Valganciclovir (Page 2 of 9)

2.6 Handling and Disposal

Caution should be exercised in the handling of valganciclovir tablets USP. Tablets should not be broken or crushed. Because valganciclovir is considered a potential teratogen and carcinogen in humans, caution should be observed in handling broken tablets, [see Warnings and Precautions ( 5.4, 5.5) ]. Avoid direct contact with broken or crushed tablets with skin or mucous membranes. If such contact occurs, wash thoroughly with soap and water, and rinse eyes thoroughly with plain water.

Handle and dispose valganciclovir tablets according to guidelines for antineoplastic drugs because ganciclovir shares some of the properties of antitumor agents (i.e., carcinogenicity and mutagenicity) 2.

3 DOSAGE FORMS AND STRENGTHS

Valganciclovir tablets, 450 mg are pink colored, oval shaped, film coated tablets debossed with ‘RDY’ on one side and ‘762’ on other side.

4 CONTRAINDICATIONS

Valganciclovir is contraindicated in patients who have had a demonstrated clinically significant hypersensitivity reaction (e.g., anaphylaxis) to valganciclovir, ganciclovir, or any component of the formulation [see Adverse Reactions (6.1)].

5 WARNINGS AND PRECAUTIONS

5.1 Hematologic Toxicity

Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, and bone marrow failure including aplastic anemia have been reported in patients treated with valganciclovir or ganciclovir. Valganciclovir should be avoided if the absolute neutrophil count is less than 500 cells/μL, the platelet count is less than 25,000/μL, or the hemoglobin is less than 8 g/dL. Valganciclovir should also be used with caution in patients with pre-existing cytopenias and in patients receiving myelosuppressive drugs or irradiation. Cytopenia may occur at any time during treatment and may worsen with continued dosing. Cell counts usually begin to recover within 3 to 7 days after discontinuing drug. In patients with severe leukopenia, neutropenia, anemia and/or thrombocytopenia, treatment with hematopoietic growth factors may be considered.

Due to the frequency of neutropenia, anemia, and thrombocytopenia in patients receiving valganciclovir [see Adverse Reactions (6.1)], complete blood counts with differential and platelet counts should be performed frequently, especially in infants, in patients with renal impairment and in patients in whom ganciclovir or other nucleoside analogues have previously resulted in leukopenia, or in whom neutrophil counts are less than 1000 cells/μL at the beginning of treatment. Increased monitoring for cytopenias may be warranted if therapy with oral ganciclovir is changed to valganciclovir, because of increased plasma concentrations of ganciclovir after valganciclovir administration [see Clinical Pharmacology (12.3)].

5.2 Acute Renal Failure

Acute renal failure may occur in:

  • Elderly patients with or without reduced renal function. Caution should be exercised when administering valganciclovir to geriatric patients, and dosage reduction is recommended for those with impaired renal function [see Dosage and Administration (2.5), Use in Specific Populations ( 8.5, 8.6) ].
  • Patients receiving potential nephrotoxic drugs. Caution should be exercised when administering valganciclovir to patients receiving potential nephrotoxic drugs.
  • Patients without adequate hydration. Adequate hydration should be maintained for all patients.

5.3 Impairment of Fertility

Based on animal data and limited human data, with ganciclovir, valganciclovir at the recommended human doses may cause temporary or permanent inhibition of spermatogenesis in males, and may cause suppression of fertility in females. Advise patients that fertility may be impaired with use of valganciclovir [see Use in Specific Populations ( 8.1, 8.3), Nonclinical Toxicology ( 13.1) ].

5.4 Fetal Toxicity

Ganciclovir may cause fetal toxicity when administered to pregnant women based on findings in animal studies. When given to pregnant rabbits at dosages resulting in 2-times the human exposure (based on AUC), ganciclovir caused malformations in multiple organs of the fetuses. Maternal and fetal toxicity were also observed in pregnant mice and rabbits. Therefore, valganciclovir has the potential to cause birth defects. Pregnancy should be avoided in female patients taking valganciclovir and in females with male partners taking valganciclovir. Females of reproductive potential should be advised to use effective contraception during treatment and for at least 30 days following treatment with valganciclovir because of the potential risk to the fetus. Similarly, males should be advised to use condoms during and for at least 90 days following treatment with valganciclovir [see Dosage and Administration (2.6), Use in Specific Populations ( 8.1, 8.3), Nonclinical Toxicology ( 13.1) ].

5.5 Mutagenesis and Carcinogenesis

Animal data indicate that ganciclovir is mutagenic and carcinogenic. Valganciclovir should therefore be considered a potential carcinogen in humans [see Dosage and Administration ( 2.6), Nonclinical Toxicology ( 13.1) ].

6 ADVERSE REACTIONS

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

  • Hematologic Toxicity [see Warnings and Precautions ( 5.1) ].
  • Acute Renal Failure [see Warnings and Precautions ( 5.2) ].
  • Impairment of Fertility [see Warnings and Precautions ( 5.3) ].
  • Fetal Toxicity [see Warnings and Precautions ( 5.4) ].
  • Mutagenesis and Carcinogenesis [see Warnings and Precautions ( 5.5) ].

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 valganciclovir 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 valganciclovir tablets are diarrhea, pyrexia, upper respiratory tract infection, urinary tract infection, vomiting, neutropenia, leukopenia, and headache.

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 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 valganciclovir.

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 valganciclovir 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 valganciclovir tablets and the group who received intravenous ganciclovir. The frequencies of neutropenia (ANC less than 500/μL) were 11% for patients receiving valganciclovir 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 valganciclovir tablets 900 mg once daily in two open-label clinical trials. Approximately 252 (68%) of these patients received valganciclovir tablets for more than nine months (maximum duration was 36 months). Table 3 and Table 4 show the pooled selected adverse reactions and abnormal laboratory values from these patients.

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

Patients with CMV Retinitis

Adverse Reactions according to Body System

Valganciclovir Tablets (N=370) %

Gastrointestinal system Diarrhea Nausea Vomiting Abdominal pain

41 30 21 15

General disorders and administrative site conditions Pyrexia

31

Nervous system disorders Headache Insomnia Neuropathy peripheral Paresthesia

22 16 9 8

Eye disorders Retinal detachment

15

Table 4 Pooled Selected Laboratory Abnormalities Reported in Patients Who Received Valganciclovir Tablets Maintenance Therapy for the Treatment of CMV Retinitis

Patients with CMV Retinitis

Laboratory Abnormalities

Valganciclovir Tablets (N=370) %

Neutropenia: ANC/μL < 500 500 to < 750 750 to < 1000

19 17 17

Anemia: Hemoglobin g/dL < 6.5 6.5 to < 8 8 to < 9.5

7 13 16

Thrombocytopenia: Platelets/μL < 25000 25000 to < 50000 50000 to < 100000

4 6 22

Serum Creatinine: mg/dL > 2.5 > 1.5 to 2.5

3 12

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

Adverse Reactions

Valganciclovir 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 post-transplant until Day 100 post-transplant followed by 100 days of placebo or valganciclovir once daily until Day 200 post-transplant. The overall safety profile of valganciclovir 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 Reactions Reported in greater than or equal to 5% of Adult Patients from a Study of Kidney Transplant Patients

Adverse Reactions

Valganciclovir Tablets Day 100 Post-transplant (N=164) %

Valganciclovir 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

Tables 7 and 8 show selected laboratory abnormalities reported with valganciclovir tablets in two trials in solid organ transplant patients.

Table 7 Selected Laboratory Abnormalities Reported in a Study of Adult Solid Organ Transplant Patients *
*
Laboratory abnormalities are those reported by investigators.

Laboratory Abnormalities

Valganciclovir Tablets (N=244) %

Ganciclovir Capsules (N=126) %

Neutropenia: ANC/μL < 500 500 to < 750 750 to < 1000

5 3 5

3 2 2

Anemia: Hemoglobin g/dL < 6.5 6.5 to < 8 8 to < 9.5

1 5 31

2 7 25

Thrombocytopenia: Platelets/μL < 25000 25000 to < 50000 50000 to < 100000

0 1 18

2 3 21

Serum Creatinine: mg/dL > 2.5 > 1.5 to 2.5

4 45

21 47

Table 8 Selected Laboratory Abnormalities Reported in a Study of Adult Kidney Transplant Patients *
*
Laboratory abnormalities are those reported by investigators.

Laboratory Abnormalities

Valganciclovir Tablets Day 100 Post-transplant (N=164) %

Valganciclovir Tablets Day 200 Post-transplant (N=156) %

Neutropenia: ANC/μL

< 500

9

10

500 to < 750

6

6

750 to < 1000

7

5

Anemia: Hemoglobin g/dL

< 6.5

0

1

6.5 to < 8

5

1

8 to < 9.5

17

15

Thrombocytopenia: Platelets/μL

< 25000

0

0

25000 to < 50000

1

0

50000 – < 100000

7

3

Serum Creatinine: mg/dL

> 2.5

17

14

> 1.5 – 2.5

50

48

Other adverse drug reactions from valganciclovir in clinical trials in CMV retinitis and solid organ transplant patients
Other adverse drug reactions with valganciclovir 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 valganciclovir 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: Valganciclovir 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 ( 8.4), Clinical Studies ( 14.2)].

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 valganciclovir 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 posttransplant 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 [see Use in Specific Populations ( 8.4), Clinical Studies ( 14.2) ]. 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 valganciclovir 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 valganciclovir 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 valganciclovir.

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