Cladribine 1 mg/mL Injection — NDC 0143-9871-01 (Billing 00143-9871-01)

WARNINGS Due to increased risk of infection in the setting of immunosuppression with chemotherapy including cladribine, it is recommended not to administer live attenuated vaccines to patients receiving Cladribine Injection. Severe bone marrow suppression, including neutropenia, anemia and thrombocytopenia, has been commonly observed in patients treated with cladribine, especially at high doses. At initiation of treatment, most patients in the clinical studies had hematologic impairment as a manifestation of active Hairy Cell Leukemia.

Following treatment with cladribine, further hematologic impairment occurred before recovery of peripheral blood counts began. During the first two weeks after treatment initiation, mean Platelet Count, ANC, and Hemoglobin concentration declined and subsequently increased with normalization of mean counts by Day 12, Week 5 and Week 8, respectively. The myelosuppressive effects of cladribine were most notable during the first month following treatment.

Forty-four percent (44%) of patients received transfusions with RBCs and 14% received transfusions with platelets during Month 1. Careful hematologic monitoring, especially during the first 4 to 8 weeks after treatment with cladribine, is recommended (see PRECAUTIONS ). Fever (T ≥ 100˚ F) was associated with the use of cladribine in approximately two-thirds of patients (131/196) in the first month of therapy.

Virtually all of these patients were treated empirically with parenteral antibiotics. Overall, 47% (93/196) of all patients had fever in the setting of neutropenia (ANC ≤ 1000), including 62 patients (32%) with severe neutropenia (i.e., ANC ≤ 500). In a Phase I investigational study using cladribine in high doses (4 to 9 times the recommended dose for Hairy Cell Leukemia) as part of a bone marrow transplant conditioning regimen, which also included high dose cyclophosphamide and total body irradiation, acute nephrotoxicity and delayed onset neurotoxicity were observed.

Thirty-one (31) poor-risk patients with drug-resistant acute leukemia in relapse (29 cases) or non-Hodgkins Lymphoma (2 cases) received cladribine for 7 to 14 days prior to bone marrow transplantation. During infusion, 8 patients experienced gastrointestinal symptoms. While the bone marrow was initially cleared of all hematopoietic elements, including tumor cells, leukemia eventually recurred in all treated patients.

Within 7 to 13 days after starting treatment with cladribine, 6 patients (19%) developed manifestations of renal dysfunction (e.g., acidosis, anuria, elevated serum creatinine, etc.) and 5 required dialysis. Several of these patients were also being treated with other medications having known nephrotoxic potential. Renal dysfunction was reversible in 2 of these patients.

In the 4 patients whose renal function had not recovered at the time of death, autopsies were performed; in 2 of these, evidence of tubular damage was noted. Eleven (11) patients (35%) experienced delayed onset neurologic toxicity. In the majority, this was characterized by progressive irreversible motor weakness (paraparesis/quadriparesis) of the upper and/or lower extremities, first noted 35 to 84 days after starting high dose therapy with cladribine.

Non-invasive testing (electromyography and nerve conduction studies) was consistent with demyelinating disease. Severe neurologic toxicity has also been noted with high doses of another drug in this class. Axonal peripheral polyneuropathy was observed in a dose escalation study at the highest dose levels (approximately 4 times the recommended dose for Hairy Cell Leukemia) in patients not receiving cyclophosphamide or total body irradiation.

Severe neurological toxicity has been reported rarely following treatment with standard cladribine dosing regimens. In patients with Hairy Cell Leukemia treated with the recommended treatment regimen (0.09 mg/kg/day for 7 consecutive days), there have been no reports of nephrologic toxicities. Serious (e.g. respir… [Excerpted — this section continues on DailyMed.]

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 10 6 /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 10 9 /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 followi… [Excerpted — this section continues on DailyMed.]

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.

PRECAUTIONS General Cladribine 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 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 x 10 9 /L by Day 12, the mean Absolute Neutrophil Count reached 1500 x 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. 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 Cy… [Excerpted — this section continues on DailyMed.]