HOW SUPPLIED

Cladribine Injection, USP is supplied as a sterile, preservative-free, isotonic solution containing 10 mg (1 mg/mL) of cladribine as 10 mL filled into a single-dose clear flint glass 20 mL vial, individually boxed, with the trademark “Novaplus”.** NDC 42658-010-91.**

Store refrigerated 2° to 8°C (36° to 46°F). Protect from light during storage.

PRECAUTIONS

General

Cladribine injection is a potent antineoplastic agent with potentially significant toxic side effects. It should be administered only under the supervision of a physician experienced with the use of cancer chemotherapeutic agents. Patients undergoing therapy should be closely observed for signs of hematologic and non-hematologic toxicity. Periodic assessment of peripheral blood counts, particularly during the first 4 to 8 weeks post-treatment, is recommended to detect the development of anemia, neutropenia and thrombocytopenia and for early detection of any potential sequelae (e.g., infection or bleeding). As with other potent chemotherapeutic agents, monitoring of renal and hepatic function is also recommended, especially in patients with underlying kidney or liver dysfunction (see WARNINGS and ADVERSE REACTIONS).

Fever was a frequently observed side effect during the first month on study. Since the majority of fevers occurred in neutropenic patients, patients should be closely monitored during the first month of treatment and empiric antibiotics should be initiated as clinically indicated. Although 69% of patients developed fevers, less than 1/3 of febrile events were associated with documented infection. Given the known myelosuppressive effects of cladribine, practitioners should carefully evaluate the risks and benefits of administering this drug to patients with active infections (see WARNINGS and ADVERSE REACTIONS).

There are inadequate data on dosing of patients with renal or hepatic insufficiency. Development of acute renal insufficiency in some patients receiving high doses of cladribine has been described. Until more information is available, caution is advised when administering the drug to patients with known or suspected renal or hepatic insufficiency (see WARNINGS).

Rare cases of tumor lysis syndrome have been reported in patients treated with cladribine with other hematologic malignancies having a high tumor burden.

Cladribine injection must be diluted in designated intravenous solutions prior to administration (see DOSAGE AND ADMINISTRATION).

Laboratory Tests

During and following treatment, the patient's hematologic profile should be monitored regularly to determine the degree of hematopoietic suppression. In the clinical studies, following reversible declines in all cell counts, the mean Platelet Count reached 100 × 10 9/L by Day 12, the mean Absolute Neutrophil Count reached 1500 × 10 6/L by Week 5 and the mean Hemoglobin reached 12 g/dL by Week 8. After peripheral counts have normalized, bone marrow aspiration and biopsy should be performed to confirm response to treatment with cladribine. Febrile events should be investigated with appropriate laboratory and radiologic studies. Periodic assessment of renal function and hepatic function should be performed as clinically indicated.

Drug Interactions

There are no known drug interactions with cladribine injection. Caution should be exercised if cladribine injection is administered before, after, or in conjunction with other drugs known to cause immunosuppression or myelosuppression. (see WARNINGS)

Carcinogenesis

No animal carcinogenicity studies have been conducted with cladribine. However, its carcinogenic potential cannot be excluded based on demonstrated genotoxicity of cladribine.

Mutagenesis

As expected for compounds in this class, the actions of cladribine yield DNA damage. In mammalian cells in culture, cladribine caused the accumulation of DNA strand breaks. Cladribine was also incorporated into DNA of human lymphoblastic leukemia cells. Cladribine was not mutagenic in vitro (Ames and Chinese hamster ovary cell gene mutation tests) and did not induce unscheduled DNA synthesis in primary rat hepatocyte cultures. However, cladribine was clastogenic both in vitro (chromosome aberrations in Chinese hamster ovary cells) and in vivo (mouse bone marrow micronucleus test).

Impairment of Fertility

The effect on human fertility is unknown. When administered intravenously to Cynomolgus monkeys, cladribine has been shown to cause suppression of rapidly generating cells, including testicular cells.

Pregnancy

Pregnancy Category D

(see WARNINGS).

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from cladribine, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. In a Phase I study involving patients 1–21 years old with relapsed acute leukemia, cladribine was given by continuous intravenous infusion in doses ranging from 3 to 10.7 mg/m 2/day for 5 days (one-half to twice the dose recommended in Hairy Cell Leukemia). In this study, the dose-limiting toxicity was severe myelosuppression with profound neutropenia and thrombocytopenia. At the highest dose (10.7 mg/m 2/day), 3 of 7 patients developed irreversible myelosuppression and fatal systemic bacterial or fungal infections. No unique toxicities were noted in this study (1) (see WARNINGS and ADVERSE REACTIONS).

Geriatric Use

Clinical studies of cladribine did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients.