PREVYMIS

Letermovir recieved approval from the FDA on November 8th, 2017 for use in prophylaxis of cytomegalovirus (CMV) infection in allogeneic hematopoietic stem cell transplant patients.

It is the first of a new class of CMV anti-infectives called DNA terminase complex inhibitors.

Letermovir has recieved both priority and orphan drug status from the FDA.

It is currently marketed under the brand name Prevymis.

Letermovir is indicated for prophylaxis against cytomegalovirus (CMV) infection and disease in recipients, ≥6 months of age and ≥6 kg, of an allogeneic hematopoietic stem cell transplant (HSCT) who are CMV-seropositive.

It is also indicated for prophylaxis against CMV disease in kidney transplant recipients, ≥12 years of age and ≥40 kg, who are at risk (i.e. donor CMV-seropositive/recipient CMV-seronegative). 7,

Letermovir inhibits the activity of the DNA terminase complex of CMV thereby preventing the cutting of viral DNA into mature length genomes for packaging into viral particles.

Letemovir inhibits the DNA terminase complex with an EC50 of 2.1nM.

Letermovir has a bioavailability of 94% in healthy subjects when administered without cyclosporin, 35% in HSCT recipients when administered without cyclosporin, and 85% in HSCT recipients when administered with cyclosporin.

Letermovir's Tmax is 45 min to 2.25 hours.

Time to steady state has been observed to be 9-10 days.

Taking Letermovir with food increases

Cmax by an average of 129.82% (range of 104.35%-161.50%).

No significant effect on

AUC has been observed.

The mean steady state volume of distribution is 45.5 L.

Letermovir undergoes a minor degree of metabolism through UGT1A1/1A3.

Letemovir is taken up by the liver through OATP1B1/3 transporters. 93% is excreted in the feces with 70% as the parent drug. 7 <2% is excreted in the urine.

The mean terminal half-life was observed to be 12 hours following administration of Letemovir 480 mg Intravenous once daily.

The mean clearance is 11.25 L/h in healthy subjects.

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There is no human data on the safety of Letemovir in pregnancy.

Embryo-fetal toxicity and malformations have been observed in rats at exposures 11 times the human exposure at the recommended human dose (RHD) of Letemovir.

No such toxicity was noted in rats at 3 times human exposure at the RHD or in rabbits at values less than human exposure with the RHD.

Total litter loss was observed in 21.7% of female rats at 2 times human exposure at RHD.

This did not occur at values similar to human exposure at RHD.

Ototoxicity has been noted in animal studies.

No human data is available regarding lactation.

Letemovir has been observed in the milk of lactating rats and in the blood of their nursing pups.

No data is available concerning the effect of Letemovir on human fertility.

Testicular toxicity leading to reduced fertility has been observed in male rats.

Patients should only consider an intravenous formulation if they are unable to take oral therapy.

They should be switched to an oral therapy as soon as possible to reduce exposure to the excipient hydroxypropyl betadex.

Accumulation of hydroxypropyl betadex may occur in adults with creatinine clearance <50 mL/min, or pediatric patients with a similar level of age-adjusted renal impairment.

Intravenous administration should not exceed 4 weeks.

No antidote exists for

Letemovir overdosage.

The effectiveness of dialysis in clearing plasma of Letemovir is unknown.

is contraindicated in patients receiving pimozide or ergot alkaloids: Pimozide: Concomitant administration of PREVYMIS in patients receiving pimozide may result in increased concentrations of pimozide due to inhibition of cytochrome P450 3A (CYP3A) by letermovir, which may lead to QT prolongation and torsades de pointes.

Ergot alkaloids

Concomitant administration of PREVYMIS in patients receiving ergot alkaloids may result in increased concentrations of ergot alkaloids (ergotamine and dihydroergotamine) due to inhibition of CYP3A by letermovir, which may lead to ergotism.

PREVYMIS is contraindicated with pitavastatin and simvastatin when co-administered with cyclosporine.

Concomitant administration of

PREVYMIS in combination with cyclosporine may result in significantly increased pitavastatin or simvastatin concentrations, which may lead to myopathy or rhabdomyolysis.

PREVYMIS is contraindicated with

Pitavastatin and simvastatin when co-administered with cyclosporine.

Patients 12 Years of Age and Older and Weighing at least 30 kg Who Are HSCT Recipients or Adult and Pediatric Patients 12 Years of Age and Older and Weighing at least 40 kg Who Are Kidney Transplant Recipients: HSCT: 480 mg administered once daily orally or as an intravenous (IV) infusion over 1 hour through 100 days post-HSCT.

In patients at risk for late

CMV infection and disease, PREVYMIS may be continued through 200 days post-HSCT.

Transplant: 480 mg administered once daily orally or as an IV infusion over 1 hour through 200 days post-transplant.

Patients 6 Months to Less than 12 Years of Age or 12 Years of Age and Older and Weighing Less than 30 kg Who Are HSCT Recipients: HSCT: Dosing based on weight administered once daily orally or as an IV infusion over 1 hour through 100 days post-HSCT.

PREVYMIS injection must be diluted prior to administration.

PREVYMIS injection must be administered through a sterile 0.2 micron or 0.22 micron polyethersulfone (PES) in-line filter.

Following the completion of

PREVYMIS prophylaxis, monitoring for CMV reactivation in HSCT recipients is recommended.

If PREVYMIS is co-administered with cyclosporine, the dosage of PREVYMIS should be decreased to 240 mg once daily in adult and pediatric patients 12 years of age and older.

If PREVYMIS is co-administered with cyclosporine in pediatric patients less than 12 years of age, dose adjustment may be required.

Instructions for

Use should be followed for preparation and administration of PREVYMIS oral pellets.

Do not use PREVYMIS injection with

IV bags and infusion set materials containing the plasticizer diethylhexyl phthalate (DEHP). 2.1 Important Dosing and Administration Information PREVYMIS is available in 3 dosage forms: PREVYMIS Tablets.

• Administer orally with or without food.

• Swallow tablets whole.

• Administer orally mixed with soft food or via nasogastric tube (NG tube) or gastric tube (G tube) .

• Do not crush or chew.

• PREVYMIS injection must be diluted prior to administration.

• Administer PREVYMIS through a sterile 0.2 micron or 0.22 micron polyethersulfone (PES) in-line filter.

• Administer by intravenous infusion via a peripheral catheter or central venous line at a constant rate over 1 hour.

• Do not administer as an intravenous bolus injection.

• PREVYMIS injection, which contains hydroxypropyl betadex, should be used only in patients unable to take oral therapy.

Patients should be switched to oral

PREVYMIS as soon as they are able to take oral medications.

If possible, intravenous administration should not exceed 4 weeks.

No dosage adjustment is necessary when switching formulations in adult and pediatric patients 12 years of age and older.

Dosage adjustment may be necessary for pediatric patients less than 12 years of age when switching between oral and intravenous formulations. 2.2 Patient Monitoring Following the completion of PREVYMIS prophylaxis, monitoring for CMV reactivation in HSCT recipients is recommended. 2.3 Recommended Dosage for Adult and Pediatric Patients 12 Years of Age and Older Who Are HSCT or Kidney Transplant Recipients HSCT: Adult and Pediatric Patients 12 Years of Age and Older and Weighing at least 30 kg The recommended dosage of PREVYMIS is 480 mg administered orally or intravenously once daily.

PREVYMIS is administered orally, the recommended dosage is one 480 mg tablet once daily or two 240 mg tablets once daily.

Four 120 mg packets of oral pellets once daily can be used for patients who cannot swallow tablets.

For preparation and administration instructions of intravenous dosing refer to instructions in subsection 2.10.

For pediatric patients less than 12 years of age or weighing less than 30 kg, refer to weight-based dosing in Table and Table 2.

Initiate PREVYMIS between Day and

Day 28 post-HSCT (before or after engraftment) and continue through Day 100 post-HSCT.

CMV infection and disease, PREVYMIS may be continued through Day 200 post-HSCT.

Dosage of

PREVYMIS should be adjusted when co-administered with cyclosporine.

Adult and Pediatric Patients 12 Years of Age and Older and Weighing at least 40 kg The recommended dosage of PREVYMIS is 480 mg administered orally or intravenously once daily.

Day 7 post-transplant and continue through Day 200 post-transplant.

PREVYMIS should be adjusted when co-administered with cyclosporine. 2.4 Dosage Adjustment When Co-administered with Cyclosporine for Adult and Pediatric Patients 12 Years of Age and Older Who Are HSCT or Kidney Transplant Recipients If oral or intravenous PREVYMIS is co-administered with cyclosporine, the dosage of PREVYMIS should be decreased to 240 mg once daily in the following populations: HSCT: adult and pediatric patients 12 years of age and older and weighing at least 30 kg or Kidney transplant: adult and pediatric patients 12 years of age and older and weighing at least 40 kg. If cyclosporine is initiated after starting PREVYMIS, the next dose of PREVYMIS should be decreased to 240 mg once daily.

If cyclosporine is discontinued after starting

PREVYMIS, the next dose of PREVYMIS should be increased to 480 mg once daily.

If cyclosporine dosing is interrupted due to high cyclosporine levels, no dose adjustment of PREVYMIS is needed. 2.5 Recommended Dosage for Pediatric Patients 6 Months to Less than 12 Years of Age or 12 Years of Age and Older and Weighing Less than 30 kg Who Are HSCT Recipients The recommended dosages of PREVYMIS for pediatric HSCT recipients 6 months to less than 12 years of age are based on weight and shown in Table 1 (tablets or oral pellets) and Table 2 (injection) .

PREVYMIS can be administered orally (tablet or pellet) or intravenously once daily.

Dosage adjustment may be necessary for pediatric patients less than 12 years of age when switching between oral and intravenous formulations.

Table 1: Recommended Daily Oral Dosage of PREVYMIS in Pediatric HSCT Recipients 6 Months to Less than 12 Years of Age or 12 Years of Age and Older and Weighing Less than 30 kg Body Weight Daily Oral Dose Tablets Oral Pellets 30 kg and above 480 mg One 480 mg tablet or Two 240 mg tablets Four 120 mg packets of oral pellets 15 kg to less than 30 kg 240 mg One 240 mg tablet Two 120 mg packets of oral pellets 7.5 kg to less than 15 kg 120 mg Not recommended One 120 mg packet of oral pellets 6 kg to less than 7.5 kg 80 mg Not recommended Four 20 mg packets of oral pellets Table 2: Recommended Daily IV Dosage of PREVYMIS in Pediatric HSCT Recipients 6 Months to Less than 12 Years of Age or 12 Years of Age and Older and Weighing Less than 30 kg Body Weight Daily IV Refer to Subsection 2.10 for intravenous preparation and administration dosing instructions Dose 30 kg and above 480 mg 15 kg to less than 30 kg 120 mg 7.5 kg to less than 15 kg 60 mg 6 kg to less than 7.5 kg 40 mg 2.6 Dosage Adjustment When Co-administered with Cyclosporine for Pediatric Patients 6 Months to Less than 12 Years of Age or 12 Years of Age and Older and Weighing Less than 30 kg Who Are HSCT Recipients If oral or intravenous PREVYMIS is co-administered with cyclosporine in pediatric HSCT recipients 6 months to less than 12 years of age, the dosage of PREVYMIS may require adjustment as shown in Table 3.

If cyclosporine is initiated after starting

PREVYMIS, the next dose of PREVYMIS should be the daily oral or intravenous dose co-administered with cyclosporine (Table 3) If cyclosporine is discontinued after starting PREVYMIS, the next dose of PREVYMIS should be the daily oral or intravenous dose administered without cyclosporine (Table 1 or Table 2) If cyclosporine dosing is interrupted due to high cyclosporine levels, no dose adjustment of PREVYMIS is needed.

Table 3: Recommended Dosage of PREVYMIS when Co-administered with Cyclosporine in Pediatric HSCT Recipients 6 Months to Less than 12 Years of Age or 12 Years of Age and Older and Weighing Less than 30 kg Body Weight Daily Oral Dose Tablets Oral Pellets Daily IV Refer to Subsection 2.10 for intravenous preparation and administration dosing instructions Dose 30 kg and above 240 mg One 240 mg tablet Two 120 mg packets of oral pellets 240 mg 15 kg to less than 30 kg 120 mg Not recommended One 120 mg packet of oral pellets 120 mg 7.5 kg to less than 15 kg 60 mg Not recommended Three 20 mg packets of oral pellets 60 mg 6 kg to less than 7.5 kg 40 mg Not recommended Two 20 mg packets of oral pellets 40 mg 2.7 Use in Patients with Renal Impairment For adult patients with creatinine clearance (CLcr) greater than 10 mL/min and pediatric patients with a similar degree of renal impairment (based on age-appropriate assessment of renal function), no dosage adjustment of PREVYMIS is required based on renal impairment.

There are insufficient data in adult patients with CLcr 10 mL/min or less or in patients on dialysis or in pediatric patients with a similar degree of renal impairment (based on age-appropriate assessment of renal function) to make PREVYMIS dosing recommendations.

In adult patients with

CLcr less than 50 mL/min and in pediatric patients with a similar degree of renal impairment (based on age-appropriate assessment of renal function) receiving PREVYMIS injection, accumulation of the intravenous vehicle, hydroxypropyl betadex, may occur.

Closely monitor serum creatinine levels in these patients. 2.8 Use in Patients with 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. 2.9 Preparation and Administration of Oral Pellets PREVYMIS oral pellets can be administered: orally after mixing with soft food or via NG tube or G tube.

Preparation and Administration Mixed with Soft Food See Instructions for Use for details on the preparation and administration of PREVYMIS oral pellets mixed with soft food.

Do not crush or chew

PREVYMIS oral pellets.

PREVYMIS oral pellets with to 3 teaspoons of soft food (such as applesauce, yogurt, or puddin.

PREVYMIS 240 mg tablet is a yellow oval tablet; each tablet is debossed with "591" on one side and corporate logo on the other side.

PREVYMIS 480 mg tablet is a pink oval, bi-convex tablet debossed with "595" on one side and corporate logo on the other side.

The 240 mg tablets are packaged into a carton (NDC 0006-3075-02) containing four Child Resistant (CR) Dosepaks®, each containing a 7-count blister card for a total of 28 tablets, or into a carton (NDC 0006-3075-04) containing two unit-dose 7-count blister cards for a total of 14 tablets.

The 480 mg tablets are packaged into a carton (NDC 0006-3076-02) containing four Child Resistant (CR) Dosepaks®, each containing a 7-count blister card for a total of 28 tablets, or into a carton (NDC 0006-3076-04) containing two unit-dose 7-count blister cards for a total of 14 tablets.

PREVYMIS tablets in the original package until use to protect from moisture.

PREVYMIS tablets at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) .

PREVYMIS oral pellets are supplied as beige round pellets in packets.

Each packet contains 20 mg of letermovir.

Each packet contains 120 mg of letermovir.

The 20 mg packets of PREVYMIS oral pellets are packaged into a carton (NDC 0006-5086-01).

Each carton contains 30 child resistant packets.

The 120 mg packets of PREVYMIS oral pellets are packaged into a carton (NDC 0006-5085-01).

PREVYMIS oral pellets in the original packet until use.

PREVYMIS oral pellets at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) .

PREVYMIS is supplied as a sterile, clear and colorless solution for intravenous use of 240 mg/12 mL (20 mg/mL) or 480 mg/24 mL (20 mg/mL) that may contain a few product-related small translucent or white particles.

The single-dose vials are supplied in cartons that contain a 240 mg single-dose vial (NDC 0006-5003-01) or a 480 mg single-dose vial (NDC 0006-5004-01).

PREVYMIS injection vials at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) .

Store in the original carton to protect from exposure to light.

PREVYMIS tablets in the original package until use to protect from moisture.

PREVYMIS tablets at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) .

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.

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.

Letermovir was administered orally to pregnant rats at 0, 10, 50 or 250 mg/kg/day from gestation days 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 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 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 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).

The safety and effectiveness of PREVYMIS have been established for: Prophylaxis of CMV infection and disease in pediatric CMV-seropositive recipients of an allogeneic HSCT 6 months of age and older and weighing at least 6 kg, and Prophylaxis of CMV disease in pediatric kidney transplant recipients 12 years of age and older and weighing at least 40 kg who are at high risk [D+/R-. HSCT Recipients: The use of PREVYMIS for prophylaxis of CMV infection and disease in pediatric recipients of an allogeneic HSCT is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data from pediatric patients in Trial P030. The safety and pharmacokinetic results were similar to those in adults. Kidney Transplant Recipients: The use of PREVYMIS for prophylaxis of CMV disease in high-risk [D+/R-] kidney transplant recipients 12 years of age and older and weighing at least 40 kg is supported by evidence from an adequate and well-controlled study in adults and safety data from pediatric HSCT recipients (Trial P030).

Letermovir exposures are expected to be similar between adult and pediatric patients 12 years of age and older and weighing at least 40 kg.

The safety and effectiveness of PREVYMIS have not been established for: HSCT recipients less than 6 months of age or weighing less than 6 kg, or Kidney transplant recipients less than 12 years of age or weighing less than 40 kg.

Of the 373 subjects treated with PREVYMIS in Trial P001, 56 (15%) subjects were 65 years of age or older.

Of the 144 subjects treated with PREVYMIS in Trial P040, 32 (22%) subjects were 65 years of age or older.

Of the 292 subjects treated with PREVYMIS in Trial P002, 48 (16%) subjects were 65 years of age or older.

Safety and efficacy were similar across older and younger subjects in each trial.

No dosage adjustment of

PREVYMIS is required based on age.