STRENSIQ

Asfotase alfa is a tissue nonspecific alkaline phosphatase (TNSALP) produced by recombinant DNA technology in a Chinese hamster ovary cell line. Asfotase alfa is a soluble glycoprotein composed of two identical polypeptide chains. Each chain contains 726 amino acids with a theoretical mass of 161 kDa. Each chain consists of the catalytic domain of human TNSALP, the human immunoglobulin G 1 Fc domain and a deca-aspartate peptide used as a bone targeting domain. The two polypeptide chains are covalently linked by two disulfide bonds. STRENSIQ (asfotase alfa) injection is a sterile, preservative-free, nonpyrogenic, clear, slightly opalescent or opalescent, colorless to slightly yellow, with few small translucent or white particles, aqueous solution for subcutaneous administration. STRENSIQ is supplied in glass single-dose vials containing asfotase alfa; dibasic sodium phosphate, heptahydrate; monobasic sodium phosphate, monohydrate; and sodium chloride at a pH between 7.2 and 7.6. Table 5 describes the content of STRENSIQ vial presentations. Table 5: Content of STRENSIQ Vial Presentations Ingredient Quantity per Vial Asfotase Alfa 18 mg/0.45 mL 28 mg/0.7 mL 40 mg/mL 80 mg/0.8 mL Dibasic sodium phosphate, heptahydrate 2.48 mg 3.85 mg 5.5 mg 4.4 mg Monobasic sodium phosphate, monohydrate 0.28 mg 0.43 mg 0.62 mg 0.5 mg Sodium chloride 3.94 mg 6.13 mg 8.76 mg 7.01 mg

STRENSIQ ® is indicated for the treatment of patients with perinatal/infantile- and juvenile-onset hypophosphatasia (HPP). STRENSIQ is a tissue nonspecific alkaline phosphatase indicated for the treatment of patients with perinatal/infantile- and juvenile-onset hypophosphatasia (HPP). ( 1 )

Perinatal/Infantile-Onset HPP ( 2.2 ) Recommended dosage regimen is 2 mg/kg administered subcutaneously three times per week, or 1 mg/kg administered six times per week. Injection site reactions may limit the tolerability of the six times per week regimen. The dose may be increased to 3 mg/kg three times per week for insufficient efficacy. Juvenile-Onset HPP ( 2.3 ) Recommended dosage regimen is 2 mg/kg administered subcutaneously three times per week, or 1 mg/kg administered six times per week. Injection site reactions may limit the tolerability of the six times per week regimen. Preparation and Weight-Based Dosing ( 2.4 ): Caution: Do not use the 80 mg/0.8 mL vial in pediatric patients weighing less than 40 kg because the systemic asfotase alfa exposure achieved with the 80 mg/0.8 mL vial (higher concentration) is lower than that achieved with the other strength vials (lower concentration). A lower exposure may not be adequate for this subgroup of patients. See full prescribing information for tables of weight-based dosing by treatment regimen. Administration ( 2.5 ): For subcutaneous injection only. Rotate injection sites. Do not administer to areas that are reddened, inflamed or swollen. 2.1 Recommendations Prior to STRENSIQ Treatment Initiate STRENSIQ under the supervision of a healthcare provider with appropriate medical monitoring and support measures [see Warnings and Precautions (5.1) ]. 2.2 Dosage for Perinatal/Infantile-Onset HPP The recommended dosage regimen of STRENSIQ for the treatment of perinatal/infantile-onset HPP is 6 mg/kg per week administered subcutaneously as either: 2 mg/kg three times per week, or 1 mg/kg six times per week. Injection site reactions may limit the tolerability of the six times per week regimen [see Adverse Reactions (6.1) ]. The dose of STRENSIQ may be increased for lack of efficacy (e.g., no improvement in respiratory status, growth, or radiographic findings) up to 9 mg/kg per week administered subcutaneously as 3 mg/kg three times per week. 2.3 Dosage for Juvenile-Onset HPP The recommended dosage regimen of STRENSIQ for the treatment of juvenile-onset HPP is 6 mg/kg per week administered subcutaneously as either: 2 mg/kg three times per week, or 1 mg/kg six times per week. Injection site reactions may limit the tolerability of the six times per week regimen [see Adverse Reactions (6.1) ]. 2.4 Preparation and Weight-Based Dosing Tables Caution: Do not use the 80 mg/0.8 mL vial of STRENSIQ in pediatric patients weighing less than 40 kg because the systemic exposure of asfotase alfa achieved with the 80 mg/0.8 mL vial (higher concentration) is lower than that achieved with the other strength vials (lower concentration). A lower exposure may not be adequate for this subgroup of patients [see Dosage Forms and Strengths (3) , Clinical Pharmacology (12.3) ] . 1. Determine the total weekly volume needed for the prescribed dosage based on the patient's weight and recommended dosage. Follow these steps to determine the patient dose. Total weekly dose (mg) = patient's weight (kg) × prescribed dose (mg/kg/week) Total injection volume (mL) per week = Total dose (mg/week) divided by the STRENSIQ concentration (40 mg/mL or 100 mg/mL). Note product concentrations are: 40 mg/mL (vial strengths 18 mg/0.45 mL, 28 mg/0.7 mL, 40 mg/mL) or 100 mg/mL (vial strength 80 mg/0.8 mL). Round total injection volume to the nearest hundredth of a mL Total number of vials per week = Total injection volume divided by vial volume (mL) 2. Determine the number of injection days per week (three or six per week). 3. Determine dose per injection day. Patient weights should be rounded to the nearest kilogram when determining dose. Use the following tables for guidance, for patients administering 2 mg/kg three times per week (Table 1), 1 mg/kg six times per week (Table 2) and for dose escalations to 3 mg/kg three times per week, recommended only for patients with perinatal/infantile-onset HPP [see Dosage and Administration (2.2) ] (Table 3). Table 1: Weight-Based Dosing for Administration of 2 mg/kg Three Times per Week Body Weight (kg) Do not use the 80 mg/0.8 mL vial of STRENSIQ in pediatric patients weighing less than 40 kg [see Clinical Pharmacology (12.3) ] . Dose to Inject Volume to Inject Vial Configuration 3 6 mg 0.15 mL 18 mg/0.45 mL 4 8 mg 0.2 mL 18 mg/0.45 mL 5 10 mg 0.25 mL 18 mg/0.45 mL 6 12 mg 0.3 mL 18 mg/0.45 mL 7 14 mg 0.35 mL 18 mg/0.45 mL 8 16 mg 0.4 mL 18 mg/0.45 mL 9 18 mg 0.45 mL 18 mg/0.45 mL 10 20 mg 0.5 mL 28 mg/0.7 mL 15 30 mg 0.75 mL 40 mg/1 mL 20 40 mg 1 mL 40 mg/1 mL 25 50 mg 1.25 mL Two 28 mg/0.7 mL vials 30 60 mg 1.5 mL Two 40 mg/1 mL vials 35 70 mg 1.75 mL Two 40 mg/1 mL vials 40 80 mg 0.8 mL 80 mg/0.8 mL 50 100 mg 1 mL Two 80 mg/0.8 mL vials 60 120 mg 1.2 mL When preparing a volume for injection greater than 1 mL, split the volume equally between two syringes, and administer two injections. When administering the two injections, use two separate injection sites. Two 80 mg/0.8 mL vials 70 140 mg 1.4 mL Two 80 mg/0.8 mL vials 80 160 mg 1.6 mL Two 80 mg/0.8 mL vials Table 2: Weight-Based Dosing for Administration of 1 mg/kg Six Times per Week Body Weight (kg) Do not use the 80 mg/0.8 mL vial of STRENSIQ in pediatric patients weighing less than 40 kg [see Clinical Pharmacology (12.3) ] . Dose to Inject Volume to Inject Vial Configuration 3 3 mg 0.08 mL 18 mg/0.45 mL 4 4 mg 0.1 mL 18 mg/0.45 mL 5 5 mg 0.13 mL 18 mg/0.45 mL 6 6 mg 0.15 mL 18 mg/0.45 mL 7 7 mg 0.18 mL 18 mg/0.45 mL 8 8 mg 0.2 mL 18 mg/0.45 mL 9 9 mg 0.23 mL 18 mg/0.45 mL 10 10 mg 0.25 mL 18 mg/0.45 mL 15 15 mg 0.38 mL 18 mg/0.45 mL 20 20 mg 0.5 mL 28 mg/0.7 mL 25 25 mg 0.63 mL 28 mg/0.7 mL 30 30 mg 0.75 mL 40 mg/1 mL 35 35 mg 0.88 mL 40 mg/1 mL 40 40 mg 1 mL 40 mg/1 mL 50 50 mg 0.5 mL 80 mg/0.8 mL 60 60 mg 0.6 mL 80 mg/0.8 mL 70 70 mg 0.7 mL 80 mg/0.8 mL 80 80 mg 0.8 mL 80 mg/0.8 mL 90 90 mg 0.9 mL Two 80 mg/0.8 mL vials 100 100 mg 1 mL Two 80 mg/0.8 mL vials Table 3: Weight-Based Dosing for Administration of 3 mg/kg Three Times per Week – Only for Perinatal/Infantile-Onset HPP A regimen of 3 mg/kg three times per week is recommended only for patients with perinatal/infantile-onset HPP [see Dosage and Administration (2.2) ] Body Weight (kg) Do not use the 80 mg/0.8 mL vial of STRENSIQ in pediatric patients weighing less than 40 kg [see Clinical Pharmacology (12.3) ] . Dose to Inject Volume to Inject Vial Configuration 3 9 mg 0.23 mL 18 mg/0.45 mL 4 12 mg 0.3 mL 18 mg/0.45 mL 5 15 mg 0.38 mL 18 mg/0.45 mL 6 18 mg 0.45 mL 18 mg/0.45 mL 7 21 mg 0.53 mL 28 mg/0.7 mL 8 24 mg 0.6 mL 28 mg/0.7 mL 9 27 mg 0.68 mL 28 mg/0.7 mL 10 30 mg 0.75 mL 40 mg/1 mL 15 45 mg 1.13 mL When preparing a volume for injection greater than 1 mL, split the volume equally between two syringes, and administer two injections. When administering the two injections, use two separate injection sites. Two 28 mg/0.7 mL vials 20 60 mg 1.5 mL Two 40 mg/1 mL vials 25 75 mg 1.88 mL Two 40 mg/1 mL vials 4. Take the unopened STRENSIQ vial(s) out of the refrigerator 15 to 30 minutes before injecting to allow the liquid to reach room temperature. Do not warm STRENSIQ in any other way (for example, do not warm it in a microwave or in hot water). 5. Inspect the solution in the vial(s) for particulate matter and discoloration. STRENSIQ is supplied as a clear, slightly opalescent or opalescent, colorless to slightly yellow aqueous solution; a few small translucent or white particles may be present. Discard any vial(s) not consistent with this appearance. 6. Assemble injection supplies. Administer STRENSIQ using sterile disposable 1 mL syringes and ½ inch injection needles, between 25 to 29 gauge are recommended. The use of two different gauge needles is recommended, a larger bore needle (e.g. 25 gauge) for withdrawal of the medication, and a smaller bore needle (e.g. 29 gauge) for the injection. For doses greater than 1 mL, the injection volume should be split equally between two 1 mL syringes. Always use a new syringe and needle for each injection. 7. Remove vial cap, aseptically prepare the vial and insert the syringe into the vial to withdraw the prescribed dose for administration. Do not shake. 8. Remove any air bubbles in the syringe and verify the correct dose. 9. STRENSIQ vials are for one time use only. Discard any unused product. 2.5 Administration STRENSIQ is for subcutaneous injection only. When administering two injections, use two separate injection sites. Administer STRENSIQ within 3 hours upon removal of the vial(s) from refrigeration. Rotate the injection from among the following sites to reduce the risk of lipodystrophy: abdominal area, thigh, deltoid, or buttocks [see Warnings and Precautions (5.2) , Adverse Reactions (6.1) ] . Do NOT administer injections in areas that are reddened, inflamed, or swollen. Inject STRENSIQ subcutaneously into the determined site and properly dispose of the syringe and the needle.

None. None. ( 4 )

The following adverse reactions are described below and elsewhere in the labeling: Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] Lipodystrophy [see Warnings and Precautions (5.2) ] Ectopic Calcifications [see Warnings and Precautions (5.3) ] Possible Immune-Mediated Clinical Effects [see Warnings and Precautions (5.4) ] Most common adverse reactions (≥ 10%) are injection site reactions, lipodystrophy, ectopic calcifications and hypersensitivity reactions. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Alexion Pharmaceuticals, Inc. at 1-844-259-6783 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. The data described below reflect exposure to STRENSIQ in 99 patients with perinatal/infantile- or juvenile onset HPP (age 1 day to 58 years) treated with STRENSIQ, most for more than 2 years (range 1 day to 312 weeks [78 months]): 51 patients received at least 96 weeks (24 months) of treatment and 39 patients received 168 weeks (42 months) or more of treatment [see Clinical Studies (14) ] . Common Adverse Reactions Overall, the most common adverse reactions reported were injection site reactions (63%) . Other common adverse reactions included lipodystrophy (28%), ectopic calcifications (14%), and hypersensitivity reactions (12%). Table 4 summarizes the adverse reactions that occurred at a rate of at least 10% in clinical trials following subcutaneous injection of STRENSIQ by patient population and STRENSIQ dosage regimen. The frequency of injection site reactions, lipodystrophy and ectopic calcification were higher in patients with juvenile-onset HPP as compared to perinatal/infantile-onset HPP patients. The majority of injection site reactions resolved within a week. Two patients experienced injection site reactions that led to reductions of their STRENSIQ dose. One patient switched from six times per week dosing to 3 times per week dosing as a result of injection site reactions. One other patient experienced a severe injection site reaction of injection site discoloration and withdrew from the trial. Table 4: Adverse Reactions Reported in at Least 10% of Patients with Perinatal/Infantile- or Juvenile-onset HPP Enrolled in STRENSIQ Clinical Trials Perinatal/Infantile-onset HPP Juvenile-onset HPP Adverse Reaction Category or Term STRENSIQ less than or equal to 6 mg/kg per week (N=66) n (%) STRENSIQ more than 6 mg/kg/week Adverse reactions are from the combined period of 6 mg/kg and above (i.e. total drug exposure regardless of starting dose and intermediary doses as long as the patient reached doses > 6 mg/kg) (N=13) n (%) Total (N=79) n (%) STRENSIQ (N=20) n (%) Injection site reactions 38 (58) 6 (46) 44 (56) 18 (90) Erythema 29 (44) 3 (23) 32 (41) 15 (75) Discoloration/ Hypopigmentation 11 (17) 1 (8) 12 (15) 8 (40) Pain/ Tenderness 10 (15) 1 (8) 11 (14) 8 (40) Pruritus/ Itching 10 (15) 0 (0) 10 (13) 7 (35) Swelling 8 (12) 0 (0) 8 (10) 6 (30) Induration 9 (14) 1 (8) 10 (13) 3 (15) Macule 4 (6) 0 (0) 4 (5) 7 (35) Reaction, not otherwise specified 6 (9) 1 (8) 7 (9) 4 (20) Bruising 6 (9) 0 (0) 6 (8) 4 (20) Nodule 2 (3) 0 (0) 2 (3) 2 (10) Other injection site reactions Other injection site reactions include injection site rash, inflammation, papule, hemorrhage, hematoma, urticaria, warmth, calcification, mass, scar and cellulitis. 10 (15) 3 (23) 13 (17) 4 (20) Ectopic calcifications 3 (5) 0 (0) 3 (4) 11 (55) Lipodystrophy 12 (18) 2 (15) 14 (18) 14 (70) Injection site atrophy 4 (6) 2 (15) 6 (8) 8 (40) Injection site hypertrophy 5 (8) 0 (0) 5 (6) 6 (30) Other lipodystrophy Other lipodystrophy includes lipohypertrophy. 4 (6) 0 (0) 4 (5) 1 (5) Hypersensitivity reactions 7 (11) 3 (23) 10 (13) 2 (10) Vomiting/emesis 2 (3) 2 (15) 4 (5) 2 (10) Other hypersensitivity reactions Other hypersensitivity reactions include erythema/redness, pyrexia/fever, irritability, nausea, pain, rigor/chills, hypoesthesia oral, headache, flushing, and anaphylaxis. 6 (9) 2 (15) 8 (10) 2 (10) Less Common Adverse Reactions Adverse reactions that occurred at rates less than 1% included: Hypocalcemia Renal Stones Chronic hepatitis Decreased vitamin B6 Long-Term Safety In long-term extension trials reflecting a median exposure to STRENSIQ of 142 weeks (range 0.1 weeks to 392 weeks) in 112 patients with perinatal/infantile- (n = 89), juvenile- (n = 22), and adult-onset (n = 1) HPP (age at enrollment = 1 day to 66.5 years), the most common adverse reactions were similar to those reported in Table 4. 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of the antibodies in the studies described below with the incidence of antibodies in other studies or to other asfotase alfa products may be misleading. During clinical trials, anti-asfotase alfa antibodies have been detected in patients receiving treatment with STRENSIQ using an electrochemiluminescent (ECL) immunoassay. Antibody positive samples were tested to determine the presence of neutralizing antibodies based on in vitro inhibition of the catalytic activity of STRENSIQ. Among STRENSIQ-treated patients with hypophosphatasia (HPP) in clinical studies who had post-baseline antibody data available, 97/109 (89%) tested positive for anti-asfotase alfa antibodies at some time point during STRENSIQ treatment. Among those 97 patients, 55 (57%) also tested positive for neutralizing antibodies at some time point during STRENSIQ treatment. No correlation was observed between the anti-asfotase alfa antibody titers and the neutralizing antibody (% inhibition) values. Formation of anti-asfotase alfa antibody resulted in a reduced systemic exposure of asfotase alfa [see Clinical Pharmacology (12.3) ] . 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of STRENSIQ. 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. Some STRENSIQ-treated patients with initial therapeutic response to STRENSIQ subsequently developed worsening in disease-associated laboratory and radiographic biomarkers (some in association with neutralizing antibodies) suggesting possible immune-mediated effects on STRENSIQ's pharmacologic action resulting in disease progression [see Warnings and Precautions (5.4) ].

Drug Interference with Laboratory Tests: Alkaline Phosphatase (ALP) is used as a detection reagent in many laboratory tests and the presence of asfotase alfa in clinical laboratory samples could result in erroneous test results. Inform laboratory personnel and discuss use of an alternative testing platform for patients on treatment. ( 7.1 ) Serum Alkaline Phosphatase : Serum ALP measurements are expected to be elevated during treatment and may be unreliable for clinical decision making. ( 7.1 ) 7.1 Drug Interference with Laboratory Tests Laboratory Tests Utilizing Alkaline Phosphatase as a Detection Reagent Studies have shown that there is analytical interference between asfotase alfa and laboratory tests that utilize an alkaline phosphatase (ALP)-conjugated test system, rendering erroneous test results in patients treated with STRENSIQ. ALP-conjugated test systems are utilized to measure substances such as hormones, bacterial antigens and antibodies. Therefore, it is recommended that laboratory assays which do not have ALP-conjugate technology be used when testing samples from patients who are receiving STRENSIQ. To avoid erroneous test results for patients treated with STRENSIQ, inform laboratory personnel that the patient is being treated with STRENSIQ and discuss the use of a testing platform which does not utilize an ALP-conjugated test system. Serum Alkaline Phosphatase High serum ALP measurements detected through clinical laboratory testing are expected in patients receiving STRENSIQ and reflect circulating concentrations of asfotase alfa . Do not rely on serum ALP measurements for clinical decision making in patients treated with STRENSIQ.

STRENSIQ vials must be stored in the original carton until the time of use under refrigerated conditions at 2°C to 8°C (36°F to 46°F) and protected from light. Once removed from refrigeration, STRENSIQ should be administered within 3 hours. Do not use beyond the expiration date stamped on the carton. DO NOT FREEZE OR SHAKE. Vials are for one time use only. Discard any unused product.