August 30, 2015
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Valcyte

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Valcyte




Side Effects
Interactions

SIDE EFFECTS

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

The most common adverse events 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, nausea, tremor, neutropenia, anemia, graft rejection, thrombocytopenia, and vomiting. The most common reported adverse events 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, hypertension, 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 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.

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.

Adverse Events 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 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 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 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 3 and Table 4 show the pooled adverse event data and abnormal laboratory values from these patients.

Table 3 : Pooled Selected Adverse Events Reported in greater than or equal to 5% of Patients who Received VALCYTE Tablets Maintenance Therapy for CMV Retinitis

Adverse Events According to Body System Patients with CMV Retinitis
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 4 : Pooled 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 Selected Solid Organ Transplantation: Table 5 shows selected adverse events regardless of severity and drug relationship 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 events were of mild or moderate intensity.

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

Table 6 shows selected adverse events regardless of severity and drug relationship 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 post-transplant until Day 100 post-transplant followed by 100 days of placebo or valganciclovir once daily starting within 10 days post-transplant until Day 200 post-transplant. 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.

Table 6 : Percentage of Selected Grades 1-4 Adverse Events Reported in greater than or equal to 5% of Adult 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 5 and Table 6, which either occurred at a frequency of greater than or equal to 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 less than 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, febrile neutropenia

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 adult solid organ transplant patients are listed in Table 7 and Table 8.

Table 7 : 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 8 : 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.

Adverse Events 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 [see Use in Specific Populations, Clinical Studies].

Prevention of CMV Disease in Pediatric Solid Organ Transplant Patients: The most frequently reported adverse events (greater than 10% of patients), regardless of seriousness and drug relationship in pediatric solid organ transplant patients taking VALCYTE until Day 100 post-transplant were diarrhea, pyrexia, upper respiratory tract infection, hypertension, vomiting, anemia, neutropenia, constipation, nausea and transplant rejection. The most frequently reported adverse events (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, dysuria, tremor, pyrexia, hypertension, anemia, blood creatinine increase, vomiting, E. coli urinary tract infection 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 events 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 [see Use in Specific Populations, Clinical Studies]. Neutropenia was reported with 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 events 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 events associated with ganciclovir might also occur with valganciclovir.

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

Read the Valcyte (valganciclovir hcl) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

In vivo drug-drug interaction studies were not conducted with valganciclovir. However, because valganciclovir is rapidly and extensively converted to ganciclovir, drug-drug interactions associated with ganciclovir will be expected for VALCYTE. Established and other potentially significant drug interactions conducted with ganciclovir are listed in Table 9.

Table 9 : Established and Other Potentially Significant Drug Interactions with Ganciclovir

Name of the Concomitant Drug Change in the Concentration of Ganciclovir or Concomitant Drug Clinical Comment
Zidovudine ↓ Ganciclovir
↑ Zidovudine
Zidovudine and VALCYTE each have the potential to cause neutropenia and anemia
Probenecid ↑ Ganciclovir Patients taking probenecid and VALCYTE should be monitored for evidence of ganciclovir toxicity
Mycophenolate Mofetil (MMF) ↔ Ganciclovir (in patients with normal renal function)
↔ MMF (in patients with normal renal function)
Patients with renal impairment should be monitored carefully as levels of MMF metabolites and ganciclovir may increase
Didanosine ↓ Ganciclovir
↑ Didanosine
Patients should be closely monitored for didanosine toxicity

Read the Valcyte Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 5/13/2015
This monograph has been modified to include the generic and brand name in many instances.

Side Effects
Interactions

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