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CLADRIBINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Cladribine, a chlorinated purine nucleoside analogue, is an antimetabolite antineoplastic.

Specific Substances

    1) 2-Chloro-2'-deoxyadenosine
    2) 2-Chlorodeoxyadenosine
    3) 2-CdA
    4) NSC 105014-F
    5) RWJ-26251
    6) CAS 4291-63-8
    1.2.1) MOLECULAR FORMULA
    1) C10-H12-Cl-N5-O3 (Sweetman, 2005)

Available Forms Sources

    A) FORMS
    1) Cladribine is available as an isotonic solution containing 10 mg (1 mg/mL) of cladribine in a 10 mL single-use vial for intravenous administration (Prod Info cladribine intravenous injection, 2014).
    B) USES
    1) Cladribine is FDA approved for the treatment of active hairy cell leukemia as defined by the presence of clinically significant anemia, neutropenia, thrombocytopenia, or disease-related symptoms (Prod Info cladribine intravenous injection, 2014).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Cladribine is FDA approved for the treatment of active hairy cell leukemia as defined by the presence of clinically significant anemia, neutropenia, thrombocytopenia, or disease-related symptoms.
    B) PHARMACOLOGY: Cladribine is considered a prodrug, making intracellular phosphorylation necessary for cytotoxic effects to occur. Cladribine passively crosses the cell membrane and in cells with a high ratio of deoxycytidine kinase to deoxynucleotidase, it is phosphorylated by deoxycytidine kinase to 2-chloro-2'-deoxy-beta-D-adenosine monophosphate (2-CdAMP). Since cladribine is resistant to deamination by adenosine deaminase and there is little deoxynucleotide deaminase in lymphocytes and monocytes, the phosphorylated metabolites accumulate intracellularly. Subsequently, 2-CdAMP is converted into triphosphate deoxynucleotide (2-CdATP). 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.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Commonly reported adverse effects, with an incidence of greater than 20%, include myelosuppression, fever, fatigue, nausea, rash, headache, and infection. Myelosuppression is the dose-limiting toxicity of cladribine. Its duration may be prolonged after discontinuation of therapy.
    2) INFREQUENT: Adverse effects that were reported less frequently with cladribine therapy include: tachycardia, edema, diaphoresis, petechiae, epistaxis, vomiting, anorexia, diarrhea, abdominal pain, constipation, myalgia, arthralgia, dizziness, insomnia, asthenia, cough, dyspnea, injection site reactions, and elevated liver enzymes.
    3) RARE: Tumor lysis syndrome has been rarely reported.
    E) WITH POISONING/EXPOSURE
    1) Cladribine overdose information is limited. Severe myelosuppression, irreversible paraparesis/quadriparesis, peripheral polyneuropathy, and acute nephrotoxicity have been associated with high doses of cladribine.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Fever is a frequent occurrence in patients receiving cladribine therapy.
    0.2.20) REPRODUCTIVE
    A) Cladribine is classified as FDA pregnancy category D. Teratogenicity has occurred in mice, rats, and rabbits and is anticipated to occur in humans following maternal administration.
    0.2.21) CARCINOGENICITY
    A) Cladribine has been associated with secondary myelodysplastic syndrome in humans.

Laboratory Monitoring

    A) Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery.
    B) Monitor serum electrolytes, renal function and hepatic enzymes.
    C) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    D) Monitor for clinical evidence of peripheral neuropathy for several weeks after overdose.

Treatment Overview

    0.4.4) EYE EXPOSURE
    A) Irrigate eyes with 0.9% saline or water. Perform an eye exam, including slit lamp, if irritation persists.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) Wash exposed skin well with soap and water and remove contaminated clothing.
    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Treat persistent nausea and vomiting with several antiemetics of different classes. Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for severe neutropenia.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Administer colony stimulating factors (filgrastim or sargramostim) as these patients are at risk for severe neutropenia. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia, or hemorrhage. Severe nausea and vomiting may respond to a combination of agents from different drug classes.
    C) INTRATHECAL INJECTION
    1) There are no reports of inadvertent intrathecal injection with cladribine. However, this drug has caused paresis/quadriparesis and polyneuropathy following high-dose intravenous administration. Severe neurotoxicity may develop after intrathecal injection. The following recommendations are based on experience with antineoplastic agents. After an overdose, keep the patient upright and immediately drain at least 20 mL of CSF; drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative free saline). Consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline through ventricular catheter, drain fluid from lumbar catheter; typical volumes 80 to 150 mL/hr for 24 hours). Dexamethasone 4 mg IV every 6 hours to prevent arachnoiditis.
    D) DECONTAMINATION
    1) Decontamination is not necessary in most situations as cladribine is administered intravenously. For dermal exposures, clean skin with soap and water, and for eye exposures, flush with water.
    E) AIRWAY MANAGEMENT
    1) Monitor airway and respiratory function as indicated. Intubate if patient is unable to protect their airway.
    F) ANTIDOTE
    1) None.
    G) MYELOSUPPRESSION
    1) Administer colony stimulating factors following a significant overdose as these patients are at risk for severe neutropenia. Filgrastim: 5 mcg/kg/day IV or subQ. Sargramostim: 250 mcg/m(2)/day IV over 4 hours OR 250 mcg/m(2)/day SubQ once daily. Monitor CBC with differential and platelet count daily for evidence of bone marrow suppression until recovery has occurred. Transfusion of platelets and/or packed red cells may be needed in patients with severe thrombocytopenia, anemia or hemorrhage. Patients with severe neutropenia should be in protective isolation. Transfer to a bone marrow transplant center should be considered.
    H) NEUTROPENIA
    1) Prophylactic therapy with a fluoroquinolone should be considered in high risk patients with expected prolonged (more than 7 days), and profound neutropenia (ANC 100 cells/mm(3) or less).
    I) FEBRILE NEUTROPENIA
    1) If fever (38.3 C) develops during the neutropenic phase (ANC 500 cells/mm(3) or less), cultures should be obtained and empiric antibiotics started. HIGH RISK PATIENT (anticipated neutropenia of 7 days or more; unstable; significant comorbidities): IV monotherapy with either piperacillin-tazobactam; a carbapenem (meropenem or imipenem-cilastatin); or an antipseudomonal beta-lactam agent (eg, ceftazidime or cefepime). LOW RISK PATIENT (anticipated neutropenia of less than 7 days; clinically stable; no comorbidities): oral ciprofloxacin and amoxicillin/clavulanate.
    J) NAUSEA AND VOMITING
    1) Treat severe nausea and vomiting with agents from several different classes. Agents to consider: dopamine (D2) receptor antagonists (eg, metoclopramide), phenothiazines (eg, prochlorperazine, promethazine), 5-HT3 serotonin antagonists (eg, dolasetron, granisetron, ondansetron), benzodiazepines (eg, lorazepam), corticosteroids (eg, dexamethasone), and antipsychotics (eg, haloperidol, olanzapine).
    K) ENHANCED ELIMINATION PROCEDURE
    1) It is unknown whether cladribine can be removed from the circulation via hemodialysis or hemofiltration; however, due to cladribine's large volume of distribution (9 L/kg) indicating extensive distribution into the tissues, it is unlikely that hemodialysis or hemofiltration would be successful as enhanced elimination techniques.
    L) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no data to support home management.
    2) ADMISSION CRITERIA: Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), and daily monitoring of CBC with differential until bone marrow suppression is resolved.
    3) CONSULT CRITERIA: Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with an overdose.
    4) TRANSFER CRITERIA: Patients with large overdoses or severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.
    M) PITFALLS
    1) Symptoms of overdose are similar to reported side effects of the medication. Early symptoms of overdose may be delayed or not evident (ie, particularly myelosuppression), so reliable follow-up is imperative. Patients taking these medications may have severe comorbidities and may be receiving other drugs that may produce synergistic effects (ie, myelosuppression, neurotoxicity).
    N) PHARMACOKINETICS
    1) Approximately 20% bound to plasma proteins. Apparent volume of distribution is approximately 9 L/kg. The metabolite of cladribine (2-chloroadenine) is formed via first-pass metabolism. The mean terminal half-life is 5.4 hours.
    O) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that may cause myelosuppression.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose of cladribine has not been established. ADULT: Polyneuropathy and acute nephrotoxicity has been reported following cladribine doses approximately 4 to 9 times the recommended dose indicated for the treatment of hairy cell leukemia. PEDIATRIC: Irreversible myelosuppression and fatal systemic bacterial or fungal infections occurred in pediatric patients who received 10.7 mg/m(2)/day for 5 days (2 times the recommended dose for treatment of hairy cell leukemia).
    B) THERAPEUTIC DOSE: ADULT: Maximum recommended dose is 0.09 mg/kg/day as a 7-day continuous infusion. PEDIATRIC: Safety and efficacy have not been established.

Clinical Effects

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) MYELOSUPPRESSION
    1) WITH THERAPEUTIC USE
    a) Myelosuppression is the main dose-limiting toxicity of cladribine. Myelosuppression is frequently observed during the first month after the initiation of therapy, although prolonged neutropenia and thrombocytopenia (lasting for more than 100 days) have been reported in patients who received more than 4 cycles of cladribine therapy (Ogura et al, 2004; Beutler et al, 1994).
    b) INCIDENCE: In one study (n=196), neutropenia (ANC less than 500 x 10(6)/L) occurred in 70% of patients (26% initially had neutropenia); severe anemia (hemoglobin less than 8.5 g/dL) occurred in 37% of patients (10% had anemia initially); and thrombocytopenia (platelets less than 20 x 10(9)/L) occurred in 12% of patients (4% had thrombocytopenia initially) (Prod Info cladribine intravenous injection, 2014). A 69% incidence of grade IV neutropenia has been reported 28 days after the initiation of therapy (Anon, 1992).
    2) WITH POISONING/EXPOSURE
    a) Irreversible myelosuppression occurred in 3 of 7 pediatric patients (1- to 21-years-old with relapsed acute leukemia) who received cladribine, 10.7 mg/m(2)/day for 5 days (2 times the recommended dose for treatment of hairy cell leukemia), during a phase I study (Prod Info cladribine intravenous injection, 2014).
    B) GRANULOMA
    1) WITH THERAPEUTIC USE
    a) Bone marrow granulomas occurred in a 38-year-old man with hairy cell leukemia following cladribine therapy. The patient received 3 months of therapy with interferon alfa, and was then switched to cladribine 4 mg/m(2)/day for 7 days. A bone marrow biopsy 3 months after cladribine therapy revealed granulomas; granulomas were not present at time of diagnosis or after interferon therapy. The authors speculate that granulomas may have formed due to necrosis of hairy cells with accompanying release of monocyte proliferation factors (Franco et al, 1994).
    C) LYMPHOCYTOPENIA
    1) WITH THERAPEUTIC USE
    a) Cladribine administration has resulted in the prolonged depression of CD4 cell counts. In a clinical trial involving 196 patients with hairy cell leukemia, the mean CD4 count was 766/mcL prior to cladribine therapy. Four to six months following treatment, the mean CD4 count was 272/mcL. Fifteen months following cladribine treatment, the CD4 counts remained below 500/mcL. The CD8 counts also maintained a similar pattern, however the CD8 counts began to increase 9 months after cladribine therapy (Prod Info cladribine intravenous injection, 2014).
    D) BONE MARROW FINDING
    1) WITH THERAPEUTIC USE
    a) HYPOCELLULARITY: Bone marrow hypocellularity (less than 35%) was reported in 42 of 124 patients 4 months following cladribine therapy during two clinical trials. The hypocellularity occurred as late as day 1010 following therapy. It is unclear whether the hypocellularity was due to disease-related marrow fibrosis or as a result of cladribine toxicity (Prod Info cladribine intravenous injection, 2014).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Rash (27%), erythema (6%), and pruritus (6%) have been reported with cladribine therapy. Rashes are reportedly mild and occur mostly in patients who are receiving or had recently been given other medications known to cause rash (Prod Info cladribine intravenous injection, 2014).
    b) Two case reports of severe skin rash have been reported in pretreated patients with long-standing hairy cell leukemia receiving cladribine (2-CdA). Both patients received a 7-day course of 2-CdA and prophylactic Septra (R) (1 patient also received allopurinol) between February and March 1997. A generalized erythematous rash developed in both patients within 4 to 5 days after the completion of chemotherapy. This was accompanied by fever and dyspnea with minimal radiologic abnormality. Disseminated intravascular coagulation developed in 1 patient. Antibiotic therapy was initiated with imipenem and subsequently changed to teicoplanin and ceftriaxone in both patients. Skin biopsy revealed erythema multiforme in 1 patient. Full recovery was attained in both patients. Skin toxicity from the other agents could NOT be ruled out (Grey et al, 2000).
    c) Twenty-one percent (7/33) of patients (median age 63 years) with hairy cell leukemia reported cutaneous reactions 7 to 31 days (mean delay was 16 days) after receiving cladribine (2-CdA) chemotherapy. Lesions consisted of a maculopapular exanthem in 6 patients and one case of toxic epidermal necrolysis (TEN). Skin biopsies revealed dermal, pericapillary lymphocytic infiltration (n=33), necrotic or vacuolized keratinocytes (n=3), and spongiosis with exocytosis (n=1). All patients received 2-CdA dosed at 0.1 milligram/kilogram/day for 7 days. Fifty-eight percent of patients received antibiotics during the study period. The intrinsic imputability scores of drugs were "very likely" and "likely" in 26% of the patients that received antibiotics; no other drug but 2-CdA was given in ONLY 2 cases. The authors conclude that a lower rate of cutaneous eruptions reported in the literature may be due to a lower percent of patients receiving additional drugs. All patients recovered except for one who had fatal TEN (Meunier et al, 1996).
    d) Co-treatment with allopurinol appears to increase the risk of cladribine-associated rash in patients with hairy cell leukemia (Chubar & Bennett, 2003)
    e) Generalized pruritic maculopapular rashes have been reported in patients receiving cladribine for chronic lymphocytic leukemia. Skin biopsies were notable for perivascular, inflammatory infiltrates including eosinophils. These patients did not have blood eosinophilia (Rossini et al, 2004).
    B) INJECTION SITE REACTION
    1) WITH THERAPEUTIC USE
    a) Injection site reactions (ie, redness, swelling, pain) were reported in 9% of patients (n=196) who received cladribine for treatment of hairy cell leukemia during a clinical trial; however, the reactions may be associated more with the infusion procedure and/or the indwelling catheter instead of due to the medication itself (Prod Info cladribine intravenous injection, 2014).
    C) EXCESSIVE SWEATING
    1) WITH THERAPEUTIC USE
    a) Diaphoresis was reported in 9% of patients (n=196) during the first 14 days of initiating cladribine therapy (Prod Info cladribine intravenous injection, 2014).
    D) PETECHIAE
    1) WITH THERAPEUTIC USE
    a) Petechiae was reported in 8% of patients (n=196) during the first 14 days of initiating cladribine therapy (Prod Info cladribine intravenous injection, 2014).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) Myalgia was reported in 7% of patients (n=196) during the first 14 days of initiating cladribine therapy (Prod Info cladribine intravenous injection, 2014).
    B) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) Arthralgia was reported in 5% of patients (n=196) during the first 14 days of initiating cladribine therapy (Prod Info cladribine intravenous injection, 2014).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) GYNECOMASTIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Unilateral gynecomastia developed in a 42-year-old patient with hairy cell leukemia treated with cladribine and interferon alfa. The patient was administered interferon alfa 3 million units subcutaneously on alternate days for 20 months. Four months after discontinuation of interferon therapy and detection of persistent leukemia, cladribine was administered at a dose of 0.1 mg/kg/day for 7 days as a continuous infusion. Complete remission was documented on bone marrow examination 3 months after cladribine therapy. Nine months following cladribine therapy, a firm non-tender mass in the left breast was detected and the diagnosis of Gynecomastia was made. Metastasis work up, thyroid function and prolactin levels were normal (Abhyankar et al, 2001).
    B) HYPERGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) Hyperglycemia was seen in 25% of patients receiving cladribine (0.14 mg/kg/day for 5 days, repeated monthly) for indolent non-Hodgkin lymphoma (Blum et al, 2006).

Reproductive

    3.20.1) SUMMARY
    A) Cladribine is classified as FDA pregnancy category D. Teratogenicity has occurred in mice, rats, and rabbits and is anticipated to occur in humans following maternal administration.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) An increase in fetal variations were reported in animals following cladribine administration of 1.5 mg/kg/day (4.5 mg/m(2)). Increased resorptions, reduced litter size, and increased fetal malformations occurred in those who received 3 mg/kg/day (9 mg/m(2)) of cladribine. Cladribine administration of 3 mg/kg/day (33 mg/m(2)) resulted in fetal deaths and malformations (Prod Info cladribine intravenous injection, 2014).
    2) Maternal intraperitoneal administration of cladribine, in doses of 25 mg/kg or greater, given as a single injection on gestational day 9.5, resulted in various fetal malformations (Lau et al, 2002).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified cladribine as FDA pregnancy category D (Prod Info cladribine intravenous injection, 2014).
    2) Do not administer this drug to a pregnant woman (Prod Info cladribine intravenous injection, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is unknown whether cladribine is excreted in human milk. Due to the potential for adverse reactions in nursing infants, either discontinue nursing or discontinue cladribine taking into account the importance of the drug to the mother (Prod Info cladribine intravenous injection, 2014).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) Cladribine suppressed testicular cells in animal clinical studies (Prod Info cladribine intravenous injection, 2014).

Summary Of Exposure

    A) USES: Cladribine is FDA approved for the treatment of active hairy cell leukemia as defined by the presence of clinically significant anemia, neutropenia, thrombocytopenia, or disease-related symptoms.
    B) PHARMACOLOGY: Cladribine is considered a prodrug, making intracellular phosphorylation necessary for cytotoxic effects to occur. Cladribine passively crosses the cell membrane and in cells with a high ratio of deoxycytidine kinase to deoxynucleotidase, it is phosphorylated by deoxycytidine kinase to 2-chloro-2'-deoxy-beta-D-adenosine monophosphate (2-CdAMP). Since cladribine is resistant to deamination by adenosine deaminase and there is little deoxynucleotide deaminase in lymphocytes and monocytes, the phosphorylated metabolites accumulate intracellularly. Subsequently, 2-CdAMP is converted into triphosphate deoxynucleotide (2-CdATP). 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.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Commonly reported adverse effects, with an incidence of greater than 20%, include myelosuppression, fever, fatigue, nausea, rash, headache, and infection. Myelosuppression is the dose-limiting toxicity of cladribine. Its duration may be prolonged after discontinuation of therapy.
    2) INFREQUENT: Adverse effects that were reported less frequently with cladribine therapy include: tachycardia, edema, diaphoresis, petechiae, epistaxis, vomiting, anorexia, diarrhea, abdominal pain, constipation, myalgia, arthralgia, dizziness, insomnia, asthenia, cough, dyspnea, injection site reactions, and elevated liver enzymes.
    3) RARE: Tumor lysis syndrome has been rarely reported.
    E) WITH POISONING/EXPOSURE
    1) Cladribine overdose information is limited. Severe myelosuppression, irreversible paraparesis/quadriparesis, peripheral polyneuropathy, and acute nephrotoxicity have been associated with high doses of cladribine.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Fever is a frequent occurrence in patients receiving cladribine therapy.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) FEVER
    a) Based on 196 patients with hairy cell leukemia receiving cladribine, 11% of patients experienced severe fever within the first month of therapy (104 degrees F or more) (Prod Info cladribine intravenous injection, 2014). Febrile episodes have occurred in 43% to 69% of patients receiving cladribine in several clinical trials (Prod Info cladribine intravenous injection, 2014; Piro, 1992; Piro et al, 1990; Estey et al, 1992; Santana et al, 1992; Kay et al, 1992).
    b) Fever, greater than 100 degrees Fahrenheit, usually occurs during the fifth to seventh day of treatment in patients with hairy-cell leukemia. Despite the appearance of fever, relatively few patients have underlying infections (Piro, 1992; Juliusson et al, 1992; Beutler et al, 1996), suggesting that the fever may be a result of the release of pyrogens from tumor cells (Guchelaar et al, 1994).
    c) Fever in the setting of neutropenia occurred in 47% of patients (n=196) who received cladribine for treatment of hairy cell leukemia during a clinical trial (Prod Info cladribine intravenous injection, 2014)

Heent

    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) EPISTAXIS was reported in 5% of patients (n=196) during the first 14 days of initiating cladribine therapy (Prod Info cladribine intravenous injection, 2014).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) Tachycardia was reported in 6% of patients (n=196) during the first 14 days of initiating cladribine therapy (Prod Info cladribine intravenous injection, 2014).
    B) EDEMA
    1) WITH THERAPEUTIC USE
    a) Edema was reported in 6% of patients (n=196) during the first 14 days of initiating cladribine therapy (Prod Info cladribine intravenous injection, 2014).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) COUGH
    1) WITH THERAPEUTIC USE
    a) Coughing was reported in 10% of patients (n=196) during the first 14 days of initiating cladribine therapy (Prod Info cladribine intravenous injection, 2014).
    B) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) Shortness of breath was reported in 7% of patients (n=196) during the first 14 days of initiating cladribine therapy (Prod Info cladribine intravenous injection, 2014).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) FATIGUE
    1) WITH THERAPEUTIC USE
    a) During a clinical trial, fatigue was reported in 45% of the patients (n=196) within the first 14 days after beginning cladribine therapy (Prod Info cladribine intravenous injection, 2014).
    B) HEADACHE
    1) WITH THERAPEUTIC USE
    a) During a clinical trial, headaches occurred in 22% of patients (n=196) within the first 14 days after beginning cladribine therapy (Prod Info cladribine intravenous injection, 2014).
    C) PARAPARESIS
    1) WITH POISONING/EXPOSURE
    a) Irreversible motor weakness, progressing to paraparesis and quadriparesis, was reported in patients after beginning high-dose cladribine therapy (4 to 9 times the recommended dose for treatment of hairy cell leukemia) as a continuous infusion. The motor weakness appeared to have a delayed onset, first occurring 35 to 84 days after beginning the high-dose therapy (Prod Info cladribine intravenous injection, 2014; Vahdat et al, 1994).
    D) POLYNEUROPATHY
    1) WITH POISONING/EXPOSURE
    a) During a dose escalation study, axonal peripheral polyneuropathy was reported following high-dose cladribine therapy at doses of 19 to 21 mg/m(2)/day (approximately 4 times the recommended dose indicated for the treatment of hairy cell leukemia) (Prod Info cladribine intravenous injection, 2014; Vahdat et al, 1994).
    E) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness was reported in 9% of patients (n=196) during the first 14 days of initiating cladribine therapy (Prod Info cladribine intravenous injection, 2014).
    F) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) Insomnia was reported in 7% of patients (n=196) during the first 14 days of initiating cladribine therapy (Prod Info cladribine intravenous injection, 2014).
    G) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) Asthenia was reported in 9% of patients (n=196) during the first 14 days of initiating cladribine therapy (Prod Info cladribine intravenous injection, 2014).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA
    1) WITH THERAPEUTIC USE
    a) Nausea was reported in 28% of patients (n=196) during the first 14 days of initiating cladribine therapy. In the majority of cases, the nausea was mild and was not accompanied by vomiting (Prod Info cladribine intravenous injection, 2014).
    B) VOMITING
    1) WITH THERAPEUTIC USE
    a) Vomiting was reported in 13% of patients (n=196) during the first 14 days of initiating cladribine therapy (Prod Info cladribine intravenous injection, 2014).
    C) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) Decreased appetite was reported in 17% of patients (n=196) during the first 14 days of initiating cladribine therapy (Prod Info cladribine intravenous injection, 2014).
    D) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea was reported in 10% of patients (n=196) during the first 14 days of initiating cladribine therapy (Prod Info cladribine intravenous injection, 2014).
    E) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Abdominal pain was reported in 6% of patients (n=196) during the first 14 days of initiating cladribine therapy (Prod Info cladribine intravenous injection, 2014).
    F) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Constipation was reported in 9% of patients (n=196) during the first 14 days of initiating cladribine therapy (Prod Info cladribine intravenous injection, 2014).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Elevated serum hepatic transaminase levels may infrequently occur with cladribine therapy (Prod Info cladribine intravenous injection, 2014; Ogura et al, 2004).
    b) In a study of patients with indolent non-Hodgkins lymphoma treated with cladribine, elevated transaminases occurred in 25% of patients (Blum et al, 2006).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ABNORMAL RENAL FUNCTION
    1) WITH POISONING/EXPOSURE
    a) Renal dysfunction, including anuria and elevated serum creatinine levels, was reported in 19% of patients (n=31) within 7 to 13 days after beginning high-dose cladribine therapy (4 to 9 times the recommended dose for treatment of hairy cell leukemia) as a continuous infusion. Several patients were also receiving other medications with a potential for nephrotoxicity. The renal dysfunction appeared to be reversible in two of the patients (Prod Info cladribine intravenous injection, 2014).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS4291-63-8 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.2) SUMMARY/HUMAN
    A) Cladribine has been associated with secondary myelodysplastic syndrome in humans.
    3.21.3) HUMAN STUDIES
    A) MYELODYSPLASTIC SYNDROME
    1) In a study of 43 patients with B-cell lymphoma or mycosis fungoides treated with cladribine, myelodysplastic syndrome developed in 4 patients 13 months to 2 years after completing therapy; 3 of these patients had associated refractory anemia (Ogura et al, 2004).

Genotoxicity

    A) Cladribine was clastogenic in the mouse bone marrow micronucleus test and as chromosome aberrations in Chinese hamster ovary cells; however, cladribine was not mutagenic in the Ames and Chinese hamster ovary cell gene mutation tests and did not induce unscheduled DNA synthesis in primary rat hepatocyte cultures (Prod Info cladribine injection, 2005).
    B) Cladribine caused the accumulation of DNS strand breaks within mammalian cells in culture and was also incorporated into the DNA of human lymphoblastic leukemia cells (Prod Info cladribine injection, 2005).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery.
    B) Monitor serum electrolytes, renal function and hepatic enzymes.
    C) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    D) Monitor for clinical evidence of peripheral neuropathy for several weeks after overdose.

Methods

    A) CHROMATOGRAPHY
    1) Reversed phase high-performance liquid chromatography with solid-phase extraction was utilized for determination of cladribine and its metabolite, 2-chloroadenine, in human plasma and urine. The limits of detection for cladribine and 2-chloroadenine in plasma were 1 and 2 nmol/L, respectively. The limit of detection for both compounds in urine was 100 nmol/L (Albertioni et al, 1994).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients should be closely monitored in an inpatient setting, with frequent monitoring of vital signs (every 4 hours for the first 24 hours), and daily monitoring of CBC with differential until bone marrow suppression is resolved.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) There is no data to support home management.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult an oncologist, medical toxicologist and/or poison center for assistance in managing patients with an overdose.
    6.3.2.4) PATIENT TRANSFER/PARENTERAL
    A) Patients with large overdoses or severe neutropenia may benefit from early transfer to a cancer treatment or bone marrow transplant center.

Monitoring

    A) Monitor serial CBC (with differential) and platelet count until there is evidence of bone marrow recovery.
    B) Monitor serum electrolytes, renal function and hepatic enzymes.
    C) Monitor for clinical evidence of infection, with particular attention to: odontogenic infection, oropharynx, esophagus, soft tissues particularly in the perirectal region, exit and tunnel sites of central venous access devices, upper and lower respiratory tracts, and urinary tract.
    D) Monitor for clinical evidence of peripheral neuropathy for several weeks after overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Decontamination is not necessary in most situations as cladribine is administered IV.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment should include recommendations listed in the PARENTERAL EXPOSURE section when appropriate.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

    A) HEMODIALYSIS
    1) It is unknown whether cladribine can be removed from the circulation via hemodialysis or hemofiltration; however, due to cladribine's large volume of distribution (9 L/kg) indicating extensive distribution into the tissues, it is unlikely that hemodialysis or hemofiltration would be successful as enhanced elimination techniques (Prod Info cladribine intravenous injection, 2014).

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose of cladribine has not been established. ADULT: Polyneuropathy and acute nephrotoxicity has been reported following cladribine doses approximately 4 to 9 times the recommended dose indicated for the treatment of hairy cell leukemia. PEDIATRIC: Irreversible myelosuppression and fatal systemic bacterial or fungal infections occurred in pediatric patients who received 10.7 mg/m(2)/day for 5 days (2 times the recommended dose for treatment of hairy cell leukemia).
    B) THERAPEUTIC DOSE: ADULT: Maximum recommended dose is 0.09 mg/kg/day as a 7-day continuous infusion. PEDIATRIC: Safety and efficacy have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) ACTIVE HAIRY CELL LEUKEMIA: 0.09 mg/kg/day as a continuous infusion for 7 days as a single course (Prod Info LEUSTATIN(R) intravenous injection, 2012)
    7.2.2) PEDIATRIC
    A) Safety and efficacy in the pediatric or adolescent population have not been established (Prod Info LEUSTATIN(R) intravenous injection, 2012).
    B) In a small study, continuous IV doses of 3 to 10.7 mg/m(2)/day for 5 days were administered to patients 1 to 21 years old with relapsed acute leukemia. Dose-limiting toxicity was severe myelosuppression with profound neutropenia and thrombocytopenia. Three out of 7 patients developed permanent myelosuppression and fatal systemic bacterial or fungal infections (Prod Info LEUSTATIN(R) intravenous injection, 2012).

Minimum Lethal Exposure

    A) PEDIATRIC: Irreversible myelosuppression and fatal systemic bacterial or fungal infections occurred in 3 of 7 pediatric patients (1- to 21- years-old with relapsed acute leukemia) who received cladribine, 10.7 mg/m(2)/day for 5 days (2 times the recommended dose for treatment of hairy cell leukemia), during a phase I study (Prod Info cladribine intravenous injection, 2014).

Maximum Tolerated Exposure

    A) During a phase I clinical trial, 21 patients received cladribine at doses of 0.10, 0.15, or 0.20 mg/kg/day as a 7-day continuous intravenous infusion for treatment of solid tumors. Following the second course of therapy, one of seven patients developed grade 4 thrombocytopenia at the 0.10 mg/kg/day dose level, and at the 0.15 mg/kg/day dose level, grade 4 thrombocytopenia was reported in 2 patients and grade 3 and 4 neutropenia were reported in 3 and 2 patients, respectively. The results of this study indicated that the maximum tolerated doses of cladribine for the treatment of solid tumors is 0.10 mg/kg/day administered as a 7-day continuous intravenous infusion (Guchelaar et al, 1994).
    B) Renal dysfunction, including anuria and elevated serum creatinine levels, was reported in 19% of the patients (n=31) within 7 to 13 days after beginning high-dose cladribine therapy (4 to 9 times the recommended dose for treatment of hairy cell leukemia) as a continuous infusion. Several patients were also receiving other medications with a potential for nephrotoxicity. The renal dysfunction appeared to be reversible in two of the patients (Prod Info cladribine intravenous injection, 2014).
    C) During a dose escalation study, axonal peripheral polyneuropathy was reported following high-dose cladribine therapy at doses of 19 to 21 mg/m(2)/day (approximately 4 times the recommended dose indicated for the treatment of hairy cell leukemia) (Prod Info cladribine intravenous injection, 2014; Vahdat et al, 1994).
    D) In a study comparing a dosing schedule of 0.12 mg/kg/day for 5 days (repeated monthly) to 0.12 mg/kg once a week for 6 weeks, no significant differences in rates of infection, neutropenia, anemia, or death were observed (Robak et al, 2007).
    E) PEDIATRIC
    1) Doses of 3 to 5.2 mg/m(2)/day for 5 days were associated with minor toxicity in a small phase I study in children with leukemia (Guchelaar et al, 1994).

Workplace Standards

    A) ACGIH TLV Values for CAS4291-63-8 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS4291-63-8 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS4291-63-8 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS4291-63-8 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (INTRAPERITONEAL)MOUSE:
    1) 150 mg/kg (RTECS, 2006)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) The exact mechanism of action of cladribine has not been fully elucidated. It is a deoxyadenosine analog substituted at the 2 position with chlorine. This substitution renders the compound relatively resistant to deamination by adenosine deaminase, such that intracellular accumulation of cladribine is permitted. Intracellularly, the drug is phosphorylated by deoxycytidine kinase and subsequently incorporated into DNA. Cladribine is considered a prodrug, making intracellular phosphorylation necessary for cytotoxic effects to occur. In vitro, nanomole concentrations of cladribine block cellular proliferation in a variety of lymphoid tissues; breaks in DNA can be observed at 4 hours, and cell death occurs within 48 hours. While this mechanism implies a selective effect on proliferating cells, cladribine is also toxic to resting lymphocytes. The mechanism by which cladribine kills slowly-dividing cells is unclear, but is thought to be related to the high deoxycytidine kinase activity and ATP depletion in lymphocytes, which would confer considerable tissue selectivity to the drug (Robak et al, 2005; Gribbin, 1991; Piro et al, 1988).
    B) In vitro studies have shown that incubation of lymphoblasts with cladribine 0.3 mcmol/L results in intracellular accumulation of cladribine triphosphate at a concentration of 2 mcmol/L within 15 minutes. DNA synthesis is inhibited by 90% within 30 minutes. Marked inhibition of metabolism of cytidine to deoxycytidine nucleotides is also observed, indicating significant inhibition of ribonucleotide reductase. Thus, intracellular depletion of deoxyribonucleotide pools may also account for the antiproliferative activity of the drug (Griffig et al, 1989).

Physicochemical

Physical Characteristics

    A) Cladribine is a clear, colorless, sterile, preservative-free, isotonic solution, with a pH range of 5.5 to 8 (Prod Info cladribine injection, 2005)

Molecular Weight

    A) 285.7 (Sweetman, 2005)

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