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Molnupiravir Tablets

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£199 £124.99

Molnupiravir also known as MK-4482/ EIDD-2801 is a new oral antiviral medicine against Covid 19 and its strains. Read more

What is Molnupiravir?

Molnupiravir also known as MK-4482/ EIDD-2801 is a new investigational oral antiviral medicine that has completed its phase II clinical trials and showed promising results.

Molnupiravir is developed by Ridgeback Biotherapeutics LP in collaboration with Merck & Co. It is a potent ribonucleoside analogue that inhibits the replication of SARS-CoV-2 that is the causative agent of COVID-19. Molnupiravir has shown its activity during several preclinical models of SARS-CoV-2. It is shown that it is effective for prophylaxis, treatment, and prevention of transmission of SARS-CoV-2. The pre-clinical and clinical data of molnupiravir have also shown that it is effective against the different variants of SARS-CoV-2.

Molnupiravir, previously known as EIDD-2801, was initially developed by Drug Innovations at Emory (DRIVE) that is a non-profit biotechnology company completely owned by Emory University. They introduced it as a broad-spectrum antiviral for the treatment of equine encephalitis and influenza, but later on, laboratory tests showed that it is effective against coronaviruses as well. Now Merck is conducting its phase III clinical trials for COVID-19.

Since the pandemic had hit several antiviral drugs have been approved and are in queue to be approved, among that are Remdesivir, oseltamivir, etc. But molnupiravir is one of the best shots till this time. It is a prodrug of N4-hydroxycytidine (NHC), and a nucleoside analog that has been investigated for decades now. Molnupiravir basically stops replication of the copies of the virus’s RNA by causing trouble to viral RNA-dependent RNA polymerase that is an absolutely critical enzyme for the replication of any RNA virus. Basically, nucleoside analogs work by pushing so many errors in the RNA replication step that the end result can't even produce a competent virus. Further, Molnupiravir has an unusually high barrier to resistance mechanisms.

The Medicines and Healthcare products Regulatory Agency (MHRA)’s makes the UK the first country in the world who approve Molnupiravir for the treatment of COVID-19. It is branded as Lagevrio in the UK and has been in the global spotlight for the treatment of Covid-19, as it showed promising results so far. It is the world’s first approved antiviral drug for the treatment of COVID-19 that can be taken by mouth rather than administered intravenously. It means it can be administered outside of a hospital setting, before the progression of Covid-19 to a severe stage. Clinical trials showed that molnupiravir show promising results only when administered at the early stages of infection. The MHRA has recommended that individuals should start treatment with molnupiravir as soon as they came to know that they are COVID-19 positive i.e., within the five days of the onset of symptoms.

How Molnupiravir works?

Molnupiavir was introduced in the early 2000s as preventative medicine and treatment against SARS-CoV, MERS, or other respiratory viruses. It is effective against many viruses that employ an RNA-dependent RNA polymerase, SARS-CoV-2 virus is also from the same class. The polymerase is an enzyme that copies the genetic material of the virus into new genetic material and produces the messenger RNAs that direct the production of all the viral proteins. Molnupiravir is a shape-shifter that is why it is called a tautomer. It has two forms, one which closely resembles uracil and the other cytosine. And, because of these two different forms, the replicating polymerase develops transition mutations, when it is recopied and causes the conversion of U nucleotide to C nucleotide and C nucleotide to U nucleotide. This newly copied RNA contains Molnupiravir that causes fatal flaws in the sequence and replication stops. This results in the shortening of infection and limiting the transmission.

In vitro studies revealed that Molnupiravir showed a dose-dependent drop in the production of viruses such as SARS-CoV-2. This is because the RdRp of SARS-CoV-2 and SARS-CoV, which the drug was initially intended to treat, have 99.1% nucleotide similarity. Whole-genome deep-sequencing showed dose-dependent accumulation of random low-frequency mutations. The effectiveness of the drug was rapid and intact upon repeat exposure of virus populations to the drug, which confirms that none of the random mutations’ mediate resistance to the drug.

The results of clinical trials released by Merck & Co. showed that Molnupiravir in its full dosage causes a reduction in days to negativity for the virus in nasopharyngeal swabs taken from participants with symptomatic SARS-CoV-2 infections. Five days after the dose administration of Molnupiravir, 0% of patients were positive for the coronavirus (0/47) as compared to 24% of the patients of the placebo group (6/25). Although the details and study size are limited a measurable drop in infection length is significant in patients taking Molnupiravir. The studies also revealed that Molnupiravir not only prevents the worsening of the infection but also prevents the transmission of the disease.

In addition to the reduction of transmission of Covid-19, Molnupiravir is also useful against influenza, ebola, and a large swath of other viruses. Its development seems to be a major advancement in virus control as it is not only effective against Covid-19 and its variants but also variants of other viruses.

Why there is a need for Molnupiravir?

The COVID-19 (SARS-CoV-2) pandemic continues to scar the world, despite the vaccination. But the emergence of new variants of COVID-19 is alarming. Many experts have said that the elimination of COVID-19 is an unrealistic goal and this pandemic could be endemic. There is a need for the development of treatment for vaccine-resistant variants.

In this scenario, where the extraordinary impact of this pandemic demands a safe, effective, and affordable antiviral drug for the prevention & treatment of COVID-19, that also limits the spread of the virus would be an invaluable tool. In such circumstances, Merck’s investigational oral drug molnupiravir reduces the risk of hospitalization by 50% in patients with COVID-19, has generated enthusiasm, and is claimed as a “breakthrough drug” and a “game-changer drug”.

As the name “Molnupiravir” (the name is a reference to Thor’s hammer, Mjölnir) suggests it could be a powerful drug. The advantage of molnupiravir is that it can be taken to the home and there is no need to get hospitalized. There is a hope that it may be useful for people with weak immune systems, and for people who may not get benefit from vaccination.

Molnupiravir can fill a crucial gap in the response to Covid-19

Treatments for Covid-19 are a vital component of the response to the pandemic. Although new drugs like molnupiravir require more testing and review, it is believed that Molnupiravir will offer a strong and targeted treatment for COVID-19. A drug like molnupiravir could be especially useful because it is administered in the early stages of the disease. Since it’s just a pill, it may spare the patient from visiting a clinic or a hospital setting for the transfusion of treatments like monoclonal antibodies. That reduces the chances of an infected patient transmitting the virus to the medical staff, and it averts potential complications associated with transfusions. Also, pills are also much easier to store and transport as compared to transfused drugs and vaccines, so they can reach more remote areas with fewer resources. Merck said that they are setting up tiered pricing for molnupiravir, meaning that it could cost less in other countries.

There is a gap due to the shortage of vaccines and also the development of new variants of COVID-19 (SARS-CoV) that are resistant to vaccines as Omicron. Also, there are many countries that do not get even a single shot of vaccine because of transportation issues and conditions for storage. There is hope that this oral antiviral drug, Molnupiravir will fill that gap and would be an effective medicine in controlling this pandemic of COVID-19. As it is proved to be an effective remedy for coronavirus.

Downside of Molnupiravir

The most obvious downside to any drug is the safety risks i.e., unexpected side effects. Such effects arise when a drug affects the other parts of the body in addition to those that it should. Molnupiravir is designed such that it hits the virus only but does not affect the bodies of the people who are taking the drug. It is, therefore, claimed to be a safe drug. But until any conclusive evidence arrives, it is hard to say that molnupiravir will be absolutely safe.

Since molnupiravir causes mutation in the genetic makeup of novel coronavirus that raises a question that: can molnupiravir induce mutational errors in DNA as well? In this regard, Merck carried out specific tests in animals to examine the drug’s potential to cause DNA mutations. Merck announced on April 15 that the totality of its data indicated that molnupiravir is neither mutagenic nor genotoxic.

ABOUT MOLNUPIRAVIR 

SUMMARY OF PRODUCT CHARACTERISTICS

Therapeutic Indication

Molnupiravir is indicated for the treatment of mild to moderate COVID-19 in adults who are SARS-COV-2 positive and have at least one risk factor that their disease can worsen and they get hospitalized. Molnupiravir reduces the risk of hospitalization by 50%.

Posology and method of administration

Posology

Adults

The recommended adult dose of Molnupiravir is 800 mg that is four capsules of 200mg taken orally twice a day (every 12 hours) continuously for 5 days.

The safety and efficacy of molnupiravir for periods longer than 5 days have not been established yet.

It needs to be noted that Molnupiravir should be administered as soon as you are diagnosed with coronavirus (COVID-19), within 5 days of onset of symptoms.

Missed dose

The patient doesn’t have to miss the dose of Molnupiravir as it is needed to take it twice a day, continuously for 5 days. You can put an alarm or reminder to take the dose. But if you forget to take your dose, you can take it immediately as soon as you remember within 10 hours. But if you remember after 10 hours then do not the missed dose, but take your regular next dose at its right time. Do not take the double dose to make up for the missed dose.

Special populations

Elderly

No dose adjustment is required for Molnupiravir 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.

Pediatric population

The safety and efficacy of Molnupiravir for patients less than 18 years of age have not been established yet. As no clinical data is available for this age group.

Method of administration

Molnupiravir is for oral use only.

Molnupiravir can be taken with or without food.

It is necessary to swallow the whole capsule with a sufficient amount of fluid (e.g., a glass of water). Do not crush, chew, or open the contents of capsules.

Contraindications

Hypersensitivity to the active substance or any of the excipients.

Special warnings and precautions for use

Sodium

Molnupiravir caspule contains less than 1 mmol sodium (23 mg) per dose of 4 capsules. It can be stated that essentially this medicine is 'sodium-free.

Interaction with other medicinal products and other forms of interaction

This medicine is under clinical trials and only limited data is available for drug interactions. So far, no drug interactions have been identified based on the available data. No clinical interaction studies have been performed with molnupiravir.

Molnupiravir is hydrolyzed inside the body to n-hydroxycytidine (NHC) before reaching the 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-metabolizing enzymes or transporters. Based on in vitro studies, neither molnupiravir nor NHC is an inhibitor or inducers of major drug-metabolizing enzymes or inhibitors of major drug transporters. Therefore, the potential for molnupiravir or NHC to interact with concomitant medications is considered unlikely.

Fertility, pregnancy, and lactation

Pregnancy

There are no data available related to the use of Molnupiravir in pregnant women. However, animal studies have shown reproductive toxicity.

Molnupiravir is not recommended to use during pregnancy. Women of childbearing potential should use effective contraceptives during the treatment with Molnupiravir and continue to use contraceptives for 4 days after the last dose of 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 affect the breastfed infant. Animal lactation studies with molnupiravir have not been conducted.

Based on the potential for adverse reactions on the infant from Molnupiravir, breastfeeding is not recommended during treatment and for 4 days after the last dose of Molnupiravir.

Fertility

There were no effects observed on female or male fertility in rats with the use of Molnupiravir. However, the effect on human fertility male/female has not been studied yet.

Effects on ability to drive and use machines

No data is available on the effects of molnupiravir, on the ability to drive and use machines.

Undesirable effects

Summary of the safety profile

In an interim analysis of Phase III clinical trials 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 diarrhea (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 listed below are according to the 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).

Tabulated list of adverse reactions

Frequency

Adverse Reaction

Nervous system disorders

Common

dizziness, headache

Gastrointestinal disorders

Common

diarrhea, nausea

Uncommon

vomiting

Skin and subcutaneous tissue disorders

Uncommon

rash, urticaria

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after authorization of the medicinal product is important. It allows a continous monitoring of the benefit / risk of the medicinal product. Healthcare professionals (doctor, nurse, pharmacist) are asked to report any suspected adverse reactions reported by their patients.

Overdose

There is no human experience of overdosage with Molnupiravir as the medicine is given under supervision of professionals to conduct clinical trials. 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.

Pharmacological properties

Pharmacodynamic properties

Pharmacotherapeutic group: Antivirals for systemic use, direct acting antivirals

ATC code: not yet assigned.

Mechanism of action

Molnupiravir is a prodrug and is metabolised to N-hydroxycytidine (NHC) that is a ribonucleoside analogue. NHC 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 clinically evaluated yet.

Resistance

No amino acid substitutions have been identified in SARS-CoV-2 that is associated with resistance to NHC in Phase 2 clinical trials of molnupiravir evaluation, for the treatment of COVID-19. However, 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 randomized subjects in the Phase 3 MOVe-OUT trial. MOVe-OUT was a randomized, placebo-controlled, double-blind clinical trial studying molnupiravir for the treatment of non-hospitalized patients with mild to moderate COVID-19 who were at risk for progressing to severe COVID-19 and/or hospitalization. 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 randomized 1:1 to receive 800 mg of Molnupiravir or placebo orally twice daily for 5 days.

At baseline, in all randomized 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.

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

Pharmacokinetic properties

Molnupiravir is a 5´-isobutyrate prodrug that is hydrolyzed to NHC before entering the systemic circulation. The pharmacokinetics of NHC are similar in healthy subjects as well as in patients with COVID-19.

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

Pharmacokinetics of NHC after administration of 800mg Molnupiravir every 12 hours

NHC Geometric Mean (%CV)

AUC0-12hr (ng×hr/mL)*

Cmax (ng/mL) †

C12hr (ng/mL)*

8260 (41.0)

2970 (16.8)

31.1 (124)

%CV: Geometric coefficient of variation.

* Values were obtained from population PK analysis.

†Values were obtained from a Phase 1 study of healthy subjects.

 

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), However, the area under the curve (AUC) was not significantly affected.

Distribution

It is found that NHC does not bind to plasma proteins.

Elimination

The effective half-life of NHC is approximately 3.3 hours and the fraction of dose excreted of 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 affect the pharmacokinetics of molnupiravir / NHC.

Pediatric Patients

The pharmacokinetics of molnupiravir has not been studied in pediatric patients.

Renal Impairment

As NHC is not meant for renal clearance. Therefore, no dose adjustment is required in patients with any degree of renal impairment. In a population PK analysis, mild or moderate renal impairment did not have a meaningful impact on the pharmacokinetics of molnupiravir / NHC. The pharmacokinetics of molnupiravir and NHC have not been evaluated in patients with eGFR less than 30 mL/min or on dialysis.

Hepatic Impairment

The pharmacokinetics of molnupiravir / 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. So, no dose adjustment is required in patients with hepatic impairment.

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Product Type: Tablets

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