Lavem 300 mg Tablets

LAVEM is indicated for the treatment of HIV-1 infection in adults aged 18 years and older.

Posology
Therapy should be initiated by a medical practitioner experienced in the management of HIV infection. Rifampicin decreases the blood levels of dolutegravir. A supplementary dose of dolutegravir should be given to patients taking LAVEM. The concentration of isoniazid is increased by concomitant administration of LAVEM.
Adults: The dose of LAVEM is one tablet taken orally, once daily, without regard to food.
For treatment-naive and treatment experienced patients the recommended dose is one tablet daily.
Renal Impairment
Dose adjustment for renal impairment: Significantly increased exposure occurred when tenofovir, as in LAVEM, was administered to patients with moderate to severe renal impairment (see section 4.3). The pharmacokinetics of tenofovir, as in LAVEM, have not been evaluated in non-haemodialysis patients with creatinine clearance< 80 ml/min); therefore, no dosing recommendations is available for these patients. LAVEM is not suitable for use in patients with renal impairment with creatinine clearance less than 50 ml/min.
Paediatric population
LAVEM is not recommended for use in patients younger than 18 years of age.
Method of administration
LAVEM is taken orally, once daily, without regard to food.

• LAVEM 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 section 4.6);
• 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 LAVEM have been established in clinical studies for the treatment of HIV patients. However, safety and efficacy of the fixed-drug combination as in LAVEM 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 LAVEM has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia.
Lipodystrophy: Combination antiretroviral therapy, including LAVEM, 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.
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 LAVEM. 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 LAVEM 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 LAVEM, 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 LAVEM. 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:
u2022 Lactate 2-5 mmol/L: monitor regularly, and be alert for clinical signs.
u2022 Lactate 5-10 mmol/L without symptoms: monitor closely.
u2022 Lactate 5-10 mmol/L with symptoms: STOP all therapy. Exclude other causes (e.g. sepsis, uraemia, diabetic ketoacidosis, thyrotoxicosis, lymphoma).
u2022 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 LAVEM alone or in combination, in the treatment of HIV infection. Most cases were women. Caution should be exercised when administering LAVEM to patients with known risk factors for liver disease. Treatment with LAVEM 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 LAVEM 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 up closely. There are no study results demonstrating the effect of LAVEM on clinical progression of HIV-1.
Mitochondrial dysfunction: Nucleoside and nucleotide analogues as contained in LAVEM 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 LAVEM. 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 LAVEM until diagnosis of pancreatitis is excluded.
Patients with renal impairment: In patients with moderate to severe renal impairment, the terminal half-life of LAVEM is increased due to decreased clearance (see section 4.3).
Liver disease: Use of LAVEM can result in hepatomegaly due to non-alcoholic fatty liver disease (hepatic steatosis). The safety and efficacy of LAVEM 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: LAVEM is a combination medicine and the dose of the individual components cannot be altered. Tenofovir and lamivudine are principally eliminated by the kidney. LAVEM 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 LAVEM.
Renal function: Since LAVEM is primarily eliminated by the kidneys, co-administration of LAVEM with medicines that reduce renal function or compete for active tubular secretion may increase serum concentrations of LAVEM 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.
Renal safety with tenofovir has only been studied to a very limited degree in adult patients with impaired renal function (creatinine clearance < 80 ml/min).
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 use 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.
LAVEM 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 phosphorus.
K65R mutation: LAVEM should be avoided in antiretroviral experienced patients with HIV-1 harbouring the K65R mutation.
Bone mineral density: Bone abnormalities such as osteomalacia which can manifest as persistent or worsening bone pain and, which can infrequently contribute to fractures may be associated with tenofovir disoproxil-induced proximal renal tubulopathy (see section 4.8). Tenofovir disoproxil may also cause a reduction in bone mineral density (BMD). Decreases in bone mineral density of spine and hip and changes in bone biomarkers from baseline are significantly greater. Clinically relevant bone fractures are reported. If bone abnormalities are suspected or detected 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. In view of the bone abnormalities associated with tenofovir disoproxil and the limitations of long-term data on the impact of tenofovir disoproxil on bone health and fracture risk, alternative treatment regimens should be considered for patients with osteoporosis that are at a high risk for fractures. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients.
Patients with HIV and hepatitis B or C virus co-infection: LAVEM is not indicated for the treatment of chronic HBV infection. The safety and efficacy of LAVEM 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 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 information 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 exacerbation of hepatitis may lead to hepatic decompensation. Liver flares are especially serious, and sometimes fatal in patients with decompensated liver disease.
Immune reactivation syndrome/ Immune reconstitution inflammatory syndrome (IRIS): In HIV infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (cART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. 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 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.
Hypersensitivity reactions: Hypersensitivity reactions have been reported with integrase inhibitors, including dolutegravir and were characterized by rash, constitutional findings and sometimes, organ dysfunction, including liver injury. Discontinue LAVEM 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 aminotransferase should be monitored and appropriate therapy initiated. Delay in stopping treatment with LAVEM or other suspect medicines after the onset of hypersensitivity may result in a life-threatening reaction.

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. Zidovudine has no effect on the pharmacokinetics of lamivudine. Lamivudine may inhibit the intracellular phosphorylation of zalcitabine when the two medicines are used concurrently. Lamivudine is therefore not recommended to be used in combination with zalcitabine. Administration of trimethoprim, a constituent of co-trimoxazole causes an increase in lamivudine plasma levels. However, unless the patient has renal impairment, no dosage adjustment of lamivudine is necessary. Lamivudine 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.
No medicine interaction studies have been conducted using LAVEM. As LAVEM contains tenofovir disoproxil fumarate and lamivudine, any interactions that have been identified with these individual medicines may occur with LAVEM. Important medicine interaction information for LAVEM is summarised in Tables 1, 2 and 3. The medicine interactions described are based on studies conducted with tenofovir disoproxil fumarate or lamivudine as individual medicines, or are potential medicine interactions. While the tables include potentially significant interactions, they are not all inclusive. Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the potential for CYP450-mediated interactions involving tenofovir with other medicines is low.
An interaction with trimethoprim, a constituent of co-trimoxazole, causes a 40 % increase in lamivudine exposure 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.
Renally eliminated medicines: Tenofovir, as in LAVEM, is primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. Co-administration of LAVEM with medicines that are eliminated by active tubular secretion may increase serum concentrations of either tenofovir or the co-administered medicine due to competition for this elimination pathway. Medicines that decrease renal function may also increase serum concentrations of tenofovir, as in LAVEM. Tenofovir has been evaluated in healthy volunteers in combination with abacavir, adefovir dipivoxil, atazanavir, didanosine, efavirenz, emtricitabine, indinavir, lamivudine lopinavir/ritonavir, methadone, oral contraceptives and ribavirin. Tables 1 and 2 summarise pharmacokinetic effects of co-administered medicine on tenofovir pharmacokinetics and effects of tenofovir on the pharmacokinetics of co-administered medicine.
When administered with multiple doses of tenofovir, the C max and AUC of didanosine 400 mg increased significantly. The mechanism of this interaction is unknown. When didanosine 250 mg enteric-coated capsules were administered with tenofovir, systemic exposures to didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions.

Pregnancy
LAVEM is contraindicated in pregnancy and lactation. Neural tube defects have been noted in an observational study in humans, where dolutegravir-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 observed in children who have been exposed to nucleoside analogues such as tenofovir and lamivudine, (see Mitochondrial Dysfunction under section 4.4).
LAVEM should not be prescribed in women who plan to become pregnant. Women of child-bearing age should not use LAVEM unless they are reliably using highly effective contraception. Treatment with LAVEM should not be initiated without a medically supervised negative pregnancy test. This test should be repeated at frequent intervals during treatment with LAVEM; and especially in the event that pregnancy is suspected.
Lactation
Mothers breastfeeding their infants should not use LAVEM. 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.

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

a. Summary of the safety profile
Not Applicable
b. Tabulated summary of adverse reactions
LAVEM can have side effects. Lamivudine: The following side-effects have been reported during therapy for HIV disease with LAVEM tablets alone and in combination with other antiretrovirals.
Blood and the lymphatic system disorders: Less frequent: Neutropenia; anaemia; thrombocytopenia 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 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 and connective tissue disorders: Frequent: arthralgia; muscle disorders Less frequent: rhabdomyolysis; decrease in bone mineral density; osteopenia; fractures
General disorders and administration 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 (ALT, AST, gamma GT); hepatitis Metabolism and nutrition disorders: Frequent: Hypophosphataemia Less frequent: Lactic acidosis Renal and urinary disorders Frequent: Renal insufficiency; acute renal failure; proximal tubulopathy; proteinuria; increases creatinine; acute tubular necrosis; nephrogenic diabetes insipidus; Fanconi syndrome, polyuria; interstitial nephritis. Respiratory, thoracic, and mediastinal disorders Frequency not known: Dyspnoea Nervous system disorders: Frequent: dizziness Musculoskeletal, connective tissue and bone disorders: Less frequent: rhabdomyolysis 1 ; muscular weakness 1 ; osteomalacia (manifested as bone pain and infrequently contributing to fractures) 1, 2 , myopathy 1 1 This side effect may occur as a consequence of proximal renal tubulopathy. It is not considered to be causally associated with tenofovir disoproxil fumarate in the absence of this condition. 2 This side effect was identified through post-marketing surveillance. General disorders and administration site conditions: Frequent: asthenia
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 not known: Abdominal pain; abdominal discomfort Hepatobiliary disorders: Frequency not known: Hepatitis Skin and subcutaneous tissue disorders: Frequent: Rash; pruritus General disorders and administration site conditions: Frequent: Fatigue

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