Adverse events (AE) profile

Cardiac AEs

The cardiac AE rate (regardless of investigator-assessed causality) was higher in subjects receiving PREVYMIS (13%) compared to subjects receiving placebo (6%). The most common cardiac AEs were tachycardia (reported in 4% of PREVYMIS subjects and in 2% of placebo subjects) and atrial fibrillation (reported in 3% of PREVYMIS subjects and in 1% of placebo subjects). Among those subjects who experienced 1 or more cardiac AEs, 85% of PREVYMIS and 92% of placebo subjects had events reported as mild or moderate in severity.

All grade AEs reported in ≥10% of patients treated with PREVYMIS at a frequency at least 2% greater than placebo

AEs	PREVYMIS (n=373)	Placebo (n=192)
Nausea	27%	23%
Diarrhea	26%	24%
Vomiting	19%	14%
Peripheral edema	14%	9%
Cough	14%	10%
Headache	14%	9%
Fatigue	13%	11%
Abdominal pain	12%	9%

Drug-related renal and hepatic AEs¹

AEs	PREVYMIS	Placebo
Renal and urinary disorders	1%	1%
Hepatobiliary disorders	0%	1%

Rates of discontinuation due to AEs were comparable between PREVYMIS and placebo (13% vs 12%, respectively)¹

No differences in incidence of or time to engraftment^a between PREVYMIS and placebo

(a) Engraftment was defined as an absolute neutrophil count ≥500/mm³ on 3 consecutive days after transplantation.

Reference

1. Data available on request from Merck Professional Services-DAP, WP1, PO Box 4, West Point, PA 19486-0004. Please specify information package US-CYT-00438.

Selected Safety Information

PREVYMIS is contraindicated in patients receiving pimozide or ergot alkaloids.
- Increased pimozide concentrations may lead to QT prolongation and torsades de pointes.
- Increased ergot alkaloids concentrations may lead to ergotism.
PREVYMIS is contraindicated with pitavastatin and simvastatin when co-administered with cyclosporine. Significantly increased pitavastatin or simvastatin concentrations may lead to myopathy or rhabdomyolysis.
The concomitant use of PREVYMIS and certain drugs may result in potentially significant drug interactions, some of which may lead to adverse reactions (PREVYMIS or concomitant drugs) or reduced therapeutic effect of PREVYMIS or the concomitant drug. Consider the potential for drug interactions prior to and during PREVYMIS therapy; review concomitant medications during PREVYMIS therapy; and monitor for adverse reactions associated with PREVYMIS and concomitant medications.
The cardiac adverse event rate (regardless of investigator-assessed causality) was higher in subjects receiving PREVYMIS than placebo (13% vs 6%). The most common cardiac adverse events were tachycardia (reported in 4% PREVYMIS subjects and 2% placebo subjects) and atrial fibrillation (reported in 3% PREVYMIS subjects and 1% placebo subjects). Among those subjects who experienced one or more cardiac adverse events, 85% of PREVYMIS and 92% of placebo subjects had events reported as mild or moderate in severity.
The rate of adverse events occurring in at least 10% of PREVYMIS-treated HSCT recipients and at a frequency at least 2% greater than placebo were nausea (27% vs 23%), diarrhea (26% vs 24%), vomiting (19% vs 14%), peripheral edema (14% vs 9%), cough (14% vs 10%), headache (14% vs 9%), fatigue (13% vs 11%), and abdominal pain (12% vs 9%).
The most frequently reported adverse event that led to study drug discontinuation was nausea (occurring in 2% of PREVYMIS subjects and 1% of placebo subjects). Hypersensitivity reaction, with associated moderate dyspnea, occurred in one subject following the first infusion of IV PREVYMIS after switching from oral PREVYMIS, leading to treatment discontinuation.
Co-administration of PREVYMIS with drugs that are inhibitors of organic anion-transporting polypeptide 1B1/3 (OATP1B1/3) transporters may result in increases in letermovir plasma concentrations.
Co-administration of PREVYMIS with inducers of transporters (e.g. P-gp) and/or enzymes (e.g. UGTs) is not recommended due to the potential for a decrease in letermovir plasma concentrations.
Co-administration of PREVYMIS with midazolam results in increased midazolam plasma concentrations. Co-administration of PREVYMIS with drugs that are CYP3A substrates may result in clinically relevant increases in the plasma concentrations of co-administered CYP3A substrates.
Co-administration of PREVYMIS with drugs that are substrates of OATP1B1/3 transporters may result in a clinically relevant increase in plasma concentrations of co-administered OATP1B1/3 substrates.
The magnitude of CYP3A- and OATP1B1/3-mediated drug interactions on co-administered drugs may be different when PREVYMIS is co-administered with cyclosporine. See the prescribing information for cyclosporine for information on drug interactions with cyclosporine.
If dose adjustments of concomitant medications are made due to treatment with PREVYMIS, doses should be readjusted after PREVYMIS treatment is completed.
Drug interactions may occur based on results from studies. Drug interactions may also occur based on predicted interactions. Potentially significant drug interactions include, but are not limited to, the following (information below applies to co-administration of PREVYMIS and the concomitant drug without cyclosporine, unless otherwise indicated):
- Anti-arrhythmic Agents
  - Amiodarone: increases ↑amiodarone concentration
- Antibiotics
  - Nafcillin: decreases ↓letermovir concentration
- Anticoagulants
  - Warfarin: decreases ↓warfarin concentration
- Anticonvulsants
  - Carbamazepine: decreases ↓letermovir concentration
  - Phenobarbital: decreases ↓letermovir concentration
  - Phenytoin: decreases ↓both phenytoin and letermovir concentrations
- Antidiabetic Agents
  - Glyburide: increases ↑glyburide concentration
  - Repaglinide: increases ↑repaglinide concentration
  - Rosiglitazone: increases ↑rosiglitazone concentration
- Antifungals
  - Voriconazole: decreases ↓voriconazole concentration
- Antimycobacterials
  - Rifabutin: decreases ↓letermovir concentration
  - Rifampin: decreases ↓letermovir concentration
- Antipsychotics
  - Pimozide: increases ↑pimozide concentration; co-administration is contraindicated
  - Thioridazine: decreases ↓letermovir concentration
- Endothelin Antagonists
  - Bosentan: decreases ↓letermovir concentration
- Ergot Alkaloids
  - Ergotamine: increases ↑ergotamine concentration; co-administration is contraindicated
  - Dihydroergotamine: increases ↑dihydroergotamine concentration; co-administration is contraindicated
- Herbal Products
  - St. John's wort (Hypericum perforatum): decreases ↓letermovir concentration
- HIV Medications
  - Efavirenz: decreases ↓letermovir concentration
  - Etravirine: decreases ↓letermovir concentration
  - Nevirapine: decreases ↓letermovir concentration
- HMG-CoA Reductase Inhibitors
  - Pitavastatin, simvastatin: increases ↑HMG-CoA reductase inhibitors concentration; co-administration is contraindicated when PREVYMIS is co-administered with cyclosporine
  - Atorvastatin: increases ↑atorvastatin concentration
  - Fluvastatin, lovastatin, pravastatin, rosuvastatin: increases ↑HMG-CoA reductase inhibitors concentration
- Immunosuppressants
  - Cyclosporine: increases ↑both cyclosporine and letermovir concentrations
  - Sirolimus: increases ↑sirolimus concentration
  - Tacrolimus: increases ↑tacrolimus concentration
- Proton Pump Inhibitors
  - Omeprazole: decreases ↓omeprazole concentration
  - Pantoprazole: decreases ↓pantoprazole concentration
- Wakefulness-Promoting Agents
  - Modafinil: decreases ↓letermovir concentration
- CYP3A Substrate Examples
  - Alfentanil, fentanyl, midazolam and quinidine: may increase ↑CYP3A substrate concentration
  - Pimozide and ergot alkaloids are contraindicated

The safety and efficacy of PREVYMIS in patients below 18 years of age have not been established.
For patients with creatinine clearance (CLcr) greater than 10 mL/min (by Cockcroft-Gault equation), no dosage adjustment of PREVYMIS is required based on renal impairment. The safety of PREVYMIS in patients with end-stage renal disease (CLcr less than 10 mL/min), including patients on dialysis, is unknown.
No dosage adjustment of PREVYMIS is required based on mild (Child-Pugh Class A) to moderate (Child-Pugh Class B) hepatic impairment. PREVYMIS is not recommended for patients with severe (Child-Pugh Class C) hepatic impairment.

Before prescribing PREVYMIS, please read the accompanying Prescribing Information. The Patient Information also is available.

Indication

PREVYMIS is indicated for prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT).

Selected Safety Information

PREVYMIS is contraindicated in patients receiving pimozide or ergot alkaloids.
- Increased pimozide concentrations may lead to QT prolongation and torsades de pointes.
- Increased ergot alkaloids concentrations may lead to ergotism.
PREVYMIS is contraindicated with pitavastatin and simvastatin when co-administered with cyclosporine. Significantly increased pitavastatin or simvastatin concentrations may lead to myopathy or rhabdomyolysis.
The concomitant use of PREVYMIS and certain drugs may result in potentially significant drug interactions, some of which may lead to adverse reactions (PREVYMIS or concomitant drugs) or reduced therapeutic effect of PREVYMIS or the concomitant drug. Consider the potential for drug interactions prior to and during PREVYMIS therapy; review concomitant medications during PREVYMIS therapy; and monitor for adverse reactions associated with PREVYMIS and concomitant medications.
The cardiac adverse event rate (regardless of investigator-assessed causality) was higher in subjects receiving PREVYMIS than placebo (13% vs 6%). The most common cardiac adverse events were tachycardia (reported in 4% PREVYMIS subjects and 2% placebo subjects) and atrial fibrillation (reported in 3% PREVYMIS subjects and 1% placebo subjects). Among those subjects who experienced one or more cardiac adverse events, 85% of PREVYMIS and 92% of placebo subjects had events reported as mild or moderate in severity.
The rate of adverse events occurring in at least 10% of PREVYMIS-treated HSCT recipients and at a frequency at least 2% greater than placebo were nausea (27% vs 23%), diarrhea (26% vs 24%), vomiting (19% vs 14%), peripheral edema (14% vs 9%), cough (14% vs 10%), headache (14% vs 9%), fatigue (13% vs 11%), and abdominal pain (12% vs 9%).
The most frequently reported adverse event that led to study drug discontinuation was nausea (occurring in 2% of PREVYMIS subjects and 1% of placebo subjects). Hypersensitivity reaction, with associated moderate dyspnea, occurred in one subject following the first infusion of IV PREVYMIS after switching from oral PREVYMIS, leading to treatment discontinuation.
Co-administration of PREVYMIS with drugs that are inhibitors of organic anion-transporting polypeptide 1B1/3 (OATP1B1/3) transporters may result in increases in letermovir plasma concentrations.
Co-administration of PREVYMIS with inducers of transporters (e.g. P-gp) and/or enzymes (e.g. UGTs) is not recommended due to the potential for a decrease in letermovir plasma concentrations.
Co-administration of PREVYMIS with midazolam results in increased midazolam plasma concentrations. Co-administration of PREVYMIS with drugs that are CYP3A substrates may result in clinically relevant increases in the plasma concentrations of co-administered CYP3A substrates.
Co-administration of PREVYMIS with drugs that are substrates of OATP1B1/3 transporters may result in a clinically relevant increase in plasma concentrations of co-administered OATP1B1/3 substrates.
The magnitude of CYP3A- and OATP1B1/3-mediated drug interactions on co-administered drugs may be different when PREVYMIS is co-administered with cyclosporine. See the prescribing information for cyclosporine for information on drug interactions with cyclosporine.
If dose adjustments of concomitant medications are made due to treatment with PREVYMIS, doses should be readjusted after PREVYMIS treatment is completed.
Drug interactions may occur based on results from studies. Drug interactions may also occur based on predicted interactions. Potentially significant drug interactions include, but are not limited to, the following (information below applies to co-administration of PREVYMIS and the concomitant drug without cyclosporine, unless otherwise indicated):
- Anti-arrhythmic Agents
  - Amiodarone: increases ↑amiodarone concentration
- Antibiotics
  - Nafcillin: decreases ↓letermovir concentration
- Anticoagulants
  - Warfarin: decreases ↓warfarin concentration
- Anticonvulsants
  - Carbamazepine: decreases ↓letermovir concentration
  - Phenobarbital: decreases ↓letermovir concentration
  - Phenytoin: decreases ↓both phenytoin and letermovir concentrations
- Antidiabetic Agents
  - Glyburide: increases ↑glyburide concentration
  - Repaglinide: increases ↑repaglinide concentration
  - Rosiglitazone: increases ↑rosiglitazone concentration
- Antifungals
  - Voriconazole: decreases ↓voriconazole concentration
- Antimycobacterials
  - Rifabutin: decreases ↓letermovir concentration
  - Rifampin: decreases ↓letermovir concentration
- Antipsychotics
  - Pimozide: increases ↑pimozide concentration; co-administration is contraindicated
  - Thioridazine: decreases ↓letermovir concentration
- Endothelin Antagonists
  - Bosentan: decreases ↓letermovir concentration
- Ergot Alkaloids
  - Ergotamine: increases ↑ergotamine concentration; co-administration is contraindicated
  - Dihydroergotamine: increases ↑dihydroergotamine concentration; co-administration is contraindicated
- Herbal Products
  - St. John's wort (Hypericum perforatum): decreases ↓letermovir concentration
- HIV Medications
  - Efavirenz: decreases ↓letermovir concentration
  - Etravirine: decreases ↓letermovir concentration
  - Nevirapine: decreases ↓letermovir concentration
- HMG-CoA Reductase Inhibitors
  - Pitavastatin, simvastatin: increases ↑HMG-CoA reductase inhibitors concentration; co-administration is contraindicated when PREVYMIS is co-administered with cyclosporine
  - Atorvastatin: increases ↑atorvastatin concentration
  - Fluvastatin, lovastatin, pravastatin, rosuvastatin: increases ↑HMG-CoA reductase inhibitors concentration
- Immunosuppressants
  - Cyclosporine: increases ↑both cyclosporine and letermovir concentrations
  - Sirolimus: increases ↑sirolimus concentration
  - Tacrolimus: increases ↑tacrolimus concentration
- Proton Pump Inhibitors
  - Omeprazole: decreases ↓omeprazole concentration
  - Pantoprazole: decreases ↓pantoprazole concentration
- Wakefulness-Promoting Agents
  - Modafinil: decreases ↓letermovir concentration
- CYP3A Substrate Examples
  - Alfentanil, fentanyl, midazolam and quinidine: may increase ↑CYP3A substrate concentration
  - Pimozide and ergot alkaloids are contraindicated

The safety and efficacy of PREVYMIS in patients below 18 years of age have not been established.
For patients with creatinine clearance (CLcr) greater than 10 mL/min (by Cockcroft-Gault equation), no dosage adjustment of PREVYMIS is required based on renal impairment. The safety of PREVYMIS in patients with end-stage renal disease (CLcr less than 10 mL/min), including patients on dialysis, is unknown.
No dosage adjustment of PREVYMIS is required based on mild (Child-Pugh Class A) to moderate (Child-Pugh Class B) hepatic impairment. PREVYMIS is not recommended for patients with severe (Child-Pugh Class C) hepatic impairment.

Before prescribing PREVYMIS, please read the accompanying Prescribing Information. The Patient Information also is available.

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US-CYT-0045201/20