Axlovir

Authorized Uses (FDA Emergency Use Authorization / EMA Conditional Approval):

• Treatment of mild‑to‑moderate COVID‑19 in adults and pediatric patients (≥ 12 years, ≥ 40 kg) at high risk for progression to severe disease, hospitalization, or death.
• Typically administered within 5 days of symptom onset.

Off‑Label / Clinically Investigated Uses:

• Prophylactic use in household contacts and high‑risk exposures (under study).
• Use in immunocompromised patients with breakthrough infections (clinically accepted but data continue to evolve).

Formulation: Oral tablets

• Nirmatrelvir: 150 mg per tablet
• Ritonavir: 100 mg per tablet

Standard Adult Regimen (≥ 12 years, ≥ 40 kg):

• Two tablets of nirmatrelvir (300 mg) + one tablet of ritonavir (100 mg), taken together orally twice daily for 5 days.

Renal Impairment:

• Moderate (eGFR 30–59 mL/min): 150 mg nirmatrelvir + 100 mg ritonavir twice daily.
• Severe (eGFR <30 mL/min): Use not recommended.

Hepatic Impairment:

• Mild to moderate (Child‑Pugh A or B): No adjustment needed.
• Severe (Child‑Pugh C): Use not recommended due to lack of data.

Pediatric (≥ 12 years, ≥ 40 kg): Same adult dosing regimen applies.

Elderly: No dosage adjustment required—use standard dosing.

Administration Notes:

• Take at approximately 12‑hour intervals with or without food.
• No titration required. Complete full 5‑day course; no re‑treatment if symptoms worsen after completion.

• Nirmatrelvir is a potent inhibitor of the SARS‑CoV‑2 main protease (Mpro or 3CLpro). By blocking this enzyme, it prevents cleavage of polyproteins essential for viral replication, thereby halting viral life cycle within infected cells.
• Ritonavir lacks direct activity against SARS‑CoV‑2 but functions as a pharmacokinetic booster by inhibiting CYP3A4 metabolism of nirmatrelvir, increasing its systemic levels and prolonging its antiviral effectiveness.

• Absorption: Rapid; peak plasma concentrations (Cmax) at ~3 hours post‑dose.
• Bioavailability: Substantial absorption; enhanced by ritonavir.
• Distribution: Widely distributed; >70% protein bound.
• Metabolism:
• Nirmatrelvir: Primarily metabolized via CYP3A4—strongly inhibited by ritonavir.
• Ritonavir: Undergoes hepatic metabolism via CYP3A and CYP2D6.
• Elimination Half-life: Nirmatrelvir ~7 hours (with boosting); ritonavir ~6 hours.
• Excretion: Nirmatrelvir primarily in feces; small percentage (~5%) excreted unchanged in urine.

• Pregnancy: Not classified under FDA categories; limited human data. Use only if potential benefits outweigh risks. Animal studies show no clear fetal harm.
• Lactation: Unknown if excreted in human milk. Caution advised; nursing mothers may consider watching infants for gastrointestinal symptoms or transferring to formula.

• Primary Class: Antiviral Therapy
• Subclass: SARS‑CoV‑2 Protease Inhibitor (nirmatrelvir) + Pharmacokinetic Booster (ritonavir)

• Known hypersensitivity to nirmatrelvir, ritonavir, or any component of the formulation.
• Severe renal impairment (eGFR <30 mL/min).
• Severe hepatic impairment (Child‑Pugh C).
• Concomitant use with medications that are highly dependent on CYP3A4 clearance when such drugs are contraindicated with ritonavir (e.g., certain statins, amiodarone, ergot derivatives).

• Drug–Drug Interactions: Ritonavir’s strong CYP3A4 inhibition can elevate levels of many co‑administered drugs—review patient’s medications for interactions.
• Hepatotoxicity: Rare; discontinue and evaluate if symptoms/signs of liver dysfunction occur.
• Use in Specific Populations: Insufficient data for pregnant women and patients <12 years or <40 kg.
• Emergence of Resistance: Possible in severely immunocompromised patients; monitor viral load and consider alternative therapies if no improvement.
• Cardiac Monitoring: QT‑prolonging drugs should be avoided due to increased exposure risk.

Common (≥5%):

• Dysgeusia (altered taste)
• Diarrhea, nausea, vomiting
• Hypertension
• Myalgia
• Headache

Less Common / Serious:

• Hepatotoxicity (elevated liver enzymes, jaundice)
• Allergic reactions (rash, pruritus)
• Exacerbation of comorbid conditions due to drug interactions

Timing & Severity:

• Typically mild to moderate; dysgeusia often begins within 1–2 days and may persist briefly after treatment completion.

• CYP3A4 Inhibitor (ritonavir):
• Raises concentrations of CYP3A4 substrates (e.g., simvastatin, midazolam) — may cause serious toxicity.
• CYP3A4 Inhibitors/Inducers:
• Co-administration can alter nirmatrelvir levels; use caution or avoid.
• St. John’s Wort (CYP3A4 inducer): Reduces nirmatrelvir exposure—avoid.
• Alcohol: No known specific interaction but may exacerbate GI upset.
• Food: No significant interaction—may be taken with or without meals.

• FDA (2023–2024): Updated alert emphasizing risk of significant drug–drug interactions; recommended use with detailed medication reconciliation.
• NIH & IDSA Guidelines: Recommend Paxlovid as first-line outpatient therapy for high-risk mild-to-moderate COVID‑19 within 5 days of symptom onset.
• WHO Living Guidelines: Include nirmatrelvir–ritonavir for treatment of COVID‑19 in high-risk populations; emphasize usage in resource-limited settings.

• Store at 20°C to 25°C (68°F to 77°F); may be kept between 15°C and 30°C.
• Keep in a dry place, protected from light.
• Handling: Keep tablets sealed in provided foil blister packs. Keep out of reach of children.
• No reconstitution or refrigeration required—discard after full treatment course if unused.