Lagevrio (Eua) (molnupiravir)

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Drug-drug interaction trials of molnupiravir and concomitant medications have not been conducted.

In vitro, molnupiravir and its active nucleoside analog (N4-hydroxycytidine (NHC)) are not substrates of CYP isoenzymes or P-glycoprotein (P-gp) and BCRP transporters. In vitro, molnupiravir and NHC are not inhibitors of CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4 or inhibitors of OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, MATE2K, MRP2, MDR1 and BCRP or inducers of CYP isoenzymes 1A2, 2B6, and 3A4.

There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Deoxycytidine Kinase Substrates/Cladribine Oral

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Clofarabine, cytarabine, emtricitabine, fludarabine, gemcitabine, lamivudine, molnupiravir, nelarabine and zalcitabine may inhibit the intracellular phosphorylation of cladribine by deoxycytidine kinase (dCK).

CLINICAL EFFECTS: Concurrent administration of clofarabine, cytarabine, emtricitabine, fludarabine, gemcitabine, lamivudine, molnupiravir, nelarabine, or zalcitabine with cladribine may result in decreased clinical efficacy of cladribine.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of lamivudine states that the concurrent use of lamivudine and cladribine is not recommended.(1) The manufacturer of cladribine states that concurrent use of compounds that require activation by intracellular phosphorylation should be avoided.(2)

DISCUSSION: Cladribine undergoes a series of phosphorylations to its active metabolites. In a case report, a patient on lamivudine who received cladribine concurrently did not experience a decrease in his lymphocyte count. After discontinuation of lamivudine and readministration of cladribine, his lymphocytes dropped as expected.(3) It is expected that other compounds phosphorylated by dCK would also decrease cladribine's efficacy.(4) Compounds phosphorylated by dCK include: clofarabine, cytarabine, emtricitabine, fludarabine, gemcitabine, lamivudine, molnupiravir, nelarabine and zalcitabine.

Selected Deoxycytidine Kinase Substrates/Islatravir

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Clofarabine, cytarabine, fludarabine, gemcitabine, molnupiravir, nelarabine and zalcitabine may inhibit the intracellular phosphorylation of islatravir by deoxycytidine kinase (dCK).(1)

CLINICAL EFFECTS: Concurrent administration of clofarabine, cytarabine, fludarabine, gemcitabine, molnupiravir, nelarabine, or zalcitabine with islatravir may result in decreased clinical efficacy of islatravir.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of the doravirine-islatravir fixed-dose combination states that co-administration with dCK substrates is not recommended.(1)

DISCUSSION: Islatravir undergoes a series of phosphorylations to its active metabolite.(1) In a clinical study in healthy participants, co-administration of multiple daily doses of 300 mg lamivudine and a single dose of 2 mg islatravir (8 times the recommended dosage) decreased intracellular ISL-TP (islatravir active metabolite) area under the curve (AUC) level by 87% and maximum concentration (Cmax) by 76% relative to islatravir alone.(1) It is expected that co-administration with other compounds phosphorylated by dCK may result in a decrease in ISL-TP exposures.(1,2) Compounds phosphorylated by dCK include: clofarabine, cytarabine, fludarabine, gemcitabine, molnupiravir, nelarabine and zalcitabine.

There are no moderate interactions for this drug.

*FDA emergency use authorization (EUA) states none.

• Lactation

• Pregnancy

There are no moderate contraindications for this drug.

Most common adverse reactions occurring in 1% or more of patients receiving molnupiravir include diarrhea, nausea, and dizziness. Post-authorization experience has identified additional adverse effects, including erythema, rash, urticaria, and hypersensitivity reactions through voluntary reporting.

Rare or Very Rare

• Abnormal hepatic function tests
• Anaphylaxis
• Angioedema
• Hypersensitivity drug reaction

Less Frequent

• Diarrhea
• Dizziness
• Nausea

Rare or Very Rare

• Erythema
• Skin rash
• Urticaria

No enhanced messaging available.

Molnupiravir is not authorized for use in pediatric patients younger than 18 years of age because of possible effect on bone and cartilage growth. Safety and efficacy of the drug have not been assessed in pediatric patients.

In a repeat-dose toxicity study in rats, impaired transformation of growth cartilage into new bone was observed in the femur and tibia.

Molnupiravir may cause fetal harm if administered to pregnant women based on animal findings.

Pregnant females or females who become pregnant while receiving molnupiravir are encouraged to enroll in the manufacturer's pregnancy surveillance program. Patients or their clinicians should call 1-877-888-4231 to enroll.

It is not known whether molnupiravir or its metabolites are distributed into human milk; however, NHC was detected in plasma of nursing pups when molnupiravir was administered to lactating rats. The effects of the drug on the breast-fed infant or on the production of milk are unknown.

Because of the potential for adverse reactions to molnupiravir in breast-fed infants, females should be advised not to breast-feed while receiving the drug and for 4 days after the final dose. Lactating females may consider pumping and discarding breast milk during molnupiravir therapy and for 4 days after the final dose.

No dosage adjustment recommended.

In the MOVe-OUT clinical trial, no difference in safety and tolerability was observed between ambulatory geriatric patients and younger adults receiving molnupiravir for the treatment of COVID-19; therefore, no dosage adjustment is necessary based on age.

The pharmacokinetics of NHC are similar in geriatric patients and younger adults.