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Cladribine
Overview
What is Cladribine?
Cladribine Injection (also commonly known as 2-chloro-2΄-deoxy- β -D-adenosine) is a synthetic antineoplastic agent for continuous intravenous infusion. It is a clear, colorless, sterile, preservative-free, isotonic solution. Cladribine Injection is available in single-use vials containing 10 mg (1 mg/mL) of cladribine, a chlorinated purine nucleoside analog. Each milliliter of Cladribine Injection 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-β-D-erythropento-furanosyl) purine and the structure is represented below:
What does Cladribine look like?
What are the available doses of Cladribine?
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What should I talk to my health care provider before I take Cladribine?
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How should I use Cladribine?
The recommended dose and schedule of Cladribine Injection for active Hairy Cell Leukemia is as a single course given by continuous infusion for 7 consecutive days at a dose of 0.09 mg/kg/day. Deviations from this dosage regimen are not advised. If the patient does not respond to the initial course of Cladribine Injection for Hairy Cell Leukemia, it is unlikely that they will benefit from additional courses. Physicians should consider delaying or discontinuing the drug if neurotoxicity or renal toxicity occurs (see ).
Specific risk factors predisposing to increased toxicity from Cladribine have not been defined. In view of the known toxicities of agents of this class, it would be prudent to proceed carefully in patients with known or suspected renal insufficiency or severe bone marrow impairment of any etiology. Patients should be monitored closely for hematologic and non-hematologic toxicity (see and ).
What interacts with Cladribine?
Cladribine Injection is contraindicated in those patients who are hypersensitive to this drug or any of its components.
What are the warnings of Cladribine?
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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 Injection, is recommended (see ).
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.
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 )
Pregnancy Category D:
Cladribine Injection should not be given during pregnancy.
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/m) and increased resorptions, reduced litter size and increased fetal malformations were observed when mice received 3.0 mg/kg/day (9 mg/m). Fetal death and malformations were observed in rabbits that received 3.0 mg/kg/day (33.0 mg/m). No fetal effects were seen in mice at 0.5 mg/kg/day (1.5 mg/m) or in rabbits at 1.0 mg/kg/day (11.0 mg/m).
Although there is no evidence of teratogenicity in humans due to Cladribine, other drugs which inhibit DNA synthesis (e.g., methotrexate and aminopterin) have been reported to be teratogenic in humans. Cladribine has been shown to be embryotoxic in mice when given at doses equivalent to the recommended dose.
There are no adequate and well controlled studies in pregnant women. 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. Women of childbearing age should be advised to avoid becoming pregnant.
What are the precautions of Cladribine?
General:
Cladribine Injection 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 and ).
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 and ).
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 ).
Rare cases of tumor lysis syndrome have been reported in patients treated with cladribine with other hematologic malignancies having a high tumor burden.
Cladribine Injection must be diluted in designated intravenous solutions prior to administration (see ).
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/L by Day 12, the mean Absolute Neutrophil Count reached 1500 x 10/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 Injection. Caution should be exercised if Cladribine Injection is administered before, after, or in conjunction with other drugs known to cause immunosuppression or myelosuppression. (see )
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 (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 (chromosome aberrations in Chinese hamster ovary cells) and (mouse bone marrow micronucleus test).
Impairment of Fertility:
When administered intravenously to Cynomolgus monkeys, cladribine has been shown to cause suppression of rapidly generating cells, including testicular cells. The effect on human fertility is unknown.
Pregnancy:
Pregnancy Category D: (see ).
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 1-21 years old with relapsed acute leukemia, Cladribine was given by continuous intravenous infusion in doses ranging from 3 to 10.7 mg/m/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/m/day), 3 of 7 patients developed irreversible myelosuppression and fatal systemic bacterial or fungal infections. No unique toxicities were noted in this study (see and ).
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.
What are the side effects of Cladribine?
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%. Other adverse experiences reported frequently during the first 14 days after initiating treatment included: fatigue (45%), nausea (28%), rash (27%), headache (22%) and injection site reactions (19%). 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/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/L) developed in 12% of patients, compared to 4% in whom it was noted initially.
During the first month, 54 of 196 patients (28%) exhibited documented evidence of infection. Serious infections (e.g., septicemia, pneumonia) were reported in 6% of all patients; the remainder were mild or moderate. Several deaths were attributable to infection and/or complications related to the underlying disease. During the second month, the overall rate of documented infection was 6%; these infections were mild to moderate and no severe systemic infections were seen. After the third month, the monthly incidence of infection was either less than or equal to that of the months immediately preceding Cladribine therapy.
During the first month, 11% of patients experienced severe fever (i.e., ≥104°F). Documented infections were noted in fewer than one-third of febrile episodes. Of the 196 patients studied, 19 were noted to have a documented infection in the month prior to treatment. In the month following treatment, there were 54 episodes of documented infection: 23 (42%) were bacterial, 11 (20%) were viral and 11 (20%) were fungal. Seven (7) of 8 documented episodes of herpes zoster occurred during the month following treatment. Fourteen (14) of 16 episodes of documented fungal infections occurred in the first two months following treatment. Virtually all of these patients were treated empirically with antibiotics. (see and
Analysis of lymphocyte subsets indicates that treatment with cladribine is associated with prolonged depression of the CD4 counts. Prior to treatment, the mean CD4 count was 766/μL. The mean CD4 count nadir, which occurred 4 to 6 months following treatment, was 272/μL. Fifteen (15) months after treatment, mean CD4 counts remained below 500/μL. CD8 counts behaved similarly, though increasing counts were observed after 9 months. The clinical significance of the prolonged CD4 lymphopenia is unclear.
Another event of unknown clinical significance includes the observation of prolonged bone marrow hypocellularity. Bone marrow cellularity of < 35% was noted after 4 months in 42 of 124 patients (34%) treated in the two pivotal trials. This hypocellularity was noted as late as day 1010. It is not known whether the hypocellularity is the result of disease related marrow fibrosis or if it is the result of cladribine toxicity. There was no apparent clinical effect on the peripheral blood counts.
The vast majority of rashes were mild and occurred in patients who were receiving or had recently been treated with other medications (e.g., allopurinol or antibiotics) known to cause rash.
Most episodes of nausea were mild, not accompanied by vomiting, and did not require treatment with antiemetics. In patients requiring antiemetics, nausea was easily controlled, most frequently with chlorpromazine.
Adverse reactions reported during the first 2 weeks following treatment initiation (regardless of relationship to drug) by > 5% of patients included:
Body as a Whole
(9%), malaise (7%), trunk pain (6%)
Gastrointestinal
(10%), constipation (9%), abdominal pain (6%)
Hemic/Lymphatic
Nervous System
Cardiovascular System
Respiratory System
Skin/Subcutaneous Tissue
Musculoskeletal System
Adverse experiences related to intravenous administration included: injection site reactions (9%) (i.e., redness, swelling, pain), thrombosis (2%), phlebitis (2%) and a broken catheter (1%). These appear to be related to the infusion procedure and/or indwelling catheter, rather than the medication or the vehicle. From Day 15 to the last follow-up visit, the only events reported by > 5% of patients were: fatigue (11%), rash (10%), headache (7%), cough (7%), and malaise (5%).
For a description of adverse reactions associated with use of high doses in non-Hairy Cell Leukemia patients, see .
The following additional adverse events have been reported since the drug became commercially available. These adverse events have been reported primarily in patients who received multiple courses of Cladribine Injection:
Hematologic
Hepatic:
Nervous System
Respiratory System
Skin/Subcutaneous
Opportunistic infections have occurred in the acute phase of treatment due to the immunosuppression mediated by Cladribine Injection.
What should I look out for while using Cladribine?
Cladribine Injection is contraindicated in those patients who are hypersensitive to this drug or any of its components.
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 Injection, is recommended (see ).
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.
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 )
What might happen if I take too much Cladribine?
High doses of Cladribine have been associated with: irreversible neurologic toxicity (paraparesis/quadriparesis), acute nephrotoxicity, and severe bone marrow suppression resulting in neutropenia, anemia and thrombocytopenia (see ). There is no known specific antidote to overdosage. Treatment of overdosage consists of discontinuation of Cladribine, careful observation and appropriate supportive measures. It is not known whether the drug can be removed from the circulation by dialysis or hemofiltration.
How should I store and handle Cladribine?
Storage:Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. When reconstituted, keep solution refrigerated. Use within 48 hours. Discard unused portion. Keep out of reach of children. PEG-3350, sodium chloride, sodium bicarbonate and potassium chloride for oral solution with Flavor Packs NDC 10572-400-01 Lemon-Lime Flavor PEG-3350, sodium chloride,sodium bicarbonate and potassium chloride for oral solution NDC 10572-302-01 Storage:Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. When reconstituted, keep solution refrigerated. Use within 48 hours. Discard unused portion. Keep out of reach of children. PEG-3350, sodium chloride, sodium bicarbonate and potassium chloride for oral solution with Flavor Packs NDC 10572-400-01 Lemon-Lime Flavor PEG-3350, sodium chloride,sodium bicarbonate and potassium chloride for oral solution NDC 10572-302-01 Storage:Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. When reconstituted, keep solution refrigerated. Use within 48 hours. Discard unused portion. Keep out of reach of children. PEG-3350, sodium chloride, sodium bicarbonate and potassium chloride for oral solution with Flavor Packs NDC 10572-400-01 Lemon-Lime Flavor PEG-3350, sodium chloride,sodium bicarbonate and potassium chloride for oral solution NDC 10572-302-01 Storage:Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. When reconstituted, keep solution refrigerated. Use within 48 hours. Discard unused portion. Keep out of reach of children. PEG-3350, sodium chloride, sodium bicarbonate and potassium chloride for oral solution with Flavor Packs NDC 10572-400-01 Lemon-Lime Flavor PEG-3350, sodium chloride,sodium bicarbonate and potassium chloride for oral solution NDC 10572-302-01 Cladribine Injection is supplied as a sterile, preservative-free, isotonic solution containing 10 mg (1 mg/mL) of Cladribine as 10 mL filled into a single-use clear flint glass vial, individually boxed. Store in refrigerator at 2° to 8°C (36° to 46°F). Protect from light during storage.Cladribine Injection is supplied as a sterile, preservative-free, isotonic solution containing 10 mg (1 mg/mL) of Cladribine as 10 mL filled into a single-use clear flint glass vial, individually boxed. Store in refrigerator at 2° to 8°C (36° to 46°F). Protect from light during storage.
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
The selective toxicity of 2-chloro-2΄-deoxy-β-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- β -D-adenosine monophosphate (2-CdAMP). Since 2-chloro-2΄-deoxy- β -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- β -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- β -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- β -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.
Non-Clinical Toxicology
Cladribine Injection is contraindicated in those patients who are hypersensitive to this drug or any of its components.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 Injection, is recommended (see ).
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.
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 )
There are no known drug interactions with Cladribine Injection. Caution should be exercised if Cladribine Injection is administered before, after, or in conjunction with other drugs known to cause immunosuppression or myelosuppression. (see )
Cladribine Injection 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 and ).
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 and ).
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 ).
Rare cases of tumor lysis syndrome have been reported in patients treated with cladribine with other hematologic malignancies having a high tumor burden.
Cladribine Injection must be diluted in designated intravenous solutions prior to administration (see ).
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%. Other adverse experiences reported frequently during the first 14 days after initiating treatment included: fatigue (45%), nausea (28%), rash (27%), headache (22%) and injection site reactions (19%). 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/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/L) developed in 12% of patients, compared to 4% in whom it was noted initially.
During the first month, 54 of 196 patients (28%) exhibited documented evidence of infection. Serious infections (e.g., septicemia, pneumonia) were reported in 6% of all patients; the remainder were mild or moderate. Several deaths were attributable to infection and/or complications related to the underlying disease. During the second month, the overall rate of documented infection was 6%; these infections were mild to moderate and no severe systemic infections were seen. After the third month, the monthly incidence of infection was either less than or equal to that of the months immediately preceding Cladribine therapy.
During the first month, 11% of patients experienced severe fever (i.e., ≥104°F). Documented infections were noted in fewer than one-third of febrile episodes. Of the 196 patients studied, 19 were noted to have a documented infection in the month prior to treatment. In the month following treatment, there were 54 episodes of documented infection: 23 (42%) were bacterial, 11 (20%) were viral and 11 (20%) were fungal. Seven (7) of 8 documented episodes of herpes zoster occurred during the month following treatment. Fourteen (14) of 16 episodes of documented fungal infections occurred in the first two months following treatment. Virtually all of these patients were treated empirically with antibiotics. (see and
Analysis of lymphocyte subsets indicates that treatment with cladribine is associated with prolonged depression of the CD4 counts. Prior to treatment, the mean CD4 count was 766/μL. The mean CD4 count nadir, which occurred 4 to 6 months following treatment, was 272/μL. Fifteen (15) months after treatment, mean CD4 counts remained below 500/μL. CD8 counts behaved similarly, though increasing counts were observed after 9 months. The clinical significance of the prolonged CD4 lymphopenia is unclear.
Another event of unknown clinical significance includes the observation of prolonged bone marrow hypocellularity. Bone marrow cellularity of < 35% was noted after 4 months in 42 of 124 patients (34%) treated in the two pivotal trials. This hypocellularity was noted as late as day 1010. It is not known whether the hypocellularity is the result of disease related marrow fibrosis or if it is the result of cladribine toxicity. There was no apparent clinical effect on the peripheral blood counts.
The vast majority of rashes were mild and occurred in patients who were receiving or had recently been treated with other medications (e.g., allopurinol or antibiotics) known to cause rash.
Most episodes of nausea were mild, not accompanied by vomiting, and did not require treatment with antiemetics. In patients requiring antiemetics, nausea was easily controlled, most frequently with chlorpromazine.
Adverse reactions reported during the first 2 weeks following treatment initiation (regardless of relationship to drug) by > 5% of patients included:
Body as a Whole
(9%), malaise (7%), trunk pain (6%)
Gastrointestinal
(10%), constipation (9%), abdominal pain (6%)
Hemic/Lymphatic
Nervous System
Cardiovascular System
Respiratory System
Skin/Subcutaneous Tissue
Musculoskeletal System
Adverse experiences related to intravenous administration included: injection site reactions (9%) (i.e., redness, swelling, pain), thrombosis (2%), phlebitis (2%) and a broken catheter (1%). These appear to be related to the infusion procedure and/or indwelling catheter, rather than the medication or the vehicle. From Day 15 to the last follow-up visit, the only events reported by > 5% of patients were: fatigue (11%), rash (10%), headache (7%), cough (7%), and malaise (5%).
For a description of adverse reactions associated with use of high doses in non-Hairy Cell Leukemia patients, see .
The following additional adverse events have been reported since the drug became commercially available. These adverse events have been reported primarily in patients who received multiple courses of Cladribine Injection:
Hematologic
Hepatic:
Nervous System
Respiratory System
Skin/Subcutaneous
Opportunistic infections have occurred in the acute phase of treatment due to the immunosuppression mediated by Cladribine Injection.
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72Tips
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