Covapravir 

Molnupiravir 200 mg

Hard capsules

▼ This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. NAME OF THE MEDICICNAL PRODUCT:

Covapravir

2. COMPOSITION:

Each Covapravir 200 mg Hard Capsule contains:

Active ingredient:

Molnupiravir 200 mg

3. PHARMACEUTICAL FORM:

Hard capsule with opaque flesh red cap & opaque flesh red body containing white to off white powder.

4. CLINICAL PARTICULARS:

4.1 Therapeutic indications

Covapravir 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.

4.2 Posology and Method of administration:

Posology:

Adults:

The recommended dose of Covapravir is 800 mg molnupiravir  (four 200 mg 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.

Covapravir 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 Covapravir 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 Covapravir 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 molnupiravir in patients below 18 years of age have not been established. No data are available.

Method of administration:

For oral use.

Covapravir 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.

4.3 Contraindications:

Hypersensitivity to the active substance or to any of the excipients.

4.4 Special warnings and precautions for use:

Sodium:

This medicinal product contains less than 1 mmol sodium (23 mg) per dose of 4 capsules, that is to say essentially ‘sodium-free’.

4.5 Interactions with other medicinal products and other forms of interactions:

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.

4.6 Fertility, Pregnancy, Lactation:

Pregnancy:

There are no data from the use of molnupiravir in pregnant women. Studies in animals have shown reproductive toxicity.

Molnupiravir 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 Covapravir (molnupiravir).

Lactation:

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 molnupiravir, breast-feeding is not recommended during treatment and for 4 days after the last dose of Covapravir (molnupiravir).

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).

4.7 Effects on ability to drive and to use machines:

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable effects:

Summary of the safety profile:

In an interim analysis of a Phase 3 trial of subjects with mild to moderate COVID-19 treated with molnupiravir, 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).

Tabulated list of adverse reactions:

The adverse reactions are listed below 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). 

Table 1: Tabulated list of adverse reactions

Reporting of suspected adverse reactions:

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions via (see details below)

Human Pharmacovigilance Department - Egyptian Pharmaceutical Vigilance Center (EPVC)- Egyptian Drug Authority (EDA)

21 Abd Elaziz Al Souad st. – Manial El-Roda – Cairo, PO Box: 11451

Tel: +2 02 23648046/ +2 02 23640368/ +2 02 23684381 Extension (Tel): 1303 Extension (Fax): 1300

Fax: +2 02 23684194

Website: www.epvc.gov.eg

E- mail: pv.followup@edaegypt.eg.

4.9 Overdose:

There is no human experience of overdosage with molnupiravir. Treatment of overdose with molnupiravir 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.

5. PHARMACOLOGICAL PROPERTIES:

5.1 Pharmacodynamic properties:

Pharmacotherapeutic group: Antivirals for systemic use, direct acting antivirals.

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.

Clinical efficacy and safety:

Clinical data are based on an interim analysis of data from 775 randomised subjects in the Phase 3 MOVe-OUT trial. MOVe-OUT was a randomised, placebo-controlled, double-blind clinical trial studying molnupiravir for the treatment of non-hospitalised patients with mild to moderate COVID-19 who were at risk for progressing to severe COVID-19 and/or hospitalisation. 

Eligible subjects were 18 years of age and older and had one or more pre-defined risk factors for disease progression: 60 years of age or older, diabetes, obesity (BMI >30), chronic kidney disease, serious heart conditions, chronic obstructive pulmonary disease, or active cancer. The study included symptomatic subjects not vaccinated against SARS-CoV-2 and who had laboratory confirmed SARS-CoV-2 infection and symptom onset within 5 days of enrolment. Subjects were randomised 1:1 to receive 800 mg of molnupiravir or placebo orally twice daily for 5 days.

At baseline, in all randomised subjects, the median age was 44 years (range: 18 to 88 years); 14% of subjects were 60 years of age or older and 3% were over 75 years of age; 52% of subjects were male; 52% were White, 6% Black or African American, 2% Asian; 58% were Hispanic or Latino. Forty-nine percent of subjects received molnupiravir or placebo within 3 days of COVID-19 symptom onset. The most common risk factors were obesity (77%), 60 years of age or older (14%), and diabetes (14%). Overall, baseline demographic and disease characteristics were well balanced between the treatment arms.

Table 2 provides the results of the primary endpoint (the percentage of subjects who were hospitalised or died through Day 29 due to any cause). Treatment with molnupiravir resulted in a 6.8 percentage point reduction in the risk of hospitalisation or death (approximately 50% relative risk reduction). All 8 subjects who died through Day 29 were in the placebo group and were hospitalised prior to their death.

Table 2: Interim Efficacy Results in Non-Hospitalised Adults with COVID-19:

Efficacy results were consistent across sub-groups including age (>60 years), at risk medical conditions (e.g., obesity, diabetes) and SARS-CoV-2 variants.

Paediatric population:

The Agency has deferred the obligation to submit the results of studies with molnupiravir in one or more subsets of the paediatric population (See section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties:

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.

The pharmacokinetics of NHC at steady-state following administration of 800 mg molnupiravir every 12 hours are provided below in Table 3.

Table 3: Pharmacokinetics of NHC after administration of 800mg molnupiravir every 12 hours

Absorption:

Following twice daily oral administration of 800 mg molnupiravir, the median time to peak plasma NHC concentrations (Tmax) was 1.5 hours.

Effect of Food on Oral Absorption:

In healthy subjects, the administration of a single 200 mg dose of molnupiravir with a high-fat meal resulted in a 35% reduction in NHC peak concentrations (Cmax), AUC was not significantly affected.

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 and Age:

Population pharmacokinetic analysis showed that age, gender, race and ethnicity do not meaningfully influence the pharmacokinetics of NHC.

Paediatric Patients:

Molnupiravir 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.

6. PHARMACEUTICAL PARTICULARS:

6.1 List of excipients:

Inactive ingredients: Microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate.

Capsule shell (cap & body): Hypromellose, titanium dioxide, red iron oxide.

6.2 Incompatibilities:

Not applicable.

6.3 Shelf life:

See outer pack

6.4 Special precautions for disposal:

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

6.5 Storage condition:

Store at temperature not exceeding 30° & in dry place.

6.6 Package:

Carton box containing one high density polyethylene (HDPE) bottle contains 40 capsule enclosed with polypropylene (PP) cap and induction inner aluminum seal & inner leaflet.