Asfotase Alfa

Class: Enzymes
Molecular Formula: C₇₁₀₈H₁₁₀₀₈N₁₉₆₈O₂₂₀₆S₅₆
CAS Number: 1174277-80-5
Brands: Strensiq

Introduction

Biosynthetic (recombinant DNA origin) form of human tissue-nonspecific alkaline phosphatase (TNSALP).^{1 3 4 5 6 7}

Uses for Asfotase Alfa

Hypophosphatasia

Enzyme replacement therapy in patients with perinatal/infantile- and juvenile-onset hypophosphatasia (HPP);^{1 3 4 5} designated an orphan drug by FDA for use in these conditions.²

Improves overall and invasive ventilation-free survival in patients with perinatal/infantile-onset HPP;^{1 3 5} improvements in growth, radiologic scores, histologic parameters, and biochemical markers also observed in such patients.^{1 3 4 5}

Improves growth, mobility, radiologic scores, histologic parameters, and biochemical markers in patients with juvenile-onset HPP.^{1 3}

HPP registry established to monitor variability and progression of HPP and long-term effects of asfotase alfa.¹ Encourage patients and their caregivers to participate in this voluntary program.¹ For more information, visit .¹

Asfotase Alfa Dosage and Administration

General

• Dosage based on patient weight.¹ Round patient's weight to the nearest whole kg when determining asfotase alfa dosage.¹

• Round calculated total injection volume to nearest 0.01 mL.¹

• When total injection volume >1 mL, divide volume equally into 2 syringes; administer at separate injection sites.¹

• 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.¹

• Do not use 100-mg/mL concentration in pediatric patients weighing <40 kg.¹ 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.¹

Administration

Sub-Q Administration

Administer by sub-Q injection only.¹

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.¹

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

Contains no preservatives; discard any unused solution.¹

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

To reduce risk of lipodystrophy, rotate injection sites at the abdominal, thigh, and deltoid areas.¹ Do not inject into areas that are reddened, inflamed, or swollen.¹

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).¹

Injection site reactions may limit tolerability of 6-times-weekly regimen.¹

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).¹

Juvenile-onset Hypophosphatasia

Sub-Q

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

Injection site reactions may limit tolerability of 6-times-weekly regimen.¹

Special Populations

No special population dosage recommendations at this time.¹

Cautions for Asfotase Alfa

Contraindications

• Manufacturer states none known.¹

Warnings/Precautions

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., anaphylaxis) reported.^{1 3} 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).¹ May occur within minutes following injection and in patients receiving therapy for >1 year.¹

If severe hypersensitivity reaction occurs, discontinue asfotase alfa and initiate appropriate treatment.¹ Consider risks and benefits of retreatment following severe hypersensitivity reaction; if retreatment instituted, monitor for signs and symptoms of severe hypersensitivity reaction.¹

Lipodystrophy

Localized lipodystrophy (e.g., lipoatrophy, lipohypertrophy) reported at injection sites following several months of therapy.¹

Advise patients to follow proper injection technique and rotate injection sites to prevent such occurrence.¹

Ectopic Calcifications

Ectopic calcification of the eye (including cornea, conjunctiva) and kidney (nephrocalcinosis) reported in 14% of patients in clinical trials.¹ Reported cases were not associated with changes in vision or renal function.¹

Patients with HPP are at increased risk for developing ectopic calcifications.¹ Not known whether asfotase alfa treatment contributed to occurrence of ectopic calcification.¹

Ophthalmologic examinations and renal ultrasound recommended at baseline and periodically during therapy.¹

Injection Site Reactions

Injection site reactions (e.g., erythema, discoloration/hypopigmentation, pain/tenderness, pruritus, swelling, induration, macules, bruising, nodules) reported in 63% of patients.¹

Incidence of such reactions higher in patients with juvenile-onset HPP than in those with perinatal/infantile-onset HPP.¹

Antibody Formation

Anti-drug antibodies reported in 78% of patients; neutralizing antibodies also reported in 45% of these patients.¹ No correlation observed between anti-drug antibody titer and neutralizing antibody (percent inhibition) values.¹ Formation of anti-drug antibody resulted in reduced systemic exposure of asfotase alfa.¹

Specific Populations

Pregnancy

No adequate and well-controlled studies in pregnant women.¹

No evidence of fetotoxicity, embryolethality, or teratogenicity in animals.¹

Lactation

Not known whether distributed into human milk.¹ Effects of drug on milk production or on breast-fed infant also unknown.¹

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.¹

Pediatric Use

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

Geriatric Use

No experience in patients ≥65 years of age; not known whether geriatric patients respond differently than younger patients.¹

Common Adverse Effects

Injection site reactions,^{1 4} ectopic calcifications,¹ lipodystrophy,¹ hypersensitivity reactions.¹

Interactions for Asfotase Alfa

No formal drug interaction studies to date.¹

Asfotase Alfa Pharmacokinetics

Absorption

Bioavailability

Approximately 62% following sub-Q administration.³

Steady-state exposure achieved as early as 3 weeks.¹

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.^{1 3}

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.¹

Pharmacokinetics dose-proportional across dosage range of 0.3–3 mg/kg.¹

Formation of anti-drug antibodies reduces systemic exposure of asfotase alfa.¹

Distribution

Extent

Not known whether distributed into human milk.¹

Elimination

Half-life

Approximately 5 days.¹

Stability

Storage

Parenteral

Injection

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

Actions

• Biosynthetic (recombinant DNA origin) form of human TNSALP, a metalloenzyme that catalyzes hydrolysis of phosphomonoesters.^{1 3 4 5 6 7}

• 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 mcmol of p-nitrophenol from p-nitrophenyl phosphate per minute at 37°C.¹

• Provides exogenous source of TNSALP, reducing accumulation of TNSALP substrates, promoting bone mineralization, and improving skeletal structure.^{1 6}

Advice to Patients

• Importance of advising patients and their caregivers to read the manufacturer's patient information and instructions for use.¹

• 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.¹ (See Dosage and Administration.)

• When volume for injection >1 mL, importance of dividing the volume equally between 2 syringes and injecting into separate sites.¹

• Importance of rotating injection sites and avoiding areas that are reddened, inflamed, or swollen.¹

• Risk of injection site reactions and other administration-associated adverse reactions (e.g., erythema, discoloration/hypopigmentation, pain/tenderness, pruritus, swelling, induration, macules, bruising, nodules).¹

• 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.¹

• Risk of lipodystrophy and localized atrophy at injection sites.¹ Importance of following proper injection technique and rotating injection sites.¹

• Importance of informing patients of the HPP registry established to monitor variability and progression of HPP and long-term effects of asfotase alfa.¹ Importance of encouraging patient participation in this voluntary program and of advising patients that participation may involve long-term follow-up.¹ (See Hypophosphatasia under Uses.)

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.¹

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

• Importance of informing patients of other important precautionary information.¹ (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.