4.1. Therapeutic indications

Kaletra is indicated in combination with other antiretroviral medicinal products for the treatment of human immunodeficiency virus (HIV-1) infected children above the age of 2 years, adolescents and adults.

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

4.2. Posology and method of administration

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

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

Posology

Adults and adolescents

The standard recommended dosage of Kaletra tablets is 400/100 mg (two 200/50 mg) tablets twice daily taken with or without food. In adult patients, in cases where once-daily dosing is considered necessary for the management of the patient, Kaletra tablets may be administered as 800/200 mg (four 200/50 mg tablets) once daily with or without food. The use of a once-daily dosing should be limited to those adult patients having only very few protease inhibitor (PI) associated mutations (i.e. less than 3 PI mutations in line with clinical trial results, see section 5.1 for the full description of the population) and should take into account the risk of a lesser sustainability of the virologic suppression (see section 5.1) and higher risk of diarrhoea (see section 4.8) compared to the recommended standard twice-daily dosing. An oral solution is available to patients who have difficulty swallowing. Refer to the Summary of Product Characteristics for Kaletra oral solution for dosing instructions.

Paediatric population (2 years of age and above)

The adult dose of Kaletra tablets (400/100 mg twice daily) may be used in children 40 kg or greater or with a Body Surface Area (BSA)* greater than 1.4 m2. For children weighing less than 40 kg or with a BSA between 0.5 and 1.4 m2 and able to swallow tablets, refer to the dosing guideline tables below. For children unable to swallow tablets, please refer to the Kaletra oral solution Summary of Product Characteristics. Based on the current data available, Kaletra should not be administered once daily in paediatric patients (see section 5.1).

Before prescribing Kaletra 100/25 mg tablets, infants and young children should be assessed for the ability to swallow intact tablets. If a child is unable to reliably swallow a Kaletra tablet, Kaletra oral solution formulation should be prescribed.

The following table contains dosing guidelines for Kaletra 100/25 mg tablets based on body weight and BSA.

Paediatric dosing guidelines without concomitant efavirenz or nevirapine*

Weight (kg)

Body Surface Area (m2)

Recommended number of 100/25 mg tablets twice-daily

15 to 25

≥ 0.5 to < 0.9

2 tablets (200/50 mg)

> 25 to 35

≥ 0.9 to < 1.4

3 tablets (300/75 mg)

> 35

≥ 1.4

4 tablets (400/100 mg)

*weight based dosing recommendations are based on limited data

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

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

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

Children less than 2 years of age

The safety and efficacy of Kaletra in children aged less than 2 years have not been established. Currently available data are described in section 5.2 but no recommendation on the posology can be made.

Concomitant Therapy: Efavirenz or nevirapine

The following table contains dosing guidelines for Kaletra 100/25 mg tablets based on BSA when used in combination with efavirenz or nevirapine in children.

Paediatric dosing guidelines with concomitant efavirenz or nevirapine

Body Surface Area (m2)

Recommended number of 100/25 mg tablets twice-daily

≥ 0.5 to < 0.8

2 tablets (200/50 mg)

≥ 0.8 to < 1.2

3 tablets (300/75 mg)

≥ 1.2 to < 1.4

4 tablets (400/100 mg)

≥ 1.4

5 tablets (500/125 mg)

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

Hepatic impairment

In HIV-infected patients with mild to moderate hepatic impairment, an increase of approximately 30% in lopinavir exposure has been observed but is not expected to be of clinical relevance (see section 5.2). No data are available in patients with severe hepatic impairment. Kaletra must not be given to these patients (see section 4.3).

Renal impairment

Since the renal clearance of lopinavir and ritonavir is negligible, increased plasma concentrations are not expected in patients with renal impairment. Because lopinavir and ritonavir are highly protein bound, it is unlikely that they will be significantly removed by haemodialysis or peritoneal dialysis.

Pregnancy and postpartum

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

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

Method of administration

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

4.3. Contraindications

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

Severe hepatic insufficiency.

Kaletra contains lopinavir and ritonavir, both of which are inhibitors of the P450 isoform CYP3A. Kaletra should not be co-administered with medicinal products that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life threatening events. These medicinal products include:

Medicinal product class

Medicinal products within class

Rationale

Concomitant medicinal product levels increased

Alpha1-adrenoreceptor antagonist

Alfuzosin

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

Antianginal

Ranolazine

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

Antiarrhythmics

Amiodarone, dronedarone

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

Antibiotic

Fusidic Acid

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

Anticancer

Neratinib

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

Venetoclax

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

Anti-gout

Colchicine

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

Antihistamines

Astemizole, terfenadine

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

Antipsychotics/ Neuroleptics

Lurasidone

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

Pimozide

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

Quetiapine

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

Ergot alkaloids

Dihydroergotamine, ergonovine, ergotamine, methylergonovine

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

GI motility agent

Cisapride

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

Hepatitis C virus direct acting antivirals

Elbasvir/grazoprevir

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

Ombitasvir/paritaprevir/ritonavir with or without dasabuvir

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

Lipid-modifying agents

HMG Co-A Reductase Inhibitors

Lovastatin, simvastatin

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

Microsomal triglyceride transfer protein (MTTP) inhibitor

Lomitapide

Increased plasma concentrations of lomitapide (see section 4.5).

Phosphodiesterase (PDE5) inhibitors

Avanafil

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

Sildenafil

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

Vardenafil

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

Sedatives/hypnotics

Oral midazolam, triazolam

Increased plasma concentrations of oral midazolam and triazolam. Thereby, increasing the risk of extreme sedation and respiratory depression from these agents.

For caution on parenterally administered midazolam, see section 4.5.

Lopinavir/ritonavir medicinal product level decreased

Herbal products

St. John's wort

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

4.4. Special warnings and precautions for use

Patients with coexisting conditions

Hepatic impairment

The safety and efficacy of Kaletra has not been established in patients with significant underlying liver disorders. Kaletra is contraindicated in patients with severe liver impairment (see section 4.3). Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer to the relevant product information for these medicinal products.

Patients with pre-existing liver dysfunction including chronic hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment should be considered.

Elevated transaminases with or without elevated bilirubin levels have been reported in HIV-1 mono-infected and in individuals treated for post-exposure prophylaxis as early as 7 days after the initiation of lopinavir/ritonavir in conjunction with other antiretroviral agents. In some cases the hepatic dysfunction was serious.

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

Renal impairment

Since the renal clearance of lopinavir and ritonavir is negligible, increased plasma concentrations are not expected in patients with renal impairment. Because lopinavir and ritonavir are highly protein bound, it is unlikely that they will be significantly removed by haemodialysis or peritoneal dialysis.

Haemophilia

There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthrosis in patients with haemophilia type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced if treatment had been discontinued. A causal relationship had been evoked, although the mechanism of action had not been elucidated. Haemophiliac patients should therefore be made aware of the possibility of increased bleeding.

Pancreatitis

Cases of pancreatitis have been reported in patients receiving Kaletra, including those who developed hypertriglyceridaemia. In most of these cases patients have had a prior history of pancreatitis and/or concurrent therapy with other medicinal products associated with pancreatitis. Marked triglyceride elevation is a risk factor for development of pancreatitis. Patients with advanced HIV disease may be at risk of elevated triglycerides and pancreatitis

Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis should occur. Patients who exhibit these signs or symptoms should be evaluated and Kaletra therapy should be suspended if a diagnosis of pancreatitis is made (see section 4.8).

Immune Reconstitution Inflammatory Syndrome

In HIV-infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymtomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jiroveci pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

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

Osteonecrosis

Although the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

PR interval prolongation

Lopinavir/ritonavir has been shown to cause modest asymptomatic prolongation of the PR interval in some healthy adult subjects. Rare reports of 2nd or 3rd degree atroventricular block in patients with underlying structural heart disease and pre-existing conduction system abnormalities or in patients receiving drugs known to prolong the PR interval (such as verapamil or atazanavir) have been reported in patients receiving lopinavir/ritonavir. Kaletra should be used with caution in such patients (see section 5.1).

Weight and metabolic parameters

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

Interactions with medicinal products

Kaletra contains lopinavir and ritonavir, both of which are inhibitors of the P450 isoform CYP3A. Kaletra is likely to increase plasma concentrations of medicinal products that are primarily metabolised by CYP3A. These increases of plasma concentrations of co-administered medicinal products could increase or prolong their therapeutic effect and adverse events (see sections 4.3 and 4.5).

Strong CYP3A4 inhibitors such as protease inhibitors may increase bedaquiline exposure which could potentially increase the risk of bedaquiline-related adverse reactions. Therefore, combination of bedaquiline with lopinavir/ritonavir should be avoided. However, if the benefit outweighs the risk, co-administration of bedaquiline with lopinavir/ritonavir must be done with caution. More frequent electrocardiogram monitoring and monitoring of transaminases is recommended (see section 4.5 and refer to the bedaquiline SmPC).

Co-administration of delamanid with a strong inhibitor of CYP3A (as lopinavir/ritonavir) may increase exposure to delamanid metabolite, which has been associated with QTc prolongation. Therefore, if co-administration of delamanid with lopinavir/ritonavir is considered necessary, very frequent ECG monitoring throughout the full delamanid treatment period is recommended (see section 4.5 and refer to the delamanid SmPC).

Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and strong inhibitors of CYP3A like ritonavir. Concomitant administration with colchicine is contraindicated in patients with renal and/or hepatic impairment (see sections 4.3 and 4.5).

The combination of Kaletra with:

- tadalafil, indicated for the treatment of pulmonary arterial hypertension, is not recommended (see section 4.5);

- riociguat is not recommended (see section 4.5);

- vorapaxar is not recommended (see section 4.5);

- fusidic acid in osteo-articular infections is not recommended (see section 4.5);

- salmeterol is not recommended (see section 4.5);

- rivaroxaban is not recommended (see section 4.5).

The combination of Kaletra with atorvastatin is not recommended. If the use of atorvastatin is considered strictly necessary, the lowest possible dose of atorvastatin should be administered with careful safety monitoring. Caution must also be exercised and reduced doses should be considered if Kaletra is used concurrently with rosuvastatin. If treatment with a HMG-CoA reductase inhibitor is indicated, pravastatin or fluvastatin is recommended (see section 4.5).

PDE5 inhibitors

Particular caution should be used when prescribing sildenafil or tadalafil for the treatment of erectile dysfunction in patients receiving Kaletra. Co-administration of Kaletra with these medicinal products is expected to substantially increase their concentrations and may result in associated adverse events such as hypotension, syncope, visual changes and prolonged erection (see section 4.5). Concomitant use of avanafil or vardenafil and lopinavir/ritonavir is contraindicated (see section 4.3). Concomitant use of sildenafil prescribed for the treatment of pulmonary arterial hypertension with Kaletra is contraindicated (see section 4.3).

Particular caution must be used when prescribing Kaletra and medicinal products known to induce QT interval prolongation such as: chlorpheniramine, quinidine, erythromycin, clarithromycin. Indeed, Kaletra could increase concentrations of the co-administered medicinal products and this may result in an increase of their associated cardiac adverse reactions. Cardiac events have been reported with Kaletra in preclinical studies; therefore, the potential cardiac effects of Kaletra cannot be currently ruled out (see sections 4.8 and 5.3).

Co-administration of Kaletra with rifampicin is not recommended. Rifampicin in combination with Kaletra causes large decreases in lopinavir concentrations which may in turn significantly decrease the lopinavir therapeutic effect. Adequate exposure to lopinavir/ritonavir may be achieved when a higher dose of Kaletra is used but this is associated with a higher risk of liver and gastrointestinal toxicity. Therefore, this co-administration should be avoided unless judged strictly necessary (see section 4.5).

Concomitant use of Kaletra and fluticasone or other glucocorticoids that are metabolised by CYP3A4, such as budesonide and triamcinolone, is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression (see section 4.5).

Other

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

Sodium

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

4.5. Interaction with other medicinal products and other forms of interaction

Kaletra contains lopinavir and ritonavir, both of which are inhibitors of the P450 isoform CYP3A in vitro. Co-administration of Kaletra and medicinal products primarily metabolised by CYP3A may result in increased plasma concentrations of the other medicinal product, which could increase or prolong its therapeutic and adverse reactions. Kaletra does not inhibit CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP2B6 or CYP1A2 at clinically relevant concentrations (see section 4.3).

Kaletra has been shown in vivo to induce its own metabolism and to increase the biotransformation of some medicinal products metabolised by cytochrome P450 enzymes (including CYP2C9 and CYP2C19) and by glucuronidation. This may result in lowered plasma concentrations and potential decrease of efficacy of co-administered medicinal products.

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

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

Known and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal products are listed in the table below. This list is not intended to be inclusive or comprehensive. Individual SmPCs should be consulted.

Interaction table

Interactions between Kaletra and co-administered medicinal products are listed in the table below (increase is indicated as “↑”, decrease as “↓”, no change as “↔”,once daily as “QD”, twice daily as “BID” and three times daily as "TID").

Unless otherwise stated, studies detailed below have been performed with the recommended dosage of lopinavir/ritonavir (i.e. 400/100 mg twice daily).

Co-administered drug by therapeutic area

Effects on drug levels

Geometric Mean Change (%) in AUC, Cmax, Cmin

Mechanism of interaction

Clinical recommendation concerning co-administration with Kaletra

Antiretroviral Agents

Nucleoside/Nucleotide reverse transcriptase inhibitors (NRTIs)

Stavudine, Lamivudine

Lopinavir: ↔

No dose adjustment necessary.

Abacavir, Zidovudine

Abacavir, Zidovudine:

Concentrations may be reduced due to increased glucuronidation by lopinavir/ritonavir.

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

Tenofovir disoproxil fumarate (DF), 300 mg QD

(equivalent to 245 mg tenofovir disoproxil)

Tenofovir:

AUC: ↑ 32%

Cmax: ↔

Cmin: ↑ 51%

Lopinavir: ↔

No dose adjustment necessary.

Higher tenofovir concentrations could potentiate tenofovir associated adverse events, including renal disorders.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Efavirenz, 600 mg QD

Lopinavir:

AUC: ↓ 20%

Cmax: ↓ 13%

Cmin: ↓ 42%

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

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

Efavirenz, 600 mg QD

(Lopinavir/ritonavir 500/125 mg BID)

Lopinavir: ↔

(Relative to 400/100 mg BID administered alone)

Nevirapine, 200 mg BID

Lopinavir:

AUC: ↓ 27%

Cmax: ↓ 19%

Cmin: ↓ 51%

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

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

Etravirine

(Lopinavir/ritonavir tablet 400/100 mg BID)

Etravirine:

AUC: ↓ 35%

Cmin: ↓ 45%

Cmax: ↓ 30%

Lopinavir:

AUC: ↔

Cmin: ↓ 20%

Cmax: ↔

No dose adjustment necessary

Rilpivirine

(Lopinavir/ritonavir capsule 400/100 mg BID)

Rilpivirine:

AUC: ↑ 52%

Cmin: ↑ 74%

Cmax: ↑ 29%

Lopinavir:

AUC: ↔

Cmin: ↓ 11%

Cmax: ↔

(inhibition of CYP3A enzymes)

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

HIV CCR5 – antagonist

Maraviroc

Maraviroc:

AUC: ↑ 295%

Cmax: ↑ 97%

Due to CYP3A inhibition by lopinavir/ritonavir.

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

Integrase inhibitor

Raltegravir

Raltegravir:

AUC: ↔

Cmax: ↔

C12: ↓ 30%

Lopinavir: ↔

No dose adjustment necessary

Co-administration with other HIV protease inhibitors (PIs)

According to current treatment guidelines, dual therapy with protease inhibitors is generally not recommended.

Fosamprenavir/ ritonavir (700/100 mg BID)

(Lopinavir/ritonavir 400/100 mg BID)

or

Fosamprenavir (1400 mg BID)

(Lopinavir/ritonavir 533/133 mg BID)

Fosamprenavir:

Amprenavir concentrations are significantly reduced.

Co-administration of increased doses of fosamprenavir (1400 mg BID) with Kaletra (533/133 mg BID) to protease inhibitor-experienced patients resulted in a higher incidence of gastrointestinal adverse events and elevations in triglycerides with the combination regimen without increases in virological efficacy, when compared with standard doses of fosamprenavir/ritonavir. Concomitant administration of these medicinal products is not recommended.

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

Indinavir, 600 mg BID

Indinavir:

AUC: ↔

Cmin: ↑ 3.5-fold

Cmax: ↓

(relative to indinavir 800 mg TID alone)

Lopinavir: ↔

(relative to historical comparison)

The appropriate doses for this combination, with respect to efficacy and safety, have not been established.

Saquinavir

1000 mg BID

Saquinavir: ↔

No dose adjustment necessary.

Tipranavir/ritonavir

(500/100 mg BID)

Lopinavir:

AUC: ↓ 55%

Cmin: ↓ 70%

Cmax: ↓ 47%

Concomitant administration of these medicinal products is not recommended.

Acid reducing agents

Omeprazole (40 mg QD)

Omeprazole: ↔

Lopinavir: ↔

No dose adjustment necessary

Ranitidine (150 mg single dose)

Ranitidine: ↔

No dose adjustment necessary

Alpha1 adrenoreceptor antagonist

Alfuzosin

Alfuzosin:

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

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

Analgesics

Fentanyl

Fentanyl:

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

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

Antianginal

Ranolazine

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

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

Antiarrhythmics

Amiodarone, Dronedarone

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

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

Digoxin

Digoxin:

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

Caution is warranted and therapeutic drug monitoring of digoxin concentrations, if available, is recommended in case of co-administration of Kaletra and digoxin. Particular caution should be used when prescribing Kaletra in patients taking digoxin as the acute inhibitory effect of ritonavir on P-gp is expected to significantly increase digoxin levels. Initiation of digoxin in patients already taking Kaletra is likely to result in lower than expected increases of digoxin concentrations.

Bepridil, Systemic Lidocaine, and Quinidine

Bepridil, Systemic Lidocaine, Quinidine:

Concentrations may be increased when co-administered with lopinavir/ritonavir.

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

Antibiotics

Clarithromycin

Clarithromycin:

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

For patients with renal impairment (CrCL < 30 ml/min) dose reduction of clarithromycin should be considered (see section 4.4). Caution should be exercised in administering clarithromycin with Kaletra to patients with impaired hepatic or renal function.

Anticancer agents and kinase inhibitors

Abemaciclib

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

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

Apalutamide

Apalutamide is a moderate to strong CYP3A4 inducer and this may lead to a decreased exposure of lopinavir/ritonavir.

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

Decreased exposure of Kaletra may result in potential loss of virological response.

In addition, co-administration of apalutamide and Kaletra may lead to serious adverse events including seizure due to higher apalutamide levels. Concomitant use of Kaletra with apalutamide is not recommended.

Afatinib

(Ritonavir 200 mg twice daily)

Afatinib:

AUC: ↑

Cmax: ↑

The extent of increase depends on the timing of ritonavir administration.

Due to BCRP (breast cancer resistance protein/ABCG2) and acute P-gp inhibition by lopinavir/ritonavir.

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

Ceritinib

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

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

Most tyrosine kinase inhibitors such as dasatinib and nilotinib, vincristine, vinblastine

Most tyrosine kinase inhibitors such as dasatinib and nilotinib, also vincristine and vinblastine:

Risk of increased adverse events due to higher serum concentrations because of CYP3A4 inhibition by lopinavir/ritonavir.

Careful monitoring of the tolerance of these anticancer agents.

Encorafenib

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

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

Fostamatinib

Increase in fostamatinib metabolite R406 exposure.

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

Ibrutinib

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

Co-administration of ibrutinib and Kaletra may increase ibrutinib exposure which may increase the risk of toxicity including risk of tumor lysis syndrome.

Co-administration of ibrutinib and Kaletra should be avoided. If the benefit is considered to outweigh the risk and Kaletra must be used, reduce the ibrutinib dose to 140 mg and monitor patient closely for toxicity.

Neratinib

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

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

Venetoclax

Due to CYP3A inhibition by lopinavir/ritonavir.

Serum concentrations may be increased due to CYP3A inhibition by lopinavir/ritonavir, resulting in increased risk of tumor lysis syndrome at the dose initiation and during the ramp-up phase (see section 4.3 and refer to the venetoclax SmPC).

For patients who have completed the ramp-up phase and are on a steady daily dose of venetoclax, reduce the venetoclax dose by at least 75% when used with strong CYP3A inhibitors (refer to the venetoclax SmPC for dosing instructions). Patients should be closely monitored for signs related to venetoclax toxicities.

Anticoagulants

Warfarin

Warfarin:

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

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

Rivaroxaban

(Ritonavir 600 mg twice daily)

Rivaroxaban:

AUC: ↑ 153%

Cmax: ↑ 55%

Due to CYP3A and P-gp inhibition by lopinavir/ritonavir.

Co-administration of rivaroxaban and Kaletra may increase rivaroxaban exposure which may increase the risk of bleeding.

The use of rivaroxaban is not recommended in patients receiving concomitant treatment with Kaletra (see section 4.4).

Dabigatran etexilate, Edoxaban

Dabigatran etexilate, Edoxaban:

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

Clinical monitoring and/or dose reduction of the direct oral anticoagulants (DOAC) should be considered when a DOAC transported by P-gp but not metabolised by CYP3A4, including dabigatran etexilate and edoxaban, is co-administered with Kaletra.

Vorapaxar

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

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

Anticonvulsants

Phenytoin

Phenytoin:

Steady-state concentrations was moderately decreased due to CYP2C9 and CYP2C19 induction by lopinavir/ritonavir.

Lopinavir:

Concentrations are decreased due to CYP3A induction by phenytoin.

Caution should be exercised in administering phenytoin with Kaletra.

Phenytoin levels should be monitored when co-administering with Kaletra.

When co-administered with phenytoin, an increase of Kaletra dosage may be envisaged. Dose adjustment has not been evaluated in clinical practice.

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

Carbamazepine and Phenobarbital

Carbamazepine:

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

Lopinavir:

Concentrations may be decreased due to CYP3A induction by carbamazepine and phenobarbital.

Caution should be exercised in administering carbamazepine or phenobarbital with Kaletra.

Carbamazepine and phenobarbital levels should be monitored when co-administering with Kaletra.

When co-administered with carbamazepine or phenobarbital, an increase of Kaletra dosage may be envisaged. Dose adjustment has not been evaluated in clinical practice.

Kaletra must not be administered once daily in combination with carbamazepine and phenobarbital.

Lamotrigine and Valproate

Lamotrigine:

AUC: ↓ 50%

Cmax: ↓ 46%

Cmin: ↓ 56%

Due to induction of lamotrigine glucuronidation

Valproate: ↓

Patients should be monitored closely for a decreased VPA effect when Kaletra and valproic acid or valproate are given concomitantly.

In patients starting or stopping Kaletra while currently taking maintenance dose of lamotrigine:

lamotrigine dose may need to be increased if Kaletra is added, or decreased if Kaletra is discontinued; therefore plasma lamotrigine monitoring should be conducted, particularly before and during 2 weeks after starting or stopping Kaletra, in order to see if lamotrigine dose adjustment is needed.

In patients currently taking Kaletra and starting lamotrigine: no dose adjustments to the recommended dose escalation of lamotrigine should be necessary.

Antidepressants and Anxiolytics

Trazodone single dose

(Ritonavir, 200 mg BID)

Trazodone:

AUC: ↑ 2.4-fold

Adverse events of nausea, dizziness, hypotension and syncope were observed following co-administration of trazodone and ritonavir.

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

Antifungals

Ketoconazole and Itraconazole

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

High doses of ketoconazole and itraconazole (> 200 mg/day) are not recommended.

Voriconazole

Voriconazole:

Concentrations may be decreased.

Co-administration of voriconazole and low dose ritonavir (100 mg BID) as contained in Kaletra should be avoided unless an assessment of the benefit/risk to patient justifies the use of voriconazole.

Anti-gout agents:

Colchicine single dose

(Ritonavir 200 mg twice daily)

Colchicine:

AUC: ↑ 3-fold

Cmax: ↑ 1.8-fold

Due to P-gp and/or CYP3A4 inhibition by ritonavir.

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

Antihistamines

Astemizole

Terfenadine

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

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

Anti-infectives

Fusidic acid

Fusidic acid:

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

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

Antimycobacterials

Bedaquiline

(single dose)

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

Bedaquiline:

AUC: ↑ 22%

Cmax: ↔

A more pronounced effect on bedaquiline plasma exposures may be observed during prolonged co-administration with lopinavir/ritonavir.

CYP3A4 inhibition likely due to lopinavir/ritonavir.

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

Delamanid (100 mg BID)

(Lopinavir/ritonavir 400/100 mg BID)

Delamanid:

AUC: ↑ 22%

DM-6705 (delamanid active metabolite):

AUC: ↑ 30%

A more pronounced effect on DM-6705 exposure may be observed during prolonged co-administration with lopinavir/ritonavir.

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

Rifabutin, 150 mg QD

Rifabutin (parent drug and active 25-O-desacetyl metabolite):

AUC: ↑ 5.7-fold

Cmax: ↑ 3.5-fold

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

Rifampicin

Lopinavir:

Large decreases in lopinavir concentrations may be observed due to CYP3A induction by rifampicin.

Co-administration of Kaletra with rifampicin is not recommended as the decrease in lopinavir concentrations may in turn significantly decrease the lopinavir therapeutic effect. A dose adjustment of Kaletra 400 mg/400 mg (i.e. Kaletra 400/100 mg + ritonavir 300 mg) twice daily has allowed compensating for the CYP 3A4 inducer effect of rifampicin. However, such a dose adjustment might be associated with ALT/AST elevations and with increase in gastrointestinal disorders. Therefore, this co-administration should be avoided unless judged strictly necessary. If this co-administration is judged unavoidable, increased dose of Kaletra at 400 mg/400 mg twice daily may be administered with rifampicin under close safety and therapeutic drug monitoring. The Kaletra dose should be titrated upward only after rifampicin has been initiated (see section 4.4).

Antipsychotics

Lurasidone

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

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

Pimozide

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

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

Quetiapine

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

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

Benzodiazepines

Midazolam

Oral Midazolam:

AUC: ↑ 13-fold

Parenteral Midazolam:

AUC: ↑ 4-fold

Due to CYP3A inhibition by lopinavir/ritonavir

Kaletra must not be co-administered with oral midazolam (see section 4.3), whereas caution should be used with co-administration of Kaletra and parenteral midazolam. If Kaletra is co-administered with parenteral midazolam, it should be done in an intensive care unit (ICU) or similar setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage adjustment for midazolam should be considered especially if more than a single dose of midazolam is administered.

Beta2-adrenoceptor agonist (long acting)

Salmeterol

Salmeterol:

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

The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.

Therefore, concomitant administration of Kaletra with salmeterol is not recommended (see section 4.4).

Calcium channel blockers

Felodipine, Nifedipine, and Nicardipine

Felodipine, Nifedipine, Nicardipine:

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

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

Corticosteroids

Dexamethasone

Lopinavir:

Concentrations may be decreased due to CYP3A induction by dexamethasone.

Clinical monitoring of antiviral efficacy is recommended when these medicines are concomitantly administered with Kaletra.

Inhaled, injectable or intranasal fluticasone propionate, budesonide, triamcinolone

Fluticasone propionate, 50 µg intranasal 4 times daily:

Plasma concentrations ↑

Cortisol levels ↓ 86%

Greater effects may be expected when fluticasone propionate is inhaled. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate; this could also occur with other corticosteroids metabolised via the P450 3A pathway e.g. budesonide and triamcinolone. Consequently, concomitant administration of Kaletra and these glucocorticoids is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects (see section 4.4). A dose reduction of the glucocorticoid should be considered with close monitoring of local and systemic effects or a switch to a glucocorticoid, which is not a substrate for CYP3A4 (e.g. beclomethasone). Moreover, in case of withdrawal of glucocorticoids progressive dose reduction may have to be performed over a longer period.

Phosphodiesterase(PDE5) inhibitors

Avanafil

(ritonavir 600 mg BID)

Avanafil:

AUC: ↑ 13-fold

Due to CYP3A inhibition by lopinavir/ritonavir.

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

Tadalafil

Tadalafil:

AUC: ↑ 2-fold

Due to CYP3A4 inhibition by lopinavir/ritonavir.

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

For erectile dysfunction:

Particular caution must be used when prescribing sildenafil or tadalafil in patients receiving Kaletra with increased monitoring for adverse events including hypotension, syncope, visual changes and prolonged erection (see section 4.4).

When co-administered with Kaletra, sildenafil doses must not exceed 25 mg in 48 hours and tadalafil doses must not exceed 10 mg every 72 hours.

Sildenafil

Sildenafil:

AUC: ↑ 11-fold

Due to CYP3A inhibition by lopinavir/ritonavir.

Vardenafil

Vardenafil:

AUC: ↑ 49-fold

Due to CYP3A inhibition by lopinavir/ritonavir.

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

Ergot alkaloids

Dihydroergotamine, ergonovine, ergotamine, methylergonovine

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

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

GI motility agent

Cisapride

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

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

HCV direct acting antivirals

Elbasvir/grazoprevir

(50/200 mg QD)

Elbasvir:

AUC: ↑ 2.71-fold

Cmax: ↑ 1.87-fold

C24: ↑ 3.58-fold

Grazoprevir:

AUC: ↑ 11.86-fold

Cmax: ↑ 6.31-fold

C24: ↑ 20.70-fold

(combinations of mechanisms including CYP3A inhibition)

Lopinavir: ↔

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

Glecaprevir/pibrentasvir

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

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

Ombitasvir/paritaprevir/ritonavir + dasabuvir

(25/150/100 mg QD + 400 mg BID)

Lopinavir/ritonavir

400/100 mg BID

Ombitasvir: ↔

Paritaprevir:

AUC: ↑ 2.17-fold

Cmax: ↑ 2.04-fold

Ctrough: ↑ 2.36-fold

(inhibition of CYP3A/efflux transporters)

Dasabuvir: ↔

Lopinavir: ↔

Co-administration is contraindicated.

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

Ombitasvir/paritaprevir/ ritonavir

(25/150/100 mg QD)

Lopinavir/ritonavir

400/100 mg BID

Ombitasvir: ↔

Paritaprevir:

AUC: ↑ 6.10-fold

Cmax: ↑ 4.76-fold

Ctrough: ↑ 12.33-fold

(inhibition of CYP3A/efflux transporters)

Lopinavir: ↔

Sofosbuvir/velpatasvir/ voxilaprevir

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

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

HCV protease inhibitors

Simeprevir 200 mg daily (ritonavir 100 mg BID)

Simeprevir:

AUC: ↑ 7.2-fold

Cmax: ↑ 4.7-fold

Cmin: ↑ 14.4-fold

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

Herbal products

St John's wort (Hypericum perforatum)

Lopinavir:

Concentrations may be reduced due to induction of CYP3A by the herbal preparation St John's wort.

Herbal preparations containing St John's wort must not be combined with lopinavir and ritonavir. If a patient is already taking St John's wort, stop St John's wort and if possible check viral levels. Lopinavir and ritonavir levels may increase on stopping St John's wort. The dose of Kaletra may need adjusting. The inducing effect may persist for at least 2 weeks after cessation of treatment with St John's wort (see section 4.3). Therefore, Kaletra can be started safely 2 weeks after cessation of St John's wort.

Immunosuppressants

Cyclosporin, Sirolimus (rapamycin), and Tacrolimus

Cyclosporin, Sirolimus (rapamycin), Tacrolimus:

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

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

Lipid lowering agents

Lovastatin and Simvastatin

Lovastatin, Simvastatin:

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

Since increased concentrations of HMG-CoA reductase inhibitors may cause myopathy, including rhabdomyolysis, the combination of these agents with Kaletra is contraindicated (see section 4.3).

Lipid-modifying agents

Lomitapide

CYP3A4 inhibitors increase the exposure of lomitapide, with strong inhibitors increasing exposure approximately 27-fold. Due to CYP3A inhibition by lopinavir/ritonavir, concentrations of lomitapide are expected to increase.

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

Atorvastatin

Atorvastatin:

AUC: ↑ 5.9-fold

Cmax: ↑ 4.7-fold

Due to CYP3A inhibition by lopinavir/ritonavir.

The combination of Kaletra with atorvastatin is not recommended. If the use of atorvastatin is considered strictly necessary, the lowest possible dose of atorvastatin should be administered with careful safety monitoring (see section 4.4).

Rosuvastatin, 20 mg QD

Rosuvastatin:

AUC: ↑ 2-fold

Cmax: ↑ 5-fold

While rosuvastatin is poorly metabolised by CYP3A4, an increase of its plasma concentrations was observed. The mechanism of this interaction may result from inhibition of transport proteins.

Caution should be exercised and reduced doses should be considered when Kaletra is co-administered with rosuvastatin (see section 4.4).

Fluvastatin or Pravastatin

Fluvastatin, Pravastatin:

No clinical relevant interaction expected.

Pravastatin is not metabolised by CYP450.

Fluvastatin is partially metabolised by CYP2C9.

If treatment with an HMG-CoA reductase inhibitor is indicated, fluvastatin or pravastatin is recommended.

Opioids

Buprenorphine, 16 mg QD

Buprenorphine: ↔

No dose adjustment necessary.

Methadone

Methadone: ↓

Monitoring plasma concentrations of methadone is recommended.

Oral contraceptives

Ethinyl Oestradiol

Ethinyl Oestradiol: ↓

In case of co-administration of Kaletra with contraceptives containing ethinyl oestradiol (whatever the contraceptive formulation e.g. oral or patch), additional methods of contraception must be used.

Smoking cessation aids

Bupropion

Buproprion and its active metabolite, hydroxybupropion:

AUC and Cmax ↓ ~50%

This effect may be due to induction of bupropion metabolism.

If the co-administration of Kaletra with bupropion is judged unavoidable, this should be done under close clinical monitoring for bupropion efficacy, without exceeding the recommended dosage, despite the observed induction.

Thyroid hormone replacement therapy

Levothyroxine

Post-marketing cases have been reported indicating a potential interaction between ritonavir containing products and levothyroxine.

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

Vasodilating agents

Bosentan

Lopinavir - ritonavir:

Lopinavir/ritonavir plasma concentrations may decrease due to CYP3A4 induction by bosentan.

Bosentan:

AUC: ↑ 5-fold

Cmax: ↑ 6-fold

Initially, bosentan Cmin: ↑ by approximately 48-fold.

Due to CYP3A4 inhibition by lopinavir/ritonavir.

Caution should be exercised in administering Kaletra with bosentan.

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

Riociguat

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

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

Other medicinal products

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

4.6. Fertility, pregnancy and lactation

Pregnancy

As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, the animal data as well as the clinical experience in pregnant women should be taken into account in order to characterise the safety for the foetus.

Lopinavir/ritonavir has been evaluated in over 3000 women during pregnancy, including over 1000 during the first trimester.

In post-marketing surveillance through the Antiretroviral Pregnancy Registry, established since January 1989, an increased risk of birth defects exposures with Kaletra has not been reported among over 1000 women exposed during the first trimester. The prevalence of birth defects after any trimester exposure to lopinavir is comparable to the prevalence observed in the general population. No pattern of birth defects suggestive of a common etiology was seen. Studies in animals have shown reproductive toxicity (see section 5.3). Based on the data mentioned, the malformative risk is unlikely in humans. Lopinavir can be used during pregnancy if clinically needed.

Breast-feeding

Studies in rats revealed that lopinavir is excreted in the milk. It is not known whether this medicinal product is excreted in human milk. As a general rule, it is recommended that women living with HIV do not breastfeed their babies in order to avoid transmission of HIV.

Fertility

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

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

a. Summary of the safety profile

The safety of Kaletra has been investigated in over 2600 patients in Phase II-IV clinical trials, of which over 700 have received a dose of 800/200 mg (6 capsules or 4 tablets) once daily. Along with nucleoside reverse transcriptase inhibitors (NRTIs), in some studies, Kaletra was used in combination with efavirenz or nevirapine.

The most common adverse reactions related to Kaletra therapy during clinical trials were diarrhoea, nausea, vomiting, hypertriglyceridaemia and hypercholesterolemia. The risk of diarrhoea may be greater with once-daily dosing of Kaletra. Diarrhoea, nausea and vomiting may occur at the beginning of the treatment while hypertriglyceridaemia and hypercholesterolemia may occur later. Treatment emergent adverse events led to premature study discontinuation for 7% of subjects from Phase II-IV studies.

It is important to note that cases of pancreatitis have been reported in patients receiving Kaletra, including those who developed hypertriglyceridaemia. Furthermore, rare increases in PR interval have been reported during Kaletra therapy (see section 4.4).

b. Tabulated list of adverse reactions

Adverse reactions from clinical trials and post-marketing experience in adult and paediatric patients:

The following events have been identified as adverse reactions. The frequency category includes all reported events of moderate to severe intensity, regardless of the individual causality assessment. The adverse reactions are displayed by system organ class. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥1/10,000 to <1/1000) and not known (cannot be estimated from the available data).

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

System organ class

Frequency

Adverse reaction

Infections and infestations

Very common

Upper respiratory tract infection

Common

Lower respiratory tract infection, skin infections including cellulitis, folliculitis and furuncle

Blood and lymphatic system disorders

Common

Anaemia, leucopenia, neutropenia, lymphadenopathy

Immune system disorders

Common

Hypersensitivity including urticaria and angioedema

Uncommon

Immune reconstitution inflammatory syndrome

Endocrine disorders

Uncommon

Hypogonadism

Metabolism and nutrition disorders

Common

Blood glucose disorders including diabetes mellitus, hypertriglyceridaemia, hypercholesterolemia, weight decreased, decreased appetite

Uncommon

Weight increased, increased appetite

Psychiatric disorders

Common

Anxiety

Uncommon

Abnormal dreams, libido decreased

Nervous system disorders

Common

Headache (including migraine), neuropathy (including peripheral neuropathy), dizziness, insomnia

Uncommon

Cerebrovascular accident, convulsion, dysgeusia, ageusia, tremor

Eye disorders

Uncommon

Visual impairment

Ear and labyrinth disorders

Uncommon

Tinnitus, vertigo

Cardiac disorders

Uncommon

Atherosclerosis such as myocardial infarction, atrioventricular block, tricuspid valve incompetence

Vascular disorders

Common

Hypertension

Uncommon

Deep vein thrombosis

Gastrointestinal disorders

Very common

Diarrhoea, nausea

Common

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

Uncommon

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

Hepatobiliary disorders

Common

Hepatitis including AST, ALT and GGT increases

Uncommon

Jaundice, hepatic steatosis, hepatomegaly, cholangitis, hyperbilirubinemia

Skin and subcutaneous tissue disorders

Common

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

Uncommon

Alopecia, capillaritis, vasculitis

Rare

Stevens-Johnson syndrome, erythema multiforme

Musculoskeletal and connective tissue disorders

Common

Myalgia, musculoskeletal pain including arthralgia and back pain, muscle disorders such as weakness and spasms

Uncommon

Rhabdomyolysis, osteonecrosis

Renal and urinary disorders

Uncommon

Creatinine clearance decreased, nephritis, haematuria

Not known

Nephrolithiasis

Reproductive system and breast disorders

Common

Erectile dysfunction, menstrual disorders - amenorrhoea, menorrhagia

General disorders and administration site conditions

Common

Fatigue including asthenia

1 See section 4.4: pancreatitis and lipids

c. Description of selected adverse reactions

Cushing's syndrome has been reported in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate; this could also occur with other corticosteroids metabolised via the P450 3A pathway e.g. budesonide (see section 4.4 and 4.5).

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

Metabolic parameters

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

In HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and can occur many months after initiation of treatment (see section 4.4).

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown (see section 4.4).

d. Paediatric populations

In children 2 years of age and older, the nature of the safety profile is similar to that seen in adults (see Table in section b).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme:

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

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

The adverse clinical signs observed in dogs included salivation, emesis and diarrhoea/abnormal stool. The signs of toxicity observed in mice, rats or dogs included decreased activity, ataxia, emaciation, dehydration and tremors.

There is no specific antidote for overdose with Kaletra. Treatment of overdose with Kaletra is to consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. If indicated, elimination of unabsorbed active substance is to be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed active substance. Since Kaletra is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.