Paxlovid

Generic Name: Nirmatrelvir and Ritonavir
Brand Name: Paxlovid

Drug Class: Antiviral agent (nirmatrelvir); Pharmacokinetic enhancer (ritonavir)
Pharmaceutical Category: SARS-CoV-2 3CL protease inhibitor (COVID-19 therapy)
Formulation: Oral tablets (co-packaged nirmatrelvir + ritonavir)
Route of Administration: Oral

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1. Pharmacological Classification

Paxlovid is an oral antiviral medication that combines:

• Nirmatrelvir: A selective inhibitor of SARS-CoV-2 main protease (Mpro or 3CLpro), essential for viral replication.

• Ritonavir: A CYP3A inhibitor that serves as a pharmacokinetic booster, increasing plasma concentrations of nirmatrelvir by inhibiting its metabolism.

This combination is designed to inhibit viral replication and improve the antiviral efficacy of nirmatrelvir by prolonging its half-life through ritonavir-mediated inhibition of CYP3A.

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2. Mechanism of Action

Nirmatrelvir

• Inhibits SARS-CoV-2 3CL-like protease (Mpro), a key enzyme for proteolytic cleavage of viral polyproteins into functional nonstructural proteins required for replication.

• Prevents viral RNA replication and assembly.

Ritonavir

• Originally developed as an HIV protease inhibitor, ritonavir now acts only as a booster in this combination.

• Inhibits CYP3A4-mediated metabolism of nirmatrelvir, increasing its plasma exposure and duration.

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3. Therapeutic Indications

Authorized Use (FDA EUA / EMA Conditional Approval)

• Treatment of mild to moderate COVID-19 in:

  • Adults and pediatric patients (≥12 years and weighing ≥40 kg)

  • Who are at high risk for progression to severe COVID-19, including hospitalization or death

Off-label or Investigational Use

• Post-exposure prophylaxis (being studied; not currently approved)

• Potential for use in immunocompromised patients with prolonged infection (case-based)

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4. Dosage and Administration

Standard Adult and Pediatric Dose (≥12 years and ≥40 kg)

• Nirmatrelvir 300 mg (2 tablets of 150 mg) + Ritonavir 100 mg (1 tablet)

• Twice daily for 5 days

Initiate treatment within 5 days of symptom onset

Renal Impairment Adjustments

• Moderate impairment (eGFR 30–59 mL/min):

  • Nirmatrelvir 150 mg (1 tablet) + Ritonavir 100 mg, twice daily for 5 days

• Severe renal impairment (eGFR <30 mL/min):

  • Contraindicated

Hepatic Impairment

• Use with caution in moderate hepatic dysfunction (Child-Pugh B)

• Contraindicated in severe hepatic impairment (Child-Pugh C)

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5. Pharmacokinetics

Nirmatrelvir

• Bioavailability: Enhanced by ritonavir

• Metabolism: Minimal hepatic metabolism

• Elimination: Primarily renal (unchanged drug)

• Half-life: ~6 hours (with ritonavir)

Ritonavir

• Absorption: Good oral bioavailability

• Metabolism: Hepatic via CYP3A4

• Inhibits CYP3A, thereby boosting nirmatrelvir

• Half-life: ~3–5 hours

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6. Contraindications

• Severe renal impairment (eGFR <30 mL/min)

• Severe hepatic impairment (Child-Pugh Class C)

• Concomitant use with drugs highly dependent on CYP3A for clearance, where elevated concentrations may lead to serious or life-threatening reactions (e.g., amiodarone, simvastatin, pethidine, sildenafil for pulmonary hypertension)

• Use with drugs that strongly induce CYP3A (e.g., carbamazepine, rifampin), which may reduce Paxlovid efficacy

• Known hypersensitivity to either component

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7. Warnings and Precautions

• Drug-Drug Interactions (DDIs): Due to ritonavir’s strong CYP3A inhibition, Paxlovid has many significant interactions

• Rebound phenomenon: Some patients experience COVID-19 symptom recurrence a few days after completing Paxlovid therapy; generally mild and self-limited

• HIV risk: May lead to HIV-1 resistance in patients with undiagnosed or untreated HIV (due to ritonavir’s monotherapy effect)

• Hypersensitivity reactions: Anaphylaxis and angioedema reported

• QT prolongation: Monitor in patients with cardiac comorbidities when used with other QT-prolonging drugs

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8. Adverse Effects

Common (≥1%)

• Dysgeusia (altered or bitter taste)

• Diarrhea

• Hypertension

• Myalgia

• Headache

• Nausea

Less Common (<1%)

• Vomiting

• Abdominal pain

• Elevated liver enzymes

• Hypersensitivity reactions

Rare

• Anaphylaxis

• Hepatotoxicity

• Severe skin reactions (e.g., rash)

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9. Drug Interactions

Due to ritonavir’s potent inhibition of CYP3A4, Paxlovid has many interactions. A few important categories:

Contraindicated Drugs

• Antiarrhythmics: Amiodarone, quinidine

• Sedatives/hypnotics: Triazolam, midazolam (oral)

• Statins: Simvastatin, lovastatin

• Ergot derivatives

• Antipsychotics: Clozapine, lurasidone, pimozide

• St. John’s Wort: CYP3A inducer → ↓ efficacy

Use with Caution or Monitor Closely

• Anticoagulants: Warfarin, rivaroxaban → monitor INR and bleeding

• Calcium channel blockers: Adjust dose, monitor BP

• Immunosuppressants: Tacrolimus, cyclosporine → significant accumulation possible

• Anticonvulsants: Carbamazepine (avoid), phenytoin (reduced Paxlovid effect)

Consult a drug interaction checker (e.g., Liverpool COVID-19 Interactions database) before prescribing Paxlovid.

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10. Pregnancy and Lactation

Pregnancy

• Limited human data

• Animal studies show no fetal harm

• Risk-benefit assessment required

• Not contraindicated, but alternative agents preferred if possible

Lactation

• No data on presence in human milk

• Due to ritonavir, use with caution

• Consider temporary interruption of breastfeeding during and for several days after treatment

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11. Special Populations

Elderly

• No dose adjustment required unless renal impairment present

• Frequently used in elderly due to higher COVID-19 risk

Pediatric

• Approved for children ≥12 years weighing ≥40 kg

• Not studied in younger or lighter pediatric populations

Renal/Hepatic Impairment

• See dose modifications above

• Avoid in severe cases

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12. Clinical Efficacy (EPIC-HR Trial)

• Randomized controlled trial in unvaccinated, non-hospitalized adults with COVID-19 at high risk

• 89% reduction in risk of hospitalization or death when initiated within 3 days of symptom onset

• Benefit decreased when started >5 days after symptoms began

• Effectiveness confirmed in Omicron era via real-world studies (with some limitations)

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13. Storage and Dispensing

• Store at room temperature (20–25°C / 68–77°F)

• Dispense in original packaging with dosing instructions

• Tablet configuration:

  • Pink tablets: Nirmatrelvir 150 mg

  • White tablets: Ritonavir 100 mg

• Each dose: 2 pink + 1 white, taken together

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14. Clinical Pearls

• Start as early as possible, ideally within 3–5 days of symptoms

• Check all concurrent medications to avoid serious DDIs

• Educate patients about bitter taste, potential for rebound symptoms, and need to complete full course

• Paxlovid is not a substitute for vaccination

• No dosage form adjustments for patients on feeding tubes—entire tablets must be swallowed