Cladribine Dailymed

Rx only

For Intravenous Infusion Only

BOXED WARNING SECTION

WARNING

Cladribine Injection should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy. Suppression of bone marrow function should be anticipated. This is usually reversible and appears to be dose dependent. Serious neurological toxicity (including irreversible paraparesis and quadraparesis) has been reported in patients who received cladribine injection by continuous infusion at high doses (4 to 9 times the recommended dose for Hairy Cell Leukemia). Neurologic toxicity appears to demonstrate a dose relationship; however, severe neurological toxicity has been reported rarely following treatment with standard cladribine dosing regimens.

Acute nephrotoxicity has been observed with high doses of cladribine (4 to 9 times the recommended dose for Hairy Cell Leukemia), especially when given concomitantly with other nephrotoxic agents/therapies.

Description

Cladribine Injection, USP (also commonly known as 2-chloro-2´-deoxy-ß-D-adenosine) is a synthetic antineoplastic agent for continuous intravenous infusion. It is a clear, colorless, sterile, preservative-free, isotonic solution. Cladribine Injection, USP is available in single-use vials containing 10 mg (1 mg/mL) of cladribine, a chlorinated purine nucleoside analog. Each mL of cladribine injection, USP contains 1 mg of the active ingredient and 9 mg (0.15 mEq) of sodium chloride as an inactive ingredient. The solution has a pH range of 5.5 to 8.0. Phosphoric acid and/or dibasic sodium phosphate may have been added to adjust the pH to 6.3 ± 0.3.

The chemical name for cladribine is 2-chloro-6-amino-9-(2-deoxy-ß-D-erythro-pentofuranosyl)purine and the structure is represented below:

Molecular Formula = C₁₀H₁₂ClN₅O₃           Molecular Weight = 285.69

Clinical Pharmacology

Cellular Resistance and Sensitivity

The selective toxicity of 2-chloro-2´-deoxy-ß-D-adenosine towards certain normal and malignant lymphocyte and monocyte populations is based on the relative activities of deoxycytidine kinase and deoxynucleotidase. Cladribine passively crosses the cell membrane. In cells with a high ratio of deoxycytidine kinase to deoxynucleotidase, it is phosphorylated by deoxycytidine kinase to 2-chloro-2´-deoxy-ß-D-adenosine monophosphate (2-CdAMP). Since 2-chloro-2´-deoxy-ß-D-adenosine is resistant to deamination by adenosine deaminase and there is little deoxynucleotide deaminase in lymphocytes and monocytes, 2-CdAMP accumulates intracellularly and is subsequently converted into the active triphosphate deoxynucleotide, 2-chloro-2´-deoxy-ß-D-adenosine triphosphate (2-CdATP). It is postulated that cells with high deoxycytidine kinase and low deoxynucleotidase activities will be selectively killed by 2-chloro-2´-deoxy-ß-D-adenosine as toxic deoxynucleotides accumulate intracellularly.

Cells containing high concentrations of deoxynucleotides are unable to properly repair single-strand DNA breaks. The broken ends of DNA activate the enzyme poly (ADP-ribose) polymerase resulting in NAD and ATP depletion and disruption of cellular metabolism. There is evidence, also, that 2-CdATP is incorporated into the DNA of dividing cells, resulting in impairment of DNA synthesis. Thus, 2-chloro-2´-deoxy-ß-D-adenosine can be distinguished from other chemotherapeutic agents affecting purine metabolism in that it is cytotoxic to both actively dividing and quiescent lymphocytes and monocytes, inhibiting both DNA synthesis and repair.

Pharmacokinetics

In a clinical investigation, 17 patients with Hairy Cell Leukemia and normal renal function were treated for 7 days with the recommended treatment regimen of cladribine (0.09 mg/kg/day) by continuous intravenous infusion. The mean steady-state serum concentration was estimated to be 5.7 ng/mL with an estimated systemic clearance of 663.5 mL/h/kg when cladribine was given by continuous infusion over 7 days. In Hairy Cell Leukemia patients, there does not appear to be a relationship between serum concentrations and ultimate clinical outcome.

In another study, 8 patients with hematologic malignancies received a two (2) hour infusion of cladribine (0.12 mg/kg). The mean end-of-infusion plasma cladribine concentration was 48 ± 19 ng/mL. For 5 of these patients, the disappearance of cladribine could be described by either a biphasic or triphasic decline. For these patients with normal renal function, the mean terminal half-life was 5.4 hours. Mean values for clearance and steady-state volume of distribution were 978 ± 422 mL/h/kg and 4.5 ± 2.8 L/kg, respectively.

Cladribine plasma concentration after intravenous administration declines multi-exponentially with an average half-life of 6.7 + 2.5 hours. In general, the apparent volume of distribution of cladribine is approximately 9 L/kg, indicating an extensive distribution in body tissues.

Cladribine penetrates into cerebrospinal fluid. One report indicates that concentrations are approximately 25% of those in plasma.

Cladribine is bound approximately 20% to plasma proteins.

Except for some understanding of the mechanism of cellular toxicity, no other information is available on the metabolism of cladribine in humans. An average of 18% of the administered dose has been reported to be excreted in urine of patients with solid tumors during a 5-day continuous intravenous infusion of 3.5 to 8.1 mg/m²/day of cladribine. The effect of renal and hepatic impairment on the elimination of cladribine has not been investigated in humans.

Clinical Studies

Two single-center open label studies of cladribine have been conducted in patients with Hairy Cell Leukemia with evidence of active disease requiring therapy. In the study conducted at the Scripps Clinic and Research Foundation (Study A), 89 patients were treated with a single course of cladribine given by continuous intravenous infusion for 7 days at a dose of 0.09 mg/kg/day. In the study conducted at the M.D. Anderson Cancer Center (Study B), 35 patients were treated with a 7 day continuous intravenous infusion of cladribine at a comparable dose of 3.6 mg/m²/day. A complete response (CR) required clearing of the peripheral blood and bone marrow of hairy cells and recovery of the hemoglobin to 12 g/dL, platelet count to 100 x 10⁹/L, and absolute neutrophil count to 1500 x 10⁶/L. A good partial response (GPR) required the same hematologic parameters as a complete response, and that fewer than 5% hairy cells remain in the bone marrow. A partial response (PR) required that hairy cells in the bone marrow be decreased by at least 50% from baseline and the same response for hematologic parameters as for complete response. A pathologic relapse was defined as an increase in bone marrow hairy cells to 25% of pretreatment levels. A clinical relapse was defined as the recurrence of cytopenias, specifically, decreases in hemoglobin ≥ 2 g/dL, ANC ≥ 25% or platelet counts ≥ 50,000. Patients who met the criteria for a complete response but subsequently were found to have evidence of bone marrow hairy cells (<25% of pretreatment levels) were reclassified as partial responses and were not considered to be complete responses with relapse.

Among patients evaluable for efficacy (N=106), using the hematologic and bone marrow response criteria described above, the complete response rates in patients treated with cladribine were 65% and 68% for Study A and Study B, respectively, yielding a combined complete response rate of 66%. Overall response rates (i.e., Complete plus Good Partial plus Partial Responses) were 89% and 86% in Study A and Study B, respectively, for a combined overall response rate of 88% in evaluable patients treated with cladribine.

Using an intent-to-treat analysis (N=123) and further requiring no evidence of splenomegaly as a criterion for CR (i.e., no palpable spleen on physical examination and ≤ 13 cm on CT scan), the complete response rates for Study A and Study B were 54% and 53%, respectively, giving a combined CR rate of 54%. The overall response rates (CR + GPR + PR) were 90% and 85%, for Studies A and B, respectively, yielding a combined overall response rate of 89%.

RESPONSE RATES TO CLADRIBINE TREATMENT IN PATIENTS WITH HAIRY CELL LEUKEMIA
	CR	Overall
Evaluable Patients N=106	66%	88%
Intent-to-treat Population N=123	54%	89%

In these studies, 60% of the patients had not received prior chemotherapy for Hairy Cell Leukemia or had undergone splenectomy as the only prior treatment and were receiving cladribine as a first-line treatment. The remaining 40% of the patients received cladribine as a second-line treatment, having been treated previously with other agents, including α-interferon and/or deoxycoformycin. The overall response rate for patients without prior chemotherapy was 92%, compared with 84% for previously treated patients. Cladribine is active in previously treated patients; however, retrospective analysis suggests that the overall response rate is decreased in patients previously treated with splenectomy or deoxycoformycin and in patients refractory to α-interferon.

OVERALL RESPONSE RATES (CR + GPR + PR) TO CLADRIBINE TREATMENT IN PATIENTS WITH HAIRY CELL LEUKEMIA
	OVERALL RESPONSE (N=123)	NR+ RELAPSE
No Prior Chemotherapy	68/74 92%	6 + 4 14%
Any Prior Chemotherapy	41/49 84%	8 + 3 22%
Previous Splenectomy	32/41* 78%	9 + 1 24%
Previous Interferon	40/48 83%	8 + 3 23%
Interferon Refractory	6/11* 55%	5 + 2 64%
Previous Deoxycoformycin	3/6* 50%	3 + 1 66%

NR = No Response ^*P<0.05 

After a reversible decline, normalization of peripheral blood counts (Hemoglobin >12 g/dL, Platelets >100 x 10⁹/L, Absolute Neutrophil Count (ANC) >1500 x 10⁶/L) was achieved by 92% of evaluable patients. The median time to normalization of peripheral counts was 9 weeks from the start of treatment (Range: 2 to 72). The median time to normalization of Platelet Count was 2 weeks, the median time to normalization of ANC was 5 weeks and the median time to normalization of Hemoglobin was 8 weeks. With normalization of Platelet Count and Hemoglobin, requirements for platelet and RBC transfusions were abolished after Months 1 and 2, respectively, in those patients with complete response. Platelet recovery may be delayed in a minority of patients with severe baseline thrombocytopenia. Corresponding to normalization of ANC, a trend toward a reduced incidence of infection was seen after the third month, when compared to the months immediately preceding cladribine therapy (see also WARNINGS, PRECAUTIONS and ADVERSE REACTIONS).

CLADRIBINE TREATMENT IN PATIENTS WITH HAIRY CELL LEUKEMIA TIME TO NORMALIZATION OF PERIPHERAL BLOOD COUNTS
Parameter	Median Time to Normalization of CountDay 1 = First day of infusion
Platelet Count	2 weeks
Absolute Neutrophil Count	5 weeks
Hemoglobin	8 weeks
ANC, Hemoglobin and Platelet Count	9 weeks

For patients achieving a complete response, the median time to response (i.e., absence of hairy cells in bone marrow and peripheral blood together with normalization of peripheral blood parameters), measured from treatment start, was approximately 4 months. Since bone marrow aspiration and biopsy were frequently not performed at the time of peripheral blood normalization, the median time to complete response may actually be shorter than that which was recorded. At the time of data cut- off, the median duration of complete response was greater than 8 months and ranged to 25+ months. Among 93 responding patients, seven had shown evidence of disease progression at the time of the data cut-off. In four of these patients, disease was limited to the bone marrow without peripheral blood abnormalities (pathologic progression), while in three patients there were also peripheral blood abnormalities (clinical progression). Seven patients who did not respond to a first course of cladribine received a second course of therapy. In the five patients who had adequate follow-up, additional courses did not appear to improve their overall response.

Indications And Usage

Cladribine Injection, USP is indicated for the treatment of active Hairy Cell Leukemia as defined by clinically significant anemia, neutropenia, thrombocytopenia or disease-related symptoms.

Contraindications

Cladribine is contraindicated in those patients who are hypersensitive to this drug or any of its components.

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. respiratory infection, pneumonia and viral skin infections), including fatal infections (e.g. sepsis) were reported (see ADVERSE REACTIONS ).

Of the 196 Hairy Cell Leukemia patients entered in the two trials, there were 8 deaths following treatment. Of these, 6 were of infectious etiology, including 3 pneumonias, and 2 occurred in the first month following cladribine therapy. Of the 8 deaths, 6 occurred in previously treated patients who were refractory to α-interferon.

Benzyl alcohol is a constituent of the recommended diluent for the 7-day infusion solution. Benzyl alcohol has been reported to be associated with a fatal “Gasping Syndrome” in premature infants (see DOSAGE AND ADMINISTRATION).

Pregnancy Category D

Cladribine can cause fetal harm when administered to a pregnant woman. Although there is no evidence of teratogenicity in humans due to cladribine, other drugs which inhibit DNA synthesis have been reported to be teratogenic in humans. Cladribine is teratogenic in animals. Advise females of reproductive potential to use highly effective contraception during treatment with cladribine. If cladribine is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Cladribine is teratogenic in mice and rabbits and consequently has the potential to cause fetal harm when administered to a pregnant woman. A significant increase in fetal variations was observed in mice receiving 1.5 mg/kg/day (4.5 mg/m²) and increased resorptions, reduced litter size and increased fetal malformations were observed when mice received 3 mg/kg/day (9 mg/m²). Fetal death and malformations were observed in rabbits that received 3 mg/kg/day (33 mg/m²). No fetal effects were seen in mice at 0.5 mg/kg/day (1.5 mg/m²) or in rabbits at 1 mg/kg/day (11 mg/m²).

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 10⁹/L by Day 12, the mean Absolute Neutrophil Count reached 1500 x 10⁶/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 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.