Leustatin Side Effects

Generic Name: cladribine

Please note - some side effects for Leustatin may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Leustatin - for the Consumer

Leustatin

All medicines may cause side effects, but many people have no, or minor side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Leustatin:

Constipation; decreased appetite; diarrhea; dizziness; headache; mild tiredness or weakness; muscle or joint pain; nausea; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur when using Leustatin:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); back or side pain; black, tarry stools; blood in the urine; chest pain or tightness; cough; fever, chills, or sore throat; irregular heartbeat; irritation or pain at the injection site; numbness, tingling, or burning of the hands or feet; painful or difficult urination; persistent loss of appetite, unusual feeling of fullness, or unusual weight loss; severe or persistent vomiting; severe tiredness or weakness; shortness of breath; swelling (eg, of the hands or feet); unusual bleeding or bruising; yellowing of the skin or eyes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Leustatin Side Effects - for the Professional

Leustatin

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 × 106/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 × 109/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 Leustatin 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.

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: fever (69%), fatigue (45%), chills (9%), asthenia (9%), diaphoresis (9%), malaise (7%), trunk pain (6%)

Gastrointestinal: nausea (28%), decreased appetite (17%), vomiting (13%), diarrhea (10%), constipation (9%), abdominal pain (6%)

Hemic/Lymphatic: purpura (10%), petechiae (8%), epistaxis (5%)

Nervous System: headache (22%), dizziness (9%), insomnia (7%)

Cardiovascular System: edema (6%), tachycardia (6%)

Respiratory System: abnormal breath sounds (11%), cough (10%), abnormal chest sounds (9%), shortness of breath (7%)

Skin/Subcutaneous Tissue: rash (27%), injection site reactions (19%), pruritis (6%), pain (6%), erythema (6%)

Musculoskeletal System: myalgia (7%), arthralgia (5%)

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 WARNINGS.

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 Leustatin Injection:

Hematologic: bone marrow suppression with prolonged pancytopenia, including some reports of aplastic anemia; hemolytic anemia, which was reported in patients with lymphoid malignancies, occurring within the first few weeks following treatment. Rare cases of myelodysplastic syndrome have been reported.

Hepatic: reversible, generally mild increases in bilirubin and transaminases.

Nervous System: Neurological toxicity; however, severe neurotoxicity has been reported rarely following treatment with standard cladribine dosing regimens.

Respiratory System: pulmonary interstitial infiltrates; in most cases, an infectious etiology was identified.

Skin/Subcutaneous: urticaria, hypereosinophilia. In isolated cases Stevens-Johnson and toxic epidermal necrolysis have been reported in patients who were receiving or had recently been treated with other medications (e.g., allopurinol or antibiotics) known to cause these syndromes.

Opportunistic infections have occurred in the acute phase of treatment due to the immunosuppression mediated by Leustatin Injection.

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Side Effects by Body System - for Healthcare Professionals

Hematologic

Hematologic side effects may be severe, life-threatening, and persistent for up to six months. Profound myelosuppression has been observed in the majority of patients. Absolute neutropenia counts of less than 500/mm3, severe anemia (hemoglobin less than 8.5 g/dL), and thrombocytopenia (less than 20,000 mm3) have been reported in 70%, 37%, and 12% of patients, respectively. (Many of these patients had preexisting bone marrow impairment to a lesser extent.) Five percent to 10% of patients develop epistaxis, purpura, or petechiae. Rare cases of serious hemorrhage, including fatal pericardial tamponade, hemorrhagic stroke, and retinal hemorrhage have been reported. Approximately 28% of all treated patients develop infection(s), and 6% develop serious infection(s), such as sepsis or pneumonia. Eleven percent to 67% of patients develop fever, of which one-third are associated with documented infection.

Forty-four percent and 14% of treated patients require red blood cell and platelet transfusions, respectively. Platelet, leukocyte, and erythrocyte counts tend to recover by day 12, week 5, and week 8, respectively. Bone marrow hypocellularity of less than 35% can persist for up to three years. (Whether bone marrow hypocellularity is secondary to disease or cladribine and the clinical significance of this hypocellularity are unknown.) Persistent erythroid macrocytosis may be observed after multiple courses of cladribine.

Cladribine can significantly reduce CD4 (and CD8) lymphocyte counts, inducing a nadir at four to six months. The risk of infection, assuming bone marrow recovery, typically reverts to pretreatment risk three months after therapy. Data have revealed the etiology of infections to be bacterial in 42%, viral in 20%, and fungal in 20% of patients.

A single case of acute autoimmune hemolytic anemia (AIHA) has been associated with the use of cladribine in a patient with chronic lymphocytic leukemia (CLL). Since AIHA can occur at any time during the natural course of CLL, the association may be coincidental.

General

General, "whole-body" side effects include fever in approximately two-thirds of patients. Fever can be severe (greater than 104 degrees Fahrenheit) in 11% of patients and is associated with documented infection in 33% of cases. (Fever in the absence of infection is thought to be due to cytokine release.) Other general side effects include fatigue in 45%, chills in 9%, asthenia in 9%, diaphoresis in 9%, malaise in 7%, and trunk pain in 6% of patients.

Renal

Renal side effects including severe and acute renal failure have developed in patients who have received supertherapeutic doses (0.26 mg/kg per day) in experimental trials in which cladribine was used to ablate the bone marrow in preparation for transplantation. Renal function returned to normal in patients who survived the other complications of bone marrow transplantation. Such toxicity has never been observed at recommended doses.

Gastrointestinal

Gastrointestinal side effects include nausea in 28%, anorexia in 17%, vomiting in 13%, diarrhea in 10%, constipation in 9%, and abdominal pain in 6% of patients. Although mucositis is usually expected after the use of antineoplastic agents, it is an uncommon side effect from cladribine, perhaps because of the short term of exposure and low recommended dosage.

Dermatologic

Dermatologic side effects have been reported. The most common dermatologic side effect is rash in up to 28% of patients. Most rashes are mild to moderate in severity, and have been reported in patients who were also receiving other drugs that may cause rash, such as allopurinol or antibiotics. Although hair loss is usually expected after the use of antineoplastic agents, alopecia is an uncommon side effect from cladribine. Rare side effects also include epidermal necrolysis.

Nervous system

Profound (proximal > distal) extremity motor weakness has been described in some patients who received relatively large doses of 0.45 to 0.52 mg/kg per day. Some affected patients were unable to walk and experienced numbness, paresthesia, and hyperesthesia. Nerve conduction velocity studies in affected patients showed markedly decreased compound muscle action potential amplitude, absent or delayed F-wave and H-reflex responses, and (per EMG) polyphasic potentials without evidence of myopathic changes. Overall, the findings were consistent with a symmetric axonal peripheral polyneuropathy with prominent motor involvement.

Nervous system side effects have included mild to moderate paresthesias, weakness, somnolence, agitation, anxiety/depression, or hearing loss has been observed in 15% of patients who receive recommended dosages. However, severe neurologic complications have been reported at higher than recommended dosages, including severe paresthesias, paralysis, coma, seizures, toxic psychosis, cerebellar necrosis, suicidal ideation, ileus, irreversible deafness, and blindness. Other nervous system side effects include headache in 22%, dizziness in 9%, and insomnia in 7% of patients.

Local

Local side effects have included injection reactions in 19% of patients, pruritus, pain, or erythema at the IV site in 6% of patients, and peripheral vein thrombosis or phlebitis in 2% of patients.

Metabolic

Preventative measures include adequate hydration and judicious use of allopurinol. Treatment often consists of treatment of electrolyte disturbances, hydration, and diuresis. In rare circumstances, hemodialysis has become necessary.

Metabolic side effects have been reported. A metabolic concern, as with most antineoplastic therapy, is the development of the tumor lysis syndrome (TLS), which may occur within hours to a few days after therapy is begun. The TLS can present with hyperkalemia, hyperuricemia, hyperphosphatemia, hypocalcemia, and acute renal failure. Electrolyte abnormalities can induce cardiac arrhythmias and/or tetany.

Cardiovascular

Cardiovascular side effects are uncommon. Edema or tachycardia have each been reported in 6% of patients.

Musculoskeletal

Musculoskeletal side effects including arthralgias and myalgias have been reported in approximately 6% of patients.

Respiratory

Respiratory side effects including abnormal respiratory sounds or dyspnea have been reported in approximately 10% of patients. Cough has been reported in up to 7% of patients up to 2 weeks after therapy is withdrawn.

Hypersensitivity

Hypersensitivity side effects are uncommon. Rare cases of Stevens-Johnson syndrome manifested initially as erythema multiforme, progressing to toxic epidermal necrolysis have been associated with the use of cladribine.

Oncologic

Oncologic side effects have included one case of bone marrow granulomas. Theoretically, cladribine could cause new cancer since it incorporates into DNA. Animal data have revealed evidence of teratogenesis.

Cladribine was given to a 38-year-old man with hairy cell leukemia because of persistent neutropenia associated with alpha-2-interferon. Serial bone marrow biopsies, beginning with the diagnostic specimen and ending with a post-cladribine biopsy, revealed epithelioid granulomas adjacent to the residual hairy cell infiltration. No organisms were identified. A review of 38 bone marrow biopsies from other cases of hairy cell leukemia, 20 of which were taken after interferon therapy, failed to reveal evidence of granulomas.

Hepatic

Hepatic side effects have essentially only been reported among pediatric patients, in whom the recommended dosages exceed the adult dose by about twofold.

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