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Drug Details

KALETRA Capsules

• Drug Class Description
  Antiviral for Systemic Use
• Generic Name
  Lopinavir and Ritonavir
• Presentation
  Film-coated tablet Pale yellow debossed with [Abbott logo] and “KC”.
• Description
  Kaletra 133.3 mg/33.3 mg Soft Capsules - The capsules are orange with a black ink imprint of [Abbott logo] and “PK”.
• Indications
  Kaletra is indicated for the treatment of HIV-1 infected children above the age of 2 years and adults, in combination with other antiretroviral agents. Most experience with Kaletra is derived from the use of the product in antiretroviral therapy naïve patients. Data in heavily pretreated protease inhibitor experienced patients are limited. There are limited data on salvage therapy on patients who have failed therapy with Kaletra. 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.

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

  Adult and adolescent use: the recommended dosage of Kaletra tablets is two 200/50 mg tablets twice daily taken with or without food. 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 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 1.4 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.

  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 BSA.

  Paediatric Dosing Guidelines
  Body Surface Area (m2 )	Recommended number of 100/25 mg tablets twice-daily
  0.5 to < 0.9	2 tablets (200/50 mg)
  0.9 to < 1.4	3 tablets (300/75 mg)
  1.4	4 tablets (400/100 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.

  * 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: Kaletra is not recommended for use in children below 2 years of age due to insufficient data on safety and efficacy.

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

  Renal impairment: no dose adjustment is necessary in patients with renal impairment. Caution is warranted when Kaletra is used in patients with severe renal impairment.

• Contra Indications
  

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

  Patients with 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, triazolam, cisapride, pimozide, amiodarone, ergot alkaloids (e.g. ergotamine, dihydroergotamine, ergonovine and methylergonovine) 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.

• 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.

  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 and 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 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 carinii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

  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 HIVdisease and/or longterm 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 HMG-CoA reductase inhibitors simvastatin and lovastatin are highly dependent on CYP3A for metabolism, thus concomitant use of Kaletra with simvastatin or lovastatin is not recommended due to an increased risk of myopathy including rhabdomyolysis. Caution must also be exercised and reduced doses should be considered if Kaletra is used concurrently with rosuvastatin or with atorvastatin, which is metabolised to a lesser extent by CYP3A4. If treatment with a HMG-CoA reductase inhibitor is indicated, pravastatin or fluvastatin is recommended.

  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 events. Cardiac events have been reported with Kaletra in preclinical studies; therefore, the potential cardiac effects of Kaletra cannot be currently ruled out.

  Coadministration 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 coadministration should be avoided unless judged strictly necessary.

  Other

  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 blood contamination. Appropriate precautions should be taken. People taking Kaletra may still develop infections or other illnesses associated with HIV disease and AIDS.

  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.

• 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 and by glucuronidation. This may result in lowered plasma concentrations and potential decrease of efficacy of co-administered medicinal products.

  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.

  Antiretroviral agents

  Nucleoside/Nucleotide reverse transcriptase inhibitors (NRTIs):

  Stavudine and Lamivudine: no change in the pharmacokinetics of lopinavir was observed when Kaletra was given alone or in combination with stavudine and lamivudine in clinical studies.

  Didanosine: it is recommended that didanosine be administered on an empty stomach; therefore, didanosine may be co-administered with Kaletra tablets without food.

  Zidovudine and Abacavir: Kaletra induces glucuronidation; therefore Kaletra has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.

  Tenofovir: when tenofovir disoproxil fumarate was coadministered with Kaletra, tenofovir concentrations were increased by approximately 30% with no changes noted in lopinavir or ritonavir concentrations. Higher tenofovir concentrations could potentiate tenofovir associated adverse events, including renal disorders.

  Non-nucleoside reverse transcriptase inhibitors (NNRTIs):

  In a study performed in healthy volunteers to explore the interaction between Kaletra tablets (400/100 mg twice daily) and efavirenz (600 mg once daily), efavirenz has been shown to decrease the lopinavir concentrations by 30 40%. When Kaletra tablet dosages were increased to 500/125 mg twice daily during coadministration of efavirenz 600 mg once daily in healthy volunteers, lopinavir pharmacokinetic parameters were similar to those obtained with Kaletra tablets 400/100 mg twice daily administered alone. Therefore, the Kaletra tablets dosage should be increased to 500/125 mg twice daily when coadministered with efavirenz 600 mg once daily.

  Similar pharmacokinetic interactions are expected for the co-administration of Kaletra tablets with the NNRTI nevirapine and with the protease inhibitors nelfinavir and amprenavir. The same recommendations for monitoring apply in these cases of co-administration.

  Co-administration with other HIV protease inhibitors (PIs):

  Kaletra (400/100 mg twice daily) has been studied in combination with reduced doses of amprenavir, indinavir, nelfinavir and saquinavir in steady-state controlled healthy volunteer studies relative to clinical doses of each HIV protease inhibitor in the absence of ritonavir. Comparisons to published pharmacokinetic data with ritonavir-enhanced amprenavir and saquinavir regimens are also described. Additionally, the effect of additional ritonavir on the pharmacokinetics of lopinavir are discussed. Note that the historical comparisons to ritonavir-enhanced protease inhibitor regimens should be interpreted with caution (see details of combinations below). Appropriate doses of HIV-protease inhibitors in combination with Kaletra with respect to safety and efficacy have not been established. Therefore, the concomitant administration of Kaletra with PIs requires close monitoring.

  Amprenavir: see recommendations described for Kaletra tablets coadministration with efavirenz.

  Fosamprenavir: co-administration of standard doses of lopinavir/ritonavir with fosamprenavir results in a significant reduction in amprenavir concentrations. Co-administration of increased doses of fosamprenavir 1400 mg twice daily with lopinavir/ritonavir 533/133 mg twice daily to protease inhibitorexperienced 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. Therefore, concomitant administration of these medicinal products is not recommended.

  Indinavir: indinavir 600 mg twice daily in combination with Kaletra produces similar indinavir AUC, higher C_min (by 3.5-fold) and lower C_max relative to indinavir 800 mg three times daily alone. Furthermore, concentrations of lopinavir do not appear to be affected when both medicinal products, Kaletra and indinivir, are combined, based on historical comparison with Kaletra alone.

  Nelfinavir: see recommendations described for Kaletra tablets coadministration with efavirenz.

  Saquinavir: saquinavir 800 mg twice daily co-administered with Kaletra produces an increase of saquinavir AUC by 9.6-fold relative to saquinavir 1200 mg three times daily given alone.

  Saquinavir 800 mg twice daily co-administered with Kaletra resulted in an increase of saquinavir AUC by approximately 30% relative to saquinavir/ritonavir 1000/100 mg twice daily, and produces similar exposure to those reported after saquinavir/ritonavir 400/400 mg twice daily.

  When saquinavir 1200 mg twice daily was combined with Kaletra, no further increase of concentrations was noted. Furthermore, concentrations of lopinavir do not appear to be affected when both medicinal products, Kaletra and saquinavir, are combined, based on historical comparison with Kaletra alone.

  Ritonavir: Kaletra co-administered with an additional 100 mg ritonavir twice daily resulted in an increase of lopinavir AUC and C_min of 33% and 64%, respectively, as compared to Kaletra alone.

  Other medicinal products:

  Acid reducing agents (omeprazole, ranitidine): in a study performed in healthy volunteers, no clinically relevant interaction has been observed when Kaletra tablets 400/100 mg twice daily was coadministered with omeprazole or with ranitidine. Kaletra can be coadministered with acid reducing agents with no dose adjustment.

  Antiarrhythmics: (bepridil, systemic lidocaine and quinidine): concentrations may be increased when co-administered with Kaletra. Caution is warranted and therapeutic concentration monitoring is recommended when available.

  Anticancer agents (eg vincristine, vinblastine): these agents may have their serum concentrations increased when coadministered with lopinavir/ritonavir resulting in the potential for increased adverse events usually associated with these anticancer agents.

  Anticoagulants: warfarin concentrations may be affected when co-administered with Kaletra. It is recommended that INR (international normalised ratio) be monitored.

  Anticonvulsants (phenobarbital, phenytoin, carbamazepine): will induce CYP3A4 and may decrease lopinavir concentrations.

  In addition, coadministration of phenytoin and lopinavir/ritonavir resulted in moderate decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when coadministering with lopinavir/ritonavir.

  Bupropion: in healthy volunteers, the AUC and C_max of bupropion and of its active metabolite, hydroxybupropion, were decreased by about 50% when co-administered with lopinavir/ritonavir capsules 400/100 mg twice daily at steady-state. This effect may be due to induction of bupropion metabolism. Therefore, if the coadministration 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.

  Trazodone: in a pharmacokinetic study performed in healthy volunteers, concomitant use of low dose ritonavir (200 mg twice daily) with a single dose of trazodone led to an increase in plasma concentrations of trazodone (AUC increased by 2.4 fold). Adverse events of nausea, dizziness, hypotension and syncope were observed following co-administration of trazodone and ritonavir in this study. However, 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.

  Digoxin: plasma concentrations of digoxin may be increased when coadministered with Kaletra. Caution is warranted and therapeutic drug monitoring of digoxin concentrations, if available, is recommended in case of coadministration 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. The increased digoxin level may lessen over time as Pgp induction develops. Initiation of digoxin in patients already taking Kaletra is expected to result in lower increase of digoxin concentrations.

  Dihydropyridine calcium channel blockers: (e.g. felodipine, nifedipine, nicardipine): may have their serum concentrations increased by Kaletra.

  Lipid lowering agents: HMG-CoA reductase inhibitors which are highly dependent on CYP3A4 metabolism, such as lovastatin and simvastatin, are expected to have markedly increased plasma concentrations when co-administered with Kaletra. Since increased concentrations of HMG-CoA reductase inhibitors may cause myopathy, including rhabdomyolysis, the combination of these medicinal products with Kaletra is not recommended. Atorvastatin is less dependent on CYP3A for metabolism. When atorvastatin was given concurrently with Kaletra, a mean 4.7-fold and 5.9-fold increase in atorvastatin C_max and AUC, respectively, was observed. When used with Kaletra, the lowest possible dose of atorvastatin should be administered. Rosuvastatin is not dependent on CYP3A. However, when given concurrently with Kaletra a mean 5fold and 2fold increase in rosuvastatin C_max and AUC, respectively, was observed. Caution should be exercised when Kaletra is coadministered with rosuvastatin. Results from an interaction study with Kaletra and pravastatin reveal no clinically significant interaction. The metabolism of pravastatin and fluvastatin is not dependent on CYP3A4, and interactions are not expected with Kaletra. If treatment with a HMG-CoA reductase inhibitor is indicated, pravastatin or fluvastatin is recommended.

  Dexamethasone: may induce CYP3A4 and may decrease lopinavir concentrations.

  Phosphodiesterase inhibitors: phosphodiesterase inhibitors which are dependent on CYP3A4 metabolism, such as tadalafil and sildenafil, are expected to result in an approximately 2fold and 11fold increase in AUC respectively, when co-administered with ritonavir containing regimens including Kaletra and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, synope, visual changes and prolonged erection. Particular caution must be used when prescribing sildenafil or tadalafil in patients receiving Kaletra with increased monitoring for adverse events. Co-administration of vardenafil with rtionavir containing regimens including Kaletra is expected to result in 49fold increase in vardenafil AUC. The use of vardenafil with Kaletra is contraindicated.

  Cyclosporin, sirolimus (rapamycin) and tacrolimus: concentrations may be increased when coadministered with Kaletra. More frequent therapeutic concentration monitoring is recommended until plasma levels of these products have been stabilised.

  Ketoconazole and itraconazole: may have serum concentrations increased by Kaletra. High doses of ketoconazole and itraconazole (> 200 mg/day) are not recommended.

  Voriconazole: due to the potential for reduced voriconazole concentrations, coadministration of voriconazole and low dose ritonavir (100 mg twice daily) as contained in Kaletra should be avoided unless an assessment of the benefit/risk to patient justifies the use of voriconazole.

  Clarithromycin: moderate increases in clarithromycin AUC are expected when co-administered with Kaletra. For patients with renal or hepatic impairment dose reduction of clarithromycin should be considered.

  Buprenorphine: buprenorphine (dosed at 16 mg daily) coadministered with lopinavir/ritonavir (dosed at 400/100 mg twice daily) showed no clinically significant interaction. Kaletra can be coadministered with buprenorphine with no dose adjustment.

  Methadone: Kaletra was demonstrated to lower plasma concentrations of methadone. Monitoring plasma concentrations of methadone is recommended.

  Contraceptives: levels of ethinyl oestradiol were decreased when oestrogen-based oral contraceptives were co-administered with Kaletra. In case of coadministration of Kaletra with contraceptives containing ethinyl oestradiol (whatever the contraceptive formulation e.g. oral or patch), alternative methods of contraception are to be used.

  Rifabutin: when rifabutin and Kaletra were co-administered for 10 days, rifabutin (parent substance and active 25-O-desacetyl metabolite) C_max and AUC were increased by 3.5- and 5.7-fold, respectively. On the basis of these data, a rifabutin dose reduction of 75% (i.e. 150 mg every other day or 3 times per week) is recommended when administered with Kaletra. Further reduction may be necessary.

  Rifampicin: coadministration of Kaletra with rifampicin is not recommended. Rifampicin administered with Kaletra causes large decreases in lopinavir concentrations which may in turn significantly decrease the lopinavir therapeutic effect. A dose adjustment of Kaletra 400 mg/400 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 coadministration should be avoided unless judged strictly necessary. If this coadministration 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.

  St John's wort: serum levels of lopinavir and ritonavir can be reduced by concomitant use of the herbal preparation St John's wort (Hypericum perforatum). This is due to the induction of drug metabolising enzymes by St John's wort. Herbal preparations containing St John's wort should therefore 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.

  Midazolam: midazolam is extensively metabolised by CYP3A4. Coadministration with Kaletra may cause a large increase in the concentration of this benzodiazepine. A phenotyping cocktail study in 14 healthy volunteers showed an increase of AUC by about 13 fold with oral midazolam and an increase by about 4 fold with parenteral midazolam. Therefore, Kaletra should not be coadministered with orally administered midazolam, whereas caution should be used with coadministration of Kaletra and parenteral midazolam. If Kaletra is coadministered 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.

  Fluticasone propionate (interaction with ritonavir): in a clinical study where ritonavir 100 mg capsules twice daily were co − administered with 50 μg intranasal fluticasone propionate (4 times daily) for seven days in healthy subjects, the fluticasone propionate plasma levels increased significantly, whereas the intrinsic cortisol levels decreased by approximately 86% (90% confidence interval 82 − 89%). 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. The effects of high fluticasone systemic exposure on ritonavir plasma levels is yet unknown.

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

• Adverse Drug Reactions
  

  The safety of Kaletra has been investigated in 612 patients in Phase II/III clinical trials, of which 442 have received a dose of 400/100 mg twice daily. In some studies, Kaletra was used in combination with efavirenz or nevirapine.

  The most common adverse reaction associated with Kaletra therapy was diarrhoea and was generally of mild to moderate severity. Discontinuation due to adverse reactions was 4.5% (naïve patients) and 9% (experienced patients) over a 48 week period.

  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.

  Increased 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.

  Adult patients

  Adverse reactions:

  The following adverse reactions of moderate to severe intensity with possible or probable relationship to Kaletra have been reported. 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, < 1/10, uncommon > 1/1000, < 1/100.

  Undesirable effects in clinical studies in adult patients
  Infections and infestations	Uncommon	Otitis media, bronchitis, sinusitis, furunculosis, bacterial infection, viral infection
  Neoplasms benign, malignant and unspecified (including cysts and polyps)	Uncommon	Skin benign neoplasm, cyst
  Blood and lymphatic system disorders	Uncommon	Anaemia, leucopenia and lymphadenopathy
  Endocrine disorders	Uncommon	Hypogonadism male, Cushing syndrome, hypothyroidism
  Metabolic and nutritional disorders	Uncommon	Avitaminosis, dehydration, oedema, increased appetite, lactic acidosis, obesity, anorexia, diabetes mellitus, hyperglycaemia, hypocholesteremia
  Psychiatric disorders	CommonUncommon	InsomniaAbnormal dreams, agitation, anxiety, confusion, depression, dyskinesia, emotional lability, decreased libido, nervousness, abnormal thinking
  Nervous system disorders	CommonUncommon	Headache, paresthesiaDizziness, amnesia, ataxia, encephalopathy, facial paralysis, hypertonia, neuropathy, peripheral neuritis, somnolence, tremor, taste loss, taste perversion, migraine, extrapyramidal syndrome
  Eye disorders	Uncommon	Abnormal vision, eye disorder
  Ear and labyrinth disorders	Uncommon	Tinnitus
  Cardiac disorders	Uncommon	Palpitation, lung oedema, myocardial infarct1
  Vascular disorders	Uncommon	Hypertension, thrombophlebitis, vasculitis, varicose vein, deep thrombophlebitis, vascular disorder
  Respiratory, thoracic and mediastinal disorders	Uncommon	Dyspnoea, rhinitis, cough increased
  Gastrointestinal disorders	Very commonCommonUncommon	DiarrhoeaNausea, vomiting, abdominal pain, abnormal stools, dyspepsia, flatulence, gastrointestinal disorderAbdomen enlarged, constipation, dry mouth, dysphagia, enterocolitis, eructation, oesophagitis, faecal incontinence, gastritis, gastroenteritis, haemorrhagic colitis, mouth ulcerations, pancreatitis2 , sialadenitis, stomatitis, ulcerative stomatitis, periodontitis
  Hepatobiliary disorders	Uncommon	Cholecystitis, hepatitis, hepatomegaly, liver fatty deposit, liver tenderness
  Skin and subcutaneous tissue disorders	CommonUncommon	Rash, lipodystrophy, acneAlopecia, dry skin, eczema, exfoliative dermatitis, maculopapular rash, nail disorder, pruritis, seborrhoea, skin discoloration, skin ulcer, face oedema, sweating, skin striae
  Musculoskeletal and connective tissue disorders	Uncommon	Arthralgia, arthrosis, myalgia, back pain, joint disorder
  Renal and urinary disorders	Uncommon	Kidney calculus, urine abnormality, albuminuria, hypercalcinuria, nephritis, hyperuricemia
  Reproductive system and breast disorders	Uncommon	Abnormal ejaculation, amenorrhoea, breast enlargement, gynecomastia, impotence, menorrhagia
  General disorders and administration site conditions	CommonUncommon	Asthenia, painChest pain, chest pain substernal, chills, fever, flu syndrome, malaise, peripheral oedema, drug interaction
  Investigations	Very common(Grade 3 or 4) Common(Grade 3 or 4) Uncommon	Increased triglycerides, increased total cholesterol, increased GGTIncreased glucose, increased amylase, increased SGOT/AST, increased SGPT/ALT, liver function tests abnormalDecreased glucose tolerance, weight gain, weight loss, increased bilirubin, hormone level altered, lab test abnormal

  ¹ This event had a fatal outcome.

  Paediatric patients

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

  Undesirable effects in clinical studies in paediatric patients
  Infections and infestations	Common	Viral infection
  Nervous system disorders	Common	Taste perversion
  Gastrointestinal disorders	Common	Constipation, vomiting, pancreatitis*
  Hepatobiliary disorders	Common	Hepatomegaly
  Skin and subcutaneous tissue disorders	Common	Rash, dry skin
  General disorders and administration site conditions	Common	Fever
  Investigations	Common(Grade 3 or 4)	Increased activated partial thromboplastin time, decreased haemoglobin, decreased platelets, increased sodium, increased potassium, increased calcium, increased bilirubin, increased SGPT/ALT, increased SGOT/AST, increased total cholesterol, increased amylase, increased uric acid, decreased sodium, decreased potassium, decreased calcium, decreased neutrophils

  Post marketing experience

  Hepatitis, and rarely jaundice, have been reported in patients on Kaletra therapy in the presence or absence of identifiable risk factors for hepatitis.

  StevensJohnson syndrome and erythema multiforme have been reported.

  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.