindicated due 
to a potential increase of colchicine-
related serious and/or 
life-threatening reactions such as 
neuromuscular toxicity (including 
rhabdomyolysis) (see sections 4.3 
and 4.4).  A reduction in colchicine 
dosage or an interruption of 
colchicine treatment is 
recommended in patients with 
normal renal or hepatic function if 
treatment with Kaletra is required.  
Refer to colchicine prescribing 
information. 

Antihistamines 
Astemizole 
Terfenadine 

Serum concentrations may be 
increased due to CYP3A 
inhibition by lopinavir/ritonavir. 

Concomitant administration of 
Kaletra and astemizole and 
terfenadine is contraindicated as it 
may increase the risk of serious 
arrhythmias from these agents (see 
section 4.3). 



 93 

Anti-infectives 
Fusidic acid Fusidic acid: 

Concentrations may be increased 
due to CYP3A inhibition by 
lopinavir/ritonavir. 

Concomitant administration of 
Kaletra with fusidic acid is contra-
indicated in dermatological 
indications due to the increased risk 
of adverse events related to fusidic 
acid, notably rhabdomyolysis (see 
section 4.3).  When used for osteo-
articular infections, where the co-
administration is unavoidable, close 
clinical monitoring for muscular 
adverse events is strongly 
recommended (see section 4.4).  

Antimycobacterials 
Bedaquiline 
(single dose) 
 
(Lopinavir/ritonavir 
400/100 mg BID, 
multiple dose) 

Bedaquiline: 
AUC: ↑ 22% 
Cmax: ↔ 
 
A more pronounced effect on 
bedaquiline plasma exposures 
may be observed during 
prolonged co-administration with 
lopinavir/ritonavir. 
 
CYP3A4 inhibition likely due to 
lopinavir/ritonavir. 
 

Due to the risk of bedaquiline 
related adverse events, the 
combination of bedaquiline and 
Kaletra should be avoided.  If the 
benefit outweighs the risk, 
co-administration of bedaquiline 
with Kaletra must be done with 
caution.  More frequent 
electrocardiogram monitoring and 
monitoring of transaminases is 
recommended (see section 4.4 and 
refer to the bedaquiline SmPC). 

Delamanid (100 mg 
BID) 
 
(Lopinavir/ritonavir 
400/100 mg BID) 

Delamanid: 
AUC: ↑ 22% 
 
DM-6705 (delamanid active 
metabolite): 
AUC: ↑ 30% 
 
A more pronounced effect on 
DM-6705 exposure may be 
observed during prolonged co-
administration with 
lopinavir/ritonavir. 

Due to the risk of QTc prolongation 
associated with DM-6705, if 
co-administration of delamanid with 
Kaletra is considered necessary, 
very frequent ECG monitoring 
throughout the full delamanid 
treatment period is recommended 
(see section 4.4 and refer to the 
delamanid SmPC). 



 94 

Rifabutin, 150 mg QD 
 

Rifabutin (parent drug and active 
25-O-desacetyl metabolite):  
AUC: ↑ 5.7-fold 
Cmax: ↑ 3.5-fold  
 
 

When given with Kaletra the 
recommended dose of rifabutin is 
150 mg 3 times per week on set 
days (for example Monday-
Wednesday-Friday).  Increased 
monitoring for rifabutin-associated 
adverse reactions including 
neutropenia and uveitis is warranted 
due to an expected increase in 
exposure to rifabutin.  Further 
dosage reduction of rifabutin to 
150 mg twice weekly on set days is 
recommended for patients in whom 
the 150 mg dose 3 times per week is 
not tolerated.  It should be kept in 
mind that the twice weekly dosage 
of 150 mg may not provide an 
optimal exposure to rifabutin thus 
leading to a risk of rifamycin 
resistance and a treatment failure.  
No dose adjustment is needed for 
Kaletra.  

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). 

Antipsychotics 
Lurasidone Due to CYP3A inhibition by 

lopinavir/ritonavir, concentrations 
of lurasidone are expected to 
increase. 

The concomitant administration 
with lurasidone is contraindicated 
(see section 4.3). 



 95 

Pimozide Due to CYP3A inhibition by 
lopinavir/ritonavir, concentrations 
of pimozide are expected to 
increase. 

Concomitant administration of 
Kaletra and pimozide is 
contraindicated as it may increase 
the risk of serious haematologic 
abnormalities or other serious 
adverse effects from this agent (see 
section 4.3) 

Quetiapine Due to CYP3A inhibition by 
lopinavir/ritonavir, concentrations 
of quetiapine are expected to 
increase. 

Concomitant administration of 
Kaletra and quetiapine is 
contraindicated as it may increase 
quetiapine-related toxicity. 

Benzodiazepines 
Midazolam 
 

Oral Midazolam:  
AUC: ↑ 13-fold  
Parenteral Midazolam: 
AUC: ↑ 4-fold 
Due to CYP3A inhibition by 
lopinavir/ritonavir 
 
 

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. 

Beta2-adrenoceptor agonist (long acting) 
Salmeterol Salmeterol: 

Concentrations are expected to 
increase due to CYP3A inhibition 
by lopinavir/ritonavir. 

The combination may result in 
increased risk of cardiovascular 
adverse events associated with 
salmeterol, including QT 
prolongation, palpitations and sinus 
tachycardia. 
Therefore, concomitant 
administration of Kaletra with 
salmeterol is not recommended (see 
section 4.4). 

Calcium channel blockers 
Felodipine, Nifedipine, 
and Nicardipine 

Felodipine, Nifedipine, 
Nicardipine: 
Concentrations may be increased 
due to CYP3A inhibition by 
lopinavir/ritonavir. 

Clinical monitoring of therapeutic 
and adverse effects is recommended 
when these medicines are 
concomitantly administered with 
Kaletra. 

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. 



 96 

Inhaled, injectable or 
intranasal fluticasone 
propionate, budesonide, 
triamcinolone 

Fluticasone propionate, 50 µg 
intranasal 4 times daily: 
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 e.g. budesonide and 
triamcinolone.  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 (e.g. 
beclomethasone).  Moreover, in 
case of withdrawal of 
glucocorticoids progressive dose 
reduction may have to be performed 
over a longer period.   

Phosphodiesterase(PDE5) inhibitors 
Avanafil  
(ritonavir 600 mg BID)  

Avanafil: 
AUC: ↑ 13-fold 
Due to CYP3A inhibition by 
lopinavir/ritonavir. 
 

The use of avanafil with Kaletra is 
contraindicated (see section 4.3). 



 97 

Tadalafil  
 
 

Tadalafil: 
AUC: ↑ 2-fold 
Due to CYP3A4 inhibition by 
lopinavir/ritonavir. 
 

For the treatment of pulmonary 
arterial hypertension: 
Co-administration of Kaletra with 
sildenafil is contraindicated (see 
section 4.3).  Co-administration of 
Kaletra with tadalafil is not 
recommended. 
 
For erectile dysfunction: 
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.   
 

Sildenafil 
 
 

Sildenafil:  
AUC: ↑ 11-fold 
Due to CYP3A inhibition by 
lopinavir/ritonavir. 
 

Vardenafil  
 
 

Vardenafil: 
AUC: ↑ 49-fold  
Due to CYP3A inhibition by 
lopinavir/ritonavir. 

The use of vardenafil with Kaletra 
is contraindicated (see section 4.3).   
 

Ergot alkaloids 
Dihydroergotamine, 
ergonovine, ergotamine, 
methylergonovine 

Serum concentrations may be 
increased due to CYP3A 
inhibition by lopinavir/ritonavir. 

Concomitant administration of 
Kaletra and ergot alkaloids are 
contraindicated as it may lead to 
acute ergot toxicity, including 
vasospasm and ischaemia (see 
section 4.3). 

GI motility agent 
Cisapride Serum concentrations may be 

increased due to CYP3A 
inhibition by lopinavir/ritonavir. 

Concomitant administration of 
Kaletra and cisapride is 
contraindicated as it may increase 
the risk of serious arrhythmias from 
this agent (see section 4.3). 

HCV direct acting antivirals 
Elbasvir/grazoprevir 
(50/200 mg QD) 

 
Elbasvir: 
AUC: ↑ 2.71-fold 
Cmax: ↑ 1.87-fold 
C24: ↑ 3.58-fold 
 
Grazoprevir: 
AUC: ↑ 11.86-fold 
Cmax: ↑ 6.31-fold 
C24: ↑ 20.70-fold 
 
(combinations of mechanisms 
including CYP3A inhibition) 
 
Lopinavir: ↔ 

Concomitant administration of 
elbasvir/grazoprevir with Kaletra is 
contraindicated (see section 4.3). 



 98 

Glecaprevir/pibrentasvir Serum concentrations may be 
increased due to P-glycoprotein, 
BCRP and OATP1B inhibition by 
lopinavir/ritonavir. 

Concomitant administration of 
glecaprevir/pibrentasvir and Kaletra 
is not recommended due to an 
increased risk of ALT elevations 
associated with increased 
glecaprevir exposure. 

Ombitasvir/paritaprevir/
ritonavir + dasabuvir 
 
(25/150/100 mg QD + 
400 mg BID) 
 
Lopinavir/ritonavir  
400/100 mg BID 

Ombitasvir: ↔  
 
Paritaprevir: 
AUC: ↑ 2.17-fold 
Cmax: ↑ 2.04-fold 
Ctrough: ↑ 2.36-fold 
 
(inhibition of CYP3A/efflux 
transporters) 
 
Dasabuvir: ↔ 
 
Lopinavir: ↔ 

Co-administration is 
contraindicated. 
 
Lopinavir/ritonavir 800/200 mg QD 
was administered with 
ombitasvir/paritaprevir/ritonavir 
with or without dasabuvir.  The 
effect on DAAs and lopinavir was 
similar to that observed when 
lopinavir/ritonavir 400/100 mg BID 
was administered (see section 4.3). 

Ombitasvir/paritaprevir/ 
ritonavir 
 
(25/150/100 mg QD) 
 
Lopinavir/ritonavir 
400/100 mg BID 

Ombitasvir: ↔ 
 
Paritaprevir: 
AUC: ↑ 6.10-fold 
Cmax: ↑ 4.76-fold 
Ctrough: ↑ 12.33-fold 
 
(inhibition of CYP3A/efflux 
transporters) 
 
Lopinavir: ↔ 
 

Sofosbuvir/velpatasvir/ 
voxilaprevir 

Serum concentrations of 
sofosbuvir, velpatasvir and 
voxilaprevir may be increased due 
to P-glycoprotein, BCRP and 
OATP1B1/3 inhibition by 
lopinavir/ritonavir. However, only 
the increase in voxilaprevir 
exposure is considered clinically 
relevant. 

It is not recommended to 
co-administer Kaletra and 
sofosbuvir/velpatasvir/ 
voxilaprevir. 

HCV protease inhibitors 
Simeprevir 200 mg 
daily (ritonavir 100 mg 
BID) 
 

Simeprevir: 
AUC: ↑ 7.2-fold 
Cmax: ↑ 4.7-fold 
Cmin: ↑ 14.4-fold 

It is not recommended to 
co-administer Kaletra and 
simeprevir. 



 99 

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 
lopinavir/ritonavir. 

More frequent therapeutic 
concentration monitoring is 
recommended until plasma levels of 
these products have been stabilised. 

Lipid lowering agents 
Lovastatin and 
Simvastatin 

Lovastatin, Simvastatin: 
Markedly increased plasma 
concentrations due to CYP3A 
inhibition by lopinavir/ritonavir. 

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). 

Lipid-modifying agents 
Lomitapide CYP3A4 inhibitors increase the 

exposure of lomitapide, with 
strong inhibitors increasing 
exposure approximately 27-fold.  
Due to CYP3A inhibition by 
lopinavir/ritonavir, concentrations 
of lomitapide are expected to 
increase. 

Concomitant use of Kaletra with 
lomitapide is contraindicated (see 
prescribing information for 
lomitapide) (see section 4.3). 

Atorvastatin Atorvastatin: 
AUC: ↑ 5.9-fold  
Cmax: ↑ 4.7-fold 
Due to CYP3A inhibition by 
lopinavir/ritonavir. 

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  
Cmax: ↑ 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). 



 100 

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 Cmax ↓ ~50%  
 
This effect may be due to 
induction of bupropion 
metabolism. 
 

If the co-administration of Kaletra 
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. 

Thyroid hormone replacement therapy 
Levothyroxine Post-marketing cases have been 

reported indicating a potential 
interaction between ritonavir 
containing products and 
levothyroxine. 

Thyroid-stimulating hormone 
(TSH) should be monitored in 
patients treated with levothyroxine 
at least the first month after starting 
and/or ending lopinavir/ritonavir 
treatment. 

Vasodilating agents 
Bosentan Lopinavir - ritonavir: 

Lopinavir/ritonavir plasma 
concentrations may decrease due 
to CYP3A4 induction by 
bosentan. 
 
Bosentan: 
AUC: ↑ 5-fold  
Cmax: ↑ 6-fold 
Initially, bosentan Cmin: ↑ by 
approximately 48-fold.  
Due to CYP3A4 inhibition by 
lopinavir/ritonavir. 

Caution should be exercised in 
administering Kaletra with 
bosentan. 
When Kaletra is administered 
concomitantly with bosentan, the 
efficacy of the HIV therapy should 
be monitored and patients should be 
closely observed for bosentan 
toxicity, especially during the first 
week of co-administration.   

Riociguat Serum concentrations may be 
increased due to CYP3A and 
P-gp inhibition by 
lopinavir/ritonavir. 

The co-administration of riociguat 
with Kaletra is not recommended 
(see section 4.4 and refer to 
riociguat SmPC). 



 101 

Other medicinal products 
Based on known metabolic profiles, clinically significant interactions are not expected between 
Kaletra and dapsone, trimethoprim/sulfamethoxazole, azithromycin or fluconazole. 

 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in 
pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, 
the animal data as well as the clinical experience in pregnant women should be taken into account in 
order to characterise the safety for the foetus. 
 
Lopinavir/ritonavir has been evaluated in over 3000 women during pregnancy, including over 1000 
during the first trimester. 
 
In post-marketing surveillance through the Antiretroviral Pregnancy Registry, established since 
January 1989, an increased risk of birth defects exposures with Kaletra has not been reported among 
over 1000 women exposed during the first trimester.  The prevalence of birth defects after any 
trimester exposure to lopinavir is comparable to the prevalence observed in the general population.  
No pattern of birth defects suggestive of a common etiology was seen.  Studies in animals have shown 
reproductive toxicity (see section 5.3).  Based on the data mentioned, the malformative risk is unlikely 
in humans.  Lopinavir can be used during pregnancy if clinically needed. 
 
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.  As a general rule, it is recommended that mothers infected by HIV 
do not breastfeed their babies under any circumstances in order to avoid transmission of HIV.  
 
Fertility 
Animal studies have shown no effects on fertility.  No human data on the effect of lopinavir/ritonavir 
on fertility are available. 
 
4.7 Effects on ability to drive and use machines 
 
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). 
 
4.8 Undesirable effects  
 
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.  The risk of diarrhoea may be 
greater with once-daily dosing of Kaletra.  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). 
 



 102 

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), rare (≥1/10,000 to <1/1000) and not known (cannot be 
estimated from the available data). 
 

Undesirable effects in clinical studies and post-marketing in adult patients 

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 inflammatory 
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 



 103 

Gastrointestinal disorders Very common 
 

Diarrhoea, nausea 
 

Common Pancreatitis1, 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 

Hepatobiliary disorders Common Hepatitis including AST, ALT and GGT 
increases 
 

Uncommon Jaundice, hepatic steatosis, hepatomegaly, 
cholangitis, hyperbilirubinemia 

Skin and subcutaneous tissue 
disorders 

Common 
 

Rash including maculopapular rash, 
dermatitis/rash including eczema and 
seborrheic dermatitis, night sweats, pruritus 
 

Uncommon Alopecia, capillaritis, vasculitis  
 

Rare 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 

 
 
Not known 

Creatinine clearance decreased, nephritis, 
haematuria 
 
Nephrolithiasis 

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. 
 
Metabolic parameters 
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 
4.4). 
 



 104 

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.  Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have 
also been reported; however, the reported time to onset is more variable and can occur many months 
after initiation of treatment (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). 
 
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).  
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important.  It 
allows continued monitoring of the benefit/risk balance of the medicinal product.  Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
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. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmaco-therapeutic group: antivirals for systemic use, antivirals for treatment of HIV infections, 
combinations, ATC code: J05AR10  
 
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 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 105 

with recommended once-daily or twice-daily LPV/r doses at steady state.  No subject experienced an 
increase in QTcF of ≥ 60 ms from baseline or a QTcF interval exceeding the potentially clinically 
relevant threshold of 500 ms. 
 
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 ms 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 IC50 of lopinavir against five different HIV-1 laboratory strains 
was 19 nM.  In the absence and presence of 50% human serum, the mean IC50 of lopinavir against 
HIV-1IIIB in MT4 cells was 17 nM and 102 nM, respectively.  In the absence of human serum, the 
mean IC50 of lopinavir was 6.5 nM against several HIV-1 clinical isolates. 
 
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 patientsIn 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 IC50 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 EC50 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 EC50 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 



 106 

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 EC50 of lopinavir against the 
56 baseline viral isolates ranged from 0.6 to 96-fold higher than the EC50 against wild type HIV.  After 
48 weeks of treatment 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 IC50 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 IC50 from 3.7- to 8-fold in the baseline and rebound isolates, respectively.  Isolates retained 
susceptibility to tipranavir with a median increase of IC50 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/mm3 (range: 2 to 
949 cells/ mm3) and mean baseline plasma HIV-1 RNA was 4.9 log10 copies/ml (range: 2.6 to 
6.8 log10 copies/ml).   
 



 107 

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/mm3) 

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 
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. 
 
Study M05-730 was a randomised, open-label, multicentre trial comparing treatment with Kaletra 
800/200 mg once daily plus tenofovir DF and emtricitabine versus Kaletra 400/100 mg twice daily 
plus tenofovir DF and emtricitabine in 664 antiretroviral treatment-naïve patients.  Given the 
pharmacokinetic interaction between Kaletra and tenofovir (see section 4.5), the results of this study 
might not be strictly extrapolable when other backbone regimens are used with Kaletra.  Patients were 
randomised in a 1:1 ratio to receive either Kaletra 800/200 mg once daily (n = 333) or Kaletra 
400/100 mg twice daily (n = 331).  Further stratification within each group was 1:1 (tablet versus soft 
capsule).  Patients were administered either the tablet or the soft capsule formulation for 8 weeks, after 
which all patients were administered the tablet formulation once daily or twice daily for the remainder 
of the study.  Patients were administered emtricitabine 200 mg once daily and tenofovir DF 300 mg 
once daily (equivalent to 245 mg tenofovir disoproxil).  Protocol defined non-inferiority of once-daily 
dosing compared with twice-daily dosing was demonstrated if the lower bound of the 95% confidence 
interval for the difference in proportion of subjects responding (once daily minus twice daily) 
excluded -12% at Week 48.  Mean age of patients enrolled was 39 years (range: 19 to 71); 75% were 
Caucasian, and 78% were male.  Mean baseline CD4+ T-cell count was 216 cells/mm3 (range: 20 to 
775 cells/mm3) and mean baseline plasma HIV-1 RNA was 5.0 log10 copies/ml (range: 1.7 to 
7.0 log10 copies/ml).   
 
Table 2 
 

Virologic Response of Study Subjects at Week 48 and Week 96 

 Week 48 Week 96 
 QD BID  Difference 

[95% CI] 
QD BID  Difference 

[95% CI] 
NC= Failure 257/333 

(77.2%) 
251/331 
(75.8%) 

1.3 % 
[-5.1, 7.8] 

216/333 
(64.9%) 

229/331 
(69.2%) 

-4.3% 
[-11.5, 2.8] 

Observed data 257/295 
(87.1%) 

250/280 
(89.3%) 

-2.2% 
[-7.4, 3.1] 

216/247 
(87.4%) 

229/248 
(92.3%) 

-4.9% 
[-10.2, 0.4] 

Mean increase from 
baseline in CD4+ T-cell 
count (cells/mm3) 

186 198  238 254  

 
Through Week 96, genotypic resistance testing results were available from 25 patients in the QD 
group and 26 patients in the BID group who had incomplete virologic response.  In the QD group, no 
patient demonstrated lopinavir resistance, and in the BID group, 1 patient who had significant protease 
inhibitor resistance at baseline demonstrated additional lopinavir resistance on study. 



 108 

 
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 3 
 

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/mm3) 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 
 
M06-802 was a randomised open-label study comparing the safety, tolerability and antiviral activity of 
once-daily and twice-daily dosing of lopinavir/ritonavir tablets in 599 subjects with detectable viral 
loads while receiving their current antiviral therapy.  Patients had not been on prior lopinavir/ritonavir 
therapy.  They were randomised in a 1:1 ratio to receive either lopinavir/ritonavir 800/200 mg once 
daily (n = 300) or lopinavir/ritonavir 400/100 mg twice daily (n = 299).  Patients were administered at 
least two nucleoside/nucleotide reverse transcriptase inhibitors selected by the investigator.  The 
enrolled population was moderately PI-experienced with more than half of patients having never 
received prior PI and around 80% of patients presenting a viral strain with less than 3 PI mutations.  
Mean age of patients enrolled was 41 years (range: 21 to 73); 51% were Caucasian and 66% were 
male.  Mean baseline CD4+ T-cell count was 254 cells/mm3 (range: 4 to 952 cells/mm3) and mean 
baseline plasma HIV-1 RNA was 4.3 log10 copies/ml (range: 1.7 to 6.6 log10 copies/ml).  Around 85% 
of patients had a viral load of < 100,000 copies/ml. 
 
Table 4 
 

Virologic Response of Study Subjects at Week 48 Study 802 

 QD BID Difference 
[95% CI] 

NC= Failure 171/300 
(57%) 

161/299 
(53.8%) 

3.2% 
[-4.8%, 11.1%] 

Observed data 171/225 
(76.0%) 

161/223 
(72.2%) 

3.8% 
[-4.3%, 11.9%] 

Mean increase from baseline in 
CD4+ T-cell count (cells/mm3) 

135 122  

 
Through Week 48, genotypic resistance testing results were available from 75 patients in the QD 
group and 75 patients in the BID group who had incomplete virologic response.  In the QD group, 



 109 

6/75 (8%) patients demonstrated new primary protease inhibitor mutations (codons 30, 32, 48, 50, 82, 
84, 90), as did 12/77 (16%) patients in the BID group. 
 
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 m2 or 
300 mg lopinavir/75 mg ritonavir per m2.  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 m2 
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/mm3 and 
mean baseline plasma HIV-1 RNA was 4.7 log10 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/mm3) 

404 284 

 
KONCERT/PENTA 18 is a prospective multicentre, randomised, open-label study that evaluated the 
pharmacokinetic profile, efficacy and safety of twice-daily versus once-daily dosing of 
lopinavir/ritonavir 100 mg/25 mg tablets dosed by weight as part of combination antiretroviral therapy 
(cART) in virologically suppressed HIV-1 infected children (n=173).  Children were eligible when 
they were aged <18 years, ≥15 kg in weight, receiving cART that included lopinavir/ritonavir, HIV-1 
ribonucleic acid (RNA) <50 copies/ml for at least 24 weeks and able to swallow tablets.  At week 48, 
the efficacy and safety with twice-daily dosing (n=87) in the paediatric population given 
lopinavir/ritonavir 100 mg/25 mg tablets was consistent with the efficacy and safety findings in 
previous adult and paediatric studies using lopinavir/ritonavir twice daily.  The percentage of patients 
with confirmed viral rebound >50 copies/ml during 48 weeks of follow-up was higher in the paediatric 
patients receiving lopinavir/ritonavir tablets once daily (12%) than in patients receiving the twice-daily 
dosing (8%, p = 0.19), mainly due to lower adherence in the once-daily group.  The efficacy data 
favouring the twice-daily regimen are reinforced by a differential in pharmacokinetic parameters 
significantly favouring the twice-daily regimen (see section 5.2).  
 
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 EC50 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 (Cmax) of 12.3 ± 5.4 µg/ml, occurring 
approximately 4 hours after administration.  The mean steady-state trough concentration prior to the 



 110 

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 
Administration of a single 400/100 mg dose of Kaletra tablets under fed conditions (high fat, 872 kcal, 
56% from fat) compared to fasted state was associated with no significant changes in Cmax and AUCinf.  
Therefore, Kaletra tablets may be taken with or without food.  Kaletra tablets have also shown less 
pharmacokinetic variability under all meal conditions compared to Kaletra soft capsules. 
 
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 14C-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 14C-lopinavir/ritonavir dose, approximately 10.4 ± 2.3% and 82.6 ± 2.5% of an 
administered dose of 14C-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. 
 
Once-daily dosing: the pharmacokinetics of once daily Kaletra have been evaluated in HIV-infected 
subjects naïve to antiretroviral treatment.  Kaletra 800/200 mg was administered in combination with 
emtricitabine 200 mg and tenofovir DF 300 mg as part of a once-daily regimen.  Multiple dosing of 
800/200 mg Kaletra once daily for 2 weeks without meal restriction (n=16) produced a mean ± SD 
lopinavir peak plasma concentration (Cmax) of 14.8 ± 3.5 µg/ml, occurring approximately 6 hours after 
administration.  The mean steady-state trough concentration prior to the morning dose was 
5.5 ± 5.4 µg/ml.  Lopinavir AUC over a 24 hour dosing interval averaged 206.5 ± 89.7 µg•h/ml. 
 
As compared to the BID regimen, the once-daily dosing is associated with a reduction in the 
Cmin/Ctrough values of approximately 50%.   
 
Special Populations 
 
Paediatrics 
There are limited pharmacokinetic data in children below 2 years of age.  The pharmacokinetics of 
Kaletra 100/25 mg tablet twice-daily weight-band dosing without nevirapine have been studied in a 
total of 53 paediatric patients.  The lopinavir mean ± standard deviation steady-state AUC, Cmax and 
C12 were 112.5 ± 37.1 μg•h/ml, 12.4 ± 3.5 μg/ml and 5.71 ± 2.99 μg/ml, respectively. The twice-daily 
weight-band dosing without nevirapine provided lopinavir plasma concentrations similar to those 
obtained in adult patients receiving the 400/100 mg twice-daily regimen without nevirapine.   



 111 

 
Gender, Race and Age   
Kaletra pharmacokinetics have not been studied in older people.  No age or gender related 
pharmacokinetic differences have been observed in adult patients.  Pharmacokinetic differences due to 
race have not been identified. 
 
Pregnancy and postpartum 
In an open-label pharmacokinetic study, 12 HIV-infected pregnant women who were less than 20 
weeks of gestation and on combination antiretroviral therapy initially received lopinavir/ritonavir 400 
mg/100 mg (two 200/50 mg tablets) twice daily up to a gestational age of 30 weeks. At 30 weeks age 
of gestation, the dose was increased to 500/125 mg (two 200/50 mg tablets plus one 100/25 mg tablet) 
twice daily until subjects were 2 weeks postpartum. Plasma concentrations of lopinavir were measured 
over four 12-hour periods during second trimester (20-24 weeks gestation), third trimester before dose 
increase (30 weeks gestation), third trimester after dose increase (32 weeks gestation), and at 8 weeks 
post-partum. The dose increase did not result in a significant increase in the plasma lopinavir 
concentration.  
 
In another open-label pharmacokinetic study, 19 HIV-infected pregnant women received 
lopinavir/ritonavir 400/100 mg twice daily as part of combination antiretroviral therapy during 
pregnancy from before conception. A series of blood samples were collected pre-dose and at intervals 
over the course of 12 hours in trimester 2 and trimester 3, at birth, and 4–6 weeks postpartum (in 
women who continued treatment post-delivery) for pharmacokinetic analysis of total and unbound 
levels of plasma lopinavir concentrations. 
 
The pharmacokinetic data from HIV-1 infected pregnant women receiving lopinavir/ritonavir tablets 
400/100 mg twice daily are presented in Table 6 (see section 4.2). 
 
Table 6 
 

Mean (%CV) Steady-State Pharmacokinetic Parameters of Lopinavir  
in HIV-Infected Pregnant Women 

Pharmacokinetic 
Parameter 

2nd Trimester 
n = 17* 

3rd Trimester 
n = 23 

Postpartum 
n = 17** 

AUC0-12 μg•hr/mL 68.7 (20.6) 61.3 (22.7) 94.3 (30.3) 
Cmax 7.9 (21.1) 7.5 (18.7) 9.8 (24.3) 

Cpredose μg /mL 4.7 (25.2) 4.3 (39.0) 6.5 (40.4) 
*   n = 18 for Cmax                  ** n = 16 for Cpredose 

 
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. 
 
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 



 112 

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. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet contents:  
Copovidone 
Sorbitan laurate 
Colloidal anhydrous silica 
Sodium stearyl fumarate 
 
Film-coating:  
Polyvinyl alcohol 
Titanium dioxide 
Talc  
Macrogols type 3350 (Polyethylene glycol 3350) 
Yellow ferric oxide E172 
 



 113 

6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
High density polyethylene (HDPE) bottles closed with propylene caps.   
Bottle containing 60 film-coated tablets.   
 
6.6 Special precautions for disposal 
 
No special requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
AbbVie Deutschland GmbH & Co. KG 
Knollstrasse 
67061 Ludwigshafen 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBERS 
 
EU/1/01/172/006 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 20 March 2001 
Date of latest renewal: 20 March 2011 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this product is available on the website of the European Medicines Agency 
http://www.ema.europa.eu 
 

  

http://www.ema.europa.eu/


 114 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE  
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND  
 USE  
 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE  
 MARKETING AUTHORISATION  
 
D.  CONDITIONS OR RESTRICTIONS WITH REGARD TO THE 

SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 

 



 115 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Kaletra oral solution: 
Aesica Queenborough Limited, Queenborough, Kent ME11 5EL, United Kingdom 
AbbVie Logistics B.V., Zuiderzeelaan 53, 8017 JV Zwolle, The Netherlands 
AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany 
 
Kaletra 200 mg film-coated tablets and Kaletra 100 mg/25 mg film-coated tablets: 
AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany 
 
Kaletra 200 mg/50 mg film-coated tablets: 
Fournier Laboratories Ireland Limited, Carrigtwohill Business Park, Anngrove, Carrigtwohill, Co. Cork, 
Ireland 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to medical prescription. 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT  
 
• Risk management plan (RMP)  
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation 
and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency;  
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result 
of an important (pharmacovigilance or risk minimisation) milestone being reached.  

 
 
 
 
 
  



 116 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 

  



 117 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



 118 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  

Oral solution - Carton containing 300 ml (5 bottles x 60 ml) oral solution  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kaletra (80 mg + 20 mg) / ml oral solution 
(lopinavir + ritonavir) 
For adults and children weighing greater than 15 kg. 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each ml contains: lopinavir 80 mg and ritonavir 20 mg. 
 
 
3. LIST OF EXCIPIENTS 
 
Includes: alcohol, high fructose corn syrup, propylene glycol, glycerol, polyoxyl 40 hydrogenated 
castor oil, potassium (as acesulfame potassium). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
300 ml (5 bottles x 60 ml) oral solution with five 5 ml oral dosing syringes. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
For volumes greater than 2 ml. 
Use the 5 ml oral dosing syringe to prepare a dose. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator 
 
 



 119 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
AbbVie Deutschland GmbH & Co. KG 
Knollstrasse 
67061 Ludwigshafen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/01/172/003 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Kaletra (80 mg + 20 mg) / ml  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 



 120 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  

Oral solution - Carton containing 120 ml (2 bottles x 60 ml) oral solution  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kaletra (80 mg + 20 mg) / ml oral solution 
(lopinavir + ritonavir) 
For children 2 weeks or older and weighing up to 15 kg 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each ml contains: lopinavir 80 mg and ritonavir 20 mg. 
 
 
3. LIST OF EXCIPIENTS 
 
Includes: alcohol, high fructose corn syrup, propylene glycol, glycerol, polyoxyl 40 hydrogenated 
castor oil, potassium (as acesulfame potassium). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
120 ml (2 bottles x 60 ml) oral solution with two 2 ml oral dosing syringes. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
For volumes up to 2 ml. 
Use the 2 ml oral dosing syringe to prepare a dose. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



 121 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
AbbVie Deutschland GmbH & Co. KG 
Knollstrasse 
67061 Ludwigshafen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/01/172/009 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Kaletra (80 mg + 20 mg) / ml  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 
  



 122 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 

Oral Solution – Bottle label 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kaletra (80 mg + 20 mg) / ml oral solution 
(lopinavir + ritonavir) 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each ml contains lopinavir 80 mg and ritonavir 20 mg. 
 
 
3. LIST OF EXCIPIENTS 
 
Includes: alcohol (42 % v/v see leaflet), high fructose corn syrup, propylene glycol, glycerol, polyoxyl 
40 hydrogenated castor oil, potassium (as acesulfame potassium). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
60 ml oral solution 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
Important to open 
Make sure you have the correct syringe for the dose. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



 123 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator 
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.  
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
AbbVie (logo) 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
 



 124 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
200 mg/50 mg tablets – Carton of 1 bottle 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kaletra 200 mg/50 mg film-coated tablets 
lopinavir/ritonavir 
 
 
 2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 200 mg of lopinavir co-formulated with 50 mg of ritonavir as a 
pharmacokinetic enhancer. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
120 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 



 125 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
AbbVie Deutschland GmbH & Co. KG 
Knollstrasse 
67061 Ludwigshafen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/01/172/004 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Kaletra 200 mg/50 mg tablets 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 
 



 126 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
200 mg/50 mg Tablets – Carton of multipack containing 360 (3 bottles of 120) film-coated tablets 
– including blue box 

 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kaletra 200 mg/50 mg film-coated tablets 
lopinavir/ritonavir 
 
 
 2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 200 mg of lopinavir co-formulated with 50 mg of ritonavir as a 
pharmacokinetic enhancer. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Multipack: 360 (3 bottles of 120) film-coated tablets 
3 month pack 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP  
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



 127 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
AbbVie Deutschland GmbH & Co. KG 
Knollstrasse 
67061 Ludwigshafen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/01/172/007 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Kaletra 200 mg/50 mg tablets 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 
  



 128 

PARTICULARS TO APPEAR ON THE ON THE IMMEDIATE PACKAGING 
 
200 mg/50 mg tablets – Bottle label 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kaletra 200 mg/50 mg film-coated tablets 
lopinavir/ritonavir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 200 mg of lopinavir co-formulated with 50 mg of ritonavir as a 
pharmacokinetic enhancer. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
120 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 



 129 

 
AbbVie Deutschland GmbH & Co. KG 
Knollstrasse 
67061 Ludwigshafen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/01/172/004 
EU/1/01/172/007 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
Not applicable 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
Not applicable 
  



 130 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
Outer carton of multipacks of 120 (3 cartons of 40 film-coated 200 mg/50 mg film-coated tablets) 
- including the blue box  
Carton of blister pack containing 120 200 mg/50 mg film-coated tablets 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kaletra 200 mg/50 mg film-coated tablets 
lopinavir/ritonavir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 200 mg of lopinavir co-formulated with 50 mg of ritonavir as a 
pharmacokinetic enhancer. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Multipack: 120 (3 packs of 40) film-coated tablets 
120 film-coated tablets  
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 



 131 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
AbbVie Deutschland GmbH & Co. KG 
Knollstrasse 
67061 Ludwigshafen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/01/172/005 – multipack: 120 (3 packs of 40) film-coated tablets 
EU/1/01/172/008 – carton of 120 film-coated tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Kaletra 200 mg/50 mg tablets 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 
  



 132 

PARTICULARS TO APPEAR ON THE INTERMEDIATE CARTON  
 
Inner carton of multipack of 120 (3 packs of 40) 200 mg/50 mg film-coated tablets) – without 
blue box 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kaletra 200 mg/50 mg film-coated tablets 
lopinavir/ritonavir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 200 mg of lopinavir co-formulated with 50 mg of ritonavir as a 
pharmacokinetic enhancer. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
40 film-coated tablets.  Component of a multipack, can’t be sold separately.  
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



 133 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
AbbVie Deutschland GmbH & Co. KG 
Knollstrasse 
67061 Ludwigshafen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/01/172/005 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Kaletra 200 mg/50 mg tablets 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
Not applicable 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
Not applicable 
  



 134 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
200 mg/50 mg tablets – Blister of 8 film-coated tablets or Blister of 12 film-coated tablets 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kaletra 200 mg/50 mg film-coated tablets 
lopinavir/ritonavir 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
AbbVie (as logo) 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 



 135 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
100 mg/ 25 mg tablets – Carton of 1 bottle 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kaletra 100 mg/25 mg film-coated tablets 
lopinavir/ritonavir 
 
 
 2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 100 mg of lopinavir co-formulated with 25 mg of ritonavir as a 
pharmacokinetic enhancer. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
60 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



 136 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
AbbVie Deutschland GmbH & Co. KG 
Knollstrasse 
67061 Ludwigshafen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/01/172/006 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Kaletra 100 mg/25 mg tablets 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 
  



 137 

PARTICULARS TO APPEAR ON THE ON THE IMMEDIATE PACKAGING 
 
100 mg/25 mg tablets - bottle label 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Kaletra 100 mg/25 mg film-coated tablets 
lopinavir/ritonavir 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 100 mg of lopinavir co-formulated with 25 mg of ritonavir as a 
pharmacokinetic enhancer. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
60 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 



 138 

 
AbbVie Deutschland GmbH & Co. KG 
Knollstrasse 
67061 Ludwigshafen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/01/172/006 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
Not applicable 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
Not applicable 
  



 139 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



 140 

  
Package leaflet: Information for the user 

 
Kaletra (80 mg + 20 mg) / ml oral solution 

(lopinavir + ritonavir) 
 

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you or your child. 
− Keep this leaflet.  You may need to read it again. 
− If you have any further questions, ask your doctor or pharmacist. 
− This medicine has been prescribed for you or your child only.  Do not pass it on to others.  It 

may harm them, even if their signs of illness are the same as yours. 
− If you get any side effects, talk to your doctor or pharmacist.  This includes any possible side 

effects not listed in this leaflet.  See section 4. 
 
What is in this leaflet: 
1. What Kaletra is and what it is used for 
2. What you need to know before you or your child takes Kaletra 
3. How to take Kaletra 
4. Possible side effects 
5. How to store Kaletra 
6. Contents of the pack and other information 
 
 
1. What Kaletra is and what it is used for 
 
• Your doctor has prescribed Kaletra to help to control your Human Immunodeficiency Virus 

(HIV) infection.  Kaletra does this by slowing down the spread of the infection in your body. 
• Kaletra is not a cure for HIV infection or AIDS. 
• Kaletra is used by children 14 days of age and older, adolescents and adults who are infected 

with HIV, the virus which causes AIDS.   
• Kaletra contains the active substances lopinavir and ritonavir.  Kaletra is an antiretroviral 

medicine.  It belongs to a group of medicines called protease inhibitors. 
• Kaletra is prescribed for use in combination with other antiviral medicines.  Your doctor will 

discuss with you and determine which medicines are best for you. 
 
 
2. What you need to know before you or your child takes Kaletra 
 
Do not take Kaletra 
• if you are allergic to lopinavir, ritonavir or any of the other ingredients of Kaletra (see section 

6);  
• if you have severe liver problems. 
 
Do not take Kaletra with any of the following medicines: 
• astemizole or terfenadine (commonly used to treat allergy symptoms – these medicines may be 

available without prescription); 
• midazolam taken orally (taken by mouth), triazolam (used to relieve anxiety and/or trouble 

sleeping); 
• pimozide (used to treat schizophrenia); 
• quetiapine (used to treat schizophrenia, bipolar disorder and major depressive disorder); 
• lurasidone (used to treat depression); 
• ranolazine (used to treat chronic chest pain [angina]); 
• cisapride (used to relieve certain stomach problems); 
• ergotamine, dihydroergotamine, ergonovine, methylergonovine (used to treat headaches); 
• amiodarone, dronedarone (used to treat abnormal heart beat); 



 141 

• lovastatin, simvastatin (used to lower blood cholesterol); 
• lomitapide (used to lower blood cholesterol); 
• alfuzosin (used in men to treat symptoms of an enlarged prostate (benign prostatic hyperplasia 

(BPH)); 
• fusidic acid (used to treat skin infections caused by Staphylococcus bacteria such as impetigo 

and infected dermatitis).  Fusidic acid used to treat long-term infections of the bones and joints 
may be taken under doctor’s supervision (see Other medicines and Kaletra section); 

• colchicine (used to treat gout) if you have kidney and/or liver problems (see the section on 
Other medicines and Kaletra); 

• elbasvir/grazoprevir (used to treat chronic hepatitis C virus [HCV]); 
• ombitasvir/paritaprevir/ritonavir with or without dasabuvir (used to treat chronic hepatitis C 

virus [HCV]); 
• neratinib (used to treat breast cancer); 
• avanafil or vardenafil (used to treat erectile dysfunction); 
• sildenafil used to treat pulmonary arterial hypertension (high blood pressure in the pulmonary 

artery).  Sildenafil used to treat erectile dysfunction may be taken under doctor’s supervision 
(see Other medicines and Kaletra section); 

• products that contain St John’s wort (Hypericum perforatum). 
 
Read the list of medicines below under ‘Other medicines and Kaletra’ for information on certain 
other medicines which require special care. 
 
If you are currently taking any of these medicines, ask your doctor about making necessary changes 
either in the treatment for your other condition(s) or in your antiretroviral treatment.  
 
Warnings and precautions 
 
Talk to your doctor or pharmacist before taking Kaletra. 
 
Important information 
 
• People taking Kaletra may still develop infections or other illnesses associated with HIV disease 

and AIDS.  It is therefore important that you remain under the supervision of your doctor while 
taking Kaletra.   

• You can still pass on HIV when taking this medicine, although the risk is lowered by 
effective antiretroviral therapy.  Discuss with your doctor the precautions needed to avoid 
infecting other people. 
 

Tell your doctor if you or your child have/had 
 
• Haemophilia type A and B as Kaletra might increase the risk of bleeding. 
• Diabetes as increased blood sugars has been reported in patients receiving Kaletra. 
• A history of liver problems as patients with a history of liver disease, including chronic 

hepatitis B or C are at increased risk of severe and potentially fatal liver side effects. 
 
Tell your doctor if you or your child experience 
 
• Nausea, vomiting, abdominal pain, difficulty breathing and severe weakness of the muscles in 

the legs and arms as these symptoms may indicate raised lactic acid levels. 
• Thirst, frequent urination, blurred vision or weight loss as this may indicate raised sugar levels 

in the blood. 
• Nausea, vomiting, abdominal pain as large increases in the amount of triglycerides (fats in the 

blood) have been considered a risk factor for pancreatitis (inflammation of the pancreas) and 
these symptoms may suggest this condition. 

• In some patients with advanced HIV infection and a history of opportunistic infection, signs and 
symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is 



 142 

started. It is believed that these symptoms are due to an improvement in the body’s immune 
response, enabling the body to fight infections that may have been present with no obvious 
symptoms. 

• In addition to the opportunistic infections, autoimmune disorders (a condition that occurs when 
the immune system attacks healthy body tissue) may also occur after you start taking medicines 
for the treatment of your HIV infection.  Autoimmune disorders may occur many months after 
the start of treatment.  If you notice any symptoms of infection or other symptoms such as 
muscle weakness, weakness beginning in the hands and feet and moving up towards the trunk of 
the body, palpitations, tremor or hyperactivity, please inform your doctor immediately to seek 
necessary treatment. 

• Joint stiffness, aches and pains (especially of the hip, knee and shoulder) and difficulty in 
movement as some patients taking these medicines may develop a bone disease called 
osteonecrosis (death of bone tissue caused by loss of blood supply to the bone).  The length of 
combination antiretroviral therapy, corticosteroid use, alcohol consumption, severe 
immunosuppression (reduction in the activity of the immune system), higher body mass index, 
among others, may be some of the many risk factors for developing this disease.   

• Muscle pain, tenderness or weakness, particularly in combination with these medicines.  On 
rare occasions these muscle disorders have been serious.  

• Symptoms of dizziness, lightheadedness, fainting or sensation of abnormal heartbeats.  Kaletra 
may cause changes in your heart rhythm and the electrical activity of your heart.  These changes 
may be seen on an ECG (electrocardiogram). 

 
Other medicines and Kaletra 
 
Tell your doctor or pharmacist if you or your child are taking, have recently taken or might take 
any other medicines.  
• antibiotics (e.g. rifabutin, rifampicin, clarithromycin); 
• anticancer medicines (e.g. abemaciclib, afatinib, apalutamide, ceritinib, encorafenib, ibrutinib, 

venetoclax, most tyrosine kinases inhibitors such as dasatinib and nilotinib, also vincristine and 
vinblastine); 

• anticoagulants (e.g. warfarin, rivaroxaban, vorapaxar); 
• antidepressants (e.g. trazodone, bupropion); 
• anti-epilepsy medicines (e.g. carbamazepine, phenytoin, phenobarbital, lamotrigine and 

valproate); 
• antifungals (e.g. ketoconazole, itraconazole, voriconazole); 
• anti-gout medicines (e.g. colchicine).  You must not take Kaletra with colchicine if you have 

kidney and/or liver problems (see also ‘Do not take Kaletra’ above); 
• anti-tuberculosis medicine (bedaquiline, delamanid); 
• antiviral medicine used to treat chronic hepatitis C virus (HCV) infection in adults (e.g. 

glecaprevir/pibrentasvir, simeprevir and sofosbuvir/velpatasvir/voxilaprevir); 
• erectile dysfunction medicines (e.g. sildenafil and tadalafil); 
• fusidic acid used to treat long-term infections of the bones and joints (e.g. osteomyelitis); 
• heart medicines including: 

− digoxin; 
− calcium channel antagonists (e.g. felodipine, nifedipine, nicardipine); 
− medicines used to correct heart rhythm (e.g. bepridil, systemic lidocaine, quinidine); 

• HIV CCR5-antagonist (e.g. maraviroc); 
• HIV-1 integrase inhibitor (e.g. raltegravir); 
• medicines used to treat low blood platelet count (e.g. fostamatinib); 
• levothyroxine (used to treat thyroid problems); 
• medicines used to lower blood cholesterol (e.g. atorvastatin, lovastatin, rosuvastatin or 

simvastatin); 
• medicines used to treat asthma and other lung-related problems such as chronic obstructive 

pulmonary disease (COPD) (e.g. salmeterol); 



 143 

• medicines used to treat pulmonary arterial hypertension (high blood pressure in the pulmonary 
artery) (e.g. bosentan, riociguat, sildenafil, tadalafil); 

• medicines affecting the immune system (e.g. cyclosporin, sirolimus (rapamycin), tacrolimus); 
• medicines used for smoking cessation (e.g. bupropion); 
• pain-relieving medicines (e.g. fentanyl); 
• morphine-like medicines (e.g. methadone); 
• oral contraceptive or using a patch contraceptive to prevent pregnancy (see section below titled 

Contraceptives); 
• protease inhibitors (e.g. fosamprenavir, indinavir,  ritonavir, saquinavir, tipranavir); 
• sedatives (e.g. midazolam administered by injection); 
• steroids (e.g. budesonide, dexamethasone, fluticasone propionate, ethinyl oestradiol, 

triamcinolone); 
• medicines that cause a reaction with alcohol (e.g. disulfiram). 
 
Read the list of medicines above ‘Do not take Kaletra with any of the following medicines’ for 
information on medicines that you must not take with Kaletra. 
 
Please tell your doctor or pharmacist if you or your child are taking, have recently taken or might take 
any other medicines, including medicines obtained without prescription. 
 
Erectile dysfunction medicines (avanafil, vardenafil, sildenafil, tadalafil) 
 
• Do not take Kaletra if you are currently taking avanafil or vardenafil. 
• You must not take Kaletra with sildenafil used to treat pulmonary arterial hypertension (high 

blood pressure in the pulmonary artery) (see also Do not take Kaletra section above). 
• If you take sildenafil or tadalafil and Kaletra together, you may be at risk of side effects such as 

low blood pressure, passing out, visual changes and penile erection lasting more than 4 hours.  
If an erection lasts longer than 4 hours, you should get medical help immediately to avoid 
permanent damage to your penis.  Your doctor can explain these symptoms to you. 

 
Contraceptives 
 
• If you are currently using an oral contraceptive or using a patch contraceptive to prevent 

pregnancy, you should use an additional or different type of contraception (e.g. condom) as 
Kaletra may reduce the effectiveness of oral and patch contraceptives. 

• Kaletra does not reduce the risk of passing HIV to others.  Appropriate precautions (e.g. use of a 
condom) should be taken to prevent passing on the disease through sexual contact. 

 
Pregnancy and breast-feeding 
 
• Tell your doctor immediately if you are planning to have a baby, you are pregnant, think you 

may be pregnant or if you are breast-feeding.   
• If you are pregnant or breastfeeding, talk to your doctor or pharmacist before taking this 

medicine because it contains propylene glycol and alcohol.  Pregnant or breast-feeding mothers 
should not take Kaletra oral solution unless specifically directed by the doctor.   

• It is recommended that HIV-infected women do not breast-feed their infants because there is a 
possibility that the baby can be infected with HIV through your breast milk. 

 
Driving or using machines 
 
Kaletra has not specifically been tested for its possible effects on the ability to drive a car or operate 
machines.  Do not drive a car or operate machinery if you experience any side effects (e.g. nausea) 
that impact your ability to do so safely.  Instead, contact your doctor. 
 
Kaletra contains 42% v/v alcohol.  The amount of alcohol in this medicine may affect your ability to 
drive or use machines and may affect your judgement and reaction times. 



 144 

 
Important information about some of the ingredients of Kaletra 
 
Kaletra contains 42% v/v alcohol and 15% propylene glycol w/v.  Each 1 ml of Kaletra oral solution 
contains 356.3 mg of alcohol and 152.7 mg of propylene glycol.  Alcohol and propylene glycol are 
potentially harmful for those suffering from liver disease, kidney disease, alcoholism, epilepsy, brain 
injury or disease, as well as for pregnant women and children.  They may modify or increase the effect 
of other medicines. 
 
At the recommended adult dose(s) of this medicine, the estimated blood alcohol concentration in your 
body is about 0.002 - 0.01 g/dL.  This is similar to an adult drinking 4-22 ml of beer or 1-4 ml of wine.   
 
Other medicines may also contain alcohol and alcohol may be consumed in food and drinks.  The 
combined effects may lead to increased blood alcohol levels and increase the side effects of alcohol. 
 
This medicinal product contains up to 0.8 g of fructose per dose when taken according to the dosage 
recommendations.  Unsuitable in hereditary fructose intolerance.  Due to the possibility of undetected 
fructose intolerance, this medicinal product should only be given to babies and infants after 
consultation with a doctor. 
 
Kaletra contains glycerol which is harmful in high doses.  Can cause headache and stomach upset and 
diarrhoea. 
 
Kaletra contains polyoxyl 40 hydrogenated castor oil.  This may cause nausea, vomiting, colic, severe 
purgation at high doses.  It should not be given when intestinal obstruction is present. 
 
Kaletra contains potassium as acesulfame potassium, which may be harmful to people on a low 
potassium diet.  High potassium in the blood can cause stomach upset and diarrhoea. 
 
Kaletra contains sodium as saccharin sodium, sodium chloride and sodium citrate, which may be 
harmful to people on a low sodium diet. 
 
 
3. How to take Kaletra 
 
 Kaletra is recommended for use in adults and children 14 days of age and older who are infected 

with HIV. 
 Take care when dosing children.  Dosing should be less than 5 ml twice daily for children weighing 

less than 40 kg. 
 
If you or your child is able to swallow tablets, Kaletra is also supplied as film-coated tablets 
containing 200 mg of lopinavir and 50 mg of ritonavir and film-coated tablets containing 100 mg of 
lopinavir and 25 mg of ritonavir. 
 
Always take this medicine exactly as your doctor has told you.  Check with your doctor or pharmacist 
if you are not sure how you should take your medicine. 
 
How much Kaletra should be taken and when? 
 
For children 14 days and older and weighing up to 15 kg 
• Your doctor will decide the right dose based on the child’s height and weight.   
• It is important that all doses of Kaletra oral solution are taken with food. 
• Use the 2 ml oral syringe provided to measure the dose. 
 
For children weighing more than 15 kg 
 
• Your doctor will decide the right dose based on the child’s height and weight.   



 145 

• It is important that all doses of Kaletra oral solution are taken with food. 
• Use the 5 ml oral syringe provided to measure the dose. 
 
Use in adults 
 
• The usual adult dose is 5 ml of the oral solution twice a day i.e. every 12 hours, in combination 

with other anti-HIV medicines.  Your doctor will advise on the amount of Kaletra to be taken.  
• It is important that all doses of Kaletra oral solution are taken with food. 
• Use the 5 ml oral syringe provided to measure the dose.  
 
How do I measure the correct dose? 
 
• If the dose is up to 2 ml - use the 2 ml oral dosing syringe to prepare a dose.   
• If the dose is between 2 ml and 5 ml - use the 5 ml oral dosing syringe to prepare a dose.  
 
Check with your pharmacist that you have the correct size of syringe.  If you are not sure how to use 
the oral dosing syringe ask your doctor, pharmacist or nurse.  They will tell you how to use the syringe 
correctly.   
 
Do not shake the bottle – this is because air bubbles can form which will affect how well you can 
measure the dose.   
 
Open the child-proof cap by pushing down on it with your palm and twisting it counter clockwise, or 
in the direction of the arrow on the top of the cap.  Talk to your pharmacist if you have difficulty 
opening the bottle. 
 

 
 
 
Using the 2 ml oral dosing syringe for doses up to 2 ml  
 
The syringe has two 
main parts, a ‘plunger’ 
and a ‘barrel’. In this 
picture we have pulled 
out the plunger so that 
you can see each part 
clearly. 
 
 
 
 
 
 

Collar 

Plunger 

Barrel 

Tip 



 146 

 
1. Push the plunger all of the 

way into the barrel.  
2. Place the tip of the syringe 

into the liquid.  
3. Pull up the plunger until 

the correct dose amount is 
shown on the plunger.  You 
should see the ‘ml’ 
marking aligned to the top 
of the collar of the barrel.  

4. Turn the syringe so that the 
tip is pointing up, gently 
tap it and push plunger to remove any air bubbles. 

5. After removing the air bubbles, look at the dose mark. 
• If the ‘ml’ mark on the collar is more than the prescribed 

dose, push the plunger to the prescribed dose.  
• If the ‘ml’ mark on the collar is less than the prescribed 

dose, draw up more solution to the prescribed dose. 
6.  Place the dosing syringe in your child’s mouth towards the 

cheek and gently push the plunger down to release the 
medicine. 

Replace the bottle cap after each dose.  
 
Using the 5 ml oral dosing syringe for doses more than 2 ml 
 
The syringe has two main parts, a 
‘plunger’ and a ‘barrel’. In this 
picture we have pulled out the 
plunger so that you can see each 
part clearly. 
 

 
 
 
 
 
 

1. Push the plunger all of the way 
into the barrel.  

2. Place the tip of the syringe into 
the liquid. 

3. Pull up the plunger until the 
black ‘O’ ring is on the correct 
dose ‘ml’ mark on the barrel. 

4. Turn the syringe so that the tip 
is pointing up, gently tap it and 
push plunger to remove any air 
bubbles.  

5. After removing the air bubbles, 
look at the dose mark. 
• If the ‘ml’ mark on the black ‘O’ ring is more than the prescribed dose, push the 

plunger to the prescribed dose.  
• If the ‘ml’ mark on the black ‘O’ ring is less than the prescribed dose, draw up 

more solution to the prescribed dose. 

‘ml’ 
mark 

Finger grip 

Black ‘O’ ring 

Tip 

Barrel 

Plunger 

‘ml’ 
mark 



 147 

6. Place the dosing syringe in your child’s mouth towards the 
cheek and gently push the plunger down to release the 
medicine. 

Replace the bottle cap after each dose.  
 
After each dose of Kaletra separate the plunger and the syringe.  Wash the plunger and the syringe 
with washing up liquid and warm water as soon as you can; you may soak both in soapy water for up 
to 15 minutes.  Rinse the syringe and plunger with clean water.  Put the syringe back together and 
draw up and expel tap water a few times to rinse.  Let the syringe dry completely before you use that 
syringe for dosing.  
 
Do not use the dosing syringes supplied with Kaletra oral solution to administer any other medicines 
you or your child may be taking.  
 
If you or your child take more Kaletra than you should 
 
• If you realise you have taken more Kaletra than you were supposed to, contact your doctor right 

away.   
• If you cannot contact your doctor, go to the hospital. 
 
If you or your child forget to take Kaletra 
 
− If you notice you miss a dose within 6 hours of your normal dosing time, take your missed dose 

as soon as possible, and then continue with your normal dose at the regular time as prescribed 
by your doctor. 

 
− If you notice you miss a dose by more than 6 hours after your normal dosing time, do not take 

the missed dose.  Take the next dose as usual.  Do not take a double dose to make up for a 
forgotten dose. 

 
If you or your child stop taking Kaletra 
 
• Do not stop or change the daily dose of Kaletra without first consulting with your doctor. 
• Kaletra should always be taken twice every day to help control your HIV infection, no matter 

how much better you feel.   
• Taking Kaletra as recommended should give you the best chance of delaying the development 

of resistance to the product. 
• If a side effect is preventing you from taking Kaletra as directed tell your doctor right away.  
• Always keep enough Kaletra on hand so you don’t run out.  When you travel or need to stay in 

the hospital make sure you will have enough Kaletra to last until you can get a new supply. 
• Continue to take this medicine until your doctor tells you otherwise. 
 
 
4. Possible side effects 
 
Like all medicines, Kaletra can cause side effects, although not everybody gets them.  It may be 
difficult to tell which side effects have been caused by Kaletra and which may occur due to other 
medicines you take at the same time or by the complications of the HIV infection.   
 
During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose.  This 
is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV 
medicines themselves.  Your doctor will test for these changes. 
 
The following side effects have been reported by patients who took this medicine.  You should tell 
your doctor promptly about these or any other symptoms.  If the condition persists or worsens, seek 
medical attention. 



 148 

 
Very common: may affect more than 1 in 10 people 
• diarrhoea;  
• nausea; 
• upper respiratory tract infection. 
 
Common: may affect up to 1 in 10 people 
• inflammation of the pancreas; 
• vomiting, enlarged abdomen, pain in the lower and upper stomach area, passing wind, 

indigestion, decreased appetite, reflux from your stomach to your oesophagus which may cause 
pain;  
− Tell your doctor if you experience nausea, vomiting or abdominal pain as these may be 

suggestive of pancreatitis (inflammation of the pancreas). 
• swelling or inflammation of the stomach, intestines and colon; 
• increased cholesterol levels in your blood, increased triglycerides (a form of fat) levels in your 

blood, high blood pressure; 
• decreased ability of the body to handle sugar including diabetes mellitus, weight loss; 
• low number of red blood cells, low number of white blood cells which are usually used to fight 

infection; 
• rash, eczema, accumulation of scales of greasy skin; 
• dizziness, anxiety, difficulty in sleeping; 
• feeling tired, lack of strength and energy, headache including migraine; 
• haemorrhoids; 
• inflammation of the liver including increased liver enzymes; 
• allergic reactions including hives and inflammation in the mouth; 
• lower respiratory tract infection; 
• enlargement of the lymph nodes; 
• impotence, abnormally heavy or extended menstrual flow or a lack of menstruation; 
• muscle disorders such as weakness and spasms, pain in the joints, muscles and back; 
• damage to nerves of the peripheral nervous system; 
• night sweats, itching, rash including raised bumps on the skin, infection of the skin, 

inflammation of skin or hair pores, accumulation of fluid in the cells or tissues.   
 
Uncommon: may affect up to 1 in 100 people   
• abnormal dreams; 
• loss or changed sense of taste; 
• hair loss; 
• an abnormality in your electrocardiogram (ECG) called atrioventricular block; 
• plaque building up inside your arteries which could lead to heart attack and stroke; 
• inflammation of blood vessels and capillaries; 
• inflammation of the bile duct; 
• uncontrolled shaking of the body; 
• constipation; 
• deep vein inflammation related to a blood clot; 
• dry mouth; 
• inability to control your bowels; 
• inflammation of the first section of the small intestine just after the stomach, wound or ulcer in 

the digestive tract, bleeding from the intestinal tract or rectum; 
• red blood cells in the urine; 
• yellowing of the skin or whites of eyes (jaundice); 
• fatty deposits in the liver, enlarged liver; 
• lack of functioning of the testes; 
• a flare-up of symptoms related to an inactive infection in your body (immune reconstitution); 
• increased appetite; 



 149 

• abnormally high level of bilirubin (a pigment produced from the breakdown of red blood cells) 
in the blood 

• decreased sexual desire; 
• inflammation of the kidney; 
• bone death caused by poor blood supply to the area; 
• mouth sores or ulcerations, inflammation of the stomach and intestine; 
• kidney failure; 
• breakdown of muscle fibres resulting in the release of muscle fibre contents (myoglobin) into 

the bloodstream; 
• a sound in one ear or both ears, such as buzzing, ringing or whistling; 
• tremor; 
• abnormal closure of one of the valves (tricuspid valve in your heart); 
• vertigo (spinning feeling); 
• eye disorder, abnormal vision; 
• weight gain. 
 
Rare: may affect up to 1 in 1,000 people  
• severe or life-threatening skin rashes and blisters (Stevens-Johnson syndrome and erythema 

multiforme). 
 
Not known: frequency cannot be estimated from the available data 
• kidney stones. 
 
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please 
inform your doctor or pharmacist. 
 
Reporting of side effects 
 
If you get any side effects, talk to your doctor or pharmacist.  This includes any possible side effects 
not listed in this leaflet.  You can also report side effects directly via the national reporting system 
listed in Appendix V.  By reporting side effects you can help provide more information on the safety 
of this medicine. 
 
 
5. How to store Kaletra 
 
• Keep this medicine out of the sight and reach of children. 
• Do not use Kaletra after the expiry date which is stated on the bottle. 
• Do not use this medicine if you notice the solution is discoloured or contains particles. 
 
How should I store Kaletra and for how long? 
 
• 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. 

• It is important to keep Kaletra in the bottle it came in and replace the bottle cap after each dose.  
Do not transfer it to any other container.  

 
How should I dispose of any unused Kaletra? 
 
Do not throw away any medicines via wastewater.  Ask your pharmacist how to throw away 
medicines you no longer use.  These measures will help protect the environment. 
 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 150 

6. Contents of the pack and other information 
 
What Kaletra contains 
 
The active substances are lopinavir and ritonavir. 
Each ml of Kaletra oral solution contains 80 mg of lopinavir and 20 mg of ritonavir. 
 
The other ingredients are:  
 
Alcohol, 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, heliotropin, 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, levomenthol. 
 
What Kaletra looks like and contents of the pack 
 
Kaletra oral solution comes in a multiple-dose 60 ml amber bottle.  Each ml of Kaletra contains 80 mg 
of lopinavir and 20 mg of ritonavir. 
 
Two pack sizes are available: 
• 120 ml (2 bottles x 60 ml).  The 2 bottle pack also contains two 2 ml syringes with 0.1 ml 

graduations.  
For volumes up to 2 ml.  For larger volumes an alternative pack is available. 

• 300 ml (5 bottles x 60 ml).  The 5 bottle pack also contains five 5 ml syringes with 0.1 ml 
graduations.   
For volumes greater than 2 ml.  For smaller volumes an alternative pack is available. 

 
Marketing Authorisation Holder:   
AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany 
 
Manufacturer:   
Aesica Queenborough Ltd, Queenborough, Kent ME11 5EL, United Kingdom 
AbbVie Logistics B.V., Zuiderzeelaan 53, 8017 JV Zwolle, The Netherlands 
AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
AbbVie SA 
Tél/Tel: +32 10  477811 

Lietuva 
AbbVie UAB  
Tel: +370 5 205 3023 
 

България 
АбВи ЕООД 
Тел.: +359 2 90 30 430 

Luxembourg/Luxemburg 
AbbVie SA 
Belgique/Belgien 
Tél/Tel: +32 10 477811 
 

Česká republika 
AbbVie s.r.o.  
Tel: +420 233 098 111 
 

Magyarország 
AbbVie Kft. 
Tel.: +36 1 455 8600 
 

Danmark 
AbbVie A/S 
Tlf: +45 72 30-20-28 

Malta 
V.J.Salomone Pharma Limited  
Tel: +356 22983201 



 151 

Deutschland 
AbbVie Deutschland GmbH & Co. KG 
Tel: 00800 222843 33 (gebührenfrei) 
Tel: +49 (0) 611 / 1720-0 
 

Nederland 
AbbVie B.V. 
Tel: +31 (0)88 322 2843 
 

Eesti 
AbbVie Biopharmaceuticals GmbH Eesti filiaal  
Tel: +372 623 1011 
 

Norge 
AbbVie AS 
Tlf: +47 67 81 80 00 
 

Ελλάδα 
AbbVie ΦΑΡΜΑΚΕΥΤΙΚΗ Α.Ε. 
Τηλ: +30 214 4165 555 
 

Österreich 
AbbVie GmbH  
Tel: +43 1 20589-0 
 

España 
AbbVie Spain, S.L.U.  
Tel: +34 9 1 384 0910 

Polska 
AbbVie Polska Sp. z o.o. 
Tel.: +48 22 372 78 00  
 

France 
AbbVie 
Tél: +33 (0)1 45 60 13 00 
 

Portugal 
AbbVie, Lda.  
Tel: +351 (0)21 1908400 
 

Hrvatska  
AbbVie d.o.o. 
Tel: +385 (0)1 5625 501 

România 
AbbVie S.R.L. 
Tel: +40 21 529 30 35 
 

Ireland 
AbbVie Limited  
Tel: +353 (0)1 4287900 

Slovenija 
AbbVie Biofarmacevtska družba d.o.o. 
Tel: +386 (1)32 08 060 
 

Ísland 
Vistor hf. 
Tel: +354 535 7000 
 

Slovenská republika 
AbbVie s.r.o. 
Tel: +421 2 5050 0777 
 

Italia 
AbbVie S.r.l.  
Tel: +39 06 928921 

Suomi/Finland 
AbbVie Oy  
Puh/Tel: +358 (0) 10 2411 200 
 

Κύπρος 
Lifepharma (Z.A.M.) Ltd 
Τηλ: +357 22 34 74 40 

Sverige 
AbbVie AB 
Tel: +46 (0)8 684 44 600 
 

Latvija 
AbbVie SIA  
Tel: +371 67605000 
 

United Kingdom 
AbbVie Ltd  
Tel: +44 (0)1628 561090 

 
This leaflet was last revised in: {MM/YYYY} 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 



 152 

Package leaflet: Information for the user 
 

Kaletra 200 mg/50 mg film-coated tablets 
lopinavir/ritonavir 

 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you or your child. 
− Keep this leaflet.  You may need to read it again. 
− If you have any further questions, ask your doctor or pharmacist. 
− This medicine has been prescribed for you or your child only.  Do not pass it on to others.  It 

may harm them, even if their signs of illness are the same as yours. 
− If you get any side effects, talk to your doctor or pharmacist.  This includes any possible side 

effects not listed in this leaflet.  See section 4. 
 
What is in this leaflet: 
1. What Kaletra is and what it is used for 
2. What you need to know before you or your child takes Kaletra 
3. How to take Kaletra 
4. Possible side effects 
5. How to store Kaletra 
6. Contents of the pack and other information 
 
 
1. What Kaletra is and what it is used for 
 
• Your doctor has prescribed Kaletra to help to control your Human Immunodeficiency Virus 

(HIV) infection.  Kaletra does this by slowing down the spread of the infection in your body. 
• Kaletra is not a cure for HIV infection or AIDS. 
• Kaletra is used by children 2 years of age or older, adolescents and adults who are infected with 

HIV, the virus which causes AIDS.   
• Kaletra contains the active substances lopinavir and ritonavir.  Kaletra is an antiretroviral 

medicine.  It belongs to a group of medicines called protease inhibitors. 
• Kaletra is prescribed for use in combination with other antiviral medicines.  Your doctor will 

discuss with you and determine which medicines are best for you. 
 
 
2. What you need to know before you or your child takes Kaletra 
 
Do not take Kaletra 
• if you are allergic to lopinavir, ritonavir or any of the other ingredients of Kaletra (see section 

6);  
• if you have severe liver problems. 
 
Do not take Kaletra with any of the following medicines: 
• astemizole or terfenadine (commonly used to treat allergy symptoms – these medicines may be 

available without prescription); 
• midazolam taken orally (taken by mouth), triazolam (used to relieve anxiety and/or trouble 

sleeping); 
• pimozide (used to treat schizophrenia); 
• quetiapine (used to treat schizophrenia, bipolar disorder and major depressive disorder); 
• lurasidone (used to treat depression); 
• ranolazine (used to treat chronic chest pain [angina]); 
• cisapride (used to relieve certain stomach problems); 
• ergotamine, dihydroergotamine, ergonovine, methylergonovine (used to treat headaches); 
• amiodarone, dronedarone (used to treat abnormal heart beat); 
• lovastatin, simvastatin (used to lower blood cholesterol); 



 153 

• lomitapide (used to lower blood cholesterol); 
• alfuzosin (used in men to treat symptoms of an enlarged prostate (benign prostatic hyperplasia 

(BPH)); 
• fusidic acid (used to treat skin infections caused by Staphylococcus bacteria such as impetigo 

and infected dermatitis).  Fusidic acid used to treat long-term infections of the bones and joints 
may be taken under doctor’s supervision (see Other medicines and Kaletra section); 

• colchicine (used to treat gout) if you have kidney and/or liver problems (see the section on 
Other medicines and Kaletra); 

• elbasvir/grazoprevir (used to treat chronic hepatitis C virus [HCV]); 
• ombitasvir/paritaprevir/ritonavir with or without dasabuvir (used to treat chronic hepatitis C 

virus [HCV]); 
• neratinib (used to treat breast cancer); 
• avanafil or vardenafil (used to treat erectile dysfunction); 
• sildenafil used to treat pulmonary arterial hypertension (high blood pressure in the pulmonary 

artery).  Sildenafil used to treat erectile dysfunction may be taken under doctor’s supervision 
(see Other medicines and Kaletra section); 

• products that contain St John’s wort (Hypericum perforatum). 
 
Read the list of medicines below under ‘Other medicines and Kaletra’ for information on certain 
other medicines which require special care. 
 
If you are currently taking any of these medicines, ask your doctor about making necessary changes 
either in the treatment for your other condition(s) or in your antiretroviral treatment.  
 
Warnings and precautions 
 
Talk to your doctor or pharmacist before taking Kaletra. 
 
Important information 
 
• People taking Kaletra may still develop infections or other illnesses associated with HIV disease 

and AIDS.  It is therefore important that you remain under the supervision of your doctor while 
taking Kaletra.   

• You can still pass on HIV when taking this medicine, although the risk is lowered by 
effective antiretroviral therapy.  Discuss with your doctor the precautions needed to avoid 
infecting other people. 
 

Tell your doctor if you or your child have/had 
 
• Haemophilia type A and B as Kaletra might increase the risk of bleeding. 
• Diabetes as increased blood sugars has been reported in patients receiving Kaletra. 
• A history of liver problems as patients with a history of liver disease, including chronic 

hepatitis B or C are at increased risk of severe and potentially fatal liver side effects. 
 
Tell your doctor if you or your child experience 
 
• Nausea, vomiting, abdominal pain, difficulty breathing and severe weakness of the muscles in 

the legs and arms as these symptoms may indicate raised lactic acid levels. 
• Thirst, frequent urination, blurred vision or weight loss as this may indicate raised sugar levels 

in the blood. 
• Nausea, vomiting, abdominal pain as large increases in the amount of triglycerides (fats in the 

blood) have been considered a risk factor for pancreatitis (inflammation of the pancreas) and 
these symptoms may suggest this condition. 

• In some patients with advanced HIV infection and a history of opportunistic infection, signs and 
symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is 
started.  It is believed that these symptoms are due to an improvement in the body’s immune 



 154 

response, enabling the body to fight infections that may have been present with no obvious 
symptoms. 

• In addition to the opportunistic infections, autoimmune disorders (a condition that occurs when 
the immune system attacks healthy body tissue) may also occur after you start taking medicines 
for the treatment of your HIV infection.  Autoimmune disorders may occur many months after 
the start of treatment.  If you notice any symptoms of infection or other symptoms such as 
muscle weakness, weakness beginning in the hands and feet and moving up towards the trunk of 
the body, palpitations, tremor or hyperactivity, please inform your doctor immediately to seek 
necessary treatment. 

• Joint stiffness, aches and pains (especially of the hip, knee and shoulder) and difficulty in 
movement as some patients taking these medicines may develop a bone disease called 
osteonecrosis (death of bone tissue caused by loss of blood supply to the bone).  The length of 
combination antiretroviral therapy, corticosteroid use, alcohol consumption, severe 
immunosuppression (reduction in the activity of the immune system), higher body mass index, 
among others, may be some of the many risk factors for developing this disease.   

• Muscle pain, tenderness or weakness, particularly in combination with these medicines.  On 
rare occasions these muscle disorders have been serious.  

• Symptoms of dizziness, lightheadedness, fainting or sensation of abnormal heartbeats.  Kaletra 
may cause changes in your heart rhythm and the electrical activity of your heart.  These changes 
may be seen on an ECG (electrocardiogram). 

 
Other medicines and Kaletra 
 
Tell your doctor or pharmacist if you or your child are taking, have recently taken or might take 
any other medicines.  
• antibiotics (e.g. rifabutin, rifampicin, clarithromycin); 
• anticancer medicines (e.g. abemaciclib, afatinib, apalutamide, ceritinib, encorafenib, ibrutinib, 

venetoclax, most tyrosine kinases inhibitors such as dasatinib and nilotinib, also vincristine and 
vinblastine); 

• anticoagulants (e.g. warfarin, rivaroxaban, vorapaxar); 
• antidepressants (e.g. trazodone, bupropion); 
• anti-epilepsy medicines (e.g. carbamazepine, phenytoin, phenobarbital, lamotrigine and 

valproate); 
• antifungals (e.g. ketoconazole, itraconazole, voriconazole); 
• anti-gout medicines (e.g. colchicine).  You must not take Kaletra with colchicine if you have 

kidney and/or liver problems (see also ‘Do not take Kaletra’ above); 
• anti-tuberculosis medicine (bedaquiline, delamanid); 
• antiviral medicine used to treat chronic hepatitis C virus (HCV) infection in adults (e.g. 

glecaprevir/pibrentasvir, simeprevir and sofosbuvir/velpatasvir/voxilaprevir); 
• erectile dysfunction medicines (e.g. sildenafil and tadalafil); 
• fusidic acid used to treat long-term infections of the bones and joints (e.g. osteomyelitis); 
• heart medicines including: 

− digoxin; 
− calcium channel antagonists (e.g. felodipine, nifedipine, nicardipine); 
− medicines used to correct heart rhythm (e.g. bepridil, systemic lidocaine, quinidine); 

• HIV CCR5-antagonist (e.g. maraviroc); 
• HIV-1 integrase inhibitor (e.g. raltegravir); 
• medicines used to treat low blood platelet count (e.g. fostamatinib); 
• levothyroxine (used to treat thyroid problems); 
• medicines used to lower blood cholesterol (e.g. atorvastatin, lovastatin, rosuvastatin or 

simvastatin);  
• medicines used to treat asthma and other lung-related problems such as chronic obstructive 

pulmonary disease (COPD) (e.g. salmeterol); 
• medicines used to treat pulmonary arterial hypertension (high blood pressure in the pulmonary 

artery) (e.g. bosentan, riociguat, sildenafil, tadalafil); 



 155 

• medicines affecting the immune system (e.g. cyclosporin, sirolimus (rapamycin), tacrolimus); 
• medicines used for smoking cessation (e.g. bupropion); 
• pain-relieving medicines (e.g. fentanyl); 
• morphine-like medicines (e.g. methadone); 
• non-nucleoside reverse transcriptase inhibitors (NNRTIs) (e.g. efavirenz, nevirapine); 
• oral contraceptive or using a patch contraceptive to prevent pregnancy (see section below titled 

Contraceptives); 
• protease inhibitors (e.g. fosamprenavir, indinavir, ritonavir, saquinavir, tipranavir); 
• sedatives (e.g. midazolam administered by injection); 
• steroids (e.g. budesonide, dexamethasone, fluticasone propionate, ethinyl oestradiol, 

triamcinolone). 
 
Read the list of medicines above ‘Do not take Kaletra with any of the following medicines’ for 
information on medicines that you must not take with Kaletra. 
 
Tell your doctor or pharmacist if you or your child are taking, have recently taken or might take any 
other medicines, including medicines obtained without prescription. 
 
Erectile dysfunction medicines (avanafil, vardenafil, sildenafil, tadalafil) 
 
• Do not take Kaletra if you are currently taking avanafil or vardenafil. 
• You must not take Kaletra with sildenafil used to treat pulmonary arterial hypertension (high 

blood pressure in the pulmonary artery) (see also Do not take Kaletra section above). 
• If you take sildenafil or tadalafil and Kaletra together, you may be at risk of side effects such as 

low blood pressure, passing out, visual changes and penile erection lasting more than 4 hours.  
If an erection lasts longer than 4 hours, you should get medical help immediately to avoid 
permanent damage to your penis.  Your doctor can explain these symptoms to you. 

 
Contraceptives 
 
• If you are currently using an oral contraceptive or using a patch contraceptive to prevent 

pregnancy, you should use an additional or different type of contraception (e.g. condom) as 
Kaletra may reduce the effectiveness of oral and patch contraceptives. 

• Kaletra does not reduce the risk of passing HIV to others.  Appropriate precautions (e.g. use of a 
condom) should be taken to prevent passing on the disease through sexual contact. 

 
Pregnancy and breast-feeding 
 
• Tell your doctor immediately if you are planning to have a baby, you are pregnant, think you 

may be pregnant or if you are breast-feeding.   
• Breast-feeding mothers should not take Kaletra unless specifically directed by the doctor.   
• It is recommended that HIV-infected women do not breast-feed their infants because there is a 

possibility that the baby can be infected with HIV through your breast milk. 
 
Driving or using machines 
 
Kaletra has not specifically been tested for its possible effects on the ability to drive a car or operate 
machines.  Do not drive a car or operate machinery if you experience any side effects (e.g. nausea) 
that impact your ability to do so safely.  Instead, contact your doctor. 
 
 
3. How to take Kaletra 
 

It is important that Kaletra tablets are swallowed whole and not chewed, broken or crushed. 
 



 156 

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure how you should take your medicine. 
 
How much Kaletra should be taken and when? 
 
Use in adults 
 
• The usual adult dose is 400 mg/100 mg twice a day i.e. every 12 hours, in combination with 

other anti-HIV medicines.  Adult patients who have not previously taken other antiviral 
medicines can also take Kaletra tablets once daily as an 800 mg/200 mg dose.  Your doctor will 
advise on the number of tablets to be taken.  Adult patients who have previously taken other 
antiviral medicines can take Kaletra tablets once daily as an 800 mg/200 mg dose if their doctor 
decides it is appropriate. 

• Kaletra must not be taken once daily with efavirenz, nevirapine, carbamazepine, phenobarbital 
and phenytoin. 

• Kaletra tablets can be taken with or without food. 
 
Use in children 
 
• For children, your doctor will decide the right dose (number of tablets) based on the child’s 

height and weight.   
• Kaletra tablets can be taken with or without food. 
 
Kaletra is also supplied as 100 mg/25 mg film-coated tablets.  Kaletra oral solution is available for 
patients who cannot take tablets. 
 
If you or your child take more Kaletra than you should 
 
• If you realise you have taken more Kaletra than you were supposed to, contact your doctor right 

away.   
• If you cannot contact your doctor, go to the hospital. 
 
If you or your child forget to take Kaletra 
 
If you are taking Kaletra twice a day 
− If you notice you miss a dose within 6 hours of your normal dosing time, take your missed dose 

as soon as possible, and then continue with your normal dose at the regular time as prescribed 
by your doctor. 

 
− If you notice you miss a dose by more than 6 hours after your normal dosing time, do not take 

the missed dose.  Take the next dose as usual.  Do not take a double dose to make up for a 
forgotten dose. 

 
If you are taking Kaletra once a day 
− If you notice you miss a dose within 12 hours of your normal dosing time, take your missed 

dose as soon as possible, and then continue with your normal dose at the regular time as 
prescribed by your doctor. 

 
− If you notice you miss a dose by more than 12 hours after your normal dosing time, do not take 

the missed dose.  Take the next dose as usual.  Do not take a double dose to make up for a 
forgotten dose. 

 
If you or your child stop taking Kaletra 
 
• Do not stop or change the daily dose of Kaletra without first consulting with your doctor. 



 157 

• Kaletra should always be taken every day to help control your HIV infection, no matter how 
much better you feel.   

• Taking Kaletra as recommended should give you the best chance of delaying the development 
of resistance to the product. 

• If a side effect is preventing you from taking Kaletra as directed tell your doctor right away.  
• Always keep enough Kaletra on hand so you don’t run out.  When you travel or need to stay in 

the hospital make sure you will have enough Kaletra to last until you can get a new supply. 
• Continue to take this medicine until your doctor tells you otherwise. 
 
 
4. Possible side effects 
 
Like all medicines, Kaletra can cause side effects, although not everybody gets them.  It may be 
difficult to tell which side effects have been caused by Kaletra and which may occur due to other 
medicines you take at the same time or by the complications of the HIV infection.   
 
During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose.  This 
is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV 
medicines themselves.  Your doctor will test for these changes. 
 
The following side effects have been reported by patients who took this medicine.  You should tell 
your doctor promptly about these or any other symptoms.  If the condition persists or worsens, seek 
medical attention. 
 
Very common: may affect more than 1 in 10 people 
• diarrhoea;  
• nausea; 
• upper respiratory tract infection. 
 
Common: may affect up to 1 in 10 people 
• inflammation of the pancreas; 
• vomiting, enlarged abdomen, pain in the lower and upper stomach area, passing wind, 

indigestion, decreased appetite, reflux from your stomach to your oesophagus which may cause 
pain; 
− Tell your doctor if you experience nausea, vomiting or abdominal pain as these may be 

suggestive of pancreatitis (inflammation of the pancreas). 
• swelling or inflammation of the stomach, intestines and colon; 
• increased cholesterol levels in your blood, increased triglycerides (a form of fat) levels in your 

blood, high blood pressure; 
• decreased ability of the body to handle sugar including diabetes mellitus, weight loss; 
• low number of red blood cells, low number of white blood cells which are usually used to fight 

infection; 
• rash, eczema, accumulation of scales of greasy skin; 
• dizziness, anxiety, difficulty in sleeping; 
• feeling tired, lack of strength and energy, headache including migraine; 
• haemorrhoids; 
• inflammation of the liver including increased liver enzymes; 
• allergic reactions including hives and inflammation in the mouth; 
• lower respiratory tract infection; 
• enlargement of the lymph nodes; 
• impotence, abnormally heavy or extended menstrual flow or a lack of menstruation; 
• muscle disorders such as weakness and spasms, pain in the joints, muscles and back; 
• damage to nerves of the peripheral nervous system; 
• night sweats, itching, rash including raised bumps on the skin, infection of the skin, 

inflammation of skin or hair pores, accumulation of fluid in the cells or tissues.   



 158 

 
Uncommon: may affect up to 1 in 100 people   
• abnormal dreams; 
• loss or changed sense of taste; 
• hair loss; 
• an abnormality in your electrocardiogram (ECG) called atrioventricular block; 
• plaque building up inside your arteries which could lead to heart attack and stroke; 
• inflammation of blood vessels and capillaries; 
• inflammation of the bile duct; 
• uncontrolled shaking of the body; 
• constipation; 
• deep vein inflammation related to a blood clot; 
• dry mouth; 
• inability to control your bowels; 
• inflammation of the first section of the small intestine just after the stomach, wound or ulcer in 

the digestive tract, bleeding from the intestinal tract or rectum; 
• red blood cells in the urine; 
• yellowing of the skin or whites of eyes (jaundice); 
• fatty deposits in the liver, enlarged liver; 
• lack of functioning of the testes; 
• a flare-up of symptoms related to an inactive infection in your body (immune reconstitution); 
• increased appetite; 
• abnormally high level of bilirubin (a pigment produced from the breakdown of red blood cells) 

in the blood 
• decreased sexual desire; 
• inflammation of the kidney; 
• bone death caused by poor blood supply to the area; 
• mouth sores or ulcerations, inflammation of the stomach and intestine; 
• kidney failure; 
• breakdown of muscle fibres resulting in the release of muscle fibre contents (myoglobin) into 

the bloodstream; 
• a sound in one ear or both ears, such as buzzing, ringing or whistling; 
• tremor; 
• abnormal closure of one of the valves (tricuspid valve in your heart); 
• vertigo (spinning feeling); 
• eye disorder, abnormal vision; 
• weight gain. 
 
Rare: may affect up to 1 in 1,000 people  
• severe or lifethreatening skin rashes and blisters (Stevens-Johnson syndrome and erythema 

multiforme). 
 
Not known: frequency cannot be estimated from the available data 
• kidney stones. 
 
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please 
inform your doctor or pharmacist. 
 
Reporting of side effects 
 
If you get any side effects, talk to your doctor or pharmacist.  This includes any possible side effects 
not listed in this leaflet.  You can also report side effects directly via the national reporting system 
listed in Appendix V.  By reporting side effects you can help provide more information on the safety 
of this medicine. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 159 

 
5. How to store Kaletra 
 
• Keep this medicine out of the sight and reach of children. 
• Do not use Kaletra after the expiry date which is stated on the pack. 
• This medicinal product does not require any special storage conditions. 
• Do not use this medicine if you notice any discolouration. 
 
How should I dispose of any unused Kaletra? 
 
Do not throw away any medicines via wastewater.  Ask your pharmacist how to throw away 
medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Kaletra contains 
 
The active substances are lopinavir and ritonavir. 
Each tablet of Kaletra contains 200 mg of lopinavir and 50 mg of ritonavir 
 
The other ingredients are:  
 
Tablet 
Copovidone, sorbitan laurate, colloidal anhydrous silica, sodium stearyl fumarate.  
 
Tablet coating 
Hypromellose, titanium dioxide, macrogols type 400 (polyethylene glycol 400), hydroxypropyl 
cellulose, talc, colloidal anhydrous silica, macrogols type 3350 (polyethylene glycol 3350), yellow 
ferric oxide E172, polysorbate 80. 
 
What Kaletra looks like and contents of the pack 
 
Kaletra film-coated tablets are yellow debossed with [Abbott logo] and “KA”.   
 
Kaletra film-coated tablets are supplied in packs containing 120 tablets (1 plastic bottle of 120 tablets) 
and multipacks comprising 3 plastic bottles each containing 120 tablets (360 tablets).  Blister 
multipacks containing 120 tablets (1 pack of 120 tablets or 3 packs each containing 40 tablets) are also 
available.   
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder:   
AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany 
 
Manufacturer:   
AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany 
Fournier Laboratories Ireland Limited, Carrigtwohill Business Park, Anngrove, Carrigtwohill, Co. 
Cork, Ireland 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 



 160 

België/Belgique/Belgien 
AbbVie SA 
Tél/Tel: +32 10  477811 

Lietuva 
AbbVie UAB  
Tel: +370 5 205 3023 
 

България 
АбВи ЕООД 
Тел.: +359 2 90 30 430 

Luxembourg/Luxemburg 
AbbVie SA 
Belgique/Belgien 
Tél/Tel: +32 10 477811 
 

Česká republika 
AbbVie s.r.o.  
Tel: +420 233 098 111 
 

Magyarország 
AbbVie Kft. 
Tel.: +36 1 455 8600 
 

Danmark 
AbbVie A/S 
Tlf: +45 72 30-20-28 

Malta 
V.J.Salomone Pharma Limited  
Tel: +356 22983201 

Deutschland 
AbbVie Deutschland GmbH & Co. KG 
Tel: 00800 222843 33 (gebührenfrei) 
Tel: +49 (0) 611 / 1720-0 
 

Nederland 
AbbVie B.V. 
Tel: +31 (0)88 322 2843 
 

Eesti 
AbbVie Biopharmaceuticals GmbH Eesti filiaal  
Tel: +372 623 1011 
 

Norge 
AbbVie AS 
Tlf: +47 67 81 80 00 
 

Ελλάδα 
AbbVie ΦΑΡΜΑΚΕΥΤΙΚΗ Α.Ε. 
Τηλ: +30 214 4165 555 
 

Österreich 
AbbVie GmbH  
Tel: +43 1 20589-0 
 

España 
AbbVie Spain, S.L.U.  
Tel: +34 9 1 384 910 

Polska 
AbbVie Polska Sp. z o.o. 
Tel.: +48 22 372 78 00  
 

France 
AbbVie 
Tél: +33 (0)1 45 60 13 00 
 

Portugal 
AbbVie, Lda.  
Tel: +351 (0)21 1908400 
 

Hrvatska  
AbbVie d.o.o. 
Tel: +385 (0)1 5625 501 

România 
AbbVie S.R.L. 
Tel: +40 21 529 30 35 
 

Ireland 
AbbVie Limited  
Tel: +353 (0)1 4287900 

Slovenija 
AbbVie Biofarmacevtska družba d.o.o. 
Tel: +386 (1)32 08 060 
 

Ísland 
Vistor hf. 
Tel: +354 535 7000 
 

Slovenská republika 
AbbVie s.r.o. 
Tel: +421 2 5050 0777 
 

Italia 
AbbVie S.r.l.  
Tel: +39 06 928921 

Suomi/Finland 
AbbVie Oy  
Puh/Tel: +358 (0) 10 2411 200 
 



 161 

Κύπρος 
Lifepharma (Z.A.M.) Ltd 
Τηλ: +357 22 34 74 40 

Sverige 
AbbVie AB 
Tel: +46 (0)8 684 44 600 
 

Latvija 
AbbVie SIA  
Tel: +371 67605000 
 

United Kingdom 
AbbVie Ltd  
Tel: +44 (0)1628 561090 

 
This leaflet was last revised in:  {MM/YYYY} 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 

 



 162 

Package leaflet: Information for the user 
 

Kaletra 100 mg/25 mg film-coated tablets 
lopinavir/ritonavir 

 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you or your child. 
• Keep this leaflet.  You may need to read it again. 
• If you have any further questions, ask your doctor or pharmacist. 
• This medicine has been prescribed for you or your child only.  Do not pass it on to others.  It 

may harm them, even if their signs of illness are the same as yours. 
• If you get any side effects, talk to your doctor or pharmacist.  This includes any possible side 

effects not listed in this leaflet.  See section 4. 
 
What is in this leaflet: 
1. What Kaletra is and what it is used for 
2. What you need to know before you or your child takes Kaletra 
3. How to take Kaletra 
4. Possible side effects 
5. How to store Kaletra 
6. Contents of the pack and other information 
 
 
1. What Kaletra is and what it is used for 
 
• Your doctor has prescribed Kaletra to help to control your Human Immunodeficiency Virus 

(HIV) infection.  Kaletra does this by slowing down the spread of the infection in your body. 
• Kaletra is not a cure for HIV infection or AIDS. 
• Kaletra is used by children 2 years of age or older, adolescents and adults who are infected with 

HIV, the virus which causes AIDS.   
• Kaletra contains the active substances lopinavir and ritonavir.  Kaletra is an antiretroviral 

medicine.  It belongs to a group of medicines called protease inhibitors. 
• Kaletra is prescribed for use in combination with other antiviral medicines.  Your doctor will 

discuss with you and determine which medicines are best for you. 
 
 
2. What you need to know before you or your child takes Kaletra 
 
Do not take Kaletra 
• if you are allergic to lopinavir, ritonavir or any of the other ingredients of Kaletra (see section 

6);  
• if you have severe liver problems. 
 
Do not take Kaletra with any of the following medicines: 
• astemizole or terfenadine (commonly used to treat allergy symptoms – these medicines may be 

available without prescription); 
• midazolam taken orally (taken by mouth), triazolam (used to relieve anxiety and/or trouble 

sleeping); 
• pimozide (used to treat schizophrenia); 
• quetiapine (used to treat schizophrenia, bipolar disorder and major depressive disorder); 
• lurasidone (used to treat depression); 
• ranolazine (used to treat chronic chest pain [angina]); 
• cisapride (used to relieve certain stomach problems); 
• ergotamine, dihydroergotamine, ergonovine, methylergonovine (used to treat headaches); 
• amiodarone, dronedarone (used to treat abnormal heart beat); 
• lovastatin, simvastatin (used to lower blood cholesterol); 



 163 

• lomitapide (used to lower blood cholesterol); 
• alfuzosin (used in men to treat symptoms of an enlarged prostate (benign prostatic hyperplasia 

(BPH)); 
• fusidic acid (used to treat skin infections caused by Staphylococcus bacteria such as impetigo 

and infected dermatitis).  Fusidic acid used to treat long-term infections of the bones and joints 
may be taken under doctor’s supervision (see Other medicines and Kaletra section); 

• colchicine (used to treat gout) if you have kidney and/or liver problems (see the section on 
Other medicines and Kaletra); 

• elbasvir/grazoprevir (used to treat chronic hepatitis C virus [HCV]); 
• ombitasvir/paritaprevir/ritonavir with or without dasabuvir (used to treat chronic hepatitis C 

virus [HCV]); 
• neratinib (used to treat breast cancer); 
• avanafil or vardenafil (used to treat erectile dysfunction); 
• sildenafil used to treat pulmonary arterial hypertension (high blood pressure in the pulmonary 

artery).  Sildenafil used to treat erectile dysfunction may be taken under doctor’s supervision 
(see Other medicines and Kaletra section); 

• products that contain St John’s wort (Hypericum perforatum). 
 
Read the list of medicines below under ‘Other medicines and Kaletra’ for information on certain 
other medicines which require special care. 
 
If you are currently taking any of these medicines, ask your doctor about making necessary changes 
either in the treatment for your other condition(s) or in your antiretroviral treatment.  
 
Warnings and precautions 
 
Talk to your doctor or pharmacist before taking Kaletra. 
 
Important information 
 
• People taking Kaletra may still develop infections or other illnesses associated with HIV disease 

and AIDS.  It is therefore important that you remain under the supervision of your doctor while 
taking Kaletra.   

• You can still pass on HIV when taking this medicine, although the risk is lowered by 
effective antiretroviral therapy.  Discuss with your doctor the precautions needed to avoid 
infecting other people. 

 
Tell your doctor if you or your child have/had 
 
• Haemophilia type A and B as Kaletra might increase the risk of bleeding. 
• Diabetes as increased blood sugars has been reported in patients receiving Kaletra. 
• A history of liver problems as patients with a history of liver disease, including chronic 

hepatitis B or C are at increased risk of severe and potentially fatal liver side effects. 
 
Tell your doctor if you or your child experience 
 
• Nausea, vomiting, abdominal pain, difficulty breathing and severe weakness of the muscles in 

the legs and arms as these symptoms may indicate raised lactic acid levels. 
• Thirst, frequent urination, blurred vision or weight loss as this may indicate raised sugar levels 

in the blood. 
• Nausea, vomiting, abdominal pain as large increases in the amount of triglycerides (fats in the 

blood) have been considered a risk factor for pancreatitis (inflammation of the pancreas) and 
these symptoms may suggest this condition. 

• In some patients with advanced HIV infection and a history of opportunistic infection, signs and 
symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is 
started.  It is believed that these symptoms are due to an improvement in the body’s immune 



 164 

response, enabling the body to fight infections that may have been present with no obvious 
symptoms.  

• In addition to the opportunistic infections, autoimmune disorders (a condition that occurs when 
the immune system attacks healthy body tissue) may also occur after you start taking medicines 
for the treatment of your HIV infection. Autoimmune disorders may occur many months after 
the start of treatment.  If you notice any symptoms of infection or other symptoms such as 
muscle weakness, weakness beginning in the hands and feet and moving up towards the trunk of 
the body, palpitations, tremor or hyperactivity, please inform your doctor immediately to seek 
necessary treatment. 

• Joint stiffness, aches and pains (especially of the hip, knee and shoulder) and difficulty in 
movement as some patients taking these medicines may develop a bone disease called 
osteonecrosis (death of bone tissue caused by loss of blood supply to the bone).  The length of 
combination antiretroviral therapy, corticosteroid use, alcohol consumption, severe 
immunosuppression (reduction in the activity of the immune system), higher body mass index, 
among others, may be some of the many risk factors for developing this disease.   

• Muscle pain, tenderness or weakness, particularly in combination with these medicines.  On 
rare occasions these muscle disorders have been serious.  

• Symptoms of dizziness, lightheadedness, fainting or sensation of abnormal heartbeats.  Kaletra 
may cause changes in your heart rhythm and the electrical activity of your heart.  These changes 
may be seen on an ECG (electrocardiogram). 

 
Other medicines and Kaletra 
 
Tell your doctor or pharmacist if you or your child are taking, have recently taken or might take 
any other medicines.  
• antibiotics (e.g. rifabutin, rifampicin, clarithromycin); 
• anticancer medicines (e.g. abemaciclib, afatinib, apalutamide, ceritinib, encorafenib, ibrutinib, 

venetoclax, most tyrosine kinases inhibitors such as dasatinib and nilotinib, also vincristine and 
vinblastine); 

• anticoagulants (e.g. warfarin, rivaroxaban, vorapaxar); 
• antidepressants (e.g. trazodone, bupropion); 
• anti-epilepsy medicines (e.g. carbamazepine, phenytoin, phenobarbital, lamotrigine and 

valproate); 
• antifungals (e.g. ketoconazole, itraconazole, voriconazole); 
• anti-gout medicines (e.g. colchicine).  You must not take Kaletra with colchicine if you have 

kidney and/or liver problems (see also ‘Do not take Kaletra’ above); 
• anti-tuberculosis medicine (bedaquiline, delamanid); 
• antiviral medicine used to treat chronic hepatitis C virus (HCV) infection in adults (e.g. 

glecaprevir/pibrentasvir, simeprevir and sofosbuvir/velpatasvir/voxilaprevir); 
• erectile dysfunction medicines (e.g. sildenafil and tadalafil); 
• fusidic acid used to treat long-term infections of the bones and joints (e.g. osteomyelitis); 
• heart medicines including: 

− digoxin; 
− calcium channel antagonists (e.g. felodipine, nifedipine, nicardipine); 
− medicines used to correct heart rhythm (e.g. bepridil, systemic lidocaine, quinidine); 

• HIV CCR5-antagonist (e.g. maraviroc); 
• HIV-1 integrase inhibitor (e.g. raltegravir); 
• medicines used to treat low blood platelet count (e.g. fostamatinib); 
• levothyroxine (used to treat thyroid problems); 
• medicines used to lower blood cholesterol (e.g. atorvastatin, lovastatin, rosuvastatin or 

simvastatin);  
• medicines used to treat asthma and other lung-related problems such as chronic obstructive 

pulmonary disease (COPD) (e.g. salmeterol); 
• medicines used to treat pulmonary arterial hypertension (high blood pressure in the pulmonary 

artery) (e.g. bosentan, riociguat, sildenafil, tadalafil); 



 165 

• medicines affecting the immune system (e.g. cyclosporin, sirolimus (rapamycin), tacrolimus); 
• medicines used for smoking cessation (e.g. bupropion); 
• pain-relieving medicines (e.g. fentanyl); 
• morphine-like medicines (e.g. methadone); 
• non-nucleoside reverse transcriptase inhibitors (NNRTIs) (e.g. efavirenz, nevirapine); 
• oral contraceptive or using a patch contraceptive to prevent pregnancy (see section below titled 

Contraceptives); 
• protease inhibitors (e.g. fosamprenavir, indinavir, ritonavir, saquinavir, tipranavir); 
• sedatives (e.g. midazolam administered by injection); 
• steroids (e.g. budesonide, dexamethasone, fluticasone propionate, ethinyl oestradiol, 

triamcinolone). 
 
Read the list of medicines above ‘Do not take Kaletra with any of the following medicines’ for 
information on medicines that you must not take with Kaletra. 
 
Tell your doctor or pharmacist if you or your child are taking, have recently taken or might take any 
other medicines, including medicines obtained without prescription. 
 
Erectile dysfunction medicines (avanafil, vardenafil, sildenafil, tadalafil) 
 
• Do not take Kaletra if you are currently taking avanafil or vardenafil. 
• You must not take Kaletra with sildenafil used to treat pulmonary arterial hypertension (high 

blood pressure in the pulmonary artery) (see also Do not take Kaletra section above). 
• If you take sildenafil or tadalafil and Kaletra together, you may be at risk of side effects such as 

low blood pressure, passing out, visual changes and penile erection lasting more than 4 hours.  
If an erection lasts longer than 4 hours, you should get medical help immediately to avoid 
permanent damage to your penis.  Your doctor can explain these symptoms to you. 

 
Contraceptives 
 
• If you are currently using an oral contraceptive or using a patch contraceptive to prevent 

pregnancy, you should use an additional or different type of contraception (e.g. condom) as 
Kaletra may reduce the effectiveness of oral and patch contraceptives. 

• Kaletra does not reduce the risk of passing HIV to others.  Appropriate precautions (e.g. use of a 
condom) should be taken to prevent passing on the disease through sexual contact. 

 
Pregnancy and breast-feeding 
 
• Tell your doctor immediately if you are planning to have a baby, you are pregnant, think you 

may be pregnant or if you are breast-feeding.   
• Breast-feeding mothers should not take Kaletra unless specifically directed by the doctor.   
• It is recommended that HIV-infected women do not breast-feed their infants because there is a 

possibility that the baby can be infected with HIV through your breast milk. 
 
Driving or using machines 
 
Kaletra has not specifically been tested for its possible effects on the ability to drive a car or operate 
machines.  Do not drive a car or operate machinery if you experience any side effects (e.g. nausea) 
that impact your ability to do so safely.  Instead, contact your doctor. 
 
 
3. How to take Kaletra 
 

It is important that Kaletra tablets are swallowed whole and not chewed, broken or crushed. 
 



 166 

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure how you should take your medicine. 
 
How much Kaletra should be taken and when? 
 
Use in adults 
 
• The usual adult dose is 400 mg/100 mg twice a day i.e. every 12 hours, in combination with 

other anti-HIV medicines.  Adult patients who have not previously taken other antiviral 
medicines can also take Kaletra tablets once daily as an 800 mg/200 mg dose.  Your doctor will 
advise on the number of tablets to be taken.  Adult patients who have previously taken other 
antiviral medicines can take Kaletra tablets once daily as an 800 mg/200 mg dose if their doctor 
decides it is appropriate.   

• Kaletra must not be taken once daily with efavirenz, nevirapine, carbamazepine, phenobarbital 
and phenytoin. 

• Kaletra tablets can be taken with or without food. 
 
Use in children of 2 years of age and above 
 
• For children, your doctor will decide the right dose (number of tablets) based on the child’s 

height and weight.   
• Kaletra tablets can be taken with or without food. 
 
Kaletra is also supplied as 200 mg/50 mg film-coated tablets.  Kaletra oral solution is available for 
patients who cannot take tablets. 
 
If you or your child take more Kaletra than you should 
 
• If you realise you have taken more Kaletra than you were supposed to, contact your doctor right 

away.   
• If you cannot contact your doctor, go to the hospital. 
 
If you or your child forget to take Kaletra 
 
If you are taking Kaletra twice a day 
− If you notice you miss a dose within 6 hours of your normal dosing time, take your missed dose 

as soon as possible, and then continue with your normal dose at the regular time as prescribed 
by your doctor. 

 
− If you notice you miss a dose by more than 6 hours after your normal dosing time, do not take 

the missed dose.  Take the next dose as usual.  Do not take a double dose to make up for a 
forgotten dose. 

 
If you are taking Kaletra once a day 
− If you notice you miss a dose within 12 hours of your normal dosing time, take your missed 

dose as soon as possible, and then continue with your normal dose at the regular time as 
prescribed by your doctor. 

 
− If you notice you miss a dose by more than 12 hours after your normal dosing time, do not take 

the missed dose.  Take the next dose as usual.  Do not take a double dose to make up for a 
forgotten dose. 

 
If you or your child stop taking Kaletra 
 
• Do not stop or change the daily dose of Kaletra without first consulting with your doctor. 



 167 

• Kaletra should always be taken every day to help control your HIV infection, no matter how 
much better you feel.   

• Taking Kaletra as recommended should give you the best chance of delaying the development 
of resistance to the product. 

• If a side effect is preventing you from taking Kaletra as directed tell your doctor right away.  
• Always keep enough Kaletra on hand so you don’t run out.  When you travel or need to stay in 

the hospital make sure you will have enough Kaletra to last until you can get a new supply. 
• Continue to take this medicine until your doctor tells you otherwise. 
 
 
4. Possible side effects 
 
Like all medicines, Kaletra can cause side effects, although not everybody gets them.  It may be 
difficult to tell which side effects have been caused by Kaletra and which may occur due to other 
medicines you take at the same time or by the complications of the HIV infection.   
 
During HIV therapy there may be an increase in weight and in levels of blood lipids and glucose.  This 
is partly linked to restored health and life style, and in the case of blood lipids sometimes to the HIV 
medicines themselves.  Your doctor will test for these changes. 
 
The following side effects have been reported by patients who took this medicine.  You should tell 
your doctor promptly about these or any other symptoms.  If the condition persists or worsens, seek 
medical attention. 
 
Very common: may affect more than 1 in 10 people 
• diarrhoea;  
• nausea; 
• upper respiratory tract infection. 
 
Common: may affect up to 1 in 10 people 
• inflammation of the pancreas; 
• vomiting, enlarged abdomen, pain in the lower and upper stomach area, passing wind, 

indigestion, decreased appetite, reflux from your stomach to your oesophagus which may cause 
pain;  
− Tell your doctor if you experience nausea, vomiting or abdominal pain as these may be 

suggestive of pancreatitis (inflammation of the pancreas). 
• swelling or inflammation of the stomach, intestines and colon; 
• increased cholesterol levels in your blood, increased triglycerides (a form of fat) levels in your 

blood, high blood pressure; 
• decreased ability of the body to handle sugar including diabetes mellitus, weight loss; 
• low number of red blood cells, low number of white blood cells which are usually used to fight 

infection; 
• rash, eczema, accumulation of scales of greasy skin; 
• dizziness, anxiety, difficulty in sleeping; 
• feeling tired, lack of strength and energy, headache including migraine; 
• haemorrhoids; 
• inflammation of the liver including increased liver enzymes; 
• allergic reactions including hives and inflammation in the mouth; 
• lower respiratory tract infection; 
• enlargement of the lymph nodes; 
• impotence, abnormally heavy or extended menstrual flow or a lack of menstruation; 
• muscle disorders such as weakness and spasms, pain in the joints, muscles and back; 
• damage to nerves of the peripheral nervous system; 
• night sweats, itching, rash including raised bumps on the skin, infection of the skin, 

inflammation of skin or hair pores, accumulation of fluid in the cells or tissues.   



 168 

 
Uncommon: may affect up to 1 in 100 people   
• abnormal dreams; 
• loss or changed sense of taste; 
• hair loss; 
• an abnormality in your electrocardiogram (ECG) called atrioventricular block; 
• plaque building up inside your arteries which could lead to heart attack and stroke; 
• inflammation of blood vessels and capillaries; 
• inflammation of the bile duct; 
• uncontrolled shaking of the body; 
• constipation; 
• deep vein inflammation related to a blood clot; 
• dry mouth; 
• inability to control your bowels; 
• inflammation of the first section of the small intestine just after the stomach, wound or ulcer in 

the digestive tract, bleeding from the intestinal tract or rectum; 
• red blood cells in the urine; 
• yellowing of the skin or whites of eyes (jaundice); 
• fatty deposits in the liver, enlarged liver; 
• lack of functioning of the testes; 
• a flare-up of symptoms related to an inactive infection in your body (immune reconstitution); 
• increased appetite; 
• abnormally high level of bilirubin (a pigment produced from the breakdown of red blood cells) 

in the blood 
• decreased sexual desire; 
• inflammation of the kidney; 
• bone death caused by poor blood supply to the area; 
• mouth sores or ulcerations, inflammation of the stomach and intestine; 
• kidney failure; 
• breakdown of muscle fibres resulting in the release of muscle fibre contents (myoglobin) into 

the bloodstream; 
• a sound in one ear or both ears, such as buzzing, ringing or whistling; 
• tremor; 
• abnormal closure of one of the valves (tricuspid valve in your heart); 
• vertigo (spinning feeling); 
• eye disorder, abnormal vision; 
• weight gain. 
 
Rare: may affect up to 1 in 1,000 people 
• severe or life-threatening skin rashes and blisters (Stevens-Johnson syndrome and erythema 

multiforme). 
 
Not known: frequency cannot be estimated from the available data 
• kidney stones. 
 
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please 
inform your doctor or pharmacist. 
 
Reporting of side effects 
 
If you get any side effects, talk to your doctor or pharmacist.  This includes any possible side effects 
not listed in this leaflet.  You can also report side effects directly via the national reporting system 
listed in Appendix V.  By reporting side effects you can help provide more information on the safety 
of this medicine. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 169 

 
5. How to store Kaletra 
 
• Keep this medicine out of the sight and reach of children. 
• Do not use Kaletra after the expiry date which is stated on the pack. 
• This medicinal product does not require any special storage conditions.  
• Do not use this medicine if you notice any discolouration. 
 
How should I dispose of any unused Kaletra? 
 
Do not throw away any medicines via wastewater.  Ask your pharmacist how to throw away 
medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Kaletra contains 
 
The active substances are lopinavir and ritonavir. 
Each tablet of Kaletra contains 100 mg of lopinavir and 25 mg of ritonavir 
 
The other ingredients are:  
 
Tablet 
Colloidal anhydrous silica, copovidone, sodium stearyl fumarate, sorbitan laurate.  
 
Tablet coating 
Polyvinyl alcohol, talc, titanium dioxide, macrogols type 3350, yellow ferric oxide E172. 
 
What Kaletra looks like and contents of the pack 
 
Kaletra film-coated tablets are pale yellow debossed with [Abbott logo] and “KC”.  
 
Kaletra 100 mg/25 mg film-coated tablets are supplied in plastic bottles containing 60 tablets.   
 
Marketing Authorisation Holder:   
AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany 
 
Manufacturer:   
AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
AbbVie SA 
Tél/Tel: +32 10  477811 

Lietuva 
AbbVie UAB  
Tel: +370 5 205 3023 
 

България 
АбВи ЕООД 
Тел.: +359 2 90 30 430 

Luxembourg/Luxemburg 
AbbVie SA 
Belgique/Belgien 
Tél/Tel: +32 10 477811 
 

Česká republika 
AbbVie s.r.o.  
Tel: +420 233 098 111 
 

Magyarország 
AbbVie Kft. 
Tel.: +36 1 455 8600 
 



 170 

Danmark 
AbbVie A/S 
Tlf: +45 72 30-20-28 
 

Malta 
V.J.Salomone Pharma Limited  
Tel: +356 22983201 
 

Deutschland 
AbbVie Deutschland GmbH & Co. KG 
Tel: 00800 222843 33 (gebührenfrei) 
Tel: +49 (0) 611 / 1720-0 
 

Nederland 
AbbVie B.V. 
Tel: +31 (0)88 322 2843 
 

Eesti 
AbbVie Biopharmaceuticals GmbH Eesti filiaal  
Tel: +372 623 1011 
 
 

Norge 
AbbVie AS 
Tlf: +47 67 81 80 00 
 

Ελλάδα 
AbbVie ΦΑΡΜΑΚΕΥΤΙΚΗ Α.Ε. 
Τηλ: +30 214 4165 555 
 

Österreich 
AbbVie GmbH  
Tel: +43 1 20589-0 
 

España 
AbbVie Spain, S.L.U.  
Tel: +34 9 1 384 910 

Polska 
AbbVie Polska Sp. z o.o. 
Tel.: +48 22 372 78 00  
 

France 
AbbVie 
Tél: +33 (0)1 45 60 13 00 
 

Portugal 
AbbVie, Lda.  
Tel: +351 (0)21 1908400 
 

Hrvatska  
AbbVie d.o.o. 
Tel: +385 (0)1 5625 501 

România 
AbbVie S.R.L. 
Tel: +40 21 529 30 35 
 

Ireland 
AbbVie Limited  
Tel: +353 (0)1 4287900 

Slovenija 
AbbVie Biofarmacevtska družba d.o.o. 
Tel: +386 (1)32 08 060 
 

Ísland 
Vistor hf. 
Tel: +354 535 7000 
 

Slovenská republika 
AbbVie s.r.o. 
Tel: +421 2 5050 0777 
 

Italia 
AbbVie S.r.l.  
Tel: +39 06 928921 

Suomi/Finland 
AbbVie Oy  
Puh/Tel: +358 (0) 10 2411 200 
 

Κύπρος 
Lifepharma (Z.A.M.) Ltd 
Τηλ: +357 22 34 74 40 

Sverige 
AbbVie AB 
Tel: +46 (0)8 684 44 600 
 

Latvija 
AbbVie SIA  
Tel: +371 67605000 
 

United Kingdom 
AbbVie Ltd  
Tel: +44 (0)1628 561090 

 
This leaflet was last revised in:  {MM/YYYY} 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 
	A. LABELLING
	B. PACKAGE LEAFLET