STRENSIQ 40mg / ml injectible solution medication leaflet

Strensiq 40 mg/ml solution for injection

Strensiq 100 mg/ml solution for injection

Strensiq 40 mg/ml solution for injection

Each ml of solution contains 40 mg of asfotase alfa*.

Each vial contains 0.3 ml solution and 12 mg of asfotase alfa (40 mg/ml).

Each vial contains 0.45 ml solution and 18 mg of asfotase alfa (40 mg/ml).

Each vial contains 0.7 ml solution and 28 mg of asfotase alfa (40 mg/ml).

Each vial contains 1.0 ml solution and 40 mg of asfotase alfa (40 mg/ml).

Strensiq 100 mg/ml solution for injection

Each ml of solution contains 100 mg of asfotase alfa*.

Each vial contains 0.8 ml solution and 80 mg of asfotase alfa (100 mg/ml).

* produced by recombinant DNA technology using mammalian Chinese Hamster Ovary (CHO) cellculture.

For the full list of excipients, see section 6.1.

Solution for injection (injection).

Clear, slightly opalescent or opalescent, colourless to slightly yellow, aqueous solution; pH 7.4. A fewsmall translucent or white particles may be present.

Strensiq is indicated for long-term enzyme replacement therapy in patients with paediatric-onsethypophosphatasia to treat the bone manifestations of the disease (see section 5.1).

Treatment should be initiated by a physician experienced in the management of patients withmetabolic or bone disorders.

Recommended dosage regimen of asfotase alfa is 2 mg/kg of body weight administeredsubcutaneously three times per week, or a dosage regimen of 1 mg/kg of body weight administeredsubcutaneously six times per week.

Maximum recommended dose of asfotase alfa is 6 mg/kg/week (see Section 5.1).

Refer to the dosing chart below for more details.

If injecting 3x per week If injecting 6 x per week

Body

Weight Dose to be Volume Vial type Dose to Volume Vial type(kg) injected to be used for be to be used forinjected injection injected injected injection3 6 mg 0.15 ml 0.3 ml4 8 mg 0.20 ml 0.3 ml5 10 mg 0.25 ml 0.3 ml6 12 mg 0.30 ml 0.3 ml 6 mg 0.15 ml 0.3 ml7 14 mg 0.35 ml 0.45 ml 7 mg 0.18 ml 0.3 ml8 16 mg 0.40 ml 0.45 ml 8 mg 0.20 ml 0.3 ml9 18 mg 0.45 ml 0.45 ml 9 mg 0.23 ml 0.3 ml10 20 mg 0.50 ml 0.7 ml 10 mg 0.25 ml 0.3 ml11 22 mg 0.55 ml 0.7 ml 11 mg 0.28 ml 0.3 ml12 24 mg 0.60 ml 0.7 ml 12 mg 0.30 ml 0.3 ml13 26 mg 0.65 ml 0.7 ml 13 mg 0.33 ml 0.45 ml14 28 mg 0.70 ml 0.7 ml 14 mg 0.35 ml 0.45 ml15 30 mg 0.75 ml 1 ml 15 mg 0.38 ml 0.45 ml16 32 mg 0.80 ml 1 ml 16 mg 0.40 ml 0.45 ml17 34 mg 0.85 ml 1 ml 17 mg 0.43 ml 0.45 ml18 36 mg 0.90 ml 1 ml 18 mg 0.45 ml 0.45 ml19 38 mg 0.95 ml 1 ml 19 mg 0.48 ml 0.7 ml20 40 mg 1.00 ml 1 ml 20 mg 0.50 ml 0.7 ml25 50 mg 0.50 ml 0.8 ml 25 mg 0.63 ml 0.7 ml30 60 mg 0.60 ml 0.8 ml 30 mg 0.75 ml 1 ml35 70 mg 0.70 ml 0.8 ml 35 mg 0.88 ml 1 ml40 80 mg 0.80 ml 0.8 ml 40 mg 1.00 ml 1 ml50 50 mg 0.50 ml 0.8 ml60 60 mg 0.60 ml 0.8 ml70 70 mg 0.70 ml 0.8 ml80 80 mg 0.80 ml 0.8 ml90 90 mg 0.90 ml 0.8 ml (x2)100 100 mg 1.00 ml 0.8 ml (x2)

If a dose of asfotase alfa is missed, a double dose should not be injected to make up for the misseddose.

Special population

Adult patients

The pharmacokinetics, pharmacodynamics, and safety of asfotase alfa have been studied in patientswith hypophosphatasia > 18 years old. Dose adjustment is not needed in adult patients with paediatric-onset hypophosphatasia (HPP) (see Sections 5.1 and 5.2).

The safety and efficacy of asfotase alfa in elderly patients have not been established and no specificdose regimen can be recommended for these patients.

The safety and efficacy of asfotase alfa in patients with renal impairment have not been evaluated andno specific dose regimen can be recommended for these patients.

The safety and efficacy of asfotase alfa in patients with hepatic impairment have not been evaluatedand no specific dose regimen can be recommended for these patients.

Strensiq is for subcutaneous use only. It is not intended for intravenous or intramuscular injection.

The maximum volume of medicinal product per injection should not exceed 1 ml. If more than 1 ml isrequired, multiple injections may be administered at the same time.

Strensiq should be administered using sterile disposable syringes and injection needles. The syringesshould be of small enough volume that the prescribed dose can be withdrawn from the vial withreasonable accuracy.

Injections sites should be rotated and carefully monitored for signs of potential reactions (see section4.4).

Patients can self-inject only if they have properly been trained on administration procedures.

For handling of the medicinal product before administration, see section 6.6.

Severe or life-threatening hypersensitivity to the active substance or to any of the excipients ifhypersensitivity is not controllable (see section 4.4).

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Hypersensitivity reactions including signs and symptoms consistent with anaphylaxis have beenreported in patients treated with asfotase alfa (see section 4.8). These symptoms included difficultybreathing, choking sensation, periorbital edema, and dizziness. The reactions have occurred withinminutes after subcutaneous administration of asfotase alfa and can occur in patients on treatment formore than 1 year. Other hypersensitivity reactions included vomiting, nausea, fever, headache,flushing, irritability, chills, skin erythema, rash, pruritus, and oral hypoaesthesia. If these reactionsoccur, immediate discontinuation of treatment is recommended and appropriate medical treatmentshould 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 asevere reaction, taking other factors into account that may contribute to the risk of a hypersensitivityreaction, 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 considerationmay be given to use of appropriate pre-medication. Patients should be monitored for recurrence ofsigns and symptoms of a severe hypersensitivity reaction.

The need for supervision for subsequent administrations and need for emergency treatment for homecare should be at the discretion of the treating physician.

Severe or potentially life-threatening hypersensitivity is a contraindication to re-challenge, ifhypersensitivity is not controllable (see section 4.3).

Injection reaction

Administration of asfotase alfa may result in local injection site reactions (including, but not limitedto, erythema, rash, discoloration, pruritus, pain, papule, nodule, atrophy) defined as any relatedadverse 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 reactionsand appropriate medical therapy administered.

Lipodystrophy

Localized lipodystrophy, including lipoatrophy and lipohypertrophy, has been reported at injectionsites 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).

Craniosynostosis

In asfotase alfa clinical studies adverse events of craniosynostosis (associated with increasedintracranial pressure), including worsening of pre-existing craniosynostosis and occurrence of Arnold-

Chiari malformation, have been reported in hypophosphatasia patients < 5 years of age. There areinsufficient data to establish a causal relationship between exposure to Strensiq and progression ofcraniosynostosis. Craniosynostosis as a manifestation of hypophosphatasia is documented in publishedliterature and occurred in 61.3% of patients between birth and 5 years of age in a natural history studyof untreated infantile-onset hypophosphatasia patients. Craniosynostosis can lead to increasedintracranial pressure. Periodic monitoring (including fundoscopy for signs of papilloedema) andprompt intervention for increased intracranial pressure is recommended in hypophosphatasia patientsbelow 5 years of age.

Ectopic calcification

In asfotase alfa clinical studies ophthalmic (conjunctival and corneal) calcification andnephrocalcinosis have been reported in patients with hypophosphatasia. There are insufficient data toestablish a causal relationship between exposure to asfotase alfa and ectopic calcification. Ophthalmic(conjunctival and corneal) calcification and nephrocalcinosis as manifestations of hypophosphatasiaare documented in published literature. Nephrocalcinosis occurred in 51.6% of patients between birthand 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 inhypophosphatasia patients.

Serum Parathyroid Hormone and Calcium

Serum parathyroid hormone concentration may increase in hypophosphatasia patients administeredasfotase alfa, most notably during the first 12 weeks of treatment. It is recommended that serumparathyroid hormone and calcium be monitored in patients treated with asfotase alfa. Supplements ofcalcium and oral vitamin D may be required. See section 5.1.

Disproportionate weight gain

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 isessentially ‘sodium-free’.

No interaction studies have been performed with asfotase alfa. Based on its structure andpharmacokinetics, asfotase alfa is unlikely to affect Cytochrome P-450 related metabolism.

Asfotase alfa contains a catalytic domain of tissue non-specific alkaline phosphatase. Administrationof asfotase alfa will interfere with routine measurement of serum alkaline phosphatase by hospitallaboratories resulting in serum alkaline phosphatase activity measurements of several thousand unitsper litre. Asfotase alfa activity results must not be interpreted as the same measure as serum alkalinephosphatase activity owing to differences in enzyme characteristics.

Alkaline Phosphatase (ALP) is used as the detection reagent in many routine laboratory assays. Ifasfotase 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 medicationaffecting 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, suggestingcross-placental transport of asfotase alfa. Animal studies are insufficient with respect to reproductivetoxicity (see section 5.3). Asfotase alfa is not recommended during pregnancy and in women ofchildbearing potential not using contraception.

There is insufficient information on the excretion of asfotase alfa in human milk. A risk to thenewborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from asfotasealfa therapy taking into account the benefit of breast-feeding for the child and the benefit of therapyfor the woman.

Preclinical fertility studies were conducted and showed no evidence of effect on fertility andembryo-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 asfotasealfa, with a treatment duration range from 1 day to 391.9 weeks [7.5 years]). The most commonadverse reactions observed were injection site reactions (74%). A few case reports ofanaphylactoid/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 beestimated from the available data). Within each frequency grouping, adverse reactions are presented inorder of decreasing seriousness.

Table 1: Adverse Reactions Reported in clinical trials in hypophosphatasia patients

System Organ Class Frequency Adverse reactioncategory

Infections and infestations Common Injection site cellulitis

Blood and lymphatic system Common Increased tendency to bruisedisorders

Immune system disorders Common Anaphylactoid reactions

Hypersensitivity2

Metabolism and nutrition Common Hypocalcaemiadisorders

Nervous system disorders Very common Headache

Vascular disorders Common Hot flush

Gastrointestinal disorders Common Hypoaesthesia oral

Nausea

Skin and subcutaneous Very common Erythematissue disorders Common Skin discolouration

Skin disorder (stretched skin)

Musculoskeletal and Very common Pain in extremityconnective tissue disorders

Common Myalgia

Renal and urinary disorders Common Nephrolithiasis

General disorders and Very common Injection site reactions1administration site Pyrexiaconditions Irritability

Common Chills

Injury, poisoning and Very common Contusionprocedural complications Common Scar1- Preferred terms considered as injection site reactions are presented in section below2- 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 commonadverse reactions observed in about 74% of the patients in clinical studies. Most injection sitereactions were mild and self-limiting, and the majority (> 99%) were reported as non-serious. In theclinical trial setting, the majority of patients who experienced an injection site reaction had the firstoccurrence within the first 12 weeks of treatment with asfotase alfa, and some patients continued toexperience 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 andsymptoms consistent with anaphylaxis (see section 4.4). A few case reports ofanaphylactoid/hypersensitivity reaction have also been received and were associated with signs andsymptoms of difficulty breathing, choking sensation, periorbital edema and dizziness.

There is potential for immunogenicity. Among 109 hypophosphatasia patients enrolled in the clinicalstudies 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. Theantibody response (with or without presence of neutralizing antibodies) was time variant in nature. Inclinical 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 mayaffect clinical efficacy.

No trends in adverse events based on antibody status were observed in clinical trials. Some patientsconfirmed positive for antidrug antibodies experienced injection site reactions (ISRs) and/orhypersensitivity, however there was no consistent trend in the frequency of these reactions over timenoted between ADA ever positive and ADA always negative patients.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is limited experience with overdose of asfotase alfa. The maximum dose of asfotase alfa used inclinical studies is 28 mg/kg/week. No dose-related toxicity or change in the safety profile has beenobserved in clinical studies. Therefore, no overdose level has been determined. For management ofadverse reactions, see sections 4.4 and 4.8.

Pharmacotherapeutic group: Other alimentary tract and metabolism products, enzymes, ATC code:

A16AB13

Asfotase alfa is a human recombinant tissue-nonspecific alkaline phosphatase-Fc-deca-aspartatefusion protein that is expressed in an engineered Chinese hamster ovary cell line. Asfotase alfa is asoluble glycoprotein comprised of two identical polypeptide chains, each with a length of 726 aminoacids made from (i) the catalytic domain of human tissue-nonspecific alkaline phosphatase, (ii) thehuman immunoglobulin G1 Fc domain and (iii) a deca-aspartate peptide domain.

Hypophosphatasia

Hypophosphatasia is a rare, severe, and potentially fatal, genetic disorder caused by loss-of-functionmutation(s) in the gene encoding tissue non-specific alkaline phosphatase. Hypophosphatasia isassociated with multiple bone manifestations including rickets/osteomalacia, altered calcium andphosphate metabolism, impaired growth and mobility, respiratory compromise that may requireventilation, and vitamin B6-responsive seizures.

Asfotase alfa, a human recombinant tissue-nonspecific alkaline phosphatase-Fc-deca-aspartate fusionprotein with enzymatic activity, promotes mineralisation of the skeleton in patients withhypophosphatasia.

Study ENB-006-09/ENB-008-10

Study ENB-006-09/ENB-008-10 was an open-label, randomised study. Thirteen patients wereenrolled, 12 completed, and 1 discontinued (discontinuation early in the study due to a previouslyplanned elective scoliosis surgery). At study completion patients had received a median of over76 months (6.3 years) of treatment (1 to 79 months). Five patients presented with symptoms ofhypophosphatasia before 6 months age and 8 patients presented after 6 months age. Age at inclusion inthe study was between 6 and 12 years old and was between 10 and 18 years old at completion, with9 patients who became between 13 and 17 years old during the study.

The study employed historical controls from the same centres as patients who received asfotase alfaand who had been subject to a similar protocol of clinical management.

The effects of asfotase alfa on x-ray appearance

Trained radiologists evaluated pre- and post-baseline x-rays of wrists and knees of patients for thefollowing signs: apparent physeal widening, metaphyseal flaring, irregularity of provisional zone ofcalcification, metaphyseal radiolucencies, metadiaphyseal sclerosis, osteopenia, ‘popcorn’calcification in metadiaphysis, demineralization of distal metaphysis, transverse subphyseal band oflucency and tongues of radiolucency. X-ray changes from baseline were then rated using the

Radiographic Global Impression of Change rating scale as follows: -3=severe worsening, -2=moderateworsening, -1=minimal worsening, 0=no change, +1=minimal healing, +2=substantial healing, +3=near-complete or complete healing. The majority of the patients who received asfotase alfa moved toscores of +2 and +3 over the first 6 months of exposure and this was sustained with on-goingtreatment. Historical controls did not show change over time.

Bone biopsy

Tetracycline for bone-labelling was administered in two 3-day courses (separated by a 14-day interval)prior to acquisition of the bone biopsy. Trans-iliac crest bone biopsies were obtained by standardprocedure. Histological analysis of biopsies used Osteomeasure software (Osteometrics, USA).

Nomenclature, symbols and units followed recommendations of the American Society for Bone and

Mineral Research. For 10 patients in the per-protocol set (excludes those patients who received oralvitamin D between baseline and week 24) who underwent biopsy of the trans-iliac bone crest beforeand after receiving asfotase alfa:

- Mean (SD) osteoid thickness was 12.8 (3.5) µm at baseline and 9.5 (5.1) µm at week 24

- Mean (SD) osteoid volume/bone volume was 11.8 (5.9)% at baseline and 8.6 (7.2)% at week

- Mean (SD) mineralisation lag-time was 93 (70) days at baseline and 119 (225) days at week 24

Growth

Height, weight and head circumference were plotted on growth charts (series of percentile curves thatillustrate distribution) available from the Centers for Disease Control and Prevention, USA. Thesereference data were drawn from a representative sample of healthy children and are not specific forchildren with special health care needs: they have been used in the absence of growth charts forchildren with hypophosphatasia.

For those patients who received asfotase alfa: 11/13 patients displayed persistent apparent catch-upheight-gain as shown by movement over time to a higher percentile on CDC growth charts.1/13 patients did not display apparent catch-up height-gain and 1 patient did not have enough data topermit judgement. Progress through Tanner stages appeared appropriate.

For the time period of observation of historical controls: 1/16 patients displayed apparent catch-upheight-gain, 12/16 patients did not display apparent catch-up height-gain and data were inconclusive in3/16 patients.

Some patients required oral vitamin D supplements during the study (see sections 4.4 and 4.8).

Study ENB-002-08/ENB-003-08

Study ENB-002-08/ENB-003-08 was an open-label, non-randomised, non-controlled study.11 patients were enrolled in the initial study and 10 patients entered the extension study, with9 patients completing the extension study. At study completion, patients had received a median of over79 months (6.6 years) of treatment (1 to >84 months). Onset of hypophosphatasia was under 6 monthsin all patients. Age at treatment initiation in the study was between 0.5 to 35 months.7/11 patients in the full analysis set achieved Radiographic Global Impression of Change scores of +2at Week 24 compared to baseline radiographs. The improvement in rickets severity was maintained forat least 72 months of follow-up treatment (including at least 84 months in 4 patients), as measured bythe RGI C.5/11 subjects displayed apparent catch-up height-gain. At last assessment (n = 10, 9 of whom had atleast 72 months of treatment), median Z-score improvements from baseline were 1.93 forlength/height and 2.43 for weight. Fluctuation in height-gain was apparent and may reflect the moresevere disease and higher rate of morbidity in these younger patients.

Study ENB-010-10

Study ENB-010-10 was a controlled open-label study in 69 patients, aged 1 day to 72 months, withperinatal/infantile-onset HPP. The mean age at sign/symptom onset was 1.49 months. Patientsreceived STRENSIQ at 6 mg/kg per week for the first 4 weeks. All patients began the study on a doseof asfotase alfa 6 mg/kg per week. The dose of asfotase alfa was increased for 11 patients during thestudy. Of these 11 patients, 9 patients had their doses increased specifically to improve clinicalresponse. Thirty-eight patients were treated for at least 2 years (24 months) and 6 patients have beentreated for at least 5 years (60 months).

At Week 48, 50/69 patients (72.5%) in the full analysis set achieved Radiographic Global Impressionof Change scores ≥ 2, and were considered responders. Improvements in median RGI-C weremaintained over the course of treatment, which ranged from 0.9 to 302.3 weeks, even if fewer patientswere followed after Week 96 (a total of 29 patients were followed after Week 96 and ≤8 patients after

Week 192).

Height, weight and head circumference were plotted on growth charts (series of percentile curves thatillustrate distribution) available from the Centers for Disease Control and Prevention (CDC), USA. Atotal of 24/69 (35%) patients displayed apparent catch-up height-gain and 32/69 (46%) patientsdisplayed apparent catch-up weight-gain, as shown by movement over time to a higher percentile on

CDC growth charts. 40/69 patients and 32/69 patients did not show apparent catch-up gain in heightand in weight, respectively. 4 patients did not have enough data to permit judgement and 1 patientcould not be determined with certainty.

Study ENB-009-10

Study ENB-009-10 was an open-label, randomised study. The patients were randomly assigned totreatment group for the primary treatment period. Nineteen patients were enrolled, 14 completed, and5 discontinued. At study completion patients had received a median of over 60 months of treatment(24 to 68 months). The onset of hypophosphatasia was under 6 months in 4 patients, between 6months and 17 years in 14 patients, and over 18 years in one patient. Age at inclusion was from 13 to66 years and was between 17 and 72 years at study completion.

The adolescent (and adult) patients in this study did not display apparent height-gain.

Patients underwent biopsy of the trans-iliac bone crest either as part of a control group or before andafter exposure to asfotase alfa:

- Control group, standard of care (5 evaluable patients): mean (SD) mineralisation lag-time was226 (248) days at baseline and 304 (211) days at week 24

- 0.3 mg/kg/day asfotase alfa group (4 evaluable patients): mean (SD) mineralisation lag-timewas 1236 (1468) days at baseline and 328 (200) days at week 48

- 0.5 mg/kg/day asfotase alfa group (5 evaluable patients): mean (SD) mineralisation lag-timewas 257 (146) days at baseline and 130 (142) days at week 48

After approximately 48 weeks all patients were adjusted to the recommended dose 1.0 mg/kg/day.

Ventilation support

In studies ENB-002-08/ENB-003-08 (11 patients) and ENB-010-10 (69 patients), both open-label,non-randomised, non-controlled studies of patients aged 0.1 to 312 weeks at baseline. 69 patientscompleted the studies, and 11 discontinued. Patients received a median duration of treatment of27.6 month (range from 1 day to 90 months). 29 of 80 patients required ventilation support at baseline:

∙ 16 patients required invasive ventilation support (intubation or tracheostomy) at baseline(one had a brief period of non-invasive ventilation at baseline before transfer).

- 7 patients were weaned off invasive ventilation (time on ventilation from 12 to168 weeks), 4 patients were off any ventilation support, and 3 patients were on non-invasive ventilation support. Five out of 7 patients achieved an RGI-C score ≥2

- 5 patients continued with invasive ventilation support, 4 of them with RGI-C score<2

- 3 patients died whilst on ventilation support

- 1 patient withdrew consent∙ 13 patients required non-invasive ventilation support at baseline.

- 10 patients were weaned off any ventilation support (time on ventilation from 3 to216 weeks). 9 out of 10 patients achieved a RGI-C score ≥2, only 1 with RGI-C <2.

- 2 patients required invasive ventilation support and 1 patient continued with non-invasive ventilation support, all 3 patients died and with RGI-C score <2

The natural history of untreated infantile-onset hypophosphatasia patients suggests high mortality ifventilation is required.

This medicinal product has been authorised under ‘exceptional circumstances’. This means that due tothe rarity of the disease it has not been possible to obtain complete information on this medicinalproduct.

The European Medicines Agency will review any new information which may become available everyyear and this SmPC will be updated as necessary.

Pharmacokinetics of asfotase alfa were evaluated in a 1-month, multicenter, open-label, dose-escalating, study in adults with hypophosphatasia. Cohort 1 (n=3) of the study received asfotase alfa3 mg/kg intravenously the first week followed by 3 doses at 1 mg/kg subcutaneous at weekly intervalsfrom weeks 2 to 4. Cohort 2 (n=3) received asfotase alfa 3 mg/kg intravenously the first weekfollowed by 3 doses at 2 mg/kg subcutaneous at weekly intervals from weeks 2 to 4. After the 3 mg/kgfor 1.08 hours intravenous infusion, the median time (Tmax) ranged between 1.25 to 1.50 hours, and themean (SD) Cmax ranged between 42694 (8443) and 46890 (6635) U/L over the studied cohorts. Theabsolute bioavailability after the first and third subcutaneous administration ranged from 45.8 to98.4%, with median Tmax ranging between 24.2 to 48.1 hours. After the 1 mg/kg weekly subcutaneousadministration in Cohort 1 the mean (SD) AUC over the dosing interval (AUC) was 66034 (19241)and 40444 (N=1) U*h/L following the first and the third dose, respectively. After the 2 mg/kg weeklysubcutaneous administration in Cohort 2 the mean (SD) AUC was 138595 (6958) and 136109(41875) following the first and the third dose, respectively.

Pharmacokinetic data from all asfotase alfa clinical trials were analysed using populationpharmacokinetic methods. The pharmacokinetic variables characterized by populationpharmacokinetic analysis represent the overall hypophosphatasia patient population with age rangefrom 1 day to 66 years, subcutaneous doses of up to 28 mg/kg/week and a range of disease onsetcohorts. Twenty five percent (15 out of 60) of the overall patient population was adult (>18 years) atbaseline. The absolute bioavailability and absorption rate following subcutaneous administration wereestimated to be 0.602 (95% CI: 0.567, 0.638) or 60.2% and 0.572 (95%CI: 0.338, 0.967)/day or57.2%, respectively. The central and peripheral volumes of distribution estimates for a patient withbody weight of 70 kg (and 95% CI) were 5.66 (2.76, 11.6) L and 44.8 (33.2, 60.5) L, respectively. Thecentral and peripheral clearance estimates for a patient with body weight of 70 kg (and 95% CI) were15.8 (13.2, 18.9) L/day and 51.9 (44.0, 61.2) L/day, respectively. The extrinsic factors affectingasfotase alfa pharmacokinetic exposures were formulation specific activity and total sialic acidcontent. The average ± SD elimination half-life following subcutaneous administration was 2.28 ±0.58 days.

In adult patients with pediatric-onset HPP, the pharmacokinetics of asfotase alfa at doses of 0.5, 2 and3 mg/kg administered three times per week was consistent with those observed in pediatric patientswith pediatric-onset HPP, and thus supported the approved dose of 6 mg/kg per week in treating adultpatients with pediatric-onset HPP.

Based on the results of population pharmacokinetic analysis it was concluded that asfotase alfaexhibits linear pharmacokinetic up to subcutaneous doses of 28 mg/kg/week. The model identifiedbody weight to affect asfotase alfa clearance and volume of distribution parameters. It is expected thatpharmacokinetic exposures will increase with body weight. The impact of immunogenicity on asfotasealfa pharmacokinetic varied over time due to the time varying nature of immunogenicity and overallwas estimated to decrease pharmacokinetic exposures by less than 20%.

In nonclinical safety testing in rats, no body system-specific adverse effects were noted at any dose orroute of administration.

Dose - and time-dependent acute injection reactions that were transient and self-limiting were noted inrats at intravenous use doses of 1 to 180 mg/kg.

Ectopic calcifications and injection site reactions were observed in monkeys when asfotase alfa wasadministered subcutaneously at daily doses up to 10 mg/kg through 26 weeks. These effects wererestricted to injection sites and were partially or completely reversible.

There was no evidence of ectopic calcification observed in any other tissues examined.

Preclinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity or toxicity to reproduction and development. However, inpregnant rabbits administered intravenous doses of up to 50 mg/kg/day asfotase alfa, anti-drugantibodies were detected in up to 75% of animals which could affect the detection of reproductivetoxicity.

No animal studies have been conducted to evaluate the genotoxic and carcinogenic potential ofasfotase alfa.

Sodium chloride

Sodium phosphate dibasic heptahydrate

Sodium phosphate monobasic monohydrate

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

30 months

Chemical and physical in-use stability has been demonstrated for up to 3 hours at a temperaturebetween 23°C to 27°C.

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Store in the original package in order to protect from light.

For storage conditions after first opening of the medicinal product, see section 6.3.

Type I glass vial with a stopper (butyl rubber) and a seal (aluminium) with a flip-off cap(polypropylene).

Strensiq 40 mg/ml solution for injection

Filled volumes of the vials are: 0.3 ml, 0.45 ml, 0.7 ml and 1.0 ml

Strensiq 100 mg/ml solution for injection

Filled volumes of the vials are: 0.8 ml

Pack sizes of 1 or 12 vials

Not all pack sizes may be marketed.

Each vial is intended for single use only and should only be punctured once. Any unused solution inthe vial should be discarded.

Strensiq should be administered using sterile disposable syringes and injection needles. The syringesshould be of small enough volume that the prescribed dose can be withdrawn from the vial withreasonable accuracy. An aseptic technique should be used.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Alexion Europe SAS103-105 rue Anatole France92300 Levallois-Perret

France

Strensiq 40 mg/ml solution for injection

EU/1/15/1015/001

EU/1/15/1015/002

EU/1/15/1015/005

EU/1/15/1015/006

EU/1/15/1015/007

EU/1/15/1015/008

EU/1/15/1015/009

EU/1/15/1015/010

Strensiq 100 mg/ml solution for injection

EU/1/15/1015/003

EU/1/15/1015/004

Date of first authorisation: 28/08/2015

Date of latest renewal: 28/04/2020

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.