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Selected Safety Information

Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Concomitant administration with pimozide.

Concomitant administration with ergot alkaloids.

Concomitant administration with St. John’s wort (Hypericum perforatum).

When letermovir is combined with cyclosporine:

Concomitant use of dabigatran, atorvastatin, simvastatin, rosuvastatin or pitavastatin is contraindicated.

Special warnings and precautions for use

Monitoring of CMV DNA in HSCT recipients
In a Phase 3 trial (P001), the safety and efficacy of letermovir has been established in HSCT patients with a negative CMV DNA test result prior to initiation of prophylaxis. CMV DNA was monitored on a weekly basis until post-transplant Week 14, and subsequently every two weeks until Week 24. In cases of clinically significant CMV DNAemia or disease, letermovir prophylaxis was stopped and standard-of-care pre-emptive therapy (PET) or treatment was initiated. In patients in whom letermovir prophylaxis was initiated and the baseline CMV DNA test was subsequently found to be positive, prophylaxis could be continued if PET criteria had not been met.

Risk of adverse reactions or reduced therapeutic effect due to medicinal product interactions
The concomitant use of PREVYMIS and certain medicinal products may result in known or potentially significant medicinal product interactions, some of which may lead to:

  • possible clinically significant adverse reactions from greater exposure of concomitant medicinal products or letermovir.
  • significant decrease of concomitant medicinal product plasma concentrations, which may lead to reduced therapeutic effect of the concomitant medicinal product.

Drug interactions
PREVYMIS should be used with caution with medicinal products that are CYP3A substrates with narrow therapeutic ranges (e.g., alfentanil, fentanyl, and quinidine) as co-administration may result in increases in the plasma concentrations of CYP3A substrates. Close monitoring and/or dose adjustment of co-administered CYP3A substrates is recommended.

Increased monitoring of cyclosporine, tacrolimus, sirolimus is generally recommended the first 2 weeks after initiating and ending letermovir as well as after changing route of administration of letermovir.

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.

Excipients
PREVYMIS 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 medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially “sodium-free”.

Undesirable effects

Summary of the safety profile
The safety assessment of PREVYMIS was based on three Phase 3 clinical trials.

HSCT
In P001, 565 HSCT recipients received PREVYMIS or placebo through Week 14 post-transplant and were followed for safety through Week 24 post-transplant. The most commonly reported adverse reactions occurring in at least 1% of subjects in the PREVYMIS group and at a frequency greater than placebo were: nausea (7.2%), diarrhoea (2.4%), and vomiting (1.9%). The most frequently reported adverse reactions that led to discontinuation of PREVYMIS were: nausea (1.6%), vomiting (0.8%), and abdominal pain (0.5%).

In P040, 218 HSCT recipients received PREVYMIS or placebo from Week 14 (~100 days) through Week 28 (~200 days) post-HSCT and were followed for safety through Week 48 post-HSCT. The adverse reactions reported were consistent with the safety profile of PREVYMIS as characterised in study P001.

Kidney transplant
In P002, 292 kidney transplant recipients received PREVYMIS through Week 28 (~200 days) post-transplant.

Tabulated summary of adverse reactions
The following adverse reactions were identified in patients taking PREVYMIS in clinical trials. The adverse reactions are listed below by body system organ class and frequency. Frequencies are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000) or very rare (< 1/10,000).

Table 2: Adverse reactions identified with PREVYMIS

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

Please see PREVYMIS SmPC for full Prescribing Information, also available at www.ema.europa.eu.

Indication

PREVYMIS is indicated for prophylaxis of cytomegalovirus (CMV) reactivation and disease in

Important Safety Information

Contraindications

Hypersensitivity to the active substance or to any of the excipients

Indication

PREVYMIS is indicated for prophylaxis of cytomegalovirus (CMV) reactivation and disease in adult CMV-seropositive recipients [R+] of an allogeneic haematopoietic stem cell transplant (HSCT).

PREVYMIS is indicated for prophylaxis of CMV disease in CMV-seronegative adults who have received a kidney transplant from a CMV-seropositive donor [D+/R-].

Important Safety Information

Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Concomitant administration with pimozide.

Concomitant administration with ergot alkaloids.

Concomitant administration with St. John’s wort (Hypericum perforatum).

When letermovir is combined with cyclosporine:

Concomitant use of dabigatran, atorvastatin, simvastatin, rosuvastatin or pitavastatin is contraindicated.

Special warnings and precautions for use

Monitoring of CMV DNA in HSCT recipients
In a Phase 3 trial (P001), the safety and efficacy of letermovir has been established in HSCT patients with a negative CMV DNA test result prior to initiation of prophylaxis. CMV DNA was monitored on a weekly basis until post-transplant Week 14, and subsequently every two weeks until Week 24. In cases of clinically significant CMV DNAemia or disease, letermovir prophylaxis was stopped and standard-of-care pre-emptive therapy (PET) or treatment was initiated. In patients in whom letermovir prophylaxis was initiated and the baseline CMV DNA test was subsequently found to be positive, prophylaxis could be continued if PET criteria had not been met.

Risk of adverse reactions or reduced therapeutic effect due to medicinal product interactions
The concomitant use of PREVYMIS and certain medicinal products may result in known or potentially significant medicinal product interactions, some of which may lead to:

  • possible clinically significant adverse reactions from greater exposure of concomitant medicinal products or letermovir.
  • significant decrease of concomitant medicinal product plasma concentrations, which may lead to reduced therapeutic effect of the concomitant medicinal product.

Drug interactions
PREVYMIS should be used with caution with medicinal products that are CYP3A substrates with narrow therapeutic ranges (e.g., alfentanil, fentanyl, and quinidine) as co-administration may result in increases in the plasma concentrations of CYP3A substrates. Close monitoring and/or dose adjustment of co-administered CYP3A substrates is recommended.

Increased monitoring of cyclosporine, tacrolimus, sirolimus is generally recommended the first 2 weeks after initiating and ending letermovir as well as after changing route of administration of letermovir.

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.

Excipients
PREVYMIS 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 medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially “sodium-free”.

Undesirable effects

Summary of the safety profile
The safety assessment of PREVYMIS was based on three Phase 3 clinical trials.

HSCT
In P001, 565 HSCT recipients received PREVYMIS or placebo through Week 14 post-transplant and were followed for safety through Week 24 post-transplant. The most commonly reported adverse reactions occurring in at least 1% of subjects in the PREVYMIS group and at a frequency greater than placebo were: nausea (7.2%), diarrhoea (2.4%), and vomiting (1.9%). The most frequently reported adverse reactions that led to discontinuation of PREVYMIS were: nausea (1.6%), vomiting (0.8%), and abdominal pain (0.5%).

In P040, 218 HSCT recipients received PREVYMIS or placebo from Week 14 (~100 days) through Week 28 (~200 days) post-HSCT and were followed for safety through Week 48 post-HSCT. The adverse reactions reported were consistent with the safety profile of PREVYMIS as characterised in study P001.

Kidney transplant
In P002, 292 kidney transplant recipients received PREVYMIS through Week 28 (~200 days) post-transplant.

Tabulated summary of adverse reactions
The following adverse reactions were identified in patients taking PREVYMIS in clinical trials. The adverse reactions are listed below by body system organ class and frequency. Frequencies are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000) or very rare (< 1/10,000).

Table 2: Adverse reactions identified with PREVYMIS

adverse reactions table

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

Please see PREVYMIS SmPC for full Prescribing Information, also available at www.ema.europa.eu.