Tenofovir Disoproxil Fumarate/ Lamivudine

Registered South African indications:

• HIV infection

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with other antiretrovirals. 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 occurred after a few or several months of treatment. Treatment with tenofovir disoproxil fumarate/lamivudine should be discontinued in the setting of symptomatic hyperlactataemia and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating aminotransferase levels. Caution should be exercised when administering 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. Tenofovir disoproxil fumarate/lamivudine is not indicated for the treatment of chronic hepatitis B virus (HBV) infection and the safety and efficacy has not been established in patients co-infected with HBV and HIV. Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with HBV and HIV and have discontinued tenofovir disoproxil fumarate/lamivudine. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue tenofovir disoproxil fumarate/lamivudine and are co-infected with HIV and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

Combination products may have additional pharmacological effects not accounted for by the action of the individual ingredients

Contraindications

• Hypersensitivity to the active ingredient or any of the excipients in this combination product
• Patients with moderate to severe renal impairment (CrCl<50ml/min), since dose adjustments are not possible with a fixed dose combination such as tenofovir disoproxil fumarate/lamivudine
• Pregnancy
• Lactation
• Patients younger than 18 years of age
• Concomitant use with zalcitabine

Cautions

Caution in the following patient groups

• Hepatic impairment
• Elderly

Lactic acidosis/severe hepatomegaly with steatosis

• Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of tenofovir disoproxil fumarate/lamivudine alone or in combination, in the treatment of HIV infection. Most cases were women
• Obesity and prolonged nucleoside exposure may increase the risk of lactic acidosis
• Patients with a history of liver disease or those with known risk factors for liver disease may be at increased risk of lactic acidosis and hepatotoxicity
• Long-term use of tenofovir disoproxil fumarate/lamivudine can result in potentially fatal lactic acidosis. Clinical features are non-specific, including nausea, vomiting, abdominal pain, dyspnoea, fatigue, and weight loss. Suspicious biochemical features include mildly raised transaminases, raised lactate dehydrogenase (LDH), and/or creatine kinase
• If patients show suspicious symptoms or biochemical features, 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, thyrotoxicosis, lymphoma)
  • Lactate > 10 mmol/ℓ: STOP all therapy (80% mortality in case studies)
• Diagnosis of lactic acidosis is confirmed by demonstrating metabolic acidosis with an increased anion gap and a raised lactate level
• Therapy should be stopped in any acidotic patient with a raised lactate level
• Blood for lactate assays should be heparinised and stored on ice
• After recovery, NRTIs should be avoided. Seek expert advice on medicine selection
• The above lactate values may not be applicable to paediatric patients

Renal disease and failure

• The tenofovir in tenofovir disoproxil fumarate/lamivudine is primarily eliminated via the kidney
• Renal failure, renal impairment, elevated creatinine, hypophosphataemia, and proximal tubulopathy (including Fanconi syndrome) have been reported with the use of tenofovir disoproxil fumarate/lamivudine
• It is recommended that creatinine clearance be calculated in all patients before initiating therapy with tenofovir disoproxil fumarate/lamivudine and renal function be monitored regularly during treatment
• Patients at risk of renal impairment should be monitored more frequently for renal function
• Tenofovir disoproxil fumarate/lamivudine is contraindicated in patients with creatinine clearance < 50ml/min, including those requiring haemodialysis

Patients with HIV and hepatitis B virus co-infection

• It is recommended that all patients with HIV be tested for the presence of hepatitis B virus (HBV) before initiating antiretroviral therapy
• Tenofovir disoproxil fumarate/lamivudine is not indicated for the treatment of chronic HBV infection and the safety and efficacy have not been established in patients co-infected with HBV and HIV
• Severe, acute exacerbations of HBV have been reported in patients after the discontinuation of the tenofovir in tenofovir disoproxil fumarate/lamivudine
• Patients co-infected with HIV and HBV should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping tenofovir treatment
• If appropriate, initiation of anti-hepatitis B therapy may be warranted

Fat redistribution

• Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, "cushingoid appearance", and elevated serum lipid and glucose levels have been observed either separately or together in some patients receiving combination antiretroviral therapy, such as tenofovir disoproxil fumarate/lamivudine
• The lipodystrophy syndrome has a multi-factorial aetiology; with for example HIV disease status, older age and duration of antiretroviral therapy all playing important, possibly synergistic roles
• The long-term consequences of these events are currently unknown
• Clinical examination should include evaluation for physical signs of fat redistribution
• Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate

Combination antiretroviral therapy is also associated with metabolic abnormalities

• Such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia

Pancreatitis

• Pancreatitis has been observed in patients receiving lamivudine, as in tenofovir disoproxil fumarate/lamivudine
• Pancreatitis must be considered whenever a patient develops abdominal pain, nausea, vomiting or elevated biochemical markers
• Discontinue use of tenofovir disoproxil fumarate/lamivudine until diagnosis of pancreatitis is excluded

Opportunistic infections

• Patients receiving tenofovir disoproxil fumarate/lamivudine may continue to develop opportunistic infections and other complications of HIV infection, and therefore they should remain under close observation by medical practitioners experienced in the treatment of patients with associated HIV disease

The risk of HIV transmission to others

• Patients should be advised that current antiretroviral therapy, including tenofovir disoproxil fumarate/lamivudine, 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 employed

Immune reconstitution syndrome

• Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including tenofovir disoproxil fumarate/lamivudine.
• During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia, or tuberculosis), which may necessitate further evaluation and treatment

Bone mineral density

• Decreases in bone mineral density of the hip and spine have been associated with tenofovir-based treatment, such as with tenofovir disoproxil fumarate/lamivudine
• However, there was no increased risk of fracture or evidence for clinically relevant bone abnormalities
• 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 for osteopenia
• Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients

Liver disease

• Safety and efficacy data are very limited in liver transplant patients
• There are limited data on the safety and efficacy of the tenofovir disoproxil fumarate in tenofovir disoproxil fumarate/lamivudine in HBV infected patients with decompensated liver disease and who have Child-Pugh-C (moderate to severe)
• These patients may be at higher risk of experiencing serious hepatic or renal adverse reactions
• Therefore, hepatobiliary and renal parameters should be closely monitored in this patient population
• Tenofovir disoproxil fumarate/lamivudine should be used with caution in patients with advanced cirrhotic liver disease due to chronic hepatitis B infection as there is a risk of rebound hepatitis post-treatment

Osteonecrosis

• 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

Paediatric use

• Safety and effectiveness in paediatric patients and patients < 18 years of age have not been established

Geriatric use

• Dose selection for the elderly patient should be cautious, keeping in mind the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other medicine therapy

Mitochondrial dysfunction

• Nucleoside and nucleotide analogues, such as contained in tenofovir disoproxil fumarate/lamivudine, 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, hyperlipasaemia)
• 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 currently 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

Lactose

• Tenofovir disoproxil fumarate/lamivudine contains lactose. Tenofovir disoproxil fumarate/lamivudine should not be administered to patients with glucose-galactose malabsorption, hereditary galactose intolerance or with the rare Lapp lactase deficiency

Effects on the ability to drive and use machinery

• Tenofovir disoproxil fumarate/lamivudine may cause dizziness; patients should be advised to refrain from driving a car or operating machinery until they know how tenofovir disoproxil fumarate/lamivudine affects them

Forms avail. in SA and covered in this monograph: tab

HIV infection

Tenofovir disoproxil fumarate/Lamivudine
300/300 (mg)

• Oral (tab): 1 tab, dly

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To be taken with food 

Not established for use in children below 18 years

Consult HIV/infectious disease specialists prior to any decisions related to ARV regimen termination/switch

Recommendations for this combination product as per highest risk category when comparing individual active ingredients

Pregnancy

• Contraindicated

Breastfeeding

• Contraindicated

Renal Impairment

• Moderate to severe (CrCl<50ml/min): Contraindicated

Hepatic Impairment

• Caution; no dose adjustment recommended (Tenofovir, Lamivudine)

Elderly

• Caution; no information available (Tenofovir)

Drugs in Sport

• Permitted - No warning

Combination products may have additional pharmacological effects not accounted for by the action of the individual ingredients

Tenofovir disoproxil fumarate
Central Nervous System Disorders

• Dizziness
• Headache

Gastrointestinal Disorders

• Diarrhoea
• Nausea and vomiting
• Abdominal pain
• Abdominal distension
• Flatulence
• Pancreatitis

Hepatobiliary Disorders

• Increased transaminases
• Hepatic steatosis
• Hepatitis

Genitourinary Disorders

• Increased creatinine
• Proximal renal tubulopathy
• Acute renal failure
• Renal failure
• Acute tubular necrosis
• Nephritis
• Nephrogenic diabetes insipidus

Endocrine and Metabolic Disorders

• Hypophosphataemia
• Hypokalaemia
• Lactic acidosis

Musculoskeletal Disorders

• Rhabdomyolysis
• Muscular weakness
• Osteomalacia 
• Myopathy

Skin and Subcutaneous Tissue Disorders

• Rash
• Angioedema

Lamivudine
Central Nervous System Disorders

• Headache
• Insomnia
• Peripheral neuropathy

Respiratory Disorders

• Cough
• Nasal symptoms

Gastrointestinal Disorders

• Nausea and vomiting
• Abdominal pain 
• Diarrhoea
• Pancreatitis
• Elevations in serum amylase

Hepatobiliary Disorders

• Transient elevations in liver enzymes
• Hepatitis

Endocrine and Metabolic Disorders

• Lactic acidosis

Musculoskeletal Disorders

• Arthralgia
• Muscle disorders
• Rhabdomyolysis

Skin and Subcutaneous Tissue Disorders

• Rash
• Alopecia
• Angioedema

Immune, Blood and Lymphatic System Disorders

• Neutropenia
• Anaemia 
• Thrombocytopenia
• Pure red cell aplasia

Others

• Fatigue
• Malaise
• Fever

Combination products may have additional pharmacological effects not accounted for by the action of the individual ingredients

Tenofovir disoproxil fumarate

• Adefovir 
• Didanosine
• Medicinal products that reduce renal function
• OAT1 substrates
• OAT3 substrates
• MRP4 substrates
• Nephrotoxic medicinal products
• Tacrolimus
• Hepatitis C virus antiviral agents
• Atazanavir
• Lopinavir/Ritonavir

Lamivudine

• Trimethoprim/sulfamethoxazole
• Cladribine
• Cytidine analogues
• Zalcitabine

• Hepatic function
• Coagulation studies
• Full blood count
• Renal function - before initiation, 1 month, 2 month, 3 month and 6 monthly thereafter

Specific cases may require

• Renal function
• Lactate levels
• Bone density

Tenofovir disoproxil fumarate
Tenofovir disoproxil fumarate, a prodrug, is converted to tenofovir. Tenofovir is a nucleotide reverse transcriptase inhibitor (nRTIs).  It is an analogue of the naturally occurring deoxynucleotides required to synthesize the viral DNA. Tenofovir inhibits HIV-1 reverse transcriptase and the HBV polymerase by direct binding competition with the natural deoxyribonucleotide substrate and, after incorporation into DNA, by DNA chain termination.

Lamivudine
Lamivudine is a nucleoside analogue which has activity against human immunodeficiency virus (HIV) and hepatitis B virus (HBV). It is metabolised intracellularly to the active moiety, lamivudine 5'-triphosphate. Its main mode of action is as a chain terminator of viral reverse transcription. The triphosphate has selective inhibitory activity against HIV-1 and HIV-2 replication and is also active against zidovudine-resistant clinical isolates of HIV.

COMBINATION PREPARATIONS

Tenofovir disoproxil fumarate/ Lamivudine

Tablet 300mg/300mg

• Cipla Lamivudine & Tenofovir (Cipla)
• Mivuten (Cipla)