TDF EFAVIRENZ &EMTRICITABINE 300/600/200MG TABLET

Indications

• HIV-1 infection
• HIV infection in combination with other antiretroviral drugs

Dosage

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

Adults: 600 mg once daily, administered orally, preferably at bedtime to minimize CNS effects.

Mechanism of action

Efavirenz inhibits the activity of viral RNA-directed DNA polymerase, also known as reverse transcriptase. This inhibition interferes with the generation of DNA copies of viral RNA, which are necessary for producing new virions. The drug diffuses into the cell and binds to the reverse transcriptase enzyme, causing a conformational change that results in enzyme inhibition. This process is vital for preventing viral replication, although it does not eliminate HIV from the body.

Pharmacodynamics

As a non-nucleoside reverse transcriptase inhibitor, efavirenz exhibits virustatic properties, meaning it inhibits viral replication without directly killing the virus. Its pharmacodynamic effects are influenced by its intracellular conversion to an active triphosphorylated form. This conversion is variable, depending on the cell type, but ultimately leads to effective inhibition of HIV replication. Efavirenz is often used in conjunction with other antiretrovirals as part of a comprehensive treatment approach for HIV.

Pharmacokinetics

Efavirenz is well-absorbed when administered orally, and its bioavailability is affected by food intake. It undergoes extensive hepatic metabolism, primarily via cytochrome P450 enzymes (CYP2B6), leading to the formation of active metabolites. The drug has a long half-life, allowing for once-daily dosing. It is important to monitor liver function due to potential hepatotoxicity, especially in patients with existing liver conditions. The pharmacokinetics may be altered by drug interactions, necessitating dose adjustments in certain situations.

Contra-indications

• Severe hypersensitivity to efavirenz or any component of the formulation
• Acute porphyrias
• History of psychiatric disorders
• History of seizures
• Severe hepatic impairment

Adverse effects

• Rash
• Dizziness
• Nausea
• Vomiting
• Abdominal pain
• Asthenia
• Diarrhoea
• Sleep disorders
• CNS effects (e.g., confusion, hallucinations)
• Fatigue
• Mood alterations
• Suicidal behavior
• Hepatocellular injury
• Seizures
• Stevens-Johnson syndrome

Interactions

• Posaconazole: severe decrease in exposure
• Antimalarials: severe decrease in exposure
• Atovaquone: severe decrease in exposure
• Benzodiazepines: severe interaction affecting effects
• Midazolam: severe interaction affecting effects
• Voriconazole: moderate decrease in exposure
• Caspofungin: moderate decrease in concentration
• Ciclosporin: moderate decrease in concentration
• Coumarins: moderate interaction affecting concentration
• Opioids: moderate decrease in exposure

Precautions

• Caution in patients with history of psychiatric disorders or seizures
• Caution in elderly patients
• Monitor liver function if receiving other hepatotoxic drugs
• Caution in patients with chronic hepatitis B or C
• Driving and skilled tasks may be affected due to CNS effects

Pregnancy

Reports of neural tube defects when used in the first trimester. Manufacturer advises avoiding use during pregnancy.

Breast-feeding

Limited information available; caution is advised.

Storage

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

Formulations

• 600 mg capsules
• 600 mg tablets

Indications

• HIV-1 infection
• HIV pre-exposure prophylaxis (PrEP)
• Chronic HIV infection in combination with other antiretroviral agents

Dosage

Children: Refer to BNF for Children for specific dosing recommendations.

Adults: Refer to local guidelines and BNF for specific dosing recommendations.

Mechanism of action

Emtricitabine is phosphorylated intracellularly to its active form, emtricitabine triphosphate. This active form competes with the natural nucleoside substrates for incorporation into the viral DNA by reverse transcriptase. Once incorporated, emtricitabine terminates the elongation of viral DNA because it lacks a 3'-hydroxyl group necessary for further nucleotide addition. This process effectively inhibits viral replication.

Pharmacodynamics

Emtricitabine exhibits a dose-dependent antiviral activity against HIV-1 and HIV-2. The drug has a high genetic barrier to resistance, meaning that the development of resistance mutations is less likely compared to some other NRTIs. Its pharmacodynamic profile is characterized by a long half-life, allowing for once-daily dosing, which is conducive to patient adherence in long-term HIV management.

Pharmacokinetics

Emtricitabine is well-absorbed following oral administration, with peak plasma concentrations occurring approximately 1 to 2 hours post-dose. It has a bioavailability of about 93%. The drug is primarily eliminated via the kidneys, with an elimination half-life of approximately 10 hours. Renal impairment necessitates dosage adjustments due to decreased clearance. Emtricitabine does not undergo significant metabolism via liver enzymes, reducing the potential for drug-drug interactions.

Contra-indications

• Hypersensitivity to emtricitabine or any excipients in the formulation
• Severe hepatic impairment

Adverse effects

• Nausea
• Diarrhea
• Headache
• Fatigue
• Rash
• Hyperpigmentation of the palms or soles
• Lactic acidosis (rare but serious)

Interactions

• May interact with other antiretroviral agents
• Caution when used with drugs that affect renal function
• Potential interactions with drugs that are substrates or inhibitors of CYP450 enzymes

Precautions

• Monitor renal function regularly, particularly in patients with pre-existing renal impairment
• Screen for HIV resistance before starting therapy
• Consider the risk of lactic acidosis, especially in patients with risk factors
• Use with caution in patients with hepatitis B or C co-infection

Pregnancy

Emtricitabine is classified as Category B3. There is limited data in pregnant women, but it is generally considered safe when used for the treatment of HIV.

Breast-feeding

Emtricitabine is excreted in human breast milk. Caution is advised, as the effects on the infant are unknown.

Storage

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

Formulations

• Oral tablets
• Oral solution

Mechanism of action

Similar to zidovudine, efavirenz inhibits the activity of viral RNA-directed DNA polymerase (i.e., reverse transcriptase). Antiviral activity of efavirenz is dependent on intracellular conversion to the active triphosphorylated form. The rate of efavirenz phosphorylation varies, depending on cell type. It is believed that inhibition of reverse transcriptase interferes with the generation of DNA copies of viral RNA, which, in turn, are necessary for synthesis of new virions. Intracellular enzymes subsequently eliminate the HIV particle that previously had been uncoated, and left unprotected, during entry into the host cell. Thus, reverse transcriptase inhibitors are virustatic and do not eliminate HIV from the body. Even though human DNA polymerase is less susceptible to the pharmacologic effects of triphosphorylated efavirenz, this action may nevertheless account for some of the drug's toxicity. Efavirenz diffuses into the cell where it binds adjacent to the active site of reverse transcriptase. This produces a conformational change in the enzyme that inhibits function.

Pharmacodynamics

Efavirenz (dideoxyinosine, ddI) is an oral non-nucleoside reverse transcriptase inhibitor (NNRTI). It is a synthetic purine derivative and, similar to zidovudine, zalcitabine, and stavudine. Efavirenz was originally approved specifically for the treatment of HIV infections in patients who failed therapy with zidovudine. Currently, the CDC recommends that Efavirenz be given as part of a three-drug regimen that includes another nucleoside reverse transcriptase inhibitor (e.g., lamivudine, stavudine, zidovudine) and a protease inhibitor or efavirenz when treating HIV infection.