Prevymis

Name: Prevymis

Indications and Usage for Prevymis

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).

Warnings and Precautions

Risk of Adverse Reactions or Reduced Therapeutic Effect Due to Drug Interactions

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 [see Contraindications (4) and Drug Interactions (7.1, 7.2, 7.3)].

See Table 3 for steps to prevent or manage these possible or known significant drug interactions, including dosing recommendations. 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.

Use in specific populations

Pregnancy

Risk Summary

No adequate human data are available to establish whether Prevymis poses a risk to pregnancy outcomes. In animal reproduction studies, embryo-fetal developmental toxicity (including fetal malformations) was observed in rats during the period of organogenesis at letermovir exposures (AUC) 11 times higher than human exposure at the recommended human dose (RHD). In rabbits, no embryo-fetal developmental toxicity was noted at exposures that were not maternally toxic (up to letermovir exposures 2 times higher than human exposure at the RHD). In a rat pre/post-natal development study, total litter loss was observed at maternal letermovir exposures approximately 2 times higher than human exposure at the RHD (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

Letermovir was administered orally to pregnant rats at 0, 10, 50 or 250 mg/kg/day from gestation days 6 to 17. Developmental toxicities, including skeletal malformations and umbilical cord shortening, were observed at 250 mg/kg/day (approximately 11 times higher than human exposure at the RHD). In addition, decreased fetal body weight and skeletal variations (due to maternal toxicity) were observed at this dose. No embryo-fetal toxicities were observed at 50 mg/kg/day (approximately 3 times higher than human exposure at the RHD).

Letermovir was administered orally to pregnant rabbits at 0, 25, 75 or 225 mg/kg/day from gestation days 6 to 20. Developmental toxicities, including spontaneous abortion, increased post-implantation loss, and skeletal variations, were observed at a maternally toxic dose (225 mg/kg/day; approximately 2 times higher than human exposure at the RHD). No embryo-fetal toxicities were observed at 75 mg/kg/day (less than human exposure at the RHD).

In the pre/post-natal development study, letermovir was administered orally to pregnant rats at 0, 10, 45 or 180 mg/kg/day from gestation day 6 to lactation day 22. At 180 mg/kg/day (approximately 2 times higher than human exposure at the RHD), total litter loss due to stillbirth or possible maternal neglect was observed in 5 of 23 pregnant females by post-partum/lactation day 4. In surviving offspring, slight developmental delays in vaginal opening and pinna unfolding were accompanied by reduced body weight gain at this dose. No toxicities were observed at 45 mg/kg/day (similar to human exposure at the RHD).

Lactation

Risk Summary

It is not known whether letermovir is present in human breast milk, affects human milk production, or has effects on the breastfed child.

When administered to lactating rats, letermovir was present in the milk of lactating rats as well as the blood of nursing pups (see Data).

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Prevymis and any potential adverse effects on the breastfed child from Prevymis or from the underlying maternal condition.

Data

In a lactation study, letermovir was excreted in milk when administered intravenously (at 10 mg/kg) to lactating rats on post-partum/lactation day 10. Letermovir was also detected in the blood of nursing pups on post-partum/lactation day 21 in the pre/post-natal developmental study.

Females and Males of Reproductive Potential

Infertility

There are no data on the effect of letermovir on human fertility. Decreased fertility due to testicular toxicity was observed in male rats [see Nonclinical Toxicology (13.1) and (13.2)].

Pediatric Use

Safety and efficacy of Prevymis in patients below 18 years of age have not been established.

Geriatric Use

Of the 373 subjects treated with Prevymis in Trial P001, 56 (15%) subjects were 65 years of age or older. Safety and efficacy were similar across older and younger subjects. No dosage adjustment of Prevymis is required based on age [see Clinical Pharmacology (12.3)].

Renal Impairment

For patients with CLcr greater than 10 mL/min (by Cockcroft-Gault equation), no dosage adjustment of Prevymis is required based on renal impairment [see Clinical Pharmacology (12.3)]. The safety of Prevymis in patients with end-stage renal disease (CLcr less than 10 mL/min), including patients on dialysis, is unknown.

In patients with CLcr less than 50 mL/min receiving Prevymis injection, accumulation of the intravenous vehicle, hydroxypropyl betadex, could occur. Closely monitor serum creatinine levels in these patients.

Hepatic Impairment

No dosage adjustment of Prevymis is required for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. Prevymis is not recommended for patients with severe (Child-Pugh Class C) hepatic impairment [see Clinical Pharmacology (12.3)].

Prevymis Description

Prevymis contains letermovir, an inhibitor of the CMV DNA terminase complex, and is administered orally or by intravenous infusion.

Prevymis is available as 240 mg and 480 mg tablets. Prevymis tablets contain either 240 mg or 480 mg of letermovir and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, povidone 25, and film-coated with a coating material containing the following inactive ingredients: hypromellose 2910, iron oxide red (only for 480 mg tablets), iron oxide yellow, lactose monohydrate, titanium dioxide, and triacetin, Carnauba wax is added as a polishing agent.

Prevymis is also available as 240 mg and 480 mg injection for intravenous infusion. Prevymis injection is a clear, preservative-free sterile solution in single-dose vials of either 240 mg or 480 mg per vial. Each 1 mL of solution contains 20 mg letermovir, hydroxypropyl betadex (150 mg), sodium chloride (3.1 mg), sodium hydroxide (1.2 mg), and Water for Injection, USP. The amount of sodium hydroxide may be adjusted to achieve a pH of approximately 7.5.

Letermovir has a molecular formula of C29H28F4N4O4 and a molecular weight of 572.55. The chemical name for letermovir is (4S)-2-{8-Fluoro-2-[4-(3- methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5- (trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetic acid. Letermovir is very slightly soluble in water.

The chemical structure of letermovir is:

PRINCIPAL DISPLAY PANEL - 24 mL Vial Carton

NDC 0006-5004-01

Prevymis™
(letermovir) Injection

480 mg/24 mL
(20 mg/mL)

For Intravenous Infusion Only

Requires dilution prior to administration.
See Package Insert.

Rx only

Single-dose vial. Discard unused portion.

Prevymis 
letermovir tablet, film coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0006-3075
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
LETERMOVIR (LETERMOVIR) LETERMOVIR 240 mg
Inactive Ingredients
Ingredient Name Strength
MICROCRYSTALLINE CELLULOSE  
CROSCARMELLOSE SODIUM  
POVIDONE K25  
SILICON DIOXIDE  
MAGNESIUM STEARATE  
LACTOSE MONOHYDRATE  
HYPROMELLOSE 2910 (6 MPA.S)  
HYPROMELLOSE 2910 (15 MPA.S)  
TITANIUM DIOXIDE  
TRIACETIN  
FERRIC OXIDE YELLOW  
CARNAUBA WAX  
Product Characteristics
Color YELLOW Score no score
Shape OVAL Size 17mm
Flavor Imprint Code 591
Contains     
Packaging
# Item Code Package Description
1 NDC:0006-3075-02 4 DOSE PACK in 1 CARTON
1 NDC:0006-3075-01 7 TABLET, FILM COATED in 1 DOSE PACK
2 NDC:0006-3075-04 14 BLISTER PACK in 1 CARTON
2 NDC:0006-3075-03 1 TABLET, FILM COATED in 1 BLISTER PACK
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA209939 11/08/2017
Prevymis 
letermovir tablet, film coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0006-3076
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
LETERMOVIR (LETERMOVIR) LETERMOVIR 480 mg
Inactive Ingredients
Ingredient Name Strength
MICROCRYSTALLINE CELLULOSE  
CROSCARMELLOSE SODIUM  
POVIDONE K25  
SILICON DIOXIDE  
MAGNESIUM STEARATE  
LACTOSE MONOHYDRATE  
HYPROMELLOSE 2910 (6 MPA.S)  
HYPROMELLOSE 2910 (15 MPA.S)  
TITANIUM DIOXIDE  
TRIACETIN  
FERRIC OXIDE YELLOW  
FERRIC OXIDE RED  
CARNAUBA WAX  
Product Characteristics
Color PINK Score no score
Shape OVAL (bi-convex) Size 21mm
Flavor Imprint Code 595
Contains     
Packaging
# Item Code Package Description
1 NDC:0006-3076-02 4 DOSE PACK in 1 CARTON
1 NDC:0006-3076-01 7 TABLET, FILM COATED in 1 DOSE PACK
2 NDC:0006-3076-04 14 BLISTER PACK in 1 CARTON
2 NDC:0006-3076-03 1 TABLET, FILM COATED in 1 BLISTER PACK
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA209939 11/08/2017
Prevymis 
letermovir injection, solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0006-5003
Route of Administration INTRAVENOUS DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
LETERMOVIR (LETERMOVIR) LETERMOVIR 20 mg  in 1 mL
Inactive Ingredients
Ingredient Name Strength
HYDROXYPROPYL BETADEX 150 mg  in 1 mL
SODIUM CHLORIDE 3.1 mg  in 1 mL
SODIUM HYDROXIDE 1.2 mg  in 1 mL
WATER  
Packaging
# Item Code Package Description
1 NDC:0006-5003-01 1 VIAL, SINGLE-DOSE in 1 CARTON
1 NDC:0006-5003-02 12 mL in 1 VIAL, SINGLE-DOSE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA209940 11/08/2017
Prevymis 
letermovir injection, solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0006-5004
Route of Administration INTRAVENOUS DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
LETERMOVIR (LETERMOVIR) LETERMOVIR 20 mg  in 1 mL
Inactive Ingredients
Ingredient Name Strength
HYDROXYPROPYL BETADEX 150 mg  in 1 mL
SODIUM CHLORIDE 3.1 mg  in 1 mL
SODIUM HYDROXIDE 1.2 mg  in 1 mL
WATER  
Packaging
# Item Code Package Description
1 NDC:0006-5004-01 1 VIAL, SINGLE-DOSE in 1 CARTON
1 NDC:0006-5004-02 24 mL in 1 VIAL, SINGLE-DOSE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA209940 11/08/2017
Labeler - Merck Sharp & Dohme Corp. (001317601)
Revised: 11/2017   Merck Sharp & Dohme Corp.

Who should not take Prevymis?

Do not take Prevymis if you take:

  • pimozide
  • ergot alkaloids

If you are taking Prevymis with cyclosporine, do not take:

  • pitavastatin or simvastatin

What should I tell my doctor before taking Prevymis?

Tell your doctor about all your medical conditions, including if you:

  • have kidney or liver problems.
  • are pregnant or plan to become pregnant. It is not known if Prevymis will harm your unborn baby.
  • are breastfeeding or plan to breastfeed. It is not known if Prevymis passes into your breast milk. Talk to your doctor about the best way to feed your baby during treatment.

Tell your doctor about all of the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Prevymis may affect the way other medicines work, and vice versa, and may cause serious side effects.

Know the medicines you take. Keep a list of medicines and show it to your doctor and pharmacist when you get a new medicine. Your doctor or pharmacist will tell you if it is safe to take Prevymis with other medicines. Do not start or stop taking another medicine without telling your doctor first.

Prevymis side effects

The most common side effects include:

  • nausea
  • diarrhea
  • vomiting
  • swelling in your arms and legs
  • cough
  • headache
  • tiredness
  • stomach (abdominal) pain

These are not all the possible side effects. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Precautions While Using Prevymis

It is very important that your doctor check your progress at regular visits to make sure that this medicine is working properly and to check for unwanted effects.

Do not use this medicine together with pimozide (Orap®) or ergot medicines (eg, dihydroergotamine, ergonovine, ergotamine, methylergonovine, Cafergot®, Ergomar®, Wigraine®).

Do not use pitavastatin (Livalo®) or simvastatin (Zocor®) when you take this medicine together with cyclosporine (Gengraf®, Neoral®, Sandimmune®).

Do not stop taking this medicine without asking your doctor first.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Breastfeeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Other Interactions

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

  • For oral dosage form (tablets):
    • For prevention of CMV infection or disease:
      • Adults—480 milligrams (mg) once a day, starting between Day 0 and Day 28, and continue until Day 100 after transplant.
      • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

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