Adco-Lamivudine Solution

ADCO-LAMIVUDINE SOLUTION is indicated as part of antiretroviral combination therapy for the treatment of HIV infected adults and children.

Adults and adolescents more than 12 years of age: The recommended dose of ADCO-LAMIVUDINE SOLUTION is 300 mg daily. This may be administered as either 300 mg once daily or 150 mg twice daily. The professional information for zidovudine must be consulted for information on its dosage and administration. For patients with low body weights (less than 50 kg), the recommended oral dose of ADCO-LAMIVUDINE SOLUTION is 2 mg/kg twice daily. Children u2265 3 months to 12 years of age: The recommended dose is 4 mg/kg twice daily up to a maximum of 300 mg daily. Children < 3 months of age: There are limited data to propose specific dosage recommendations (see section 5.2). ADCO-LAMIVUDINE SOLUTION can be taken with or without food. Renal and hepatic impairment Renal impairment, whether disease- or age-related, affects lamivudine elimination. For recommended dosage regimens in patients with a creatinine clearance below 50 ml/min see table below.

Adults and adolescents > 12 years of age: Creatinine Clearance (ml/min) Recommended dose of ADCO-LAMIVUDINE SOLUTION u2265 50 150 mg twice daily 30 u2013 49 150 mg once daily 15 u2013 29 150 mg first dose, then 100 mg once daily 5 u2013 14 150 mg first dose, then 50 mg once daily < 5 50 mg first dose, then 25 mg once daily

Children > 3 months to 12 years: Creatinine Clearance (ml/min) Recommended dose of ADCO-LAMIVUDINE SOLUTION u2265 50 4 mg/kg first dose, then 4 mg/kg twice daily 30 u2013 49 4 mg/kg first dose, then 4 mg/kg once daily 15 u2013 29 4 mg/kg first dose, then 2,6 mg/kg once daily 5 u2013 14 4 m/kg first dose, then 1,3 mg/kg once daily < 5 1,3 mg/kg first dose, then 0,7 mg/kg once daily

Hypersensitivity to lamivudine or to any of the components listed in section 6.1.

Opportunistic infections Patients receiving ADCO-LAMIVUDINE SOLUTION and other antiretroviral agents should be advised that they may continue to develop opportunistic infections and other complications of HIV infection, and therefore they should remain under close observation by healthcare professionals experienced in the treatment of patients with HIV-associated diseases. Regular monitoring of viral load and CD4 counts needs to be done.

The risk of HIV transmission to others Patients should be advised that current antiretroviral therapy, including ADCO-LAMIVUDINE SOLUTION, does not prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be employed.

Lactic acidosis/hyperlactataemia Use of ADCO-LAMIVUDINE SOLUTION can result in potentially fatal lactic acidosis as a consequence of mitochondrial dysfunction. Clinical features are non-specific, and include nausea, vomiting, abdominal pain, dyspnoea, fatigue and weight loss. In patients with suspicious symptoms or biochemistry, measure the venous lactate level (normal < 2 mmol/L) and the serum bicarbonate, and respond as follows:

• Lactate 2 to 5 mmol/L with minimum symptoms: switch to agents that are less likely to cause lactic acidosis.
• Lactate 5 to 10 mmol/L with symptoms and/or with reduced standard bicarbonate: Stop NRTIs and change treatment option. Once lactate has settled, use medicines that are less likely to cause lactic acidosis. Exclude other causes (e.g. sepsis, uraemia, diabetic ketoacidosis, thyrotoxicosis and hyperthyroidism).
• Lactate > 10 mmol/L: STOP all therapy (80 % mortality).

The above lactate values may not be applicable to paediatric patients.

Caution should be exercised when administering ADCO-LAMIVUDINE SOLUTION to patients with known risk factors for liver disease. Treatment with ADCO-LAMIVUDINE SOLUTION should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity.

Pancreatitis Pancreatitis has been observed in some patients receiving ADCO-LAMIVUDINE SOLUTION. Pancreatitis must be considered whenever a patient develops abdominal pain, nausea, vomiting or elevated biochemical markers. Discontinue use of ADCO-LAMIVUDINE SOLUTION until diagnosis of pancreatitis is excluded.

Patients with moderate to severe renal impairment In patients with moderate to severe renal impairment, the terminal half-life of ADCO-LAMIVUDINE SOLUTION is increased due to decreased clearance. The dose of ADCO-LAMIVUDINE SOLUTION should therefore be adjusted (see section 4.2).

Lipodystrophy and metabolic abnormalities Combination antiretroviral therapy has been associated with the redistribution/accumulation of body fat, including central obesity, dorso-cervical fat, enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and elevated serum lipid and glucose levels in HIV patients. Clinical examination should include evaluation for physical signs of fat redistribution. Patients with evidence of lipodystrophy should 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, cytomegalovirus retinitis, 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 Graves' disease) 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). 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 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 post-natally to nucleoside analogues. Apart from lactic acidosis/hyperlactataemia (see above) other manifestations of mitochondrial dysfunction include haematological disorders (anaemia, neutropenia), and peripheral neuropathy. Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). It is not known whether the neurological disorders are transient or permanent. Any foetus exposed in utero to nucleoside and nucleotide analogues, even HIV negative infants/children, should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant sign and symptoms.

Liver disease Use of ADCO-LAMIVUDINE SOLUTION can result in hepatomegaly due to non-alcoholic fatty liver disease (hepatic steatosis). The safety and efficacy of ADCO-LAMIVUDINE SOLUTION has not been established in patients with significant underlying liver disorders/diseases. In case of concomitant antiviral therapy for hepatitis B or C, please also consult the relevant professional information for these medicines. 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. If there is evidence of worsening liver disease in such patients, temporary or permanent discontinuation of treatment must be considered.

Patients with HIV and hepatitis B or C virus co-infection 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. Patients co-infected with HIV and HBV who discontinue ADCO-LAMIVUDINE SOLUTION should be closely monitored with both clinical and laboratory follow-up after stopping treatment. In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation. Discontinuation of ADCO-LAMIVUDINE SOLUTION therapy in patients co-infected with HIV and HBV may be associated with severe, acute exacerbations of hepatitis.

Excipients ADCO-LAMIVUDINE SOLUTION contains sucrose. This should be taken into account in patients with diabetes mellitus. Sucrose may be harmful to teeth. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take ADCO-LAMIVUDINE SOLUTION.

Zidovudine plasma levels are not significantly altered when co-administered with ADCO-LAMIVUDINE SOLUTION (see section 5.2). An interaction with trimethoprim, a constituent of co-trimoxazole, causes a 40 % increase in lamivudine plasma concentrations at therapeutic doses. This does not require dose adjustment unless the patient also has renal impairment. Administration of co-trimoxazole with the ADCO-LAMIVUDINE SOLUTION /zidovudine combination in patients with renal impairment should be carefully assessed. ADCO-LAMIVUDINE SOLUTION may inhibit the intracellular phosphorylation of zalcitabine when the two medicinal products are used concurrently. Use of ADCO-LAMIVUDINE SOLUTION in combination with zalcitabine is therefore not recommended. Due to similarities, ADCO-LAMIVUDINE SOLUTION should not be administered concomitantly with other cytidine analogues, such as emtricitabine. In vitro lamivudine inhibits the intracellular phosphorylation of cladribine leading to a potential risk of cladribine loss of efficacy in case of combination in the clinical setting. Some clinical findings also support a possible interaction between lamivudine and cladribine. Therefore, the concomitant use of lamivudine with cladribine is not recommended. Coadministration of sorbitol solution (3,2 g, 10,2 g, 13,4 g) with a single 300 mg dose of lamivudine oral solution resulted in dose-dependent decreases of 14 %, 32 %, and 36 % in lamivudine exposure (AUCu221e) and 28 %, 52 %, and 55 % in the C max of lamivudine in adults. When possible, avoid chronic coadministration of ADCO-LAMIVUDINE SOLUTION with medicinal products containing sorbitol or other osmotic acting poly-alcohols or monosaccharide alcohols (e.g. xylitol, mannitol, lactitol, maltitol). Consider more frequent monitoring of HIV-1 viral load when chronic coadministration cannot be avoided.

Pregnancy As a general rule, when deciding to use antiretroviral agents for the treatment of HIV infection in pregnant women and consequently for reducing the risk of HIV vertical transmission to the newborn, the animal data as well as the clinical experience in pregnant women should be taken into account. Animal studies with lamivudine showed an increase in early embryonic deaths in rabbits but not in rats. Placental transfer of lamivudine has been shown to occur in humans. More than 1000 outcomes from first trimester and more than 1000 outcomes from second and third trimester exposure in pregnant women indicate no malformative and foeto/neonatal effect. Lamivudine can be used during pregnancy if clinically needed. The malformative risk is unlikely in humans based on those data. For patients co-infected with hepatitis who are being treated with lamivudine and subsequently become pregnant, consideration should be given to the possibility of a recurrence of hepatitis on discontinuation of lamivudine. Mitochondrial dysfunction: Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in infants exposed in utero and/or post-natally to nucleoside analogues (see section 4.4).

Breastfeeding Following oral administration lamivudine was excreted in breast milk at similar concentrations to those found in serum. Based on more than 200 mother/child pairs treated for HIV, serum concentrations of lamivudine in breastfed infants of mothers treated for HIV are very low (< 4 % of maternal serum concentrations) and progressively decrease to undetectable levels when breastfed infants reach 24 weeks of age. There are no data available on the safety of lamivudine when administered to babies less than three months old. It is recommended that HIV infected women do not breastfeed their infants under any circumstances in order to avoid transmission of HIV.

Fertility Studies in animals showed that lamivudine had no effect on fertility.

No data available.

The following side effects have been reported during therapy of HIV disease with ADCO-LAMIVUDINE SOLUTION alone, and in combination with other anti-retrovirals.

System Organ Class Frequency Side effects Blood and lymphatic system disorders Less frequent Neutropenia, thrombocytopenia, anaemia, pure red cell aplasia Metabolism and nutrition disorders Less frequent Lactic acidosis Nervous system disorders Frequent Peripheral neuropathy, paraesthesia, headache, insomnia Respiratory, thoracic and mediastinal disorders Frequent Cough, nasal symptoms Gastrointestinal disorders Frequent Upper abdominal pain or cramps, nausea, vomiting, diarrhoea, pancreatitis Frequency unknown Rises in serum amylase Hepato-biliary disorders Less frequent Hepatitis Frequency unknown Transient rises in serum liver enzymes (AST, ALT) Skin and subcutaneous tissue disorders Frequent Skin rash Less frequent Angioedema Frequency unknown Alopecia Musculoskeletal and connective tissue disorders Frequent Arthralgia and muscle disorders Frequency unknown Rhabdomyolysis General disorders and administration site conditions Frequent Malaise, fatigue and fever

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

Treatment is symptomatic and supportive.