ADVERSE EVENTS
Experience With Valcyte Tablets
Valganciclovir, a prodrug of ganciclovir, is rapidly converted to ganciclovir after oral administration. Adverse events known to be associated with ganciclovir usage can therefore be expected to occur with Valcyte tablets.
Treatment of CMV Retinitis in AIDS Patients
As shown in Table 8, the safety profiles of Valcyte tablets and intravenous ganciclovir during 28 days of randomized therapy (21 days induction dose and 7 days maintenance dose) in 158 patients were comparable, with the exception of catheter-related infection, which occurred with greater frequency in patients randomized to receive IV ganciclovir.
Table 8 Percentage of Selected Adverse Events Occurring During the Randomized Phase of Study WV15376 | Adverse Event | Valcyte Arm
N=79 | Intravenous Ganciclovir Arm
N=79 |
|---|
| Diarrhea | 16% | 10% |
| Neutropenia | 11% | 13% |
| Nausea | 8% | 14% |
| Headache | 9% | 5% |
| Anemia | 8% | 8% |
| Catheter-related infection | 3% | 11% |
Tables 9 and 10 show the pooled adverse event data and abnormal laboratory values from two single arm, open-label clinical trials, WV15376 and WV15705. A total of 370 patients received maintenance therapy with Valcyte tablets 900 mg once daily. Approximately 252 (68%) of these patients received Valcyte tablets for more than nine months (maximum duration was 36 months).
Table 9 Pooled Selected Adverse Events Reported in ≥5% of Patients in Two Clinical Studies in CMV Retinitis | Patients with CMV Retinitis (Studies WV15376 and WV15705) |
|---|
| Adverse Events According to Body System | Valcyte
(N=370)
% |
|---|
| Gastrointestinal system | |
| Diarrhea | 41 |
| Nausea | 30 |
| Vomiting | 21 |
| Abdominal pain | 15 |
| Body as a whole | |
| Pyrexia | 31 |
| Headache | 22 |
| Hemic and lymphatic system | |
| Neutropenia | 27 |
| Anemia | 26 |
| Thrombocytopenia | 6 |
| Central and peripheral nervous system | |
| Insomnia | 16 |
| Peripheral neuropathy | 9 |
| Paresthesia | 8 |
| Special senses | |
| Retinal detachment | 15 |
Table 10 Pooled Laboratory Abnormalities Reported in Two Clinical Studies in the Treatment of CMV Retinitis | CMV Retinitis Patients (Studies WV15376 and WV15705) |
|---|
| Laboratory Abnormalities | Valcyte
(N=370)
% |
|---|
| Neutropenia: ANC/µL | |
| <500 | 19 |
| 500 –<750 | 17 |
| 750 –<1000 | 17 |
| Anemia: Hemoglobin g/dL | |
| <6.5 | 7 |
| 6.5 –<8.0 | 13 |
| 8.0 –<9.5 | 16 |
| Thrombocytopenia: Platelets/µL | |
| <25000 | 4 |
| 25000 –<50000 | 6 |
| 50000 –<100000 | 22 |
| Serum Creatinine: mg/dL | |
| >2.5 | 3 |
| >1.5 – 2.5 | 12 |
Prevention of CMV Disease in Selected Solid Organ Transplantation
Table 11 shows selected adverse events regardless of severity and drug relationship with an incidence of ≥5% from a clinical trial, PV16000 (up to 28 days after study treatment) where heart, kidney, kidney-pancreas and liver transplant patients received Valcyte (N=244) or oral ganciclovir (N=126). The majority of the adverse events were of mild or moderate intensity.
Table 11 Percentage of Selected Grades 1-4 Adverse Events Reported in ≥5% of Selected Solid Organ Transplant Patients in Study PV16000 | Adverse Event | Valcyte
(N=244)
% | Oral Ganciclovir
(N=126)
% |
|---|
| Diarrhea | 30 | 29 |
| Tremors | 28 | 25 |
| Graft rejection | 24 | 30 |
| Nausea | 23 | 23 |
| Headache | 22 | 27 |
| Insomnia | 20 | 16 |
| Hypertension | 18 | 15 |
| Vomiting | 16 | 14 |
| Leukopenia | 14 | 7 |
| Pyrexia | 13 | 14 |
Laboratory adverse events are those reported by investigators.
Adverse events not included in Table 11, which either occurred at a frequency of ≥5% in clinical study PV16000, or were selected serious adverse events reported in studies WV15376, WV15705, or PV16000 with a frequency of<5% are listed below.
Allergic reactions: valganciclovir hypersensitivity
Bleeding complications: potentially life-threatening bleeding associated with thrombocytopenia
Central and peripheral nervous system: paresthesia, dizziness (excluding vertigo), convulsion
Gastrointestinal disorders: abdominal pain, constipation, dyspepsia, abdominal distention, ascites
General disorders and administration site disorders: fatigue, pain, edema, peripheral edema, weakness
Hemic system: anemia, neutropenia, thrombocytopenia, pancytopenia, bone marrow depression, aplastic anemia
Hepatobiliary disorders: abnormal hepatic function
Infections and infestations: pharyngitis/nasopharyngitis, upper respiratory tract infection, urinary tract infection, local and systemic infections and sepsis, postoperative wound infection
Injury, poisoning and procedural complications: postoperative complications, postoperative pain, increased wound drainage, wound dehiscence
Metabolism and nutrition disorders: hyperkalemia, hypokalemia, hypomagnesemia, hyperglycemia, appetite decreased, dehydration, hypophosphatemia, hypocalcemia
Musculoskeletal and connective tissue disorders: back pain, arthralgia, muscle cramps, limb pain
Psychiatric disorders: depression, psychosis, hallucinations, confusion, agitation
Renal and urinary disorders: renal impairment, dysuria, decreased creatinine clearance
Respiratory, thoracic and mediastinal disorders: cough, dyspnea, rhinorrhea, pleural effusion
Skin and subcutaneous tissue disorders: dermatitis, pruritus, acne
Vascular disorders: hypotension
Laboratory abnormalities reported with Valcyte tablets in one study in solid organ transplant patients are listed in Table 12.
Table 12 Laboratory Abnormalities Reported in Selected Solid Organ Transplant Patients in Study PV16000 | Laboratory Abnormalities | Valcyte
(N=244)
% | Ganciclovir Capsules
(N=126)
% |
|---|
| Neutropenia: ANC/µL | | |
| <500 | 5 | 3 |
| 500 –<750 | 3 | 2 |
| 750 –<1000 | 5 | 2 |
| Anemia: Hemoglobin g/dL | | |
| <6.5 | 1 | 2 |
| 6.5 –<8.0 | 5 | 7 |
| 8.0 –<9.5 | 31 | 25 |
| Thrombocytopenia: Platelets/µL | | |
| <25000 | 0 | 2 |
| 25000 –<50000 | 1 | 3 |
| 50000 –<100000 | 18 | 21 |
| Serum Creatinine: mg/dL | | |
| >2.5 | 14 | 21 |
| >1.5 – 2.5 | 45 | 47 |
Experience With Ganciclovir
Valganciclovir is rapidly converted to ganciclovir upon oral administration. Adverse events reported with Valcyte in general were similar to those reported with ganciclovir. Please refer to the Cytovene-IV product information and ganciclovir capsule product information for more information on postmarketing adverse events associated with ganciclovir.
|
