AVONZA 300/300/400MG 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 infection in combination with other antiretroviral drugs
• Chronic hepatitis B infection with evidence of viral replication and active liver inflammation or fibrosis

Dosage

Children: For children aged 3 months to

Adults: For HIV infection, the adult dose is 150 mg every 12 hours or alternatively 300 mg once daily. For chronic hepatitis B, the recommended dose is 300 mg once daily.

Mechanism of action

Lamivudine is phosphorylated intracellularly to its active form, lamivudine triphosphate (L-TP). This active metabolite is incorporated into viral DNA by HIV reverse transcriptase and HBV polymerase, leading to DNA chain termination. Lamivudine competes with deoxycytidine triphosphate for binding to reverse transcriptase, and its incorporation into DNA results in the disruption of DNA synthesis due to the absence of a 3'-OH group necessary for chain elongation.

Pharmacodynamics

As a nucleoside reverse transcriptase inhibitor (NRTI), lamivudine disrupts the viral DNA synthesis pathway, particularly for HIV-1 and HBV. The active metabolite formed competes with natural nucleotides and incorporates into the growing viral DNA chain, ultimately leading to chain termination. This action inhibits the replication of the virus, thereby reducing viral load in infected individuals.

Pharmacokinetics

Lamivudine is absorbed via passive diffusion and is rapidly phosphorylated to its active triphosphate form within cells. Its bioavailability is approximately 80-85% when taken orally. The drug has a half-life of about 5-7 hours in plasma and is primarily eliminated via the kidneys through glomerular filtration and active tubular secretion. Renal impairment necessitates dose adjustments, particularly in patients with creatinine clearance below 50 mL/min.

Contra-indications

• Severe hypersensitivity to lamivudine or any of its excipients
• Patients with decompensated liver disease when used for chronic hepatitis B

Adverse effects

• Peripheral neuropathy
• Headache
• Nausea
• Diarrhea
• Fatigue
• Insomnia
• Malaise
• Cough
• Pharyngitis
• Respiratory tract infections
• Alopecia
• Arthralgia

Interactions

• Trimethoprim may increase exposure to lamivudine
• Concomitant use with other antiretroviral drugs should be evaluated for cross-resistance

Precautions

• Monitor liver function tests every 3 months in patients with chronic hepatitis B
• Recurrent hepatitis may occur upon discontinuation in chronic hepatitis B patients
• Use with caution in renal impairment; dose adjustments may be necessary if creatinine clearance is less than 50 mL/min

Pregnancy

Lamivudine is classified as category B, indicating that there are no known risks in humans, but caution should be exercised. It may be used during pregnancy if deemed necessary by the healthcare provider.

Breast-feeding

Lamivudine can be used with caution while breastfeeding, provided adequate measures are taken to prevent hepatitis B infection in infants.

Storage

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

Formulations

• Lamivudine 150 mg tablets
• Lamivudine 300 mg tablets
• Epivir 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.

Mechanism of action

Lamivudine is a synthetic nucleoside analogue and is phosphorylated intracellularly to its active 5'-triphosphate metabolite, lamivudine triphosphate (L-TP). This nucleoside analogue is incorporated into viral DNA by HIV reverse transcriptase and HBV polymerase, resulting in DNA chain termination. Lamivudine enters cells by passive diffusion and is phosphorylated to its active metabolite, lamivudine triphosphate. Lamivudine triphosphate competes with deoxycytidine triphosphate for binding to reverse transcriptase, and incorporation into DNA results in chain termination. Lamivudine has very low affinity for human alpha and omega DNA polymerases, moderate affinity for beta DNA polymerase, and higher affinity for gamma DNA polymerase.

Pharmacodynamics

Lamivudine is a nucleoside reverse transcriptase inhibitor (NRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1) and hepatitis B (HBV) to disrupt viral DNA synthesis. When phosphorylated, lamivudine can form active metabolites that compete for incorporation into viral DNA. Via DNA incorporation, lamivudine metabolites competitively inhibit the activity of the HIV reverse transcriptase enzyme and act as a chain terminator of DNA synthesis. Due to the lack of a 3'-OH group, incorporated nucleoside analogues prevent the formation of a 5' to 3' phosphodiester linkage that is essential for DNA chain elongation.