LOPINAVIR / RITONAVIR ACCORD

Lopinavir / Ritonavir tablets 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 Adult 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. An oral solution is available on the market to patients who have difficulty swallowing. 4 m2. 4 m2. 1). * Body surface area can be calculated with the following equation: BSA (m2) = √ (Height (cm) X Weight (kg) / 3600) Children less than 2 years of age: the safety and efficacy of Lopinavir / Ritonavir tablets 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* Lopinavir / Ritonavir tablets must not be chewed, broken or crushed. * This dose cannot be achieved with this product as the use of a 100/25 mg strength is necessary. The availability of a lopinavir/ritonavir 100/25 mg strength from other brands should be checked.

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.

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.

a. 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). 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 and 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 Very common Upper respiratory tract infectionInfections and infestations Common Lower respiratory tract infection, skin infections including cellulitis, folliculitis and Blood and lymphatic system disorders Common Anaemia, leucopenia, neutropenia, lymphadenopathy Common Hypersensitivity including urticaria and angioedema Immune system disorders Uncommon Immune reconstitution inflammatory syndrome Endocrine disorders Uncommon Hypogonadism Common Blood glucose disorders including diabetes mellitus, hypertriglyceridaemia, hypercholesterolemia, weight decreased, decreased appetite Metabolism and nutrition disorders Uncommon Weight increased, increased appetite Common AnxietyPsychiatric disorders Uncommon Abnormal dreams, libido decreased Common Headache (including migraine), neuropathy (including peripheral neuropathy), dizziness, insomnia Nervous system disorders 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 Common HypertensionVascular disorders Uncommon Deep vein thrombosis Very common Diarrhoea, nausea Common Pancreatitis1, vomiting, gastrooesophageal reflux disease, gastroenteritis and colitis, abdominal pain (upper and lower), abdominal distension, dyspepsia, haemorrhoids, flatulence.

Patients with coexisting conditions Hepatic impairment The safety and efficacy of Lopinavir / Ritonavir tablets 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 tablets contains lopinavir and ritonavir, both of which are inhibitors of the P450 isoform CYP3A. Lopinavir / Ritonavir tablets 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). 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). 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). 5 for co- administration of sildenafil in patients with erectile dysfunction.

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