KALETRA 200mg / 50mg tablets medication leaflet

Kaletra 200 mg/50 mg film-coated tablets

Each film-coated tablet contains 200 mg of lopinavir co-formulated with 50 mg of ritonavir as apharmacokinetic enhancer.

For the full list of excipients, see section 6.1.

Film-coated tablet

Red debossed with “AL” on one side.

Kaletra is indicated in combination with other antiretroviral medicinal products for the treatment ofhuman immunodeficiency virus (HIV-1) infected adults, adolescents and children above the age of2 years.

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.

Kaletra tablets must be swallowed whole and not chewed, broken or crushed.

Adults and adolescents

The standard recommended dosage of Kaletra tablets is 400/100 mg (two 200/50 mg) tablets twicedaily taken with or without food. In adult patients, in cases where once-daily dosing is considerednecessary for the management of the patient, Kaletra tablets may be administered as 800/200 mg (four200/50 mg tablets) once daily with or without food. The use of a once-daily dosing should be limitedto those adult patients having only very few protease inhibitor (PI) associated mutations (i.e. less than3 PI mutations in line with clinical trial results, see section 5.1 for the full description of thepopulation) and should take into account the risk of a lesser sustainability of the virologic suppression(see section 5.1) and higher risk of diarrhoea (see section 4.8) compared to the recommended standardtwice-daily dosing. An oral solution is available to patients who have difficulty swallowing. Refer tothe Summary of Product Characteristics for Kaletra oral solution for dosing instructions.

Paediatric population (2 years of age and above)

The adult dose of Kaletra tablets (400/100 mg twice daily) may be used in children 40 kg or greater orwith a Body Surface Area (BSA)* greater than 1.4 m2. For children weighing less than 40 kg or witha BSA between 0.5 and 1.4 m2 and able to swallow tablets, please refer to the Kaletra 100 mg/25 mgtablets Summary of Product Characteristics. For children unable to swallow tablets, please refer to the

Kaletra oral solution Summary of Product Characteristics. Based on the current data available, Kaletrashould not be administered once daily in paediatric patients (see section 5.1).

* Body surface area can be calculated with the following equation:

BSA (m2) =  (Height (cm) X Weight (kg)/3600)

Children less than 2 years of age

The safety and efficacy of Kaletra in children aged less than 2 years have not yet been established.

Currently available data are described in section 5.2 but no recommendation on a posology can bemade.

Concomitant Therapy: Efavirenz or nevirapine

The following table contains dosing guidelines for Kaletra tablets based on BSA when used incombination with efavirenz or nevirapine in children.

Paediatric dosing guidelines withconcomitant efavirenz or nevirapine

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

The adequate dosing may be achieved withthe two available strengths of Kaletratablets: 100/25 mg and 200/50 mg.* 0.5 to < 0.8 200/50 mg 0.8 to < 1.2 300/75 mg 1.2 to < 1.4 400/100 mg 1.4 500/125 mg

* Kaletra tablets must not be chewed, broken or crushed.

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.

* No dose adjustment is required for lopinavir/ritonavir during pregnancy and postpartum.

* Once-daily administration of lopinavir/ritonavir is not recommended for pregnant women due tothe lack of pharmacokinetic and clinical data.

Kaletra tablets are administered orally and must be swallowed whole and not chewed, broken orcrushed. Kaletra tablets can be taken with or without food.

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- Alfuzosin Increased plasma concentrations ofadrenoreceptor alfuzosin which may lead to severeantagonist hypotension. 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 tumorlysis syndrome at the dose initiationand during the ramp-up phase (seesection 4.5).

Anti-gout Colchicine Increased plasma concentrations ofcolchicine. Potential for serious and/orlife-threatening reactions in patientswith renal and/or hepatic impairment(see sections 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 fromthis agent (see section 4.5).

Quetiapine Increased plasma concentrations ofquetiapine which may lead to coma.

The concomitant administration withquetiapine is contraindicated (seesection 4.5).

Ergot alkaloids Dihydroergotamine, ergonovine, Increased plasma concentrations ofergotamine, methylergonovine ergot 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 therisk of alanine transaminase (ALT)elevations (see section 4.5).

Lipid-modifying agents

HMG Co-A Lovastatin, simvastatin Increased plasma concentrations of

Reductase 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 sildenafilin patients 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 parenterallyadministered midazolam, see section4.5.

Lopinavir/ritonavir medicinal product level decreased

Herbal products St. John’s wort Herbal preparations containing St

John’s wort (Hypericum perforatum)due to the risk of decreased plasmaconcentrations and reduced clinicaleffects of lopinavir and ritonavir (seesection 4.5).

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 a 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).

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.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, 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.

All interaction studies, when otherwise not stated, were performed using Kaletra capsules, which givesan approximately 20% lower exposure of lopinavir than the 200/50 mg tablets.

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 Effects on drug levels Clinical recommendationby therapeutic area concerning co-administration with

Geometric Mean Change (%) in 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 reduced

Concentrations may be reduced abacavir and zidovudinedue to increased glucuronidation concentrations is unknown.by lopinavir/ritonavir.

Tenofovir disoproxil Tenofovir: No dose adjustment necessary.

fumarate (DF), 300 mg AUC: ↑ 32% Higher tenofovir concentrations could

QD Cmax: ↔ potentiate tenofovir associated

Cmin: ↑ 51% adverse events, including renal(equivalent to 245 mg disorders.

tenofovir disoproxil) Lopinavir: ↔

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

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

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

Cmax: ↓ 13% when co-administered with efavirenz.

Cmin: ↓ 42% Kaletra must not be administered

Efavirenz, 600 mg QD once daily in combination with

Lopinavir: ↔ efavirenz.

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

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

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

Cmax: ↓ 19% when co-administered with

Cmin: ↓ 51% nevirapine.

Kaletra must not be administeredonce daily in combination withnevirapine.

Etravirine Etravirine: No dose adjustment necessary

AUC: ↓ 35%(Lopinavir/ritonavir Cmin: ↓ 45%tablet 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 Cmin: ↑ 74% plasma concentrations of rilpivirine,capsule 400/100 mg Cmax: ↑ 29% but no dose adjustment is required.

BID)

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 Kaletra

Due to CYP3A inhibition by 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/ Fosamprenavir: Co-administration of increased dosesritonavir (700/100 mg Amprenavir concentrations are of fosamprenavir (1400 mg BID)

BID) significantly reduced. with Kaletra (533/133 mg BID) toprotease inhibitor-experienced(Lopinavir/ritonavir patients resulted in a higher incidence400/100 mg BID) of gastrointestinal adverse events andelevations in triglycerides with theor combination regimen withoutincreases in virological efficacy,

Fosamprenavir when compared with standard doses(1400 mg BID) of fosamprenavir/ritonavir.

Concomitant administration of these(Lopinavir/ritonavir medicinal products is not533/133 mg BID) recommended.

Kaletra must not be administeredonce daily in combination withamprenavir.

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

AUC: ↔ combination, with respect to efficacy

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

Cmax: ↓(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 these(500/100 mg BID) AUC: ↓ 55% medicinal products is not

Cmin: ↓ 70% recommended.

Cmax: ↓ 47%

Acid reducing agents

Omeprazole (40 mg Omeprazole: ↔ No dose adjustment necessary

QD)

Lopinavir: ↔

Ranitidine (150 mg Ranitidine: ↔ No dose adjustment necessarysingle dose)

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, includingincrease. hypotension, may be increased.

Analgesics

Fentanyl Fentanyl: Careful monitoring of adverse effects

Increased risk of side-effects (notably respiratory depression but(respiratory depression, sedation) also sedation) is recommended whendue to higher plasma fentanyl is concomitantlyconcentrations because of administered with Kaletra.

CYP3A4 inhibition bylopinavir/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, Amiodarone, Dronedarone: Concomitant administration of

Dronedarone Concentrations may be increased Kaletra and amiodarone ordue to CYP3A4 inhibition by dronedarone is contraindicated (seelopinavir/ritonavir. section 4.3) as the risk of arrhythmiasor other serious adverse reactionsmay be increased.

Digoxin Digoxin: Caution is warranted and therapeutic

Plasma concentrations may be drug monitoring of digoxinincreased due to P-glycoprotein concentrations, if available, isinhibition by lopinavir/ritonavir. recommended in case of

The increased digoxin level may co-administration of Kaletra andlessen over time as P-gp digoxin. Particular caution should beinduction develops. used when prescribing Kaletra inpatients taking digoxin as the acuteinhibitory effect of ritonavir on P-gpis expected to significantly increasedigoxin levels. Initiation of digoxinin patients already taking Kaletra islikely to result in lower than expectedincreases of digoxin concentrations.

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

Lidocaine, and Quinidine: drug concentration monitoring is

Quinidine Concentrations may be increased recommended when available.

when co-administered withlopinavir/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). Cautionlopinavir/ritonavir. should be exercised in administeringclarithromycin with Kaletra topatients with impaired hepatic orrenal 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 the abemaciclib

SmPC for dosage adjustmentrecommendations. Monitor for

ADRs related to abemaciclib.

Apalutamide Apalutamide is a moderate to Decreased exposure of Kaletra maystrong CYP3A4 inducer and this result in potential loss of virologicalmay lead to a decreased exposure response.

of lopinavir/ritonavir. In addition, co-administration ofapalutamide and Kaletra may lead to

Serum concentrations of serious adverse events includingapalutamide may be increased due seizure due to higher apalutamideto 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)

The extent of increase depends on dosage adjustment recommendations.

the timing of ritonavir Monitor for 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 P-gp administering ceritinib with Kaletra.

inhibition by lopinavir/ritonavir. Refer to the ceritinib SmPC fordosage adjustment recommendations.

Monitor for ADRs related toceritinib.

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

vincristine, 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 serious adverseevents such as QT intervalprolongation. Co-administration ofencorafenib and Kaletra should beavoided. If the benefit is consideredto outweigh the risk and Kaletra mustbe used, patients should be carefullymonitored for safety.

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. Refer tothe 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 the riskof toxicity including risk of tumorlysis syndrome. Co-administration ofibrutinib and Kaletra should beavoided. If the benefit is consideredto outweigh the risk and Kaletra mustbe used, reduce the ibrutinib dose to140 mg and monitor patient closelyfor toxicity.

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 completed theramp-up phase and are on a steadydaily dose of venetoclax, reduce thevenetoclax dose by at least 75%when used with strong CYP3Ainhibitors (refer to the venetoclax

SmPC for dosing instructions).

Patients should be closely monitoredfor signs related to venetoclaxtoxicities.

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 and

AUC: ↑ 153% Kaletra may increase rivaroxaban(Ritonavir 600 mg twice Cmax: ↑ 55% exposure which may increase the riskdaily) Due to CYP3A and P-gp 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, includingdabigatran etexilate and edoxaban, isco-administered with Kaletra.

Vorapaxar Serum concentrations may be The co-administration of vorapaxarincreased due to CYP3A with Kaletra is not recommended (seeinhibition by lopinavir/ritonavir. section 4.4 and refer to the vorapaxar

SmPC).

Anticonvulsants

Phenytoin Phenytoin: Caution should be exercised in

Steady-state concentrations was administering phenytoin with Kaletra.

moderately decreased due to Phenytoin levels should be monitored

CYP2C9 and CYP2C19 induction when co-administering with Kaletra.by lopinavir/ritonavir. When co-administered withphenytoin, an increase of Kaletra

Lopinavir: dosage may be envisaged. Dose

Concentrations are decreased due adjustment has not been evaluated into CYP3A induction by clinical practice.

phenytoin. Kaletra must not be administeredonce daily in combination withphenytoin.

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. Carbamazepine and phenobarbitallevels should be monitored when

Lopinavir: co-administering with Kaletra.

Concentrations may be decreased When co-administered withdue to CYP3A induction by carbamazepine or phenobarbital, ancarbamazepine and phenobarbital. increase of Kaletra dosage may beenvisaged. Dose adjustment has notbeen evaluated in clinical practice.

Kaletra must not be administeredonce daily in combination withcarbamazepine and phenobarbital.

Lamotrigine and Lamotrigine: Patients should be monitored closely

Valproate AUC: ↓ 50% for a decreased VPA effect when

Cmax: ↓ 46% Kaletra and valproic acid or valproate

Cmin: ↓ 56% 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 is discontinued;therefore plasma lamotriginemonitoring should be conducted,particularly before and during 2weeks after starting or stopping

Kaletra, in order to see if lamotriginedose adjustment is needed.

In patients currently taking Kaletraand starting lamotrigine: no doseadjustments to the recommendeddose escalation of lamotrigine shouldbe 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 similar increase in trazodone

BID) Adverse events of nausea, exposure. The combination shoulddizziness, hypotension and be used with caution and a lower dosesyncope were observed following of trazodone should be considered.

co-administration of trazodoneand ritonavir.

Antifungals

Ketoconazole and Ketoconazole, Itraconazole: High doses of ketoconazole and

Itraconazole Serum concentrations may be itraconazole (> 200 mg/day) are notincreased due to CYP3A 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 Kaletra should beavoided unless an assessment of thebenefit/risk to patient justifies the useof voriconazole.

Anti-gout agents

Colchicine single dose Colchicine: Concomitant administration of

AUC: ↑ 3-fold Kaletra with colchicine in patients(Ritonavir 200 mg Cmax: ↑ 1.8-fold with renal and/or hepatic impairmenttwice-daily) Due to P-gp and/or CYP3A4 is contraindicated due to a potentialinhibition by ritonavir. increase of colchicine-related seriousand/or life-threatening reactions suchas neuromuscular toxicity (includingrhabdomyolysis) (see sections 4.3 and4.4). A reduction in colchicinedosage or an interruption ofcolchicine treatment is recommendedin patients with normal renal orhepatic function if treatment with

Kaletra is required. Refer tocolchicine prescribing information.

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 increased riskof adverse events related to fusidicacid, notably rhabdomyolysis (seesection 4.3). When used for osteo-articular infections, where the co-administration is unavoidable, closeclinical monitoring for muscularadverse events is stronglyrecommended (see section 4.4).

Antimycobacterials

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

Cmax: ↔ bedaquiline and Kaletra should be(Lopinavir/ritonavir avoided. If the benefit outweighs the400/100 mg BID, A more pronounced effect on risk, co-administration of bedaquilinemultiple dose) bedaquiline plasma exposures with Kaletra must be done withmay be observed during caution. More frequentprolonged co-administration with electrocardiogram monitoring andlopinavir/ritonavir. monitoring of transaminases isrecommended (see section 4.4 and

CYP3A4 inhibition likely due to refer to the bedaquiline SmPC).

lopinavir/ritonavir.

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

BID) AUC: ↑ 22% associated with DM-6705, ifco-administration of delamanid with(Lopinavir/ritonavir DM-6705 (delamanid active Kaletra is considered necessary, very400/100 mg BID) metabolite): frequent ECG monitoring throughout

AUC: ↑ 30% the full delamanid treatment period isrecommended (see section 4.4 and

A more pronounced effect on refer to the delamanid SmPC).

DM-6705 exposure may beobserved 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 days

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

Friday). Increased monitoring forrifabutin-associated adverse reactionsincluding neutropenia and uveitis iswarranted due to an expected increasein exposure to rifabutin. Furtherdosage reduction of rifabutin to150 mg twice weekly on set days isrecommended for patients in whomthe 150 mg dose 3 times per week isnot tolerated. It should be kept inmind that the twice weekly dosage of150 mg may not provide an optimalexposure to rifabutin thus leading to arisk 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 dose adjustmentof Kaletra 400 mg/400 mg (i.e.

Kaletra 400/100 mg + ritonavir300 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-administration should beavoided unless judged strictlynecessary. If this co-administration isjudged unavoidable, increased doseof 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 has beeninitiated (see section 4.4).

Antipsychotics

Lurasidone Due to CYP3A inhibition by The concomitant administration withlopinavir/ritonavir, concentrations lurasidone is contraindicated (seeof lurasidone are expected to section 4.3).increase.

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

Quetiapine Due to CYP3A inhibition by Concomitant administration oflopinavir/ritonavir, concentrations Kaletra and quetiapine isof quetiapine are expected to contraindicated as it may increaseincrease. 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 used

AUC: ↑ 4-fold with co-administration of Kaletra and

Due to CYP3A inhibition by parenteral midazolam. If Kaletra islopinavir/ritonavir co-administered with parenteralmidazolam, it should be done in anintensive care unit (ICU) or similarsetting which ensures close clinicalmonitoring and appropriate medicalmanagement in case of respiratorydepression and/or prolonged sedation.

Dosage adjustment for midazolamshould be considered especially ifmore than a single dose of midazolamis administered.

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 and sinustachycardia.

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

Calcium channel blockers

Felodipine, Nifedipine, Felodipine, Nifedipine, Clinical monitoring of therapeuticand Nicardipine Nicardipine: and adverse effects is recommended

Concentrations may be increased when these medicines aredue to CYP3A inhibition by concomitantly administered withlopinavir/ritonavir. Kaletra.

Dexamethasone Lopinavir: Clinical monitoring of antiviral

Concentrations may be decreased efficacy is recommended when thesedue to CYP3A induction by 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's syndromeand adrenal suppression have beenreported in patients receivingritonavir and inhaled or intranasallyadministered fluticasone propionate;this could also occur with othercorticosteroids metabolised via the

P450 3A pathway e.g. budesonideand triamcinolone. Consequently,concomitant administration of Kaletraand these glucocorticoids is notrecommended unless the potentialbenefit of treatment outweighs therisk of systemic corticosteroid effects(see section 4.4). A dose reduction ofthe glucocorticoid should beconsidered with close monitoring oflocal and systemic effects or a switchto a glucocorticoid, which is not asubstrate for CYP3A4 (e.g.beclomethasone). Moreover, in caseof withdrawal of glucocorticoidsprogressive dose reduction may haveto be performed 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 (see

Sildenafil Sildenafil: section 4.3). Co-administration of

AUC: ↑ 11-fold Kaletra with tadalafil is not

Due to CYP3A inhibition by recommended.

lopinavir/ritonavir.

For erectile dysfunction:

Particular caution must be used whenprescribing sildenafil or tadalafil inpatients receiving Kaletra withincreased monitoring for adverseevents including hypotension,syncope, visual changes andprolonged erection (see section 4.4).

When co-administered with Kaletra,sildenafil doses must not exceed25 mg in 48 hours and tadalafil dosesmust not exceed 10 mg every 72hours.

Vardenafil Vardenafil: The use of vardenafil with Kaletra is

AUC: ↑ 49-fold 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 increase therisk of serious arrhythmias from thisagent (see section 4.3).

HCV direct acting antivirals

Elbasvir/grazoprevir Concomitant administration of(50/200 mg QD) Elbasvir: elbasvir/grazoprevir with Kaletra is

AUC: ↑ 2.71-fold contraindicated (see section 4.3).

Cmax: ↑ 1.87-fold

C24: ↑ 3.58-fold

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 Kaletra

BCRP and OATP1B inhibition by is not recommended due to anlopinavir/ritonavir. increased risk of ALT elevationsassociated with increased glecaprevirexposure.

Ombitasvir/paritaprevir/ Ombitasvir: ↔ Co-administration is contraindicated.

ritonavir + dasabuvir

Paritaprevir: Lopinavir/ritonavir 800/200 mg QD(25/150/100 mg QD + AUC: ↑ 2.17-fold was administered with400 mg BID) Cmax: ↑ 2.04-fold ombitasvir/paritaprevir/ritonavir with

Ctrough: ↑ 2.36-fold or without dasabuvir. The effect on

Lopinavir/ritonavir DAAs and lopinavir was similar to400/100 mg BID (inhibition of CYP3A/efflux that observed whentransporters) lopinavir/ritonavir 400/100 mg BIDwas administered (see section 4.3).

Dasabuvir: ↔

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/ voxilaprevir.to P-glycoprotein, BCRP and

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

HCV protease inhibitors

Simeprevir 200 mg Simeprevir: It is not recommended todaily (ritonavir 100 mg AUC: ↑ 7.2-fold co-administer Kaletra and simeprevir.

BID) Cmax: ↑ 4.7-fold

Cmin: ↑ 14.4-fold

Herbal products

St John’s wort Lopinavir: Herbal preparations containing St(Hypericum perforatum) 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. Lopinavirand ritonavir levels may increase onstopping 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, Kaletra canbe 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 levels ofdue to CYP3A inhibition by these products have been stabilised.

lopinavir/ritonavir.

Lipid lowering agents

Lovastatin and Lovastatin, Simvastatin: Since increased concentrations of

Simvastatin Markedly increased plasma HMG-CoA reductase inhibitors mayconcentrations due to CYP3A cause myopathy, includinginhibition by lopinavir/ritonavir. rhabdomyolysis, the combination ofthese 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. If

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

Due to CYP3A inhibition by strictly necessary, the lowest possiblelopinavir/ritonavir. dose of atorvastatin 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 considered

Cmax: ↑ 5-fold when Kaletra is co-administered with

While rosuvastatin is poorly rosuvastatin (see section 4.4).metabolised by CYP3A4, anincrease of its plasmaconcentrations was observed. Themechanism of this interaction mayresult from inhibition of transportproteins.

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

Pravastatin reductase inhibitor is indicated,

No clinical relevant interaction fluvastatin or pravastatin isexpected. recommended.

Pravastatin is not metabolised by

CYP450.

Fluvastatin is partiallymetabolised by CYP2C9.

Opioids

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

QD

Methadone Methadone: ↓ Monitoring plasma concentrations ofmethadone 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 of contraceptionmust 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 recommended dosage,metabolism. despite the observed induction.

Thyroid hormone replacement therapy

Levothyroxine Post-marketing cases have been Thyroid-stimulating hormone (TSH)reported indicating a potential should be monitored in patientsinteraction between ritonavir treated with levothyroxine at least thecontaining products and first month after starting and/orlevothyroxine. ending lopinavir/ritonavir treatment.

Vasodilating agents

Bosentan Lopinavir - ritonavir: Caution should be exercised in

Lopinavir/ritonavir plasma administering Kaletra with bosentan.

concentrations may decrease due When Kaletra is administeredto CYP3A4 induction by concomitantly with bosentan, thebosentan. efficacy of the HIV therapy shouldbe monitored and patients should be

Bosentan: closely observed for bosentan

AUC: ↑ 5-fold toxicity, especially during the first

Cmax: ↑ 6-fold week of co-administration.

Initially, bosentan Cmin: ↑ byapproximately 48-fold.

Due to CYP3A4 inhibition bylopinavir/ritonavir.

Riociguat Serum concentrations may be The co-administration of riociguatincreased due to CYP3A and P-gp with Kaletra is not recommendedinhibition by lopinavir/ritonavir. (see section 4.4 and refer to riociguat

SmPC).

Other medicinal products

Based on known metabolic profiles, clinically significant interactions are not expected between

Kaletra and dapsone, trimethoprim/sulfamethoxazole, azithromycin or fluconazole.

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).

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. The risk of diarrhoea may begreater with once-daily dosing of Kaletra. Diarrhoea, nausea and vomiting may occur at the beginningof the treatment while hypertriglyceridaemia and hypercholesterolemia may occur later. Treatmentemergent adverse events led to premature study discontinuation for 7% of subjects from Phase II-IVstudies.

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 infarction,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 Stevens-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 2 years of age and older, the nature of the safety profile is similar to that seen in adults (see

Table in section b).

Reporting 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.

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.

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 resistance

HIV-1 isolates with reduced susceptibility to lopinavir have been selected in vitro. HIV-1 has beenpassaged in vitro with lopinavir alone and with lopinavir plus ritonavir at concentration ratiosrepresenting the range of plasma concentration ratios observed during Kaletra therapy. Genotypic andphenotypic analysis of viruses selected in these passages suggest that the presence of ritonavir, at theseconcentration ratios, does not measurably influence the selection of lopinavir-resistant viruses.

Overall, the in vitro characterisation of phenotypic cross-resistance between lopinavir and otherprotease inhibitors suggest that decreased susceptibility to lopinavir correlated closely with decreasedsusceptibility to ritonavir and indinavir, but did not correlate closely with decreased susceptibility toamprenavir, 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 of 3mutations 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.

Study M05-730 was a randomised, open-label, multicentre trial comparing treatment with Kaletra800/200 mg once daily plus tenofovir DF and emtricitabine versus Kaletra 400/100 mg twice dailyplus tenofovir DF and emtricitabine in 664 antiretroviral treatment-naïve patients. Given thepharmacokinetic interaction between Kaletra and tenofovir (see section 4.5), the results of this studymight not be strictly extrapolable when other backbone regimens are used with Kaletra. Patients wererandomised in a 1:1 ratio to receive either Kaletra 800/200 mg once daily (n = 333) or Kaletra400/100 mg twice daily (n = 331). Further stratification within each group was 1:1 (tablet versus softcapsule). Patients were administered either the tablet or the soft capsule formulation for 8 weeks, afterwhich all patients were administered the tablet formulation once daily or twice daily for the remainderof the study. Patients were administered emtricitabine 200 mg once daily and tenofovir DF 300 mgonce daily (equivalent to 245 mg tenofovir disoproxil). Protocol defined non-inferiority of once-dailydosing compared with twice-daily dosing was demonstrated if the lower bound of the 95% confidenceinterval for the difference in proportion of subjects responding (once daily minus twice daily)excluded -12% at Week 48. Mean age of patients enrolled was 39 years (range: 19 to 71); 75% were

Caucasian, and 78% were male. Mean baseline CD4+ T-cell count was 216 cells/mm3 (range: 20 to775 cells/mm3) and mean baseline plasma HIV-1 RNA was 5.0 log10 copies/ml (range: 1.7 to7.0 log10 copies/ml).

Table 2

Virologic Response of Study Subjects at Week 48 and Week 96

Week 48 Week 96

QD BID Difference QD BID Difference[95% CI] [95% CI]

NC= Failure 257/333 251/331 1.3 % 216/333 229/331 -4.3%(77.2%) (75.8%) [-5.1, 7.8] (64.9%) (69.2%) [-11.5, 2.8]

Observed data 257/295 250/280 -2.2% 216/247 229/248 -4.9%(87.1%) (89.3%) [-7.4, 3.1] (87.4%) (92.3%) [-10.2, 0.4]

Mean increase from 186 198 238 254baseline in CD4+ T-cellcount (cells/mm3)

Through Week 96, genotypic resistance testing results were available from 25 patients in the QDgroup and 26 patients in the BID group who had incomplete virologic response. In the QD group, nopatient demonstrated lopinavir resistance, and in the BID group, 1 patient who had significant proteaseinhibitor resistance at baseline demonstrated additional lopinavir resistance on study.

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 3

Outcomes at Week 360: Study M97-720

Kaletra (N=100)

HIV RNA < 400 copies/ml 61%

HIV RNA < 50 copies/ml 59%

Mean increase from baseline in CD4+ T-cell count (cells/mm3) 501

Through 360 weeks of treatment, genotypic analysis of viral isolates was successfully conducted in 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

M06-802 was a randomised open-label study comparing the safety, tolerability and antiviral activity ofonce-daily and twice-daily dosing of lopinavir/ritonavir tablets in 599 subjects with detectable viralloads while receiving their current antiviral therapy. Patients had not been on prior lopinavir/ritonavirtherapy. They were randomised in a 1:1 ratio to receive either lopinavir/ritonavir 800/200 mg oncedaily (n = 300) or lopinavir/ritonavir 400/100 mg twice daily (n = 299). Patients were administered atleast two nucleoside/nucleotide reverse transcriptase inhibitors selected by the investigator. Theenrolled population was moderately PI-experienced with more than half of patients having neverreceived prior PI and around 80% of patients presenting a viral strain with less than 3 PI mutations.

Mean age of patients enrolled was 41 years (range: 21 to 73); 51% were Caucasian and 66% weremale. Mean baseline CD4+ T-cell count was 254 cells/mm3 (range: 4 to 952 cells/mm3) and meanbaseline plasma HIV-1 RNA was 4.3 log10 copies/ml (range: 1.7 to 6.6 log10 copies/ml). Around 85%of patients had a viral load of < 100,000 copies/ml.

Table 4

Virologic Response of Study Subjects at Week 48 Study 802

QD BID Difference[95% CI]

NC= Failure 171/300 161/299 3.2%(57%) (53.8%) [-4.8%, 11.1%]

Observed data 171/225 161/223 3.8%(76.0%) (72.2%) [-4.3%, 11.9%]

Mean increase from baseline in 135 122

CD4+ T-cell count (cells/mm3)

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

Paediatric Use

M98-940 was an open-label study of a liquid formulation of Kaletra in 100 antiretroviral naïve (44%)and experienced (56%) paediatric patients. All patients were non-nucleoside reverse 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)

KONCERT/PENTA 18 is a prospective multicentre, randomised, open-label study that evaluated thepharmacokinetic profile, efficacy and safety of twice-daily versus once-daily dosing oflopinavir/ritonavir 100 mg/25 mg tablets dosed by weight as part of combination antiretroviral therapy(cART) in virologically suppressed HIV-1 infected children (n=173). Children were eligible whenthey were aged <18 years, ≥15 kg in weight, receiving cART that included lopinavir/ritonavir, HIV-1ribonucleic acid (RNA) <50 copies/ml for at least 24 weeks and able to swallow tablets. At week 48,the efficacy and safety with twice-daily dosing (n=87) in the paediatric population givenlopinavir/ritonavir 100 mg/25 mg tablets was consistent with the efficacy and safety findings inprevious adult and paediatric studies using lopinavir/ritonavir twice daily. The percentage of patientswith confirmed viral rebound >50 copies/ml during 48 weeks of follow-up was higher in the paediatricpatients receiving lopinavir/ritonavir tablets once daily (12%) than in patients receiving the twice-dailydosing (8%, p = 0.19), mainly due to lower adherence in the once-daily group. The efficacy datafavouring the twice-daily regimen are reinforced by a differential in pharmacokinetic parameterssignificantly favouring the twice-daily regimen (see section 5.2).

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

Administration of a single 400/100 mg dose of Kaletra tablets under fed conditions (high fat, 872 kcal,56% from fat) compared to fasted state was associated with no significant changes in Cmax and AUCinf.

Therefore, Kaletra tablets may be taken with or without food. Kaletra tablets have also shown lesspharmacokinetic variability under all meal conditions compared to Kaletra soft capsules.

At steady state, lopinavir is approximately 98 − 99% bound to serum proteins. Lopinavir binds to bothalpha-1-acid glycoprotein (AAG) and albumin however, it has a higher affinity for AAG. At steadystate, 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.

Once-daily dosing: the pharmacokinetics of once daily Kaletra have been evaluated in HIV-infectedsubjects naïve to antiretroviral treatment. Kaletra 800/200 mg was administered in combination withemtricitabine 200 mg and tenofovir DF 300 mg as part of a once-daily regimen. Multiple dosing of800/200 mg Kaletra once daily for 2 weeks without meal restriction (n=16) produced a mean ± SDlopinavir peak plasma concentration (Cmax) of 14.8 ± 3.5 g/ml, occurring approximately 6 hours afteradministration. The mean steady-state trough concentration prior to the morning dose was5.5 ± 5.4 g/ml. Lopinavir AUC over a 24 hour dosing interval averaged 206.5 ± 89.7 g*h/ml.

As compared to the BID regimen, the once-daily dosing is associated with a reduction in the

Cmin/Ctrough values of approximately 50%.

Paediatrics

There are limited pharmacokinetic data in children below 2 years of age. The pharmacokinetics of

Kaletra oral solution 300/75 mg/m2 twice daily and 230/57.5 mg/m2 twice daily have been studied in atotal of 53 paediatric patients, ranging in age from 6 months to 12 years. The lopinavir mean steady-state AUC, Cmax, and Cmin were 72.6  31.1 g*h/ml, 8.2  2.9 g/ml and 3.4  2.1 g/ml, respectivelyafter Kaletra oral solution 230/57.5 mg/m2 twice daily without nevirapine (n=12), and were85.8  36.9 g*h/ml, 10.0  3.3 g/ml and 3.6  3.5 g/ml, respectively after 300/75 mg/m2 twicedaily with nevirapine (n=12). The 230/57.5 mg/m2 twice-daily regimen without nevirapine and the300/75 mg/m2 twice-daily regimen with nevirapine provided lopinavir plasma concentrations similarto those obtained in adult patients receiving the 400/100 mg twice-daily regimen without nevirapine.

Gender, Race and Age

Kaletra pharmacokinetics have not been studied in older people. No age or gender relatedpharmacokinetic differences have been observed in adult patients. Pharmacokinetic differences due torace have not been identified.

In an open-label pharmacokinetic study, 12 HIV-infected pregnant women who were less than 20weeks of gestation and on combination antiretroviral therapy initially received lopinavir/ritonavir 400mg/100 mg (two 200/50 mg tablets) twice daily up to a gestational age of 30 weeks. At 30 weeks ageof gestation, the dose was increased to 500/125 mg (two 200/50 mg tablets plus one 100/25 mg tablet)twice daily until subjects were 2 weeks postpartum. Plasma concentrations of lopinavir were measuredover four 12-hour periods during second trimester (20-24 weeks gestation), third trimester before doseincrease (30 weeks gestation), third trimester after dose increase (32 weeks gestation), and at 8 weekspost-partum. The dose increase did not result in a significant increase in the plasma lopinavirconcentration.

In another open-label pharmacokinetic study, 19 HIV-infected pregnant women receivedlopinavir/ritonavir 400/100 mg twice daily as part of combination antiretroviral therapy duringpregnancy from before conception. A series of blood samples were collected pre-dose and at intervalsover the course of 12 hours in trimester 2 and trimester 3, at birth, and 4-6 weeks postpartum (inwomen who continued treatment post-delivery) for pharmacokinetic analysis of total and unboundlevels of plasma lopinavir concentrations.

The pharmacokinetic data from HIV-1 infected pregnant women receiving lopinavir/ritonavir tablets400/100 mg twice daily are presented in Table 6 (see section 4.2).

Table 6

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

Pharmacokinetic 2nd Trimester 3rd Trimester Postpartum

Parameter n = 17* n = 23 n = 17**

AUC0-12 μg*hr/mL 68.7 (20.6) 61.3 (22.7) 94.3 (30.3)

Cmax 7.9 (21.1) 7.5 (18.7) 9.8 (24.3)

Cpredose μg /mL 4.7 (25.2) 4.3 (39.0) 6.5 (40.4)

* n = 18 for Cmax

** n = 16 for Cpredose

Renal Insufficiency

Kaletra pharmacokinetics have not been studied in patients with renal insufficiency; however, 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.

Tablet contents:

Copovidone

Sorbitan laurate

Colloidal anhydrous silica

Sodium stearyl fumarate

Hypromellose

Titanium dioxide

Macrogols type 400 (Polyethylene glycol 400)

Hydroxypropyl cellulose

Talc

Colloidal anhydrous silica

Macrogols type 3350 (Polyethylene glycol 3350)

Red ferric oxide E172

Polysorbate 80

Not applicable.

Bottle packs: 2 years.

Store below 25°C.

High density polyethylene (HDPE) bottles closed with propylene caps. Each bottle contains 120tablets.

Two pack sizes are available:

- 1 bottle of 120 tablets

- multipack containing 360 (3 bottles of 120) film-coated tablets

Not all pack sizes may be marketed.

No special requirements.

AbbVie Deutschland GmbH & Co. KG

Knollstrasse67061 Ludwigshafen

Germany

EU/1/01/172/004

EU/1/01/172/007

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