necessary [0.05:12 g/dL, Platelets >100 x 10 9 /L, Absolute Neutrophil Count (ANC) >1,500 x 10 6 /L) was achieved by 92% of evaluable patients. The median time to normalization of peripheral counts was nine weeks from the start of treatment (Range: 2 to 72). The median time to normalization of Platelet Count was two weeks, the median time to normalization of ANC was five weeks and the median time to normalization of Hemoglobin was eight weeks. With normalization of Platelet Count and Hemoglobin, requirements for platelet and RBC transfusions were abolished after Months 1 and 2, respectively, in those patients with complete response. Platelet recovery may be delayed in a minority of patients with severe baseline thrombocytopenia. Corresponding to normalization of ANC, a trend toward a reduced incidence of infection was seen after the third month, when compared to the months immediately preceding Cladribine injection therapy (see also WARNINGS , PRECAUTIONS and ADVERSE REACTIONS ). Cladribine INJECTION TREATMENT IN PATIENTS WITH HAIRY CELL LEUKEMIA TIME TO NORMALIZATION OF PERIPHERAL BLOOD COUNTS Parameter Median Time to Normalization of Count* Platelet Count 2 weeks Absolute Neutrophil Count 5 weeks Hemoglobin 8 weeks ANC, Hemoglobin and Platelet Count 9 weeks *Day 1 = First day of infusion For patients achieving a complete response, the median time to response (i.e., absence of hairy cells in bone marrow and peripheral blood together with normalization of peripheral blood parameters), measured from treatment start, was approximately four months. Since bone marrow aspiration and biopsy were frequently not performed at the time of peripheral blood normalization, the median time to complete response may actually be shorter than that which was recorded. At the time of data cut-off, the median duration of complete response was greater than eight months and ranged to 25+ months. Among 93 responding patients, seven had shown evidence of disease progression at the time of the data cut-off. In four of these patients, disease was limited to the bone marrow without peripheral blood abnormalities (pathologic progression), while in three patients there were also peripheral blood abnormalities (clinical progression). Seven patients who did not respond to a first course of Cladribine injection received a second course of therapy. In the five patients who had adequate follow-up, additional courses did not appear to improve their overall response. INDICATIONS AND USAGE: Cladribine Injection, USP is indicated for the treatment of active Hairy Cell Leukemia as defined by clinically significant anemia, neutropenia, thrombocytopenia or disease-related symptoms. CONTRAINDICATIONS: Cladribine Injection is contraindicated in those patients who are hypersensitive to this drug or any of its components. WARNINGS: Due to increased risk of infection in the setting of immunosuppression with chemotherapy including Cladribine, it is recommended not to administer live attenuated vaccines to patients receiving Cladribine injection. Severe bone marrow suppression, including neutropenia, anemia and thrombocytopenia, has been commonly observed in patients treated with Cladribine injection, 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 injection, 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 injection 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 four to eight weeks after treatment with Cladribine injection, is recommended (see PRECAUTIONS ). Fever (T 100 F) was associated with the use of Cladribine injection 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 1,000), including 62 patients (32%) with severe neutropenia (i.e., ANC 500). In a Phase I investigational study using Cladribine injection in high doses (four to nine 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 (two cases) received Cladribine for 7 to 14 days prior to bone marrow transplantation. During infusion, eight 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, six patients (19%) developed manifestations of renal dysfunction (e.g., acidosis, anuria, elevated serum creatinine, etc.) and five required dialysis. Several of these patients were also being treated with other medications having known nephrotoxic potential. Renal dysfunction was reversible in two of these patients. In the four patients whose renal function had not recovered at the time of death, autopsies were performed; in two 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 four 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 seven consecutive days), there have been no reports of nephrologic toxicities. Serious (e.g. respiratory infection, pneumonia and viral skin infections), including fatal infections (e.g., sepsis) were reported (see ADVERSE REACTIONS ). Of the 196 Hairy Cell Leukemia patients entered in the two trials, there were eight deaths following treatment. Of these, six were of infectious etiology, including three pneumonias, and two occurred in the first month following Cladribine therapy. Of the eight deaths, six occurred in previously treated patients who were refractory to α-interferon. Benzyl alcohol is a constituent of the recommended diluent for the seven-day infusion solution. Benzyl alcohol has been reported to be associated with a fatal Gasping Syndrome in premature infants (see DOSAGE AND ADMINISTRATION ). Pregnancy Category D Cladribine can cause fetal harm when administered to a pregnant woman. Although there is no evidence of teratogenicity in humans due to Cladribine, other drugs which inhibit DNA synthesis have been reported to be teratogenic in humans. Cladribine is teratogenic in animals. Advise females of reproductive potential to use highly effective contraception during treatment with Cladribine. If Cladribine is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Cladribine is teratogenic in mice and rabbits and consequently has the potential to cause fetal harm when administered to a pregnant woman. A significant increase in fetal variations was observed in mice receiving 1.5 mg/kg/day (4.5 mg/m 2 ) and increased resorptions, reduced litter size and increased fetal malformations were observed when mice received 3 mg/kg/day (9 mg/m 2 ). Fetal death and malformations were observed in rabbits that received 3 mg/kg/day (33 mg/m 2 ). No fetal effects were seen in mice at 0.5 mg/kg/day (1.5 mg/m 2 ) or in rabbits at 1 mg/kg/day (11 mg/m 2 ). PRECAUTIONS: 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 four to eight weeks posttreatment, is recommended to detect the development of anemia, neutropenia and thrombocytopenia and for early detection of any potential sequelae (e.g., infection or bleeding). As with other potent chemotherapeutic agents, monitoring of renal and hepatic function is also recommended, especially in patients with underlying kidney or liver dysfunction (see WARNINGS and ADVERSE REACTIONS ). Fever was a frequently observed side effect during the first month on study. Since the majority of fevers occurred in neutropenic patients, patients should be closely monitored during the first month of treatment and empiric antibiotics should be initiated as clinically indicated. Although 69% of patients developed fevers, less than 1/3 of febrile events were associated with documented infection. Given the known myelosuppressive effects of Cladribine, practitioners should carefully evaluate the risks and benefits of administering this drug to patients with active infections (see WARNINGS and ADVERSE REACTIONS ). There are inadequate data on dosing of patients with renal or hepatic insufficiency. Development of acute renal insufficiency in some patients receiving high doses of Cladribine has been described. Until more information is available, caution is advised when administering the drug to patients with known or suspected renal or hepatic insufficiency (see WARNINGS ). Rare cases of tumor lysis syndrome have been reported in patients treated with Cladribine with other hematologic malignancies having a high tumor burden. Cladribine injection must be diluted in designated intravenous solutions prior to administration (see DOSAGE AND ADMINISTRATION ). Laboratory Tests During and following treatment, the patient s hematologic profile should be monitored regularly to determine the degree of hematopoietic suppression. In the clinical studies, following reversible declines in all cell counts, the mean Platelet Count reached 100 x 10 9 /L by Day 12, the mean Absolute Neutrophil Count reached 1,500 x 10 6 /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 WARNINGS ). Carcinogenesis No animal carcinogenicity studies have been conducted with Cladribine. However, its carcinogenic potential cannot be excluded based on demonstrated genotoxicity of Cladribine. Mutagenesis As expected for compounds in this class, the actions of Cladribine yield DNA damage. In mammalian cells in culture, Cladribine caused the accumulation of DNA strand breaks. Cladribine was also incorporated into DNA of human lymphoblastic leukemia cells. Cladribine was not mutagenic in vitro (Ames and Chinese hamster ovary cell gene mutation tests) and did not induce unscheduled DNA synthesis in primary rat hepatocyte cultures. However, Cladribine was clastogenic both in vitro (chromosome aberrations in Chinese hamster ovary cells) and in vivo (mouse bone marrow micronucleus test). Impairment of Fertility The effect on human fertility is unknown. When administered intravenously to Cynomolgus monkeys, Cladribine has been shown to cause suppression of rapidly generating cells, including testicular cells. Pregnancy Pregnancy Category D (see WARNINGS ). Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Cladribine, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother. Pediatric Use Safety and effectiveness in pediatric patients have not been established. In a Phase I study involving patients 1 to 21 years old with relapsed acute leukemia, Cladribine injection was given by continuous intravenous infusion in doses ranging from 3 to 10.7 mg/m 2 /day for five 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 2 /day), three of seven patients developed irreversible myelosuppression and fatal systemic bacterial or fungal infections. No unique toxicities were noted in this study (1) (see WARNINGS and ADVERSE REACTIONS ). Geriatric Use Clinical studies of Cladribine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients. ADVERSE REACTIONS: Clinical Trials Experience Adverse drug reactions reported by 1% of Cladribine-treated patients with HCL noted in the HCL clinical dataset (studies K90-091 and L91-048, n=576) are shown in the table below. Adverse Drug Reactions in 1% of Patients Treated with Cladribine in HCL Clinical Trials System Organ Class Preferred Term Cladribine (n=576) % Blood and Lymphatic System Disorder (see also sections WARNINGS and PRECAUTIONS ) Anemia 1 Febrile neutropenia 8 Psychiatric Disorders Anxiety 1 Insomnia 3 Nervous System Disorders Dizziness 6 Headache 14 Cardiac Disorders Tachycardia 2 Respiratory, Thoracic and Mediastinal Disorders Breath sounds abnormal 4 Cough 7 Dyspnea* 5 Rales 1 Gastrointestinal Disorders Abdominal pain** 4 Constipation 4 Diarrhea 7 Flatulence 1 Nausea 22 Vomiting 9 Skin and Subcutaneous Tissue Disorders Ecchymosis 2 Hyperhidrosis 3 Petechiae 2 Pruritus 2 Rash*** 16 Musculoskeletal, Connective Tissue, and Bone Disorders Arthralgia 3 Myalgia 6 Pain**** 6 General Disorders and Administration Site Conditions (see also sections WARNINGS and PRECAUTIONS ) Administration site reaction***** 11 Asthenia 6 Chills 2 Decreased appetite 8 Fatigue 31 Malaise 5 Muscular weakness 1 Edema peripheral 2 Pyrexia 33 Injury, Poisoning and Procedural Complications Contusion 1 * Dyspnea includes dyspnea, dyspnea exertional, and wheezing ** Abdominal pain includes abdominal discomfort, abdominal pain, and abdominal pain (lower and upper) *** Rash includes erythema, rash, and rash (macular, macula-papular, papular, pruritic, pustular and erythematous) **** Pain includes pain, back pain, chest pain, arthritis pain, bone pain, and pain in extremity *****Administration site reaction includes administration site reaction, catheter site (cellulitis, erythema, hemorrhage, and pain), and infusion site reaction (erythema, edema, and pain) The following 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%. Most non-hematologic adverse experiences were mild to moderate in severity. Myelosuppression was frequently observed during the first month after starting treatment. Neutropenia (ANC]} FEATURED: CAR-T Cell Therapy Overview Mechanism of Action KTE-C19 Studies KTE-C19 Cancer Targets Adverse Events Manufacturing Drug Status Rx Availability Prescription only D Pregnancy Category Positive evidence of risk N/A CSA Schedule Not a controlled drug Approval History Drug history at FDA Manufacturers Mylan Pharmaceuticals Inc. Fresenius Kabi USA, LLC Drug Class Antimetabolites Related Drugs antimetabolites methotrexate , fluorouracil , hydroxyurea , Xeloda , capecitabine , Hydrea Hairy Cell Leukemia Intron A , Leustatin , Roferon-A , More... Cladribine Rating 1 User Review 9.5 /10 1 User Review 9.5 Rate it!} } try to
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