Divtrida 300 mg FC tablet

The DIVTRIDA is a triple combination therapy which is indicated for the treatment of human immunodeficiency virus (HIV) infection in adults aged 18 years and older.

Therapy should be initiated by a medical practitioner experienced in the management of HIV infection.

Adults: The dose of DIVTRIDA is one tablet taken orally, once daily, without regard to food.

Paediatrics: DIVTRIDA is not recommended for use in patients younger than 18 years of age.

Renal impairment: Significantly increased exposure occurred when tenofovir, as in DIVTRIDA, was administered to patients with moderate to severe renal impairment (see CONTRA-INDICATIONS). The pharmacokinetics of tenofovir, as in DIVTRIDA, have not been evaluated in non-haemodialysis patients with creatinine clearance u02c2 80 ml/min); therefore, no dosing recommendations is available for these patients. For treatment-nau00efve and treatment experienced patients the recommended dose of DIVTRIDA is one tablet once daily. DIVTRIDA is contraindicated in patients with moderate or severe hepatic impairment (see CONTRA-INDICATIONS). DIVTRIDA is contra-indicated in patients with renal impairment with creatinine clearance less than 80 ml/min.

DIVTRIDA tablets are contra-indicated in patients with known hypersensitivity to lamivudine, tenofovir or dolutegravir or to any of the components of the tablets.

Impairment of renal function.

Pregnancy and lactation (see HUMAN REPRODUCTION).

Women of child-bearing age not using highly effective contraception.

Concomitant use with adefovir dipivoxil.

Co-administration with dofetilide and pilsicainide.

Co-administration with didanosine.

Co-administration with metformin.

Patients younger than 18 years of age.

Moderate and severe hepatic impairment.

Safety and efficacy of the individual active ingredients in various antiretroviral combination regimens with similar dosages as contained in DIVTRIDA have been established in clinical studies for the treatment of HIV patients. However, safety and efficacy of the fixed-drug combination as in DIVTRIDA for the treatment of HIV has not been established in clinical studies. The complete professional informations of the other medicines used in combination should be consulted before initiation of therapy.

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

Lipodystrophy: Combination antiretroviral therapy, including DIVTRIDA, 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 reactions present 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 jirovecii, 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, Polymyositis) 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 DIVTRIDA. Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Opportunistic infections: Patients receiving DIVTRIDA may continue to develop opportunistic infections and other complications of HIV infection and therefore patients should remain under close clinical observation by doctors experienced in the treatment of patients with HIV associated diseases.

The risk of HIV transmission to others: Patients should be advised that treatment with DIVTRIDA 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.

Lactic acidosis/severe hepatomegaly with steatosis: Lactic acidosis, usually associated with hepatic steatosis, including fatal cases, has been reported with the use of nucleoside analogues, such as in DIVTRIDA. Early symptoms (symptomatic hyperlactataemia) include benign digestive symptoms (nausea, vomiting and abdominal pain), non-specific malaise, loss of appetite, weight loss, respiratory symptoms (rapid and/or deep breathing) or neurological symptoms (including motor weakness). Lactic acidosis has a high mortality and may be associated with pancreatitis, liver failure or renal failure. Lactic acidosis generally occurs after a few or several months of treatment. Treatment with nucleoside analogues should be discontinued in the setting of symptomatic hyperlactataemia and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating aminotransferase levels. Suspicious biochemical features include mild raised transaminases, raised lactate dehydrogenase (LDH) and/or creatine kinase. In patients with suspicious symptoms or biochemistry, measure the venous lactate level (normal < 2 mmol/L) and respond as follows:

• Lactate 2-5 mmol/L: monitor regularly, and be alert for clinical signs.
• Lactate 5-10 mmol/L without symptoms, monitor closely.
• Lactate 5-10 mmol/L with symptoms: STOP all therapy. Exclude other causes (e.g. sepsis, uraemia, diabetic ketoacidosis, hyperthyroidism, lymphoma).
• Lactate > 10 mmol/L: STOP all therapy (80 % mortality in case studies).

The above lactate values may not be applicable to paediatric patients. Diagnosis of lactic acidosis is confirmed by demonstrating metabolic acidosis with an increased anion gap and raised lactate level. Therapy should be stopped in any acidotic patient with a raised lactate level. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases have been reported with the use of DIVTRIDA alone or in combination, in the treatment of HIV infection. Most cases were women. Caution should be exercised when administering DIVTRIDA to patients with known risk factors for liver disease. Treatment with DIVTRIDA should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity. Caution should be exercised when administering nucleoside analogues as contained in DIVTRIDA to any patient (particularly obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease and hepatic steatosis (including certain medicines and alcohol). Patients co-infected with Hepatitis C and treated with alpha interferon and ribavirin may constitute a special risk. Patients at increased risk should be followed closely. However, cases have also been reported in patients with no known risk factors.

There are no study results demonstrating the effect of DIVTRIDA on clinical progression of HIV-1.

Mitochondrial dysfunction: Nucleoside and nucleotide analogues as contained in DIVTRIDA 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 hematological disorders (anaemia, neutropenia), metabolic disorders (hyperlactatemia, hyperlipidemia). 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 or symptoms.

Pancreatitis: Pancreatitis has been observed in some patients receiving lamivudine, as in DIVTRIDA. It is unclear whether this is due to lamivudine or to underlying HIV disease. Pancreatitis must be considered whenever a patient develops abdominal pain, nausea, vomiting or elevated biochemical markers. Discontinue use of DIVTRIDA until a diagnosis of pancreatitis is excluded.

Patients with renal impairment: In patients with moderate to severe renal impairment, the terminal half-life of DIVTRIDA is increased due to decreased clearance (see CONTRA-INDICATIONS).

Liver disease: Use of DIVTRIDA can result in hepatomegaly due to non-alcoholic fatty liver disease (hepatic steatosis). The safety and efficacy of DIVTRIDA has not been established in patients with significant underlying liver disorders. Patients with pre-existing liver dysfunction including chronic active hepatitis, have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.

Renal Impairment: DIVTRIDA is a combination medicine and the dose of the individual components cannot be altered. Since DIVTRIDA is primarily eliminated by the kidneys, co-administration of DIVTRIDA with medicines that reduce renal function or compete for active tubular secretion may increase serum concentrations of DIVTRIDA and/or increase the concentrations of other renally eliminated medicines. Some examples include, but are not limited to adefovir dipivoxil, cidofovir, aciclovir, valaciclovir, ganciclovir and valganciclovir. DIVTRIDA is not recommended for patients with creatinine clearance < 80 mL/min or patients who require haemodialysis. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia) has been reported in association with the use of tenofovir disoproxil fumarate in clinical practice. Careful monitoring of renal function (serum creatinine and serum phosphate) is therefore recommended before taking DIVTRIDA.

Renal monitoring: It is recommended that renal function (creatinine clearance and serum phosphate) is assessed in all patients prior to initiating therapy with tenofovir disoproxil fumarate and that it is also monitored every four weeks during the first year of tenofovir disoproxil fumarate therapy, and then every three months. In patients at risk for renal impairment, including patients who have previously experienced renal events while receiving adefovir dipivoxil, consideration should be given to more frequent monitoring of renal function.

Co-administration and risk of renal toxicity: Use of tenofovir disoproxil fumarate should be avoided with concurrent or recent of a nephrotoxic medicine (e.g. aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir, or interleukin-2). If concomitant use of tenofovir disoproxil fumarate and nephrotoxic medicines is unavoidable, renal function should be monitored weekly. Tenofovir disoproxil fumarate has not been clinically evaluated in patients receiving medicines which are secreted by the same renal pathway, including the transport proteins human organic anion transporter (hOAT) 1 and 3 or MRP 4 (e.g. cidofovir, a known nephrotoxic medicine). These renal transport proteins may be responsible for tubular secretion and in part, renal elimination of tenofovir and cidofovir. Consequently, the pharmacokinetics of these medicines, which are secreted by the same renal pathway including transport proteins hOAT 1 and 3 or MRP 4; might be modified if they are co-administered. Unless clearly necessary, concomitant use of these medicines which are secreted by the same renal pathway is not recommended, but if such use is unavoidable, renal function should be monitored weekly.

DIVTRIDA should be avoided with concurrent or recent use of a nephrotoxic medicine. Patients at risk of, or with a history of, renal dysfunction and patients receiving concomitant nephrotoxic substances should be carefully monitored for changes in serum creatinine and phosphorous.

K65R mutation: DIVTRIDA should be avoided in antiretroviral experienced patients with HIV-1 harbouring the K65R mutation.

Bone mineral density: Decreases in bone mineral density of spine and changes in bone biomarkers from baseline are significantly greater with tenofovir disoproxil fumarate as contained in DIVTRIDA. Decreases in bone mineral density of the hip are significantly greater. Clinically relevant bone fractures are reported. If bone abnormalities are suspected then appropriate consultation should be obtained. Bone monitoring should be considered for HIV infected patients who have a history of pathologic bone fracture or are at risk of osteopenia. DIVTRIDA may cause a reduction in bone mineral density. The effects of tenofovir disoproxil fumarate-associated changes in bone mineral density on long-term bone health and future fracture risk are currently unknown. Bone monitoring should be considered for HIV infected patients who have a history of pathologic bone fracture or are at risk for osteopenia. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected then appropriate consultation should be obtained. Bone abnormalities (infrequently contributing to fractures) may be associated with proximal renal tubulopathy.

Patients with HIV and Hepatitis B or C virus co-infection: DIVTRIDA is not indicated for the treatment of chronic HBV infection. The safety and efficacy of DIVTRIDA has not been established for the treatment of patients co-infected with HBV and HIV. Patients with chronic hepatitis B or C and treated with antiretroviral therapy DIVTRIDA are at an increased risk for severe and potentially fatal hepatic adverse reactions. Medical practitioners should refer to current HIV treatment guidelines for the optimal management of HIV infection in patients co-infected with hepatitis B virus (HBV). In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant professional informations for these medicines.

Exacerbations of hepatitis: Flares on treatment: Spontaneous exacerbations in chronic hepatitis B are relatively common and are characterised by transient increases in serum ALT. After initiating antiviral therapy, serum ALT may increase in some patients. In patients with compensated liver disease, these increases in serum ALT are generally not accompanied by an increase in serum bilirubin concentrations or hepatic decompensation. Patients with cirrhosis may be at a higher risk for hepatic decompensation following hepatitis exacerbation, and therefore should be monitored closely during therapy. Flares after treatment discontinuation: Acute exacerbations of hepatitis have been reported in patients after the discontinuation of hepatitis B therapy. Post-treatment exacerbations are usually associated with rising HBV DNA, and the majority appears to be self-limited. However, severe exacerbations, including fatalities, have been reported. Hepatic function should be monitored at repeated intervals with both clinical and laboratory follow-up for at least 6 months after discontinuation of hepatitis B therapy. If appropriate, resumption of hepatitis B therapy may be warranted. In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since post-treatment exacerbations of hepatitis may lead to hepatic decompensation. Liver flares are especially serious, and sometimes fatal in patients with decompensated liver disease.

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

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

Paediatric use: Safety and effectiveness in paediatric patients and patients < 18 years of age have not been established.

Elderly use: Clinical studies did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

Effects on ability to drive and use machines: DIVTRIDA 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 DIVTRIDA affects them.

DIVTRIDA can have side effects. Lamivudine: The following side effects have been reported during therapy for HIV disease with DIVTRIDA tablets alone and in combination with other antiretrovirals.

Blood and the lymphatic system disorders: Less frequent: Anaemia, neutropenia, thrombocytopaenia Frequency unknown: pure red cell aplasia.

Metabolism and nutrition disorders: Frequent: Hyperlactataemia Less frequent: Lactic acidosis, lipodystrophy (redistribution/accumulation of body fat).

Nervous system disorders: Frequent: Headache, insomnia Less frequent: Peripheral neuropathy (or paraesthesia), late onset neurological disorders in children exposed in utero.

Gastrointestinal disorders: Frequent: Nausea, vomiting; upper abdominal pain or cramps; diarrhoea; stomatitis Less frequent: Pancreatitis, elevations in serum amylase.

Hepato-biliary disorders: Less frequent: Transient rises in liver enzymes (AST, ALT).

Skin and subcutaneous tissue disorders: Frequent: Rash, alopecia.

Musculoskeletal, connective tissue and bone disorders: Frequent: Arthralgia, muscle disorders Less frequent: Rhabdomyolysis, decrease in bone mineral density, osteopenia, fractures.

General disorders and administrative site conditions: Frequent: Fatigue, malaise, fever.

Tenofovir disoproxil fumarate: Immune system disorders: Less frequent: allergic reaction.

Gastrointestinal disorders: Frequent: Abdominal pain, anorexia, dyspepsia, flatulence Less frequent: Increased amylase, pancreatitis.

Hepato-biliary disorders: Less frequent: Increased liver enzymes, hepatitis.

Metabolism and nutrition disorders: Frequency unknown: Hypophosphatemia, lactic acidosis.

Renal and urinary disorders: Frequent: Renal insufficiency, renal failure, proximal tubulopathy, proteinuria, increased creatinine, acute tubular necrosis, nephrogenic diabetes insipidus.

Respiratory, thoracic and mediastinal disorders: Frequency unknown: Dyspnoea.

Dolutegravir: Immune system disorders: Less frequent: Hypersensitivity, immune reconstitution syndrome.

Psychiatric disorders: Frequent: Insomnia.

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

Gastrointestinal disorders: Frequent: Nausea, diarrhoea Less frequent: Vomiting, flatulence, upper abdominal pain Frequency unknown: Abdominal pain, abdominal discomfort.

Hepatobiliary disorders: Frequency unknown: Hepatitis.

Skin and subcutaneous tissue disorders: Frequent: Rash, pruritus.

Tenofovir disoproxil fumarate: If overdose occurs the patient must be monitored for evidence of toxicity and palliative supportive treatment be applied as necessary. Tenofovir can be removed by haemodialysis; the median haemodialysis clearance of tenofovir is 134 ml/min. The elimination of tenofovir by peritoneal dialysis has not been studied.

Lamivudine: Limited data are available on the consequences of ingestion of acute overdose in humans. If overdosage occurs the patient should be monitored, and palliative supportive treatment applied are required.

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