Remdevir

A. Approved Indications

1.        Coronavirus Disease 2019 (COVID-19):

o    Indicated for the treatment of COVID-19 in:

§  Adult and pediatric patients (≥28 days old and weighing ≥3 kg) who are:

§  Hospitalized, or

§  Non-hospitalized with mild to moderate disease at high risk of progression to severe COVID-19, including hospitalization or death.

B. Off-label / Investigational Uses

• Investigated for Ebola virus infection (initially developed for this purpose; not FDA-approved for it).
• Under study for use against other RNA viruses, including Marburg virus and Nipah virus.
• Research interest in post-exposure prophylaxis in high-risk COVID-19 exposure settings (not yet approved).

A. Adults and Pediatric Patients (≥12 years old or ≥40 kg)

• Hospitalized COVID-19 (requiring supplemental oxygen):
• Loading dose: 200 mg IV on Day 1
• Maintenance dose: 100 mg IV once daily from Day 2
• Duration: 5 to 10 days depending on clinical response and severity
• Non-hospitalized patients with mild-to-moderate COVID-19 at high risk for progression:
• 200 mg IV on Day 1
• 100 mg IV on Days 2 and 3
• Total Duration: 3 days

B. Pediatric Patients (≥28 days and ≥3 kg)

• Dosage is weight-based:
• <40 kg:
• Loading dose: 5 mg/kg IV on Day 1
• Maintenance dose: 2.5 mg/kg IV once daily from Day 2
• Duration: Same as adult

Route: Intravenous infusion only
Infusion Time: Typically over 30 to 120 minutes, depending on formulation
Dilution Required: Yes (based on vial concentration)

Renal Impairment:

• eGFR <30 mL/min: Use not recommended due to cyclodextrin accumulation risk (in lyophilized powder); caution advised

Hepatic Impairment:

• ALT ≥10x ULN: Discontinue use
• Hepatic dysfunction: Use with caution; monitor liver enzymes closely

Remdesivir is a nucleoside analog prodrug that, once metabolized intracellularly, forms an active adenosine triphosphate (ATP) analog. This active metabolite competes with endogenous ATP and incorporates into viral RNA chains by the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). The result is premature termination of viral RNA transcription, effectively halting viral replication. It has broad antiviral activity against various RNA viruses due to its targeted inhibition of viral RNA polymerases.

• Absorption: Not orally bioavailable; administered IV
• Distribution: Widely distributed in plasma and tissues
• Volume of distribution: ~100 L
• Plasma protein binding: ~88–93%
• Metabolism:
• Rapid conversion in plasma and cells to GS-441524 (active nucleoside analog)
• Further phosphorylated to the pharmacologically active nucleoside triphosphate
• Enzymes involved include esterases, CYP3A4, and hydrolases
• Elimination:
• Half-life of Remdesivir: ~1 hour
• Half-life of active triphosphate: ~25–27 hours
• Excretion: ~74% in urine (major component GS-441524), ~18% in feces
• Onset of Action: Within hours post-infusion, based on viral suppression data

Pregnancy:

• FDA Category: Not formally assigned (Emergency Use basis initially)
• Animal studies did not show teratogenicity, but human data are limited
• Use only if benefits outweigh potential risks, particularly in severe COVID-19

Lactation:

• Unknown whether Remdesivir is excreted into human milk
• Theoretical low oral absorption in neonates suggests minimal risk
• Breastfeeding may continue with monitoring and caution during treatment

• Primary Class: Antiviral agent
• Subclass: Nucleoside analog (RNA polymerase inhibitor)
• Virus Targeted: SARS-CoV-2 and other RNA viruses

• Known hypersensitivity to Remdesivir or any excipients
• ALT ≥10× upper limit of normal (ULN) at baseline
• Signs of liver inflammation or acute hepatitis
• Severe renal impairment (eGFR <30 mL/min) when using the cyclodextrin-containing formulation (solution)

• Hepatic Toxicity:
• Monitor liver enzymes (ALT, AST) before and during therapy
• Discontinue if ALT >10× ULN or if liver inflammation develops
• Renal Toxicity:
• Use caution in patients with renal dysfunction due to excipient accumulation
• Consider lyophilized powder over solution for reduced cyclodextrin exposure
• Hypersensitivity Reactions:
• Infusion-related reactions, including hypotension, nausea, diaphoresis, and anaphylaxis have been reported
• Drug Resistance:
• Prolonged use may theoretically promote viral mutations; always combine with appropriate supportive care
• Monitoring Required:
• Renal function
• Liver enzymes
• Clinical signs of hypersensitivity

Common Adverse Effects (≥5%):

• Gastrointestinal: Nausea, vomiting, constipation
• Hepatic: Elevated ALT and AST
• Renal: Creatinine elevation (less frequent)
• Hematologic: Anemia
• General: Headache, fever, fatigue

Serious Adverse Effects:

• Hepatotoxicity (ALT/AST elevation, rarely liver failure)
• Acute kidney injury (especially in patients with underlying renal impairment)
• Infusion-related reactions: Hypotension, bradycardia, rash
• Hypersensitivity and anaphylaxis (rare but serious)

Timing & Severity:

• Side effects generally occur during the course of treatment, typically within the first 3–5 days
• Most are mild to moderate in severity; severe reactions are rare but require immediate discontinuation

Major Interactions:

• Chloroquine and Hydroxychloroquine:
• Antagonistic interaction; co-administration not recommended as it may reduce Remdesivir's antiviral activity
• CYP Enzyme Involvement:
• Metabolized partly by CYP3A4 and hydrolases
• Limited data on CYP inhibition/induction; monitor if co-administered with strong CYP3A4 inducers or inhibitors
• P-gp Substrate:
• Drugs affecting P-glycoprotein activity may alter Remdesivir's disposition

Food & Alcohol:

• Not orally administered; no known food interaction
• Alcohol: Caution advised in liver-compromised patients

• FDA Full Approval:
• October 2020: Initial Emergency Use Authorization (EUA)
• October 2020: Full FDA approval for adults and pediatric patients ≥12 years and ≥40 kg
• January 2022: Expanded to pediatric patients ≥28 days and ≥3 kg
• WHO Guidelines (2022–2023):
• Conditional recommendation for hospitalized patients not requiring mechanical ventilation
• Not routinely recommended for critically ill ventilated patients unless early in the disease course
• NIH COVID-19 Treatment Guidelines:
• Recommended as part of first-line antiviral treatment in high-risk outpatients or hospitalized non-ventilated patients
• Use early (within 7 days of symptom onset) for optimal outcomes

• Lyophilized Powder Vial:
• Store at 20°C to 25°C (68°F to 77°F)
• Protect from light and moisture
• Solution Vial:
• Store at 2°C to 8°C (36°F to 46°F); refrigerate
• Do not freeze
• Reconstitution Instructions (Powder):
• Reconstitute with sterile water
• Further dilute in 0.9% sodium chloride prior to infusion
• Use immediately or within recommended time if refrigerated
• Handling Precautions:
• Use aseptic technique
• Discard any unused portion after single-use
• Do not shake or freeze once prepared