TENOFOVIR DISOPROXIL FUMERATE TABLETS

Indications

• HIV-1 infection
• Chronic hepatitis B virus (HBV) infection

Dosage

Children: Refer to the BNF for

Adults: Refer to the relevant clinical guidelines or BNF for the appropriate dosing recommendations.

Mechanism of action

Disoproxil is converted intracellularly to its active form, tenofovir diphosphate. This active metabolite competes with natural deoxyadenosine triphosphate (dATP) for incorporation into viral DNA by the viral reverse transcriptase enzyme. Once incorporated, it leads to chain termination, thereby inhibiting viral replication. Additionally, tenofovir diphosphate interferes with the activity of HIV reverse transcriptase and HBV polymerase, further contributing to its antiviral effects.

Pharmacodynamics

Disoproxil exhibits a dose-dependent decrease in HIV-1 viral load and improves CD4 cell counts in patients. Its antiviral activity is primarily against HIV-1 and HBV, with a mechanism that does not exhibit cross-resistance with other classes of antiretroviral drugs. The drug has a long half-life, allowing for once-daily dosing, which improves adherence in patients. It is effective in both naïve and treatment-experienced patients.

Pharmacokinetics

Disoproxil is absorbed following oral administration; its bioavailability is approximately 25% when taken without food. The drug is extensively distributed in the body, with a volume of distribution of about 1.3 L/kg. It undergoes renal clearance, with about 70% of the drug eliminated unchanged in the urine. The elimination half-life of disoproxil is around 17 hours, allowing for once-daily dosing. It is not significantly metabolized by the liver, which reduces the risk of drug-drug interactions associated with hepatic metabolism.

Contra-indications

• Hypersensitivity to disoproxil or any component of the formulation
• Severe renal impairment

Adverse effects

• Nausea
• Diarrhea
• Headache
• Fatigue
• Renal toxicity
• Liver function abnormalities
• Bone mineral density loss
• Lactic acidosis

Interactions

• Potential interactions with nephrotoxic drugs
• May interact with other antiviral agents
• Can affect the metabolism of drugs that are substrates of CYP450 enzymes

Precautions

• Monitor renal function regularly during therapy
• Assess bone mineral density before and during treatment
• Use with caution in patients with a history of pancreatitis
• Evaluate liver function before initiation and during treatment

Pregnancy

Disoproxil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Limited data on human use.

Breast-feeding

Disoproxil is excreted in breast milk. A decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Oral tablets
• Oral solution

Dosage

Children: Refer to official dosing guidelines for paediatric indications and dosages.

Adults: Refer to official dosing guidelines for specific indications and dosages.

Mechanism of action

Fumarate acts primarily as an intermediate in the TCA cycle, where it is converted to malate by the enzyme fumarase. This process is essential for the continuation of aerobic respiration, facilitating the conversion of carbohydrates, fats, and proteins into energy. Additionally, fumarate can participate in redox reactions, influencing cellular metabolism and signaling pathways.

Pharmacodynamics

Fumarate influences various metabolic pathways, including the urea cycle and glycolysis, by participating in electron transfer processes. Its role in the TCA cycle is vital for ATP production, and its interaction with other metabolic pathways helps regulate energy homeostasis and the balance of nitrogen in the body.

Pharmacokinetics

The pharmacokinetics of fumarate involve its absorption, distribution, metabolism, and excretion. Fumarate is readily absorbed when introduced into the body and is distributed to various tissues where it participates in metabolic processes. The metabolic conversion of fumarate occurs primarily in the mitochondria through the TCA cycle, and its elimination from the body is facilitated by renal pathways.

Pregnancy

There are no established guidelines regarding the use of fumerate during pregnancy. Consult healthcare professionals for individual risk assessment.

Breast-feeding

The safety of fumerate during breastfeeding has not been established. Caution is advised and consultation with healthcare professionals is recommended.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Indications

• HIV infection
• Chronic hepatitis B

Dosage

Children: Refer to BNF for Children for specific pediatric dosing information.

Adults: Refer to BNF for specific dosing information.

Mechanism of action

Once tenofovir is activated by bi-phosphorylation, it functions as an antiviral acyclic nucleoside phosphonate. It inhibits viral reverse transcriptase, exhibiting an inhibitory constant of approximately 0.022 micromolar. Tenofovir competes with deoxyadenosine 5'-triphosphate to generate new viral DNA, leading to chain termination and inhibition of viral replication. Its safety profile is maintained due to its low affinity for cellular DNA polymerases, including mitochondrial DNA polymerase gamma.

Pharmacodynamics

Tenofovir has demonstrated high efficacy in treatment-naive HIV patients, showing comparable effectiveness to efavirenz while exhibiting lower toxicity than some other antiretrovirals, such as stavudine. In patients with hepatitis B, tenofovir treatment has been associated with undetectable viral DNA levels after one year.

Pharmacokinetics

Tenofovir is absorbed after oral administration and is primarily eliminated by the kidneys. It has a half-life that allows for once-daily dosing and achieves therapeutic concentrations in plasma and tissues. The metabolism of tenofovir involves conversion to its active form, which is then incorporated into viral DNA, leading to its antiviral effects.

Contra-indications

• Hypersensitivity to tenofovir or any excipients in the formulation
• Severe renal impairment (CrCl < 30 mL/min) without appropriate dosage adjustment

Adverse effects

• Nausea
• Diarrhea
• Headache
• Fatigue
• Renal impairment
• Bone density loss
• Lactic acidosis

Interactions

• Antiepileptics (carbamazepine, fosphenytoin, oxcarbazepine, phenobarbital, phenytoin, primidone) with tenofovir alafenamide: Severe (decreases exposure)
• Tipranavir with tenofovir alafenamide: Severe (decreases exposure)
• Rifamycins with tenofovir alafenamide: Severe (decreases exposure)
• St John’s Wort with tenofovir alafenamide: Severe (decreases exposure)
• Fostemsavir with tenofovir disoproxil: Moderate (increases exposure)
• Fostemsavir with tenofovir alafenamide: Moderate (increases exposure)
• Ciclosporin with tenofovir alafenamide: Unknown (increases exposure)
• Ciclosporin with tenofovir disoproxil: Unknown (increases exposure)
• Eltrombopag with tenofovir alafenamide: Unknown (increases exposure)
• Eltrombopag with tenofovir disoproxil: Unknown (increases exposure)

Precautions

• Monitor renal function regularly during treatment
• Use with caution in patients with a history of renal disease
• Consider bone density monitoring in patients on long-term therapy

Pregnancy

Tenofovir is categorized as a pregnancy category B drug. Animal studies have not shown any harm, but human data is limited. Weigh risks and benefits when prescribing during pregnancy.

Breast-feeding

Tenofovir is excreted in breast milk, but the amount is considered low. The benefits of breastfeeding should be considered against the potential risk of HIV transmission.

Storage

Store at room temperature (20-25°C) in a tightly closed container. Keep away from light and moisture.

Mechanism of action

Once tenofovir is activated by a bi-phosphorylation it acts as an antiviral acyclic nucleoside phosphonate. It is a potent inhibitor of the viral reverse transcriptase with an inhibitory constant of approximately 0.022 micromolar. Once activated, tenofovir acts with different mechanisms including the inhibition of viral polymerase causing chain termination and the inhibition of viral synthesis. All these activities are attained by its competition with deoxyadenosine 5'-triphosphate in the generation of new viral DNA. Once tenofovir is incorporated in the chain, it induces a chain termination which in order inhibits viral replication. The safety of tenofovir relies on its low affinity towards the cellular DNA polymerase including the mitochondrial DNA polymerase gamma.

Pharmacodynamics

Tenofovir has been shown to be highly effective in patients that have never had an antiretroviral therapy and it seemed to have lower toxicity than other antivirals such as [stavudine]. In phase 3 clinical trials, tenofovir presented a similar efficacy than [efavirenz] in treatment-naive HIV patients. In hepatitis B infected patients, after one year of tenofovir treatment, the viral DNA levels were undetectable.