Tladeez 300 mg FC tablets

TLADEEZ is indicated for the treatment of HIV-1 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 TLADEEZ is one tablet taken orally, once daily, without regard to food.

Paediatrics: TLADEEZ is not recommended for use in patientu2019s younger than 18 years of age.

Renal impairment: Significantly increased exposure occurred when tenofovir, as in TLADEEZ, was administered to patients with renal impairment (see Contraindications). The pharmacokinetics of tenofovir, as in TLADEEZ, have not been evaluated in non-haemodialysis patients with creatinine clearance < 80 mL/min); therefore, no dosing recommendations are available or possible with this combination for these patients. TLADEEZ is contraindicated in patients with renal impairment with creatinine clearance less than 80 mL/min.

TLADEEZ tablets are contraindicated in patients with:

• known hypersensitivity to lamivudine, tenofovir or dolutegravir or to any of the components of the tablets.
• impaired renal failure.
• pregnancy and lactation (see Fertility, pregnancy, and lactation).
• 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 TLADEEZ have been established in clinical studies for the treatment of HIV patients. However, safety and efficacy of the fixed drug combination as in TLADEEZ for the treatment of HIV have not been established in clinical studies. The complete professional information of the other medicines used in combination should be consulted before initiation of therapy.

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

Lipodystrophy: Combination antiretroviral therapy, including TLADEEZ, 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. 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 / Immune Reactivation Syndrome: In HIV infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy, an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. This 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. Typically, such reactions have been observed within the first few weeks or months of initiation of combination Anti-Retroviral Therapy (cART). Such reactions typically present with 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, generalised and/or focal mycobacterial infections, including atypical mycobacterial infections, cytomegalovirus retinitis, Pneumocystis jerovecii (carinii) and cryptococcal meningitis. Any inflammatory symptoms should be evaluated, and 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 Graves' 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 TLADEEZ. 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 TLADEEZ may continue to develop opportunistic infections and other complications of HIV infection, and therefore 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 must be advised that treatment with antiretroviral TLADEEZ, have not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions must continue to be used.

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 TLADEEZ. 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 TLADEEZ alone or in combination, in the treatment of HIV infection. Most cases were women. Caution should be exercised when administering TLADEEZ to patients with known risk factors for liver disease. Treatment with TLADEEZ 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 TLADEEZ 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. Patients at increased risk should be followed closely.

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

Mitochondrial dysfunction: Nucleoside and nucleotide analogues as contained in TLADEEZ 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 or symptoms.

Pancreatitis: Pancreatitis has been observed in some patients receiving lamivudine, as in TLADEEZ. 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 TLADEEZ until diagnosis of pancreatitis is excluded.

Patients with renal impairment: In patients with renal impairment, the terminal half-life of TLADEEZ is increased due to decreased clearance (see Contraindications).

Liver disease: Use of TLADEEZ can result in hepatomegaly due to non-alcoholic fatty liver disease (hepatic steatosis). The safety and efficacy of TLADEEZ 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: TLADEEZ is a combination product, and the dose of the individual components cannot be altered. Tenofovir and lamivudine are principally eliminated by the kidney. TLADEEZ 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 hypophosphataemia) has been reported 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 TLADEEZ.

Renal function: Since TLADEEZ is primarily eliminated by the kidneys, co-administration of TLADEEZ with medicines that reduce renal function or compete for active tubular secretion may increase serum concentrations of TLADEEZ 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.

There have been no medicine interaction studies conducted using TLADEEZ. TLADEEZ contains tenofovir, lamivudine and dolutegravir. Interactions that have been identified with these individual medicines may occur with TLADEEZ.

Lamivudine: The likelihood of interactions is low due to the limited metabolism as plasma protein binding and almost complete renal clearance. Zidovudine plasma levels are not significantly altered when co-administered with lamivudine, as in TLADEEZ. Zidovudine has no effect on the pharmacokinetics of lamivudine as in TLADEEZ. Lamivudine may inhibit the intracellular phosphorylation of zalcitabine when the two medicinal products are used concurrently. Lamivudine, as in TLADEEZ, is therefore not recommended to be used in combination with zalcitabine. An interaction with trimethoprim, a constituent of co-trimoxazole, causes a 40 % increase in lamivudine exposed at therapeutic doses. This does not require dose adjustment unless the patient also has renal impairment. Administration of co-trimoxazole with the lamivudine/zidovudine combination in patients with renal impairment should be carefully assessed. Lamivudine, as in TLADEEZ, has no effect on the pharmacokinetics of co-trimoxazole. The possibility of interactions with other medicines administered concurrently should be considered, particularly when the main route is renal. Other medicines that are eliminated only in part by this route, such as cimetidine and ranitidine, were shown not to interact with lamivudine, as in TLADEEZ, hence no dosage adjustments are required. TLADEEZ may inhibit the intracellular phosphorylation of cladribine when the two medicines are used concurrently. TLADEEZ is therefore not recommended to be used in combination with cladribine.

TLADEEZ is contraindicated in pregnancy and lactation. Tenofovir 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, in utero (see Mitochondrial Dysfunction under Special warnings and precautions for use). TLADEEZ should not be prescribed in women who plan to become pregnant. Woman of child-bearing age should not use TLADEEZ unless they are reliably using highly effect contraception. Treatment with TLADEEZ should not be initiated without a medically supervised negative pregnancy test. This test should be repeated at frequent intervals during treatment with TLADEEZ; and especially in the event that pregnancy is suspected.

Lactation: Mothers breastfeeding their infants should not use TLADEEZ. Lamivudine is excreted in human milk at similar concentrations to those found in serum; tenofovir is excreted in breast milk.

Dolutegravir: 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 TLADEEZ in women of childbearing potential to exclude inadvertent (unintentional) use of TLADEEZ 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.

TLADEEZ may make the patient feel tired, weak, lightheaded, or dizzy and 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 TLADEEZ affects them.

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

Blood and lymphatic system disorders: Less frequent: neutropenia, anaemia, thrombocytopenia, pure red cell aplasia

Metabolism and nutrition disorders: Frequent: hyperlactataemia Less frequent: lactic acidosis, lipodystrophy (redistribution/accumulation of body fat) (see Warnings and special precautions)

Psychiatric disorders: Frequent: insomnia and other sleep disorders; depressive disorders

Nervous system disorders: Frequent: headache Less frequent: paraesthesia, peripheral neuropathy has been reported, although a causal relationship to treatment is uncertain, late onset neurological disorders in children exposed in utero

Gastrointestinal disorders: Frequent: nausea, vomiting, upper abdominal pain; diarrhoea, cramps Less frequent: pancreatitis, although a causal relationship to treatment is uncertain. Rise in serum amylase

Respiratory, thoracic, and mediastinal disorders: Frequent: cough, nasal symptoms

Hepatobiliary disorders: Less frequent: transient rises in liver enzymes (AST, ALT), hepatitis

Skin and subcutaneous tissue disorders: Frequent: rash, alopecia

Musculoskeletal and connective tissue disorders: Frequent: arthralgia, muscle disorders, musculoskeletal pain Less frequent: rhabdomyolysis, decrease in bone mineral density, osteopenia, fractures, myalgia, osteonecrosis, myositis

General disorders and administration site conditions: Frequent: fatigue, malaise, fever

Investigations: Frequent: absolute neutrophil count < 750/mm 3 ; reduction in haemoglobin ( 5,0 x ULN (upper limit of normal) Less frequent: reduced platelets ( 2,5 x ULN)

Tenofovir disoproxil fumarate: Immune system disorders: Less frequent: allergic reaction (including angioedema), immune reconstitution inflammatory syndrome

Metabolism and nutrition disorders: Frequency unknown: hypophosphataemia, lactic acidosis

Psychiatric disorders: Frequent: depression, insomnia, anxiety

Nervous system disorders: Frequent: dizziness, peripheral neuropathy; headache

Respiratory, thoracic, and mediastinal disorders: Frequency unknown: dyspnoea

Gastrointestinal disorders Frequency unknown: abdominal pain, anorexia, dyspepsia, flatulence, increased amylase; pancreatitis

Hepatobiliary disorders Frequency unknown: increased liver enzymes, hepatitis, hepatomegaly, steatosis

Skin and subcutaneous tissue disorders: Freqency unknown: rash

Musculoskeletal, connective tissue system and bone disorders: Freqency unknown: myopathy, osteomalacia (both associated with proximal renal tubulopathy

Renal and urinary disorders Frequency unknown: renal insufficiency, renal failure, acute renal failure, Fanconi syndrome, proximal tubulopathy, proteinuria, increased creatinine, acute tubular necrosis, nephrogenic diabetes insipidus, nephritis

General disorder and administration site disorders: Frequent: asthenia, fatigue, pain, fever, abdominal pain, back pain

Investigations: Frequent: increased fasting cholesterol, raised creatinine kinase; rise in serum amylase, increases in AST and ALT, haematuria, decreased neutrophil count, increased fasting triglyceride levels

Dolutegravir: Immune system disorders: Less frequent: hypersensitivity, immune reconstitution syndrome

Psychiatric disorders: Frequent: insomnia, anxiety, depression, paranoia, suicidal ideation

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

Ear and labyrinth disorders: Frequent: vertigo

Gastrointestinal disorders: Frequent: nausea, diarrhoea, vomiting, flatulence, upper abdominal pain Less frequent: abdominal pain, abdominal discomfort, gastritis

Hepatobiliary disorders: Less frequent: hepatitis

Skin and subcutaneous tissue disorders: Frequent: rash, pruritus

Musculoskeletal, connective tissue and bone disorders: Less frequent: athralgia, myalgia

Renal and urinary disorders: Less frequent: renal impairment

General disorders and administration site conditions: Frequent: fatigue

Investigations: Frequent: alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) elevations, creatine phosphokinase (CPK) elevations raised bilirubin levels, hyperglycaemia, increased lipase levels, decreased neutrophil counts, changes in serum cholesterol and triglyceride levels

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 overdoses in humans. If overdosage occurs the patient should be monitored, and palliative supportive treatment applied as 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 TLADEEZ. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary. As TLADEEZ is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.