Valganciclovir: Package Insert and Label Information

VALGANCICLOVIR- valganciclovir hydrochloride tablet, film coated
Dr. Reddy’s Laboratories Limited

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WARNING: HEMATOLOGIC TOXICITY, IMPAIRMENT OF FERTILITY, FETAL TOXICITY, MUTAGENESIS AND CARCINOGENESIS

WARNING: HEMATOLOGIC TOXICITY, IMPAIRMENT OF FERTILITY, FETAL TOXICITY, MUTAGENESIS AND CARCINOGENESIS

  • Hematologic Toxicity: Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, and bone marrow failure including aplastic anemia have been reported in patients treated with valganciclovir [see Warnings and Precautions (5.1)].
  • Impairment of Fertility: Based on animal data and limited human data, valganciclovir may cause temporary or permanent inhibition of spermatogenesis in males and suppression of fertility in females [see Warnings and Precautions (5.3)].
  • Fetal Toxicity: Based on animal data, valganciclovir has the potential to cause birth defects in humans [see Warnings and Precautions (5.4)].
  • Mutagenesis and Carcinogenesis: Based on animal data, valganciclovir has the potential to cause cancers in humans [see Warnings and Precautions (5.5)].

1 INDICATIONS AND USAGE

1.1 Adult Patients

Treatment of Cytomegalovirus (CMV) Retinitis:

Valganciclovir tablets are indicated for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS) [see Clinical Studies (14.1)].

Prevention of CMV Disease:

Valganciclovir tablets are indicated for the prevention of CMV disease in kidney, heart, and kidney-pancreas transplant patients at high risk (Donor CMV seropositive/Recipient CMV seronegative [D+/R-]) [see Clinical Studies (14.1)].

1.2 Pediatric Patients

Prevention of CMV Disease: Valganciclovir tablets are indicated for the prevention of CMV disease in kidney transplant patients (4 months to 16 years of age) and heart transplant patients (1 month to 16 years of age) at high risk [see Clinical Studies (14.2)].

2 DOSAGE AND ADMINISTRATION

2.1 General Dosing Information

  • Adult patients should use valganciclovir tablets, not valganciclovir for oral solution.
  • Valganciclovir tablets should be taken with food [see Clinical Pharmacology (12.3)].

2.2 Recommended Dosage in Adult Patients with Normal Renal Function

For dosage recommendations in adult patients with renal impairment [see Dosage and Administration (2.5)].

Treatment of CMV Retinitis:

  • Induction: The recommended dosage is 900 mg (two 450 mg tablets) taken orally twice a day for 21 days.
  • Maintenance: Following induction treatment, or in adult patients with inactive CMV retinitis, the recommended dosage is 900 mg (two 450 mg tablets) taken orally once a day.

Prevention of CMV Disease:

  • For adult patients who have received a heart or kidney-pancreas transplant, the recommended dosage is 900 mg (two 450 mg tablets) taken orally once a day starting within 10 days of transplantation until 100 days post-transplantation.
  • For adult patients who have received a kidney transplant, the recommended dosage is 900 mg (two 450 mg tablets) taken orally once a day starting within 10 days of transplantation until 200 days post-transplantation.

2.3 Recommended Dosage in Pediatric Patients

Prevention of CMV Disease in Pediatric Kidney Transplant Patients: For pediatric kidney transplant patients 4 months to 16 years of age, the recommended once daily mg dose (7 x BSA x CrCl) should start within 10 days of post-transplantation until 200 days post-transplantation.

Prevention of CMV Disease in Pediatric Heart Transplant Patients: For pediatric heart transplant patients 1 month to 16 years of age, the recommended once daily mg dose (7x BSA x CrCl) should start within 10 days of transplantation until 100 days post-transplantation.

The recommended once daily dosage of valganciclovir tablets is based on body surface area (BSA) and creatinine clearance (CrCl) derived from a modified Schwartz formula, and is calculated using the equation below:

Pediatric Dose (mg) = 7 x BSA x CrCl (calculated using a modified Schwartz formula). If the calculated Schwartz creatinine clearance exceeds 150 mL/min/1.73m2 , then a maximum value of 150 mL/min/1.73m2 should be used in the equation. The k values used in the modified Schwartz formula are based on pediatric patient age, as shown in Table 1.

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Table 1 k Values According to Pediatric Patient Age*

k value Pediatric Patient Age
0.33 Infants less than 1 year of age with low birth weight for gestational age
0.45 Infants less than 1 year of age with birth weight appropriate for gestational age
0.45 Children aged 1 to less than 2 years
0.55 Boys aged 2 to less than 13 years Girls aged 2 to less than 16 years
0.7 Boys aged 13 to 16 years

*The k values provided are based on the Jaffe method of measuring serum creatinine, and may require correction when enzymatic methods are used1 .

Monitor serum creatinine levels regularly and consider changes in height and body weight and adapt the dose as appropriate during prophylaxis period.

All calculated doses should be rounded to the nearest 25 mg increment for the actual deliverable dose. If the calculated dose exceeds 900 mg, a maximum dose of 900 mg should be administered. Valganciclovir for oral solution is the preferred formulation since it provides the ability to administer a dose calculated according to the formula above; however, valganciclovir tablets may be used if the calculated doses are within 10% of available tablet strength (450 mg). For example, if the calculated dose is between 405 mg and 495 mg, one 450 mg tablet may be taken. Before prescribing valganciclovir tablets, pediatric patients should be assessed for the ability to swallow tablets.

2.5 Dosage Recommendation for Adult Patients with Renal Impairment

Serum creatinine levels or estimated creatinine clearance should be monitored regularly during treatment. Dosage recommendations for adult patients with reduced renal function are provided in Table 2. For adult patients on hemodialysis (CrCl less than 10 mL/min), a dose recommendation for valganciclovir tablets cannot be given [see Use in Specific Populations (8.5, 8.6 ), Clinical Pharmacology (12.3)].

Table 2 Dosage Recommendations for Adult Patients with Impaired Renal Function

Valganciclovir 450 mg Tablets
CrCl*(mL/min) Induction Dose Maintenance/ Prevention Dose
≥ 60 900 mg twice daily 900 mg once daily
40 to 59 450 mg twice daily 450 mg once daily
25 to 39 450 mg once daily 450 mg every 2 days
10 to 24 450 mg every 2 days 450 mg twice weekly
< 10 (on hemodialysis) not recommended not recommended

*An estimated creatinine clearance in adults is calculated from serum creatinine by the following formulas:

For males= (140 – age [years]) x (body weight [kg])

_______________________________

(72) x (serum creatinine [mg/dL])

For females= 0.85 x male value

Dosing in pediatric patients with renal impairment can be done using the recommended equations because CrCl is a component in the calculation [see Dosage and Administration (2.3)].

2.6 Handling and Disposal

Caution should be exercised in the handling of valganciclovir tablets. 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, USP 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, 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 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 191717
Anemia: Hemoglobin g/dL < 6.5 6.5 to < 8 8 to < 9.5 71316
Thrombocytopenia: Platelets/μL < 25000 25000 to < 50000 50000 to < 100000 4622
Serum Creatinine: mg/dL > 2.5 > 1.5 to 2.5 312

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 to 4 Adverse Reactions Reported in greater than or equal to 5% of 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

Table 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 Valganciclovir Tablets (N=244) % Ganciclovir Capsules (N=126) %
Neutropenia: ANC/μL < 500 500 to < 750 750 to < 1000 535 322
Anemia: Hemoglobin g/dL < 6.5 6.5 to < 88 to < 9.5 1531 2725
Thrombocytopenia: Platelets/μL < 25000 25000 to < 50000 50000 to < 100000 0118 2321
Serum Creatinine: mg/dL > 2.5 > 1.5 to 2.5 1445 2147

*Laboratory abnormalities are those reported by investigators.

Table 8 Laboratory Abnormalities Reported in a Study of Adult Kidney Transplant Patients*

Laboratory Abnormalities V alganciclovir Tablets Day 100 Post-transplant (N=164) % V alganciclovir 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> 1.5 – 2.5 1750 1448

*Laboratory abnormalities are those reported by investigators.

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