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Drug Details

Kaletra 80mg/20mg Oral Solution

• Drug Class Description
  antivirals for systemic use, protease inhibitors - ATC code: J05AE06
• Generic Name
  ritonavir, lopinavir
• Presentation
  Oral solution The solution is light yellow to golden.
• Description
  Each 5 ml of Kaletra oral solution contains 400 mg of lopinavir co-formulated with 100 mg of ritonavir as a pharmacokinetic enhancer. Excipients: Each 5 ml contains 356.3 mg of alcohol (42% v/v), 168.6 mg of high fructose corn syrup, 152.7 mg of propylene glycol (see section 4.3), 10.2 mg of polyoxyl 40 hydrogenated castor oil and 4.1 mg of acesulfame potassium
• Indications
  

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

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

• Adult Dosage
  

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

  Posology

  Adult and adolescent use: the recommended dosage of Kaletra is 5 ml of oral solution (400/100 mg) twice daily taken with food.

  Paediatric use (2 years of age and above): the recommended dosage of Kaletra is 230/57.5 mg/m² twice daily taken with food, up to a maximum dose of 400/100 mg twice daily. The 230/57.5 mg/m² dosage might be insufficient in some children when co-administered with nevirapine or efavirenz. An increase of the dose of Kaletra to 300/75 mg/m² should be considered in these patients. Dose should be administered using a calibrated oral dosing syringe.

  The oral solution is the recommended option for the most accurate dosing in children based on body surface area. However, if it is judged necessary to resort to soft capsules in children, they should be used with particular caution since they are associated with less precise dosing capabilities. Therefore, children receiving soft capsules might have higher exposure (with the risk of increased toxicity) or suboptimal exposure (with the risk of insufficient efficacy). Consequently when dosing children with soft capsules, therapeutic drug monitoring may be a useful tool to ensure appropriate lopinavir exposure in an individual patient.

  Paediatric dosing guidelines for the dose 230/57.5 mg/m2
  Body Surface Area* (m2)	Twice daily oral solution dose (dose in mg)	Twice daily soft capsule dose (dose in mg)
  0.25	0.7 ml (57.5/14.4 mg)	NA
  0.40	1.2 ml (96/24 mg)	1 soft capsule (133.3/33.3 mg)
  0.50	1.4 ml (115/28.8 mg)	1 soft capsule (133.3/33.3 mg)
  0.75	2.2 ml (172.5/43.1 mg)	1 soft capsule (133.3/33.3 mg)
  0.80	2.3 ml (184/46 mg)	2 soft capsules (266.6/66.6 mg)
  1.00	2.9 ml (230/57.5 mg)	2 soft capsules (266.6/66.6 mg)
  1.25	3.6 ml (287.5/71.9 mg)	2 soft capsules (266.6/66.6 mg)
  1.3	3.7 ml (299/74.8 mg)	2 soft capsules (266.6/66.6 mg)
  1.4	4.0 ml (322/80.5 mg)	3 soft capsules (400/100 mg)
  1.5	4.3 ml (345/86.3 mg)	3 soft capsules (400/100 mg)
  1.7	5 ml (402.5/100.6 mg)	3 soft capsules (400/100 mg)

  * Body surface area can be calculated with the following equation

  BSA (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.

  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. No data are available in patients with severe hepatic impairment. Kaletra must not be given to these patients.

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

  Method of administration

  Kaletra is administered orally and should always be taken with food.

• Child Dosage
  Children less than 2 years of age: Kaletra is not recommended for use in children below 2 years of age due to insufficient data on safety and efficacy. Paediatric use (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 1.3 m2. For children weighing less than 40 kg or with a BSA of less than 1.3 m2, please refer to the Kaletra oral solution Summary of Product Characteristics.
• Contra Indications
  

  Hypersensitivity to the active substances or to any of the excipients.

  Severe hepatic insufficiency.

  Kaletra contains lopinavir and ritonavir, both of which are inhibitors of the P450 isoform CYP3A. Kaletra should not be co-administered with medicinal products that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life threatening events. These medicinal products include astemizole, terfenadine, oral midazolam (for caution on parenterally administered midazolam, see Interactions), triazolam, cisapride, pimozide, amiodarone, ergot alkaloids (e.g. ergotamine, dihydroergotamine, ergonovine and methylergonovine) lovastatin, simvastatin, sildenafil used for the treatment of pulmonary arterial hypertension (for the use of sildenafil in patients with erectile dysfunction, see Interactions) and vardenafil.

  Herbal preparations containing St John's wort (Hypericum perforatum) must not be used while taking lopinavir and ritonavir due to the risk of decreased plasma concentrations and reduced clinical effects of lopinavir and ritonavir.

  Kaletra oral solution is contraindicated in children below the age of 2 years, pregnant women, patients with hepatic or renal failure and patients treated with disulfiram or metronidazole due to the potential risk of toxicity from the excipient propylene glycol

• Special Precautions
  

  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. Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer to the relevant product information for these medicinal products.

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

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

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

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

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

  Lipid elevations

  Treatment with Kaletra has resulted in increases, sometimes marked, in the concentration of total cholesterol and triglycerides. Triglyceride and cholesterol testing is to be performed prior to initiating Kaletra therapy and at periodic intervals during therapy. Particular caution should be paid to patients with high values at baseline and with history of lipid disorders. Lipid disorders are to be managed as clinically appropriate.

  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.

  Hyperglycaemia

  New onset diabetes mellitus, hyperglycaemia or exacerbation of existing diabetes mellitus has been reported in patients receiving protease inhibitors. In some of these the hyperglycaemia was severe and in some cases also associated with ketoacidosis. Many patients had confounding medical conditions some of which required therapy with agents that have been associated with the development of diabetes mellitus or hyperglycaemia.

  Fat redistribution & metabolic disorders

  Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and protease inhibitors (PIs) and lipoatrophy and nucleoside reverse transcriptase inhibitors (NRTIs) has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with drug related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate.

  Immune Reactivation Syndrome

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

  Osteonecrosis

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

  PR interval prolongation

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

  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.

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

  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. Concomitant use of vardenafil and lopinavir/ritonavir is contraindicated. Concomitant use of sildenafil prescribed for the treatment of pulmonary arterial hypertension with Kaletra is contraindicated.

  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.

  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.

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

  Other

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

  Kaletra is not a cure for HIV infection or AIDS. It does not reduce the risk of passing HIV to others through sexual contact or contamination with blood. Appropriate precautions should be taken. People taking Kaletra may still develop infections or other illnesses associated with HIV disease and AIDS.

  Besides propylene glycol as described above, Kaletra oral solution contains alcohol (42% v/v) which is potentially harmful for those suffering from liver disease, alcoholism, epilepsy, brain injury or disease as well as for pregnant women and children. It may modify or increase the effects of other medicines. Kaletra oral solution contains up to 0.8 g of fructose per dose when taken according to the dosage recommendations. This may be unsuitable in hereditary fructose intolerance. Kaletra oral solution contains up to 0.3 g of glycerol per dose. Only at high inadvertent doses, it can cause headache and gastrointestinal upset. Furthermore, polyoxol 40 hydrogenated castor oil and potassium present in Kaletra oral solution may cause only at high inadvertent doses gastrointestinal upset. Patients on a low potassium diet should be cautioned.

• Interactions
  

  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.

  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 ContraIndications.

  Known and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal products are listed in the table below.

  Interaction table

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

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

  Co-administered drug by therapeutic Area	Effects on drug levels 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 Kaletra.	The clinical significance of reduced abacavir and zidovudine concentrations is unknown.
  Tenofovir, 300 mg QD	Tenofovir: AUC: ↑ 32% Cmax: ↔ Cmin: ↑ 51% Lopinavir: ↔	No dose adjustment necessary. Higher tenofovir concentrations could potentiate tenofovir associated adverse events, including renal disorders.
  Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
  Efavirenz, 600 mg QD	Lopinavir: AUC: 20% Cmax: 13% Cmin: 42%	The Kaletra tablets dosage should be increased to 500/125 mg twice daily when co-administered with efavirenz.
  Efavirenz, 600 mg QD (Lopinavir/ritonavir 500/125 mg BID)	Lopinavir: ↔ (Relative to 400/100 mg BID administered alone)
  Nevirapine, 200 mg BID	Lopinavir: AUC: 27% Cmax: 19% Cmin: 51%	The Kaletra tablets dosage should be increased to 500/125 mg twice daily when co-administered with nevirapine.
  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 lopinavir/ritonavir (533/133 mg BID) to protease inhibitor-experienced patients resulted in a higher incidence of gastrointestinal adverse events and elevations in triglycerides with the combination regimen without increases in virological efficacy, when compared with standard doses of fosamprenavir/ritonavir. Concomitant administration of these medicinal products is not recommended.
  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.
  Nelfinavir	Lopinavir: Concentrations	The appropriate doses for this combination, with respect to efficacy and safety, have not been established.
  Saquinavir 1000 mg BID	Saquinavir: ↔	No dose adjustment necessary.
  Tipranavir/ritonavir (500/100 mg BID)	Lopinavir: AUC: 55% Cmin: 47% Cmax: 70%	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
  Analgesics
  Fentanyl	Fentanyl: Increased risk of side-effects (respiratory depression, sedation) due to higher plasma concentrations because of CYP3A4 inhibition by Kaletra	Careful monitoring of adverse effects (notably respiratory depression but also sedation) is recommended when fentanyl is concomitantly administered with Kaletra.
  Antiarrhythmics
  Digoxin	Digoxin: Plasma concentrations may be increased due to P-glycoprotein inhibition by Kaletra. The increased digoxin level may lessen over time as Pgp induction develops.	Caution is warranted and therapeutic drug monitoring of digoxin concentrations, if available, is recommended in case of co-administration of Kaletra and digoxin. Particular caution should be used when prescribing Kaletra in patients taking digoxin as the acute inhibitory effect of ritonavir on Pgp is expected to significantly increase digoxin levels. Initiation of digoxin in patients already taking Kaletra is likely to result in lower than expected increases of digoxin concentrations.
  Bepridil, Systemic Lidocaine, and Quinidine	Bepridil, Systemic Lidocaine, Quinidine: Concentrations may be increased when co-administered with Kaletra.	Caution is warranted and therapeutic drug concentration monitoring is recommended when available.
  Antibiotics
  Clarithromycin	Clarithromycin: Moderate increases in clarithromycin AUC are expected due to CYP3A inhibition by Kaletra.	For patients with renal impairment (CrCL <30 ml/min) dose reduction of clarithromycin should be considered. Caution should be exercised in administering clarithromycin with Kaletra to patients with impaired hepatic or renal function.
  Anticancer agents
  Most tyrosine kinase inhibitors such as dasatinib and nilotinib, Vincristine, Vinblastine	Most tyrosine kinase inhibitors such as dasatinib and nilotinib, also vincristine and vinblastine: Risk of increased adverse events due to higher serum concentrations because of CYP3A4 inhibition by Kaletra.	Careful monitoring of the tolerance of these anticancer agents.
  Anticoagulants
  Warfarin	Warfarin: Concentrations may be affected when co-administered with Kaletra due to CYP2C9 induction.	It is recommended that INR (international normalised ratio) be monitored.
  Anticonvulsants
  Phenytoin	Phenytoin: Steady-state concentrations were moderately decreased due to CYP2C9 and CYP2C19 induction by Kaletra. 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 lopinavir/ritonavir. When co-administered with phenytoin, an increase of Kaletra dosage may be envisaged. Dose adjustment has not been evaluated in clinical practice.
  Carbamazepine and Phenobarbital	Carbamazepine: Serum concentrations may be increased due to CYP3A inhibition by Kaletra. 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 lopinavir/ritonavir. When co-administered with carbamazepine or phenobarbital, an increase of Kaletra dosage may be envisaged. Dose adjustment has not been evaluated in clinical practice
  Antidepressants and Anxiolytics
  Trazodone single dose (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 lopinavir/ritonavir causes a similar increase in trazodone exposure. The combination should be used with caution and a lower dose of trazodone should be considered.
  Antifungals
  Ketoconazole and Itraconazole	Ketoconazole, Itraconazole: Serum concentrations may be increased due to CYP3A inhibition by Kaletra.	High doses of ketoconazole and itraconazole (> 200 mg/day) are not recommended.
  Voriconazole	Voriconazole: Concentrations may be decreased.	Co-administration of voriconazole and low dose ritonavir (100 mg BID) as contained in Kaletra should be avoided unless an assessment of the benefit/risk to patient justifies the use of voriconazole.
  Antimycobacterials
  Rifabutin, 150 mg QD	Rifabutin (parent drug and active 25-O-desacetyl metabolite): AUC: ↑ 5.7-fold 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.
  Benzodiazepines
  Midazolam	Oral Midazolam: AUC: ↑ 13-fold Parenteral Midazolam: AUC: ↑ 4-fold Due to CYP3A inhibition by Kaletra	Kaletra must not be co-administered with oral midazolam, whereas caution should be used with co-administration of Kaletra and parenteral midazolam. If Kaletra is co-administered with parenteral midazolam, it should be done in an intensive care unit (ICU) or similar setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage adjustment for midazolam should be considered especially if more than a single dose of midazolam is administered.
  Calcium channel blockers
  Felodipine, Nifedipine, and Nicardipine	Felodipine, Nifedipine, Nicardipine: Concentrations may be increased due to CYP3A inhibition by Kaletra.	Clinical monitoring of therapeutic and adverse effects is recommended when these medicines are concomitantly administered with Kaletra.
  Corticosteroids
  Dexamethasone	Lopinavir: Concentrations may be decreased due to CYP3A induction by dexamethasone.	Clinical monitoring of antiviral efficacy is recommended when these medicines are concomitantly administered with Kaletra.
  Fluticasone propionate, 50 μg intranasal 4 times daily (100 mg ritonavir BID)	Fluticasone propionate: Plasma concentrations ↑ Cortisol levels 86%	Greater effects may be expected when fluticasone propionate is inhaled. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate; this could also occur with other corticosteroids metabolised via the P450 3A pathway eg budesonide. Consequently, concomitant administration of Kaletra and these glucocorticoids is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. A dose reduction of the glucocorticoid should be considered with close monitoring of local and systemic effects or a switch to a glucocorticoid, which is not a substrate for CYP3A4 (eg beclomethasone). Moreover, in case of withdrawal of glucocorticoids progressive dose reduction may have to be performed over a longer period.
  Erectile Dysfunction, Phosphodiesterase(PDE5) inhibitors
  Tadalafil	Tadalafil: AUC: ↑ 2-fold Due to CYP3A inhibition by Kaletra.	Particular caution must be used when prescribing sildenafil or tadalafil in patients receiving Kaletra with increased monitoring for adverse events including hypotension, syncope, visual changes and prolonged erection. When co-administered with Kaletra, sildenafil doses must not exceed 25 mg in 48 hours and tadalafil doses must not exceed 10 mg every 72 hours. Co-administration of Kaletra with sildenafil used for the treatment of pulmonary arterial hypertension is contra-indicated.
  Sildenafil	Sildenafil: AUC: ↑ 11-fold Due to CYP3A inhibition by Kaletra.
  Vardenafil	Vardenafil: AUC: ↑ 49-fold Due to CYP3A inhibition by Kaletra.	The use of vardenafil with Kaletra is contraindicated.
  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. Therefore, Kaletra can be started safely 2 weeks after cessation of St. John's wort.
  Immunosuppressants
  Cyclosporin, Sirolimus (rapamycin), and Tacrolimus	Cyclosporin, Sirolimus (rapamycin), Tacrolimus: Concentrations may be increased due to CYP3A inhibition by Kaletra.	More frequent therapeutic concentration monitoring is recommended until plasma levels of these products have been stabilised.
  Lipid lowering agents
  Lovastatin and Simvastatin	Lovastatin, Simvastatin: Markedly increased plasma concentrations due to CYP3A inhibition by Kaletra.	Since increased concentrations of HMG-CoA reductase inhibitors may cause myopathy, including rhabdomyolysis, the combination of these agents with Kaletra is contraindicated.
  Atorvastatin	Atorvastatin: AUC: ↑ 5.9-fold Cmax: ↑ 4.7-fold Due to CYP3A inhibition by Kaletra.	The combination of Kaletra with atorvastatin is not recommended. If the use of atorvastatin is considered strictly necessary, the lowest possible dose of atorvastatin should be administered with careful safety monitoring.
  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.
  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	Bupropion and its active metabolite, hydroxybupropion: AUC and Cmax ~50% This effect may be due to induction of bupropion metabolism.	If the co-administration of lopinavir/ritonavir with bupropion is judged unavoidable, this should be done under close clinical monitoring for bupropion efficacy, without exceeding the recommended dosage, despite the observed induction.
  Other medicinal products
  Based on known metabolic profiles, clinically significant interactions are not expected between Kaletra and dapsone, trimethoprim/sulfamethoxazole, azithromycin or fluconazole.

• Adverse Drug Reactions
  

  a. Summary of the safety profile

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

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

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

  b. Tabulated list of adverse reactions

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

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

  Events noted as having frequency “Not known” were identified via post-marketing surveillance.

  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 syndrome
  Endocrine disorders	Uncommon	Hypogonadism
  Metabolism and nutrition disorders	Common	Blood glucose disorders including diabetes mellitus, hypertriglyceridaemia, hypercholesterolemia, weight decreased, decreased appetite
  	Uncommon	Weight increased, increased appetite
  Psychiatric disorders	Common	Anxiety
  	Uncommon	Abnormal dreams, libido decreased
  Nervous system disorders	Common	Headache (including migraine), neuropathy (including peripheral neuropathy), dizziness, insomnia
  	Uncommon	Cerebrovascular accident, convulsion, dysgeusia, ageusia, tremor
  Eye disorders	Uncommon	Visual impairment
  Ear and labyrinth disorders	Uncommon	Tinnitus, vertigo
  Cardiac disorders	Uncommon	Atherosclerosis such as myocardial infarction1, atrioventricular block, tricuspid valve incompetence
  Vascular disorders	Common	Hypertension
  	Uncommon	Deep vein thrombosis
  Gastrointestinal disorders	Very common	Diarrhoea, nausea
  	Common	Pancreastitis1, 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	Hepatic steatosis, hepatomegaly, cholangitis, hyperbilirubinemia
  	Not known	Jaundice
  Skin and subcutaneous tissue disorders	Common	Lipodystrophy acquired including facial wasting, rash including maculopapular rash, dermatitis/rash including eczema and seborrheic dermatitis, night sweats, pruritis
  	Uncommon	Alopecia, capillaritis, vasculitis
  	Not known	Steven-Johnson syndrome, erythema multiforme
  Musculoskeletal and connective tissue disorders	Common	Myalgia, musculoskeletal pain including arthralgia and back pain, muscle disorders such as weakness and spasms
  	Uncommon	Rhabdomyolysis, osteonecrosis
  Renal and urinary disorders	Uncommon	Creatinine clearance decreased, nephritis, haematuria
  Reproductive system and breast disorders	Common	Erectile dysfunction, menstrual disorders - amenorrhoea, menorrhagia
  General disorders and administration site conditions	Common	Fatigue including asthenia

  ¹ See Precautions: 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.

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

  Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump).

  Combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia.

  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.

  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.

  d. Paediatric populations

  In children 2 years of age and older, the nature of the safety profile is similar to that seen in adults.