Lopinavir/Ritonavir Viatris (previously Ritonavir Mylan) · 4.3 Contraindications · 1

HOS-217117 · has-adverse-reaction-information · PDF-Seite 27

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. Furthermore, rare increases in PR interval have been reported during lopinavir/ritonavir therapy (see section 4.4). 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). 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 Common Anaemia, leucopenia, neutropenia, disorders lymphadenopathy

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HOS-217113 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. Severe hepatic insufficiency. Lopinavir/Ritonavir Viatris 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 Medicinal products within Rationale class class Concomitant medicinal product levels increased Alpha1 -adrenoreceptor Alfuzosin Increased plasma concentrations of antagonist alfuzosin which may lead to severe hypotension. The concomitant administration with alfuzosin is contraindicated (see section 4.5). 4 Medicinal product Medicinal products within Rationale class class Antianginal Ranolazine Increased plasma concentrations of ranolazine which may increase the potential for serious and/or life-threatening reactions (see section 4.5). Antiarrhythmics Amiodarone, Increased plasma concentrations of dronedarone amiodarone and dronedarone. Thereby, increasing the risk of arrhythmias or other serious adverse reactions (see section 4.5). Antibiotic Fusidic Acid Increased plasma concentrations of fusidic acid. The concomitant administration with fusidic acid is contraindicated in dermatological infections (see section 4.5). Anticanc

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HOS-217112 · has-indication-information · PDF-Seite 2

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

HOS-217115 · has-interaction-information · PDF-Seite 9

Lopinavir/Ritonavir Viatris tablets contain lopinavir and ritonavir, both of which are inhibitors of the P450 isoform CYP3A in vitro. Co-administration of lopinavir/ritonavir 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. Lopinavir/ritonavir does not inhibit CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP2B6 or CYP1A2 at clinically relevant concentrations (see section 4.3). Lopinavir/ritonavir has been shown in vivo to induce its own metabolism and to increase the biotransformation of some medicinal products metabolised by cytochrome P450 enzymes (including CYP2C9 and CYP2C19) and by glucuronidation. This may result in lowered plasma concentrations and potential decrease of efficacy of co-administered medicinal products. Medicinal products that are contraindicated specifically due to the expected magnitude of interaction and potential for serious adverse events are listed in section 4.3. All interaction studies, when otherwise not stated, were performed using lopinavir/ritonavir capsules, which gives an approximately 20% lower exposure of lopinavir than the 200/50 mg tablets. 9 Known and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal products are listed in the table below. This list is not intended to be inclusive or comprehensive. Individual SmPCs should be consulted. Interaction table Interactions between lopinavir/ritonavir 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 Effects on drug levels Clinical recommendation therapeutic area Geometric Mean Change (%) in concerning co-administration with AUC, Cmax , Cmin Lopinavir/Ritonavir Viatris Mechanism of interaction Antiretroviral Agents Nucleoside/Nucleotide reverse transcriptase inhibitors (NRTIs) Lamivudine Lopinavir: ↔ No dose adjustment necessa

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HOS-217116 · has-pregnancy-information · PDF-Seite 26

Pregnancy As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, the animal data as well as the clinical experience in pregnant women should be taken into account in order to characterise the safety for the foetus. Lopinavir/ritonavir has been evaluated in over 3000 women during pregnancy, including over 1000 during the first trimester. In post-marketing surveillance through the Antiretroviral Pregnancy Registry, established since January 1989, an increased risk of birth defects exposures with lopinavir/ritonavir has not been reported among over 1000 women exposed during the first trimester. The prevalence of birth defects after any trimester exposure to lopinavir is comparable to the prevalence observed in the general population. No pattern of birth defects suggestive of a common etiology was seen. Studies in animals have shown reproductive toxicity (see 26 section 5.3). Based on the data mentioned, the malformative risk is unlikely in humans. Lopinavir can be used during pregnancy if clinically needed. Breast-feeding Studies in rats revealed that lopinavir is excreted in the milk. It is not known whether this medicinal product is excreted in human milk. As a general rule, it is recommended that women living with HIV do not breast- feed their babies in order to avoid transmission of HIV. Fertility Animal studies have shown no effects on fertility. No human data on the effect of lopinavir/ritonavir on fertility are available.

HOS-217114 · has-warning-information · PDF-Seite 6

Patients with coexisting conditions Hepatic impairment The safety and efficacy of lopinavir/ritonavir has not been established in patients with significant underlying liver disorders. Lopinavir/ritonavir is contraindicated in patients with severe liver impairment (see section 4.3). Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer to the relevant product information for these medicinal products. Patients with pre-existing liver dysfunction including chronic hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment should be considered. Elevated transaminases with or without elevated bilirubin levels have been reported in HIV-1 mono-infected and in individuals treated for post-exposure prophylaxis as early as 7 days after the initiation of 6 lopinavir/ritonavir in conjunction with other antiretroviral agents. In some cases the hepatic dysfunction was serious. Appropriate laboratory testing should be conducted prior to initiating therapy with lopinavir/ritonavir and close monitoring should be performed during treatment. Renal impairment Since the renal clearance of lopinavir and ritonavir is negligible, increased plasma concentrations are not expected in patients with renal impairment. Because lopinavir and ritonavir are highly protein bound, it is unlikely that they will be significantly removed by haemodialysis or peritoneal dialysis. Haemophilia There have been reports of increased bleeding, including spontaneous skin haematomas and haemarthrosis in patients with haemophilia type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced if treatment had been discontinued. A causal relationship had been evoked, although the mechanism of action had not been elucidated. Haemophiliac patients should therefore be made aware of the possibility of increased bleeding. Pancreatitis Cases of pancreatitis have been reported in patients receiving

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