Tenofovir Alafenamide

These indications are based on manufacturer information for both originator and generic products. For product specific registered indications, please refer to product specific manufacturer information

Registered South African indications:

• Chronic hepatitis B with compensated hepatic disease/ function

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Concomitant use with medicines containing tenofovir alafenamide, tenofovir disoproxil fumarate and adefovir dipivoxil

Contraindications registered in other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients

South African recommendations

• Pregnancy
• Breastfeeding
• Renal impairment (CrCl<15 ml/min without haemodialysis)
• Severe hepatic impairment (Child-Pugh Turcotte (CPT)>9 ( i.e. class C))
• Known risk factors of hepatic disease
  - Decompensated hepatic disease
  - Cirrhosis
  - Advanced hepatic disease
• Prolonged treatment
• Discontinuation of treatment
  (See additional prescribing points)
• Risk of HBV transmission
  - Sexual contact
  - Contamination with blood
  (See additional prescribing points)
• Coinfection of HBV and hepatitis C or D virus
  (See additional prescribing points)
• Coinfection of HBV and HIV
  (See additional prescribing points)
• Galactose intolerance
• Total lactase deficiency
• Glucose-galactose malabsorption
• May impair ability to drive and operate machinery

Recommendations in other jurisdictions

• Pregnancy
• Breastfeeding
• Renal impairment (CrCl<15ml/min without haemodialysis)
  - Evidence of proximal renal tubulopathy
• Severe hepatic impairment (Child-Pugh class C)
  - Known risk factors of hepatic disease
  - Decompensated hepatic disease
  - Cirrhosis
  - Advanced hepatic disease
• Discontinuation of treatment
  (See additional prescribing points)
• Prolonged treatment
• Risk of HBV transmission
  - Sexual contact
  - Contamination with blood
• Coinfection of HBV and hepatitis C or D virus
  (See additional prescribing points)
• Coinfection of HBV and HIV
  (See additional prescribing points)
• Galactose intolerance
• Total lactase deficiency
• Glucose-galactose malabsorption
• May impair ability to drive and operate machinery

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

South African registered indications and dosages

Infections caused by: Hepatitis B virus; HIV-1; HIV-2 

Specific doses based on individual indications

Please note that the dosages below should be used in combination with regional guidelines, taking into account local antibiotic sensitivities

Therapy should be initiated by an experienced medical practitioner in the management of chronic hepatitis B

Chronic hepatitis B with compensated hepatic disease/ function

• Oral (fct): 25mg, dly

See additional prescribing points for treatment discontinuation and missed dose

Tenofovir alafenamide should be taken orally with food

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

South African registered indications and dosages

Infections caused by: Hepatitis B virus; HIV-1; HIV-2

Specific doses based on individual indications

Please note that the dosages below should be used in combination with regional guidelines, taking into account local antibiotic sensitivities

Therapy should be initiated by an experienced medical practitioner in the management of chronic hepatitis B

Chronic hepatitis B with compensated hepatic disease/ function

Younger than 6 years (<25kg)

• Not established for use

6 years and older (≥25kg)

• See adult dosage

See additional prescribing points for treatment discontinuation and missed dose

Tenofovir alafenamide should be taken orally with food

Pregnancy

South African recommendations

• Caution; not recommended
• Safety in pregnancy has not been established and possible harm to the embryo/ developing foetus cannot be excluded
• The use of tenofovir alafenamide is not recommended in pregnancy unless no other appropriate medicine that is known to be safe in pregnancy is available, not tolerated or has failed
• The use of tenofovir alafenamide should be accompanied by the use of effective contraception

Recommendations in other jurisdictions

• Caution; no evidence of risk in studies
• There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of tenofovir alafenamide in pregnant women. However, a large amount of data on pregnant women (more than 1000 exposed outcomes) indicate no malformative nor foeto/ neonatal toxicity associated with the use of tenofovir disoproxil
• Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity
• The use of tenofovir alafenamide may be considered during pregnancy, if necessary

Breastfeeding

South African recommendations

• Caution; not recommended 
• Women on treatment with tenofovir alafenamide should not breastfeed their babies as harm to the newborn baby/ infant cannot be excluded
• It is not known whether tenofovir alafenamide is excreted in human milk. However, in animal studies it has been shown that tenofovir is excreted into milk
• There is insufficient information on the effects of tenofovir in newborns/ infants

Recommendations in other jurisdictions

• Caution; not recommended 
• It is not known whether tenofovir alafenamide is secreted in human milk. However, in animal studies it has been shown that tenofovir is secreted into milk
• There is insufficient information on the effects of tenofovir in newborns/ infants
• A risk to the breastfed newborns/ infants cannot be excluded; therefore, tenofovir alafenamide should not be used during breastfeeding

Fertility

• No human data on the effect of tenofovir alafenamide on fertility are available
• Animal studies do not indicate harmful effects of tenofovir alafenamide on fertility

Recommendations below are applicable to South Africa and other jurisdictions

• CrCl≥15ml/min or CrCl<15ml/min with haemodialysis: No dose adjustment recommended
  ≥12 years and ≥35kg body weight
  On the days of haemodialysis, tenofovir alafenamide should be administered after completion of haemodialysis treatment
• CrCl<15ml/min without haemodialysis: Caution; not recommended

South African recommendations

• Mild or moderate: No dose adjustment recommended 
• Severe: Caution; not recommended
  There are no data on the safety and efficacy of tenofovir alafenamide in HBV infected patients with decompensated hepatic disease and who have a Child-Pugh Turcotte (CPT) >9 ( i.e class C). Patients with Child-Pugh Turcotte, class C may be at higher risk of experiencing serious hepatic or renal adverse reaction. Therefore, there is no dose recommendation for these patients and tenofovir alafenamide is not recommended for use in these patients

Recommendations in other jurisdictions

• Mild to moderate (Child-Pugh class A and B): No dose adjustment recommended 
• Severe (Child-Pugh class C): Caution; no information available 
  Should changes in hepatic and/or renal parameters be observed following the use of tenofovir alafenamide, the manufacturer recommendation is to closely monitor hepatobiliary and renal parameters in patients with decompensated liver disease for the duration of tenofovir alafenamide therapy

Recommendations below are applicable to South Africa and other jurisdictions

• No dose adjustment recommended

Central Nervous System Disorders

• Headache
• Dizziness
• Fatigue

Gastrointestinal Disorders

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

Hepatobiliary Disorders

• Increased alanine aminotransferase
  - Transient increases in serum alanine aminotransferase
• Exacerbations of hepatitis

Genitourinary Disorders

• Proximal renal tubulopathy

Endocrine and Metabolic Disorders

• Increased body weight
• Increased serum lipids
• Increased blood glucose

Musculoskeletal Disorders

• Arthralgia

Skin and Subcutaneous Tissue Disorders

• Rash
• Pruritus
• Urticaria

Immune, Blood and Lymphatic System Disorders

• Angioedema

• Other medicinal products containing tenofovir alafenamide
• Tenofovir disoproxil
• Adefovir dipivoxil
• P-glycoprotein inducers
• Anticonvulsants
• Carbamazepine
• Oxcarbazepine
• Phenobarbital
• Phenytoin
• Antimycobacterials
• Rifampicin
• Rifabutin
• Rifapentine
• Strong P-glycoprotein inhibitors
• Antifungal agents
• Itraconazole
• Ketoconazole
• Protease inhibitors
• Atazanavir/cobicistat
• Atazanavir/ritonavir
• Darunavir/cobicistat
• Darunavir/ritonavir
• Lopinavir/ritonavir
• Tipranavir/ritonavir

Other interactions

• St. John's wort

• Renal function
  - Serum creatinine
  - Estimated creatinine clearance
• Urine tests (prior to initiation and as clinically indicated)
  - Glucose
  - Protein
• HIV status
• Hepatic function
• Hepatitis B virus DNA (HBV DNA) (every 3 months until undetectable and then every 3-6 months thereafter)
• Hepatitis B e antigen (HBeAg)
• Anti-HBe
  - In those who are HBeAg positive to monitor for seroconversion
• Hepatitis B surface antigen (HBsAg)

Specific cases may require

• Serum phosphorus
• Lactic acid levels
• Recurrent viraemia
• Alanine aminotransferase flares
• Seroreversion
• Clinical decompensation (every 3 months for ≥1 year)

Additional observations

• Risk of hepatocellular carcinoma

Treatment discontinuation

• In HBeAg-positive patients without cirrhosis, treatment should be administered for at least 6-12 months after HBe seroconversion (HBeAg loss and HBV DNA loss with anti-HBe detection) is confirmed or until HBs seroconversion or until there is loss of efficacy
• Regular reassessment is recommended after treatment discontinuation to detect virological relapse
• In HBeAg-negative patients without cirrhosis, treatment should be administered at least until HBs seroconversion or until there is evidence of loss of efficacy
• With prolonged treatment >2 years, regular reassessment is recommended to confirm that continuing the selected therapy remains appropriate for the patient

Missed dose

• If a dose is missed and less than 18 hours have passed from the time it is usually taken, the patient should take tenofovir alafenamide as soon as possible and then resume their normal dosing schedule
• If more than 18 hours have passed from the time it is usually taken, the patient should not take the missed dose and should simply resume the normal dosing schedule
• If the patient vomits within 1 hour of taking tenofovir alafenamide, the patient should take another tablet
• If the patient vomits more than 1 hour after taking tenofovir alafenamide, the patient does not need to take another tablet

HBV transmission

• Patients must be advised that tenofovir alafenamide does not prevent the risk of transmission of HBV to others through sexual contact or blood contamination
• Therefore, appropriate precautions must be continued to prevent the transmission of HBV

Lactic acidosis and severe hepatomegaly

• Lactic acidosis and severe hepatomegaly including fatal cases, have been reported with the use of nucleoside analogues, including tenofovir disoproxil fumarate, another prodrug of tenofovir, alone or in combination with other antiretrovirals
• Treatment with tenofovir alafenamide should be discontinued in patients who develop clinical and/or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity which may include hepatomegaly and steatosis even in the absence of marked increase in transaminase
• Lactic acidosis clinical symptoms are non-specific and include gastrointestinal symptoms (i.e. abdominal pain, nausea and vomiting, dyspnoea, fatigue and weight loss)
• In patients with suspicious symptoms or biochemistry, measure the venous lactate (normal <2mmol/l) and the serum bicarbonate and the following responses are to be implemented
  - Lactate: 2–5mmol/l with minimum symptoms: the patient should be switched to medicines that are less likely to cause lactic acidosis
  - Lactate: 5–10mmol/l  with symptoms and/ or with reduced standard bicarbonate: Stop NRTIs and change treatment option. When the lactate has settled, use medication that is less likely to cause lactic acidosis. Other causes must be excluded such as sepsis, uraemia, diabetic ketoacidosis, and thyrotoxicosis/ hyperthyroidism
  - Lactate: >10mmol/l: All therapy must be STOPPED. There is 80% fatality above these levels
• The above lactate levels may not be applicable to paediatric patients
• Caution should be exercised when administering tenofovir alafenamide to patients with known risks factors for hepatic disease

Exacerbation of hepatitis
Flares on treatment

• Spontaneous exacerbation in chronic hepatitis B are relatively common and are characterised by transient increases in serum alanine aminotransferase (ALT)
• After initiating antiviral therapy, serum ALT may increase in some patients
• In patients with compensated hepatic 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 higher risk for hepatic decompensation following hepatitis exacerbation, and therefore should be monitored closely during therapy

Flares after treatment discontinuation

• Acute exacerbation of hepatitis has been reported in patients who have discontinued treatment for hepatitis B, usually in association with rising HBV DNA levels in plasma
• The majority of cases are self-limited but severe exacerbations, including fatal outcomes, may occur after discontinuation of treatment for hepatitis B
• Hepatic function should be monitored at repeated intervals with both clinical and laboratory follow-up for at least 6 months after discontinuation of treatment for hepatitis B
• If appropriate, resumption of hepatitis B therapy may be warranted
• In patients with advanced hepatic disease or cirrhosis, treatment discontinuation is not recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation
• Hepatic flares are especially serious, and sometimes fatal in patients with decompensation hepatic disease

Hepatitis B and HIV coinfection

• HIV antibody testing should be offered to all HBV-infected patients whose HIV-1 infection status is unknown before initiating therapy with tenofovir alafenamide
• In patients who are coinfected with HBV and HIV, tenofovir alafenamide should be coadministered with other antiretroviral agents to ensure that the patient receives an appropriate regimen for treatment of HIV

Tenofovir alafenamide is a nucleoside and nucleotide reverse transcriptase inhibitor (NRTI). Tenofovir alafenamide is a phosphonamidate prodrug of tenofovir (2'-deoxyadenosine monophosphate analogue). Tenofovir alafenamide enters primary hepatocytes by passive diffusion and by the hepatic uptake transporters OATP1B1 and OATP1B3. Tenofovir alafenamide is primarily hydrolysed to form tenofovir by carboxylesterase 1 in primary hepatocytes. Intracellular tenofovir is subsequently phosphorylated to the pharmacologically active metabolite tenofovir diphosphate. Tenofovir diphosphate inhibits HBV replication through incorporation into viral DNA by the HBV reverse transcriptase, which results in DNA chain termination.

Tenofovir has activity that is specific to hepatitis B virus and human immunodeficiency virus (HIV-1 and HIV-2). Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases that include mitochondrial DNA polymerase γ and there is no evidence of mitochondrial toxicity in vitro based on several assays including mitochondrial DNA analyses.

Spectrum of activity: Hepatitis B virus; HIV-1; HIV-2

Film-coated tablet 25mg

• Tefumid (Cipla Medpro)
• Venlamid (Cipla Medpro)