Cladribine

WARNING: MALIGNANCIES AND RISK OF TERATOGENICITY Malignancies Treatment with cladribine tablets may increase the risk of malignancy. 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 [see Contraindications (4) and Warnings and Precautions ( 5.1 )] . Risk of Teratogenicity Cladribine tablets are contraindicated for use in pregnant women and in females and males of reproductive potential who do not plan to use effective contraception because of the potential for fetal harm. Malformations and embryolethality occurred in animals. Exclude pregnancy before the start of treatment with cladribine tablets in females of reproductive potential. Advise females and males of reproductive potential 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. Stop cladribine tablets if the patient becomes pregnant [see Contraindications (4), Warnings and Precautions (5.2), and Use in Specific Populations (8.1, 8.3)] . WARNING: MALIGNANCIES and RISK OF TERATOGENICITY See full prescribing information for complete boxed warning. Malignancies Cladribine tablets may increase the risk of malignancy. Cladribine tablets are contraindicated in patients with current malignancy; evaluate the benefits and risks on an individual basis for patients with prior or increased risk of malignancy. ( 5.1 ) Risk of Teratogenicity 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 because of the risk of fetal harm. ( 5.2 )

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 lymphocyte count. In clinical studies, 87% of cladribine-treated patients experienced lymphopenia. The lowest absolute lymphocyte counts occurred approximately 2 to 3 months after the start of each treatment course and were lower with each additional treatment course. In patients treated with a cumulative dose of cladribine tablets 3.5 mg per kg over 2 courses as monotherapy, 26% and 1% had nadir absolute lymphocyte counts less than 500 and less than 200 cells per microliter, respectively. At the end of the second treatment course, 2% of clinical study patients had lymphocyte counts less than 500 cells per microliter; median time to recovery to at least 800 cells per microliter was approximately 28 weeks. Additive hematological adverse reactions may be expected if cladribine tablets are administered prior to or concomitantly with other drugs that affect the hematological profile [ see Drug Interactions (7.3) ]. The incidence of lymphopenia less than 500 cells per microliter was higher in patients who had used drugs to treat relapsing forms of MS prior to study entry (32.1%), compared to those with no prior use of these drugs (23.8%). Obtain complete blood count (CBC) with differential including lymphocyte count prior to, during, and after treatment with cladribine tablets. See Dosage and Administration (2.1, 2.5) and Warnings and Precautions (5.4) for timing of CBC measurements and additional instructions based on the patient’s lymphocyte counts and clinical status (e.g., infections). 5.4 Infections Serious, including life-threatening or fatal, bacterial, viral, parasitic, and fungal infections have been reported in patients receiving cladribine tablets. Cladribine tablets reduces the body's immune defense, and an increased risk of infections has been observed in patients receiving cladribine tablets. Infections occurred in 49% of cladribine-treated patients compared to 44% of placebo patients in clinical studies; serious or severe infections occurred in 2.4% of cladribine-treated patients and 2% of placebo-treated patients. The most frequent serious infections in cladribine-treated patients included herpes zoster and pyelonephritis ( see Herpes Virus Infections ). Fungal infections were observed, including cases of coccidioidomycosis. In the postmarketing setting, serious infections have been reported, including nocardiosis, varicella zoster, histoplasmosis, cryptococcosis, and toxoplasmosis. The majority of patients with these infections who had an available absolute lymphocyte count at the time of the event had concurrent lymphopenia, consistent with the mechanism of action of cladribine tablets [see Warnings and Precautions ( 5.3 )]. HIV infection, active tuberculosis, and active hepatitis must be excluded before initiation of each treatment course of cladribine tablets [ see Contraindications (4) ]. Delay initiation of cladribine tablets in patients with an acute infection until the infection is fully resolved or controlled. Initiation of cladribine tablets in patients currently receiving immunosuppressive or myelosuppressive therapy is not recommended [see Drug Interactions ( 7.1 )] . Concomitant use of cladribine tablets with these therapies could increase the risk of immunosuppression. Tuberculosis Three of 1,976 (0.2%) cladribine-treated patients in the clinical program developed tuberculosis. All three cases occurred in regions where tuberculosis is endemic. One case of tuberculosis was fatal, and two cases resolved with treatment. Perform tuberculosis screening prior to initiation of the first and second treatment course of cladribine tablets. Latent tuberculosis infections may be activated with use of cladribine tablets. In patients with tuberculosis infection, delay initiation of cladribine tablets until the infection has been adequately treated. Hepatitis One clinical study patient died from fulminant hepatitis B infection. Perform screening for hepatitis B and C prior to initiation of the first and second treatment course of cladribine tablets. Latent hepatitis infections may be activated with use of cladribine tablets. Patients who are carriers of hepatitis B or C virus may be at risk of irreversible liver damage caused by virus reactivation. In patients with hepatitis infection, delay initiation of cladribine tablets until the infection has been adequately treated. Herpes Virus Infections In controlled clinical studies, 6% of cladribine-treated patients developed a herpes viral infection compared to 2% of placebo patients. The most frequent types of herpes viral infections were herpes zoster infections (2.0% vs. 0.2%) and oral herpes (2.6% vs. 1.2%). Serious herpes zoster infections occurred in 0.2% of cladribine-treated patients. Vaccination of patients who are seronegative for varicella zoster virus is recommended prior to initiation of cladribine tablets. Administer live-attenuated or live vaccines at least 4 to 6 weeks prior to starting cladribine tablets. Vaccination with zoster vaccine recombinant, adjuvanted is recommended for patients who are seropositive to VZV, either prior to or during cladribine treatment, including when their lymphocyte counts are less than or equal to 500 cells per microliter. The incidence of herpes zoster was higher during the period of absolute lymphocyte count less than 500 cells per microliter, compared to the time when the patients were not experiencing this degree of lymphopenia. Administer anti-herpes prophylaxis in patients with lymphocyte counts less than 200 cells per microliter. Patients with lymphocyte counts below 500 cells per microliter should be monitored for signs and symptoms suggestive of infections, including herpes infections. If such signs and symptoms occur, initiate treatment as clinically indicated. Consider interruption or delay of cladribine tablets until resolution of the infection. Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. No case of PML has been reported in clinical studies of cladribine in patients with multiple sclerosis. In patients treated with parenteral cladribine for oncologic indications, cases of PML have been reported in the postmarketing setting. Obtain a baseline (within 3 months) magnetic resonance imaging (MRI) before initiating the first treatment course of cladribine tablets. At the first sign or symptom suggestive of PML, withhold cladribine tablets and perform an appropriate diagnostic evaluation. MRI findings may be apparent before clinical signs or symptoms. Vaccinations 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, because of a risk of active vaccine infection (see Herpes Virus Infections) . Avoid vaccination with live-attenuated or live vaccines during and after cladribine treatment while the patient’s white blood cell counts are not within normal limits. 5.5 Hematologic Toxicity In addition to lymphopenia [see Warnings and Precautions ( 5.3 )] , decreases in other blood cells and hematological parameters have been reported with cladribine in clinical studies. Mild to moderate decreases in neutrophil counts (cell count between 1,000 cells per microliter and < lower limit of normal (LLN)) were observed in 27% of cladribine-treated patients, compared to 13% of placebo patients whereas severe decreases in neutrophil counts (cell count below 1,000 cells per microliter) were observed in 3.6% of cladribine-treated patients, compared to 2.8% of placebo patients. Decreases in hemoglobin levels, in general mild to moderate (hemoglobin 8 g per dL to < LLN), were observed in 26% of cladribine-treated patients, compared to 19% of placebo patients. Decreases in platelet counts were generally mild (cell count 75,000 cells per microliter to < LLN) and were observed in 11% of cladribine- treated patients, compared to 4% of placebo patients. In clinical studies at dosages similar to or higher than the approved cladribine dosage, serious cases of thrombocytopenia, neutropenia, and pancytopenia (some with documented bone marrow hypoplasia) requiring transfusion and granulocyte-colony stimulating factor treatment have been reported [ see Warnings and Precautions (5.6) for information regarding graft-versus- host disease with blood transfusion ]. Obtain complete blood count (CBC) with differential prior to, during, and after treatment with cladribine tablets [ see Dosage and Administration (2.1, 2.5) ]. 5.6 Risk of Graft-Versus-Host Disease With Blood Transfusion Transfusion-associated graft-versus-host disease has been observed rarely after transfusion of nonirradiated blood in patients treated with cladribine for non-MS treatment indications. In patients who require blood transfusion, irradiation of cellular blood components is recommended prior to administration to decrease the risk of transfusion-related graft-versus-host disease. Consultation with a hematologist is advised. 5.7 Liver Injury Cladribine tablets can cause liver injury. In clinical studies, 0.3% of cladribine-treated patients had liver injury (serious or causing treatment discontinuation) considered related to treatment, compared to 0 placebo patients. Onset ranged from a few weeks to several months after initiation of treatment with cladribine. Signs and symptoms of liver injury, including elevation of serum aminotransferases to greater than 20-fold the upper limit of normal, were observed. These abnormalities resolved upon treatment discontinuation. Clinically significant and life-threatening liver injury has been reported in patients treated with cladribine tablets in the postmarketing setting. Patients with pre-existing liver disease and patients taking other hepatotoxic drugs may be at increased risk for developing liver injury when taking cladribine tablets. Most reported cases of liver injury associated with cladribine tablets occurred approximately 30 days after initiation (i.e., course 1, cycle 1) of treatment. Cladribine tablets are not recommended in patients with moderate to severe hepatic impairment (Child-Pugh score greater than 6) [see Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3 )]. Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels prior to each treatment cycle and course [ see Dosage and Administration (2.1) ]. If a patient develops clinical signs, including unexplained liver enzyme elevations, or symptoms suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine), promptly measure serum transaminases and total bilirubin and interrupt or discontinue treatment with cladribine tablets, as appropriate. 5.8 Hypersensitivity In clinical studies, 11% of cladribine-treated patients had hypersensitivity reactions, compared to 7% of placebo patients. Hypersensitivity reactions that were serious and/or led to discontinuation of cladribine tablets (e.g., dermatitis, pruritus) occurred in 0.5% of cladribine-treated patients, compared to 0.1% of placebo patients. One patient had a serious hypersensitivity reaction with rash, mucous membrane ulceration, throat swelling, vertigo, diplopia, and headache after the first dose of cladribine tablets. If a hypersensitivity reaction is suspected, discontinue cladribine therapy. Do not use cladribine tablets in patients with a history of hypersensitivity to cladribine [ see Contraindications (4) ]. 5.9 Cardiac Failure In clinical studies, one cladribine-treated patient experienced life-threatening acute cardiac failure with myocarditis, which improved after approximately one week. Cases of cardiac failure have also been reported with parenteral cladribine used for treatment indications other than multiple sclerosis. Instruct patients to seek medical advice if they experience symptoms of cardiac failure (e.g., shortness of breath, rapid or irregular heartbeat, swelling).

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 toxoplasmosis [see Warnings and Precautions ( 5.4 )]. Hepatobiliary Disorders: liver injury [see Warnings and Precautions ( 5.7 )]

<table frame="box" rules="all"><thead><tr><td> </td><td align="center"><content styleCode="bold">Cladribine (N=440)</content><content styleCode="bold"/><content styleCode="bold"> %</content></td><td align="center"><content styleCode="bold">Placebo (N=435)</content><content styleCode="bold"/><content styleCode="bold"> %</content></td></tr></thead><tbody align="center"><tr><td> Upper respiratory tract infection </td><td> 38 </td><td> 32 </td></tr><tr><td align="left"> Headache </td><td> 25 </td><td> 19 </td></tr><tr><td align="left"> Lymphopenia </td><td> 24 </td><td> 2 </td></tr><tr><td align="left"> Nausea </td><td> 10 </td><td> 9 </td></tr><tr><td align="left"> Back pain </td><td> 8 </td><td> 6 </td></tr><tr><td align="left"> Arthralgia and arthritis </td><td> 7 </td><td> 5 </td></tr><tr><td align="left"> Insomnia </td><td> 6 </td><td> 4 </td></tr><tr><td align="left"> Bronchitis </td><td> 5 </td><td> 3 </td></tr><tr><td align="left"> Hypertension </td><td> 5 </td><td> 3 </td></tr><tr><td align="left"> Fever </td><td> 5 </td><td> 3 </td></tr><tr><td align="left"> Depression </td><td> 5 </td><td> 3 </td></tr></tbody></table>