ASPEN-NEVIRAPINE*200 200MG TABLET

Indications

• HIV infection in antiretroviral treatment-experienced adults
• HIV infection in antiretroviral treatment-experienced paediatric patients from 2 years of age

Dosage

Children: For children aged 3–17 years: 200 mg once daily for body surface area 0.

Adults: Initially 200 mg once daily for the first 14 days, followed by 200 mg twice daily. If treatment is interrupted for more than 7 days, restart with 200 mg once daily for 14 days.

Mechanism of action

Nevirapine binds directly to reverse transcriptase (RT) and inhibits its RNA-dependent and DNA-dependent DNA polymerase activities by disrupting the enzyme's catalytic site. This binding occurs in a deep pocket on the enzyme, affecting the alignment of essential components for the chemical reaction necessary for viral DNA synthesis, which ultimately hinders HIV replication.

Pharmacodynamics

As a non-nucleoside reverse transcriptase inhibitor, nevirapine exhibits selective activity against HIV-1, showing no inhibitory effects on HIV-2 RT or human DNA polymerases. It is generally prescribed when the immune system is compromised and in the presence of opportunistic infections. Nevirapine is effective only when used in combination with other antiretroviral agents, as monotherapy can lead to the development of drug resistance.

Pharmacokinetics

Nevirapine is well absorbed after oral administration, with peak plasma concentrations typically occurring within 4 hours. It undergoes extensive hepatic metabolism primarily via the cytochrome P450 system, particularly CYP3A4. The elimination half-life of nevirapine ranges from 25 to 30 hours, allowing for less frequent dosing. It is primarily excreted in urine as metabolites, with minimal unchanged drug excreted.

Contra-indications

• Acute porphyrias

Adverse effects

• Hypersensitivity reactions
• Rash
• Eosinophilia
• Fever
• General malaise
• Myalgia
• Arthralgia
• Blistering
• Oral lesions
• Conjunctivitis
• Hepatitis
• Diarrhoea
• Drowsiness
• Dry mouth
• Dyslipidaemia
• Dyspnoea
• Gastrointestinal discomfort
• Headache
• Hyperglycaemia
• Hypertension
• Memory loss
• Myocardial infarction
• Nausea
• Peripheral neuropathy
• Renal failure
• Abnormal skin reactions
• Sleep disorders
• Angina pectoris
• Angioedema
• Atrial fibrillation
• Bronchospasm
• Concentration impaired
• Confusion
• Gynaecomastia
• Haematemesis
• Hepatic disorders
• Inflammatory syndrome
• Pancreatitis
• Seizure
• Syncope
• Tremor
• Vertigo
• Weight increased
• Osteonecrosis

Interactions

• Nevirapine + ketoconazole: Severe (decreases exposure)
• Nevirapine + voriconazole: Moderate (decreases exposure)
• Nevirapine + midazolam: Moderate (decreases concentration)
• Nevirapine + caspofungin: Moderate (decreases concentration)
• Nevirapine + antiepileptics: Unknown (decreases concentration)
• Nevirapine + carbamazepine: Unknown (decreases concentration)
• Nevirapine + fosphenytoin: Unknown (decreases concentration)
• Nevirapine + phenobarbital: Unknown (decreases concentration)
• Nevirapine + phenytoin: Unknown (decreases concentration)
• Nevirapine + primidone: Unknown (decreases concentration)

Precautions

• C

Mechanism of action

Nevirapine binds directly to reverse transcriptase (RT) and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by causing a disruption of the enzyme's catalytic site. The activity of nevirapine does not compete with template or nucleoside triphosphates. The binding site for nevirapine on HIV-1 reverse transcriptase is near, but not at the proposed site of active polymerization, in a deep pocket lying between the beta sheets of the palm and at the base of the thumb subdomains of the enzyme's p66 subunit. In the absence of nevirapine, the binding of deoxynucleoside triphosphate to the reverse transcriptase-template complex results in a change in the conformation of reverse transcriptase. This conformational change is followed by a magnesium-dependent chemical reaction in which deoxynucleoside triphosphate is incorporated into the newly forming viral DNA; the conformational change appears to be the rate-limiting step of the reverse transcriptase catalysis of viral DNA formation. Nevirapine appears to have no appreciable effect on the rate of or equilibrium constant for the conformational change but may slow the chemical reaction, which then becomes the rate-limiting step in the catalytic sequence. When nevirapine binds to the reverse transcriptase-template complex, changes may occur in the position of aspartic acid carboxyl groups in reverse transcriptase so that magnesium ions are not in proper alignment for the chemical reaction to occur efficiently, and the reaction is slowed. Therefore, although the nevirapine-reverse transcriptase-template complex may continue to bind deoxynucleoside triphosphate and to catalyze its incorporation into the newly forming viral DNA, it appears to do so at a slower rate. The mechanism of action of nevirapine differs from that of nucleoside reverse transcriptase inhibitors (e.g., abacavir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine). Nucleoside antiretroviral agents require intracellular conversion to triphosphate metabolites, which then compete with naturally occurring deoxynucleoside triphosphates for incorporation into viral DNA by reverse transcriptase and cause premature viral DNA chain termination by preventing further 5 to 3 phosphodiester linkages. Nevirapine, however, is noncompetitive with respect to primer-template or nucleoside triphosphate binding and is specific for HIV-1 reverse transcriptase. The drug binds directly to heterodimeric HIV-1 reverse transcriptase and appears to inhibit viral RNA- and DNA-dependent DNA polymerase activities by disrupting the catalytic site of the enzyme. Nevirapine diffuses into the cell and binds to reverse transcriptase adjacent to the catalytic site. This induces conformational changes that inactivate the enzyme. Resistance develops rapidly in cells exposed to nevirapine. High-level resistance is associated with mutations at reverse transcriptase codons 101, 103, 106,108, 135, 181, 188, and 190. A single mutation at either codon 103 or 181 decreases susceptibility more than 100 fold. Cross-resistance may extend to all FDA-approved nonnucleoside reverse transcriptase inhibitors, especially with the codon 103 mutation. Nevirapine is a highly specific inhibitor of HIV-1 reverse transcriptase, and results of in vitro studies indicate that nevirapine does not appear to inhibit cellular DNA polymerases, including human alpha-, beta-, Gamma-, or Delta-polymerases.

Pharmacodynamics

Nevirapine is a non-nucleoside reverse transcriptase inhibitor (nNRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). HIV-2 RT and eukaryotic DNA polymerases (such as human DNA polymerases alpha, beta, or sigma) are not inhibited by nevirapine. Nevirapine is, in general, only prescribed after the immune system has declined and infections have become evident. It is always taken with at least one other HIV medication such as Retrovir or Videx. The virus can develop resistance to nevirapine if the drug is taken alone, although even if used properly, nevirapine is effective for only a limited time.