Letermovir

Registered South African indications:

• Prophylaxis of cytomegalovirus (CMV) reactivation and disease in CMV-seropositive recipients [R+] of an allogeneic haematopoietic stem cell transplant (HSCT)

Contraindications

Registered contraindications in South Africa & other jurisdictions

• Hypersensitivity to the active substance or to any of the excipients
• Coadministration with pimozide
• Coadministration with ergot alkaloids
• Coadministration with St. John’s wort (Hypericum perforatum)
• When letermovir is combined with ciclosporin: Concomitant use of dabigatran, atorvastatin, simvastatin, rosuvastatin or pitavastatin is contraindicated

Cautions

Registered contraindications in South Africa & other jurisdictions

Caution in the following patient groups

• Pregnancy
• Breastfeeding
• Moderate to severe renal impairment combined with moderate hepatic impairment
• End stage renal disease (ESRD)
• Severe hepatic impairment (Child-Pugh Class C)

Risk of adverse reactions or reduced therapeutic effect due to medicinal product interactions

• The concomitant use of letermovir and certain medicinal products may result in known or potentially significant medicinal product interactions
• Some interactions may lead to clinically significant adverse reactions from greater exposure of concomitant medicinal products or letermovir
• Significant decreases in concomitant medicinal product plasma concentrations may occur, which can lead to a reduced therapeutic effect of the concomitant medicinal product

Drug interactions

• Letermovir should be used with caution with medicinal products that are CYP3A substrates with narrow therapeutic ranges
• Increased monitoring of ciclosporin, tacrolimus, sirolimus is generally recommended
• Letermovir is a moderate inducer of enzymes and transporters. Induction may give rise to reduced plasma concentrations of some metabolised and transported medicinal products. Therapeutic drug monitoring (TDM) is therefore recommended for voriconazole
• Concomitant use of dabigatran should be avoided due to risk of reduced dabigatran efficacy
• Letermovir may increase the plasma concentrations of medicinal products transported by OATP1B1/3 such as many of the statins

Administration through a sterile 0.2 or 0.22 micron PES in-line filter

• Letermovir concentrate for solution for infusion may contain a few product-related small translucent or white particles
• Administration of letermovir diluted solution always requires the use of a sterile 0.2 micron or 0.22 micron PES in-line filter

Excipients

• Letermovir IV formulation 240mg concentrate for solution for infusion contains 23mg sodium per vial. This should be taken into consideration by patients on a controlled sodium diet
• Letermovir tablet contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product
• This tablet contains less than 1 mmol sodium (23mg) per tablet, that is to say essentially 'sodium-free'(Recommendations in other jurisdictions)

Effects on ability to drive and use machines

• Letermovir may have minor influence on the ability to drive or use machines. Fatigue and vertigo have been reported in some patients during treatment, which may influence a patient's ability to drive and use machines

Forms avail. in SA and covered in this monograph: fct, inf

South African registered indications and dosages

Letermovir should be initiated by a medical practitioner experienced in the management of patients who have had an allogeneic haematopoietic stem cell transplant

Prophylaxis of cytomegalovirus (CMV) reactivation and disease in adult CMV-seropositive recipients [R+] of an allogeneic haematopoietic stem cell transplant (HSCT)

• Oral (fct): 480mg, once dly started on the day of transplant and no later than 28 days post-transplant; Letermovir may be started before or after engraftment; Duration of treatment: Prophylaxis should continue through 100 days post-transplant
• IV: 480mg, once dly admin. via peripheral or central venous catheter using a total time of approx. 60min started on the day of transplant and no later than 28 days post-transplant; Letermovir may be started before or after engraftment; Duration of treatment: Prophylaxis should continue through 100 days post-transplant

Consideration should be given to official guidance on the appropriate use of antiviral medicines

Letermovir tablets and IV formulations may be used interchangeably at the discretion of the medical practitioner, and no dose adjustment is necessary

The safety and efficacy of letermovir use for more than 100 days has not been studied in clinical trials. Prolonged letermovir prophylaxis beyond 100 days post-transplant may be of benefit in some patients at high risk for late CMV reactivation. Use of letermovir prophylaxis for greater than 100 days requires a careful assessment of the benefit-risk balance

Method of administration
The tablet(s) should be swallowed whole and may be taken with or without food. The tablet(s) should not be divided, crushed or chewed
Letermovir infusion is for intravenous infusion only and requires dilution prior to administration. Letermovir should not be administered as an intravenous push or bolus (refer to product specific information for preparation and compatibility)

Missed dose
Patients should be instructed that if they miss a dose of letermovir, they should take it as soon as they remember. If they do not remember until it is time for the next dose, they should skip the missed dose and go back to the regular schedule. Patients should not double their next dose or take more than the prescribed one

Dosage adjustment with ciclosporin co-administration
If co-administered with ciclosporin, adjust letermovir dosage to 240mg once daily
If ciclosporin is initiated after starting letermovir, decrease the next letermovir dose to 240mg once daily
If ciclosporin is discontinued after starting letermovir, increase the next letermovir dose to 480mg once daily
No dose adjustment is needed if ciclosporin dosing is temporarily interrupted

Not established for use in patients below 18 years of age

Pregnancy 

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; not recommended
• There are no data from the use of letermovir in pregnant women. Studies in animals have shown reproductive toxicity
• Letermovir is not recommended during pregnancy and in women of childbearing potential not using contraception

Breastfeeding

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; not recommended
• It is unknown whether letermovir is excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of letermovir in milk
• A risk to the newborns/infants cannot be excluded
• A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from letermovir therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman

Fertility

Recommendations below are applicable to South Africa and other jurisdictions

• There were no effects on female fertility in rats. Irreversible testicular toxicity and impairment of fertility was observed in male rats, but not in male mice or male monkeys

Recommendations below are applicable to South Africa and other jurisdictions

• Mild, moderate, or severe: No dose adjustment recommended
• Moderate to severe combined with moderate hepatic impairment: Caution; not recommended
• End stage renal disease (ESRD): Caution; no information available
  No dose recommendation can be made for patients with ESRD with or without dialysis. Efficacy and safety has not been demonstrated for patients with ESRD

Recommendations below are applicable to South Africa and other jurisdictions

• Mild to moderate (Child-Pugh Class A and B): No dose adjustment recommended
• Severe (Child-Pugh Class C): Caution; not recommended
• Moderate combined with moderate or severe renal impairment: Caution; not recommended

Recommendations below are applicable to South Africa and other jurisdictions

• No dose adjustment recommended

• HMG-CoA reductase inhibitors
• Atorvastatin
• Simvastatin
• Pitavastatin
• Rosuvastatin
• Fluvastatin
• Pravastatin
• Strong and moderate inducers of transporters (e.g. P-gp) and/or enzymes (e.g. UGTs)
• Rifampicin
• Phenytoin
• Carbamazepine
• Rifabutin
• Phenobarbital
• Thioridazine
• Modafinil
• Ritonavir
• Lopinavir
• Efavirenz
• Etravirine
• OATP1B1/3 inhibitors
• Gemfibrozil
• Erythromycin
• Clarithromycin
• Protease inhibitors
• Atazanavir
• Simeprevir
• Ciclosporin
• Medicinal products metabolised by CYP3A
• Tacrolimus
• Sirolimus
• Amiodarone
• Pimozide
• Ergot alkaloids
• Fexofenadine
• Medicinal products metabolised by CYP2C8
• Repaglinide
• Glyburide
• Medicinal products metabolised by CYP2C9 and/or CYP2C19
• Warfarin
• Voriconazole
• Diazepam
• Lansoprazole
• Omeprazole
• Esomeprazole
• Pantoprazole
• Tilidine
• Tolbutamide
• Medicinal products transported by P-gp in the intestine
• Dabigatran
• Sofosbuvir
• Medicinal products metabolised by CYP2B6, UGT1A1 or transported by BCRP or OATP2B1
• Bupropion
• Raltegravir
• Dolutegravir
• Rosuvastatin
• Sulfasalazine
• Celiprolol
• Medicinal products transported by the renal transporter OAT3
• Ciprofloxacin
• Tenofovir
• Imipenem
• Cilastin
• Nafcillin
• Bosentan
• Nevirapine
• Systemically acting oral contraceptive steroids (excluding ethinylestradiol (EE)/ levonorgestrel (LNG))
• Midazolam
• Alfentanil
• Fentanyl
• Quinidine

Other interactions

• St. John's Wort

• Cytomegalovirus (CMV) reactivation

Specific cases may require

• Serum creatinine

Letermovir inhibits the CMV DNA terminase complex which is required for cleavage and packaging of viral progeny DNA. Letermovir affects the formation of proper unit length genomes and interferes with virion maturation.