Olegra 50 mg FC tablet

OLEGRA is indicated for the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretroviral agents in adults aged 18 years and older.

OLEGRA therapy should be initiated by a medical practitioner experienced in the management of HIV infection. OLEGRA can be taken with or without food.

Method of Administration:

• Adults:
• Treatment-nau00efve: For patients initiating antiretroviral therapy for the first time (treatment-nau00efve) the recommended dose of OLEGRA is 50 mg once daily.
• Treatment-experienced, and integrase inhibitor nau00efve: For patients who are treatment experienced and have not previously been treated with an integrase inhibitor, the recommended dose of OLEGRA is 50 mg once daily.
• Integrase inhibitor resistant: For patients with integrase inhibitor resistance, the recommended dose of OLEGRA is 50 mg twice daily.
• Elderly: There are limited data available on the use of OLEGRA in patients aged 65 years and over. However, there is no evidence that elderly patients require a different dose than younger adult patients.
• Renal impairment: No dosage adjustment is required in patients with mild, moderate or severe (CrCl < 30 mL/min, not on dialysis) renal impairment. No data are available in subjects receiving dialysis, although differences in pharmacokinetics are not expected in this population.

OLEGRA is contra-indicated in patients with known hypersensitivity to dolutegravir or to any of the excipients. OLEGRA is contra-indicated in combination with dofetilide and pilsicainide. OLEGRA is contra-indicated in moderate and severe hepatic impairment. Metformin is contra-indicated in patients taking OLEGRA.

Hypersensitivity reactions: Hypersensitivity reactions have been reported with integrase inhibitors, including OLEGRA and were characterised by rash, constitutional findings and sometimes, organ dysfunction, including liver injury. Discontinue OLEGRA and other suspect medicines immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial oedema, hepatitis, eosinophilia, angioedema). Clinical status including liver aminotransferases should be monitored and appropriate therapy initiated. Delay in stopping treatment with OLEGRA or other suspect medicines after the onset of hypersensitivity may result in a life-threatening reaction.

Lipodystrophy and metabolic abnormalities: Combination antiretroviral therapy (cART) has been associated with the redistribution/accumulation of body fat, including central obesity, dorso-cervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement and elevated serum lipid and glucose levels in HIV patients. Clinical examination should include evaluation for physical signs of fat redistribution. Patients with evidence of lipodystrophy should have a thorough cardiovascular risk assessment.

Immune Reconstitution Syndrome: In HIV-infected patients with severe immune deficiency at the time of initiation of antiretroviral therapy (ART), an inflammatory reaction to asymptomatic or residual opportunistic infections 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 ART. Relevant examples are tuberculosis, cytomegalovirus retinitis, generalised and/or focal atypical mycobacterial infections and Pneumocystis jiroveci (P. carinii) pneumonia. Any inflammatory symptoms must be evaluated without delay and treatment initiated when necessary. Auto-immune disorders (such as Graves' disease, polymyositis and Guillain-Barre syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable and can occur many months after initiation of treatment and sometimes can be an atypical presentation.

Liver chemistry elevations: Liver chemistry elevations consistent with immune reconstitution syndrome were observed in some hepatitis B and/or C co-infected patients at the start of OLEGRA therapy. Monitoring of liver chemistry is recommended in patients with hepatitis B and/or C co-infection. Particular diligence should be applied in initiating or maintaining effective hepatitis B therapy (referring to treatment guidelines) when starting dolutegravir-based therapy in hepatitis B co-infected patients (see SIDE EFFECTS).

Osteonecrosis: Although the aetiology 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 HIV-disease and/or long-term exposure to cART. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Hepatic impairment: The unbound fraction of OLEGRA in the blood is doubled in patients with moderate hepatic impairment. OLEGRA is contra-indicated in patients with moderate or severe hepatic impairment (see CONTRA-INDICATIONS).

Caution should be given to co-administering medicines (prescription and non-prescription) that may change the exposure of OLEGRA or medicines that may have their exposure changed by OLEGRA (see CONTRA-INDICATIONS and INTERACTIONS). The co-administration of OLEGRA with etravirine (ETR) is not recommended unless the patient is also receiving concomitant atazanavir and ritonavir (ATV + RTV), lopinavir and ritonavir (LPV + RTV) or darunavir and ritonavir (DRV + RTV) (see INTERACTIONS). The recommended dose of OLEGRA is 50 mg twice daily when co-administered with efavirenz, nevirapine, tipranavir/ritonavir, or rifampicin (see INTERACTIONS). OLEGRA should not be co-administered with polyvalent cation-containing antacids. OLEGRA is recommended to be administered 2 hours before or 6 hours after these medicines (see u201cINTERACTIONSu201d). Metformin concentrations may be increased by OLEGRA. Metformin is contra-indicated in patients taking OLEGRA (see CONTRA-INDICATIONS).

Pregnancy: Women of childbearing potential should be counselled about the potential risk of neural tube defects with dolutegravir (see below), including consideration of using effective contraceptive measures. Perform pregnancy testing before initiation of PN in women of childbearing potential to exclude inadvertent (unintentional) use of OLEGRA during the first trimester of pregnancy. If a woman plans pregnancy, the benefits and the risks of starting or continuing treatment with dolutegravir versus using another antiretroviral regimen should be discussed with her. Use of dolutegravir during pregnancy was associated with a small increase in the prevalence of neural tube defects (0.19%) compared to non-dolutegravir regimens (0.11%). Most neural tube defects occur within the first 4 weeks of embryonic development after conception (approximately 6 weeks after the last menstrual period). If a pregnancy is confirmed in the first trimester while on dolutegravir, the benefits and risks of continuing dolutegravir versus switching to another antiretroviral regimen should be discussed with the patient, taking the gestational age and the critical time period of neural tube defect development into account. Dolutegravir may be used during the second and third trimester of pregnancy when the expected benefit outweighs the potential risk to the foetus. Dolutegravir was shown to cross the placenta in humans, leading to significant exposure to the foetus, but the implications of such exposure are not yet known.

Breast-feeding: HIV infected women should not breast-feed their infants in order to avoid transmission of HIV or follow appropriate guidelines. Dolutegravir is excreted in human breast milk, and there is significant exposure to the neonate/infants due to slow elimination; the half-life of dolutegravir in the newborn was 33 hr compared to 14 hr in the adults. There is insufficient information on the effects of dolutegravir in neonates/infants.

Fertility: There are no data on the effects of dolutegravir on human male or female fertility. Animal studies indicate no effects of dolutegravir on male or female fertility (see section 5.3).

The clinical reports of the patient and the adverse event profile of OLEGRA should be borne in mind when considering the patient's ability to drive or operate machinery.

Immune system disorders: Less frequent: Hypersensitivity, Immune Reconstitution Syndrome

Psychiatric disorders: Frequent: Insomnia, depression Less frequent: Suicidal ideation or suicide attempt

Nervous system disorders: Frequent: Headache, dizziness, abnormal dreams

Gastrointestinal disorders: Frequent: Nausea, diarrhoea, vomiting, flatulence, upper abdominal pain Less frequent: Abdominal pain, abdominal discomfort

Hepatobiliary disorders: Frequent: Hepatitis

Skin and subcutaneous tissue disorders: Frequent: Rash, pruritus

General disorders and administration site conditions: Frequent: Fatigue

Investigation: Frequent: Increased AST, ALT, CPK, bilirubin

Changes in laboratory chemistries: Increases in serum creatinine occurred within the first week of treatment with OLEGRA and remained stable through 48 weeks. In treatment nau00efve patients a mean change from baseline of 9.96 u03bcmol/L (range: - 53 u03bcmol/L to 54.8 u03bcmol/L) was observed after 48 weeks of treatment. Creatinine increases were comparable by background NRTIs and were similar in treatment experienced patients. These changes are not considered to be clinically relevant since they do not reflect a change in glomerular filtration rate. Small increases in total bilirubin (without clinical jaundice) were observed on OLEGRA and raltegravir (but not efavirenz) arms in the programme. These changes are not considered clinically relevant as they likely reflect competition between OLEGRA and unconjugated bilirubin for a common clearance pathway (UGT1A1) (see Pharmacokinetic properties u2013 Metabolism). Asymptomatic creatine phosphokinase (CPK) elevations mainly in association with exercise have also been reported with OLEGRA therapy.

Symptoms may be an exacerbation of side effects. Management should be as clinically indicated or as recommended by the national poisons centre, where available. There is no specific treatment for an overdose of OLEGRA. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary. As OLEGRA is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.