Tivicay 50 Mg Film-Coated Tablets

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

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

Adults:

• Treatment-nau00efve: For patients initiating antiretroviral therapy for the first time (treatment-nau00efve) the recommended dose of TIVICAY 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 TIVICAY is 50 mg once daily.
• Integrase inhibitor resistant: For patients with integrase inhibitor resistance, the recommended dose of TIVICAY is 50 mg twice daily.

Elderly: There are limited data available on the use of TIVICAY in patients aged 65 years and over. However, there is no evidence that elderly patients require a different dose than younger adult patients (see Pharmacokinetic properties u2013 Special Patient Populations).

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 (see Pharmacokinetic properties u2013 Special Patient Populations).

Treatment with TIVICAY resulted in an early small increase of mean serum creatinine levels by 10-14 % which remained stable over time and is not considered clinically relevant (see SIDE EFFECTS).

Hepatic impairment: No dosage adjustment is required in patients with mild hepatic impairment (Child-Pugh grade A or B). TIVICAY is contraindicated in patients with moderate or severe hepatic impairment (see CONTRAINDICATIONS).

TIVICAY is contraindicated in combination with dofetilide and pilsicainide. TIVICAY is contraindicated in patients with known hypersensitivity to dolutegravir or to any of the excipients of TIVICAY. TIVICAY is contraindicated in moderate and severe hepatic impairment. Metformin is contraindicated in patients taking TIVICAY. TIVICAY is contraindicated in the first trimester of pregnancy.

Hypersensitivity reactions: Hypersensitivity reactions have been reported with integrase inhibitors, including TIVICAY and were characterised by rash, constitutional findings and, sometimes, organ dysfunction including liver injury. Discontinue TIVICAY and other suspect agents 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 TIVICAY or other suspect agents after the onset of hypersensitivity may result in a life-threatening reaction.

Lipodystrophy and metabolic abnormalities: Combination antiretroviral therapy 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 jirovecii (P. carinii) pneumonia. Any inflammatory symptoms must be evaluated without delay, and treatment initiated when necessary. Auto-immune disorders (such as Gravesu2019 disease, polymyositis and Guillain -Barru00e9 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 can sometimes be an atypical presentation. Liver chemistry elevations consistent with immune reconstitution syndrome were observed in some hepatitis B and/or C co-infected patients at the start of TIVICAY therapy. Monitoring of liver chemistries 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 combination antiretroviral therapy (cART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

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

Woman of childbearing potential: 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 TIVICAY in women of childbearing potential to exclude inadvertent (unintentional) use of TIVICAY during the first trimester of pregnancy. If a woman plans pregnancy, the benefits and the risks of starting or continuing treatment with TIVICAY versus using another antiretroviral regimen should be discussed with her.

Pregnancy: 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.

Lactation: HIV infected women should not breastfeed 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.

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

Adverse drug reactions (ADRs) identified in an analysis of pooled data from clinical studies are listed below, by system organ class and by frequency. Frequencies are defined as: very common (u22651/10), common (u22651/100 and <1/10), uncommon (u22651/1 000 and <1/100), rare (u22651/10 000 and <1/1 000) and very rare (<1/10 000), including isolated reports.

Table 3: Adverse reactions

• Immune system disorders
  • Uncommon: Hypersensitivity (see WARNINGS AND SPECIAL PRECAUTIONS)
  • Uncommon: Immune Reconstitution Syndrome (see WARNINGS AND SPECIAL PRECAUTIONS)
• Psychiatric disorders
  • Common: Insomnia
• Nervous system disorders
  • Very common: Headache
  • Common: Dizziness
  • Common: Abnormal dreams
• Gastrointestinal disorders
  • Very common: Nausea
  • Very common: Diarrhoea
  • Common: Vomiting
  • Common: Flatulence
  • Common: Upper abdominal pain
  • Uncommon: Abdominal pain
  • Uncommon: Abdominal discomfort
• Hepatobiliary disorders
  • Uncommon: Hepatitis
• Skin and subcutaneous tissue disorders
  • Common: Rash
  • Common: Pruritus
• General disorders and administration site conditions
  • Common: Fatigue

The safety profile was similar across the treatment-nau00efve, treatment-experienced (and integrase-nau00efve) and integrase-resistant patient populations. Changes in laboratory chemistries: Increases in serum creatinine occurred within the first week of treatment with TIVICAY and remained stable through 48 weeks. In treatment-nau00efve patients a mean change from baseline of 9,96 u03bcmol/u2113 (range: -53 u03bcmol/u2113 to 54,8 u03bcmol/u2113) 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 (see Pharmacodynamic properties - Effects on Renal Function). Small increases in total bilirubin (without clinical jaundice) were observed on TIVICAY and raltegravir (but not efavirenz) arms in the programme. These changes are not considered clinically relevant as they likely reflect competition between TIVICAY and unconjugated bilirubin for a common clearance pathway (UGT1A1) (see Pharmacokinetic properties - Metabolism). Asymptomatic creatine phosphokinase (CPK) elevations mainly in association with exercise have also been reported with TIVICAY therapy.

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 TIVICAY. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary. As TIVICAY is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.