Asfotase alfa is an enzyme replacement therapy for treatment of perinatal/infantile- and juvenile-onset hypophosphatasia (HPP). HPP is caused by mutations in the tissue nonspecific alkaline phosphatase (TNSALP) enzyme, which is encoded by the alkaline phosphatase (ALP) gene. TNSALP is responsible for formation of an essential mineral in normal bone; deficient TNSALP results in defective bone mineralization that can result in bone and skeletal system abnormalities, as well as systemic complications such as muscle weakness and respiratory failure. HPP is a genetic, chronic, progressive, and potentially life-threatening metabolic disease that affects less than 20 patients per one million in the general population. Asfotase alfa is produced by genetically engineered Chinese hamster ovary cells and replaces the deficient TNSALP in patients with HPP. Asfotase alfa was evaluated in four prospective, open-label studies involving 99 patients (ages 1 day to 58 years) with perinatal, infantile-, or juvenile-onset HPP (who received treatment for up to 6.5 years); data was also included from two retrospective natural history studies used as control cohorts. In patients with perinatal/infantile-onset HPP, treatment with asfotase alfa improved overall survival and ventilator-free survival. At 48 weeks, 97% of treated patients were alive compared to 42% for the historical control patients. Patients with juvenile-onset HPP treated with asfotase alfa showed improvements in mobility, growth, and bone health compared to untreated historical control patients. All treated patients had improvements in low weight or short stature compared to approximately 20% of control patients that had growth delays over time. Juvenile-onset HPP patients also showed improvements in bone mineralization and demonstrated healing of rickets on x-rays while some of the control patients showed increasing signs of rickets over time. Because ectopic calcification of the eyes and kidneys can occur, ophthalmologic examinations and renal ultrasounds are recommended at baseline and periodically during treatment. Asfotase alfa was approved by the FDA in October 2015.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-Asfotase alfa is a clear, slightly opalescent or opalescent, colorless to slightly yellow aqueous solution; few small translucent or white particles may be present.
Subcutaneous Administration
NOTE: Do not use the 80 mg/0.8 mL vial of asfotase alfa in pediatric patients weighing less than 40 kg. 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 concentrations). A lower exposure may not be adequate for this subgroup of patients.
-Remove unopened vial(s) from refrigerator 15 to 30 minutes prior to injection to allow liquid to reach room temperature. Do NOT warm vials (e.g. do not warm in a microwave or hot water). Do NOT shake.
-Use solution as supplied; no dilution necessary.
-Using a sterile 1 mL syringe and 1/2 inch needle (e.g., 25 gauge), withdraw solution from vial to provide prescribed dose. Use the smaller bore needle (e.g., 29 gauge) to administer the injection.
-When preparing a volume for injection that is greater than 1 mL, split the volume equally between 2 syringes, and administer 2 injections at 2 separate sites. Always use a new syringe and needle.
-Administer by subcutaneous injection into the abdominal area, thigh, deltoid, or buttocks. Rotate the injection site to reduce the risk of lipodystrophy.
-Do not administer injections in areas that are reddened, inflamed, or swollen.
-Administer asfotase alfa within 3 hours upon removal of the vial(s) from refrigeration.
-Storage: Asfotase vials are single use only; discard any unused product.
Pre-marketing clinical trials were conducted in 99 patients (ages 1 day to 58 years) receiving asfotase alfa for perinatal/infantile-onset hypophosphatasia (HPP) (n = 79) or for juvenile-onset HPP (n = 20); most patients received asfotase alfa for more than 2 years. Overall, the frequency of adverse events was higher in patients with juvenile-onset HPP as compared to perinatal/infantile-onset HPP. A registry has been established in order to better understand HPP and to monitor and evaluate long-term treatment effects of asfotase alfa. Patients and their caregivers should be encouraged to participate; additional information may be obtained from www.hppregistry.com.
Injection site reactions were the most common adverse events in asfotase alfa clinical trials, occurring in more than 60% of patients. Most injection site reactions resolved within a week. Injection site reaction led to dosage reductions in 2 patients. One patient switched from 6 times/week dosing to 3 times/week dosing. An additional patient withdrew from the trial after experiencing a severe injection site reaction resulting in discoloration. Injection site reactions were more frequent in patients with juvenile-onset HPP compared than those with perinatal/infantile-onset HPP. Injection site reactions occurred in 56% of perinatal/infantile-onset HPP patients compared to 90% of juvenile-onset HPP patients. Erythema occurred in 41% of perinatal/infantile-onset HPP patients and 75% of juvenile-onset HPP patients, and skin hypopigmentation or discoloration occurred in 15% of perinatal/infantile-onset HPP patients compared to 40% of juvenile-onset HPP patients. Pain/tenderness occurred in 14% of perinatal/infantile-onset HPP patients compared to 40% of juvenile-onset HPP patients, and itching occurred in 13% of perinatal/infantile-onset HPP patients compared to 35% of juvenile-onset HPP patients. Swelling occurred in 10% of perinatal/infantile-onset HPP patients compared to 30% of juvenile-onset HPP patients. Induration occurred in 13% of perinatal/infantile-onset HPP patients compared to 15% of juvenile-onset HPP patients. A macule formed in 5% of perinatal/infantile-onset HPP patients compared to 35% of juvenile-onset HPP patients, and 3% of perinatal/infantile-onset HPP patients and 10% of juvenile-onset HPP patients developed a nodule at the injection site. Bruising occurred in 8% of perinatal/infantile-onset HPP patients compared to 20% of juvenile-onset HPP patients. Other reaction (not otherwise specified) occurred in 9% of perinatal/infantile-onset HPP patients compared to 20% of juvenile-onset HPP patients. Other injection site reactions occurred in 17% of perinatal/infantile-onset HPP patients compared to 20% of juvenile-onset HPP patients and included the following: injection site rash, inflammation, papule, hemorrhage, hematoma, localized hives at injection site only, warmth, calcification, mass, scar, and cellulitis.
Localized lipodystrophy, including lipohypertrophy (the accumulation of subcutaneous fat around a site of injection that has been used repeatedly) and lipoatrophy (the breakdown of adipose tissue at the injection site, causing an indentation in the skin), has been reported at injections sites after several months of asfotase therapy. In clinical trials, lipodystrophy, lipohypertrophy, or lipoatrophy were reported in 18% of perinatal/infantile-onset HPP patients compared to 70% of juvenile-onset HPP patients. Lipodystrophy can be minimized by rotating injection sites and following proper injection technique.
Patients with HPP are at increased risk for developing ectopic calcification. In pre-marketing clinical trials, 14 cases (14%) of ectopic calcification of the eye (including the cornea and conjunctiva) and the kidneys (nephrocalcinosis) were reported in patients receiving asfotase alfa. Ectopic calcifications occurred in 3/79 (4%) of perinatal/infantile-onset HPP patients compared to 11/20 (55%) of juvenile-onset HPP patients. Due to insufficient information, it could not be determined whether the reported events were consistent with the disease or due to asfotase alfa. No visual changes or changes in renal function were reported resulting from the occurrence of ectopic calcifications. Ophthalmology examinations and renal ultrasounds are recommended at baseline and periodically during treatment with asfotase alfa to monitor for signs and symptoms of ophthalmic and renal ectopic calcifications and for changes in vision or renal function. Additionally, hypocalcemia, renal stones (nephrolithiasis), chronic hepatitis, and decreased vitamin B6 occurred in less than 1% of patients during asfotase alfa clinical trials.
Hypersensitivity reactions, including anaphylactoid reactions, have been reported in patients receiving asfotase alfa during pre-marketing clinical trials. Hypersensitivity reactions occurred in 13% of perinatal/infantile-onset HPP patients compared to 10% of juvenile-onset HPP patients. Signs and symptoms consistent with anaphylactoid reactions include difficulty breathing, choking sensation, nausea, periorbital edema, and dizziness. Other hypersensitivity reactions have also been reported in asfotase alfa-treated patients and include vomiting (5 to 10%), erythema (redness), pyrexia (fever), pain, headache, flushing, irritability, chills or rigors, skin erythema, rash (unspecified), pruritus, urticaria, and oral hypoesthesia. If severe hypersensitivity reactions occur, discontinue asfotase alfa treatment and initiate appropriate medical treatment. Consider the risks and benefits of re-administering asfotase alfa to patients with a severe reaction.
As with all therapeutic proteins, there is a potential for immunogenicity. In clinical trials, 97 out of 109 patients (89%) tested positive for anti-drug antibody formation at some point after receiving asfotase alfa treatment. Among those 97 patients, 55 (57%) also showed the presence of neutralizing antibodies. No correlation was observed between the anti-drug antibody titer and neutralizing antibody values. The formation of anti-drug antibodies resulted in reduced systemic exposure of asfotase alfa. In postmarketing reports, some patients with initial therapeutic response developed recurrence and worsening in disease-associated laboratory and radiographic biomarkers, including some associated with neutralizing antibodies, suggesting possible immune-mediated effects on asfotase alfa's pharmacologic action.
Asfotase alfa is associated with a risk of serious hypersensitivity reactions or anaphylaxis. Hypersensitivity reactions, including anaphylaxis, have been reported in treated patients. Signs and symptoms consistent with anaphylaxis included difficulty breathing, choking sensation, nausea, periorbital edema, and dizziness. These reactions have occurred within minutes after subcutaneous administration and can occur in patients on treatment for more than 1 year. Other hypersensitivity reactions have also been reported, including vomiting, fever, headache, flushing, irritability, chills, skin erythema, rash, pruritus and oral hypoesthesia. If a severe hypersensitivity reaction occurs, discontinue asfotase alfa treatment and initiate appropriate medical treatment. Consider the risks and benefits of re-administering the drug to individual patients following a severe reaction. If the decision is made to re-administer the product, monitor patients for a reoccurrence of signs and symptoms of a severe hypersensitivity reaction.
There are no available data regarding use asfotase alfa during pregnancy to inform a drug-associated risk. Animal data did not reveal evidence of impaired fertility or harm to the fetus when administered at doses causing plasma exposures up to 21 and 24 times, respectively, the exposure at the recommended human dose.
There are no data on the presence of asfotase alfa in human milk, the effects on a breast-fed infant, or the effects on milk production. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Laboratory test interference may occur between asfotase alfa therapy and laboratory tests that utilize an alkaline phosphatase (ALP)-conjugated test system potentially resulting in erroneous test results. ALP-conjugated test systems are used to measure substances such as hormones, bacterial antigens, and antibodies. To avoid erroneous test results for patients receiving asfotase alfa, a testing platform which does not utilize ALP-conjugated technology is recommended.
Anti-asfotase alfa antibodies and neutralizing antibodies have been identified in patients treated with asfotase alfa. The clinical consequences of these neutralizing antibodies are not fully understood but resulted in reduced systemic exposure of asfotase alfa during clinical studies. Some patients with an initial therapeutic response with asfotase alfa develop recurrence and worsening of disease after development of anti-asfotase alfa antibodies and/or neutralizing antibodies. The effect of anti-asfotase alfa antibody formation on the long-term efficacy of asfotase alfa is unknown. Test for anti-asfotase alfa antibodies in patients who show signs of loss of efficacy during treatment. Contact the manufacturer at 1-888-765-4747 or by email at [email protected] for neutralizing antibody testing. Close clinical follow up is recommended.
General dosing information:
-Because ectopic calcification of the eyes and kidneys can occur, ophthalmologic examinations and renal ultrasounds are recommended at baseline and periodically during treatment. Monitor for signs and symptoms of changes in vision or renal function.
For the treatment of patients with perinatal/infantile-onset or juvenile-onset hypophosphatasia (HPP):
Subcutaneous dosage:
Adults, Adolescents, Children, Infants, and Neonates: 2 mg/kg/dose subcutaneously 3 times/week or 1 mg/kg/dose subcutaneously 6 times/week. Injection site reactions may limit the tolerability of the 6 times/week regimen. For perinatal/infantile-onset HPP, the dose may be increased to 3 mg/kg/dose subcutaneously 3 times/week for insufficient efficacy (e.g., no improvement in respiratory status, growth, or radiographic findings).
Maximum Dosage Limits:
6 mg/kg/week subcutaneously for juvenile-onset HPP; 9 mg/kg/week subcutaneously for perinatal/infantile-onset HPP.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
There are no drug interactions associated with Asfotase alfa products.
Hypophosphatasia (HPP) is caused by mutations in the tissue nonspecific alkaline phosphatase (TNSALP) enzyme, which is encoded by the alkaline phosphatase (ALP) gene. When a mutation of this gene occurs, the protein product may be faulty, inefficient, or absent. TNSALP is necessary for the proper development and mineralization of bones and teeth and is expressed in the liver and kidneys as well as bone. Mutations in the ALPL gene result in insufficient levels of functional TNSALP, which, in turn, leads to the accumulation of several TNSALP substrates, including phosphoethanolamine, pyridoxal 5'-phosphate, and inorganic pyrophosphate (PPi), which help to regulate bone mineralization. Elevated extracellular levels of PPi block hydroxyapatite crystal growth which inhibits bone mineralization and causes an accumulation of unmineralized bone matrix resulting in rickets and bone deformation in infants and children and as osteomalacia once growth plates close, along with muscle weakness. TNSALP enzyme activity correlates with disease severity, usually less residual enzyme activity correlates with more severe disease. Asfotase alfa therapy replaces the TNSALP enzyme and reduces the elevated enzyme substrate levels. By reducing the elevated substrate levels, the body's ability to mineralize bone is improved.
Asfotase alfa is administered as a subcutaneous injection. Its pharmacokinetics exhibit dose proportionality across the dose range of 0.3 to 3 mg/kg and appear to be time-dependent. Steady state exposure is achieved as early as 3 weeks after the first dose is administered. The elimination half-life after subcutaneous administration is approximately 5 days. Weight is a major covariate of asfotase alfa clearance and product formulation concentration impacts the systemic exposure of asfotase alfa in HPP patients. The 80 mg/0.8 mL concentration achieves approximately 25% lower systemic asfotase alfa exposure (i.e., concentrations and AUC) compared to the 18 mg/0.45 mL concentration at the same dose. Formation of anti-drug antibodies result in reduced systemic exposure of asfotase alfa.
Perinatal/infantile- and juvenile-onset HPP patients treated with asfotase alfa had reductions in plasma tissue nonspecific alkaline phosphatase (TNSALP) substrates inorganic pyrophosphate (PPi) and pyridoxal 5-phosphate (PLP) within 6 to 12 weeks of treatment. However, reductions in plasma PPi and PLP concentrations did not correlate with clinical outcomes. Bone biopsy data from perinatal/infantile-onset and juvenile-onset HPP patients treated with asfotase alfa demonstrated decreases in osteoid volume and thickness indicating improved bone mineralization.
-Special Populations
Pediatrics
Infants and Children
Two pharmacokinetic studies were performed in pediatric patients with HPP (one study of 14 patients aged 5 years and younger, and a second study of 6 patients aged 6 to 12 years) receiving multiple doses of asfotase alfa 2 mg/kg/dose given 3 times/week. The pharmacokinetics were similar between patients in both studies. The Tmax was 14.9 +/- 10.4 hours in children younger than 5 years and 20.8 +/- 10 hours in children 6 to 12 years, Cmax was 1,794 +/- 690 ng/mL (young children) and 2,108 +/- 788 ng/mL (older children), AUC was 66,042 +/- 25,758 h x ng/mL (young children) and 88,877 +/- 33,248 h x ng/mL (older children), and the accumulation rate (AUC over a dosing interval of 4.8 hours) was 1.5 (young children) and 3.9 (older children).