PRODUCT MONOGRAPH INCLUDING PATIENT MEDICATION INFORMATION

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PRODUCT MONOGRAPH INCLUDING PATIENT MEDICATION INFORMATION Pr PROCYSBI TM Cysteamine delayed-release capsules 25 mg and 75 mg cysteamine (as cysteamine bitartrate, also called mercaptamine bitartrate)
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PRODUCT MONOGRAPH INCLUDING PATIENT MEDICATION INFORMATION Pr PROCYSBI TM Cysteamine delayed-release capsules 25 mg and 75 mg cysteamine (as cysteamine bitartrate, also called mercaptamine bitartrate) ATC code: A16AA04 Amino Acids and Derivatives Horizon Pharma Ireland Ltd. Connaught House, 1 st Floor 1 Burlington Road Dublin 4, D04 C5Y6 Ireland Date of Preparation: June 08, 2017 Imported and distributed by: Innomar Strategies Inc Superior Ct. Oakville, Ontario L6L 0C4 Canada Submission Control No: PROCYSBI cysteamine delayed-release capsules Page 1 of 33 Table of Contents PART I: HEALTH PROFESSIONAL INFORMATION...3 SUMMARY PRODUCT INFORMATION...3 INDICATIONS AND CLINICAL USE...3 CONTRAINDICATIONS...3 WARNINGS AND PRECAUTIONS...4 ADVERSE REACTIONS...7 DRUG INTERACTIONS...11 DOSAGE AND ADMINISTRATION...12 OVERDOSAGE...16 ACTION AND CLINICAL PHARMACOLOGY...17 STORAGE AND STABILITY...20 DOSAGE FORMS, COMPOSITION AND PACKAGING...20 PART II: SCIENTIFIC INFORMATION...21 PHARMACEUTICAL INFORMATION...21 CLINICAL TRIALS...22 DETAILED PHARMACOLOGY...25 TOXICOLOGY...27 PATIENT MEDICATION INFORMATION...28 PROCYSBI cysteamine delayed-release capsules Page 2 of 33 PROCYSBI Cysteamine delayed-release capsules (as cysteamine bitartrate, also called mercaptamine bitartrate) PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION Route of Administration Oral Dosage Form/ Strength Delayed-release capsules, 25 mg and 75 mg cysteamine (as cysteamine bitartrate) Clinically Relevant Nonmedicinal Ingredients Methacrylic acid copolymer For a complete listing of ingredients see Dosage Forms, Composition and Packaging section. INDICATIONS AND CLINICAL USE PROCYSBI (cysteamine delayed-release capsules) is indicated for the treatment of nephropathic cystinosis. PROCYSBI treatment should be initiated under the supervision of a physician experienced in the treatment of cystinosis. Pediatrics ( 18 years): The safety and efficacy of PROCYSBI in patients under 2 years of age have not been established. See WARNINGS AND PRECAUTIONS, Special Populations and CLINICAL TRIALS. Geriatrics ( 65 years of age): The safety and efficacy of PROCYSBI in patients 65 years and older with cystinosis have not been established. See WARNINGS AND PRECAUTIONS, Special Populations and CLINICAL TRIALS. CONTRAINDICATIONS PROCYSBI is contraindicated for use in patients: who are hypersensitive to cysteamine bitartrate, any form of cysteamine or to any ingredient in the formulation, including non-medicinal ingredients, or to any component of the container. For a complete listing of ingredients, see the Dosage Forms, Composition and Packaging section of the product monograph. who are hypersensitive to penicillamine. PROCYSBI cysteamine delayed-release capsules Page 3 of 33 WARNINGS AND PRECAUTIONS General Ehlers-Danlos-like Syndrome: Skin and bone lesions that resemble clinical features of Ehlers- Danlos syndrome have been reported in patients treated with high doses of immediate-release cysteamine bitartrate or other cysteamine salts. These include purplish hemorrhagic lesions (which have been described as molluscoid pseudotumors), skin striae, bone lesions (including osteopenia, compression fractures, scoliosis and genu valgum), leg pain and joint hyperextension. One patient on immediate-release cysteamine bitartrate with serious skin lesions subsequently died of acute cerebral ischemia with marked vasculopathy. Monitor patients for development of skin or bone lesions and interrupt PROCYSBI dosing if patients develop these lesions. PROCYSBI may be restarted at a lower dose under close supervision, then slowly increased to the appropriate therapeutic dose. Gastrointestinal Gastrointestinal (GI) ulceration and bleeding have been reported in patients receiving immediaterelease cysteamine bitartrate. GI tract symptoms including nausea, vomiting, anorexia and abdominal pain, sometimes severe, have been associated with PROCYSBI. Physicians should remain alert for signs of ulceration and bleeding and should inform patients and/or guardians about the signs and symptoms of serious GI toxicity and what steps to take if they occur. If severe GI tract symptoms develop, consider decreasing the dose of PROCYSBI. Strictures of the ileo-caecum and large bowel (fibrosing colonopathy) was first described in cystic fibrosis patients who were given high doses of pancreatic enzymes in the form of tablets with an enteric coating of methacrylic acid- ethyl acrylate copolymer, one of the excipients in PROCYSBI. As a precaution, unusual abdominal symptoms or changes in abdominal symptoms should be medically assessed to exclude the possibility of fibrosing colonopathy. Hepatic PROCYSBI has not been studied in patients with hepatic impairment. Closer monitoring of the WBC cystine levels is recommended in these patients. Monitoring and Laboratory Tests: White blood cell (WBC) cystine levels WBC cystine levels should be routinely monitored to assess the effect of PROCYSBI treatment on intracellular cystine depletion. Refer to the assay-specific therapeutic target for cystine depletion provided by individual testing laboratories. The target WBC cystine concentration measured using the traditional mixed leukocyte assay is less than 1.0 nmol ½ cystine/mg protein. Assays using specific WBC subsets (e.g. granulocyte method) have different treatment targets. PROCYSBI cysteamine delayed-release capsules Page 4 of 33 Obtain blood samples for WBC cystine concentration measurement at drug trough (as close to 30 minutes post dosing as possible). See DOSAGE AND ADMINISTRATION. In addition, it is important to accurately record the time of the last dose, the actual dose consumed, and the time the blood sample was taken. The recommended frequency of monitoring WBC cystine concentration is as follows: For cysteamine-naive patients: Obtain measurement every two to four weeks while titrating the dose of PROCYSBI until reaching the maintenance PROCYSBI dose (see Table 4, DOSAGE AND ADMINISTRATION for maintenance doses), then monthly for 3 months, quarterly for 1 year, and twice-yearly thereafter, at a minimum. For patients switching from immediate-release cysteamine to PROCYSBI: Obtain measurement every two weeks while titrating the dose of PROCYSBI, quarterly for 6 months, and twice yearly thereafter, at a minimum. More frequent monitoring of WBC cystine concentration is recommended when drugs that increase the gastric ph are introduced and when dose adjustments occur. See DRUG INTERACTIONS. Because the measured WBC cystine concentration depends on the assays used for cystine and total protein content, individual patient sample concentration values from different assays and laboratories may not be interchangeable. Consideration of assay results must be made with knowledge of the specific assays used. Therefore, communication should be maintained with the laboratory performing the assay. Leukopenia Cysteamine, as an immediate-release formulation, has been associated with reversible leukopenia levels. Monitor WBC counts. If WBC levels remain abnormally decreased, consider decreasing the dose or discontinuing PROCYSBI until values revert to normal. Alkaline Phosphatase Cysteamine, as an immediate-release formulation, has been associated with elevated alkaline phosphatase levels. Monitor alkaline phosphate levels. If values remain elevated, consider decreasing the dose or discontinuing PROCYSBI until values revert to normal. Neurologic Central nervous system (CNS) symptoms such as seizures, lethargy, somnolence, depression, and encephalopathy have been associated with immediate-release cysteamine bitartrate. Carefully evaluate and monitor patients who develop CNS symptoms. Interrupt medication or adjust the dose as necessary for patients with severe symptoms or with symptoms that persist or progress. Benign intracranial hypertension (pseudotumor cerebri; PTC) and/or papilledema have been reported in patients receiving immediate-release cysteamine bitartrate treatment. Physicians PROCYSBI cysteamine delayed-release capsules Page 5 of 33 should monitor patients for signs and symptoms of PTC, including headache, tinnitus, dizziness, nausea, diplopia, blurry vision, loss of vision, pain behind the eye or pain with eye movement. If signs/symptoms persist, interrupt dosing or decrease the dose and refer the patient to an ophthalmologist. If the diagnosis is confirmed, permanently discontinue use of PROCYSBI. Ophthalmologic Oral cysteamine has not been shown to prevent eye deposition of cystine crystals. Therefore, where cysteamine ophthalmic solution is used for that purpose, its use should continue. Renal The effect of severe renal impairment and end stage renal disease on the pharmacokinetics of PROCYSBI have not been evaluated. See ACTION AND CLINICAL PHARMACOLOGY, Special Populations. Some forms of cysteamine are less well tolerated (i.e. leading to more adverse events) when patients are on dialysis. Closer monitoring of the WBC cystine levels is recommended in patients with severe or end stage renal disease. Skin Serious skin rashes such as erythema multiforme bullosa, Stevens-Johnson Syndrome (SJS), or toxic epidermal necrolysis have been reported in patients receiving immediate-release cysteamine bitartrate. If serious skin rashes develop, permanently discontinue use of PROCYSBI. Special Populations Pregnant Women: There are no available data on PROCYSBI use in pregnant women. Cysteamine (administered as cysteamine bitartrate) was teratogenic and fetotoxic in rats at doses less than the recommended human maintenance dose. See TOXICOLOGY. Before starting PROCYSBI in a woman of child-bearing potential, pregnancy status should be confirmed. Patients should be advised of the potential risk to a fetus and the importance of ensuring adequate contraception while taking PROCYSBI. Women who become pregnant or are planning to become pregnant should be instructed to immediately contact their physician. In the event of pregnancy, interruption of treatment with PROCYSBI should be considered or appropriate medical care instituted. Breastfeeding: There is no information on the presence of cysteamine in human milk, or its effects on the breastfed infant. Cysteamine is present in the milk of lactating rats. Growth retardation and a decrease PROCYSBI cysteamine delayed-release capsules Page 6 of 33 in survival occurred in neonatal rats nursed by mothers receiving cysteamine. See TOXICOLOGY, Reproductive Toxicology. Because of the potential for serious adverse reactions in breastfed infants from cysteamine, breastfeeding is not recommended. Pediatrics ( 18 years of age): There are no data in children 2 years of age from clinical trials of PROCYSBI. See CLINICAL TRIALS. Geriatrics ( 65 years of age): The safety and efficacy of PROCYSBI in patients aged 65 years and older have not been established. ADVERSE REACTIONS Adverse Drug Reaction Overview The adverse drug reactions (ADRs) reported most frequently ( 5%) for PROCYSBI in a shortterm trial (Study 03) included nausea, vomiting (11.6% each), and abdominal pain (7.0%). ADRs reported most frequently with long-term treatment with PROCYSBI (Study 04) included vomiting (33.9%), nausea (15.3%), abdominal pain (13.6%), breath odour (13.6%), diarrhea (8.5%), and skin odour abnormal (8.5%). In Study 03, one serious adverse event (SAE), abdominal discomfort in a patient receiving treatment with PROCYSBI, was considered drug-related. In Study 04, six SAEs were assessed as drug-related: renal failure, constipation, vomiting (two SAEs), diarrhea and acute gastroenteritis. Clinical Trial Adverse Drug Reactions Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. Sixty-two patients with cystinosis (38 males and 24 females) received PROCYSBI in two clinical trials (Studies 03 and 04) at doses ranging from 0.29 grams/m 2 per day to 2.19 grams/m 2 per day. All patients were transitioned from immediate-release cysteamine bitartrate to PROCYSBI. Forty-three patients, aged 7 to 24 years, received PROCYSBI in an 9-week, openlabel, randomized sequence, cross-over trial comparing 3 weeks of treatment with PROCYSBI to 3 weeks of treatment with immediate-release cysteamine bitartrate (Study 03). Forty of 43 patients continued PROCYSBI treatment in an open-label, uncontrolled extension trial, and were treated with PROCYSBI for an average of 3 years (Study 04). An additional 19 patients (6 PROCYSBI cysteamine delayed-release capsules Page 7 of 33 patients with a renal transplant, and 13 patients aged 2 to 6 years) were enrolled directly into this trial and were treated with PROCYSBI. Overall, 14 patients (32.6%) in Study 03 experienced one or more treatment-emergent adverse events (TEAEs) that were assessed as treatment-related. ADRs reported with a frequency of 1% are shown in Table 1. In the long-term extension trial, Study 04, 35 patients (59%) experienced one or more TEAEs which were assessed as treatment-related. ADRs reported with a frequency of 1% are shown in Table 2. ADRs are consistent with those reported in Study 03 and with those previously described for immediate-release cysteamine bitartrate. ADRs within the subpopulations of patients 6 years of age (n=13) and in the renal transplant recipients (n=6) suggest a similar safety profile to that observed in patients from Study 03 (n=40). Abnormal Hematologic and Clinical Chemistry Findings There were no changes observed in laboratory tests results for PROCYSBI during the clinical trials beyond that expected with nephropathic cystinosis. Post-Market Adverse Drug Reactions As post-market reports of adverse reactions are reported voluntarily from a population of uncertain size and demographics, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Post-marketing experience with PROCYSBI In cumulative post-market data for PROCYSBI reported from the United States (US) and the European Union (EU), the most frequently reported serious adverse events include renal disorders (such as interstitial nephritis, renal transplant, kidney transplant rejection, renal failure, and dialysis) and dehydration. Post-marketing experience with immediate-release cysteamine The following adverse reactions have been identified during post-market approval of immediate release cysteamine: Musculoskeletal (joint hyperextension, leg pain, osteopenia, compression fracture, scoliosis, genu valgum); Skin (erythema multiforme bullosa, toxic epidermal necrolysis, Ehlers-Danlos-like syndrome, molluscoid pseudotumours, skin striae, skin fragility); Central Nervous System (seizures, lethargy, somnolence, depression, and encephalopathy, benign intracranial hypertension and/or papilledema); and Renal (nephrotic syndrome, due to membranous glomerulonephritis of renal allograft in one case, hypersensitivity interstitial nephritis in another). See WARNINGS AND PRECAUTIONS. PROCYSBI cysteamine delayed-release capsules Page 8 of 33 Table 1: Adverse Reactions a that Occurred in One or More Patients in the Randomized, Crossover Clinical Trial (Study 03) MedDRA System Organ Class Preferred Term Cardiac disorders PROCYSBI n= 43 n (%) Immediate-Release Cysteamine Bitartrate n= 41 n (%) Atrioventricular block 0 (0) 1 (2.4) Gastrointestinal disorders b Vomiting 5 (11.6) 3 (7.3) Nausea 5 (11.6) 2 (4.9) Abdominal pain 3 (7.0) 0 (0) Abdominal discomfort 1 (2.3) 0 (0) Diarrhoea 1 (2.3) 1 (2.4) General disorders and administration site conditions Malaise 1 (2.3) 0 (0) Metabolism and nutrition disorders Decreased appetite 1 (2.3) 1 (2.4) Nervous system disorders Dizziness 1 (2.3) 0 (0) Headache 1 (2.3) 0 (0) Renal and urinary disorders Renal impairment 2 (4.7) 0 (0) Skin and subcutaneous tissue disorders Cold sweat 1 (2.3) 0 (0) Vascular disorders Flushing 1 (2.3) 0 (0) Note: A patient is counted once if he/she reported one or more events. Percentages are based on the number of patients in the safety population within each treatment group. Coded using MedDRA, Version a Defined as treatment emergent adverse events that have been assessed by the study Investigator to be possibly or probably related to study treatment. b Use of gastric acid reducing medications, including proton pump inhibitors, was allowed during treatment with immediate-release cysteamine bitartrate but restricted to intolerable gastric upset during RP103 treatment. PROCYSBI cysteamine delayed-release capsules Page 9 of 33 Table 2: (Study 04) MedDRA System Organ Class Preferred Term Adverse Reactions a that Occurred in One or More Patients while Receiving PROCYSBI in a Long-Term Clinical Trial Overall (N=59) N (%) Blood and lymphatic system disorders Neutropenia 1 (1.7%) Pancytopenia 1 (1.7%) Gastrointestinal disorders Vomiting 20 (33.9%) Nausea 9 (15.3%) Abdominal pain 8 (13.6%) Breath odour 8 (13.6%) Diarrhea 5 (8.5%) Abdominal pain upper 2 (3.4%) Constipation 1 (1.7%) Dyspepsia 1 (1.7%) Dysphagia 1 (1.7%) Flatulence 1 (1.7%) Gastroesophageal reflux disease 1 (1.7%) Peptic ulcer 1 (1.7%) General disorders and administration site conditions Device occlusion 2 (3.4%) Fatigue 2 (3.4%) Pain 1 (1.7%) Infections and infestations Gastroenteritis 1 (1.7%) Nasopharyngitis 1 (1.7%) Metabolism and nutrition disorders Decreased appetite 3 (5.1%) Nervous system disorders Headache 2 (3.4%) Renal and urinary disorders Renal failure 1 (1.7%) Skin and subcutaneous tissue disorders Skin odour abnormal 5 (8.5%) Alopecia areata 1 (1.7%) Skin hypopigmentation 1 (1.7%) Vascular disorders Hot flush 1 (1.7%) Note: A patient is counted once if he/she reported one or more events. Coded using MedDRA, Version a Defined as treatment emergent adverse events that have been assessed by the study Investigator to be possibly or probably related to the use of PROCYSBI. PROCYSBI cysteamine delayed-release capsules Page 10 of 33 DRUG INTERACTIONS Overview There is some potential for drug interaction based on the induction of CYP1A2 and CYP3A4 (and possibly CYP2B6) by cysteamine bitartrate based on in vitro data. When drugs that increase the gastric ph are introduced, more frequent monitoring of WBC cystine concentration is recommended. Dose adjustment of PROCYSBI may be required when taken with these drugs. Bicarbonate or carbonate should be administered at least one hour before or one hour after PROCYSBI. Other than bicarbonate/carbonate (see above), PROCYSBI can be co-administered with electrolytes and mineral replacements necessary for management of Fanconi Syndrome, as well as vitamin D and thyroid hormone. See DOSAGE AND ADMINISTRATION, Administration. Alcohol should be avoided while taking PROCYSBI. Drug-Drug Interactions Drugs that Increase Gastric ph Drugs that increase the gastric ph (e.g. proton pump inhibitors, medications containing bicarbonate or carbonate) may cause premature release of cysteamine from PROCYSBI, and thus increase WBC cystine concentration. Therefore, more frequent monitoring of WBC cystine concentration is recommended when drugs that increase the gastric ph are introduced. See WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests. Dose adjustment of PROCYSBI may be required if taken with these drugs. Bicarbonate or carbonate should be administered at least one hour before or one hour after PROCYSBI to avoid potential earlier release of cysteamine. See DOSAGE AND ADMINISTRATION. Concomitant administration of 20 mg, multiple dose omeprazole did not significantly affect the pharmacokinetics of cysteamine when PROCYSBI was administered with 240 ml of orange juice. The effect of omeprazole on the pharmacokinetics of cysteamine was not studied after PRO
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