DOLTAVIR-X TABLETS

Indications

• HIV infection
• Chronic hepatitis B virus infection

Dosage

Children: Refer to the BNF for Children for appropriate dosing guidelines in paediatric patients.

Adults: Refer to the BNF for specific dosing recommendations based on the condition being treated and individual patient factors.

Mechanism of action

Disproxil is converted intracellularly to tenofovir diphosphate, which competes with the natural substrate deoxyadenosine 5'-triphosphate for incorporation into viral DNA by reverse transcriptase. This incorporation leads to premature termination of the viral DNA chain, thereby inhibiting viral replication.

Pharmacodynamics

Disproxil exhibits a potent antiviral effect against HIV and HBV by inhibiting the reverse transcriptase enzyme, which is crucial for the conversion of viral RNA into DNA. The drug demonstrates a high barrier to resistance, making it a preferred option in antiretroviral therapy. Its efficacy is enhanced when used in combination with other antiretrovirals, which can target different stages of the viral life cycle.

Pharmacokinetics

Disproxil is well absorbed after oral administration, with a bioavailability of approximately 25% due to extensive first-pass metabolism. The peak plasma concentration occurs about 1 hour after dosing. It has a half-life of approximately 12-18 hours, allowing for once-daily dosing in most cases. The drug is primarily excreted via the kidneys, with renal clearance being a significant route of elimination. Caution is advised in patients with renal impairment, as dosage adjustments may be necessary.

Adverse effects

• Nausea
• Diarrhea
• Abdominal pain
• Headache
• Fatigue
• Dizziness
• Rash
• Liver function abnormalities
• Renal impairment

Interactions

• Potential interactions with other nephrotoxic drugs
• Antiretroviral medications may alter pharmacokinetics
• Caution with drugs that affect liver enzymes

Precautions

• Monitor renal function regularly
• Assess liver function prior to and during treatment
• Use with caution in patients with pre-existing kidney disease
• Consider potential drug interactions

Pregnancy

Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. Consult relevant guidelines.

Breast-feeding

Excreted in breast milk; caution is advised when administering to nursing mothers.

Storage

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

Formulations

• Oral tablets
• Oral solution

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.