VALCYTE SIDE EFFECTS

SIDE EFFECTS

The following serious adverse reactions are discussed in greater detail in other sections of the labeling:

• Hematologic Toxicity
• Acute Renal Failure
• Impairment of Fertility
• Fetal Toxicity
• Mutagenesis and Carcinogenesis

The most common adverse reactions and laboratory abnormalities reported in at least one indication by greater than or equal to 20% of adult patients treated with VALCYTE tablets are diarrhea, pyrexia, fatigue, nausea, tremor, neutropenia, anemia, leukopenia, thrombocytopenia, headache, insomnia, urinary tract infection, and vomiting. The most common reported adverse reactions and laboratory abnormalities reported in greater than or equal to 20% of pediatric solid organ transplant recipients treated with VALCYTE for oral solution or tablets are diarrhea, pyrexia, upper respiratory tract infection, urinary tract infection, vomiting, neutropenia, leukopenia, and headache.

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 rates observed in practice.

Valganciclovir, a prodrug of ganciclovir, is rapidly converted to ganciclovir after oral administration. Adverse reactions known to be associated with ganciclovir usage can therefore be expected to occur with VALCYTE.

Adverse Reactions In Adults

Treatment Of CMV Retinitis In AIDS Patients

In a clinical study for the treatment of CMV retinitis in HIV-infected patients, the adverse reactions 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%), and headache (9%, 5%). The incidence of adverse reactions was similar between the group who received VALCYTE tablets and the group who received intravenous ganciclovir. The frequencies of neutropenia (ANC less than 500/μL) were 11% for patients receiving VALCYTE tablets compared with 13% for patients receiving intravenous ganciclovir. Anemia (Hgb less than 8 g/dL) occurred in 8% of patients in each group. Other laboratory abnormalities occurred with similar frequencies in the two groups.

Adverse reactions and laboratory abnormalities 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 1 and Table 2 show pooled selected adverse reactions and abnormal laboratory values from these patients.

Table 1 : Pooled Selected Adverse Reactions Reported in greater than or equal to 5% of Patients who Received VALCYTE Tablets Maintenance Therapy for CMV Retinitis

Adverse Reactions according to Body System	Patients with CMV Retinitis
	VALCYTE Tablets (N=370) %
Gastrointestinal system
Diarrhea	41
Nausea	30
Vomiting	21
Abdominal pain	15
General disorders and administrative site conditions
Pyrexia	31
Nervous system disorders
Headache	22
Insomnia	16
Neuropathy peripheral	9
Paresthesia	8
Eye disorders
Retinal detachment	15

 

Table 2 : Pooled Selected Laboratory Abnormalities Reported in Patients Who Received VALCYTE Tablets Maintenance Therapy for the Treatment of CMV Retinitis

Laboratory Abnormalities	Patients with CMV Retinitis
	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 Solid Organ Transplant Patients

Table 3 shows selected adverse reactions regardless of severity with an incidence of greater than or equal to 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 reactions were of mild or moderate intensity.

Table 3 : Percentage of Selected Grades 1-4 Adverse Reactions Reported in greater than or equal to 5% of Adult Patients From a Study of Solid Organ Transplant Patients

Adverse Reactions	VALCYTE Tablets (N=244) %	Oral Ganciclovir (N=126) %
Gastrointestinal disorders
Diarrhea	30	29
Nausea	23	23
Vomiting	16	14
Nervous system disorders
Tremors	28	25
Headache	22	27
Insomnia	20	16
General disorders and administration site conditions
Pyrexia	13	14

 

Table 6 shows selected adverse reactions regardless of severity with an incidence of greater than or equal to 5% from another clinical trial where kidney transplant patients received either valganciclovir once daily starting within 10 days posttransplant until Day 100 post-transplant followed by 100 days of placebo or valganciclovir once daily until Day 200 posttransplant. The overall safety profile of VALCYTE did not change with the extension of prophylaxis until Day 200 posttransplant in high risk kidney transplant patients.

Table 4 : Percentage of Selected Grades 1-4 Adverse Reactions Reported in greater than or equal to 5% of Adult Patients from a Study of Kidney Transplant Patients

Adverse Reactions	VALCYTE Tablets Day 100 Post-transplant (N=164) %	VALCYTE Tablets Day 200 Post-transplant (N=156) %
Gastrointestinal disorders
Diarrhea	26	31
Nausea	11	11
Vomiting	3	6
Nervous system disorders
Tremors	12	17
Headache	10	6
Insomnia	7	6
General disorders and administration site conditions
Pyrexia	12	9

 

Table 5 and Table 6 show selected laboratory abnormalities reported with VALCYTE tablets in two trials in solid organ transplant patients.

Table 5 : Selected Laboratory Abnormalities Reported in a Study of Adult Solid Organ Transplant Patients*

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
*Laboratory abnormalities are those reported by investigators.

 

Table 6 : Selected Laboratory Abnormalities Reported in a Study of Adult Kidney Transplant Patients*

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
*Laboratory abnormalities are those reported by investigators.

 

Other adverse drug reactions from VALCYTE in clinical trials in CMV retinitis and solid organ transplant patients

Other adverse drug reactions with VALCYTE in clinical trials in either patients with CMV retinitis or solid organ transplant patients that occurred in at least 5% of patients are listed below.

Eye disorders: retinal detachment, eye pain

Gastrointestinal disorders: dyspepsia, constipation, abdominal distention, mouth ulceration

General disorders and administration site conditions: fatigue, pain, malaise, asthenia, chills, peripheral edema

Hepatobiliary disorders: hepatic function abnormal

Infections and infestations: candida infections including oral candidiasis, upper respiratory tract infection, influenza, urinary tract infection, pharyngitis/nasopharyngitis, postoperative wound infection

Injury, poisoning, and procedural complications: postoperative complications, wound secretion

Metabolic and nutrition disorders: decreased appetite, hyperkalemia, hypophosphatemia, weight decreased

Musculoskeletal and connective tissue disorders: back pain, myalgia, arthralgia, muscle spasms

Nervous system disorders: insomnia, neuropathy peripheral, dizziness

Psychiatric disorders: depression, anxiety

Renal and urinary disorders: renal impairment, creatinine clearance renal decreased, blood creatinine increased, hematuria

Respiratory, thoracic and mediastinal disorders: cough, dyspnea

Skin and subcutaneous tissues disorders: dermatitis, night sweats, pruritus

Vascular disorders: hypotension

Other adverse reactions with VALCYTE in clinical trials in either patients with CMV retinitis or solid organ transplant patients that occurred in less than 5% of patients are listed below.

Blood and lymphatic disorders: febrile neutropenia, pancytopenia, bone marrow failure (including aplastic anemia)

Cardiovascular disorders: arrhythmia

Ear and labyrinth disorders: deafness

Eye disorders: macular edema

Gastrointestinal disorders: pancreatitis

Hemorrhage: potentially life-threatening bleeding associated with thrombocytopenia

Immune system disorders: hypersensitivity

Infections and infestations: cellulitis, sepsis

Injury, poisoning, and procedural complications: postoperative pain, wound dehiscence Investigations: aspartate aminotransferase increased, alanine aminotransferase increased

Musculoskeletal and connective tissue disorders: limb pain

Nervous system disorders: seizure, dysguesia (taste disturbance)

Psychiatric disorders: confusional state, agitation, psychotic disorder, hallucinations

Renal and urinary disorders: renal failure

Adverse Reactions In Pediatric Patients

VALCYTE for oral solution and tablets have been studied in 179 pediatric solid organ transplant patients who were at risk for developing CMV disease (aged 3 weeks 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 200 days.

Prevention Of CMV Disease In Pediatric Solid Organ Transplant Patients

The most frequently reported adverse reactions (greater than 10% of patients), regardless of seriousness, in pediatric solid organ transplant patients taking VALCYTE until Day 100 post-transplant were diarrhea, pyrexia, upper respiratory tract infection, vomiting, anemia, neutropenia, constipation and nausea. The most frequently reported adverse reactions (greater than 10% of patients) in pediatric kidney transplant patients treated with valganciclovir until Day 200 post-transplant were upper respiratory tract infection, urinary tract infection, diarrhea, leukopenia, neutropenia, headache, abdominal pain, tremor, pyrexia, anemia, blood creatinine increased, vomiting, and hematuria.

In general, the safety profile was similar in pediatric patients compared to that observed in adult patients. However, the rates of certain adverse reactions, and laboratory abnormalities, such as upper respiratory tract infection, pyrexia, nasopharyngitis, anemia, and abdominal pain were reported more frequently in pediatric patients than in adults. Neutropenia was reported at a higher incidence in the two pediatric studies as compared to adults, but there was no correlation between neutropenia and infections observed in the pediatric population.

The overall safety profile of VALCYTE was similar with the extension of prophylaxis until Day 200 post-transplant in high risk pediatric kidney transplant patients. However, the incidence of severe neutropenia (ANC < 500/μL) was higher in pediatric kidney transplant patients treated with VALCYTE until Day 200 (17/57, 30%) compared to pediatric kidney transplant patients treated until Day 100 (3/63, 5%). There were no differences in the incidence of severe (Grade 4) anemia or thrombocytopenia in patients treated 100 or 200 days with VALCYTE.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of VALCYTE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. As VALCYTE is rapidly and extensively converted to ganciclovir, any adverse reactions associated with ganciclovir might also occur with valganciclovir.

• Anaphylactic reaction
• Agranulocytosis
• Granulocytopenia

In general, the adverse reactions reported during the postmarketing use of VALCYTE were similar to those identified during the clinical trials.

 

SRC: NLM .