KALETRA 80mg / 20mg / ml oral solution medication leaflet

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

Each 1 ml of Kaletra oral solution contains 80 mg of lopinavir co-formulated with 20 mg of ritonaviras a pharmacokinetic enhancer.

Each 1 ml contains 356.3 mg of alcohol (42.4% v/v), 168.6 mg of high fructose corn syrup, 152.7 mgof propylene glycol (15.3% w/v) (see section 4.3), 10.2 mg of polyoxyl 40 hydrogenated castor oil and4.1 mg of acesulfame potassium (see section 4.4).

For the full list of excipients, see section 6.1.

Oral solution

The solution is light yellow to orange.

Kaletra is indicated in combination with other antiretroviral medicinal products for the treatment ofhuman immunodeficiency virus (HIV-1) infected adults, adolescents and children aged from 14 daysand older.

The choice of Kaletra to treat protease inhibitor experienced HIV-1 infected patients should be basedon individual viral resistance testing and treatment history of patients (see sections 4.4 and 5.1).

Kaletra should be prescribed by physicians who are experienced in the treatment of HIV infection.

Adults and adolescents

The recommended dosage of Kaletra is 5 ml of oral solution (400/100 mg) twice daily taken withfood.

Paediatric population aged from 14 days and older

The oral solution formulation is the recommended option for the most accurate dosing in childrenbased on body surface area or body weight. However, if it is judged necessary to resort to solid oraldosage form for children weighing less than 40 kg or with a BSA between 0.5 and 1.4 m2 and able toswallow 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 andnot chewed, broken or crushed. Please refer to the Kaletra 100 mg/25 mg film-coated tablets

Summary of Product Characteristics.

Total amounts of alcohol and propylene glycol from all medicines, including Kaletra oral solution, thatare 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 guidelines2 weeks to 6 months

Based on weight Based on BSA (mg/m )* Frequency(mg/kg)16/4 mg/kg 300/75 mg/m2 Given twice daily(corresponding to 0.2 ml/kg) (corresponding to 3.75 ml/m2) 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 inpatients 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 Volume of oral solution(dose in mg/kg) twice daily taken with food(80 mg lopinavir/20 mgritonavir per ml)**7 to < 15 kg 12/3 mg/kg7 to 10 kg 1.25 ml> 10 to < 15 kg 1.75 ml≥ 15 to 40 kg 10/2.5 mg/kg15 to 20 kg 2.25 ml> 20 to 25 kg 2.75 ml> 25 to 30 kg 3.50 ml> 30 to 35 kg 4.00 ml> 35 to 40 kg 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

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

Body Surface Area* (m ) 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 withnevirapine or efavirenz. An increase of the dose of Kaletra to 300/75 mg/m2 is needed in thesepatients. 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 ofthe mother’s last menstrual period to birth plus the time elapsed after birth) of 42 weeks and apostnatal age of at least 14 days has been reached (see section 4.4).

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 section5.2). No data are available in patients with severe hepatic impairment. Kaletra must not be given tothese patients (see section 4.3).

Since the renal clearance of lopinavir and ritonavir is negligible, increased plasma concentrations arenot expected in patients with renal impairment. Because lopinavir and ritonavir are highly proteinbound, it is unlikely that they will be significantly removed by haemodialysis or peritoneal dialysis.

Kaletra is administered orally and should always be taken with food (see section 5.2). The doseshould be administered using a calibrated 2 ml or 5 ml oral dosing syringe best corresponding to thevolume prescribed.

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 CYP3Afor clearance and for which elevated plasma concentrations are associated with serious and/or lifethreatening events. These medicinal products include:

Medicinal product Medicinal products within Rationaleclass class

Concomitant medicinal product levels increased

Alpha1-adrenoreceptor Alfuzosin Increased plasma concentrations ofantagonist alfuzosin which may lead to severehypotension. The concomitantadministration with alfuzosin iscontraindicated (see section 4.5).

Antianginal Ranolazine Increased plasma concentrations ofranolazine which may increase thepotential for serious and/or life-threatening reactions (see section 4.5).

Antiarrhythmics Amiodarone, dronedarone Increased plasma concentrations ofamiodarone and dronedarone. Thereby,increasing the risk of arrhythmias orother serious adverse reactions (seesection 4.5).

Antibiotic Fusidic Acid Increased plasma concentrations offusidic acid. The concomitantadministration with fusidic acid iscontraindicated in dermatologicalinfections (see section 4.5).

Anticancer Neratinib Increased plasma concentrations ofneratinib which may increase thepotential for serious and/orlife-threatening reactions (see section4.5).

Venetoclax Increased plasma concentrations ofvenetoclax. Increased risk of tumor lysissyndrome at the dose initiation andduring the ramp-up phase (see section4.5).

Anti-gout Colchicine Increased plasma concentrations ofcolchicine. Potential for serious and/orlife-threatening reactions in patients withrenal and/or hepatic impairment (seesections 4.4 and 4.5).

Antihistamines Astemizole, terfenadine Increased plasma concentrations ofastemizole and terfenadine. Thereby,increasing the risk of seriousarrhythmias from these agents (seesection 4.5).

Antipsychotics/ Lurasidone Increased plasma concentrations of

Neuroleptics lurasidone which may increase thepotential for serious and/or life-threatening reactions (see section 4.5).

Pimozide Increased plasma concentrations ofpimozide. Thereby, increasing the riskof serious haematologic abnormalities,or other serious adverse effects from thisagent (see section 4.5).

Quetiapine Increased plasma concentrations ofquetiapine which may lead to coma. Theconcomitant administration withquetiapine is contraindicated (see section4.5).

Ergot alkaloids Dihydroergotamine, ergonovine, Increased plasma concentrations of ergotergotamine, methylergonovine derivatives leading to acute ergottoxicity, including vasospasm andischaemia (see section 4.5).

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

Hepatitis C virus Elbasvir/grazoprevir Increased risk of alanine transaminasedirect acting antivirals (ALT) elevations (see section 4.5).

Ombitasvir/paritaprevir/ritonavir Increased plasma concentrations ofwith or without dasabuvir paritaprevir; thereby, increasing the riskof alanine transaminase (ALT)elevations (see section 4.5).

Lipid-modifying agents

HMG Co-A Reductase Lovastatin, simvastatin Increased plasma concentrations of

Inhibitors lovastatin and simvastatin; thereby,increasing the risk of myopathyincluding rhabdomyolysis (see section4.5).

Microsomal Lomitapide Increased plasma concentrations oftriglyceride transfer lomitapide (see section 4.5).

protein (MTTP)inhibitor

Phosphodiesterase Avanafil Increased plasma concentrations of(PDE5) inhibitors avanafil (see sections 4.4 and 4.5).

Sildenafil Contraindicated when used for thetreatment of pulmonary arterialhypertension (PAH) only. Increasedplasma concentrations of sildenafil.

Thereby, increasing the potential forsildenafil-associated adverse events(which include hypotension andsyncope). See section 4.4 and section4.5 for co-administration of sildenafil inpatients with erectile dysfunction.

Vardenafil Increased plasma concentrations ofvardenafil (see sections 4.4 and 4.5)

Sedatives/hypnotics Oral midazolam, triazolam Increased plasma concentrations of oralmidazolam and triazolam. Thereby,increasing the risk of extreme sedationand respiratory depression from theseagents.

For caution on parenterally administeredmidazolam, see section 4.5.

Lopinavir/ritonavir medicinal product level decreased

Herbal products St. John’s wort Herbal preparations containing St John’swort (Hypericum perforatum) due to therisk of decreased plasma concentrationsand reduced clinical effects of lopinavirand ritonavir (see section 4.5).

Kaletra oral solution is contraindicated in children below the age of 14 days, pregnant women, patientswith hepatic or renal failure and patients treated with disulfiram or metronidazole due to the potentialrisk of toxicity from the excipient propylene glycol (see section 4.4).

Patients with coexisting conditions

The safety and efficacy of Kaletra has not been established in patients with significant underlying liverdisorders. 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 anincreased risk for severe and potentially fatal hepatic adverse reactions. In case of concomitantantiviral therapy for hepatitis B or C, please refer to the relevant product information for thesemedicinal products.

Patients with pre-existing liver dysfunction including chronic hepatitis have an increased frequency ofliver function abnormalities during combination antiretroviral therapy and should be monitoredaccording 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-1mono-infected and in individuals treated for post-exposure prophylaxis as early as 7 days after theinitiation of lopinavir/ritonavir in conjunction with other antiretroviral agents. In some cases thehepatic dysfunction was serious.

Appropriate laboratory testing should be conducted prior to initiating therapy with lopinavir/ritonavirand close monitoring should be performed during treatment.

Since the renal clearance of lopinavir and ritonavir is negligible, increased plasma concentrations arenot expected in patients with renal impairment. Because lopinavir and ritonavir are highly proteinbound, 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 andhaemarthrosis in patients with haemophilia type A and B treated with protease inhibitors. In somepatients additional factor VIII was given. In more than half of the reported cases, treatment withprotease inhibitors was continued or reintroduced if treatment had been discontinued. A causalrelationship 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.

Cases of pancreatitis have been reported in patients receiving Kaletra, including those who developedhypertriglyceridaemia. In most of these cases patients have had a prior history of pancreatitis and/orconcurrent therapy with other medicinal products associated with pancreatitis. Marked triglycerideelevation is a risk factor for development of pancreatitis. Patients with advanced HIV disease may beat risk of elevated triglycerides and pancreatitis.

Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) orabnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive ofpancreatitis 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).

In HIV-infected patients with severe immune deficiency at the time of institution of combinationantiretroviral therapy (CART), an inflammatory reaction to asymtomatic or residual opportunisticpathogens 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 andtreatment instituted when necessary.

Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) have also been reported tooccur in the setting of immune reconstitution; however, the reported time to onset is more variable andcan occur many months after initiation of treatment.

Although the etiology is considered to be multifactorial (including corticosteroid use, alcoholconsumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have beenreported particularly in patients with advanced HIV-disease and/or long-term exposure to combinationantiretroviral therapy (CART). Patients should be advised to seek medical advice if they experiencejoint 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 insome healthy adult subjects. Rare reports of 2nd or 3rd degree atroventricular block in patients withunderlying structural heart disease and pre-existing conduction system abnormalities or in patientsreceiving drugs known to prolong the PR interval (such as verapamil or atazanavir) have been reportedin patients receiving lopinavir/ritonavir. Kaletra should be used with caution in such patients (seesection 5.1).

An increase in weight and in levels of blood lipids and glucose may occur during antiretroviraltherapy. Such changes may in part be linked to disease control and life style. For lipids, there is insome cases evidence for a treatment effect, while for weight gain there is no strong evidence relatingthis to any particular treatment. For monitoring of blood lipids and glucose, reference is made toestablished HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

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 primarilymetabolised by CYP3A. These increases of plasma concentrations of co-administered medicinalproducts could increase or prolong their therapeutic effect and adverse events (see sections 4.3 and4.5).

Strong CYP3A4 inhibitors such as protease inhibitors may increase bedaquiline exposure which couldpotentially increase the risk of bedaquiline-related adverse reactions. Therefore, combination ofbedaquiline 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 frequentelectrocardiogram monitoring and monitoring of transaminases is recommended (see section 4.5 andrefer to the bedaquiline SmPC).

Co-administration of delamanid with a strong inhibitor of CYP3A (as lopinavir/ritonavir) mayincrease exposure to delamanid metabolite, which has been associated with QTc prolongation.

Therefore, if co-administration of delamanid with lopinavir/ritonavir is considered necessary, veryfrequent ECG monitoring throughout the full delamanid treatment period is recommended (see section4.5 and refer to the delamanid SmPC).

Life-threatening and fatal drug interactions have been reported in patients treated with colchicine andstrong inhibitors of CYP3A like ritonavir. Concomitant administration with colchicine iscontraindicated 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 isconsidered strictly necessary, the lowest possible dose of atorvastatin should be administered withcareful 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 isindicated, 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 erectiledysfunction in patients receiving Kaletra. Co-administration of Kaletra with these medicinal productsis expected to substantially increase their concentrations and may result in associated adverse eventssuch as hypotension, syncope, visual changes and prolonged erection (see section 4.5). Concomitantuse of avanafil or vardenafil and lopinavir/ritonavir is contraindicated (see section 4.3). Concomitantuse of sildenafil prescribed for the treatment of pulmonary arterial hypertension with Kaletra iscontraindicated (see section 4.3).

Particular caution must be used when prescribing Kaletra and medicinal products known to induce QTinterval prolongation such as: chlorpheniramine, quinidine, erythromycin, clarithromycin. Indeed,

Kaletra could increase concentrations of the co-administered medicinal products and this may result inan 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 currentlyruled 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 thelopinavir therapeutic effect. Adequate exposure to lopinavir/ritonavir may be achieved when a higherdose 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 treatmentoutweighs the risk of systemic corticosteroid effects, including Cushing’s syndrome and adrenalsuppression (see section 4.5).

Patients taking the oral solution, particularly those with renal impairment or with decreased ability tometabolise propylene glycol (e.g. those of Asian origin), should be monitored for adverse reactionspotentially related to propylene glycol toxicity (i.e. seizures, stupor, tachycardia, hyperosmolarity,lactic acidosis, renal toxicity, haemolysis) (see section 4.3).

Kaletra is not a cure for HIV infection or AIDS. People taking Kaletra may still develop infections orother illnesses associated with HIV disease and AIDS.

Besides propylene glycol as described above, Kaletra oral solution contains alcohol (42% v/v) whichis potentially harmful for those suffering from liver disease, alcoholism, epilepsy, brain injury ordisease as well as for pregnant women and children. It may modify or increase the effects of othermedicines. Kaletra oral solution contains up to 0.8 g of fructose per dose when taken according to thedosage recommendations. This may be unsuitable in hereditary fructose intolerance. Kaletra oralsolution contains up to 0.3 g of glycerol per dose. Only at high inadvertent doses, it can causeheadache and gastrointestinal upset. Furthermore, polyoxol 40 hydrogenated castor oil and potassiumpresent 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 contains42.4% alcohol (v/v) and 15.3% propylene glycol (w/v). Each 1 ml of Kaletra oral solution contains356.3 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 themedication order, dispensing information and dosing instructions to minimize the risk for medicationerrors 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 infantsshould be taken into account in order to avoid toxicity from these excipients. Infants should bemonitored closely for toxicity related to Kaletra oral solution including: hyperosmolality, with orwithout 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 andrespiratory complications leading to death have been reported, predominantly in preterm neonatesreceiving Kaletra oral solution (see sections 4.3 and 4.9).

Based on the findings in a paediatric study (observed exposures were approximately 35% AUC12 and75% lower Cmin than in adults), young children from 14 days to 3 months could have sub-optimalexposure with a potential risk of inadequate virologic suppression and emergence of resistance (seesection 5.2).

Because Kaletra oral solution contains alcohol, it is not recommended for use with polyurethanefeeding tubes due to potential incompatibility.

This medicine contains less than 1 mmol sodium (23 mg) per 1 ml, that is to say essentially ‘sodium-free’.

Kaletra contains lopinavir and ritonavir, both of which are inhibitors of the P450 isoform CYP3Ain vitro. Co-administration of Kaletra and medicinal products primarily metabolised by CYP3A mayresult in increased plasma concentrations of the other medicinal product, which could increase orprolong 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 ofsome medicinal products metabolised by cytochrome P450 enzymes (including CYP2C9 and

CYP2C19) and by glucuronidation. This may result in lowered plasma concentrations and potentialdecrease of efficacy of co-administered medicinal products.

Medicinal products that are contraindicated specifically due to the expected magnitude of interactionand potential for serious adverse events are listed in section 4.3.

Known and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinalproducts are listed in the table below. This list is not intended to be inclusive or comprehensive.

Individual SmPCs should be consulted.

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 oflopinavir/ritonavir (i.e. 400/100 mg twice daily).

Co-administered drug by Effects on drug levels Clinical recommendationtherapeutic area concerning co-administration

Geometric Mean Change (%) in with Kaletra

AUC, Cmax, Cmin

Mechanism of interaction

Antiretroviral Agents

Nucleoside/Nucleotide reverse transcriptase inhibitors (NRTIs)

Stavudine, Lamivudine Lopinavir: ↔ No dose adjustment necessary.

Abacavir, Zidovudine Abacavir, Zidovudine: The clinical significance of

Concentrations may be reduced reduced abacavir and zidovudinedue to increased glucuronidation concentrations is unknown.

by lopinavir/ritonavir.

Tenofovir disoproxil Tenofovir: No dose adjustment necessary.fumarate (DF), 300 mg QD AUC: ↑ 32% Higher tenofovir concentrations

Cmax: ↔ could potentiate tenofovir(equivalent to 245 mg Cmin: ↑ 51% associated adverse events,tenofovir disoproxil) including renal disorders.

Lopinavir: ↔

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Efavirenz, 600 mg QD Lopinavir: The Kaletra tablets dosage should

AUC: ↓ 20% be increased to 500/125 mg twice

Cmax: ↓ 13% daily when co-administered with

Cmin: ↓ 42% efavirenz.

Efavirenz, 600 mg QD

Lopinavir: ↔(Lopinavir/ritonavir (Relative to 400/100 mg BID500/125 mg BID) administered alone)

Nevirapine, 200 mg BID Lopinavir: The Kaletra tablets dosage should

AUC: ↓ 27% be increased to 500/125 mg twice

Cmax: ↓ 19% daily when co-administered with

Cmin: ↓ 51% nevirapine.

Etravirine Etravirine: No dose adjustment necessary

AUC: ↓ 35%(Lopinavir/ritonavir tablet Cmin: ↓ 45%400/100 mg BID) Cmax: ↓ 30%

Lopinavir:

AUC: ↔

Cmin: ↓ 20%

Cmax: ↔

Rilpivirine Rilpivirine: Concomitant use of Kaletra with

AUC: ↑ 52% rilpivirine causes an increase in the(Lopinavir/ritonavir C : ↑ 74% plasma concentrations ofmincapsule 400/100 mg BID) C : ↑ 29% rilpivirine, but no dose adjustmentmaxis required.

Lopinavir:

AUC: ↔

Cmin: ↓ 11%

Cmax: ↔(inhibition of CYP3A enzymes)

HIV CCR5 - antagonist

Maraviroc Maraviroc: The dose of maraviroc should be

AUC: ↑ 295% decreased to 150 mg twice daily

Cmax: ↑ 97% during co-administration with

Due to CYP3A inhibition by Kaletra 400/100 mg twice daily.

lopinavir/ritonavir.

Integrase inhibitor

Raltegravir Raltegravir: No dose adjustment necessary

AUC: ↔

Cmax: ↔

C12: ↓ 30%

Lopinavir: ↔

Co-administration with other HIV protease inhibitors (PIs)

According to current treatment guidelines, dual therapy with protease inhibitors is generally notrecommended.

Fosamprenavir/ ritonavir Fosamprenavir: Co-administration of increased(700/100 mg BID) Amprenavir concentrations are doses of fosamprenavir (1400 mgsignificantly reduced. BID) with Kaletra (533/133 mg(Lopinavir/ritonavir BID) to protease400/100 mg BID) inhibitor-experienced patientsresulted in a higher incidence ofor gastrointestinal adverse events andelevations in triglycerides with the

Fosamprenavir (1400 mg combination regimen without

BID) increases in virological efficacy,when compared with standard(Lopinavir/ritonavir doses of fosamprenavir/ritonavir.533/133 mg BID) Concomitant administration ofthese medicinal products is notrecommended.

Indinavir, 600 mg BID Indinavir: The appropriate doses for this

AUC: ↔ combination, with respect to

Cmin: ↑ 3.5-fold efficacy and safety, have not been

Cmax: ↓ established.(relative to indinavir 800 mg TIDalone)

Lopinavir: ↔(relative to historical comparison)

Saquinavir Saquinavir: ↔ No dose adjustment necessary.

1000 mg BID

Tipranavir/ritonavir Lopinavir: Concomitant administration of(500/100 mg BID) AUC: ↓ 55% these medicinal products is not

Cmin: ↓ 70% recommended.

Cmax: ↓ 47%

Acid reducing agents

Omeprazole (40 mg QD) Omeprazole: ↔ No dose adjustment necessary

Lopinavir: ↔

Ranitidine (150 mg single Ranitidine: ↔ No dose adjustment necessarydose)

Alpha1 adrenoreceptor antagonist

Alfuzosin Alfuzosin: Concomitant administration of

Due to CYP3A inhibition by Kaletra and alfuzosin is contra-lopinavir/ritonavir, concentrations indicated (see section 4.3) asof alfuzosin are expected to alfuzosin-related toxicity,increase. including hypotension, may beincreased.

Analgesics

Fentanyl Fentanyl: Careful monitoring of adverse

Increased risk of side-effects effects (notably respiratory(respiratory depression, sedation) depression but also sedation) isdue to higher plasma recommended when fentanyl isconcentrations because of concomitantly administered with

CYP3A4 inhibition by Kaletra.lopinavir/ritonavir.

Antianginal

Ranolazine Due to CYP3A inhibition by The concomitant administration oflopinavir/ritonavir, concentrations Kaletra and ranolazine isof ranolazine are expected to contraindicated (see section 4.3).

increase.

Antiarrhythmics

Amiodarone, Dronedarone Amiodarone, Dronedarone: Concomitant administration of

Concentrations may be increased Kaletra and amiodarone ordue to CYP3A4 inhibition by dronedarone is contraindicated (seelopinavir/ritonavir. section 4.3) as the risk ofarrhythmias or other seriousadverse reactions may beincreased.

Digoxin Digoxin: Caution is warranted and

Plasma concentrations may be therapeutic drug monitoring ofincreased due to P-glycoprotein digoxin concentrations, ifinhibition by lopinavir/ritonavir. available, is recommended in case

The increased digoxin level may of co-administration of Kaletra andlessen over time as P-gp digoxin. Particular caution shouldinduction develops. be used when prescribing Kaletrain patients taking digoxin as theacute inhibitory effect of ritonaviron P-gp is expected to significantlyincrease digoxin levels. Initiationof digoxin in patients alreadytaking Kaletra is likely to result inlower than expected increases ofdigoxin concentrations.

Bepridil, Systemic Bepridil, Systemic Lidocaine, Caution is warranted and

Lidocaine, and Quinidine Quinidine: therapeutic drug concentration

Concentrations may be increased monitoring is recommended whenwhen co-administered with available.lopinavir/ritonavir.

Antibiotics

Clarithromycin Clarithromycin: For patients with renal impairment

Moderate increases in (CrCL < 30 ml/min) dose reductionclarithromycin AUC are expected of clarithromycin should bedue to CYP3A inhibition by considered (see section 4.4).

lopinavir/ritonavir. Caution should be exercised inadministering clarithromycin with

Kaletra to patients with impairedhepatic or renal function.

Anticancer agents and kinase inhibitors

Abemaciclib Serum concentrations may be Co-administration of abemaciclibincreased due to CYP3A and Kaletra should be avoided. Ifinhibition by ritonavir. this co-administration is judgedunavoidable, refer to theabemaciclib SmPC for dosageadjustment recommendations.

Monitor for ADRs related toabemaciclib.

Apalutamide Apalutamide is a moderate to Decreased exposure of Kaletra maystrong CYP3A4 inducer and this result in potential loss ofmay lead to a decreased exposure virological response.of lopinavir/ritonavir. In addition, co-administration ofapalutamide and Kaletra may lead

Serum concentrations of to serious adverse events includingapalutamide may be increased seizure due to higher apalutamidedue to CYP3A inhibition by levels. Concomitant use of Kaletralopinavir/ritonavir. with apalutamide is notrecommended.

Afatinib Afatinib: Caution should be exercised in

AUC: ↑ administering afatinib with Kaletra.

(Ritonavir 200 mg twice Cmax: ↑ Refer to the afatinib SmPC fordaily) dosage adjustment

The extent of increase depends on recommendations. Monitor forthe timing of ritonavir ADRs related to afatinib.

administration.

Due to BCRP (breast cancerresistance protein/ABCG2) andacute P-gp inhibition bylopinavir/ritonavir.

Ceritinib Serum concentrations may be Caution should be exercised inincreased due to CYP3A and administering ceritinib with

P-gp inhibition by Kaletra. Refer to the ceritiniblopinavir/ritonavir. SmPC for dosage adjustmentrecommendations. Monitor for

ADRs related to ceritinib.

Most tyrosine kinase Most tyrosine kinase inhibitors Careful monitoring of the toleranceinhibitors such as dasatinib such as dasatinib and nilotinib, of these anticancer agents.and nilotinib, vincristine, also vincristine and vinblastine:

vinblastine Risk of increased adverse eventsdue to higher serumconcentrations because of

CYP3A4 inhibition bylopinavir/ritonavir.

Encorafenib Serum concentrations may be Co-administration of encorafenibincreased due to CYP3A with Kaletra may increaseinhibition by lopinavir/ritonavir. encorafenib exposure which mayincrease the risk of toxicity,including the risk of seriousadverse events such as QT intervalprolongation. Co-administration ofencorafenib and Kaletra should beavoided. If the benefit isconsidered to outweigh the risk and

Kaletra must be used, patientsshould be carefully monitored forsafety.

Fostamatinib Increase in fostamatinib Co-administration of fostamatinibmetabolite R406 exposure. with Kaletra may increasefostamatinib metabolite R406exposure resulting in dose-relatedadverse events such ashepatotoxicity, neutropenia,hypertension, or diarrhoea. Referto the fostamatinib SmPC for dosereduction recommendations if suchevents occur.

Ibrutinib Serum concentrations may be Co-administration of ibrutinib andincreased due to CYP3A Kaletra may increase ibrutinibinhibition by lopinavir/ritonavir. exposure which may increase therisk of toxicity including risk oftumor lysis syndrome.

Co-administration of ibrutinib and

Kaletra should be avoided. If thebenefit is considered to outweighthe risk and Kaletra must be used,reduce the ibrutinib dose to 140 mgand monitor patient closely fortoxicity.

Neratinib Serum concentrations may be Concomitant use of neratinib withincreased due to CYP3A Kaletra is contraindicated due toinhibition by ritonavir. serious and/or life-threateningpotential reactions includinghepatotoxicity (see section 4.3).

Venetoclax Due to CYP3A inhibition by Serum concentrations may belopinavir/ritonavir. increased due to CYP3A inhibitionby lopinavir/ritonavir, resulting inincreased risk of tumor lysissyndrome at the dose initiation andduring the ramp-up phase (seesection 4.3 and refer to thevenetoclax SmPC).

For patients who have completedthe ramp-up phase and are on asteady daily dose of venetoclax,reduce the venetoclax dose by atleast 75% when used with strong

CYP3A inhibitors (refer to thevenetoclax SmPC for dosinginstructions). Patients should beclosely monitored for signs relatedto venetoclax toxicities.

Anticoagulants

Warfarin Warfarin: It is recommended that INR

Concentrations may be affected (international normalised ratio) bewhen co-administered with monitored.

lopinavir/ritonavir due to

CYP2C9 induction.

Rivaroxaban Rivaroxaban: Co-administration of rivaroxaban

AUC: ↑ 153% and Kaletra may increase(Ritonavir 600 mg twice Cmax: ↑ 55% rivaroxaban exposure which maydaily) Due to CYP3A and P-gp increase the risk of bleeding.inhibition by lopinavir/ritonavir. The use of rivaroxaban is notrecommended in patients receivingconcomitant treatment with

Kaletra (see section 4.4).

Dabigatran etexilate, Dabigatran etexilate, Clinical monitoring and/or dose

Edoxaban Edoxaban: reduction of the direct oral

Serum concentrations may be anticoagulants (DOAC) should beincreased due to P-gp inhibition considered when a DOACby lopinavir/ritonavir. transported by P-gp but notmetabolised by CYP3A4,including dabigatran etexilate andedoxaban, is co-administered with

Kaletra.

Vorapaxar Serum concentrations may be The co-administration ofincreased due to CYP3A vorapaxar with Kaletra is notinhibition by lopinavir/ritonavir. recommended (see section 4.4 andrefer to the vorapaxar SmPC).

Anticonvulsants

Phenytoin Phenytoin: Caution should be exercised in

Steady-state concentrations was administering phenytoin withmoderately decreased due to Kaletra.

CYP2C9 and CYP2C19 inductionby lopinavir/ritonavir. Phenytoin levels should bemonitored when co-administering

Lopinavir: with Kaletra.

Concentrations are decreased dueto CYP3A induction by When co-administered withphenytoin. phenytoin, an increase of Kaletradosage may be envisaged. Doseadjustment has not been evaluatedin clinical practice.

Carbamazepine and Carbamazepine: Caution should be exercised in

Phenobarbital Serum concentrations may be administering carbamazepine orincreased due to CYP3A phenobarbital with Kaletra.inhibition by lopinavir/ritonavir.

Lopinavir: Carbamazepine and phenobarbital

Concentrations may be decreased levels should be monitored whendue to CYP3A induction by co-administering with Kaletra.

carbamazepine and phenobarbital.

When co-administered withcarbamazepine or phenobarbital, anincrease of Kaletra dosage may beenvisaged. Dose adjustment hasnot been evaluated in clinicalpractice

Lamotrigine and Valproate Lamotrigine: Patients should be monitored

AUC: ↓ 50% closely for a decreased VPA effect

Cmax: ↓ 46% when Kaletra and valproic acid or

Cmin: ↓ 56% valproate are given concomitantly.

Due to induction of lamotrigine In patients starting or stoppingglucuronidation Kaletra while currently takingmaintenance dose of lamotrigine:

Valproate: ↓ lamotrigine dose may need to beincreased if Kaletra is added, ordecreased if Kaletra isdiscontinued; therefore plasmalamotrigine monitoring should beconducted, particularly before andduring 2 weeks after starting orstopping Kaletra, in order to see iflamotrigine dose adjustment isneeded.

In patients currently taking Kaletraand starting lamotrigine: no doseadjustments to the recommendeddose escalation of lamotrigineshould be necessary.

Antidepressants and Anxiolytics

Trazodone single dose Trazodone: It is unknown whether the

AUC: ↑ 2.4-fold combination of Kaletra causes a(Ritonavir, 200 mg BID) similar increase in trazodone

Adverse events of nausea, exposure. The combination shoulddizziness, hypotension and be used with caution and a lowersyncope were observed following dose of trazodone should beco-administration of trazodone considered.

and ritonavir.

Antifungals

Ketoconazole and Ketoconazole, Itraconazole: High doses of ketoconazole and

Itraconazole Serum concentrations may be itraconazole (> 200 mg/day) areincreased due to CYP3A not recommended.

inhibition by lopinavir/ritonavir.

Voriconazole Voriconazole: Co-administration of voriconazole

Concentrations may be decreased. and low dose ritonavir (100 mg

BID) as contained in Kaletrashould be avoided unless anassessment of the benefit/risk topatient justifies the use ofvoriconazole.

Anti-gout agents

Colchicine single dose Colchicine: Concomitant administration of

AUC: ↑ 3-fold Kaletra with colchicine in patients(Ritonavir 200 mg twice Cmax: ↑ 1.8-fold with renal and/or hepaticdaily) Due to P-gp and/or CYP3A4 impairment is contraindicated dueinhibition by ritonavir. to a potential increase ofcolchicine-related serious and/orlife-threatening reactions such asneuromuscular toxicity (includingrhabdomyolysis) (see sections 4.3and 4.4). A reduction in colchicinedosage or an interruption ofcolchicine treatment isrecommended in patients withnormal renal or hepatic function iftreatment with Kaletra is required.

Refer to colchicine prescribinginformation.

Antihistamines

Astemizole Serum concentrations may be Concomitant administration of

Terfenadine increased due to CYP3A Kaletra and astemizole andinhibition by lopinavir/ritonavir. terfenadine is contraindicated as itmay increase the risk of seriousarrhythmias from these agents (seesection 4.3).

Anti-infectives

Fusidic acid Fusidic acid: Concomitant administration of

Concentrations may be increased Kaletra with fusidic acid is contra-due to CYP3A inhibition by indicated in dermatologicallopinavir/ritonavir. indications due to the increasedrisk of adverse events related tofusidic acid, notablyrhabdomyolysis (see section 4.3).

When used for osteo-articularinfections, where the co-administration is unavoidable,close clinical monitoring formuscular adverse events isstrongly recommended (see section4.4).

Antimycobacterials

Bedaquiline Bedaquiline: Due to the risk of bedaquiline(single dose) AUC: ↑ 22% related adverse events, the

Cmax: ↔ combination of bedaquiline and(Lopinavir/ritonavir Kaletra should be avoided. If the400/100 mg BID, multiple A more pronounced effect on benefit outweighs the risk,dose) bedaquiline plasma exposures co-administration of bedaquilinemay be observed during with Kaletra must be done withprolonged co-administration with caution. More frequentlopinavir/ritonavir. electrocardiogram monitoring andmonitoring of transaminases is

CYP3A4 inhibition likely due to recommended (see section 4.4 andlopinavir/ritonavir. refer to the bedaquiline SmPC).

Delamanid (100 mg BID) Delamanid: Due to the risk of QTc prolongation

AUC: ↑ 22% associated with DM-6705, if(Lopinavir/ritonavir co-administration of delamanid400/100 mg BID) DM-6705 (delamanid active with Kaletra is consideredmetabolite): necessary, very frequent ECG

AUC: ↑ 30% monitoring throughout the fulldelamanid treatment period is

A more pronounced effect on recommended (see section 4.4 and

DM-6705 exposure may be refer to the delamanid SmPC).

observed during prolonged co-administration withlopinavir/ritonavir.

Rifabutin, 150 mg QD Rifabutin (parent drug and active When given with Kaletra the25-O-desacetyl metabolite): recommended dose of rifabutin is

AUC: ↑ 5.7-fold 150 mg 3 times per week on set

Cmax: ↑ 3.5-fold days (for example Monday-

Wednesday-Friday). Increasedmonitoring for rifabutin-associatedadverse reactions includingneutropenia and uveitis iswarranted due to an expectedincrease in exposure to rifabutin.

Further dosage reduction ofrifabutin to 150 mg twice weeklyon set days is recommended forpatients in whom the 150 mg dose 3times per week is not tolerated. Itshould be kept in mind that thetwice weekly dosage of 150 mgmay not provide an optimalexposure to rifabutin thus leading toa risk of rifamycin resistance and atreatment failure. No doseadjustment is needed for Kaletra.

Rifampicin Lopinavir: Co-administration of Kaletra with

Large decreases in lopinavir rifampicin is not recommended asconcentrations may be observed the decrease in lopinavirdue to CYP3A induction by concentrations may in turnrifampicin. significantly decrease the lopinavirtherapeutic effect. A doseadjustment of Kaletra400 mg/400 mg (i.e. Kaletra400/100 mg + ritonavir 300 mg)twice daily has allowedcompensating for the CYP 3A4inducer effect of rifampicin.

However, such a dose adjustmentmight be associated with ALT/ASTelevations and with increase ingastrointestinal disorders.

Therefore, this co-administrationshould be avoided unless judgedstrictly necessary. If thisco-administration is judgedunavoidable, increased dose of

Kaletra at 400 mg/400 mg twicedaily may be administered withrifampicin under close safety andtherapeutic drug monitoring. The

Kaletra dose should be titratedupward only after rifampicin hasbeen initiated (see section 4.4).

Antipsychotics

Lurasidone Due to CYP3A inhibition by The concomitant administrationlopinavir/ritonavir, with lurasidone is contraindicatedconcentrations of lurasidone are (see section 4.3).

expected to increase.

Pimozide Due to CYP3A inhibition by Concomitant administration oflopinavir/ritonavir, Kaletra and pimozide isconcentrations of pimozide are contraindicated as it may increaseexpected to increase. the risk of serious haematologicabnormalities or other seriousadverse effects from this agent (seesection 4.3)

Quetiapine Due to CYP3A inhibition by Concomitant administration oflopinavir/ritonavir, Kaletra and quetiapine isconcentrations of quetiapine are contraindicated as it may increaseexpected to increase. quetiapine-related toxicity.

Benzodiazepines

Midazolam Oral Midazolam: Kaletra must not be co-administered

AUC: ↑ 13-fold with oral midazolam (see section

Parenteral Midazolam: 4.3), whereas caution should be

AUC: ↑ 4-fold used with co-administration of

Due to CYP3A inhibition by Kaletra and parenteral midazolam.lopinavir/ritonavir If Kaletra is co-administered withparenteral midazolam, it should bedone in an intensive care unit (ICU)or similar setting which ensuresclose clinical monitoring andappropriate medical management incase of respiratory depressionand/or prolonged sedation. Dosageadjustment for midazolam should beconsidered especially if more than asingle dose of midazolam isadministered.

Beta2-adrenoceptor agonist (long acting)

Salmeterol Salmeterol: The combination may result in

Concentrations are expected to increased risk of cardiovascularincrease due to CYP3A inhibition adverse events associated withby lopinavir/ritonavir. salmeterol, including QTprolongation, palpitations andsinus tachycardia.

Therefore, concomitantadministration of Kaletra withsalmeterol is not recommended(see section 4.4).

Calcium channel blockers

Felodipine, Nifedipine, and Felodipine, Nifedipine, Clinical monitoring of therapeutic

Nicardipine Nicardipine: and adverse effects is

Concentrations may be increased recommended when thesedue to CYP3A inhibition by medicines are concomitantlylopinavir/ritonavir. administered with Kaletra.

Dexamethasone Lopinavir: Clinical monitoring of antiviral

Concentrations may be decreased efficacy is recommended whendue to CYP3A induction by these medicines are concomitantlydexamethasone. administered with Kaletra.

Inhaled, injectable or Fluticasone propionate, 50 g Greater effects may be expectedintranasal fluticasone intranasal 4 times daily: when fluticasone propionate ispropionate, budesonide, Plasma concentrations ↑ inhaled. Systemic corticosteroidtriamcinolone Cortisol levels ↓ 86% effects including Cushing'ssyndrome and adrenal suppressionhave been reported in patientsreceiving ritonavir and inhaled orintranasally administeredfluticasone propionate; this couldalso occur with othercorticosteroids metabolised via the

P450 3A pathway e.g. budesonideand triamcinolone. Consequently,concomitant administration of

Kaletra and these glucocorticoidsis not recommended unless thepotential benefit of treatmentoutweighs the risk of systemiccorticosteroid effects (see section4.4). A dose reduction of theglucocorticoid should beconsidered with close monitoringof local and systemic effects or aswitch to a glucocorticoid, whichis not a substrate for CYP3A4 (e.g.

beclomethasone). Moreover, incase of withdrawal ofglucocorticoids progressive dosereduction may have to beperformed over a longer period.

Phosphodiesterase(PDE5) inhibitors

Avanafil Avanafil: The use of avanafil with Kaletra is(ritonavir 600 mg BID) AUC: ↑ 13-fold contraindicated (see section 4.3).

Due to CYP3A inhibition bylopinavir/ritonavir.

Tadalafil Tadalafil: For the treatment of pulmonary

AUC: ↑ 2-fold arterial hypertension:

Due to CYP3A4 inhibition by Co-administration of Kaletra withlopinavir/ritonavir. sildenafil is contraindicated (seesection 4.3). Co-administration of

Sildenafil Sildenafil: Kaletra with tadalafil is not

AUC: ↑ 11-fold recommended.

Due to CYP3A inhibition bylopinavir/ritonavir. For erectile dysfunction:

Particular caution must be usedwhen prescribing sildenafil ortadalafil in patients receiving

Kaletra with increased monitoringfor adverse events includinghypotension, syncope, visualchanges and prolonged erection(see section 4.4).

When co-administered with

Kaletra, sildenafil doses must notexceed 25 mg in 48 hours andtadalafil doses must not exceed10 mg every 72 hours

Vardenafil Vardenafil: The use of vardenafil with Kaletra

AUC: ↑ 49-fold is contraindicated (see section 4.3).

Due to CYP3A inhibition bylopinavir/ritonavir.

Ergot alkaloids

Dihydroergotamine, Serum concentrations may be Concomitant administration ofergonovine, ergotamine, increased due to CYP3A Kaletra and ergot alkaloids aremethylergonovine inhibition by lopinavir/ritonavir. contraindicated as it may lead toacute ergot toxicity, includingvasospasm and ischaemia (seesection 4.3).

GI motility agent

Cisapride Serum concentrations may be Concomitant administration ofincreased due to CYP3A Kaletra and cisapride isinhibition by lopinavir/ritonavir. contraindicated as it may increasethe risk of serious arrhythmiasfrom this agent (see section 4.3).

HCV direct acting antivirals

Elbasvir/grazoprevir Elbasvir: Concomitant administration of(50/200 mg QD) AUC: ↑ 2.71-fold elbasvir/grazoprevir with Kaletra

Cmax: ↑ 1.87-fold is contraindicated (see section

C24: ↑ 3.58-fold 4.3).

AUC: ↑ 11.86-fold

Cmax: ↑ 6.31-fold

C24: ↑ 20.70-fold(combinations of mechanismsincluding CYP3A inhibition)

Lopinavir: ↔

Glecaprevir/pibrentasvir Serum concentrations may be Concomitant administration ofincreased due to P-glycoprotein, glecaprevir/pibrentasvir and

BCRP and OATP1B inhibition by Kaletra is not recommended duelopinavir/ritonavir. to an increased risk of ALTelevations associated withincreased glecaprevir exposure.

Ombitasvir/paritaprevir/rito Ombitasvir: ↔ Co-administration isnavir + dasabuvir contraindicated.

Paritaprevir:(25/150/100 mg QD + AUC: ↑ 2.17-fold Lopinavir/ritonavir 800/200 mg400 mg BID) Cmax: ↑ 2.04-fold QD was administered with

Ctrough: ↑ 2.36-fold ombitasvir/paritaprevir/ritonavir

Lopinavir/ritonavir with or without dasabuvir. The400/100 mg BID (inhibition of CYP3A/efflux effect on DAAs and lopinavir wastransporters) similar to that observed whenlopinavir/ritonavir 400/100 mg

Dasabuvir: ↔ BID was administered (seesection 4.3).

Lopinavir: ↔

Ombitasvir/paritaprevir/ Ombitasvir: ↔ritonavir

Paritaprevir:

(25/150/100 mg QD) AUC: ↑ 6.10-fold

Cmax: ↑ 4.76-fold

Lopinavir/ritonavir Ctrough: ↑ 12.33-fold400/100 mg BID(inhibition of CYP3A/effluxtransporters)

Lopinavir: ↔

Sofosbuvir/velpatasvir/ Serum concentrations of It is not recommended tovoxilaprevir sofosbuvir, velpatasvir and co-administer Kaletra andvoxilaprevir may be increased due sofosbuvir/velpatasvir/to P-glycoprotein, BCRP and voxilaprevir.

OATP1B1/3 inhibition bylopinavir/ritonavir. However,only the increase in voxilaprevirexposure is considered clinicallyrelevant.

HCV protease inhibitors

Simeprevir 200 mg daily Simeprevir: It is not recommended to(ritonavir 100 mg BID) AUC: ↑ 7.2-fold co-administer Kaletra and

Cmax: ↑ 4.7-fold simeprevir.

Cmin: ↑ 14.4-fold

Herbal products

St John’s wort (Hypericum Lopinavir: Herbal preparations containing Stperforatum) Concentrations may be reduced John’s wort must not be combineddue to induction of CYP3A by the with lopinavir and ritonavir. If aherbal preparation St John’s wort. patient is already taking St John’swort, stop St John’s wort and ifpossible check viral levels.

Lopinavir and ritonavir levels mayincrease on stopping

St John’s wort. The dose of

Kaletra may need adjusting. Theinducing effect may persist for atleast 2 weeks after cessation oftreatment with St John’s wort (seesection 4.3). Therefore, Kaletracan be started safely 2 weeks aftercessation of St John's wort.

Immunosuppressants

Cyclosporin, Sirolimus Cyclosporin, Sirolimus More frequent therapeutic(rapamycin), and (rapamycin), Tacrolimus: concentration monitoring is

Tacrolimus Concentrations may be increased recommended until plasma levelsdue to CYP3A inhibition by of these products have beenlopinavir/ritonavir. stabilised.

Lipid lowering agents

Lovastatin and Simvastatin Lovastatin, Simvastatin: Since increased concentrations of

Markedly increased plasma HMG-CoA reductase inhibitorsconcentrations due to CYP3A may cause myopathy, includinginhibition by lopinavir/ritonavir. rhabdomyolysis, the combinationof these agents with Kaletra iscontraindicated (see section 4.3).

Lipid-modifying agents

Lomitapide CYP3A4 inhibitors increase the Concomitant use of Kaletra withexposure of lomitapide, with lomitapide is contraindicated (seestrong inhibitors increasing prescribing information forexposure approximately 27-fold. lomitapide) (see section 4.3).

Due to CYP3A inhibition bylopinavir/ritonavir, concentrationsof lomitapide are expected toincrease.

Atorvastatin Atorvastatin: The combination of Kaletra with

AUC: ↑ 5.9-fold atorvastatin is not recommended.

Cmax: ↑ 4.7-fold If the use of atorvastatin is

Due to CYP3A inhibition by considered strictly necessary, thelopinavir/ritonavir. lowest possible dose ofatorvastatin should beadministered with careful safetymonitoring (see section 4.4).

Rosuvastatin, 20 mg QD Rosuvastatin: Caution should be exercised and

AUC: ↑ 2-fold reduced doses should be

Cmax: ↑ 5-fold considered when Kaletra is

While rosuvastatin is poorly co-administered with rosuvastatinmetabolised by CYP3A4, an (see section 4.4).increase of its plasmaconcentrations was observed.

The mechanism of this interactionmay result from inhibition oftransport proteins.

Fluvastatin or Pravastatin Fluvastatin, Pravastatin: If treatment with an HMG-CoA

No clinical relevant interaction reductase inhibitor is indicated,expected. fluvastatin or pravastatin is

Pravastatin is not metabolised by recommended.

CYP450.

Fluvastatin is partiallymetabolised by CYP2C9.

Opioids

Buprenorphine, 16 mg QD Buprenorphine: ↔ No dose adjustment necessary.

Methadone Methadone: ↓ Monitoring plasma concentrationsof methadone is recommended.

Ethinyl Oestradiol Ethinyl Oestradiol: ↓ In case of co-administration of

Kaletra with contraceptivescontaining ethinyl oestradiol(whatever the contraceptiveformulation e.g. oral or patch),additional methods ofcontraception must be used.

Smoking cessation aids

Bupropion Buproprion and its active If the co-administration of Kaletrametabolite, hydroxybupropion: with bupropion is judged

AUC and Cmax ↓ ~50% unavoidable, this should be doneunder close clinical monitoring for

This effect may be due to bupropion efficacy, withoutinduction of bupropion exceeding the recommendedmetabolism. dosage, despite the observedinduction.

Thyroid hormone replacement therapy

Levothyroxine Post-marketing cases have been Thyroid-stimulating hormonereported indicating a potential (TSH) should be monitored ininteraction between ritonavir patients treated with levothyroxinecontaining products and at least the first month afterlevothyroxine. starting and/or endinglopinavir/ritonavir treatment.

Vasodilating agents

Bosentan Lopinavir - ritonavir: Caution should be exercised in

Lopinavir/ritonavir plasma administering Kaletra withconcentrations may decrease due bosentan.

to CYP3A4 induction by When Kaletra is administeredbosentan. concomitantly with bosentan, theefficacy of the HIV therapy should

Bosentan: be monitored and patients should

AUC: ↑ 5-fold be closely observed for bosentan

Cmax: ↑ 6-fold toxicity, especially during the first

Initially, bosentan Cmin: ↑ by week of co-administration.

approximately 48-fold.

Due to CYP3A4 inhibition bylopinavir/ritonavir.

Riociguat Serum concentrations may be The co-administration of riociguatincreased due to CYP3A and with Kaletra is not recommended

P-gp inhibition by (see section 4.4 and refer tolopinavir/ritonavir. 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.

As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection inpregnant 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 inorder to characterise the safety for the foetus.

Lopinavir/ritonavir has been evaluated in over 3000 women during pregnancy, including over 1000during 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 amongover 1000 women exposed during the first trimester. The prevalence of birth defects after anytrimester 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 shownreproductive toxicity (see section 5.3). Based on the data mentioned, the malformative risk is unlikelyin humans. Lopinavir can be used during pregnancy if clinically needed.

Studies in rats revealed that lopinavir is excreted in the milk. It is not known whether this medicinalproduct is excreted in human milk. As a general rule, it is recommended that women living with HIVdo not breast-feed their babies in order to avoid transmission of HIV.

Animal studies have shown no effects on fertility. No human data on the effect of lopinavir/ritonaviron fertility are available.

No studies on the effects on the ability to drive and use machines have been performed. Patientsshould be informed that nausea has been reported during treatment with Kaletra (see section 4.8).

Kaletra oral solution contains approximately 42% v/v alcohol.

The safety of Kaletra has been investigated in over 2600 patients in Phase II-IV clinical trials, ofwhich over 700 have received a dose of 800/200 mg (6 capsules or 4 tablets) once daily. Along withnucleoside reverse transcriptase inhibitors (NRTIs), in some studies, Kaletra was used in combinationwith 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 vomitingmay occur at the beginning of the treatment while hypertriglyceridaemia and hypercholesterolemiamay occur later. Treatment emergent adverse events led to premature study discontinuation for 7% ofsubjects 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 havebeen reported during Kaletra therapy (see section 4.4).

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 allreported events of moderate to severe intensity, regardless of the individual causality assessment. Theadverse reactions are displayed by system organ class. Within each frequency grouping, undesirableeffects are presented in order of decreasing seriousness: very common (≥1/10), common (≥ 1/100to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥1/10,000 to <1/1000) and not known (cannot beestimated 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, skininfections including cellulitis, folliculitis andfuruncle

Blood and lymphatic system Common Anaemia, leucopenia, neutropenia,disorders lymphadenopathy

Immune system disorders Common Hypersensitivity including urticaria andangioedema

Uncommon Immune reconstitution inflammatorysyndrome

Endocrine disorders Uncommon Hypogonadism

Metabolism and nutrition Common Blood glucose disorders including diabetesdisorders 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 valveincompetence

Vascular disorders Common Hypertension

Uncommon Deep vein thrombosis

Gastrointestinal disorders Very common Diarrhoea, nausea

Common Pancreatitis1, vomiting, gastrooesophagealreflux disease, gastroenteritis and colitis,abdominal pain (upper and lower), abdominaldistension, dyspepsia, haemorrhoids,flatulence

Uncommon Gastrointestinal haemorrhage includinggastrointestinal ulcer, duodenitis, gastritis andrectal haemorrhage, stomatitis and oral ulcers,faecal incontinence, constipation, dry mouth

Hepatobiliary disorders Common Hepatitis including AST, ALT and GGTincreases

Uncommon Jaundice, hepatic steatosis, hepatomegaly,cholangitis, hyperbilirubinemia

Skin and subcutaneous tissue Common Rash including maculopapular rash,disorders dermatitis/rash including eczema andseborrheic dermatitis, night sweats, pruritus

Uncommon Alopecia, capillaritis, vasculitis

Rare Steven-Johnson syndrome, erythemamultiforme

Musculoskeletal and Common Myalgia, musculoskeletal pain includingconnective tissue disorders arthralgia and back pain, muscle disorderssuch as weakness and spasms

Uncommon Rhabdomyolysis, osteonecrosis

Renal and urinary disorders Uncommon Creatinine clearance decreased, nephritis,haematuria

Not known Nephrolithiasis

Reproductive system and breast Common Erectile dysfunction, menstrual disorders -disorders amenorrhoea, menorrhagia

General disorders and Common Fatigue including astheniaadministration site conditions1 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 intranasallyadministered fluticasone propionate; this could also occur with other corticosteroids metabolised viathe P450 3A pathway e.g. budesonide (see section 4.4 and 4.5).

Increased creatine phosphokinase (CPK), myalgia, myositis, and rarely, rhabdomyolysis have beenreported with protease inhibitors, particularly in combination with nucleoside reverse transcriptaseinhibitors.

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section4.4).

In HIV-infected patients with severe immune deficiency at the time of initiation of combinationantiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunisticinfections may arise. Autoimmune disorders (such as Graves’ disease and autoimmune hepatitis) havealso been reported; however, the reported time to onset is more variable and can occur many monthsafter initiation of treatment (see section 4.4).

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged riskfactors, 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 suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

To date, there is limited human experience of acute overdose with Kaletra.

Overdoses with Kaletra oral solution have been reported (including fatal outcome). The followingevents have been reported in association with unintended overdoses in preterm neonates: completeatrioventricular 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 toconsist of general supportive measures including monitoring of vital signs and observation of theclinical status of the patient. If indicated, elimination of unabsorbed active substance is to be achievedby emesis or gastric lavage. Administration of activated charcoal may also be used to aid in removalof unabsorbed active substance. Since Kaletra is highly protein bound, dialysis is unlikely to bebeneficial in significant removal of the active substance.

However, dialysis can remove both alcohol and propylene glycol in the case of overdose with Kaletraoral solution.

Pharmaco-therapeutic group: antivirals for systemic use, antivirals for treatment of HIV infections,combinations, ATC code: J05AR10

Lopinavir provides the antiviral activity of Kaletra. Lopinavir is an inhibitor of the HIV-1 and HIV-2proteases. Inhibition of HIV protease prevents cleavage of the gag-pol polyprotein resulting in theproduction 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. Themaximum mean (95% upper confidence bound) differences in QTcF from placebo were 3.6 (6.3) and13.1(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 doselopinavir/ritonavir (800/200 mg twice daily) contributes to QT prolongation. The two regimensresulted in exposures on Day 3 which were approximately 1.5 and 3-fold higher than those observedwith recommended once daily or twice daily LPV/r doses at steady state. No subject experienced anincrease in QTcF of  60 ms from baseline or a QTcF interval exceeding the potentially clinicallyrelevant threshold of 500 ms.

Modest prolongation of the PR interval was also noted in subjects receiving lopinavir/ritonavir in thesame study on Day 3. The mean changes from baseline in PR interval ranged from 11.6 ms to 24.4 msin the 12 hour interval post dose. Maximum PR interval was 286 ms and no second or third degreeheart block was observed (see section 4.4).

The in vitro antiviral activity of lopinavir against laboratory and clinical HIV strains was evaluated inacutely infected lymphoblastic cell lines and peripheral blood lymphocytes, respectively. In theabsence of human serum, the mean IC50 of lopinavir against five different HIV-1 laboratory strainswas 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, themean IC50 of lopinavir was 6.5 nM against several HIV-1 clinical isolates.

In vitro selection of resistanceHIV-1 isolates with reduced susceptibility to lopinavir have beenselected in vitro. HIV-1 has been passaged in vitro with lopinavir alone and with lopinavir plusritonavir 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 thatthe presence of ritonavir, at these concentration ratios, does not measurably influence the selection oflopinavir-resistant viruses. Overall, the in vitro characterisation of phenotypic cross-resistancebetween lopinavir and other protease inhibitors suggest that decreased susceptibility to lopinavircorrelated closely with decreased susceptibility to ritonavir and indinavir, but did not correlate closelywith 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 lopinavirhas 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 wascharacterised by analysing the longitudinal isolates from 19 protease inhibitor-experienced subjects in2 Phase II and one Phase III studies who either experienced incomplete virologic suppression or viralrebound subsequent to initial response to Kaletra and who demonstrated incremental in vitro resistancebetween baseline and rebound (defined as emergence of new mutations or 2-fold change in phenotypicsusceptibility to lopinavir). Incremental resistance was most common in subjects whose baselineisolates had several protease inhibitor-associated mutations, but < 40-fold reduced susceptibility tolopinavir 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-foldincrease 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 otherprotease inhibitors. The in vitro antiviral activity of lopinavir against 112 clinical isolates taken frompatients failing therapy with one or more protease inhibitors was assessed. Within this panel, thefollowing 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 atthe 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 containedmutations at positions 10, 54, 63 plus 82 and/or 84. In addition, they contained a median of3 mutations at amino acid positions 20, 24, 46, 53, 71 and 90. In addition to the mutations describedabove, mutations V32I and I47A have been observed in rebound isolates with reduced lopinavirsusceptibility from protease inhibitor experienced patients receiving Kaletra therapy, and mutations

I47A and L76V have been observed in rebound isolates with reduced lopinavir susceptibility frompatients receiving Kaletra therapy.

Conclusions regarding the relevance of particular mutations or mutational patterns are subject tochange with additional data, and it is recommended to always consult current interpretation systemsfor 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 assessingthe virologic response to Kaletra therapy, with respect to baseline viral genotype and phenotype, in 56patients previous failing therapy with multiple protease inhibitors. The EC50 of lopinavir against the56 baseline viral isolates ranged from 0.6 to 96-fold higher than the EC50 against wild type HIV. After48 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. Inaddition, virologic response was observed in 91% (21/23), 71% (15/21) and 33% (2/6) patients with0 − 5, 6 − 7, and 8 − 10 mutations of the above mutations in HIV protease associated with reducedin 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 controlarm of patients not receiving Kaletra.

Activity of other protease inhibitors against isolates that developed incremental resistance to lopinavirafter Kaletra therapy in protease inhibitor experienced patients: The presence of cross resistance toother protease inhibitors was analysed in 18 rebound isolates that had demonstrated evolution ofresistance 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 reboundwas 6.9- and 63-fold, respectively, compared to wild type virus. In general, rebound isolates eitherretained (if cross-resistant at baseline) or developed significant cross-resistance to indinavir,saquinavir and atazanavir. Modest decreases in amprenavir activity were noted with a medianincrease of IC50 from 3.7- to 8-fold in the baseline and rebound isolates, respectively. Isolates retainedsusceptibility to tipranavir with a median increase of IC50 in baseline and rebound isolates of 1.9- and1.8-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 ofresponse, in treatment of lopinavir-resistant HIV-1 infection.

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 of48 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 patientsinvestigating Kaletra (400/100 mg twice daily) compared to nelfinavir (750 mg three times daily) plusstavudine and lamivudine. Mean baseline CD4+ T-cell count was 259 cells/mm3 (range: 2 to949 cells/ mm3) and mean baseline plasma HIV-1 RNA was 4.9 log10 copies/ml (range: 2.6 to6.8 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 207 195

CD4+ T-cell count (cells/mm3)

* 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, isolatesfrom 96 nelfinavir-treated patients and 51 lopinavir/ritonavir-treated patients could be amplified forresistance testing. Resistance to nelfinavir, defined as the presence of the D30N or L90M mutation inprotease, was observed in 41/96 (43%) patients. Resistance to lopinavir, defined as the presence ofany primary or active site mutations in protease (see above), was observed in 0/51 (0%) patients. Lackof resistance to lopinavir was confirmed by phenotypic analysis.

Sustained virological response to Kaletra (in combination with nucleoside/nucleotide reversetranscriptase inhibitors) has been also observed in a small Phase II study (M97-720) through 360weeks of treatment. One hundred patients were originally treated with Kaletra in the study (including51 patients receiving 400/100 mg twice daily and 49 patients at either 200/100 mg twice daily or400/200 mg twice daily). All patients converted to open-label Kaletra at the 400/100 mg twice dailydose 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-onepatients completed the study (35 patients received the recommended 400/100 mg twice daily dosethroughout 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 19of 28 patients with confirmed HIV RNA above 400 copies/ml revealed no primary or active sitemutations in protease (amino acids at positions 8, 30, 32, 46, 47, 48, 50, 82, 84 and 90) or proteaseinhibitor phenotypic resistance.

Patients with prior antiretroviral therapy

M97-765 is a randomised, double-blind trial evaluating Kaletra at two dose levels (400/100 mg and400/200 mg, both twice daily) plus nevirapine (200 mg twice daily) and two nucleoside reversetranscriptase inhibitors in 70 single protease inhibitor experienced, non-nucleoside reversetranscriptase inhibitor naïve patients. Median baseline CD4 cell count was 349 cells/mm3 (range72 to 807 cells/mm3) and median baseline plasma HIV-1 RNA was 4.0 log10 copies/ml (range2.9 to 5.8 log10 copies/ml).

Table 3

Outcomes at Week 24: Study M97-765

Kaletra 400/100 mg(N=36)

HIV RNA < 400 copies/ml (ITT)* 75%

HIV RNA < 50 copies/ml (ITT)* 58%

Mean increase from baseline in CD4+ T-cell count (cells/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 nucleosidereverse transcriptase inhibitors in 57 multiple protease inhibitor experienced, non-nucleoside reversetranscriptase inhibitor naïve patients. Between week 24 and 48, patients randomised to a dose of400/100 mg were converted to a dose of 533/133 mg. Median baseline CD4 cell count was220 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 transcriptaseinhibitor naïve. Patients were randomised to either 230 mg lopinavir/57.5 mg ritonavir per m2 or300 mg lopinavir/75 mg ritonavir per m2. Naïve patients also received nucleoside reverse transcriptaseinhibitors. Experienced patients received nevirapine plus up to two nucleoside reverse transcriptaseinhibitors. Safety, efficacy and pharmacokinetic profiles of the two dose regimens were assessed after3 weeks of therapy in each patient. Subsequently, all patients were continued on the 300/75 mg per m2dose. Patients had a mean age of 5 years (range 6 months to 12 years) with 14 patients less than 2years old and 6 patients one year or less. Mean baseline CD4+ T-cell count was 838 cells/mm3 andmean baseline plasma HIV-1 RNA was 4.7 log10 copies/ml.

Table 5

Outcomes at Week 48: Study M98-940*

Antiretroviral Naïve Antiretroviral(N=44) Experienced (N=56)

HIV RNA < 400 copies/ml 84% 75%

Mean increase from baseline in 404 284

CD4+ T-cell count (cells/mm3)

* 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 twicedaily 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 was41 (16-59).

Table 6

Outcomes at Week 24: Study P1030

Age: ≥ 14 days and Age: ≥ 6 weeks and< 6 weeks < 6 months(N=10) (N=21)

HIV RNA < 400 copies/ml* 70% 48%

Median change from baseline - 1% (95% CI: -10, 18) + 4% (95% CI: -1, 9)in CD4+ T-cell count (n=6) (n=19)(cells/mm3)

*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 therapyin subjects 2 to 36 months of age infected with HIV-1 who had (Cohort I) and had not (Cohort II) beenexposed 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 oncedaily for 14 days, then 160-200 mg/m2 every 12 hours. Both treatment arms included zidovudine180 mg/m2 every 12 hours and lamivudine 4 mg/kg every 12 hours. The median follow-up was48 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 withresistance data available no resistance to lopinavir/ritonavir was found.

Table 7

Outcomes at Week 24: Study P1060

Cohort I Cohort IIlopinavir/ritonavir nevirapine lopinavir/ritonavir nevirapine(N=82) (N=82) (N=140) (N=147)

Virologic 21.7% 39.6% 19.3% 40.8%failure*

*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 differencesacross age strata, weighted by the precision of the estimate within each age stratump=0.015 (Cohort I); p< 0.001 (Cohort II)

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

Table 8

Hazard Ratio for Death or Failure of First-line Therapy Relativeto ART Deferred Treatment: CHER Study40 week arm (N=13) 96 week arm (N=13)

Hazard ratio fordeath or failure 0.319 0.332of therapy*

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

The pharmacokinetic properties of lopinavir co-administered with ritonavir have been evaluated inhealthy adult volunteers and in HIV-infected patients; no substantial differences were observedbetween the two groups. Lopinavir is essentially completely metabolised by CYP3A. Ritonavirinhibits 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 plasmaconcentrations 15 to 20-fold higher than those of ritonavir in HIV-infected patients. The plasma levelsof ritonavir are less than 7% of those obtained after the ritonavir dose of 600 mg twice daily. Thein vitro antiviral EC50 of lopinavir is approximately 10-fold lower than that of ritonavir. Therefore, theantiviral activity of Kaletra is due to lopinavir.

Multiple dosing with 400/100 mg Kaletra twice daily for 2 weeks and without meal restrictionproduced a mean  SD lopinavir peak plasma concentration (Cmax) of 12.3  5.4 g/ml, occurringapproximately 4 hours after administration. The mean steady-state trough concentration prior to themorning dose was 8.1  5.7 g/ml. Lopinavir AUC over a 12 hour dosing interval averaged113.2  60.5 g*h/ml. The absolute bioavailability of lopinavir co-formulated with ritonavir inhumans 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 amoderate 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, thecorresponding increases in lopinavir AUC and Cmax were 80% and 54%, respectively. Administrationof 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. Toenhance bioavailability and minimise variability Kaletra is to be taken with food.

At steady state, lopinavir is approximately 98 − 99% bound to serum proteins. Lopinavir binds toboth alpha-1-acid glycoprotein (AAG) and albumin however, it has a higher affinity for AAG. Atsteady state, lopinavir protein binding remains constant over the range of observed concentrations after400/100 mg Kaletra twice daily, and is similar between healthy volunteers and HIV-positive patients.

In vitro experiments with human hepatic microsomes indicate that lopinavir primarily undergoesoxidative metabolism. Lopinavir is extensively metabolised by the hepatic cytochrome P450 system,almost exclusively by isozyme CYP3A. Ritonavir is a potent CYP3A inhibitor which inhibits themetabolism of lopinavir and therefore, increases plasma levels of lopinavir. A 14C-lopinavir study inhumans showed that 89% of the plasma radioactivity after a single 400/100 mg Kaletra dose was dueto 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, butcomprise only minute amounts of total plasma radioactivity. Ritonavir has been shown to inducemetabolic enzymes, resulting in the induction of its own metabolism, and likely the induction oflopinavir metabolism. Pre-dose lopinavir concentrations decline with time during multiple dosing,stabilising after approximately 10 days to 2 weeks.

After a 400/100 mg 14C-lopinavir/ritonavir dose, approximately 10.4  2.3% and 82.6  2.5% of anadministered dose of 14C-lopinavir can be accounted for in urine and faeces, respectively. Unchangedlopinavir 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 theurine. The effective (peak to trough) half-life of lopinavir over a 12 hour dosing interval averaged5 − 6 hours, and the apparent oral clearance (CL/F) of lopinavir is 6 to 7 l/h.

Paediatrics

Data from clinical trials in children below 2 years of age include the pharmacokinetics of Kaletra300/75 mg/m2 twice daily studied in a total of 31 paediatric patients, ranging in age from 14 days to6 months. The pharmacokinetics of Kaletra 300/75 mg/m2 twice daily with nevirapine and230/57.5 mg/ m2 twice daily alone have been studied in 53 paediatric patients ranging in age from6 months to 12 years. The mean (SD) for the studies are reported in the table below. The230/57.5 mg/m2 twice daily regimen without nevirapine and the 300/75 mg/m2 twice daily regimenwith nevirapine provided lopinavir plasma concentrations similar to those obtained in adult patientsreceiving the 400/100 mg twice daily regimen without nevirapine.

Cmax (g/ml) Cmin (g/ml) AUC12 (g*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)a10.0 (3.3)b 3.6 (3.5)b 85.8 (36.9)b

Adultc12.3 (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 relatedpharmacokinetic differences have been observed in adult patients. Pharmacokinetic differences due torace have not been identified.

Renal Insufficiency

Kaletra pharmacokinetics have not been studied in patients with renal insufficiency; however, sincethe renal clearance of lopinavir is negligible, a decrease in total body clearance is not expected inpatients with renal insufficiency.

Hepatic Insufficiency

The steady state pharmacokinetic parameters of lopinavir in HIV-infected patients with mild tomoderate hepatic impairment were compared with those of HIV-infected patients with normal hepaticfunction in a multiple dose study with lopinavir/ritonavir 400/100 mg twice daily. A limited increasein total lopinavir concentrations of approximately 30% has been observed which is not expected to beof clinical relevance (see section 4.2).

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 focaldegeneration. While exposure eliciting these changes were comparable to or below human clinicalexposure, dosages in animals were over 6-fold the recommended clinical dose. Mild renal tubulardegeneration was confined to mice exposed with at least twice the recommended human exposure; thekidney was unaffected in rats and dogs. Reduced serum thyroxin led to an increased release of TSHwith resultant follicular cell hypertrophy in the thyroid glands of rats. These changes were reversiblewith withdrawal of the active substance and were absent in mice and dogs. Coombs-negativeanisocytosis and poikilocytosis were observed in rats, but not in mice or dogs. Enlarged spleens withhistiocytosis were seen in rats but not other species. Serum cholesterol was elevated in rodents but notdogs, while triglycerides were elevated only in mice.

During in vitro studies, cloned human cardiac potassium channels (HERG) were inhibited by 30% atthe highest concentrations of lopinavir/ritonavir tested, corresponding to a lopinavir exposure 7-foldtotal and 15-fold free peak plasma levels achieved in humans at the maximum recommendedtherapeutic dose. In contrast, similar concentrations of lopinavir/ritonavir demonstrated norepolarisation delay in the canine cardiac Purkinje fibres. Lower concentrations of lopinavir/ritonavirdid not produce significant potassium (HERG) current blockade. Tissue distribution studiesconducted in the rat did not suggest significant cardiac retention of the active substance; 72-hour AUCin heart was approximately 50% of measured plasma AUC. Therefore, it is reasonable to expect thatcardiac 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 electrolytedisturbance.

The clinical relevance of these preclinical data is unknown, however, the potential cardiac effects ofthis 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 ofpups) was observed at maternally toxic dosages. The systemic exposure to lopinavir/ritonavir at thematernal and developmental toxic dosages was lower than the intended therapeutic exposure inhumans.

Long-term carcinogenicity studies of lopinavir/ritonavir in mice revealed a nongenotoxic, mitogenicinduction of liver tumours, generally considered to have little relevance to human risk.

Carcinogenicity studies in rats revealed no tumourigenic findings. Lopinavir/ritonavir was not foundto be mutagenic or clastogenic in a battery of in vitro and in vivo assays including the Ames bacterialreverse mutation assay, the mouse lymphoma assay, the mouse micronucleus test and chromosomalaberration assays in human lymphocytes.

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),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, propyleneglycol),acesulfame potassium,saccharin sodium,sodium chloride,peppermint oil,sodium citrate,citric acid,levomenthol.

Not applicable.

2 years

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 unusedcontents after 42 days (6 weeks). It is advised to write the date of removal from the refrigerator on thepackage.

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.

No special requirements.

AbbVie Deutschland GmbH & Co. KG

Knollstrasse67061 Ludwigshafen

Germany

EU/1/01/172/003

EU/1/01/172/009

Date of first authorisation: 20 March 2001

Date of latest renewal: 20 March 2011

Detailed information on this product is available on the website of the European Medicines Agencyhttps://www.ema.europa.eu