Myltega 50 mg FC tablet

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

Posology:
MYLTEGA therapy should be initiated by a medical practitioner experienced in the management of HIV infection. MYLTEGA can be taken without food.

Method of Administration:
Adults:
Treatment-nau00efve:
For patients initiating antiretroviral therapy for the first time (Treatment-nau00efve) the recommended dose of MYLTEGA 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 MYLTEGA is 50 mg once daily.
Integrase inhibitor resistant:
For patients with integrase inhibitor resistance, the recommended dose MYLTEGA is 50 mg twice daily.
Elderly:
There are limited data available on the use of MYLTEGA 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. Treatment with MYLTEGA 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 section 4.8).
Hepatic impairment:
No dosage adjustment is required in patients with mild hepatic impairment (Child-Pugh grade A). MYLTEGA is contra-indicated in patients with moderate or severe hepatic impairment (see section 4.3).

• Hypersensitivity to dolutegravir or any of the inactive ingredients of MYLTEGA (see section 6.1).
• MYLTEGA is contraindicated in combination with dofetilide and pilsicainide.
• MYLTEGA is contraindicated in moderate and severe hepatic impairment.
• Metformin is contraindicated in patients taking MYLTEGA.
• In the peri-conception period and the first trimester of pregnancy.
• Safety in pregnancy and lactation has not been established (see section 4.6).

Hypersensitivity reactions:
Hypersensitivity reactions have been reported with integrase inhibitors, including MYLTEGA and were characterised by rash, constitutional findings and sometimes, organ dysfunction, including liver injury. Discontinue MYLTEGA and other suspect medicines immediately if signs or symptoms of hypersensitivity reaction 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 MYLTEGA or other suspect medicines 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 distribution. 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 Gravesu2019 disease, polymyositis and Guillian-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 consistent with immune reconstitution syndrome were observed in some hepatitis B and/or C co-infected patients at the start of MYLTEGA 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 section 4.8).

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.

Hepatic impairment:
The unbound fraction of dolutegravir in the blood is doubled in patients with moderate hepatic impairment. MYLTEGA is contra-indicated in patients with moderate to severe hepatic impairment (see section 4.3).

Caution should be given to co-administering medications (prescription and non-prescription) that may change the exposure of MYLTEGA or medications that may have their exposure changed by MYLTEGA (see sections 4.3 and 4.5). The co-administration of MYLTEGA 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 section 4.5). The recommended dose of MYLTEGA is 50 mg twice daily when co-administered with efavirenz, nevirapine, tipranavir/ritonavir, or rifampicin (see section 4.5). MYLTEGA should not be co-administered with polyvalent cation-containing antacids. MYLTEGA is recommended to be administered 2 hours before or 6 hours after these agents (see section 4.5). Metformin concentrations may be increased by MYLTEGA. Metformin is contra-indicated in patients taking MYLTEGA (see section 4.3).

Co-infection with Hepatitis B or C:
Overall, the safety profile in patients co-infected with hepatitis B and/or C was similar to that observed in patients without hepatitis B or C co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis B and/or C for all treatment groups. Liver chemistry elevations consistent with immune reconstitution syndrome were observed in some subjects with hepatitis B and/or C co-infection at the start of MYLTEGA therapy, particularly in those anti-hepatitis B therapy was withdrawn.

Opportunistic infections:
Patients receiving MYLTEGA or any other antiretroviral therapy may still develop opportunistic infections and other complications of HIV infection. Therefore patients should remain under close clinical observation by medical practitioners experienced in the treatment of these associated HIV diseases.

Transmission of infection:
Patients should be advised that current antiretroviral therapy, including MYLTEGA, has not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be taken.

Women 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 MYLTEGA in women of childbearing potential to exclude inadvertent (unintentional) use of MYLTEGA 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.

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. 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 new born 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).

Patients should be informed that dizziness has been reported during treatment with dolutegravir. The clinical status of the patient and the adverse reaction profile of dolutegravir should be borne in mind when considering the patient's ability to drive or operate machinery.

The undesirable effects are listed by system organ classes.
Immune system disorders:
Less frequent: Hypersensitivity, Immune Reconstitution Syndrome
Psychiatric disorders:
Frequent: Insomnia, abnormal dreams, depression, anxiety
Less frequent: Suicidal ideation or suicide attempt
Nervous system disorders:
Frequent: Headache, dizziness
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
Musculoskeletal and connective tissue disorders:
Less frequent: Arthralgia, myalgia.
General disorders and administration site conditions:
Frequent: Fatigue
Investigations:
Frequent: Increased AST, ALT, CPK, bilirubin
Changes in laboratory chemistries: Increases in serum creatinine occurred within the first week of treatment with MYLTEGA 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 MYLTEGA and raltegravir (but not efavirenz) arms in the programme. These changes are not considered clinically relevant as they likely reflect competition between MYLTEGA and unconjugated bilirubin for a common clearance pathway (UGT1A1) (see section 5.2). Asymptomatic creatine phosphokinase (CPK) elevations mainly in association with exercise have also been reported with MYLTEGA 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 MYLTEGA. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary. As MYLTEGA is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.