Cladribine (Page 3 of 5)

Drug Interactions

There are no known drug interactions with cladribine. Caution should be exercised if cladribine 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

Teratogenic Effects; 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 to 21 years old with relapsed acute leukemia, cladribine was given by continuous intravenous infusion in doses ranging from 3 to 10.7 mg/m2 /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/m2 /day), 3 of 7 patients developed irreversible myelosuppression and fatal systemic bacterial or fungal infections. No unique toxicities were noted in this study1 (see WARNINGS and ADVERSE REACTIONS).

Geriatric Use

Clinical studies of cladribine did not include sufficient numbers of subjects aged 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.

ADVERSE REACTIONS

Clinical Trials Experience

Adverse drug reactions reported by ≥ 1% of cladribine-treated patients with HCL noted in the HCL clinical dataset (studies K90-091 and L91-048, n=576) are shown in the table below.

Adverse Drug Reactions in ≥ 1% of Patients Treated With Cladribine in HCL Clinical Trials

System Organ Class

Preferred Term

Cladribine (n=576)

%

Blood and Lymphatic System Disorder (see also sections WARNINGS and PRECAUTIONS)

Anemia

1

Febrile neutropenia

8

Psychiatric Disorders

Anxiety

1

Insomnia

3

Nervous System Disorders

Dizziness

6

Headache

14

Cardiac Disorders

Tachycardia

2

Respiratory, Thoracic and Mediastinal Disorders

Breath sounds abnormal

4

Cough

7

Dyspnea*

5

Rales

1

Gastrointestinal Disorders

Abdominal pain**

4

Constipation

4

Diarrhea

7

Flatulence

1

Nausea

22

Vomiting

9

Skin and Subcutaneous Tissue Disorders

Ecchymosis

2

Hyperhidrosis

3

Petechiae

2

Pruritus

2

Rash***

16

Musculoskeletal, Connective Tissue, and Bone Disorders

Arthralgia

3

Myalgia

6

Pain****

6

General Disorders and Administration Site Conditions (see also sections WARNINGS and PRECAUTIONS)

Administration site reaction*****

11

Asthenia

6

Chills

2

Decreased appetite

8

Fatigue

31

Malaise

5

Muscular weakness

1

Edema peripheral

2

Pyrexia

33

Injury, Poisoning and Procedural Complications

Contusion

1

* Dyspnea includes dyspnea, dyspnea exertional, and wheezing
** Abdominal pain includes abdominal discomfort, abdominal pain, and abdominal pain (lower and upper)
*** Rash includes erythema, rash, and rash (macular, macula-papular, papular, pruritic, pustular and erythematous)
**** Pain includes pain, back pain, chest pain, arthritis pain, bone pain, and pain in extremity***** Administration site reaction includes administration site reaction, catheter site (cellulitis, erythema, hemorrhage, and pain), and infusion site reaction(erythema, edema, and pain)

The following safety data are based on 196 patients with Hairy Cell Leukemia: the original cohort of 124 patients plus an additional 72 patients enrolled at the same two centers after the original enrollment cutoff. In Month 1 of the Hairy Cell Leukemia clinical trials, severe neutropenia was noted in 70% of patients, fever in 69%, and infection was documented in 28%. Most non-hematologic adverse experiences were mild to moderate in severity.

Myelosuppression was frequently observed during the first month after starting treatment. Neutropenia (ANC < 500 x 106 /L) was noted in 70% of patients, compared with 26% in whom it was present initially. Severe anemia (Hemoglobin <8.5 g/dL) developed in 37% of patients, compared with 10% initially and thrombocytopenia (Platelets < 20 x 109 /L) developed in 12% of patients, compared to 4% in whom it was noted initially.

During the first month, 54 of 196 patients (28%) exhibited documented evidence of infection. Serious infections (e.g., septicemia, pneumonia) were reported in 6% of all patients; the remainder were mild or moderate. Several deaths were attributable to infection and/or complications related to the underlying disease. During the second month, the overall rate of documented infection was 6%; these infections were mild to moderate and no severe systemic infections were seen. After the third month, the monthly incidence of infection was either less than or equal to that of the months immediately preceding cladribine therapy.

During the first month, 11% of patients experienced severe fever (i.e., ≥104°F). Documented infections were noted in fewer than one-third of febrile episodes. Of the 196 patients studied, 19 were noted to have a documented infection in the month prior to treatment. In the month following treatment, there were 54 episodes of documented infection: 23 (42%) were bacterial, 11 (20%) were viral and 11 (20%) were fungal. Seven (7) of 8 documented episodes of herpes zoster occurred during the month following treatment. Fourteen (14) of 16 episodes of documented fungal infections occurred in the first two months following treatment. Virtually all of these patients were treated empirically with antibiotics (see WARNINGS and PRECAUTIONS).

Analysis of lymphocyte subsets indicates that treatment with cladribine is associated with prolonged depression of the CD4 counts. Prior to treatment, the mean CD4 count was 766/µL. The mean CD4 count nadir, which occurred 4 to 6 months following treatment, was 272/µL. Fifteen (15) months after treatment, mean CD4 counts remained below 500/µL. CD8 counts behaved similarly, though increasing counts were observed after 9 months. The clinical significance of the prolonged CD4 lymphopenia is unclear.

Another event of unknown clinical significance includes the observation of prolonged bone marrow hypocellularity. Bone marrow cellularity of <35% was noted after 4 months in 42 of 124 patients (34%) treated in the two pivotal trials. This hypocellularity was noted as late as day 1010. It is not known whether the hypocellularity is the result of disease related marrow fibrosis or if it is the result of cladribine toxicity. There was no apparent clinical effect on the peripheral blood counts.

The vast majority of rashes were mild. Most episodes of nausea were mild, not accompanied by vomiting, and did not require treatment with antiemetics. In patients requiring antiemetics, nausea was easily controlled, most frequently with chlorpromazine.

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