Cladribine

Boxed Warning ( 2.1 )..............................................................................................................................5/2026 Contraindications ( 5.4 , 5.7 )....................................................................................................................5/2026

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 )

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 …

3 DOSAGE FORMS AND STRENGTHS Cladribine tablets are available as 10 mg tablets. The tablets are white to off white, round, biconvex tablets debossed with “10” on one side and plain on the other side. Tablets: 10 mg (3)

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)

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 …

7 DRUG INTERACTIONS Table 3 Drug Interactions with cladribine tablets 7.1 Immunomodulatory, Immunosuppressive, or Myelosuppressive Drugs Clinical Impact Concomitant use of cladribine with immunomodulatory, immunosuppressive, or myelosuppressive drugs may increase the risk of adverse reactions because of the additive effects on the immune system [see Warnings and Precautions ( 5.4 )]. Prevention or Management Concomitant use with myelosuppressive or other immunosuppressive drugs is not recommended. Acute short-term therapy with corticosteroids can be administered. In patients who have previously been treated with immunomodulatory or immunosuppressive drugs, consider potential additive effect, the mode of action, and duration of effect of the other drugs prior to initiation of cladribine. 7.2 Interferon-Beta Clinical Impact Concomitant use of cladribine with interferon-beta did not change the exposure of cladribine to a clinically significant effect; however, lymphopenia risk may be increased [ see Warnings and Precautions (5.3) ]. Prevention or Management Concomitant use is not recommended. 7.3 Hematotoxic Drugs Clinical Impact Concomitant use of cladribine with hematotoxic drugs may increase the risk of adverse reactions because of the additive hematological effects [ see Warnings and Precautions (5.5) ]. Prevention or Management Monitor hematological parameters. 7.4 Antiviral and Antiretroviral Drugs Clinical Impact Compounds that require intracellular phosphorylation to become active (e.g., lamivudine, zalcitabine, ribavirin, stavudine, and zidovudine) could interfere with the intracellular phosphorylation and activity of cladribine. Prevention or Management Avoid concomitant use. 7.5 Potent ENT, CNT and BCRP Transporter Inhibitors Clinical Impact Cladribine is a substrate of breast cancer resistance protein (BCRP), equilibrative nucleoside (ENT1), and concentrative nucleoside (CNT3) transport proteins. The bioavailability, intracellular distribution, and renal elimination of cladribine may be altered by potent ENT1, CNT3, and BCRP transporter inhibitors. Prevention or Management Avoid co-administration of potent ENT1, CNT3, or BCRP transporter inhibitors (e.g., ritonavir, eltrombopag, curcumin, cyclosporine, dilazep, nifedipine, nimodipine, cilostazol, sulindac, dipyridamole, or reserpine) during the 4 to 5 day cladribine treatment cycles. If this is not possible, consider selection of alternative concomitant drugs with no or minimal ENT1, CNT3, or BCRP transporter inhibiting properties. If this is not possible, dose reduction to the minimum mandatory dose of drugs containing these compounds, separation in the timing of administration, and careful patient monitoring is recommended. 7.6 Potent BCRP and P-gp Transporter Inducers Clinical Impact Possible decrease in cladribine exposure if potent BCRP or P-gp transporter inducers are co-administered. Prevention or Management Consider a possible decrease in cladribine efficacy if potent BCRP (e.g., corticosteroids) or P-gp (e.g., rifampicin, St. John's Wort) transporter inducers are co-administered. Immunosuppressive drugs: Consider overlapping effects on immune system, when used sequentially. Concomitant use not recommended. (7.1) Hematotoxic drugs: Monitor patients for additive effects on the hematological profile. (7.3) Antiviral and antiretroviral drugs: Avoid concomitant use. (7.4) BCRP or ENT/CNT inhibitors: May alter bioavailability of cladribine. Avoid concomitant use. (7.5)

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Cladribine tablets are contraindicated in pregnant women and in females and males of reproductive potential who do not plan to use effective contraception. There are no adequate data on the developmental risk associated with use of cladribine in pregnant women. Cladribine was embryolethal when administered to pregnant mice and produced malformations in mice and rabbits [ see Data ]. The observed developmental effects are consistent with the effects of cladribine on DNA [ see Contraindications (4) and Warnings and Precautions (5.2) ]. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data When cladribine was administered intravenously (0, 0.5, 1.5, or 3 mg/kg/day) to pregnant mice during the period of organogenesis, fetal growth retardation and malformations (including exencephaly and cleft palate) and embryofetal death were observed at the highest dose tested. An increase in skeletal variations was observed at all but the lowest dose tested. There was no evidence of maternal toxicity. When cladribine was administered intravenously (0, 0.3, 1, and 3 mg/kg/day) to pregnant rabbits during the period of organogenesis, fetal growth retardation and a high incidence of craniofacial and limb malformations were observed at the highest dose tested, in the absence of maternal toxicity. When cladribine was administered intravenously (0, 0.5, 1.5, or 3 mg/kg/day) to mice throughout pregnancy and lactation, skeletal anomalies and embryolethality were observed at all but the lowest dose tested. 8.2 Lactation Risk Summary Cladribine tablets are contraindicated in breastfeeding females because of the potential for serious adverse reactions in breastfed infants, including infections and hematologic toxicity [ see Contraindications (4) and Warnings and Precautions (5) ]. Advise women not to breastfeed during dosing with cladribine and for 10 days after the last dose [see Clinical Pharmacology (12.3)] . Literature data show that cladribine is present in human milk. There are no data on the effects on the breastfed infant, or the effects on milk production. 8.3 Females and Males of Reproductive Potential Pregnancy Testing In females of reproductive potential, pregnancy should be excluded before the initiation of each treatment course of cladribine [see Use in Specific Populations ( 8.1 )]. Contraception Females Females of reproductive potential should prevent pregnancy by use of effective contraception during cladribine dosing and for at least 6 months after the last dose in each treatment course. Females who become pregnant during cladribine tablets therapy should discontinue treatment [ see Warnings and Precautions (5.2) ]. Males As cladribine interferes with DNA synthesis, adverse effects on human gametogenesis could be expected. Therefore, male patients of reproductive potential should take precautions to prevent pregnancy of their partner during cladribine dosing and for at least 6 months after the last dose in each treatment course [ see Warnings and Precautions (5.2) and Nonclinical Toxicology (13.1) ]. 8.4 Pediatric Use The safety and effectiveness in pediatric patients (below 18 years of age) have not been established. Use of cladribine is not recommended in pediatric patients because of the risk of malignancies [ see Warnings and Precautions (5.1) ]. 8.5 Geriatric Use Clinical studies with cladribine did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Caution is recommended when cladribine is used in elderly patients, taking into account the pote …

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.

11 DESCRIPTION Cladribine tablets contains the nucleoside metabolic inhibitor cladribine, which is a white to off-white crystalline powder with the molecular formula C 10 H 12 ClN 5 O 3 and molecular weight 285.69 g/mol. It differs in structure from the naturally occurring nucleoside, deoxyadenosine, by the substitution of chlorine for hydrogen in the 2-position of the purine ring. The chemical name of cladribine is 2-chloro-2′-deoxy-adenosine. The structural formula is shown below: Cladribine is stable at slightly basic and at neutral pH. The main degradation pathway is hydrolysis and at acidic pH significant decomposition occurs with time. The ionization behavior of the molecule over the pH range 0 to 12 is characterized by a single pKa of approximately 1.21. Cladribine tablets are provided as 10 mg tablet for oral use. Each 10 mg tablet contains cladribine as an active ingredient and magnesium stearate and sorbitol as inactive ingredients. Cladribine tablets also contain hydroxypropyl betadex.

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.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Cladribine tablets, 10 mg, are white to off white, round, biconvex tablets debossed with “10” on one side and plain on the other side. Each tablet is packaged in a child-resistant day pack containing one or two tablets in a blister card. Dispense one box for each treatment cycle with a Medication Guide [ see Dosage and Administration (2.2) ]. Presentations NDC 60505-4791-4 NDC 60505-4791-5 NDC 60505-4791-6 NDC 60505-4791-7 NDC 60505-4791-8 NDC 60505-4791-9 NDC 60505-4791-1 Box of 4 tablets: Four day packs each containing one tablet. Box of 5 tablets: Five day packs each containing one tablet. Box of 6 tablets: One day pack containing two tablets. Four day packs each containing one tablet. Box of 7 tablets: Two day packs each containing two tablets. Three day packs each containing one tablet. Box of 8 tablets: Three day packs each containing two tablets. Two day packs each containing one tablet. Box of 9 tablets: Four day packs each containing two tablets. One day pack containing one tablet. Box of 10 tablets: Five day packs each containing two tablets. 16.2 Storage and Handling Store at controlled room temperature, 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store in original package in order to protect from moisture. Cladribine tablets are a cytotoxic drug. Follow applicable special handling and disposal procedures [see References ( 15 )] . 1