Each hard gelatin capsule contains Molnupiravir 200 mg or 400 mg.
Pharmacotherapeutic group: Antivirals for systemic use, direct acting antivirals. ATC code: not yet assigned.
Pharmacology: Pharmacodynamics: Mechanism of action: Molnupiravir is a prodrug that is metabolised to the ribonucleoside analogue N-hydroxycytidine (NHC) which distributes into cells where it is phosphorylated to form the pharmacologically active ribonucleoside triphosphate (NHC-TP). NHC-TP acts by a mechanism known as viral error catastrophe. NHC-TP incorporation into viral RNA by the viral RNA polymerase, results in an accumulation of errors in the viral genome leading to inhibition of replication.
Antiviral Activity: NHC was active in cell culture assays against SARS-CoV-2 with 50% effective concentrations (EC50) ranging between 0.67 to 2.66 μM in A-549 cells and 0.32 to 2.03 μM in Vero E6 cells. NHC had similar activity against SARS-CoV-2 variants B.1.1.7 (Alpha), B.1351 (Beta), P.1 (Gamma), and B.1.617.2 (Delta) with EC50 values of 1.59, 1.77 and 1.32 and 1.68 μM, respectively. No impact was observed on the in vitro antiviral activity of NHC against SARS-CoV-2 when NHC was tested in combination with abacavir, emtricitabine, hydroxychloroquine, lamivudine, nelfinavir, remdesivir, ribavirin, sofosbuvir, or tenofovir.
Pharmacodynamic effects: The relationship between NHC and intracellular NHC-TP with antiviral efficacy has not been evaluated clinically.
Resistance: No amino acid substitutions in SARS-CoV-2 associated with resistance to NHC have been identified in Phase 2 clinical trials evaluating molnupiravir for the treatment of COVID-19. Studies to evaluate selection of resistance to NHC with SARS-CoV-2 in cell culture have not been completed.
Pharmacokinetics: Molnupiravir is a 5'-isobutyrate prodrug that is hydrolysed to NHC prior to reaching systemic circulation. The pharmacokinetics of NHC are similar in healthy subjects and patients with COVID-19.
Absorption: Following twice daily oral administration of 800 mg molnupiravir, the median time to peak plasma NHC concentrations (Tmax) was 1.5 hours.
Distribution: NHC does not bind to plasma proteins.
Elimination: The effective half-life of NHC is approximately 3.3 hours. The fraction of dose excreted as NHC in the urine was <3% in healthy participants.
Other special populations: Gender, Race, Age: Population pharmacokinetic analysis showed that age, gender, race and ethnicity do not meaningfully influence the pharmacokinetics of NHC.
Paediatric Patients: MOLNUPAC 200 has not been studied in paediatric patients.
Renal Impairment: Renal clearance is not a meaningful route of elimination for NHC. No dose adjustment in patients with any degree of renal impairment is needed. In a population PK analysis, mild or moderate renal impairment did not have a meaningful impact on the pharmacokinetics of NHC. The pharmacokinetics of molnupiravir and NHC has not been evaluated in patients with eGFR less than 30 mL/min or on dialysis.
Hepatic Impairment: The pharmacokinetics of molnupiravir and NHC has not been evaluated in patients with hepatic impairment. Preclinical data indicate that hepatic elimination is not expected to be a major route of NHC elimination therefore hepatic impairment is unlikely to affect NHC exposure. No dose adjustment in patients with hepatic impairment is needed.
MOLNUPAC 200/MOLNUPAC 400 is indicated for treatment of mild to moderate coronavirus disease 2019 (COVID-19) in adults with a positive SARS-COV-2 diagnostic test and who have at least one risk factor for developing severe illness.
Adults: The recommended dose of MOLNUPAC is 800 mg (four 200mg capsules or two 400mg capsules) taken orally every 12 hours for 5 days.
The safety and efficacy of molnupiravir when administered for periods longer than 5 days have not been established. MOLNUPAC 200/MOLNUPAC 400 should be administered as soon as possible after a diagnosis of COVID-19 has been made and within 5 days of symptom onset.
Missed dose: If the patient misses a dose of MOLNUPAC 200/MOLNUPAC 400 within 10 hours of the time it is usually taken, the patient should take as soon as possible and resume the normal dosing schedule. If a patient misses a dose by more than 10 hours, the patient should not take the missed dose and instead take the next dose at the regularly scheduled time. The patient should not double the dose to make up for a missed dose.
Special populations: Elderly: No dose adjustment of MOLNUPAC 200/MOLNUPAC 400 is required based on age.
Renal impairment: No dose adjustment is required for patients with renal impairment.
Hepatic impairment: No dose adjustment is required for patients with hepatic impairment.
Paediatric population: The safety and efficacy of MOLNUPAC 200/MOLNUPAC 400 in patients below 18 years of age have not been established. No data are available.
METHOD OF ADMINISTRATION: For oral use.
MOLNUPAC 200/MOLNUPAC 400 capsules can be taken with or without food.
The capsules should be swallowed whole with a sufficient amount of fluid (e.g., a glass of water). The capsules should not be opened, crushed or chewed.
There is no human experience of overdosage with MOLNUPAC 200/MOLNUPAC 400. Treatment of overdose with MOLNUPAC 200/MOLNUPAC 400 should consist of general supportive measures including the monitoring of the clinical status of the patient. Haemodialysis is not expected to result in effective elimination of NHC.
Hypersensitivity to the active substance or to any of the excipients.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive and use machines have been performed.
Pregnancy: There are no data from the use of MOLNUPAC 200/MOLNUPAC 400 in pregnant women. Studies in animals have shown reproductive toxicity. MOLNUPAC 200/MOLNUPAC 400 is not recommended during pregnancy. Women of childbearing potential should use effective contraception for the duration of treatment and for 4 days after the last dose of MOLNUPAC 200/MOLNUPAC 400 (molnupiravir).
Breast-feeding: It is unknown whether molnupiravir or any of the components of molnupiravir are present in human milk, affect human milk production, or have effect on the breastfed infant. Animal lactation studies with molnupiravir have not been conducted.
Based on the potential for adverse reactions on the infant from MOLNUPAC 200/MOLNUPAC 400, breast-feeding is not recommended during treatment and for 4 days after the last dose of MOLNUPAC 200/MOLNUPAC 400.
Fertility: There were no effects on female or male fertility in rats at NHC exposures approximately 2 and 6 times respectively, the exposure in humans at the recommended human dose (RHD).
Summary of safety profile: In an interim analysis of a Phase 3 trial of subjects with mild to moderate COVID-19 treated with molnupiravir (n=386), the most common adverse reactions (≥1% of subjects) reported during treatment and during 14 days after the last dose were diarrhoea (3%), nausea (2%), dizziness (1%) and headache (1%) all of which were Grade 1 (mild) or Grade 2 (moderate).
The adverse reactions are listed as follows by system organ class and frequency. Frequencies are defined as follows: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000). (See table.)
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No drug interactions have been identified based on the limited available data. No clinical interaction studies have been performed with molnupiravir. Molnupiravir is hydrolysed to n-hydroxycytidine (NHC) prior to reaching systemic circulation. Uptake of NHC and metabolism to NHC-TP are mediated by the same pathways involved in endogenous pyrimidine metabolism. NHC is not a substrate of major drug metabolising enzymes or transporters. Based on in vitro studies, neither molnupiravir nor NHC are inhibitors or inducers of major drug metabolising enzymes or inhibitors of major drug transporters. Therefore, the potential for molnupiravir or NHC to interact with concomitant medications is considered unlikely.
Store below 30°C in a dry place. Protect from light.
J05 - ANTIVIRALS FOR SYSTEMIC USE ; Used in the systemic treatment of viral infections.
J05AB - Nucleosides and nucleotides excl. reverse transcriptase inhibitors ; Used in the systemic treatment of viral infections.
Molnupac 200: Hard cap 200 mg x 4 x 10's, 40's.
Molnupac 400: Hard cap 400 mg x 2 x 10's.
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