Intravenous Cytomegalovirus prophylaxis in haematopoietic stem cell transplant recipients
Adult: Prophylaxis of cytomegalovirus (CMV) reactivation and disease in CMV-seropositive recipients [R+] of allogeneic haematopoietic stem cell transplant (HSCT): 480 mg once daily via IV infusion over 60 minutes using 0.2 micron or 0.22 micron polyethersulfone (PES) in-line filter. Start treatment between Day 0 and Day 28 post-transplant (before or after engraftment) and then continue through Day 100 post-transplantation. Treatment beyond 100 days post-transplantation may be considered in patients at high risk for late CMV reactivation.
Intravenous Cytomegalovirus prophylaxis in kidney transplant recipients
Adult: Prophylaxis of cytomegalovirus (CMV) disease in patients at high risk (donor CMV-seropositive/recipient CMV-seronegative [D+/R-]): 480 mg once daily via IV infusion over 60 minutes using 0.2 micron or 0.22 micron polyethersulfone (PES) in-line filter. Start treatment between Day 0 and Day 7 post-kidney transplant and then continue through Day 200 post-transplantation. Treatment recommendations may vary among local guidelines (refer to specific country guidelines).
Oral Cytomegalovirus prophylaxis in haematopoietic stem cell transplant recipients
Adult: Prophylaxis of cytomegalovirus (CMV) reactivation and disease in CMV-seropositive recipients [R+] of allogeneic haematopoietic stem cell transplant (HSCT): 480 mg once daily, start treatment between Day 0 and Day 28 post-transplant (before or after engraftment) and then continue through Day 100 post-transplantation. Treatment beyond 100 days post-transplantation may be considered in patients at high risk for late CMV reactivation.
Oral Cytomegalovirus prophylaxis in kidney transplant recipients
Adult: Prophylaxis of cytomegalovirus (CMV) disease in patients at high risk (donor CMV-seropositive/recipient CMV-seronegative [D+/R-]): 480 mg once daily, start treatment between Day 0 and Day 7 post-kidney transplant and then continue through Day 200 post-transplantation. Treatment recommendations may vary among local guidelines (refer to specific country guidelines).
Special Patient Group
Patients taking ciclosporin: If ciclosporin is started after initiating letermovir, reduce the next letermovir dose to 240 mg once daily. If ciclosporin is discontinued after initiating letermovir, increase the next letermovir dose to 480 mg once daily. If ciclosporin dose is temporarily interrupted due to high levels of ciclosporin, no dose adjustment of letermovir is necessary.
Hepatic Impairment
Moderate (Child-Pugh class B) hepatic impairment combined with moderate or severe renal impairment; Severe (Child-Pugh class C) hepatic impairment: Not recommended.
Administration
film-coated tab: May be taken with or without food.
Reconstitution
IV infusion: Add contents of a vial containing 480 mg or 240 mg letermovir to 250 mL pre-filled IV bag containing dextrose 5% or NaCl 0.9% solution. Mix by gentle inversion, do not shake.
Incompatibility
IV: Incompatible with amphotericin B (liposomal), amiodarone hydrochloride, aztreonam, cefepime hydrochloride, ciclosporin, ciprofloxacin, diltiazem hydrochloride, filgrastim, gentamicin sulfate, linezolid, levofloxacin, lorazepam, midazolam hydrochloride, mycophenolate mofetil hydrochloride, ondansetron, and palonosetron. Incompatible with IV bags and infusion set materials containing polyurethane or the plasticiser diethylhexyl phthalate (DEHP).
Contraindications
Hypersensitivity. Concomitant use with pimozide, ergot alkaloids, and St. John's wort. Concomitant use with dabigatran, atorvastatin, simvastatin, lovastatin, rosuvastatin, and pitavastatin when co-administered with ciclosporin.
Special Precautions
Patient taking ciclosporin. Renal impairment (CrCl <50 mL/min; particularly with IV use). Moderate hepatic impairment combined with moderate or severe renal impairment; severe hepatic impairment. Pregnancy and lactation.
Adverse Reactions
Blood and lymphatic system disorders: Decreased platelet count and Hb. Cardiac disorders: Tachycardia, atrial fibrillation. Ear and labyrinth disorders: Vertigo. Gastrointestinal disorders: Nausea, vomiting, diarrhoea, abdominal pain, dysgeusia. General disorders and administration site conditions: Fatigue, peripheral oedema. Immune system disorders: Hypersensitivity. Investigations: Increased blood creatinine, ALT, or AST. Metabolism and nutrition disorders: Decreased appetite. Musculoskeletal and connective tissue disorders: Muscle spasms. Nervous system disorders: Headache.
Monitoring Parameters
Monitor for CMV reactivation; serum creatinine levels (for patients with CrCl <50 mL/min who are receiving IV infusion). Assess for signs and symptoms of infection or changes in urination.
Drug Interactions
May increase the plasma concentrations of CYP3A substrates (e.g. alfentanil, fentanyl, quinidine, midazolam, ciclosporin, sirolimus, tacrolimus), OATP1B1/3 substrates (e.g. glibenclamide, fexofenadine, repaglinide), or agents transported by organic anion transporter 3 [OAT3] (e.g. ciprofloxacin, tenofovir). May decrease the plasma concentrations of CYP2C9 and/or CYP2C19 substrates (e.g. diazepam, esomeprazole, lansoprazole, omeprazole, pantoprazole, tolbutamide, voriconazole, warfarin). May increase or decrease the plasma concentrations of CYP2B6 substrates (e.g. bupropion), UGT1A1 substrates (e.g. dolutegravir, raltegravir), or agents transported by BCRP (e.g. sulfasalazine) or OATP2B1 (e.g. celiprolol). Increased plasma concentrations with OATP1B1/3 inhibitors (e.g. ciclosporin, erythromycin, clarithromycin, gemfibrozil, atazanavir, simeprevir). Reduced plasma concentrations with strong and moderate inducers of transporters and/or enzymes (e.g. carbamazepine, rifampicin, rifabutin, phenytoin, phenobarbital, efavirenz, etravirine, lopinavir, modafinil, ritonavir). Potentially Fatal: May increase the serum concentrations of pimozide and ergot alkaloids (e.g. ergotamine, dihydroergotamine), which may lead to QT interval prolongation or torsades de pointes and ergotism, respectively. May significantly increase the serum concentrations of HMG-CoA reductase inhibitors (e.g. atorvastatin, simvastatin, rosuvastatin, pitavastatin, lovastatin), which may lead to myopathy or rhabdomyolysis. May reduce the plasma concentrations and efficacy of drugs that are transported by P-gp in the intestine (e.g. dabigatran).
Food Interaction
Decreased plasma concentration with St. John's wort.
Action
Description: Mechanism of Action: Letermovir is a quinazoline antiviral agent that inhibits cytomegalovirus (CMV) DNA terminase complex, an enzyme required for viral DNA cleavage and packaging which has several protein subunits (pUL51, pUL56, pUL89). It affects the production of proper unit length genomes and interferes with virion maturation. Pharmacokinetics: Absorption: Rapidly absorbed. Bioavailability: HSCT recipients: 35% (without ciclosporin), 85% (with ciclosporin); kidney transplant recipients: 56% (without ciclosporin). Time to peak plasma concentration: 1.5-3 hours. Distribution: Plasma protein binding: 99%. Metabolism: Metabolised in the liver via glucuronidation by UGT1A1/1A3 (minor). Excretion: Via faeces (93%; 70% as unchanged drug); urine (<2%). Elimination half-life: Approx 12 hours (IV).
Chemical Structure
Letermovir Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 45138674, Letermovir. https://pubchem.ncbi.nlm.nih.gov/compound/Letermovir. Accessed Mar. 22, 2024.
Storage
Tab: Store between 15-30°C. Solution for inj: Store intact vials between 15-30°C. Protect from light, do not shake. Diluted IV solution is stable for up to 24 hours at room temperature or up to 48 hours under refrigeration (between 2-8°C), including duration of IV infusion.
J05AX18 - letermovir ; Belongs to the class of other antivirals. Used as a direct acting antiviral in the systemic treatment of viral infections.
References
Anon. Letermovir. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 29/11/2023.Anon. Letermovir. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 29/11/2023.Buckingham R (ed). Letermovir. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 29/11/2023.Joint Formulary Committee. Letermovir. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 29/11/2023.Merck Sharp & Dohme (New Zealand) Ltd. Prevymis Film Coated Tablet and Concentrated Injection for Infusion data sheet 26 February 2021. Medsafe. http://www.medsafe.govt.nz. Accessed 29/11/2023.Prevymis 240 mg Film-coated Tablets (Merck Sharp & Dohme [UK] Limited). MHRA. https://products.mhra.gov.uk. Accessed 29/11/2023.Prevymis 240 mg or 480 mg Tablets and Injection (MSD [Thailand] Ltd.). MIMS Thailand. http://www.mims.com/thailand. Accessed 29/11/2023.Prevymis 480 mg Concentrate for Solution for Infusion (Merck Sharp & Dohme [UK] Limited). MHRA. https://products.mhra.gov.uk. Accessed 29/11/2023.Prevymis Film-coated Tablets and Concentrate for Solution for Infusion (Merck Sharp & Dohme [Malaysia] Sdn. Bhd.). National Pharmaceutical Regulatory Agency - Ministry of Health Malaysia. https://www.npra.gov.my. Accessed 29/11/2023.Prevymis Film-coated Tablets and Concentrate for Solution for Infusion (Merck Sharp & Dohme B.V.). European Medicines Agency [online]. Accessed 12/02/2024.Prevymis Tablet, Film Coated and Injection, Solution (Merck Sharp & Dohme LLC). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 29/11/2023.
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