Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

VALCYTE (NDA-021304)

(VALGANCICLOVIR HYDROCHLORIDE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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08/02/2018 (SUPPL-14)

Approved Drug Label (PDF)

Boxed Warning

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

Additions and/or revisions underlined:

Impairment of Fertility: Based on animal data and limited human data, VALCYTE may cause temporary or permanent inhibition of spermatogenesis in males and suppression of fertility in females.

5 Warnings and Precautions

Additions and/or revisions underlined:

5.1 Hematologic Toxicity

… complete blood counts with differential and platelet counts should be performed frequently, especially in infants, in patients with renal impairment … or in whom neutrophil counts are less than 1000 cells/?L at the beginning …

5.3 Impairment of Fertility

Based on animal data and limited human data, VALCYTE at the recommended human …

8 Use in Specific Populations

8.3 Females and Males of Reproductive Potential

Newly added information:

Data

Human Data

In a small, open-label, non-randomized clinical study, adult male renal transplant patients receiving VALCYTE for CMV prophylaxis for up to 200 days post-transplantation were compared to an untreated control group. Patients were followed- up for six months after VALCYTE discontinuation. Among 24 evaluable patients in the VALCYTE group, the mean sperm density at the end of treatment visit decreased by 11 million/mL from baseline; whereas, among 14 evaluable patients in the control group the mean sperm density increased by 33 million/mL. However, at the follow-up visit among 20 evaluable patients in the VALCYTE group the mean sperm density was comparable to that observed among 10 evaluable patients in the untreated control group (the mean sperm density at the end of follow-up visit increased by 41 million/mL from baseline in the VALCYTE group and by 43 million/mL in the untreated group).

06/22/2017 (SUPPL-12)

Approved Drug Label (PDF)

Boxed Warning

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

Additions and/or revisions underlined:

Hematologic Toxicity: Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, and bone marrow failure including aplastic anemia have been reported in patients treated with VALCYTE.
Impairment of Fertility: Based on animal data, VALCYTE may cause temporary or permanent inhibition of spermatogenesis in males and suppression of fertility in females …

5 Warnings and Precautions

5.1 Hematologic Toxicity

Additions and/or revisions underlined:

Severe leukopenia, neutropenia, anemia, thrombocytopenia, pancytopenia, and bone marrow failure including aplastic anemia have been reported in patients treated with VALCYTE or ganciclovir. VALCYTE 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. VALCYTE 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 VALCYTE. complete blood counts with differential and platelet counts should be performed frequently, especially 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 …

5.4 Fetal Toxicity

Additions and/or revisions underlined:

… Females of reproductive potential should be advised to use effective contraception during treatment and for at least 30 days following treatment with VALCYTE 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 VALCYTE

6 Adverse Reactions

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

Addition of the following:

Impairment of Fertility
Fetal Toxicity
Mutagenesis and Carcinogenesis

Additions and/or revisions underlined:

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 …

6.1 Clinical Trials Experience

Reaction(s) replaces event(s) in all instances in this subsection and in the tables.

Following Table 8, addition of the following:

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 infections, 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: arrhythmias

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: seizures, dysguesia (taste disturbance)

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

Renal and urinary disorders: renal failure

Laboratory abnormalities reported with VALCYTE tablets in two trials in solid organ transplant patients.

6.2 Postmarketing Experience

The following adverse reactions have been identified …

Addition of the following:

Anaphylactic reactions
Agranulocytosis
Granulocytopenia

7 Drug Interactions

Additions and/or revisions underlined:

… However, because valganciclovir is rapidly and extensively converted to ganciclovir, drug-drug interactions associated with ganciclovir will be expected for VALCYTE. Drug-drug interaction studies with ganciclovir were conducted in patients with normal renal function. Following concomitant administration of VALCYTE and other renally excreted drugs, patients with impaired renal function may have increased concentrations of ganciclovir and the coadministered drug. Therefore, these patients should be closely monitored …

8 Use in Specific Populations

8.2 Lactation

Risk Summary

Addition of the following sentence to this subsection:

Animal data indicate that ganciclovir is excreted in the milk of lactating rats

8.3 Females and Males of Reproductive Potential

Contraception

Males

Condoms replace barrier contraception in this section.

8.5 Geriatric Use

Additions and/or revisions underlined:

… Because renal clearance decreases with age, VALCYTE should be administered with consideration of their renal status. Renal function should be monitored …

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Serious Adverse Reactions

Monitored replaces performed

Pregnancy and Contraception

Condoms replace barrier contraception

Impairment of Cognitive Ability

Seizures replace convulsions

PATIENT INFORMATION

What is VALCYTE?

In children, VALCYTE tablets or oral solution are used:

Addition of the following:

It is not known if VALCTYE is safe and effective in children for prevention of CMV disease in liver transplant, in kidney transplant in infants less than 4 months of age, in heart transplant in infants less than 1 month of age, in children with AIDS who have CMV retinitis, and in infants with congenital CMV infection.

What are the possible side effects of VALCYTE?

The most common side effects of VALCYTE in adults include:

Addition of the following:

Fatigue
Headache
Urinary tract infection

The most common side effects of VALCYTE in children include:

Addition of the following:

Diarrhea
Fever
Vomiting
Low white blood cell counts in blood tests