ADVERSE REACTIONS
The following serious adverse events are discussed in greater detail in other sections of the labeling:
- Hematologic adverse events [see Boxed Warning, Warnings and Precautions].
- Acute renal failure [see Warnings and Precautions].
The most common adverse events and laboratory abnormalities reported in at least one indication by ≥ 20% of adult patients treated with Valcyte tablets are diarrhea, pyrexia, nausea, tremor, neutropenia, anemia, graft rejection, thrombocytopenia, and vomiting. The most common reported adverse events and laboratory abnormalities reported in > 10% of pediatric solid organ transplant recipients treated with Valcyte for oral solution or tablets are diarrhea, pyrexia, hypertension, upper respiratory tract infection, vomiting, anemia, neutropenia, constipation, nausea, and cough.
Clinical Trial Experience in Adult Patients
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.
Because clinical trials are conducted under widely varying conditions, adverse event 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 rates observed in practice.
Treatment of CMV Retinitis in AIDS Patients
: In a clinical study for the treatment of CMV retinitis in HIV-infected patients, the adverse events reported by patients receiving Valcyte tablets (n=79) or intravenous ganciclovir (n=79) for 28 days of randomized therapy (21 days induction dose and 7 days maintenance dose), respectively, included diarrhea (16%, 10%), nausea (8%, 14%), headache (9%, 5%), and catheter-related infections (3%, 11%). The incidence of adverse events was similar between the group who received Valcyte tablets and the group who received intravenous ganciclovir, with the exception of catheter-related infections, which occurred with greater frequency in patients randomized to receive intravenous ganciclovir. The frequencies of neutropenia (ANC < 500/µL) were 11% for patients receiving Valcyte tablets compared with 13% for patients receiving intravenous ganciclovir. Anemia (Hgb < 8 g/dL) occurred in 8% of patients in each group. Other laboratory abnormalities occurred with similar frequencies in the two groups.
Adverse events and abnormal laboratory values data are available for 370 patients who received maintenance therapy with Valcyte tablets 900 mg once daily in two open-label clinical trials. Approximately 252 (68%) of these patients received Valcyte tablets for more than nine months (maximum duration was 36 months).
Table 2
and
Table 3
show the pooled adverse event data and abnormal laboratory values from these patients.
Table 2 Pooled Selected Adverse Events Reported in ≥ 5% of Patients who Received Valcyte Tablets Maintenance Therapy for CMV Retinitis
|
Patients with CMV Retinitis |
| Adverse Events According to Body System |
Valcyte Tablets
(N=370)
% |
|
Gastrointestinal system
|
|
| Diarrhea |
41 |
| Nausea |
30 |
| Vomiting |
21 |
| Abdominal pain |
15 |
|
Body as a whole
|
|
| Pyrexia |
31 |
| Headache |
22 |
|
Central and peripheral nervous system
|
|
| Insomnia |
16 |
| Peripheral neuropathy |
9 |
| Paresthesia |
8 |
|
Special senses
|
|
| Retinal detachment |
15 |
Table 3 Pooled Laboratory Abnormalities Reported in Patients Who Received Valcyte Tablets Maintenance Therapy for the Treatment of CMV Retinitis
|
Patients with CMV Retinitis |
| Laboratory Abnormalities |
Valcyte Tablets
(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 4
shows selected adverse events regardless of severity and drug relationship with an incidence of ≥ 5% from a clinical trial (up to 28 days after study treatment) where heart, kidney, kidney-pancreas and liver transplant patients received Valcyte tablets (N=244) or oral ganciclovir (N=126) until Day 100 post-transplant. The majority of the adverse events were of mild or moderate intensity.
Table 4 Percentage of Selected Grades 1-4 Adverse Events Reported in ≥ 5% of Patients From a Study of Selected Solid Organ Transplant Patients
| Adverse Event |
Valcyte Tablets
(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 |
| Pyrexia |
13 |
14 |
The overall safety profile of Valcyte did not change with the extension of prophylaxis until Day 200 post-transplant in high risk kidney transplant patients (see
Table 5).
Table 5 Percentage of Selected Grades 1-4 Adverse Events Reported in ≥ 5% of Patients from a Study of Kidney Transplant Patients
| Adverse Event |
Valcyte Tablets Day 100 Post-transplant
(N=164)
% |
Valcyte Tablets Day 200 Post-transplant
(N=156)
% |
| Diarrhea |
26 |
31 |
| Tremors |
12 |
17 |
| Hypertension |
13 |
12 |
| Nausea |
11 |
11 |
| Pyrexia |
12 |
9 |
| Transplant rejection |
9 |
6 |
| Headache |
10 |
6 |
| Insomnia |
7 |
6 |
| Vomiting |
3 |
6 |
Adverse events not included in
Table 4
and
Table 5, which either occurred at a frequency of ≥ 5% in clinical studies with solid organ transplant patients, or were selected serious adverse events reported in studies with patients with CMV retinitis or in studies with solid organ transplant patients 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 two studies in solid organ transplant patients are listed in
Table 6
and
Table 7.
Table 6 Laboratory Abnormalities Reported in a Study of Selected Solid Organ Transplant PatientsLaboratory abnormalities are those reported by investigators.
| Laboratory Abnormalities |
Valcyte Tablets
(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 |
Table 7 Laboratory Abnormalities Reported in a Study of Kidney Transplant PatientsLaboratory abnormalities are those reported by investigators.
| Laboratory Abnormalities |
Valcyte Tablets Day 100 Post-transplant
(N=164)
% |
Valcyte Tablets Day 200 Post-transplant
(N=156)
% |
| Neutropenia: ANC/µL |
|
|
| < 500 |
9 |
10 |
| 500 – < 750 |
6 |
6 |
| 750 – < 1000 |
7 |
5 |
| Anemia: Hemoglobin g/dL |
|
|
| < 6.5 |
0 |
1 |
| 6.5 – < 8.0 |
5 |
1 |
| 8.0 – < 9.5 |
17 |
15 |
| Thrombocytopenia: Platelets/µL |
|
|
| < 25000 |
0 |
0 |
| 25000 – < 50000 |
1 |
0 |
| 50000 – < 100000 |
7 |
3 |
| Serum Creatinine: mg/dL |
|
|
| > 2.5 |
17 |
14 |
| > 1.5 – 2.5 |
50 |
48 |
Clinical Trial Experience in Pediatric Patients
Valcyte for oral solution and tablets have been studied in 109 pediatric solid organ transplant patients who were at risk for developing CMV disease (aged 4 months to 16 years) and in 24 neonates with symptomatic congenital CMV disease (aged 8 to 34 days), with duration of ganciclovir exposure ranging from 2 to 100 days. The overall safety profile was similar in pediatric patients as compared to adult patients. However, the rates of certain adverse events and laboratory abnormalities, such as upper respiratory tract infection, pyrexia, nasopharyngitis, anemia, and neutropenia, were reported more frequently in pediatric patients than in adults [see Use in Specific Populations, Clinical Studies].
Postmarketing Experience
In general, the adverse events reported during the postmarketing use of Valcyte were similar to those identified during the clinical trials and to those reported during the postmarketing use of ganciclovir. Please also refer to the intravenous ganciclovir product information and ganciclovir capsule product information for more information on postmarketing adverse events associated with ganciclovir.
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