Cladribine

1 INDICATIONS AND USAGE Cladribine tablets are indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include relapsing-remitting disease and active secondary progressive disease in adults. Because of its safety profile, use of cladribine tablets is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate drug indicated for the treatment of MS [ see Warnings and Precautions (5) ]. Limitations of Use Cladribine tablets are not recommended for use in patients with clinically isolated syndrome (CIS) because of its safety profile [ see Warnings and Precautions (5) ]. Cladribine tablets are purine antimetabolite indicated for the treatment of relapsing form of multiple sclerosis (MS), to include relapsing-remitting disease in adults. Because of its safety profile, use of cladribine tablets are generally recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate drug indicated for the treatment of MS. ( 1 , 5 ) Limitations of Use Cladribine tablets are not recommended for use in patients with clinically isolated syndrome (CIS) because of its safety profile. ( 1 , 5 )

12.1 Mechanism of Action The mechanism by which cladribine exerts its therapeutic effects in patients with multiple sclerosis has not been fully elucidated but is thought to involve cytotoxic effects on B and T lymphocytes through impairment of DNA synthesis, resulting in depletion of lymphocytes.

2 DOSAGE AND ADMINISTRATION Assessments are required prior to starting each cladribine treatment course. (2.1) Cumulative dosage of 3.5 mg/kg administered orally and divided into 2 treatment courses (1.75 mg/kg per treatment course). Each treatment course is divided into 2 treatment cycles. (2.2) Cladribine tablets are a cytotoxic drug. (2.4) Separate administration from any other oral drug by at least 3 hours. (2.4) 2.1 Assessments Prior to Starting Each Cladribine Treatment Course Cancer Screening Follow standard cancer screening guidelines because of the risk of malignancies [ see Boxed Warning and Warnings and Precautions (5.1) ]. Pregnancy Exclude pregnancy prior to treatment with cladribine tablets in females of reproductive potential [ see Contraindications (4) , Warnings and Precautions (5.2) , and Use in Specific Populations (8.1, 8.3) ]. Complete Blood Count (CBC) Obtain a CBC with differential including lymphocyte count [ see Dosage and Administration (2.5) and Warnings and Precautions (5.3) ]. Lymphocytes must be: within normal limits before initiating the first treatment course at least 800 cells per microliter before initiating the second treatment course If necessary, delay the second treatment course for up to 6 months to allow for recovery of lymphocytes to at least 800 cells per microliter. If this recovery takes more than 6 months, the patient should not receive further treatment with cladribine tablets. Infections [ see Warnings and Precautions (5.4) ] Exclude HIV infection. Perform tuberculosis screening. Screen for hepatitis B and C. Evaluate for acute infection. Consider a delay in cladribine treatment until any acute infection is fully controlled. Vaccination of patients who are seronegative for VZV is recommended prior to initiation of cladribine tablets. Vaccination of patients who are seropositive to VZV is recommended with zoster vaccine recombinant, adjuvanted. Patients may be administered zoster vaccine recombinant, adjuvanted at any time prior to or during the year 1 or year 2 course of cladribine treatment. These patients may also be administered the vaccine if their lymphocyte counts are ≤ 500 cells per microliter. Administer all immunizations (except as noted for VZV) according to immunization guidelines prior to starting cladribine tablets. Administer live-attenuated or live vaccines at least 4 to 6 weeks prior to starting cladribine tablets. Obtain a baseline (within 3 months) magnetic resonance imaging prior to the first treatment course because of the risk of progressive multifocal leukoencephalopathy (PML). Liver Injury Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels prior to each treatment cycle and course [ see Warnings and Precautions (5.7) ]. 2.2 Recommended Dosage The recommended cumulative dosage of cladribine tablets is 3.5 mg per kg body weight administered orally and divided into 2 yearly treatment courses (1.75 mg per kg per treatment course) (see Table 1). Each treatment course is divided into 2 treatment cycles: Administration of First Treatment Course First Course/First Cycle: start any time. First Course/Second Cycle: administer 23 to 27 days after the last dose of First Course/First Cycle. Administration of Second Treatment Course Second Course/First Cycle: administer at least 43 weeks after the last dose of First Course/Second Cycle. Second Course/Second Cycle: administer 23 to 27 days after the last dose of Second Course/First Cycle. Table 1 Dose of Cladribine tablets per Cycle by Patient Weight in Each Treatment Course Weight Range Dose in mg (Number of 10 mg Tablets) per Cycle kg First Cycle Second Cycle 40* to less than 50 40 mg (4 tablets) 40 mg (4 tablets) 50 to less than 60 50 mg (5 tablets) 50 mg (5 tablets) 60 to less than 70 60 mg (6 tablets) 60 mg (6 tablets) 70 to less than 80 70 mg (7 tablets) 70 mg (7 tablets) 80 to less than 90 80 mg (8 tablets) 70 mg (7 tablets) 90 to less than 100 90 mg (9 tablets) 80 mg (8 tablets) 100 to l

6 ADVERSE REACTIONS The following serious adverse reactions and potential risks are discussed, or discussed in greater detail, in other sections of the labeling: Malignancies [ see Warnings and Precautions (5.1) ] Risk of Teratogenicity [ see Warnings and Precautions (5.2) ] Lymphopenia [ see Warnings and Precautions (5.3)] Infections [ see Warnings and Precautions (5.4) ] Hematologic Toxicity [ see Warnings and Precautions (5.5) ] Graft-Versus-Host Disease With Blood Transfusion [ see Warnings and Precautions (5.6) ] Liver Injury [ see Warnings and Precautions (5.7) ] Hypersensitivity [ see Warnings and Precautions (5.8) ] Cardiac Failure [ see Warnings and Precautions (5.9) ] Most common adverse reactions (incidence > 20%) are upper respiratory tract infection, headache, and lymphopenia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. In the clinical trial program of cladribine in MS, 1,976 patients received cladribine for a total of 9,509 patient years. The mean time on study including follow-up was approximately 4.8 years, and approximately 24% of cladribine-treated patients had approximately 8 years of time on study including follow-up. Of these, 923 patients aged 18 to 66 years received cladribine as monotherapy at a cumulative dose of 3.5 mg per kg. Table 2 shows adverse reactions in Study 1 [ see Clinical Studies (14) ] with an incidence of at least 5% for cladribine and higher than placebo. The most common (> 20%) adverse reactions reported in Study 1 are upper respiratory tract infection, headache, and lymphopenia. Table 2 Adverse Reactions in Study 1 with an Incidence of at Least 5% for Cladribine tablets and Higher than Placebo Cladribine (N=440) % Placebo (N=435) % Upper respiratory tract infection 38 32 Headache 25 19 Lymphopenia 24 2 Nausea 10 9 Back pain 8 6 Arthralgia and arthritis 7 5 Insomnia 6 4 Bronchitis 5 3 Hypertension 5 3 Fever 5 3 Depression 5 3 Hypersensitivity In clinical studies, 11% of cladribine patients had hypersensitivity adverse reactions, compared to 7% of placebo patients [see Warnings and Precautions ( 5.8 )]. Alopecia Alopecia occurred in 3% of cladribine-treated patients compared to 1% of placebo patients. Myelodysplastic Syndrome Cases of myelodysplastic syndrome have been reported in patients that had received parenteral cladribine at a higher dosage than that approved for cladribine. These cases occurred several years after treatment. Herpes Meningoencephalitis Fatal herpes meningoencephalitis occurred in one cladribine-treated patient, at a higher dosage and longer duration of therapy than the approved cladribine dosage and in combination with interferon beta-1a treatment. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) SJS and TEN are identified risks of parenteral cladribine for the treatment of oncologic indications. Seizures In clinical studies, serious events of seizure occurred in 0.3% of cladribine-treated patients compared to 0 placebo patients. Serious events included generalized tonic-clonic seizures and status epilepticus. It is unknown whether these events were related to the effects of multiple sclerosis alone, to cladribine, or to a combination of both. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of cladribine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Infections and Infestations: nocardiosis, varicella zoster, histoplasmosis, cryptococcosis, and toxoplasmos

5 WARNINGS AND PRECAUTIONS Lymphopenia: Monitor lymphocyte counts before, during and after treatment. (5.3) Infections: Serious, including life-threatening and fatal infections, have occurred. Screen patients for active and latent infections; delay treatment until infection is fully resolved or controlled. Vaccination of patients seronegative to varicella zoster virus (VZV) is recommended prior to treatment. Vaccination of patients seropositive to VZV with zoster vaccine recombinant, adjuvanted, is recommended prior to or during treatment. Administer anti-herpes prophylaxis in patients with lymphocyte counts less than 200 cells per microliter. Monitor for infections. (5.4) Hematologic toxicity: Monitor complete blood count before, during and after treatment. (5.5) Graft-versus-host-disease with blood transfusion: Irradiation of cellular blood components is recommended. (5.6) Liver injury: Clinically significant liver injury has occurred. Obtain tests prior to treatment. Discontinue if clinically significant injury is suspected. (5.7) 5.1 Malignancies Treatment with cladribine tablets may increase the risk of malignancy. In controlled and extension clinical studies worldwide, malignancies occurred more frequently in cladribine-treated patients [10 events in 3,754 patient-years (0.27 events per 100 patient-years)], compared to placebo patients [3 events in 2,275 patient-years (0.13 events per 100 patient-years)]. Malignancy cases in cladribine patients included metastatic pancreatic carcinoma, malignant melanoma (2 cases), ovarian cancer, compared to malignancy cases in placebo patients, all of which were curable by surgical resection [basal cell carcinoma, cervical carcinoma in situ (2 cases)]. The incidence of malignancies in United States cladribine clinical study patients was higher than the rest of the world [4 events in 189 patient-years (2.21 events per 100 patient-years) compared to 0 events in United States placebo patients]; however, the United States results were based on a limited amount of patient data. After the completion of 2 treatment courses, do not administer additional cladribine treatment during the next 2 years [ see Dosage and Administration (2.2) ]. In clinical studies, patients who received additional cladribine treatment within 2 years after the first 2 treatment courses had an increased incidence of malignancy [7 events in 790 patient-years (0.91 events per 100 patient-years) calculated from the start of cladribine treatment in Year 3]. The risk of malignancy with reinitiating cladribine tablets more than 2 years after the completion of 2 treatment courses has not been studied. Cladribine tablets are contraindicated in patients with current malignancy. In patients with prior malignancy or with increased risk of malignancy, evaluate the benefits and risks of the use of cladribine tablets on an individual patient basis. Follow standard cancer screening guidelines in patients treated with cladribine tablets. 5.2 Risk of Teratogenicity Cladribine tablets may cause fetal harm when administered to pregnant women. Malformations and embryolethality occurred in animals [ see Use in Specific Populations (8.1) ] . Advise women of the potential risk to a fetus during cladribine tablets dosing and for 6 months after the last dose in each treatment course. In females of reproductive potential, pregnancy should be excluded before initiation of each treatment course of cladribine tablets and prevented by the use of effective contraception during cladribine tablets dosing and for at least 6 months after the last dose of each treatment course. Women who become pregnant during treatment with cladribine tablets should discontinue treatment [ see Use in Specific Populations (8.1 , 8.3) ] . Cladribine tablets are contraindicated for use in pregnant women and in women and men of reproductive potential who do not plan to use effective contraception. 5.3 Lymphopenia Cladribine tablets cause a dose-dependent reduction in lympho

4 CONTRAINDICATIONS Cladribine tablets are contraindicated: in patients with current malignancy [ see Warnings and Precautions (5.1) ] . in pregnant women and in females and males of reproductive potential who do not plan to use effective contraception during cladribine tablets dosing and for 6 months after the last dose in each treatment course for females, and 14 weeks for males. May cause fetal harm [ see Warnings and Precautions (5.2) and Use in Specific Populations (8.1, 8.3 )]. in patients infected with the human immunodeficiency virus (HIV) [ see Warnings and Precautions (5.4) ]. in patients with active chronic infections (e.g., hepatitis or tuberculosis) [ see Warnings and Precautions (5.4) ]. in patients with a history of hypersensitivity to cladribine [ see Warnings and Precautions (5.8) ]. in females intending to breastfeed on a cladribine treatment day and for 10 days after the last dose [ see Use in Specific Populations (8.2) ]. Patients with current malignancy. (4) Pregnant women, and females and males of reproductive potential who do not plan to use effective contraception during cladribine tablets dosing and for 6 months after the last dose in each treatment course for females, and 14 weeks for males. (4, 8.3) HIV infection. (4) Active chronic infections (e.g., hepatitis or tuberculosis). (4) History of hypersensitivity to cladribine. (4, 5.8) Females intending to breastfeed on a cladribine treatment day and for 10 days after the last dose. (4, 8.2)

10 OVERDOSAGE There is no experience with overdose of cladribine tablets. Lymphopenia is known to be dose- dependent. Particularly close monitoring of hematological parameters is recommended in patients who have been exposed to an overdose of cladribine tablets [ see Warnings and Precautions (5.3, 5.5) ]. There is no known specific antidote to an overdose of cladribine tablets. Treatment consists of careful observation and initiation of appropriate supportive measures. Discontinuation of cladribine tablets may need to be considered. Because of the rapid and extensive intracellular and tissue distribution, hemodialysis is unlikely to eliminate cladribine to a significant extent.