Asfotase Alfa (Monograph)

Brand name: Strensiq
Drug class: Enzymes
Molecular formula: C₇₁₀₈H₁₁₀₀₈N₁₉₆₈O₂₂₀₆S₅₆
CAS number: 1174277-80-5

Introduction

Biosynthetic (recombinant DNA origin) form of human tissue-nonspecific alkaline phosphatase (TNSALP).

Uses for Asfotase Alfa

Hypophosphatasia

Enzyme replacement therapy in patients with perinatal/infantile- and juvenile-onset hypophosphatasia (HPP); designated an orphan drug by FDA for use in these conditions.

Improves overall and invasive ventilation-free survival in patients with perinatal/infantile-onset HPP; improvements in growth, radiologic scores, histologic parameters, and biochemical markers also observed in such patients.

Improves growth, mobility, radiologic scores, histologic parameters, and biochemical markers in patients with juvenile-onset HPP.

HPP registry established to monitor variability and progression of HPP and long-term effects of asfotase alfa. Encourage patients and their caregivers to participate in this voluntary program. For more information, visit [Web].

Asfotase Alfa Dosage and Administration

General

Dosage based on patient weight. Round patient's weight to the nearest whole kg when determining asfotase alfa dosage.
Round calculated total injection volume to nearest 0.01 mL.
When total injection volume >1 mL, divide volume equally into 2 syringes; administer at separate injection sites.
For more detailed information on weight-based dosage of this drug by treatment regimen as well as required volume of injection and concentration/number of vials, consult dosage tables in the manufacturer's labeling.
Do not use 100-mg/mL concentration in pediatric patients weighing <40 kg. Systemic exposure of asfotase alfa achieved with this concentration is lower than that associated with 40-mg/mL concentration and may provide inadequate efficacy in such patients.

Administration

Sub-Q Administration

Administer by sub-Q injection only.

Asfotase alfa injection will appear clear, slightly opalescent or opalescent, and colorless to slightly yellow, possibly with a few small translucent or white particles; discard solutions not consistent with this appearance.

Administer within 1 hour after removing vial(s) from refrigeration.

Contains no preservatives; discard any unused solution.

Administer using disposable 1-mL syringes and ½-inch, 25- to 29-gauge needles; use new syringe and needle for each injection.

To reduce risk of lipodystrophy, rotate injection sites at the abdominal, thigh, and deltoid areas. Do not inject into areas that are reddened, inflamed, or swollen.

Dosage

Pediatric Patients

Hypophosphatasia

Perinatal/Infantile-onset Hypophosphatasia

Sub-Q

6 mg/kg weekly (as either 2 mg/kg 3 times weekly or 1 mg/kg 6 times weekly).

Injection site reactions may limit tolerability of 6-times-weekly regimen.

Dosage may be increased up to 9 mg/kg weekly (as 3 mg/kg 3 times weekly) for lack of efficacy (e.g., no improvement in respiratory status, growth, or radiographic findings).

Juvenile-onset Hypophosphatasia

Sub-Q

6 mg/kg weekly (as 2 mg/kg 3 times weekly or 1 mg/kg 6 times weekly).

Injection site reactions may limit tolerability of 6-times-weekly regimen.

Special Populations

No special population dosage recommendations at this time.

Cautions for Asfotase Alfa

Contraindications

Manufacturer states none known.

Warnings/Precautions

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., anaphylaxis) reported. Manifestations included vomiting, fever, headache, flushing, irritability, chills, erythema, rash, pruritus, oral hypoesthesia, signs and symptoms consistent with anaphylaxis (e.g. difficulty breathing, choking sensation, nausea, periorbital edema, dizziness). May occur within minutes following injection and in patients receiving therapy for >1 year.

If severe hypersensitivity reaction occurs, discontinue asfotase alfa and initiate appropriate treatment. Consider risks and benefits of retreatment following severe hypersensitivity reaction; if retreatment instituted, monitor for signs and symptoms of severe hypersensitivity reaction.

Lipodystrophy

Localized lipodystrophy (e.g., lipoatrophy, lipohypertrophy) reported at injection sites following several months of therapy.

Advise patients to follow proper injection technique and rotate injection sites to prevent such occurrence.

Ectopic Calcifications

Ectopic calcification of the eye (including cornea, conjunctiva) and kidney (nephrocalcinosis) reported in 14% of patients in clinical trials. Reported cases were not associated with changes in vision or renal function.

Patients with HPP are at increased risk for developing ectopic calcifications. Not known whether asfotase alfa treatment contributed to occurrence of ectopic calcification.

Ophthalmologic examinations and renal ultrasound recommended at baseline and periodically during therapy.

Injection Site Reactions

Injection site reactions (e.g., erythema, discoloration/hypopigmentation, pain/tenderness, pruritus, swelling, induration, macules, bruising, nodules) reported in 63% of patients.

Incidence of such reactions higher in patients with juvenile-onset HPP than in those with perinatal/infantile-onset HPP.

Antibody Formation

Anti-drug antibodies reported in 78% of patients; neutralizing antibodies also reported in 45% of these patients. No correlation observed between anti-drug antibody titer and neutralizing antibody (percent inhibition) values. Formation of anti-drug antibody resulted in reduced systemic exposure of asfotase alfa.

Specific Populations

Pregnancy

No adequate and well-controlled studies in pregnant women.

No evidence of fetotoxicity, embryolethality, or teratogenicity in animals.

Lactation

Not known whether distributed into human milk. Effects of drug on milk production or on breast-fed infant also unknown.

Consider known benefits of breast-feeding along with mother's clinical need for asfotase alfa and any potential effects of drug or disease on the infant.

Pediatric Use

Most patients (90%) included in clinical trials were pediatric patients 1 day to 16 years of age.

Geriatric Use

No experience in patients ≥65 years of age; not known whether geriatric patients respond differently than younger patients.

Common Adverse Effects

Injection site reactions, ectopic calcifications, lipodystrophy, hypersensitivity reactions.

Drug Interactions

No formal drug interaction studies to date.

Asfotase Alfa Pharmacokinetics

Absorption

Bioavailability

Approximately 62% following sub-Q administration.

Steady-state exposure achieved as early as 3 weeks.

Concentration of asfotase alfa injection affects drug exposure; at same dosage, exposure approximately 25% lower with 100-mg/mL concentration compared with 40-mg/mL concentration.

Time to peak plasma concentrations following multiple sub-Q doses of 2 mg/kg 3 times weekly in patients with HPP approximately 15 or 21 hours in patients ≤5 years of age or those >5 to 12 years of age, respectively.

Pharmacokinetics dose-proportional across dosage range of 0.3–3 mg/kg.

Formation of anti-drug antibodies reduces systemic exposure of asfotase alfa.

Distribution

Extent

Not known whether distributed into human milk.

Elimination

Half-life

Approximately 5 days.

Stability

Storage

Parenteral

Injection

2–8°C. Protect from light; store in original carton until time of use. Do not freeze or shake. Administer within 1 hour after removal from refrigeration.

Actions

Biosynthetic (recombinant DNA origin) form of human TNSALP, a metalloenzyme that catalyzes hydrolysis of phosphomonoesters.
Specific activity of asfotase alfa is 620–1250 units/mg, with 1 unit defined as amount of asfotase alfa that results in formation of 1 µmol of p-nitrophenol from p-nitrophenyl phosphate per minute at 37°C.
Provides exogenous source of TNSALP, reducing accumulation of TNSALP substrates, promoting bone mineralization, and improving skeletal structure.

Advice to Patients

Importance of advising patients and their caregivers to read the manufacturer's patient information and instructions for use.
Importance of instructing patients and/or caregiver regarding proper dosage, preparation, and administration of asfotase alfa, including use of aseptic technique and safe disposal of needles and syringes. (See Dosage and Administration.)
When volume for injection >1 mL, importance of dividing the volume equally between 2 syringes and injecting into separate sites.
Importance of rotating injection sites and avoiding areas that are reddened, inflamed, or swollen.
Risk of injection site reactions and other administration-associated adverse reactions (e.g., erythema, discoloration/hypopigmentation, pain/tenderness, pruritus, swelling, induration, macules, bruising, nodules).
Importance of informing patients of signs and symptoms of hypersensitivity reactions (difficulty breathing, nausea, periorbital edema, dizziness); advise patients to seek immediate medical care if such symptoms occur.
Risk of lipodystrophy and localized atrophy at injection sites. Importance of following proper injection technique and rotating injection sites.
Importance of informing patients of the HPP registry established to monitor variability and progression of HPP and long-term effects of asfotase alfa. Importance of encouraging patient participation in this voluntary program and of advising patients that participation may involve long-term follow-up. (See Hypophosphatasia under Uses.)
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.