Cladribine

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All contaminated disposables should be contained in sealable bags for transfer to larger waste containers. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All bottles must be discarded as contaminated waste after decontamination of the biohazard cabinet. All protective apparel (gown, gloves, goggles, and respirator) should be discarded as contaminated waste. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The contaminated filters must be removed, bagged in thick plastic and prepared for disposal in a hazardous waste dump site or incinerator licensed by the Environmental Protection Agency (EPA). /Antineoplastic agents/

For more Disposal Methods (Complete) data for CLADRIBINE (8 total), please visit the HSDB record page.

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Accidental contamination of the health-care environment, resulting in exposure of personnel, patients, visitors, and family members to hazardous substances, is prevented by maintaining the physical integrity and security of packages of hazardous drugs. 1. Access to all areas where hazardous drugs are stored is limited to specified authorized staff. 2. A method should be present for identifying to personnel those drugs that require special precautions (eg, cytotoxics). One way to accomplish this is to apply appropriate warning labels to all hazardous drug containers, shelves, and bins where the drug products are stored. ... 3. A method of identifying, for patients and family members, those drugs that require special precautions in the home should be in place. This may be accomplished in the health-care setting, by providing specific labeling for discharge medications, along with written instructions. 4. Methods for identifying shipping cartons of hazardous drugs should be required from manufacturers and distributors of these drugs. 5. Written procedures for handling damaged packages of hazardous drugs should be maintained. Personnel involved in shipping and receiving hazardous drugs should be trained in these procedures, including the proper use of protective garments and equipment. Damaged shipping cartons of hazardous drugs should be received and opened in an isolated area (eg, in a laboratory fume hood, if available, not in a vertical laminar airflow biological safety cabinet used for preparing sterile products). /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Facilities (eg, shelves, carts, counters, and trays) for storing hazardous drugs are designed to prevent breakage and to limit contamination in the event of leakage. Bins, shelves with barriers at the front, or other design features that reduce the chance of drug containers falling to the floor should be used. Hazardous drugs requiring refrigeration should be stored separately from nonhazardous drugs in individual bins designed to prevent breakage and to contain leakage. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Until the reproductive risks (or lack thereof) associated with handling hazardous drugs within a safety program have been substantiated, staff who are pregnant or breast-feeding should be allowed to avoid contact with these drugs. Policies should be in effect that provide these individuals with alternative tasks or responsibilities if they so desire. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The pharmacy should provide access to information on toxicity, treatment of acute exposure (if available), chemical inactivators, solubility and stability of hazardous drugs (including investigational agents) used in the workplace. /Antineoplastic agents/

For more Preventive Measures (Complete) data for CLADRIBINE (20 total), please visit the HSDB record page.

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Protective apparel: Disposable closed-front gown or coveralls, disposable utility gloves over disposable latex gloves, NIOSH-approved air-purifying half-mask respirator equipped with a high efficiency filter, and eye protection should be worn. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Class 100 clean-air work stations, both horizontal and vertical airflow (with no containment characteristics), are inappropriate engineering controls for handling hazardous drugs because they provide no personnel protection and permit environmental contamination. Although there are no engineering controls designed specifically for the safe handling of hazardous chemicals as sterile products, Class II contained vertical-flow biological safety cabinets (biohazard cabinets) have been adopted for this use. Biohazard cabinetry is, however, designed for the handling of infectious agents, not hazardous chemicals. ... Based on design, ease of use, and cost considerations, Class II contained-vertical-flow biohazard cabinetry is currently recommended for use in preparing sterile doses of hazardous drugs. Class II cabinetry design and performance specifications are defined in NSF Standard 49. Biological safety cabinets selected for use with hazardous drugs should meet NSF Standard 49 specifications to ensure the maximum protection from these engineering controls. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers should wear powder free, disposable surgical latex gloves of good quality when preparing hazardous drugs. Selection criteria for gloves should include thickness (especially at the fingertips where stress is the greatest), fit, length, and tactile sensation. ... The practice of double gloving is supported by research that indicates that many glove materials vary in drug permeability even within lots; therefore, double gloving is recommended. ... In general, surgical latex gloves fit better, have appropriate elasticity for double gloving and maintaining the integrity of the glove-gown interface, and have sufficient tactile sensation (even during double gloving) for stringent aseptic procedures. ... Powdered gloves should be avoided. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers who are not protected by the containment environment of a biohazard cabinet should use respiratory protection when handling hazardous drugs. Respiratory protection should be an adjunct to and not a substitute for engineering controls. Surgical masks of all types provide no respiratory protection against powdered or liquid aerosols of hazardous drugs. In situations where workers may be exposed to potential eye contact with hazardous drugs, an appropriate plastic face shield or splash goggles should be worn. /Antineoplastic agents/

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ During compounding of hazardous drugs (eg, crushing, dissolving, and preparing an ointment), workers should wear low permeability gowns and double gloves. Compounding should take place in a protective area such as a disposable glove box. If compounding must be done in the open, an area away from drafts and traffic must be selected, and the worker should use appropriate respiratory protection. /Antineoplastic agents/

Cladribine may raise the concentration of blood uric acid; dosage adjustment of antigout agents (e.g., allopurinol, colchicine, probenecid or sulfinpyrazone) may be necessary to control hyperuricemia and gout; allopurinol may be preferred to prevent or reverse cladribine-induced hyperuricemia because of risk of uric acid nephropathy with uricosuric antigout agents

Additive bone marrow depression may occur /with cladribine/; dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively.

Because normal defense mechanisms may be suppressed by cladribine therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, and/or may decrease the patient's antibody response to the vaccine; immunization of these patients should be undertaken only with extreme caution after careful review of the patient's hematologic status and only with the knowledge and consent of the physician managing the cladribine therapy. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression- causing medication used, the underlying disease, and other factors. In addition, immunization with oral poliovirus vaccine should be postponed in persons in close contact with the patient, especially family members.

because normal defense mechanisms may be suppressed by cladribine therapy, the patient's antibody response to a killed virus vaccine may be decreased. The interval between discontinuation of medications that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medication used, the underlying disease, and other factors.

In clinical trials, cladribine was associated with low rates of mild to moderate elevations in serum enzymes or bilirubin levels during or after therapy. However, at least one case of fatal reactivation of hepatitis B occurred. Since its approval and more wide scale use in multiple sclerosis there have been rare reports of clinically apparent liver injury attributed to its use. However, in most cases other agents used for multiple sclerosis were being given and the injury was not clearly due to cladribine. Most frequently, patients had received 3 to 5 days of high dose intravenous corticosteroids as therapy of an acute relapse just before cladribine was started. The subsequent injury resembled an acute hepatitis, with marked hepatocellular enzyme elevations arising within 3 to 8 weeks of the intravenous corticosteroids. In some instances, cladribine was restarted without recurrence of the hepatocellular injury.；Likelihood score: D (possible rare cause of clinically apparent liver injury).

In clinical trials, cladribine’s most serious adverse effects have included lymphopenia and infections. These side effects delayed the drug's approval in Europe and the USA. In a retrospective data analysis from the CLARITY and CLARITY Extension trials, severe lymphopenia was unlikely to occur with an oral cladribine dose of 3.5 mg/kg. More than 85% of patients taking FDA-approved doses of oral cladribine recovered to Common Terminology Criteria for Adverse Events grade 0 or 1 lymphocyte counts, and no patients developed grade 4 lymphopenia.；Severe lymphopenia did not occur in cladribine patients with a normal absolute lymphocyte count at CLARITY baseline and recovered to grade 0 or 1 lymphocyte counts before retreatment with cladribine tablets. Side effects include headaches, increased risk for herpetic infections or complications, nasopharyngitis, rashes, and alopecia. Although CLARITY investigators and others expressed initial concern that oral cladribine might increase the risk of malignancy in people with multiple sclerosis, neither the landmark ORACLE nor follow-up safety registry data from the PREMIERE study found any evidence of this risk, when given according to FDA-approved dosing guidelines of 3.5 mg/kg.

Cladribine is structurally related to fludarabine and pentostatin but has a different mechanism of action. Although the exact mechanism of action has not been fully determined, evidence shows that cladribine is phosphorylated by deoxycytidine kinase to the nucleotidecladribine triphosphate (CdATP; 2-chloro-2ду_-deoxyadenosine 5ду_-triphosphate), which accumulates and is incorporated into DNA in cells such as lymphocytes that contain high levels of deoxycytidine kinase and low levels of deoxynucleotidase, resulting in DNA strand breakage and inhibition of DNA synthesis and repair. High levels of CdATP also appear to inhibit ribonucleotide reductase, which leads to an imbalance in triphosphorylated deoxynucleotide (dNTP) pools and subsequent DNA strand breaks, inhibition of DNA synthesis and repair, nicotinamide adenine dinucleotide (NAD) and ATP depletion, and cell death. Unlike other antimetabolite drugs, cladribine has cytotoxic effects on resting as well as proliferating lymphocytes. However, it does cause cells to accumulate at the G1/S phase junction, suggesting that cytotoxicity is associated with events critical to cell entry into S phase. It also binds purine nucleoside phosphorylase (PNP), however no relationship between this binding and a mechanism of action has been established.

/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ There is no method available for routine monitoring of personnel for evidence of hazardous drug exposure. Tests for the presence of mutagens or chromosomal damage are not drug specific and are of value only in controlled studies. Chemical analysis of urine for the presence of hazardous drugs at the sensitivity level needed to detect occupational exposure is limited to a few drugs and is not yet commercially available. /Antineoplastic agents/

/HUMAN EXPOSURE STUDIES/ Long-term serial hematologic observations have been made on 29 patients with multiple sclerosis undergoing experimental therapy with monthly courses of cladribine, each of which consisted of 0.087-0.1 mg/kg per day for 7 days. The characteristic hematologic responses of the patients consisted of acute transient monocytopenia, prolonged, profound lymphopenia especially of CD4-positive cells, and modest lowering of the granulocyte count and hemoglobin with development of long-lasting macrocytosis. Two patients developed severe aplastic anemia, requiring transfusion both of red cells and platelets. One of these had previously received extensive therapy with chlorambucil, while the other had received carbamazepine (Tegretol) and was ingesting phenytoin (Dilantin) at the time of cladribine therapy. Both patients recovered after several months of marrow suppression.

/HUMAN EXPOSURE STUDIES/ In clinical trials involving 196 patients with hairy cell leukemia receiving currently recommended dosages of cladribine, 8 deaths occurred following treatment with the drug. Six of these deaths resulted from infectious etiology (including three pneumonias), and two occurred in the first month after therapy with the drug was initiated. Six of the deaths occurred in previously treated patients who were refractory to interferon alfa.

/CASE REPORTS/ /The authors/ report a case of chronic lymphocytic leukemia (CCL) treated successfully with 2-CdA, where isolated diffuse large B-cell lymphoma (LBCL) developed 2 years after the diagnosis of CLL Rai II and one year after the completion of 2-CdA treatment. Richter's syndrome was first manifested as a pathologic fracture of the left femur. The LBCL was clonally distinct from the original CLL cells. The patient was successfully treated with CHOP and radiotherapy and obtained complete response of the LBCL.

/CASE REPORTS/ /Investigators/ present a case report of development of unilateral gynecomastia in a case of hairy cell leukemia treated with cladribine and question whether this was induced by the chemotherapy.

/CASE REPORTS/ /The authors/ describe a case of a patient with Hairy cell leukemia (HCL), who had prolonged pancytopenia after a single course of cladribine. Fifteen months after the diagnosis of HCL the patient developed acute myeloid leukemia (AML) and died shortly afterwards. Review of the literature shows few reports of acute leukemia in HCL patients. All of the 11 reported cases of leukemia in patients with HCL have been in patients who have been treated with either interferon alpha or purine analogs, and developed several years (mean 4.3 years; range 1.6-6.4 years) after the diagnosis of HCL. /This/ case is unusual in that the patient developed AML shortly (1.2 years) after the diagnosis and treatment of HCL.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Cladribine

vLess-DILI-concern

3

Warnings & precautions

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Fetal death and malformations were observed in rabbits receiving 3 mg/kg (33 mg/sq m) daily.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ A substantial increase in fetal variations occurred in mice receiving cladribine 1.5 mg/kg (4.5 mg/sq m) daily, and increased resorptions, reduced litter size, and increased fetal malformations occurred at a dosage of 3 mg/kg (9 mg/sq m) daily.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Cladribine was shown to cause fetal death and malformations in rabbits at a dose of 3 mg/kg (33 mg per square meter of body surface) per day . No fetal effects were produced in mice at a dose of 0.5 mg/kg (1.5 mg per square meter of body surface) per day or in rabbits at a dose of 1 mg/kg (11 mg per square meter of body surface) per day.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Intravenous administration of cladribine to Cynomolgus monkeys has been shown to cause suppression of rapidly generating cells, including testicular cells.

For more Non-Human Toxicity Excerpts (Complete) data for CLADRIBINE (6 total), please visit the HSDB record page.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl cladribine approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Treatment of active hairy cell leukemia.

THERAP CAT: Antineoplastic

For the treatment of active hairy cell leukemia (leukemic reticuloendotheliosis) as defined by clinically significant anemia, neutropenia, thrombocytopenia, or disease-related symptoms. Also used as an alternative agent for the treatment of chronic lymphocytic leukemia (CLL), low-grade non-Hodgkin's lymphoma, and cutaneous T-cell lymphoma.

9-(2-deoxy-beta-D-erythro-pentofurnaosyl)-9H-purin-2,6-diamine; 9-(2-deoxy-beta-D-erythro-pentofurnaosyl)-2-methoxy-9H-purin-6-amine; 2-chloro-7H-purin-6-amine; 2-chloro-9-(2-deoxy-alpha-D-erythro-pentofurnaosyl)-9H-purin-6-amine; 2-deoxy-D-erythro-pentofurnaose; 4-methylbenzamide; methyl 4-methylbenzoate

By condensing 2,6-dichloropurine with 1-chloro-2-deoxy-3,5-di-o-(p-tolyl)-alpha-D-erythro-pentofuranose in acetonitrile, the products(s) purified and separated by chromatography and the 7-substituted isomer heated with ammonia-saturated methanol, whereby the free chloro group is replaced by amino, to give the product.