Trifalda 50 mg, 300 mg, 25 mg Tablet

TRIFALDA is indicated for use alone as a complete regimen for the treatment of human immunodeficiency virus type I (HIV-1) infection in adults and children weighing at least 40 kg. Limitation of Use: TRIFALDA alone is not recommended in patients with resistance-associated integrase substitutions or clinically suspected integrase strand transfer inhibitor resistance because the dose of TRIFALDA is insufficient in these subpopulations. See the full prescribing information for dolutegravir.

Posology: Therapy should be initiated by a medical practitioner experienced in the management of HIV infection. Testing Prior to Initiation and During Treatment with TRIFALDA: Perform pregnancy testing before initiation of TRIFALDA in adolescents and adults of childbearing potential (see section 4.4). Prior to or when initiating TRIFALDA, test patients for hepatitis B virus (HBV) infection (see section 4.4). Prior to initiation and during treatment with TRIFALDA, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus (see section 4.4). Recommended Dosage: TRIFALDA is a fixed-dose combination medicine containing 50 mg of dolutegravir, 300 mg of lamivudine (3TC), and 25 mg of tenofovir alafenamide (TAF). The recommended dosage regimen of TRIFALDA in adults and children weighing at least 40 kg is one tablet once daily orally with or without food. Special populations Dosage Adjustment for special population: Because TRIFALDA is a fixed-dose combination formulation and cannot be dose adjusted, it is not recommended in patients requiring dosage adjustment. Elderly Use: Clinical trials of individual components of TRIFALDA did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. Caution should be exercised in the administration of TRIFALDA in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other medicine therapy (see section 5.1). Renal Impairment: TRIFALDA tablets are not recommended for patients with severe renal impairment (estimated creatinine clearance below 30 mL) because TRIFALDA is a fixed-dose combination and the dosage of the individual components cannot be adjusted. No dosage adjustment of TRIFALDA tablets is recommended in patients with mild or moderate renal impairment (estimated creatinine clearance greater than or equal to 30 mL per minute). Hepatic Impairment: No dosage adjustment of TRIFALDA tablets is recommended in patients with mild (Child-Pugh Class A) hepatic impairment. The effect of moderate or severe hepatic impairment (Child-Pugh Class B or C) on the pharmacokinetics of dolutegravir, lamivudine and tenofovir alafenamide has not been studied. Therefore, TRIFALDA tablets are not recommended for use in patients with severe hepatic impairment (see sections 4.3 and 5.1). Paediatric Use: TRIFALDA tablets should only be administered to paediatric patients with a body weight of at least 40 kg because they are a fixed-dose combination that cannot be adjusted. The safety and efficacy have been established for the individual components in this weight group. Method of administration: TRIFALDA is for oral administration and can be taken with or without food.

TRIFALDA is contraindicated in:

• Patients with known hypersensitivity to dolutegravir, lamivudine, tenofovir alafenamide or any of the excipients of the TRIFALDA (listed in section 6.1).
• Patients receiving dofetilide due to the potential for increased dofetilide plasma concentrations and the risk for serious and/or life-threatening events with concomitant use of dolutegravir (see section 4.5).
• Pregnancy and lactation (see section 4.6).
• Co-administration with metformin, adefovir, pilsicainide or didanosine.
• Woman of childbearing age.
• Patients younger than 18 years.
• Moderate and severe hepatic impairment.
• Uncontrolled renal failure.

Metabolic abnormalities: Combination antiretroviral therapy, including TRIFALDA has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia.

Lipodystrophy: Combination antiretroviral therapy, including TRIFALDA, has also been associated with the redistribution/accumulation of body fat, including central obesity, dorso-cervical fat, enlargement (buffalo hump), peripheral wasting, facial wasting and breast enlargement in HIV patients. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with medicine related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Fasting serum lipids and blood glucose levels should be monitored. Lipid disorders should be managed as clinically appropriate. Patients with evidence of lipodystrophy should also have a thorough cardiovascular risk assessment.

Immune Reconstitution Inflammatory Syndrome: Immune reconstitution inflammatory syndrome (IRIS) is an immunopathological response resulting from the rapid restoration of pathogen-specific immune responses to pre-existing antigens combined with immune dysregulation, which occurs shortly after starting combination Anti-Retroviral Therapy (cART). Typically, such reaction presents by paradoxical deterioration of opportunistic infections being treated or with unmasking of an asymptomatic opportunistic disease, often with an atypical inflammatory presentation. IRIS usually develops within the first three months of initiation of ART and occurs more commonly in patients with low CD4 counts. Common examples of IRIS reactions to opportunistic diseases are tuberculosis, atypical mycobacterial infections, cytomegalovirus retinitis, pneumocystis jerovecii and cryptococcal meningitis. Appropriate treatment of the opportunistic disease should be instituted or continued, and ART continued. Inflammatory manifestations generally subside after a few weeks. Severe cases may respond to glucocorticoids, but there is only limited evidence for this in patients with tuberculosis IRIS.

Autoimmune disorders (such as Gravesu2019 disease, Guillain-Barre Syndrome, Polymyositi) have also been reported as IRIS reactions; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.

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) including components of TRIFALDA. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness, or difficulty in movement.

Mitochondrial dysfunction: Nucleoside and nucleotide analogues as contained in TRIFALDA have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues. The main adverse events reported are haematological disorders (anaemia, neutropenia), metabolic disorders (hyperlactataemia, hyperlipidaemia). These events are often transitory. Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether the neurological disorders are transient or permanent is unknown. Any child exposed in utero to nucleoside and nucleotide analogues, even HIV negative children, should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant signs of symptoms.

Severe Acute Exacerbation of Hepatitis B in Patients with HBV Infection: All patients should be tested for the presence of chronic hepatitis B virus (HBV) before or when initiating TRIFALDA. Discontinuation of anti-HBV therapy, including 3TC and TAF, two components of TRIFALDA, may be associated with severe acute exacerbations of hepatitis B. Patients infected with HBV who discontinue dolutegravir, lamivudine and tenofovir alafenamide tablets should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, resumption of anti-hepatitis B therapy may be warranted.

Hypersensitivity Reactions: Hypersensitivity reactions have been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury. Discontinue TRIFALDA 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 or peeling of the skin, oral blisters or lesions, conjunctivitis, facial oedema, hepatitis, eosinophilia, angioedema, difficulty breathing). Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated. Delay in stopping treatment with TRIFALDA or other suspect medicines after the onset of hypersensitivity may result in a life-threatening reaction.

Hepatotoxicity: Hepatic adverse events have been reported in patients receiving a dolutegravir-containing regimen. Patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with use of TRIFALDA (see section 4.8). In some cases, the elevations in transaminases were consistent with immune reconstitution syndrome or hepatitis B reactivation particularly in the setting where anti-hepatitis therapy was withdrawn. Cases of hepatic toxicity, including elevated serum liver biochemistries, hepatitis, and acute liver failure have been reported in patients receiving a dolutegravir-containing regimen without pre-existing hepatic disease or other identifiable risk factors. Drug-induced liver injury leading to liver transplant has been reported with combination abacavir, dolutegravir, and lamivudine. Monitoring for hepatotoxicity is recommended.

Embryo-Foetal Toxicity: Preliminary data from an observational study showed that dolutegravir, a component of TRIFALDA, was associated with increased risk of neural tube defects when administered at the time of conception and in early pregnancy. As there is limited understanding of reported types of neural tube defects associated with dolutegravir use and because the date of conception may not be determined with precision, avoid use of TRIFALDA at the time of conception through the first trimester of pregnancy (see section 4.6). If there are plans to become pregnant or if pregnancy is confirmed within the first trimester while on TRIFALDA, if possible, switch to an alternative regimen. Perform pregnancy testing before initiation of TRIFALDA in adolescents and adults of childbearing potential to exclude use of TRIFALDA during the first trimester of pregnancy (see section 4.6). Advise adolescents and adults of childbearing potential to consistently use effective contraception (see section 4.6).

The concomitant use of TRIFALDA and other medicines may result in known or potentially significant interactions, some of which may lead to (see sections 4.3 and 4.5):

• Loss of therapeutic effect of TRIFALDA and possible development of resistance.
• Possible clinically significant adverse reactions from greater exposures of concomitant medicines.

See Table 4 for steps to prevent or manage these possible and known significant medicine interactions, including dosing recommendations. Consider the potential for medicine interactions prior to and during therapy with TRIFALDA; review concomitant medications during therapy with TRIFALDA; and monitor for the adverse reactions associated with the concomitant medicines.

Women of childbearing potential /Contraception in males and females: Pregnancy Testing: Perform pregnancy testing in adolescents and adults of childbearing potential before initiation of TRIFALDA. Contraception: Adolescents and adults of childbearing potential should avoid use of TRIFALDA at the time of conception through the first trimester of pregnancy because of the potential risk of neural tube defects. Advise adolescents and adults of childbearing potential who are taking TRIFALDA to consistently use effective contraception.

Pregnancy: TRIFALDA is contraindicated in pregnancy and lactation. Neural tube defects have been noted in an observational study in humans, where DTG-based regimens were used at the time of conception and early pregnancy (see section 4.3). Tenofovir, dolutegravir and lamivudine were shown to cross the placenta in reproductive toxicity studies in animals. Late onset neurological disorders, including seizures, have been observed in children who have been exposed to nucleoside analogues such as tenofovir and lamivudine, (see Mitochondrial Dysfunction under section 4.4). TRIFALDA should not be prescribed in women who plan to become pregnant. Woman of child-bearing age should not use TRIFALDA unless they are reliably using highly effective contraception. Treatment with TRIFALDA should not be initiated without a medically supervised negative pregnancy test. This test should be repeated at frequent intervals during treatment with TRIFALDA, and especially in the event that pregnancy is suspected. If there are plans to become pregnant or if pregnancy is confirmed while on dolutegravir during the first trimester, the patient must be switched to an alternative regimen.

Breastfeeding: Mothers breastfeeding their infants should not use TRIFALDA. Lamivudine is excreted in human milk at similar concentrations to those found in serum; tenofovir is excreted in breast milk and it is not known whether dolutegravir is excreted in human milk.

TRIFALDA may cause dizziness and fatigue which may affect the ability to drive and use machines. Patients should ensure that they do not engage in driving or using machines until they know how TRIFALDA affects them.

Tabulated list of adverse reactions: The following adverse reactions have been classified according to the following categories, frequent, less frequent and frequency unknown.

MedDRA system organ Class Frequency Side effects

• Blood and the lymphatic system disorders Frequent Neutropenia Frequency unknown Anaemia
• Immune system disorders Frequent Allergic reaction, including angioedema Less frequent Hypersensitivity, Immune Reconstitution Syndrome (see section 4.4)
• Metabolism and nutrition disorders Frequent Hypertriglyceridaemia, hyperglycaemia Frequency unknown Hypophosphataemia, lactic acidosis, hypokalaemia
• Psychiatric disorders Frequent Insomnia, abnormal dreams, suicidal ideation, attempt, behaviour, or completion. These events were observed primarily in subjects with a pre-existing history of depression or other psychiatric illness
• Nervous system disorders Frequent Headache, dizziness
• Respiratory, thoracic and mediastinal disorders Frequent Dyspnoea
• Gastrointestinal disorders Frequent Nausea, diarrhoea, vomiting, flatulence, upper abdominal pain, dyspepsia, amylase elevation, lipase elevation Less frequent Abdominal pain, abdominal discomfort Frequency unknown Pancreatitis
• Hepatobiliary disorders Frequent Hyperbilirubinaemia, increased liver enzymes (including increased AST, increased ALT and/or gamma GT) Less frequent Hepatitis Frequency unknown Hepatic steatosis
• Skin and subcutaneous tissue disorders Frequent Rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, pustular rash, skin discolouration
• Musculoskeletal, connective tissue and bone disorders Frequent Creatine kinase elevation, myositis, arthralgia Frequency unknown Myopathy, osteomalacia, rhabdomyolysis, muscular weakness
• Renal and urinary disorders Frequent Renal impairment Frequency unknown Increased creatinine, renal insufficiency, renal failure, acute renal failure, Fanconi syndrome, proximal tubulopathy, nephrogenic diabetes insipidus, proteinuria, acute tubular necrosis, polyuria, interstitial nephritis
• General disorders and administration site conditions Frequent Fatigue, pain, asthenia

Description of selected adverse reactions: Changes in laboratory chemistries: Increases in serum creatinine occurred within the first week of treatment with dolutegravir 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 with dolutegravir. These changes are not considered clinically relevant as they likely reflect competition between dolutegravir and unconjugated bilirubin for a common clearance pathway (UGT1A1). Asymptomatic creatine phosphokinase (CPK) elevations mainly in associate with exercise have also been reported with dolutegravir therapy. Hepatitis B and/or Hepatitis C Virus Co-infection: In Phase 3 trails, subjects with hepatitis B and/or C virus co-infection were permitted to enrol provided that baseline liver chemistry tests did not exceed 5 times the upper limit of normal. Overall, the safety profile in subjects with hepatitis B and/or C virus co-infection was similar to that observed in subjects 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 virus co-infection for all treatment groups. Grades 2 to 4 ALT abnormalities in hepatitis B and/or C co-infected compared with HIV mono-infected subjects receiving dolutegravir were observed in 18 % vs. 3 % with the 50 mg once-daily dose and 13 % vs. 8 % with the 50 mg twice-daily dose. Liver chemistry elevations consistent with immune reconstitution syndrome were observed in some subjects with hepatitis B and/or C at the start of therapy with dolutegravir, particularly in the setting where anti-hepatitis therapy was withdrawn (see section 4.4). Not for use in subjects <40 kg.

There is no known specific treatment for overdose with dolutegravir, lamivudine and tenofovir alafenamide tablets. If overdose occurs, the patient should be monitored, and standard supportive treatment applied as required. Dolutegravir: As dolutegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis. 3TC: Because a negligible amount of 3TC was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a 3TC overdose event. TAF: Limited clinical experience is available at doses higher than the recommended dose of TAF. A single dose of 125 mg TAF (5 times the TAF dose in dolutegravir, lamivudine and tenofovir alafenamide tablets) was administered to 48 healthy subjects; no serious adverse reactions were reported. The effects of higher doses are unknown. Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54 %.