Consumer medicine information

Lagevrio Capsules

Molnupiravir

BRAND INFORMATION

Brand name

Lagevrio

Active ingredient

Molnupiravir

Schedule

SUMMARY CMI

LAGEVRIO^® Capsules

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about taking this medicine, speak to your doctor or pharmacist.

▼ This is a new medicine. Please report any side effects that you may experience with this medicine. See the full CMI for further details.

1. Why am I taking LAGEVRIO?

LAGEVRIO contains the active ingredient molnupiravir. You are being given LAGEVRIO for the treatment of coronavirus disease (COVID-19). LAGEVRIO may help you to feel better and stay out of hospital. More information can be found in Section 1. Why am I taking LAGEVRIO? in the full CMI.

2. What should I know before I take LAGEVRIO?

Do not take LAGEVRIO if you have ever had an allergic reaction to molnupiravir or any of the ingredients listed at the end of this CMI.

LAGEVRIO is not recommended in pregnancy. If there is a chance you might be pregnant, talk to your doctor about having a pregnancy test prior to commencing LAGEVRIO. Use effective birth control while you are taking LAGEVRIO and for 4 days after the last dose if there is a possibility of you getting pregnant. If you are a male who is sexually active with a partner who has the potential to become pregnant, use a reliable method of contraception during treatment and for 3 months after the last dose of LAGEVRIO.

Breastfeeding is not recommended during treatment and for 4 days after the last dose of LAGEVRIO.

Talk to your doctor if you have any other medical conditions, take any other medicines, have any allergies, or are pregnant or plan to become pregnant or are breastfeeding or plan to breastfeed.

More information can be found in Section 2. What should I know before I take LAGEVRIO? in the full CMI.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins, or supplements that you buy without a prescription from your pharmacy, supermarket, or health food shop.

More information can be found in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I take LAGEVRIO?

Take LAGEVRIO exactly as your doctor tells you.
Take 4 capsules of LAGEVRIO every 12 hours (for example, at 8 am and at 8 pm).
Take LAGEVRIO for 5 days.
Take LAGEVRIO with or without food.

More information can be found in Section 4. How do I take LAGEVRIO? in the full CMI.

5. What should I know while taking LAGEVRIO?

Things you should do	Tell the doctor, dentist, or pharmacist you visit that you are taking LAGEVRIO.
Things you should not do	Do not stop taking this medicine without talking to your doctor first.
Looking after your medicine	Store LAGEVRIO in the original bottle in a cool dry place below 30°C, away from heat or sunlight.

More information can be found in Section 5. What should I know while taking LAGEVRIO? in the full CMI.

6. Are there any side effects?

All medicines can have side effects. If they do occur, they are usually minor and temporary. Do not be alarmed by this list. You may not experience any of them. The most common side effects (unintended or undesirable effects) of LAGEVRIO in adults are diarrhoea, nausea, and dizziness. More information, including what to do if you have any side effects, can be found in Section 6. Are there any side effects? in the full CMI.

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.

FULL CMI

LAGEVRIO^® Capsules

Active ingredient(s): molnupiravir

LAGEVRIO has provisional approval to treat COVID-19 in adults who are at increased risk for hospitalisation or death. The decision to approve this medicine has been made on the basis of results of data available at the time of provisional approval. More evidence is required to be submitted when available to fully confirm the benefit and safety of LAGEVRIO for this use.

Consumer Medicine Information (CMI)

This leaflet provides important information about taking LAGEVRIO. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about taking LAGEVRIO.

Where to find information in this leaflet:

1. Why am I taking LAGEVRIO?
2. What should I know before I take LAGEVRIO?
3. What if I am taking other medicines?
4. How do I take LAGEVRIO?
5. What should I know while taking LAGEVRIO?
6. Are there any side effects?
7. Product details

1. Why am I taking LAGEVRIO?

LAGEVRIO contains the active ingredient molnupiravir.

LAGEVRIO has provisional approval to treat COVID-19 in adults who are at increased risk for hospitalisation or death.

The decision to approve this medicine has been made on the basis of results of data available at the time of provisional approval. More evidence is required to be submitted when available to fully confirm the benefit and safety of LAGEVRIO for this use.

LAGEVRIO is an antiviral drug that works against the virus that causes COVID-19.

You are being given LAGEVRIO for the treatment of coronavirus disease 2019 (COVID-19). LAGEVRIO may help you to feel better and stay out of hospital.

What is COVID-19?

COVID-19 is caused by a virus called SARS CoV-2.
You can get COVID-19 through contact with another person who has the virus.

COVID-19 illnesses have ranged from very mild (including some with no reported symptoms) to severe, including illness resulting in death. While information so far suggests that most COVID-19 illness is mild, serious illness including breathing problems can happen and may cause some of your other medical conditions to become worse.

Older people and people of all ages with severe, long lasting (chronic) medical conditions like heart disease, lung disease, obesity, and diabetes, for example seem to be at higher risk of being hospitalised for COVID-19.

What are the symptoms of COVID-19?

The symptoms of COVID-19 may include fever, cough, and shortness of breath.

2. What should I know before I take LAGEVRIO?

Do not take LAGEVRIO if:

You are allergic to molnupiravir, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can take this medicine.

Check with your doctor if you:

have any other medical conditions
take any medicines for any other condition
have any allergies

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and Reproduction

Animal studies with molnupiravir have shown harmful effects to the unborn animal.
LAGEVRIO has not been studied in pregnancy in humans and it is not known if LAGEVRIO will harm your baby while you are pregnant.
LAGEVRIO is not recommended in pregnancy. Discuss the need for a pregnancy test with your doctor if you are of childbearing potential and sexually active.
Tell your doctor if you are pregnant or plan to become pregnant.
Use effective birth control while you are taking LAGEVRIO and for 4 days after the last dose of LAGEVRIO if there is a possibility of you getting pregnant.
Animal studies have not shown effects on fertility. It is not known how LAGEVRIO may affect sperm in humans. If you are a male who is sexually active with a partner who has the potential to become pregnant, use a reliable method of contraception during treatment and for 3 months after the last dose of LAGEVRIO.

Breastfeeding

It is not known if LAGEVRIO gets into breast milk and will be passed to the baby.
Tell your doctor if you are breastfeeding or plan to breastfeed before taking LAGEVRIO.
Breastfeeding is not recommended during treatment and for 4 days after the last dose of LAGEVRIO.

3. What if I am taking other medicines?

Some medicines may interfere with LAGEVRIO and affect how it works.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect LAGEVRIO.

4. How do I take LAGEVRIO?

How to take LAGEVRIO

Take LAGEVRIO exactly as your doctor tells you.
Take 4 capsules of LAGEVRIO every 12 hours (for example, at 8 am and at 8pm).
Take LAGEVRIO every day for 5 days.
Take LAGEVRIO with or without food.

If you forget to take LAGEVRIO

LAGEVRIO should be taken regularly at the same times each day. It is important that you do not miss or skip doses of this medicine. What to do if you miss a dose?

If it has been less than 10 hours since the missed dose, take it as soon as you remember.
If it has been more than 10 hours since the missed dose, skip the missed dose and take your dose at the next scheduled time.

Do not take a double dose to make up for the dose you missed. Call your doctor or pharmacist if you are not sure what to do.

If you take too much LAGEVRIO

If you think that you have taken too much LAGEVRIO, you may need urgent medical attention.

You should immediately:

phone the Poisons Information Centre
(by calling 13 11 26), or
call your doctor or pharmacist, or
go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while taking LAGEVRIO?

Things you should do

Tell the doctor, dentist, or pharmacist you visit that you are taking LAGEVRIO and follow their advice.

Things you should not do

Do not stop taking this medicine without talking to your doctor first.

Looking after your medicine

Follow the instructions on the carton on how to store your medicine properly.

Store LAGEVRIO in the original bottle in a cool dry place below 30°C, away from heat or sunlight; for example, do not store it:

in the bathroom or near a sink, or
in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to take this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not take this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effects	What to do
diarrhoea nausea vomiting dizziness itching	Speak to your doctor if you have any of these less serious side effects and they worry you.

Allergic reactions can happen in people taking LAGEVRIO, even after only 1 dose. Stop taking LAGEVRIO and call your healthcare provider right away if you get any of the following symptoms of an allergic reaction:

hives
rapid heartbeat
trouble swallowing or breathing
swelling of the mouth, lips or face
throat tightness
hoarseness
skin rash

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What LAGEVRIO contains

Active ingredient
(main ingredient)

Molnupiravir 200 mg

Other ingredients
(inactive ingredients)

croscarmellose sodium
hyprolose
magnesium stearate
microcrystalline cellulose
purified water

Capsule shell:

hypromellose
iron oxide red
titanium dioxide

White ink on the capsule:

tert-butyl alcohol
ethanol absolute
isopropyl alcohol
potassium hydroxide
propylene glycol
purified water
shellac
strong ammonia solution
titanium dioxide

Do not take this medicine if you are allergic to any of these ingredients.

What LAGEVRIO looks like

LAGEVRIO is supplied in a bottle containing 40 capsules.

LAGEVRIO is available as a Swedish Orange opaque capsule with corporate logo and “82” printed with white ink for oral administration (AUST R 372650).

Who distributes LAGEVRIO

Merck Sharp & Dohme (Australia) Pty Limited
Level 1, Building A, 26 Talavera Road
Macquarie Park NSW 2113

This leaflet was prepared in October 2023

RCN: 000026043

Published by MIMS December 2023

BRAND INFORMATION

Brand name

Lagevrio

Active ingredient

Molnupiravir

Schedule

1 Name of Medicine

Molnupiravir.

2 Qualitative and Quantitative Composition

Each capsule contains 200 mg of molnupiravir.
Molnupiravir is a white to off-white solid that is soluble in water.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Lagevrio is available as a 'Swedish Orange' opaque capsule with the corporate logo and "82" printed with white ink. Each capsule is approximately 21.7 mm in length.

4 Clinical Particulars

4.1 Therapeutic Indications

Lagevrio (molnupiravir) has provisional approval for the treatment of adults with COVID-19 who do not require initiation of oxygen due to COVID-19 and who are at increased risk for hospitalisation or death [see Section 5.1 Pharmacodynamic Properties, Clinical trials].
The decision to approve this indication has been made on the basis of the analysis of efficacy and safety data from a Phase 3 trial. Continued approval of this indication depends on additional data.

4.2 Dose and Method of Administration

The recommended dose of Lagevrio in adult patients is 800 mg (four 200 mg capsules) taken orally every 12 hours for 5 days, with or without food.
The safety and efficacy of Lagevrio when administered for periods longer than 5 days have not been established.
Lagevrio should be administered as soon as possible after a diagnosis of COVID-19 has been made and within 5 days of symptom onset in adults who are at risk for progression to severe COVID-19, including hospitalisation or death.
In women of childbearing potential, health care providers should discuss the chance that they may be pregnant and consider the need for a pregnancy test.

Missed dose.

If the patient misses a dose of Lagevrio within 10 hours of the time it is usually taken, the patient should take it 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.

Paediatric patients.

Safety and efficacy of Lagevrio have not been established in patients less than 18 years of age, therefore use in paediatric patients is not recommended [see Section 4.4 Special Warnings and Precautions for Use, Paediatric use; Section 5.2 Pharmacokinetic Properties, Special populations].

Elderly patients.

No dose adjustment of Lagevrio is recommended for geriatric patients [see Section 4.4 Special Warnings and Precautions for Use, Use in the elderly; Section 5.2 Pharmacokinetic Properties, Special populations].

Renal impairment.

No dose adjustment of Lagevrio is required in patients with renal impairment [see Section 5.2 Pharmacokinetic Properties, Special populations].

Hepatic impairment.

No dose adjustment of Lagevrio is recommended in patients with hepatic impairment [see Section 5.2 Pharmacokinetic Properties, Special populations].

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in Section 6.1 List of Excipients.

4.4 Special Warnings and Precautions for Use

Paediatric use.

Safety and efficacy of Lagevrio have not been established in patients less than 18 years of age, therefore use in paediatric patients is not recommended [see Section 4.2 Dose and Method of Administration, Paediatric patients; Section 5.2 Pharmacokinetic Properties, Paediatric population; Section 5.3 Preclinical Safety Data, General toxicity].

Use in the elderly.

In MOVe-OUT, there was no difference in safety and tolerability between patients > 65 years of age and younger patients who were treated with molnupiravir. No dose adjustment is recommended based on age. Based on population PK analysis, PK of N4-hydroxycytidine (NHC) was similar in geriatric patients compared to younger patients [see Section 4.2 Dose and Method of Administration, Elderly patients].

Hypersensitivity.

Hypersensitivity reactions have been reported with Lagevrio [see Section 4.8 Adverse Effects (Undesirable Effects), Post-marketing experience]. If signs or symptoms of a clinically significant hypersensitivity reaction occur, immediately discontinue Lagevrio and initiate appropriate medications and/or supportive care.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No drug interactions have been identified based on the limited available data.
Clinical drug-drug interaction trials of Lagevrio with concomitant medications have not been conducted. Molnupiravir is hydrolyzed to NHC prior to reaching systemic circulation. Uptake and metabolism of NHC are mediated by the same pathways involved in endogenous pyrimidine metabolism. NHC is not a substrate of major drug metabolizing enzymes or transporters. Neither molnupiravir nor NHC are inhibitors or inducers of major drug metabolizing enzymes or transporters. Therefore, the potential for molnupiravir or NHC to interact with concomitant medications is considered unlikely.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There were no effects on female or male fertility in rats at oral doses up to 500 mg/kg/day, with NHC exposures (based on AUC) of approximately 2 and 6 times respectively, the exposure in humans at the recommended human dose (RHD).
(Category D)
The use of Lagevrio is not recommended during pregnancy.
Advise women of childbearing potential to use effective contraception for the duration of treatment and for 4 days after the last dose of Lagevrio (molnupiravir). Based on animal data, Lagevrio may cause fetal harm when administered to pregnant women. There are no available data on the use of Lagevrio in pregnant women to evaluate the risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.
In an animal reproduction study, oral administration of molnupiravir to pregnant rats during the period of organogenesis resulted in embryofetal lethality and teratogenicity at 1000 mg/kg/day (8 times the human NHC exposures at the recommended human dose (RHD)) and reduced fetal growth at ≥ 500 mg/kg/day (3 times the human NHC exposure at the RHD). Oral administration of molnupiravir to rabbits during the period of organogenesis resulted in reduced fetal body weights at 750 mg/kg/day (18 times the human NHC exposure at the RHD).
In a pre- and post-natal developmental study, molnupiravir was administered orally to female rats at doses up to 500 mg/kg/day from GD6 through lactation day 20. There were no effects on gestation and postnatal development of offspring at up to 500 mg/kg/day (1.6 times the human NHC exposure at the RHD).
It is unknown whether molnupiravir or any of the metabolites of molnupiravir are present in human milk, affect human milk production, or have effect on the breastfed infant.
Based on the potential for adverse reactions on the infant from Lagevrio, breastfeeding is not recommended during treatment and for 4 days after the last dose of Lagevrio.
NHC was detected in the plasma of nursing pups (~ 0.01 - 0.09% of mean plasma concentrations in maternal rats) from lactating rats administered molnupiravir.

Contraception.

There is no data available in relation to whether molnupiravir affects sperm. It is recommended that men who are sexually active with a partner of childbearing potential use an adequate form of contraception during and 3 months after treatment with molnupiravir.
It is recommended that sexually active women of childbearing potential use contraception during and for 4 days after treatment with molnupiravir.

4.7 Effects on Ability to Drive and Use Machines

Lagevrio is predicted to have no or negligible influence on the ability to drive and use machines.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials experience.

The safety of Lagevrio was evaluated based on an analysis of a Phase 3 double-blind trial (MOVe-OUT) in which 1,411 non-hospitalised subjects with COVID-19 were randomised and treated with Lagevrio (N=710) or placebo (N=701) for up to 5 days and followed through Day 29. Adverse events were those reported while subjects were on study intervention or within 14 days of study intervention completion/discontinuation [see Section 5.1 Pharmacodynamic Properties, Clinical trials].
Discontinuation of study intervention due to an adverse event occurred in 1% of subjects receiving molnupiravir and 3% of subjects receiving placebo. Serious adverse events occurred in 7% of subjects receiving molnupiravir and 10% receiving placebo; none was considered drug-related by the investigator and most were COVID-19 related. Adverse events leading to death occurred in < 1% of the subjects receiving molnupiravir and 2% of subjects receiving placebo.
The most common adverse reactions in the molnupiravir treatment group in MOVe-OUT are presented in Table 1, all of which were Grade 1 (mild) or Grade 2 (moderate).

Laboratory abnormalities.

Selected laboratory abnormalities reported through Day 29 are presented in Table 2.

Post-marketing experience.

The following adverse reactions have been identified during post-marketing use of Lagevrio. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Gastrointestinal disorders.

Vomiting.

Immune system disorders.

Hypersensitivity [see Section 4.4 Special Warnings and Precautions for Use].

Skin and subcutaneous tissue disorders.

Angioedema, erythema, pruritus, rash, urticaria.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

There is no human experience of overdosage with Lagevrio. Treatment of overdose with Lagevrio 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.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antivirals for systemic use.
ATC code: Not yet assigned.

Mechanism of action.

Lagevrio is a prodrug that is metabolised to the cytidine nucleoside analogue NHC, which distributes into cells where it is phosphorylated to form the pharmacologically active ribonucleoside triphosphate (NHC-TP). 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. This mechanism of action is known as viral error catastrophe.

Clinical trials.

Clinical data are based on data from 1,433 randomised subjects in the Phase 3 MOVe-OUT trial. MOVe-OUT is a randomised, placebo-controlled, double-blind clinical trial studying molnupiravir for the treatment of non-hospitalised patients with mild to moderate COVID-19 (defined by SpO₂ > 93%, respiratory rate < 30 breaths per minute, heart rate < 125 beats per minute) who are 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: over 60 years of age, 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 randomisation. 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 43 years (range: 18 to 90); 17% of subjects were over 60 years of age and 3% were 75 years of age or older; 49% of subjects were male; 57% were White, 5% Black or African American, 3% Asian, 50% Hispanic or Latino. The majority of subjects were enrolled from sites in Latin America (46%) and Europe (33%); 12% were enrolled in Africa, 6% were enrolled in North America and 3% were enrolled in Asia. Forty-eight percent of subjects received molnupiravir or placebo within 3 days of COVID-19 symptom onset. The most common risk factors were obesity (74%), over 60 years of age (17%), and diabetes (16%). Among 792 subjects (55% of total randomised population) with available baseline SARS-CoV-2 variant/clade identification results, 58% were infected with Delta (B.1.617.2 and AY lineages), 20% were infected with Mu (B.1.621), 11% were infected with Gamma (P.1), and the remainder were infected with other variants/clades. Overall, baseline demographic and disease characteristics were well balanced between the treatment arms.
Table 3 provides the results of the primary endpoint (the percentage of subjects who were hospitalised or died through Day 29 due to any cause).

An exploratory analysis assessing the primary endpoint in prespecified subgroups is provided in Figure 1. For the majority of subgroups, the point estimate favours molnupiravir.

The Kaplan-Meier curve shows time to hospitalisation or death, and results are consistent with the primary results (Figure 2).

Higher percentages of subjects reported sustained improvement or resolution in most self-reported COVID-19 signs and symptoms, as recorded on a daily symptom diary, in the molnupiravir group compared to the placebo group (Figure 3).

Microbiology.

The relationship between NHC and intracellular NHC-TP with antiviral efficacy has not been evaluated clinically.

Antiviral activity.

NHC was active in cell culture assays against SARS-CoV-2 (USA-WA1/2020 isolate) with 50% effective concentrations (EC₅₀) ranging between 0.67 to 2.66 microM in A-549 cells and 0.32 to 2.03 microM in Vero E6 cells. NHC had similar antiviral activity against SARS-CoV-2 variants Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), Lambda (C.37), Mu (B.1.621) and Omicron (BA.1.1.529/BA.1, BA.1.1, BA.2, BA.4 and BA.5) with mean EC₅₀ values of 0.55-2.95 microM.

Resistance.

No amino acid substitutions in SARS-CoV-2 associated with resistance to NHC have been identified in clinical trials. Studies to evaluate selection of resistance to NHC with SARS-CoV-2 in cell culture showed a low likelihood of resistance development to NHC. Following 30 passages in cell culture, no substantial change in susceptibility (< 2-fold) was observed and no NHC resistance-associated amino acid substitutions were identified.

Cross-resistance.

NHC retained activity in vitro against virus with polymerase substitutions (e.g. F480L, V557L and E802D) associated with decreased remdesivir sensitivity.

Viral RNA rebound.

Post-treatment increases in SARS-CoV-2 RNA shedding levels (i.e. viral RNA rebound) in nasopharyngeal samples were observed on Day 10, Day 15, and/or Day 29 in a subset of Lagevrio and placebo recipients in the Phase 3 MOVe-OUT trial. Approximately 1% of both Lagevrio and placebo recipients had evidence of recurrent COVID-19 symptoms coinciding with a rebound in viral RNA levels in nasopharyngeal samples.
Post-treatment viral RNA rebound was not associated with the primary clinical outcome of hospitalisation or death through Day 29 following the single 5-day course of Lagevrio treatment. Post-treatment viral RNA rebound also was not associated with the detection of cell culture infectious virus in nasopharyngeal swab samples.

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 in Table 4.

Absorption.

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

Effect of food.

In healthy subjects, the administration of a single 200 mg dose of molnupiravir with a high-fat meal resulted in a 35% reduction in C_max, but AUC was not significantly affected. Molnupiravir can be taken with or without food.

Distribution.

NHC does not bind to plasma proteins.

Metabolism.

Molnupiravir is hydrolysed by carboxylesterases to NHC prior to reaching systemic circulation. Uptake and metabolism of NHC are mediated by the same pathways involved in endogenous pyrimidine metabolism. NHC is not a substrate of major drug metabolizing enzymes or transporters.
Neither molnupiravir nor NHC are inhibitors or inducers of major drug metabolizing enzymes or transporters.

Excretion.

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.

Special populations.

Paediatric population.

The pharmacokinetics of molnupiravir in paediatric patients less than 18 years of age have not been evaluated.

Renal impairment.

Renal clearance is not a meaningful route of elimination for NHC. No dose adjustment of Lagevrio is required 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 PK of NHC. While the PK of NHC has not been evaluated in patients with eGFR less than 30 mL/min/1.73 m² or on dialysis, severe renal impairment and end-stage renal disease (ESRD) are not expected to have a significant effect on NHC exposure [see Section 4.2 Dose and Method of Administration, Renal impairment].

Hepatic impairment.

The PK 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 [see Section 4.2 Dose and Method of Administration, Hepatic impairment].

Gender, race and age.

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

5.3 Preclinical Safety Data

General toxicity.

Reversible, dose-related bone marrow toxicity (decreased cellularity) affecting all haematopoietic cell lines was observed in dogs at ≥ 17 mg/kg/day (0.4 times the human NHC exposure at the RHD). Mild decreases in peripheral blood cell and platelet counts were seen after 7 days of molnupiravir treatment progressing to more severe haematological changes after 14 days of treatment.
Neither bone marrow nor haematological toxicity was observed in a 1-month toxicity study in mice up to 2000 mg/kg/day (19 times the human NHC exposure at the RHD) and a 3-month toxicity study in rats up to 1000 mg/kg/day (9 and 15 times the human NHC exposure at the RHD in female and male rats, respectively).
Bone and cartilage toxicity, consisting of an increase in the thickness of physeal and epiphyseal growth cartilage with decreases in trabecular bone was observed in the femur and tibia of rapidly growing rats in a 3-month toxicity study at ≥ 500 mg/kg/day (5 times the human NHC exposure at the RHD). There was no bone or cartilage toxicity in a 1-month toxicity study in rapidly growing rats up to 500 mg/kg/day (4 and 8 times the human NHC exposure at the RHD in female and male rats, respectively), in dogs dosed for 14 days up to 50 mg/kg/day (2 times the human NHC exposure at the RHD), or in a 1-month toxicity study in mice up to 2000 mg/kg/day (19 times the human NHC exposure at the RHD). Growth cartilage is not present in mature skeletons, therefore the bone and cartilage findings are not relevant for adult humans but may be relevant for paediatric patients.

Genotoxicity.

Molnupiravir and NHC were positive in the in vitro bacterial reverse mutation assay (Ames assay) with and without metabolic activation. Molnupiravir was negative for induction of chromosomal damage in an in vitro micronucleus assay (with and without metabolic activation). Molnupiravir was negative for induction of chromosomal damage in the in vivo rat micronucleus assay. In the in vivo Pig-a mutagenicity assay, the results were equivocal. In the in vivo Big Blue (cII Locus) transgenic rodent assay, molnupiravir did not induce increased mutation rates. Based on the totality of the genotoxicity data, molnupiravir is of low risk for genotoxicity or mutagenicity in clinical use.

Carcinogenicity.

Molnupiravir was not carcinogenic in a 6-month oral carcinogenicity study in RasH2 transgenic (Tg.RasH2) mice at any dose tested (30, 100 or 300 mg/kg/day).

6 Pharmaceutical Particulars

6.1 List of Excipients

Each Lagevrio capsule contains the following inactive ingredients: Croscarmellose sodium, hyprolose, magnesium stearate, microcrystalline cellulose, purified water.
The capsule shell contains: Hypromellose, iron oxide red, titanium dioxide.
The white ink contains: Tert-butyl alcohol, ethanol absolute, isopropyl alcohol, potassium hydroxide, propylene glycol, purified water, shellac, strong ammonia solution, titanium dioxide.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store Lagevrio below 30°C.
Store Lagevrio in the original bottle.

6.5 Nature and Contents of Container

HDPE bottle containing 40 capsules.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Molnupiravir is the 5'-isobutyrate prodrug of the antiviral ribonucleoside analogue NHC.
The chemical name for molnupiravir is {(2R,3S,4R,5R)-3,4-Dihydroxy- 5-[(4Z)-4-(hydroxyimino)-2-oxo-3,4-dihydropyrimidin- 1(2H)-yl}oxolan-2-yl]methyl 2-methylpropanoate.
It has an empirical formula of C₁₃H₁₉N₃O₇ and its molecular weight is 329.31 g/mol.
Its structural formula is:

Molnupiravir is a white to off-white solid that is soluble in water.

CAS number.

2492423-29-5.

7 Medicine Schedule (Poisons Standard)

Prescription only medicine (Schedule 4).

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Lagevrio Capsules

Molnupiravir

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