Velmanase Alfa-Tycv

1 INDICA TIONS AND USAGE LAMZEDE is indicated for the treatment of non-central nervous system manifestations of alpha-mannosidosis in adult and pediatric patients. LAMZEDE is recombinant human lysosomal alpha-mannosidase indicated for the treatment of non-central nervous system manifestations of alpha-mannosidosis in adult and pediatric patients. ( 1 )

2 DOSAGE AND ADMINISTRATION For females of reproductive potential, verify that the patient is not pregnant prior to initiating treatment. ( 2.1 ) Consider pretreating with antihistamines, antipyretics, and/or corticosteroids prior to LAMZEDE administration. ( 2.2 ) Recommended LAMZEDE dosage is 1 mg/kg (actual body weight) administered once every week as an intravenous infusion. ( 2.2 ) See the full prescribing information for dosage modifications due to hypersensitivity reactions or IARs. ( 2.3 ) See the full prescribing information for reconstitution and administration instructions. ( 2.4 , 2.5 ) 2.1 Important Recommendations Prior to LAMZEDE Treatment Initiation For females of reproductive potential, verify that the patient is not pregnant [see Use in Specific Populations ( 8.1 , 8.3 )] . 2.2 Recommended Dosage and Administration Prior to LAMZEDE administration, consider pre-treating with antihistamines, antipyretics, and/or corticosteroids [see Warnings and Precautions ( 5.1 , 5.2 )] . The recommended dosage of LAMZEDE is 1 mg/kg (actual body weight) administered once every week as an intravenous infusion. The total volume of infusion is determined by the patient’s actual body weight and should be administered over a minimum of 60 minutes for patients weighing up to 49 kg. Patients weighing 50 kg and greater should be infused at a maximum infusion rate of 25 mL/hour to control the protein load [ s ee Dosage and Administration ( 2.4 )] . If one or more doses are missed, restart the treatment as soon as possible, as long as it is at least 3 days from the next scheduled dose. If it is within 3 days from the next scheduled dose, give only the next dose per schedule. 2. 3 Dosage and Administration Modifications Due to Hypersensitivity Reactions and/or Infusion-Associated Reactions In the event of a severe hypersensitivity reaction (including anaphylaxis) or severe infusion-associated reaction (IAR), immediately discontinue LAMZEDE administration and initiate appropriate medical treatment. For additional recommendations in the event of a severe hypersensitivity reaction or IAR, see Warnings and Precautions ( 5.1 , 5.2 ). In the event of a mild to moderate hypersensitivity reaction or a mild to moderate IAR, consider temporarily holding the infusion for 15 to 30 minutes, slowing the infusion rate to 25% to 50% of the recommended rate, and initiating appropriate medical treatment [see Warnings and Precautions ( 5.1 , 5.2 )] . If symptoms: Persist despite temporarily holding or slowing the infusion, stop the infusion and monitor the patient. If symptoms continue to persist, discontinue the infusion, and consider re-initiating the infusion within 7 to 14 days at 25% to 50% of the recommended rate with appropriate pretreatment. Subside following holding or slowing the infusion, resume infusion at 25% to 50% the recommended rate. If tolerated, increase the infusion rate by increments of 25% of the recommended rate until the recommended infusion rate is reached. Closely monitor the patient. 2. 4 Reconstitution Instructions Use aseptic technique during preparation. Reconstitute LAMZEDE in the following manner: Determine the number of LAMZEDE vials to be reconstituted based on the patient’s weight in kg and the recommended dose [see Dosage and Administration ( 2.2 ) ] . Round the number of vials up to the next whole number. Remove vials from the refrigerator and set aside for approximately 30 minutes to allow vials to come to room temperature. Reconstitute each vial by slowly injecting 5 mL of Sterile Water for Injection, down the inside wall of each vial. Avoid adding the Sterile Water for Injection to the vial forcefully or directly onto the lyophilized powder to minimize foaming. Allow the reconstituted vials to stand on the table for 5 – 15 minutes. Then gently tilt and roll each vial for 15 – 20 seconds to enhance the dissolution process. Each vial will yield a concentration of 2 mg/mL. Do not invert, swirl, or shake the vials. Visually inspect the reconstituted solution in the vials for particulate matter and discoloration. The solution should be clear to slightly opalescent. Due to the nature of LAMZEDE, the solution may occasionally contain some proteinaceous particles in the form of thin white strands or translucent fibers which will be removed by the in line filter during infusion. Discard if opaque particles are present or the solution is discolored. Slowly withdraw the required volume from the vials with caution to avoid foaming in the syringe. If the volume of the solution exceeds one syringe capacity, prepare the required number of syringes in order to replace the syringe quickly during the infusion. Discard unused portion remaining in the vials. Storage of the Reconstituted Solution If the reconstituted LAMZEDE vial is not used immediately, store the vial refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours inclusive of infusion time. Protect from light during refrigeration. Do not freeze. Reconstituted LAMZEDE vial must be infused within 10 hours after removal from the refrigerator, inclusive of total infusion time. Discard if not used within 10 hours. Infuse reconstituted solution within 24 hours from the time of preparation, which includes the storage time in the refrigerator, the time at room temperature, and the duration of the infusion. 2. 5 Administration Instructions Use an infusion set equipped with a pump and a low protein binding, 0.2-micron, in-line filter to administer LAMZEDE. Do not shake the syringe. The total volume of infusion is determined by the patient’s actual body weight and should be administered over a minimum of 60 minutes for patients weighing up to 49 kg. Patients weighing 50 kg and greater should be infused at a maximum infusion rate of 25 mL/hour to control the protein load. When the last syringe is empty, replace the dosage syringe with a 20 mL syringe filled with 0.9% Sodium Chloride Injection, and then continue to infuse an additional 10 mL of 0.9% Sodium Chloride Injection through the infusion system to infuse the remaining fraction of LAMZEDE in the line to the patient.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity Reactions Including Anaphylaxis [see Warnings and Precautions ( 5.1 )] Infusion-Associated Reactions (IARs) [see Warnings and Precautions ( 5.2 ) ] Most common adverse reactions (incidence > 20%) are hypersensitivity reactions including anaphylaxis ( 5.1 ), nasopharyngitis, pyrexia, headache, and arthralgia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Chiesi USA, Inc. at 1-888-661-9260 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials 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 trials of another drug and may not reflect the rates observed in practice. Adverse Reactions F rom Trial 1 The safety of LAMZEDE was evaluated in Trial 1, which included a total of 15 LAMZEDE-treated patients (8 adult patients aged 18-35 years old and 7 pediatric patients aged 6-17 years old; 9 male, 6 female) with alpha-mannosidosis [see Clinical Studies ( 14 )]. All patients received LAMZEDE 1 mg/kg weekly via intravenous infusion for 52 weeks. A serious adverse reaction of acute renal failure was reported in 1 (7%) LAMZEDE-treated patient (see Description of Selected Adverse Reactions) . Table 1 lists adverse reactions that occurred in at least 2 LAMZEDE-treated patients in Trial 1. Table 1: Adverse Reactions (≥2 patients) in Adult and Pediatric Patients with Alpha-Mannosidosis Treated with LAMZEDE in Trial 1 Adverse Reaction LAMZEDE N=15 n (%) Placebo N=10 n (%) Nasopharyngitis 10 (66) 7 (70) Pyrexia 6 (40) 5 (50) Headache 5 (33) 3 (30) Arthralgia 3 (20) 1 (10) Acute tonsillitis 2 (13) 0 Urinary tract infection 1 2 (13) 1 (10) Eye pruritus 2 (13) 0 Gastroenteritis 2 (13) 0 Hypersensitivity 2 (13) 0 Influenza 2 (13) 0 Syncope 2 (13) 0 Toothache 2 (13) 0 Back pain 2 (13) 1 (10) Ear infection 2 (13) 1 (10) 1 “Urinary tract infection” is composed of similar terms. Adverse Reactions from Trials 2 and 3 In Trial 2, 5 pediatric patients aged 3 to 5 years old (3 male, 2 female) with alpha-mannosidosis received LAMZEDE weekly for a mean exposure of 121 weeks [see Clinical Studies ( 14 )] . One patient treated with LAMZEDE (20%) presented serious reactions (chills and hyperthermia on the same occasion). The adverse reactions that occurred in at least 2 of 5 patients (and are in addition to the adverse reactions already identified in Trial 1 above) included: cough, otitis media, rhinitis, conjunctivitis, fall, ligament sprain, oropharyngeal pain, swelling face, and upper respiratory tract infection. Trial 3 is an integrated analysis that pooled the cumulative databases from LAMZEDE phase 1, 2, and 3 trials in patients with alpha-mannosodosis. A total of 33 patients (20 male, 13 female) aged 6 to 35 years old (14 adults, 19 pediatric) received LAMZEDE weekly for a mean exposure of 89 weeks in adult patients and 155 weeks in pediatric patients. One patient was withdrawn from the trial due to repeated IARs and successfully reintroduced after 89 weeks of pause. The adverse reactions that occurred in at least 10% of patients (and are in addition to the adverse reactions already identified in Trial 1 and 2 above) included abdominal pain upper, contusion, excoriation, post-lumbar puncture syndrome, wound, weight increased, erythema, rash, and tooth extraction. Description of S elected A dverse R eactions Acute R enal F ailure One patient out of 38 (3%) experienced one episode of acute renal failure. This patient paused LAMZEDE treatment for 4 weeks and acute renal failure resolved within 12 weeks of diagnosis. This patient is noted to have received the concomitant medication of ibuprofen. Immunoglobulin A V asculitis One episode of immunoglobulin A vasculitis (IgAV), reported as Henoch Schonlein Purpura , occurred in one patient out of 38 (3%) who developed high anti-drug antibody (ADA) levels. Seizure One patient out of 38 (3%), with no prior history of seizures experienced more than one episode of seizures. A relationship between the occurrence of seizures in this patient and exposure to LAMZEDE cannot be excluded. Pediatric Patients Hypersensitivity reactions overall were reported in 36% of adult patients and 58% of pediatric patients. Immunogenicity: Anti - D rug Antibody-Associated Adverse Reactions Infusion-associated reactions (including anaphylaxis and severe hypersensitivity reactions) occurred in a higher incidence in LAMZEDE-treated patients who developed anti-velmanase alfa-tycv antibodies (anti-drug antibodies, ADA) compared to patients who were ADA-negative (80% versus 20%) [see Clinical Pharmacology ( 12.6 ) ] . In Trial 1 following treatment with LAMZEDE for up to 52 weeks, 1 out of 5 ADA-positive patients developed severe hypersensitivity and this patient developed the highest ADA level among all the ADA-positive patients in the trial. In Trial 2 following treatment with LAMZEDE for up to 174 weeks, 2 out of 4 ADA-positive pediatric patients experienced IARs. In Trial 3, 3 out of 33 patients (9.1%) reported IARs; two of these patients were ADA positive (one of these two patients is described in Trial 1); one patient was ADA negative. 6. 2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of velmanase alfa outside of the United States. 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. Cardiac disorders: aortic valve incompetence, palpitations, tachycardia Ear and labyrinth disorders: deafness Eye disorders: lacrimation increased Gastrointestinal disorders: odynophagia General disorders and administration site conditions: asthenia, fatigue Infections and infestations: endocarditis, staphylococcal infection, bacterial disease carrier, furuncle Metabolism and nutrition disorders: decreased appetite Musculoskeletal and connective tissue disorders: joint swelling, joint warmth Nervous system disorders: ataxia, nervous system disorder, somnolence Psychiatric disorders : psychotic disorder, agitation, encopresis, nervousness Respiratory, thoracic and mediastinal disorders: pharyngeal edema, wheezing Skin, subcutaneous tissue disorders: angioedema Vascular disorders: vascular fragility, hypotension

12.3 Pharmacokinetics The pharmacokinetics of velmanase alfa-tycv were evaluated in adult patients with alpha-mannosidosis and are presented as mean (standard deviation, SD) unless otherwise specified. The steady state maximum plasma velmanase alfa-tycv concentration (C max ) was 7.9 (0.9) μg/mL and area under the concentration-time curve (AUC 0-t ) was 159.8 (24.4) μg∙h/mL at the approved recommended dosage of 1 mg/kg. Distribution The volume of distribution of velmanase alfa-tycv was 276 (43) mL/kg in patients with alpha-mannosidosis. Elimination The total body clearance of velmanase alfa-tycv was 5.7 (0.9) mL/h/kg and the mean terminal half-life (t 1/2 ) was 33.6 hours in patients with alpha-mannosidosis. Metabolism Velmanase alfa-tycv is expected to be metabolized into small peptides by catabolic pathways. Speci fic Population Pediatric Patie nts In pediatric patients (6 to 17 years of age) with alpha-mannosidosis, the C max and AUC 0- t at steady state were 6.6 (1.0) μg/mL and 109.8 (17.8) μg∙h/mL, respectively, at the recommended dose of 1 mg/kg velmanase alfa-tycv administered once a week. In pediatric patients (3 to <6 years of age) with alpha-mannosidosis, the C max and AUC 0- t at steady state were 7.0 (2.3) μg/mL and 75.9 (39.7) μg∙h/mL at the recommended dose of 1 mg/kg velmanase alfa-tycv amininistered once a week.