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Drug Safety-related Labeling Changes (SrLC)

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FLUDARABINE PHOSPHATE (NDA-022137)

(FLUDARABINE PHOSPHATE)

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

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11/19/2024 (SUPPL-15)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Neurologic Toxicities

Additions and/or revisions underlined:

Severe central nervous system (CNS) adverse reactions, including coma, seizures, agitation and confusion, can occur in patients treated with Fludarabine Phosphate Injection. CNS adverse reactions may occur either early or late after the initiation of Fludarabine Phosphate Injection (range 7 to 225 days).

CNS adverse reactions are dose dependent and occur at greater incidence and severity in patients treated at doses higher than the recommended dose of Fludarabine Phosphate Injection [see Overdosage (10)].

Monitor patients for signs and symptoms of neurologic toxicity during and after treatment with Fludarabine Phosphate Injection. Consider delaying or discontinuing Fludarabine Phosphate Injection if neurotoxicity occurs. Do not administer Fludarabine Phosphate Injection at doses higher than the recommended dose.

Advise patients that Fludarabine Phosphate Injection may reduce the ability to drive or use mechanical equipment, since fatigue, weakness, visual disturbances, confusion, agitation, or seizures may occur.

5.2 Myelosuppression

Subsection title revised
Additions and/or revisions underlined:

Fludarabine phosphate can cause severe and fatal myelosuppression, which may include neutropenia, thrombocytopenia, or anemia. Cases of trilineage bone marrow hypoplasia or aplasia resulting in pancytopenia, sometimes resulting in death, have been reported.

The median time to nadir of counts was approximately 13 days (range, 3 to 25 days) for granulocytes and 16 days (range, 2 to 32 days) for platelets. The duration of the cytopenia in reported cases has ranged from approximately 2 months to approximately 1 year.

Monitor complete blood counts at baseline, prior to and during each treatment cycle, and as clinically needed. Consider dosage delays, dose reductions, or permanent discontinuation if recovery has not occurred by the first day of the next scheduled cycle.

5.3 Autoimmune Cytopenias

Subsection title revised
Additions and/or revisions underlined:

Life-threatening and fatal autoimmune hemolytic anemia, autoimmune thrombocytopenia/idiopathic thrombocytopenic purpura (ITP), Evans syndrome, and acquired hemophilia can occur in patients treated with fludarabine phosphate with or without a previous history of autoimmune hemolytic anemia or a positive Coombs' test.

The majority of patients rechallenged with fludarabine phosphate developed a recurrence in the hemolytic process. The mechanism(s) which predispose patients to the development of this complication has not been identified.

Closely monitor patients during treatment with Fludarabine Phosphate Injection for autoimmune cytopenias and manage as clinically indicated.

5.4 Transfusion Associated Graft-Versus-Host Disease

Additions and/or revisions underlined:

Transfusion-associated graft-versus-host disease has been observed after transfusion of non-irradiated blood in patients treated with fludarabine phosphate. Fatal outcome as a consequence of this disease has been reported. Therefore, to minimize the risk of transfusion-associated graft-versus-host disease, patients who require blood transfusion and who are undergoing, or who have received, treatment with Fludarabine Phosphate Injection should receive irradiated blood only.

5.5 Tumor Lysis Syndrome

Subsection title revised
Additions and/or revisions underlined:

Tumor lysis syndrome (TLS) can occur in patients treated with Fludarabine Phosphate Injection. TLS has been reported in patients with CLL who have large tumor burdens and can occur as early as the first week of treatment. Closely monitor patients at risk for TLS, consider appropriate prophylaxis including hydration, and manage as clinically indicated.

5.6 Pulmonary Toxicity in Patients with CLL When Fludarabine Phosphate is Used with Pentostatin

Subsection title revised
Additions and/or revisions underlined:

In clinical trials, patients experienced fatal pulmonary toxicity when treated with fludarabine phosphate and pentostatin for refractory CLL. Avoid concomitant use of Fludarabine Phosphate Injection with pentostatin [see Drug Interactions (7.1)].

5.8 Embryo-Fetal Toxicity

Subsection title revised
Additions and/or revisions underlined:

Based on findings in animals and its mechanism of action, Fludarabine Phosphate Injection can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of fludarabine phosphate to pregnant animals during organogenesis resulted in adverse developmental outcomes, including embryo-fetal mortality and structural abnormalities at maternal doses below (rabbits) and above (rats) those in patients at the recommended human dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Fludarabine Phosphate Injection and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Fludarabine Phosphate Injection and for 3 months after the last dose [see Use in Specific Populations (8.1)]

6 Adverse Reactions

6.1 Clinical Trials Experience

Extensive changes; please refer to label for complete information

6.2 Postmarketing Experience

Additions and/or revisions underlined:

The following adverse reactions have been identified during postapproval use of fludarabine phosphate. 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.

Blood and Lymphatic: Bone marrow hypoplasia or aplasia resulting in pancytopenia (range: 2 months to 12 months after treatment initiation; some fatal); myelodysplastic syndrome and acute myeloid leukemia

Infection: Progressive multifocal leukoencephalopathy (range: 3 weeks to one year after treatment initiation; some fatal)

Pulmonary: Acute Respiratory Distress Syndrome (ARDS), respiratory distress, pulmonary hemorrhage, pulmonary fibrosis, pneumonitis, respiratory failure

7 Drug Interactions

7.1 Pentostatin

Additions and/or revisions underlined:

Avoid use of Fludarabine Phosphate Injection in combination with pentostatin due to the risk of severe and fatal pulmonary toxicity [see Warnings and Precautions (5.6)].

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Risk Summary

Based on findings in animals and its mechanism of action [see Clinical Pharmacology (12.1)], Fludarabine Phosphate Injection can cause fetal harm when administered to a pregnant woman. There are no available data on Fludarabine Phosphate Injection use in pregnant women to evaluate for a drug-associated risk. In animal reproduction studies, administration of fludarabine phosphate to pregnant animals during organogenesis resulted in adverse developmental outcomes, including embryo-fetal mortality and structural abnormalities at maternal doses below (rabbits) and above (rats) those in patients at the recommended human dose (see Data). Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

In rats, repeated intravenous doses of fludarabine phosphate at 2.4 times and 7.2 times the recommended human intravenous dose (25 mg/m2) administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations (cleft palate, exencephaly, and fetal vertebrae deformities) and decreased fetal body weights. Maternal toxicity was not apparent at 2.4 times the human intravenous dose, and was limited to slight body weight decreases at 7.2 times the human intravenous dose. In rabbits, repeated intravenous doses of fludarabine phosphate at 3.8 times the human intravenous dose administered during organogenesis increased embryo and fetal lethality as indicated by increased resorptions and a decrease in live fetuses. A significant increase in malformations including cleft palate, hydrocephaly, adactyly, brachydactyly, fusions of the digits, diaphragmatic hernia, heart/great vessel defects, and vertebrae/rib anomalies were seen in all dose levels (greater than or equal to 0.5 times the human intravenous dose).

8.2 Lactation

Additions and/or revisions underlined:

Risk Summary

There are no data on the presence of fludarabine phosphate or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise patients that breastfeeding is not recommended during treatment with Fludarabine Phosphate Injection, and for 1 week after the last dose.

8.3 Females and Males of Reproductive Potential

Newly added subsection:

Fludarabine Phosphate Injection can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiation of Fludarabine Phosphate Injection [see Use in Specific Populations (8.1)].

Contraception

Females

Advise female patients of reproductive potential to use effective contraception during treatment with Fludarabine Phosphate Injection and for 6 months after the last dose.

Males

Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with Fludarabine Phosphate Injection and for 3 months after the last dose [see Nonclinical Toxicology (13.1)].

Infertility

Males

Based on findings in animals and humans, Fludarabine Phosphate Injection may impair male fertility. Fludarabine phosphate may damage testicular tissue and spermatozoa. Possible sperm DNA damage raises concerns about loss of fertility and genetic abnormalities in fetuses. The reversibility of this effect is unknown [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of Fludarabine Phosphate Injection have not been established in pediatric patients.

Safety and effectiveness were assessed, but not established for Fludarabine Phosphate Injection in pediatric patients 1 year to < 17 years with refractory acute leukemia or solid tumors. No new safety signals were observed in pediatric patients across these studies.

8.5 Geriatric Use

Additions and/or revisions underlined:

Among patients with CLL evaluated in two randomized active-controlled trials treated with fludarabine, cyclophosphamide, and rituximab, 36% were 65 years of age or older; of these, 15% were 70 years of age or older. The incidence of Grade 3 and 4 adverse reactions was higher among patients receiving fludarabine in combination with cyclophosphamide and rituximab who were 70 years or older compared to younger patients for neutropenia, febrile neutropenia, anemia, thrombocytopenia, pancytopenia, and infections.

Clinical studies of fludarabine as a single agent for patients with B-cell CLL did not include a sufficient numbers of younger adults to determine if patients with B-cell CLL who are 65 years of age and older respond differently from younger adults.

8.6 Renal Impairment

Additions and/or revisions underlined:

Reduce the dosage in patients with CLcr 30 to 79 mL/min. A dosage has not been established for patients with severe renal impairment (CLcr < 30 mL/min) [see Dosage and Administration (2.2)].

The total body clearance of 2-fluoro-ara-A is correlated with the creatinine clearance [see Clinical Pharmacology (12.3)]; however, the effect of varying degrees of renal impairment on the pharmacokinetics of this metabolite has not been fully characterized.

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Neurologic Toxicities

Inform patients that Fludarabine Phosphate Injection can cause severe CNS adverse reactions, including coma, seizures, agitation, and confusion. Advise patients of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Inform patients to contact their healthcare provider immediately if they experience signs or symptoms of CNS adverse reactions [see Warnings and Precautions (5.1)].

Myelosuppression

Inform patients Fludarabine Phosphate Injection can cause a decrease in white blood cells, platelets, and red blood cells, and the need for frequent monitoring of blood counts. Advise patients to report shortness of breath, significant fatigue, bleeding, fever, or other signs of infection [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].

Autoimmune Cytopenias

Inform patients that Fludarabine Phosphate Injection can cause autoimmune hemolytic anemia, autoimmune thrombocytopenia/ITP, Evans syndrome, and acquired hemophilia. Advise patients to seek immediate medical attention if any signs or symptoms of autoimmune cytopenias occur [see Warnings and Precautions (5.3)].

Tumor Lysis Syndrome

Inform patients about the risk of and the signs and symptoms of tumor lysis syndrome. Advise patients to notify their healthcare provider if they experience these symptoms [see Warnings and Precautions (5.5)].

Vaccination

Advise patients they should avoid vaccinations with live vaccines during and after treatment [see Warnings and Precautions (5.7)].

Nausea and Vomiting

Advise patients that Fludarabine Phosphate Injection may cause nausea and/or vomiting. Inform patients to report nausea and vomiting so that symptomatic treatment may be provided when this occurs [see Adverse Reactions (6.1)].

Rash

Advise patients that a rash or itching may occur during treatment with Fludarabine Phosphate Injection. Advise patients to immediately report severe or worsening rash or itching [see Adverse Reactions (6.1)].

Embryo-Fetal Toxicity

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise female patients to contact their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.8), Use in Specific Populations (8.1)].

Advise females of reproductive potential to use effective contraception during treatment with Fludarabine Phosphate Injection and for 6 months after the last dose [see Use in Specific Populations (8.3)].

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Fludarabine Phosphate Injection and for 3 months after the last dose [see Use in Specific Populations (8.3)].

Lactation

Advise women not to breastfeed during treatment and for 1 week after the last dose of Fludarabine Phosphate Injection [see Use in Specific Populations (8.2)].

Infertility

Advise males of reproductive potential that Fludarabine Phosphate Injection may impair fertility [see Use in Specific Populations (8.3)].