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Adverse events (AE) in hematopoietic stem cell transplantation (HSCT) patients

Safety profile through Week 14 (~100 days) post-HSCT in adults

Safety profile from Week 14 (~100 days) through Week 28 (~200 days) post-HSCT in adults

Safety profile in pediatric R+ recipients of an allogeneic HSCT

Safety profile through Week 14 (~100 days) post-HSCT in adults

Cardiac AEs

The cardiac AE rate was higher in subjects receiving PREVYMIS (13%) compared to subjects receiving placebo (6%). The most common cardiac AEs were tachycardia (reported in 4% of PREVYMIS subjects and in 2% of placebo subjects) and atrial fibrillation (reported in 3% of PREVYMIS subjects and in 1% of placebo subjects). Among those subjects who experienced 1 or more cardiac AEs, 85% of PREVYMIS and 92% of placebo subjects had events reported as mild or moderate in severity.

All grade AEs reported in ≥10% of patients treated with PREVYMIS at a frequency at least 2% greater than placebo

Drug-related renal and hepatic AEs1

Drug-Related Renal and Hepatic Adverse Events Reported in a Clinical Trial.

Rates of discontinuation due to AEs were comparable between PREVYMIS and placebo (13% vs 12%, respectively).

The median time to engraftment (defined as absolute neutrophil count ≥ 500/mm3 on 3 consecutive days after transplantation) was 19 days in the PREVYMIS group and 18 days in the placebo group.

Safety profile from Week 14 (~100 days) through Week 28 (~200 days) post-HSCT in adults

  • The most commonly reported adverse events with prophylaxis with PREVYMIS from Week 14 through Week 28 post-HSCT were similar to those reported with prophylaxis with PREVYMIS through Week 14 post-HSCT.
  • Study drug was discontinued due to an adverse event in 5% of PREVYMIS subjects and 1% of placebo subjects.
  • The cardiac adverse event rate was 4% in the PREVYMIS and placebo groups.
  • The rates of hematologic laboratory abnormalities were comparable in the PREVYMIS and placebo groups. Serum creatinine abnormalities >1.5 mg/dL occurred in 15% of PREVYMIS and 8% of placebo subjects.

Safety profile in pediatric recipients of an allogeneic HSCT

The safety of PREVYMIS was evaluated in 63 pediatric subjects aged 2 months to less than 18 years of age who received an allogeneic HSCT (P030). PREVYMIS was administered orally (tablet or pellet) or intravenously. The duration of PREVYMIS exposure ranged from 3 days to 102 days (median duration 84 days).

The safety profile in pediatric patients was consistent with the safety profile observed in clinical trials of PREVYMIS in adults.

PREVYMIS is indicated for pediatric recipients of an allogeneic HSCT aged 6 months and older and weighing at least 6 kg.

P030 Study Design

References

  1. Data available on request from the Merck National Service Center via email at daprequests@merck.com. Please specify information package US-CYT-01957.

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INDICATIONS

PREVYMIS® (letermovir) is indicated for prophylaxis of cytomegalovirus (CMV) infection and disease in adult and pediatric patients 6 months of age and older and weighing at least 6 kg who are CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT).

 

PREVYMIS is indicated for prophylaxis of CMV disease in adult and pediatric patients 12 years of age and older and weighing at least 40 kg who are kidney transplant recipients at high risk (Donor CMV seropositive/Recipient CMV seronegative [D+/R-]).

SELECTED SAFETY INFORMATION

  • PREVYMIS is contraindicated in patients receiving pimozide or ergot alkaloids.
      • Increased pimozide concentrations may lead to QT prolongation and torsades de pointes.
      • Increased ergot alkaloids concentrations may lead to ergotism.
  • PREVYMIS is contraindicated with pitavastatin and simvastatin when co-administered with cyclosporine. Significantly increased pitavastatin or simvastatin concentrations may lead to myopathy or rhabdomyolysis.
  • The concomitant use of PREVYMIS and certain drugs may result in potentially significant drug interactions, some of which may lead to adverse reactions (PREVYMIS or concomitant drugs) or reduced therapeutic effect of PREVYMIS or the concomitant drug.
  • Intravenous formulation of PREVYMIS contains the excipient hydroxypropyl betadex. PREVYMIS injection should be used only in patients unable to take oral therapy and 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.
  • In patients with renal impairment, accumulation of hydroxypropyl betadex may occur. 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, closely monitor serum creatinine levels.
  • Animal studies have shown the potential for hydroxypropyl betadex to cause ototoxicity. The active ingredient, letermovir, is not known to be associated with ototoxicity.
  • The rate of adverse events occurring in at least 10% of adult HSCT recipients treated with PREVYMIS and at a frequency at least 2% greater than placebo were nausea (27% vs 23%), diarrhea (26% vs 24%), vomiting (19% vs 14%), peripheral edema (14% vs 9%), cough (14% vs 10%), headache (14% vs 9%), fatigue (13% vs 11%), and abdominal pain (12% vs 9%).
  • Hypersensitivity reaction, with associated moderate dyspnea, occurred in one adult HSCT recipient following the first infusion of IV PREVYMIS after switching from oral PREVYMIS, leading to treatment discontinuation.
  • The most common adverse event occurring in at least 10% of adult kidney transplant recipients treated with PREVYMIS and at a frequency greater than valganciclovir was diarrhea (32% vs 29%).
  • The safety profile of PREVYMIS in pediatric subjects was consistent with the safety profile observed in clinical trials of PREVYMIS in adults.
  • If PREVYMIS is co-administered with cyclosporine, the dosage of PREVYMIS should be decreased to 240 mg once daily.
  • If PREVYMIS is co-administered with cyclosporine in pediatric HSCT patients less than 12 years of age, dose adjustment may be required.
  • Co-administration of PREVYMIS may alter the plasma concentrations of other drugs and other drugs may alter the plasma concentrations of PREVYMIS. Consult the full Prescribing Information prior to and during treatment for potential drug interactions.
  • Closely monitor serum creatinine levels in patients with CLcr less than 50 mL/min using PREVYMIS injection.
  • PREVYMIS is not recommended for patients with severe (Child-Pugh Class C) hepatic impairment.
  • 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.
  • For patients with creatinine clearance (CLcr) greater than 10 mL/min (by Cockcroft-Gault equation), no dosage adjustment of PREVYMIS is required based on renal impairment. The safety of PREVYMIS in patients with end-stage renal disease (CLcr less than 10 mL/min), including patients on dialysis, is unknown.

Before prescribing PREVYMIS® (letermovir), please read the accompanying Prescribing Information. The Patient Information and Instructions for Use also are available.

INDICATIONS
SELECTED SAFETY INFORMATION

PREVYMIS® (letermovir) is indicated for prophylaxis of cytomegalovirus (CMV) infection and disease in adult and pediatric patients 6 months of age and older and weighing at least 6 kg who are CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT).

 

PREVYMIS is indicated for prophylaxis of CMV disease in adult and pediatric patients 12 years of age and older and weighing at least 40 kg who are kidney transplant recipients at high risk (Donor CMV seropositive/Recipient CMV seronegative [D+/R-]).

SELECTED SAFETY INFORMATION

  • PREVYMIS is contraindicated in patients receiving pimozide or ergot alkaloids.
      • Increased pimozide concentrations may lead to QT prolongation and torsades de pointes.
      • Increased ergot alkaloids concentrations may lead to ergotism.
  • PREVYMIS is contraindicated with pitavastatin and simvastatin when co-administered with cyclosporine. Significantly increased pitavastatin or simvastatin concentrations may lead to myopathy or rhabdomyolysis.
  • The concomitant use of PREVYMIS and certain drugs may result in potentially significant drug interactions, some of which may lead to adverse reactions (PREVYMIS or concomitant drugs) or reduced therapeutic effect of PREVYMIS or the concomitant drug.
  • Intravenous formulation of PREVYMIS contains the excipient hydroxypropyl betadex. PREVYMIS injection should be used only in patients unable to take oral therapy and 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.
  • In patients with renal impairment, accumulation of hydroxypropyl betadex may occur. 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, closely monitor serum creatinine levels.
  • Animal studies have shown the potential for hydroxypropyl betadex to cause ototoxicity. The active ingredient, letermovir, is not known to be associated with ototoxicity.
  • The rate of adverse events occurring in at least 10% of adult HSCT recipients treated with PREVYMIS and at a frequency at least 2% greater than placebo were nausea (27% vs 23%), diarrhea (26% vs 24%), vomiting (19% vs 14%), peripheral edema (14% vs 9%), cough (14% vs 10%), headache (14% vs 9%), fatigue (13% vs 11%), and abdominal pain (12% vs 9%).
  • Hypersensitivity reaction, with associated moderate dyspnea, occurred in one adult HSCT recipient following the first infusion of IV PREVYMIS after switching from oral PREVYMIS, leading to treatment discontinuation.
  • The most common adverse event occurring in at least 10% of adult kidney transplant recipients treated with PREVYMIS and at a frequency greater than valganciclovir was diarrhea (32% vs 29%).
  • The safety profile of PREVYMIS in pediatric subjects was consistent with the safety profile observed in clinical trials of PREVYMIS in adults.
  • If PREVYMIS is co-administered with cyclosporine, the dosage of PREVYMIS should be decreased to 240 mg once daily.
  • If PREVYMIS is co-administered with cyclosporine in pediatric HSCT patients less than 12 years of age, dose adjustment may be required.
  • Co-administration of PREVYMIS may alter the plasma concentrations of other drugs and other drugs may alter the plasma concentrations of PREVYMIS. Consult the full Prescribing Information prior to and during treatment for potential drug interactions.
  • Closely monitor serum creatinine levels in patients with CLcr less than 50 mL/min using PREVYMIS injection.
  • PREVYMIS is not recommended for patients with severe (Child-Pugh Class C) hepatic impairment.
  • 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.
  • For patients with creatinine clearance (CLcr) greater than 10 mL/min (by Cockcroft-Gault equation), no dosage adjustment of PREVYMIS is required based on renal impairment. The safety of PREVYMIS in patients with end-stage renal disease (CLcr less than 10 mL/min), including patients on dialysis, is unknown.

Before prescribing PREVYMIS® (letermovir), please read the accompanying Prescribing Information. The Patient Information and Instructions for Use also are available.