Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Alexion Europe SAS, 103-105 rue Anatole France, 92300, Levallois-Perret, France
Severe or life-threatening hypersensitivity to the active substance or to any of the excipients if hypersensitivity is not controllable (see section 4.4).
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Hypersensitivity reactions including signs and symptoms consistent with anaphylaxis have been reported in patients treated with asfotase alfa (see section 4.8). These symptoms included difficulty breathing, choking sensation, periorbital edema, and dizziness. The reactions have occurred within minutes after subcutaneous administration of asfotase alfa and can occur in patients on treatment for more than 1 year. Other hypersensitivity reactions included vomiting, nausea, fever, headache, flushing, irritability, chills, skin erythema, rash, pruritus, and oral hypoaesthesia. If these reactions occur, immediate discontinuation of treatment is recommended and appropriate medical treatment should be initiated. The current medical standards for emergency treatment should be observed.
Consider the risks and benefits of re-administering asfotase alfa to individual patients following a severe reaction, taking other factors into account that may contribute to the risk of a hypersensitivity reaction, such as concurrent infection and/or use of antibiotics. If the decision is made to re-administer the product, the re-challenge should be made under medical supervision and consideration may be given to use of appropriate pre-medication. Patients should be monitored for recurrence of signs and symptoms of a severe hypersensitivity reaction.
The need for supervision for subsequent administrations and need for emergency treatment for home care should be at the discretion of the treating physician.
Severe or potentially life-threatening hypersensitivity is a contraindication to re-challenge, if hypersensitivity is not controllable (see section 4.3).
Administration of asfotase alfa may result in local injection site reactions (including, but not limited to, erythema, rash, discoloration, pruritus, pain, papule, nodule, atrophy) defined as any related adverse event occurring during the injection or until the end of the injection day (see section 4.8). Rotation of injection sites may help to minimize these reactions. Strensiq administration should be interrupted in any patient experiencing severe injection reactions and appropriate medical therapy administered.
Localized lipodystrophy, including lipoatrophy and lipohypertrophy, has been reported at injection sites after several months in patients treated with asfotase alfa in clinical trials (see section 4.8). Patients are advised to follow proper injection technique and to rotate injection sites (see section 4.2).
In asfotase alfa clinical studies adverse events of craniosynostosis (associated with increased intracranial pressure), including worsening of pre-existing craniosynostosis and occurrence of Arnold- Chiari malformation, have been reported in hypophosphatasia patients <5 years of age. There are insufficient data to establish a causal relationship between exposure to Strensiq and progression of craniosynostosis. Craniosynostosis as a manifestation of hypophosphatasia is documented in published literature and occurred in 61.3% of patients between birth and 5 years of age in a natural history study of untreated infantile-onset hypophosphatasia patients. Craniosynostosis can lead to increased intracranial pressure. Periodic monitoring (including fundoscopy for signs of papilloedema) and prompt intervention for increased intracranial pressure is recommended in hypophosphatasia patients below 5 years of age.
In asfotase alfa clinical studies ophthalmic (conjunctival and corneal) calcification and nephrocalcinosis have been reported in patients with hypophosphatasia. There are insufficient data to establish a causal relationship between exposure to asfotase alfa and ectopic calcification. Ophthalmic (conjunctival and corneal) calcification and nephrocalcinosis as manifestations of hypophosphatasia are documented in published literature. Nephrocalcinosis occurred in 51.6% of patients between birth and 5 years of age in a natural history study of untreated infantile-onset hypophosphatasia patients. Ophthalmology examination and renal ultrasounds are recommended at baseline and periodically in hypophosphatasia patients.
Serum parathyroid hormone concentration may increase in hypophosphatasia patients administered asfotase alfa, most notably during the first 12 weeks of treatment. It is recommended that serum parathyroid hormone and calcium be monitored in patients treated with asfotase alfa. Supplements of calcium and oral vitamin D may be required. See section 5.1.
Patients may display disproportionate weight increase. Dietary supervision is recommended.
This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. the product is essentially ‘sodium-free’.
No interaction studies have been performed with asfotase alfa. Based on its structure and pharmacokinetics, asfotase alfa is unlikely to affect Cytochrome P-450 related metabolism.
Asfotase alfa contains a catalytic domain of tissue non-specific alkaline phosphatase. Administration of asfotase alfa will interfere with routine measurement of serum alkaline phosphatase by hospital laboratories resulting in serum alkaline phosphatase activity measurements of several thousand units per litre. Asfotase alfa activity results must not be interpreted as the same measure as serum alkaline phosphatase activity owing to differences in enzyme characteristics.
Alkaline Phosphatase (ALP) is used as the detection reagent in many routine laboratory assays. If asfotase alfa is present in clinical laboratory samples, aberrant values could be reported.
The treating physician should inform the testing lab that the patient is treated with medication affecting the ALP levels. Alternative assays (i.e. not utilizing an ALP-conjugated reporter system) may be considered in patients treated with Strensiq.
There are insufficient data from the use of asfotase alfa in pregnant women. Following repeated subcutaneous administration to pregnant mice in the therapeutic dose range (>0.5 mg/kg), asfotase alfa levels were quantifiable in fetuses at all doses tested, suggesting cross-placental transport of asfotase alfa. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Asfotase alfa is not recommended during pregnancy and in women of childbearing potential not using contraception.
There is insufficient information on the excretion of asfotase alfa in human milk. A risk to the newborns/infants cannot be excluded.
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from asfotase alfa therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Preclinical fertility studies were conducted and showed no evidence of effect on fertility and embryo-fetal development (see section 5.3).
Strensiq has no or negligible influence on the ability to drive and use machines.
Supportive safety data reflect exposure in 112 patients with perinatal/infantile (n=89), juvenile-onset (n=22), adult onset (n=1) HPP (age at enrollment from 1 day to 66.5 years) treated with asfotase alfa, with a treatment duration range from 1 day to 391.9 weeks [7.5 years]). The most common adverse reactions observed were injection site reactions (74%). A few case reports of anaphylactoid/hypersensitivity reaction have been received
Adverse reactions with asfotase alfa are listed by system organ class and preferred term using MedDRA frequency convention very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 1. Adverse Reactions Reported in clinical trials in hypophosphatasia patients:
Common: Injection site cellulitis
Common: Increased tendency to bruise
Common: Anaphylactoid reactions, Hypersensitivity2
Common: Hypocalcaemia
Very common: Headache
Common: Hot flush
Common: Hypoaesthesia oral, Nausea
Very common: Erythema
Common: Skin discolouration, Skin disorder (stretched skin)
Very common: Pain in extremity
Common: Myalgia
Common: Nephrolithiasis
Very common: Injection site reactions1, Pyrexia, Irritability
Common: Chills
Very common: Contusion
Common: Scar
1 Preferred terms considered as injection site reactions are presented in section below
2 Preferred terms considered as hypersensitivity are presented in the section below
Injection site reactions (including injection site atrophy, abscess, erythema, discolouration, pain, pruritus, macule, swelling, contusion, bruising, lipodystrophy (lipoatrophy or lipohypertrophy), induration, reaction, nodule, rash, papule, haematoma, inflammation, urticarial, calcification, warmth, haemorrhage, cellulitis, scar, mass, extravasation, exfoliation and vesicles) are the most common adverse reactions observed in about 74% of the patients in clinical studies. Most injection site reactions were mild and self-limiting, and the majority (>99%) were reported as non-serious. In the clinical trial setting, the majority of patients who experienced an injection site reaction had the first occurrence within the first 12 weeks of treatment with asfotase alfa, and some patients continued to experience injection site reactions until 1 or more years after initiating asfotase alfa dosing. One patient withdrew from the trial due to injection site hypersensitivity.
Hypersensitivity reactions include erythema/redness, pyrexia/fever, rash, pruritis, irritability, nausea, vomiting, pain, rigor/chills, hypoaesthesia oral, headache, flushing, tachycardia, cough, and signs and symptoms consistent with anaphylaxis (see section 4.4). A few case reports of anaphylactoid/hypersensitivity reaction have also been received and were associated with signs and symptoms of difficulty breathing, choking sensation, periorbital edema and dizziness.
There is potential for immunogenicity. Among 109 hypophosphatasia patients enrolled in the clinical studies and who have post baseline antibody data available, 97/109 (89.0%) tested positive for anti-drug antibodies at some time point after starting Strensiq treatment. Among those 97 patients, 55 (56.7%) also showed the presence of neutralizing antibodies at some time point post-baseline. The antibody response (with or without presence of neutralizing antibodies) was time variant in nature. In clinical trials, the development of antibodies has not been shown to affect clinical efficacy or safety (see section 5.2). Data from post-marketing cases suggests that the development of antibodies may affect clinical efficacy.
No trends in adverse events based on antibody status were observed in clinical trials. Some patients confirmed positive for antidrug antibodies experienced injection site reactions (ISRs) and/or hypersensitivity, however there was no consistent trend in the frequency of these reactions over time noted between ADA ever positive and ADA always negative patients.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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