Data from FDA - Curated by EPG Health - Last updated 15 May 2018

Indication(s)

1 INDICATIONS AND USAGE 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)

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Advisory information

contraindications
4 CONTRAINDICATIONS None. None. (4)
Adverse reactions
6 ADVERSE REACTIONS 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)] 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. 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/weekAdverse 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 (%) (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 reactionsOther 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 lipodystrophyOther 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 reactionsOther 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 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. During clinical trials, anti-drug 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 98 patients with hypophosphatasia (HPP) enrolled in the clinical trials and who had post-baseline antibody data, 76 (78%) tested positive for anti-drug antibodies at some time point after receiving STRENSIQ treatment. Among those 76 patients, 34 (45%) also showed the presence of neutralizing antibodies. No correlation was observed between the anti-drug antibody titer and neutralizing antibody (% inhibition) values. Formation of anti-drug antibody resulted in a reduced systemic exposure of asfotase alfa. [see Clinical Pharmacology (12.3)]. The detection of antibody formation is 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 to STRENSIQ with the incidence of antibodies to other products may be misleading.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Perinatal/Infantile-Onset HPP (2.1) 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 (2.2) 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. Preparation and Weight-Based Dosing (2.3): 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 (2.4): For subcutaneous injection only. Rotate injection sites. Do not administer to areas that are reddened, inflamed or swollen. 2.1 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. 2.2 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)]. 2.3 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 volume needed for the prescribed dosage based on the patient's weight and recommended dosage. Follow these steps to determine the patient dose. Total dose (mg) = patient's weight (kg) × prescribed dose (mg/kg) Total injection volume (mL) = Total dose (mg) divided by concentration (40 mg/mL or 80 mg/0.8 mL) Round total injection volume to the nearest hundredth of a mL Total number of vials = Total injection volume divided by vial volume (mL) 2.Determine frequency of weekly injections. 3.Determine dose. 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 (2.1)] (Table 3). 4.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. 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/mL 20 40 mg 1 mL 40 mg/mL 25 50 mg 1.25 mL Two 28 mg/0.7 mL vials 30 60 mg 1.5 mL Two 40 mg/mL vials 35 70 mg 1.75 mL Two 40 mg/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 mLWhen 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/mL 35 35 mg 0.88 mL 40 mg/mL 40 40 mg 1 mL 40 mg/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 HPPA regimen of 3 mg/kg three times per week is recommended only for patients with perinatal/infantile-onset HPP [see Dosage and Administration (2.1)] 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/mL 15 45 mg 1.13 mLWhen 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/mL vials 25 75 mg 1.88 mL Two 40 mg/mL vials 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; 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. 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. 7.Remove vial cap, aseptically prepare the vial and insert the syringe into the vial to withdraw the prescribed dose for administration. 8.Remove any air bubbles in the syringe and verify the correct dose. 2.4 Administration STRENSIQ is for subcutaneous injection only. 1.Administer STRENSIQ within 1 hour upon removal of the vial(s) from refrigeration. 2.Rotate the injection from among the following sites to reduce the risk of lipodystrophy: abdominal area, thigh, or deltoid [see Warnings and Precautions (5.2), Adverse Reactions (6.1)]. 3. Do NOT administer injections in areas that are reddened, inflamed, or swollen. 4.Inject STRENSIQ subcutaneously into the determined site and properly dispose of the needle. 5.STRENSIQ vials are single use only. Discard any unused product.
Use in special populations
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available human data on STRENSIQ use in pregnant women to inform a drug associated risk. In animal reproduction studies, asfotase alfa administered intravenously to pregnant rats and rabbits during the period of organogenesis showed no evidence of fetotoxicity, embryolethality or teratogenicity at doses causing plasma exposures up to 21 and 24 times, respectively, the exposure at the recommended human dose [see Data]. 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. Data Animal Data Asfotase alfa administered during the period of organogenesis to rats (from gestation Day 6 to Day 19 post-partum) and rabbits (on gestation days 7 to 19) at intravenous doses up to 50 mg/kg/day, approximately 21 and 24 times the human AUC of 65486 ng.h/mL at 2 mg/kg dose administered three times weekly for a 50 kg individual, respectively did not cause any adverse effects on embryofetal development. A pre- and post-natal development study in pregnant rats showed no evidence of adverse effects on pre- and post-natal development at intravenous doses (from Day 6 of gestation to Day 19 postpartum) of asfotase alfa up to 50 mg/kg/day approximately 21 times the human AUC of 65486 ng.h/mL at 2 mg/kg dose administered three times weekly for a 50 kg individual. 8.2 Lactation Risk Summary There are no data on the presence of asfotase alfa in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for STRENSIQ and any potential adverse effects on the breastfed infant from asfotase alfa or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of STRENSIQ have been established in pediatric patients. Use of STRENSIQ is based on 4 prospective, open-label clinical trials conducted in 99 adult and pediatric patients with perinatal/infantile-onset or juvenile-onset HPP. The majority of patients were pediatric patients 1 day to 16 years of age (89/99 [90%]) [see Clinical Studies (14)]. 8.5 Geriatric Use No patients with perinatal/infantile- or juvenile-onset HPP aged 65 years were enrolled in clinical trials of STRENSIQ. Therefore, there is no information available to determine whether patients aged 65 years and over respond differently from younger patients.

Interactions

7 DRUG INTERACTIONS 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.

More information

Category Value
Authorisation number BLA125513
Agency product number Z633861EIM
Orphan designation No
Product NDC 25682-010,25682-019,25682-013,25682-016
Date Last Revised 07-02-2018
Type HUMAN PRESCRIPTION DRUG
Storage and handling 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 1 hour. Do not use beyond the expiration date stamped on the carton. DO NOT FREEZE OR SHAKE. Vials are single-use only. Discard any unused product.
Marketing authorisation holder Alexion Pharmaceuticals Inc.