Letermovir

Indications

Letermovir is used for: Prophylaxis of cytomegalovirus (CMV), reactivation & disease in adult CMV-seropositive recipients [R+] of an allogeneic haematopoietic stem cell transplant (HSCT).

Adult Dose

Cytomegalovirus Infection Prophylaxis Indicated for prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT) 480 mg PO/IV qDay; initiate between Day 0 and Day 28 posttransplantation (before or after engraftment) and continue through Day 100 Following the completion of prophylaxis, monitoring for CMV reactivation recommended Use IV only in patients unable to take oral therapy; switch to oral administration as soon as feasible Tablet and injection may be used interchangeably at the discretion of the physician; no dosage adjustment is necessary when switching formulations Hepatic impairment Mild or moderate (Child-Pugh A or B): No dosage adjustment required Severe (Child-Pugh C): Not recommended

Child Dose

<18 years: Safety and efficacy not established

Renal Dose

Renal impairment CrCl >10 mL/min: No dosage adjustment required CrCl ?10 mL/min or patient on dialysis: Data are insufficient to make dosing recommendations Hydroxypropyl betadex (IV vehicle) may accumulate if CrCl <50 mL/min; closely monitor serum creatinine levels in patients receiving IV letermovir

Administration

May be taken with or without food: Swallow whole, do not divide/crush/chew.

Contra Indications

Hypersensitivity. Concomitant administration w/ pimozide; ergot alkaloids. If combined w/ cyclosporine, concomitant use of dabigatran, atorvastatin, simvastatin, rosuvastatin or pitavastatin is contraindicated.

Precautions

Monitor CMV DNA. Concomitant use w/ medicinal products that are CYP3A substrates w/ narrow therapeutic ranges (eg, alfentanil, fentanyl, & quinidine); cyclosporine, tacrolimus, sirolimus; voriconazole & phenytoin; dabigatran; OATP1B1/3 substrates (eg, statins). Rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption. Minor influence on the ability to drive or use machines. Not recommended during pregnancy & in women of childbearing potential not using contraception. Lactation.

Pregnancy-Lactation

Pregnancy No data are available regarding use in pregnant women 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) Infertility: No data are available on the effect of letermovir on human fertility; decreased fertility due to testicular toxicity observed in male rats Lactation Unknown if 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 The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for the drug and any potential adverse effects on the breastfed child or from the underlying maternal condition

Interactions

Possible subtherapeutic exposure w/ moderate (thioridazine, modafinil, ritonavir, lopinavir, efavirenz & etravirine) & strong (rifampicin, phenytoin, carbamazepine, St. John's wort, rifabutin & phenobarb) enzyme inducers. Increased plasma conc w/ OATP1B1/3 transporter inhibitors [eg, rifampicin, gemfibrozil, erythromycin, clarithromycin, & several PIs (atazanavir, lopinavir, ritonavir, simeprevir)]. Decreased plasma exposure & reduced efficacy of drugs eliminated through metabolism or by active transport; CYP2C9 &/or CYP2C19 substrates (eg, warfarin, phenytoin, voriconazole, diazepam, lansoprazole, omeprazole, esomeprazole, pantoprazole, tilidine, tolbutamide). Increased plasma conc of CYP3A substrates [eg, midazolam, certain immunosuppressants (eg, cyclosporine, tacrolimus, sirolimus) HMG-CoA reductase inhibitors, amiodarone, pimozide, ergot alkaloids]; OATP1B1/3 substrates (eg, HMG-CoA reductase inhibitors, fexofenadine, repaglinide & glyburide); OAT3 transporter substrates (eg, ciprofloxacin, tenofovir, imipenem, & cilastatin). Concomitant use w/ CYP2C8 substrates (eg, repaglinide) is not recommended. Decreased plasma conc of intestinal P-gp substrates (eg, dabigatran & sofosbuvir). Increased or decreased plasma conc of substrates of CYP2B6 (eg, bupropion & efavirenz), UGT1A1 (eg, raltegravir & dolutegravir), BRCP transporter (eg, rosuvastatin & sulfasalazine), OATP2B1 (eg, celiprolol).

Adverse Effects

Side effects of Letermovir : >10% Nausea (27%) Diarrhea (26%) Vomiting (19%) Peripheral edema (14%) Cough (14%) Headache (14%) Fatigue (13%) Abdominal pain (12%) Laboratory abnormalities with incidence greater than placebo Platelets <25, 000 cells/mcL 27% (placebo 21%) 1-10% Tachycardia (4%) Atrial fibrillation (3%)

Mechanism of Action

Antiviral drug against CMV; inhibits the CMV DNA terminase complex (pUL51, pUL56, and pUL89), which is required for viral DNA processing and packaging by affecting the production of proper unit length genomes and interfering with virion maturation