MARAVIROC

Therapy should be initiated by a physician experienced in the management of HIV infection. e. CXCR4 or dual/mixed tropic virus not detected) using an adequately validated and sensitive detection method on a newly drawn blood sample. 1).

The viral tropism cannot be safely predicted by treatment history and assessment of stored samples. There are currently no data regarding the reuse of maraviroc in patients that currently have only CCR5-tropic HIV-1 detectable, but have a history of failure on maraviroc (or other CCR5 antagonists) with a CXCR4 or dual/mixed tropic virus.

There are no data regarding the switch from a medicinal product of a different antiretroviral class to maraviroc in virologically suppressed patients. Alternative treatment options should be considered. 5). Children and Adolescents weighing less than 30 kg If a child or adolescent weighs less than 30 kg or is unable to reliably swallow maraviroc tablets, the oral solution (20 mg per mL) should be prescribed (refer to Summary of Product Characteristics for maraviroc oral solution).

The recommended dose of maraviroc differs depending on interactions with concomitant antiretroviral therapy and other medicinal products. 5 for corresponding adult dosage. Many medicines have profound effects on maraviroc exposure due to drug- drug interactions.

5 to carefully determine the corresponding adult dose. The corresponding adolescent dose can then be obtained from Table 1 below. If uncertainty still exists, contact a pharmacist for advice. Table 1 Recommended dosing regimen in adolescents based on weight Dose of maraviroc in adolescents based on weightAdult dosage* Concomitant Medications 30 to less than 40 kg at least 40 kg 150 mg twice daily Maraviroc with products that are potent CYP3A inhibitors (with or without a CYP3A inducer) Oral solution (refer to Summary of Product Characteristics for maraviroc oral solution) 150 mg twice daily 300 mg twice daily Maraviroc with products that are not potent CYP3A inhibitors or potent CYP3A inducers 300 mg twice daily 300 mg twice daily 600 mg twice daily Maraviroc with products that are CYP3A inducers (without a potent CYP3A inhibitor) Data to support these doses are lacking and maraviroc is not recommended in children taking concomitant interacting medicinal products that in adults would require a 600 mg twice daily dose.

2), therefore maraviroc should be used with caution in this population. 5). Examples of agents/regimens with such potent CYP3A4-inhibiting activity are: • ritonavir-boosted protease inhibitors (with the exception of tipranavir/ritonavir), • cobicistat, • itraconazole, voriconazole, clarithromycin and telithromycin, • telaprevir and boceprevir.

1). The most frequently reported adverse reactions occurring in the Phase 2b/3 studies were nausea, diarrhoea, fatigue and headache. These adverse reactions were common (≥ 1/100 to < 1/10). Tabulated list of adverse reactions The adverse reactions are listed by system organ class (SOC) and frequency.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1,000), not known (cannot be estimated from the available data).

The adverse reactions and laboratory abnormalities presented below are not exposure adjusted. 4). Skin and liver reactions can occur as single events, or in combination. 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.

4). 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). 4). Cases of syncope caused by postural hypotension have been reported.

Laboratory abnormalities Table 4 shows the incidence ≥1% of Grade 3-4 Abnormalities (ACTG Criteria) based on the maximum shift in laboratory test values without regard to baseline values. 9 ULN: Upper Limit of Normal OBT: Optimised Background Therapy * Percentages based on total patients evaluated for each laboratory parameter The MOTIVATE studies were extended beyond 96 weeks, with an observational phase extended to 5 years in order to assess the long-term safety of maraviroc.

The Long-Term Safety/Selected Endpoints (LTS/SE) included death, AIDS-defining events, hepatic failure, Myocardial infarction/cardiac ischaemia, malignancies, rhabdomyolysis and other serious infectious events with maraviroc treatment.

Hepatic disease The safety and efficacy of maraviroc have not been specifically studied in patients with significant underlying liver disorders. Cases of hepatotoxicity and hepatic failure with allergic features have been reported in association with maraviroc.

8). 8). Patients with pre-existing liver dysfunction, including chronic active hepatitis, can have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice.

g. pruritic rash, eosinophilia or elevated IgE). 1). Caution should be exercised when treating these patients. In case of concomitant antiviral therapy for hepatitis B and/or C, please refer to the relevant product information for these medicinal products.

2). Severe skin and hypersensitivity reactions Hypersensitivity reactions including severe and potentially life threatening events have been reported in patients taking maraviroc, in most cases concomitantly with other medicinal products associated with these reactions.

These reactions included rash, fever, and sometimes organ dysfunction and hepatic failure. Discontinue maraviroc and other suspect agents immediately if signs or symptoms of severe skin or hypersensitivity reactions develop. Clinical status and relevant blood chemistry should be monitored and appropriate symptomatic therapy initiated.

Cardiovascular safety Limited data exist with the use of maraviroc in patients with severe cardiovascular disease, therefore special caution should be exercised when treating these patients with maraviroc. In the pivotal studies of treatment-experienced patients coronary heart disease events were more common in patients treated with maraviroc than with placebo (11 during 609 PY vs 0 during 111 PY of follow-up).

In treatment-naïve patients such events occurred at a similarly low rate with maraviroc and control (efavirenz). Postural hypotension When maraviroc was administered in studies with healthy volunteers at doses higher than the recommended dose, cases of symptomatic postural hypotension were seen at a greater frequency than with placebo.

1.