LOPINAVIR/RITONAVIR MYLAN

Lopinavir/ritonavir should be prescribed by physicians who are experienced in the treatment of HIV infection. Lopinavir/ritonavir tablets must be swallowed whole and not chewed, broken or crushed. Posology Adults and adolescents The standard recommended dosage of lopinavir/ritonavir 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, lopinavir/ritonavir tablets may be administered as 800/200 mg (four 200/50 mg tablets) once daily with or without food. e.

8) compared to the recommended standard twice daily dosing. 4 m2. 4 m2 and able to swallow tablets, please refer to the dosing guideline tables below. 1). Before prescribing lopinavir/ritonavir 100/25 mg tablets, infants and young children should be assessed for the ability to swallow intact tablets.

For infants and young children unable to swallow tablets, more suitable formulations containing lopinavir/ritonavir should be checked for their availability. The following table contains dosing guidelines for lopinavir/ritonavir 100/25 mg tablets based on body weight and BSA.

4 4 tablets (400/100 mg) * weight based dosing recommendations are based on limited data If more convenient for patients, the lopinavir/ritonavir 200/50 mg tablets may also be considered alone or in combination with the lopinavir/ritonavir 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 lopinavir/ritonavir in children aged less than 2 years have not yet been established.

2 but no recommendation on a posology can be made.

Concomitant Therapy:

Efavirenz or nevirapine The following table contains dosing guidelines for lopinavir/ritonavir 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 lopinavir/ritonavir dosing (mg) twice daily.

4 500/125 mg * The tablets must not be chewed, broken or crushed. 2). No data are available in patients with severe hepatic impairment. 3). Renal impairment Since the renal clearance of lopinavir and ritonavir is negligible, increased plasma concentrations are not expected in patients with renal impairment.

Summary of the safety profile The safety of lopinavir/ritonavir 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, lopinavir/ritonavir was used in combination with efavirenz or nevirapine.

The most common adverse reactions related to lopinavir/ritonavir therapy during clinical trials were diarrhoea, nausea, vomiting, hypertriglyceridaemia and hypercholesterolemia. The risk of diarrhoea may be greater with once daily dosing of lopinavir/ritonavir.

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 lopinavir/ritonavir, including those who developed hypertriglyceridaemia. 4). 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).

g. 5). Increased creatine phosphokinase (CPK), myalgia, myositis, and rarely, rhabdomyolysis have been reported with protease inhibitors, particularly in combination with nucleoside reverse transcriptase inhibitors. 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.

Patients with coexisting conditions Hepatic impairment The safety and efficacy of lopinavir/ritonavir has not been established in patients with significant underlying liver disorders. 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.

1. Severe hepatic insufficiency. Lopinavir/Ritonavir Mylan tablets contain lopinavir and ritonavir, both of which are inhibitors of the P450 isoform CYP3A. Lopinavir/ritonavir 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.

5). 5). Antiarrhythmics Amiodarone, dronedarone Increased plasma concentrations of amiodarone and dronedarone. 5). Medicinal product class Medicinal products within class Rationale Antibiotic Fusidic Acid Increased plasma concentrations of fusidic acid.

5). 5). Anticancer Venetoclax Increased plasma concentrations of venetoclax. 5). Anti-gout Colchicine Increased plasma concentrations of colchicine. 5). Antihistamines Astemizole, terfenadine Increased plasma concentrations of astemizole and terfenadine.

5). 5) Pimozide Increased plasma concentrations of pimozide. 5). Antipsychotics/ Neuroleptics Quetiapine Increased plasma concentrations of quetiapine which may lead to coma. 5). 5). Medicinal product class Medicinal products within class Rationale GI motility agent Cisapride Increased plasma concentrations of cisapride.

5). 5). 5). 5). 5). 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).