Nevirapine (Viramune) is a non-nucleoside reverse transcriptase inhibitor that acts against the human immune deficiency virus (HIV).

Nevirapine Uses:

• HIV-1 infection:

  • It is used concurrently with other antiretroviral drugs for treating HIV-1 in adults and children ≥15 days of age (immediate-release) and ≥6 years of age with a BSA of ≥1.17 m (extended-release).

  • Limitations of use:

    • It is not prescribed unless the benefit outweighs the risk, in adult females with CD4 cell counts >250 cells/mm³ or adult males with CD4 cell counts >400 cells/mm³.

• Off Label Use of Nevirapine in Adult

  • Prevention of perinatal HIV transmission.

Nevirapine dose in Adults

Nevirapine dose in adults for the treatment of HIV-1 infection: 

• Loading dose:

  • Initial dose of 200 mg immediate release tablets per oral once daily for 2 weeks.

• Maintenance dose:

  • The immediate-release dose of 200 mg b.i.d daily in addition to other antiretroviral agents if the initial dose is well tolerated.
  • Extended-release:
    • 400 mg once daily maintenance therapy using the extended-release after two weeks of initial loading with immediate-release formulation unless the patient is already maintained on a nevirapine immediate release regimen.

Note:

• The dose should not be increased if there is a rash with the initial drug therapy that has not subsided.
• A lead-in period is advised with immediate-release formulation and regimen and alternate therapy should be started if the regimen exceeds 28 days.
• Liver functions should be monitored if the rash appears within 3 months of therapy, the therapy should be stopped in case of deranged LFTs or un-resolving rash.
• If therapy with any formulation is interrupted for >7 days, the initial dose (immediate-release)should be restarted for 2 weeks.

Nevirapine dose in Children

Nevirapine dose in children for the treatment of HIV-1 infection:

Note:

• The drug should be offered in combination with other antiretroviral agents. Gene mutation and ARV resistance patterns should be looked for
• Although lead-in dosing is not required in children <2 years of age for enzymatic autoinduction and reducing the occurrence of the rash if compared to patients ≥2 years of age.
• In the case of the development of a rash, the protocol is the same as in adults.

AIDSinfo guidelines:

• Immediate release:

  • Infants and Children <8 years:

    • With lead-in dosing:

      • The initial dose of 200 mg/m per oral once daily
      • The maximum dose: 200 mg/dose for the 2 weeks titrated to 200 mg/m²/dose b.i.d daily (maximum dose: 200 mg/dose) if no rash or other adverse effects occur.

    • Without lead-in dosing:

      • Infants and Children <2 years:

      • 200 mg/m² per oral b.id daily (maximum dose: 200 mg/dose) monitor patients for rash.

      • Children ≥8 years:

        • Initial (lead-in dosing):
          • 120 to 150 mg/m /dose once daily (maximum dose: 200 mg/dose) for the 2 weeks titrated to to 120 to 150 mg/m /dose b.id daily
          • The maximum dose is 200 mg/dose if no rash or other adverse effects occur.
        • Note: The dose should not be changed in growing age.

      • Adolescents:

        • Initial: 200 mg per oral once daily for 2 weeks titrated to 200 mg every 12 hours if no rash or other adverse effects occur.
        • Conversion of maintenance dose to the extended-release formulation is acceptable if the patient is able to swallow tablets whole (400 mg once daily).

• Extended-release tablets:

Note:

• Extended-release preparation can be started without lead-in dosing in patients established on full dose nevirapine.
• Initially, once-daily dose (immediate release, according to the age) for 2 weeks titrated to the once-daily extended-release formulation if there is no rash.
• Extended-release tablets should not be divided to achieve daily dose.

• Children ≥6 years:

• Must be able to swallow tablets whole: BSA-directed dosing:
  • BSA 0.58 to 0.83 m²: 200 mg per oral once daily.
  • BSA 0.84 to 1.16 m²: 300 mg per oral once daily.
  • BSA ≥1.17 m²: 400 mg per oral once daily.

  • Adolescents:

    • 400 mg per oral once daily.

Nevirapine (Viramune)treatment dose of HIV-1 perinatal transmission as empiric therapy in neonates at high risk of transmission (3 drug regimen):

Note:

• Empiric dosing should be switched to the treatment regimen if the newborn is diagnosed with HIV.
• The empirical regime includes combination with zidovudine and lamivudine in neonates at a higher risk of perinatal transmission.
• Some studies recommend full 6 weeks of therapy and others suggest that antiretroviral therapy can be stopped once a negative nucleic acid test (NAT) is returned.

• Infant ≤6 weeks:

  • Immediate release: 200 mg/m /dose per oral b.i.d daily
  • The maximum dose: 200 mg/dose.

Pregnancy Risk Factor: B

• Nevirapine crosses easily the human placenta.
• Maternal antiretroviral therapy can increase the risk of stillbirth, preterm birth, low birth weight, and infant mortality.
• Concerns about adverse neonatal outcomes should not stop maternal therapy.
• Potential mitochondrial dysfunction should be checked in infants who have been exposed to antiretroviral medication or other significant organ system abnormalities of unknown origin (especially the heart or CNS).
• [US Boxed Warning]
  • Nevirapine can cause serious hepatotoxicity in the first three months.
  • Women with CD4+ cell counts greater than 250 cells/mm3 and pregnant women receiving treatment for HIV are at risk.
  • Because of the potential for fatal adverse events and complex dosing, Nevirapine should not be used as a first-line treatment during pregnancy.
  • It is not recommended for pregnant women who are trying to conceive, pregnant women who have received antiretroviral treatment in the past and who are restarting it, or anyone who needs an alternative therapy.
  • If viral suppression is successful and the regimen is well-tolerated, you can use the same dose of Nevirapine during pregnancy.
  • Postpartum HIV treatment should continue. It can also be modified after delivery.

Nevirapine use during breastfeeding:

• Breast milk contains Nevirapine, which can cause rash or hyperbilirubinemia in nursing infants.
• Postnatal HIV transmission is still possible with maternal/infant antiretroviral treatment.

Nevirapine dose adjustmen in renal disease:

• Creatinine clearance ≥20 mL/minute:

  • No dosage adjustment necessary.

• Creatinine clearance<20 mL/minute:

  • There are no dosage adjustments provided in the manufacturer's labeling.

• Hemodialysis:

  • An additional 200 mg immediate-release dose is recommended following dialysis.

Nevirapine dose adjustment in liver disease:

• It should be stopped in case of liver derangement symptoms.

  • Mild impairment (Child-Pugh class A):

    • There are no dosage adjustments provided in the manufacturer's labeling.

  • Moderate to severe impairment (Child-Pugh class B or C):

    • Use is contraindicated.

Common Side Effects of Nevirapine (Viramune):

• Endocrine & Metabolic:

  • Increased Serum Cholesterol
  • Increased LDL Cholesterol

• Hematologic & Oncologic:

  • Decreased Serum Phosphate
  • Neutropenia

• Hepatic:

  • Increased Serum Alanine Aminotransferase

Uncommon Side Effects Of Viramune (Nevirapine):

• Central Nervous System:

  • Fatigue
  • Headache

• Dermatologic:

  • Skin Rash

• Endocrine & Metabolic:

  • Increased Amylase

• Gastrointestinal:

  • Nausea
  • Abdominal Pain
  • Diarrhea

• Hematologic & Oncologic:

  • Granulocytopenia

• Hepatic:

  • Increased Serum Aspartate Aminotransferase
  • Increased Serum Transaminases
  • Hepatic Disease
  • Hepatitis

• Neuromuscular & Skeletal:

  • Arthralgia

• Miscellaneous:

  • Fever

• Dermatologic:

  • Erythematous maculopapular rash
  • Pruritus

Contraindication to Nevirapine (Viramune):

These include severe to moderate hepatic impairment.

• Non-occupational or occupational postexposure prophylaxis.
• Hypersensitivity to nevirapine and any component of the formulation
• Severe rash
• Hepatitis, AST/ALT >5 times the upper limit/normal (pretreatment or while using nevirapine prior to treatment)
• Galactose intolerance conditions include galactosemia and lactase deficiencies, as well as glucose-galactose malabsorption.
• Add St John's Wort to your therapy.

Warnings and precautions

• Fat redistribution

  • Can cause fat accumulation, including central obesity, buffalo hip, peripheral wasting and breast enlargement.

• Immune reconstitution syndrome:

  • There are two possible outcomes: opportunistic HIV infection or activation of autoimmune disorders like Graves disease, polymyositis, Guillain Barre syndrome later on in treatment.

• Rhabdomyolysis

  • The treatment has been associated with rhabdomyolysis. In severe cases, it is important to stop the therapy.

• Skin reactions: [US Boxed Warning]

  • In the first six weeks of treatment, severe, life-threatening skin reactions such as Stevens-Johnson Syndrome, toxic epidermal nécrolysis, hypersensitivity reactions, rash, and fatal organ dysfunction are common.
  • To reduce the risk of rash, the Lead-in period of 2 weeks should be observed. Intensive monitoring is advised during the first three month of therapy.
  • The drug should be stopped in case of rash/hypersensitivity and should not be rechallenged with nevirapine.
  • Combining prednisone with prednisone for the first six weeks of treatment can increase the severity and incidence of the rash.

• Hepatic impairment

  • Patients with severe to moderate impairment (Child Puugh class B orC) are not advised to take it.

Nevirapine: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

• Complete blood count
• Liver function tests
• Viral load.
• Life-threatening hepatic, dermatologic, and hypersensitivity reactions during the first three months of therapy

How to administer Nevirapine (Viramune)?

• It can be given orally with or without food with an antacid /didanosine and should be given with an oral dosing syringe.
• Shake suspension gently before administration. If using a dosing cup, rinse the cup with water after giving medicine and also administer rinse.
• The extended-release tablets must be swallowed whole without crushing, chewing, or dividing.

Mechanism of action of Nevirapine (Viramune):

• Nevirapine is a non-nucleoside, reverse transcriptase inhibitor.
• It works by binding to reverse transcriptionase, which blocks the RNA/DNA dependent DNA polymerase activities (e.g., HIV-1 replication). 
• Antiviral activity does not require intracellular phosphorylation.

Absorption:

• Rapid and readily absorbed Immediate release: >90% CSF penetration approximates 40% to 50% of the plasma concentration.

Plasma protein binding:

• 60%

Metabolism:

• Extensively occurs in the liver via CYP3A4 and CYP2B6 by hydroxylation to inactive compounds, may undergo enterohepatic recycling.
• Nevirapine is more rapidly metabolized in children than in adults

Bioavailability:

• 93% (immediate-release tablet);
• 75% (extended-release tablet)
• 91% (oral solution)

Half-life elimination:

• Decreases over 2- to 4-week time with chronic dosing due to autoinduction (ie, half-life = 45 hours initially [single dose] and decreases to 25 to 30 hours [multiple dosing])

Time to peak serum concentration:

• Immediate-release: 4 hours
• Extended-release:24 hours

Excretion:

• Occurs in Urine (81%, primarily as metabolites, <3% as unchanged drug); feces (10%)
• Clearance: Women have a 13.8% lower clearance compared to men; body size does not totally explain the gender difference  

Nevirapine Brand Names (International):

• Viramune
• Viramune XR
• APO-Nevirapine XR
• Auro-Nevirapine
• JAMP Nevirapine
• MYLAN-Nevirapine
• TEVA-Nevirapine
• Viramune XR
• Viramune
• Ciplanevimune
• Hirapine
• Hivirex
• Nepine
• Nepiralin
• Nerapin
• Neravir
• Nevifutal
• Nevimat
• Nevimune
• Nevimuno
• Nevipan
• Nevira
• Neviran
• Nevivir
• Nuo Lan Pin
• Viramune
• Viramune XR

Nevirapine Brand Names in Pakistan: