PREVYMIS
Generic: LETERMOVIR
Basic Information
Manufacturer
Merck Sharp & Dohme LLC
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
ORAL
FDA Set ID
1b49df80-be4f-47e0-a0b7-123f3e69395b
Indications & Usage
1 INDICATIONS AND USAGE PREVYMIS is a CMV DNA terminase complex inhibitor 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).
( 1.1 ) 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-]).
( 1.2 ) 1.1 CMV Prophylaxis in Hematopoietic Stem Cell Transplant (HSCT) Recipients PREVYMIS ® 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).
1.2 CMV Prophylaxis in Kidney Transplant Recipients 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-]).
( 1.1 ) 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-]).
( 1.2 ) 1.1 CMV Prophylaxis in Hematopoietic Stem Cell Transplant (HSCT) Recipients PREVYMIS ® 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).
1.2 CMV Prophylaxis in Kidney Transplant Recipients 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-]).
Adverse Reactions
6 ADVERSE REACTIONS Adult HSCT Patients: Most common adverse events (occurring in at least 10% of subjects in the PREVYMIS group and at a frequency at least 2% greater than placebo) are nausea, diarrhea, vomiting, peripheral edema, cough, headache, fatigue, and abdominal pain.
( 6.1 ) Adult Kidney Transplant Patients: Most common adverse event (occurring in at least 10% of subjects in the PREVYMIS group and at a frequency greater than valganciclovir) is diarrhea.
( 6.1 ) Pediatric Patients: Adverse events in pediatric patients are similar to adults.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme LLC at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adult CMV-seropositive Recipients [R+] of an Allogeneic HSCT Prophylaxis Through Week 14 (~100 days) Post-HSCT The safety of PREVYMIS was evaluated in a Phase 3 randomized, double-blind, placebo-controlled trial (P001) in which 565 subjects were randomized and treated with PREVYMIS (N=373) or placebo (N=192) through Week 14 post-HSCT.
Adverse events were those reported while subjects were on study medication or within two weeks of study medication completion/discontinuation.
The mean time for reporting adverse events and laboratory abnormalities was approximately 22% longer in the PREVYMIS arm compared to the placebo arm.
Cardiac Adverse Events The cardiac adverse event rate was higher in subjects receiving PREVYMIS (13%) compared to subjects receiving placebo (6%).
The most common cardiac adverse events 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 one or more cardiac adverse events, 85% of PREVYMIS and 92% of placebo subjects had events reported as mild or moderate in severity.
Common Adverse Events The rate of adverse events occurring in at least 10% of subjects in the PREVYMIS group and at a frequency at least 2% greater than placebo are outlined in Table 8.
Table 8: Trial P001 All Grade Adverse Events Reported in ≥ 10% of PREVYMIS-Treated HSCT Recipients at a Frequency at least 2% Greater than Placebo Adverse Events PREVYMIS (N=373) Placebo (N=192) nausea 27% 23% diarrhea 26% 24% vomiting 19% 14% peripheral edema 14% 9% cough 14% 10% headache 14% 9% fatigue 13% 11% abdominal pain 12% 9% Overall, similar proportions of subjects in each group discontinued study medication due to an adverse event (13% of PREVYMIS subjects vs.
12% of placebo subjects).
The most frequently reported adverse event that led to study drug discontinuation was nausea, occurring in 2% of PREVYMIS subjects and 1% of placebo subjects.
Hypersensitivity reaction, with associated moderate dyspnea, occurred in one subject following the first infusion of IV PREVYMIS after switching from oral PREVYMIS, leading to treatment discontinuation.
Laboratory Abnormalities Selected laboratory abnormalities reported during treatment or within 2 weeks of stopping treatment are presented in Table 9.
Table 9: Trial P001 Selected Laboratory Abnormalities PREVYMIS N=373 Placebo N=192 Absolute neutrophil count (cells/μL) < 500 19% 19% 500 – < 750 4% 7% 750 – < 1000 8% 9% Hemoglobin (g/dL) < 6.5 2% 1% 6.5 – < 8.0 14% 15% 8.0 – < 9.5 41% 43% Platelets (cells/μL) < 25000 27% 21% 25000 – < 50000 17% 18% 50000 – < 100000 20% 30% Serum creatinine (mg/dL) > 2.5 2% 3% > 1.5 – 2.5 17% 20% The median time to engraftment (defined as absolute neutrophil count ≥ 500/mm 3 on 3 consecutive days after transplantation) was 19 days in the PREVYMIS group and 18 days in the placebo group.
Prophylaxis From Week 14 (~100 days) Through Week 28 (~200 days) Post-HSCT The safety of PREVYMIS was evaluated in a Phase 3 randomized, double-blind, placebo-controlled trial (P040) in which 218 subjects who completed PREVYMIS prophylaxis through ~100 days post-HSCT were randomized to treatment with PREVYMIS (N=144) or placebo (N=74) through Week 28 (~200 days) post-HSCT.
Adverse events were those reported while subjects were on study drug or within two weeks of study drug completion/discontinuation.
The most commonly reported adverse events in P040 were similar to those reported in P001.
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.
Adult Kidney Transplant Recipients [D+/R-] The safety of PREVYMIS was evaluated in a Phase 3 randomized, double-blind, active comparator-controlled trial (P002) in which 589 subjects were treated with PREVYMIS (N=292) or valganciclovir (N=297) through Week 28 post-transplant.
Adverse events were those reported while subjects were on study medication or within two weeks of study medication completion/discontinuation.
In these subjects, diarrhea was reported in at least 10% of subjects in the PREVYMIS group and at a frequency greater than valganciclovir (PREVYMIS, 32%; valganciclovir, 29%).
Study drug was discontinued due to an adverse event in 4% of PREVYMIS subjects and 14% of valganciclovir subjects.
The most frequently reported adverse events that led to study drug discontinuation were neutropenia (PREVYMIS, 1%; valganciclovir, 2%) and leukopenia (PREVYMIS, 1%; valganciclovir, 5%).
Laboratory Abnormalities Selected laboratory abnormalities reported through Week 28 post-transplant are presented in Table 10.
Table 10: Trial P002 Selected Laboratory Abnormalities PREVYMIS N=292 Valganciclovir N=297 Absolute neutrophil count (cells/μL) < 500 2% 7% 500 – < 750 1% 4% 750 – < 1000 1% 8% Total < 1000 5% 18% Hemoglobin (g/dL) < 6.5 2% 0% 6.5 – < 8.0 4% 5% 8.0 – < 9.5 29% 32% Total < 9.5 34% 37% Platelets (cells/μL) < 50000 0% 0% 50000 – < 100000 1% 3% Total < 100000 1% 3% Leukocytes (cells/μL) < 1000 1% 2% 1000 – < 2000 5% 19% 2000 – < 2500 4% 14% Total < 2500 10% 35% Serum creatinine (mg/dL) > 2.5 24% 22% > 1.5 – 2.5 49% 52% Total > 1.5 73% 73% 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 was consistent with the safety profile observed in clinical trials of PREVYMIS in adults [see Use in Specific Populations (8.4) and Clinical Studies (14.4) ].
( 6.1 ) Adult Kidney Transplant Patients: Most common adverse event (occurring in at least 10% of subjects in the PREVYMIS group and at a frequency greater than valganciclovir) is diarrhea.
( 6.1 ) Pediatric Patients: Adverse events in pediatric patients are similar to adults.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme LLC at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adult CMV-seropositive Recipients [R+] of an Allogeneic HSCT Prophylaxis Through Week 14 (~100 days) Post-HSCT The safety of PREVYMIS was evaluated in a Phase 3 randomized, double-blind, placebo-controlled trial (P001) in which 565 subjects were randomized and treated with PREVYMIS (N=373) or placebo (N=192) through Week 14 post-HSCT.
Adverse events were those reported while subjects were on study medication or within two weeks of study medication completion/discontinuation.
The mean time for reporting adverse events and laboratory abnormalities was approximately 22% longer in the PREVYMIS arm compared to the placebo arm.
Cardiac Adverse Events The cardiac adverse event rate was higher in subjects receiving PREVYMIS (13%) compared to subjects receiving placebo (6%).
The most common cardiac adverse events 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 one or more cardiac adverse events, 85% of PREVYMIS and 92% of placebo subjects had events reported as mild or moderate in severity.
Common Adverse Events The rate of adverse events occurring in at least 10% of subjects in the PREVYMIS group and at a frequency at least 2% greater than placebo are outlined in Table 8.
Table 8: Trial P001 All Grade Adverse Events Reported in ≥ 10% of PREVYMIS-Treated HSCT Recipients at a Frequency at least 2% Greater than Placebo Adverse Events PREVYMIS (N=373) Placebo (N=192) nausea 27% 23% diarrhea 26% 24% vomiting 19% 14% peripheral edema 14% 9% cough 14% 10% headache 14% 9% fatigue 13% 11% abdominal pain 12% 9% Overall, similar proportions of subjects in each group discontinued study medication due to an adverse event (13% of PREVYMIS subjects vs.
12% of placebo subjects).
The most frequently reported adverse event that led to study drug discontinuation was nausea, occurring in 2% of PREVYMIS subjects and 1% of placebo subjects.
Hypersensitivity reaction, with associated moderate dyspnea, occurred in one subject following the first infusion of IV PREVYMIS after switching from oral PREVYMIS, leading to treatment discontinuation.
Laboratory Abnormalities Selected laboratory abnormalities reported during treatment or within 2 weeks of stopping treatment are presented in Table 9.
Table 9: Trial P001 Selected Laboratory Abnormalities PREVYMIS N=373 Placebo N=192 Absolute neutrophil count (cells/μL) < 500 19% 19% 500 – < 750 4% 7% 750 – < 1000 8% 9% Hemoglobin (g/dL) < 6.5 2% 1% 6.5 – < 8.0 14% 15% 8.0 – < 9.5 41% 43% Platelets (cells/μL) < 25000 27% 21% 25000 – < 50000 17% 18% 50000 – < 100000 20% 30% Serum creatinine (mg/dL) > 2.5 2% 3% > 1.5 – 2.5 17% 20% The median time to engraftment (defined as absolute neutrophil count ≥ 500/mm 3 on 3 consecutive days after transplantation) was 19 days in the PREVYMIS group and 18 days in the placebo group.
Prophylaxis From Week 14 (~100 days) Through Week 28 (~200 days) Post-HSCT The safety of PREVYMIS was evaluated in a Phase 3 randomized, double-blind, placebo-controlled trial (P040) in which 218 subjects who completed PREVYMIS prophylaxis through ~100 days post-HSCT were randomized to treatment with PREVYMIS (N=144) or placebo (N=74) through Week 28 (~200 days) post-HSCT.
Adverse events were those reported while subjects were on study drug or within two weeks of study drug completion/discontinuation.
The most commonly reported adverse events in P040 were similar to those reported in P001.
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.
Adult Kidney Transplant Recipients [D+/R-] The safety of PREVYMIS was evaluated in a Phase 3 randomized, double-blind, active comparator-controlled trial (P002) in which 589 subjects were treated with PREVYMIS (N=292) or valganciclovir (N=297) through Week 28 post-transplant.
Adverse events were those reported while subjects were on study medication or within two weeks of study medication completion/discontinuation.
In these subjects, diarrhea was reported in at least 10% of subjects in the PREVYMIS group and at a frequency greater than valganciclovir (PREVYMIS, 32%; valganciclovir, 29%).
Study drug was discontinued due to an adverse event in 4% of PREVYMIS subjects and 14% of valganciclovir subjects.
The most frequently reported adverse events that led to study drug discontinuation were neutropenia (PREVYMIS, 1%; valganciclovir, 2%) and leukopenia (PREVYMIS, 1%; valganciclovir, 5%).
Laboratory Abnormalities Selected laboratory abnormalities reported through Week 28 post-transplant are presented in Table 10.
Table 10: Trial P002 Selected Laboratory Abnormalities PREVYMIS N=292 Valganciclovir N=297 Absolute neutrophil count (cells/μL) < 500 2% 7% 500 – < 750 1% 4% 750 – < 1000 1% 8% Total < 1000 5% 18% Hemoglobin (g/dL) < 6.5 2% 0% 6.5 – < 8.0 4% 5% 8.0 – < 9.5 29% 32% Total < 9.5 34% 37% Platelets (cells/μL) < 50000 0% 0% 50000 – < 100000 1% 3% Total < 100000 1% 3% Leukocytes (cells/μL) < 1000 1% 2% 1000 – < 2000 5% 19% 2000 – < 2500 4% 14% Total < 2500 10% 35% Serum creatinine (mg/dL) > 2.5 24% 22% > 1.5 – 2.5 49% 52% Total > 1.5 73% 73% 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 was consistent with the safety profile observed in clinical trials of PREVYMIS in adults [see Use in Specific Populations (8.4) and Clinical Studies (14.4) ].