Consumer medicine information

Strensiq

Asfotase alfa

BRAND INFORMATION

Brand name

Strensiq

Active ingredient

Asfotase alfa

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Strensiq.

What is in this leaflet

This leaflet answers some common questions about Strensiq. It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you using Strensiq against the benefits they expect it will have for you.

If you have any concerns about this medicine, ask your doctor.

Keep this leaflet. You may need to read it again.

What Strensiq is used for

Strensiq is a medicine containing the active substance, asfotase alfa rch.

Strensiq is an enzyme replacement therapy for patients with hypophosphatasia or HPP (diagnosed before the age of 18 years).

How it works

Patients with hypophosphatasia (HPP) have low levels of an enzyme called alkaline phosphatase, which is naturally present in the body and necessary for the proper hardening of bones and teeth. Patients have problems with bone growth and strength, which can lead to broken bones, bone pain, and difficulty walking, as well as difficulties with breathing and a risk of seizures (fits).

Strensiq has been shown to benefit patients’ mineralization of the skeleton and growth.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

This medicine is available only with a doctor’s prescription.

Before you use Strensiq

When you must not use Strensiq

Do not use Strensiq if you have had an allergic reaction to:

  • Asfotase alfa rch, or any of the ingredients listed at the end of this leaflet, or
  • any other protein of Chinese hamster origin.

Symptoms of an allergic reaction may include;

  • shortness of breath, wheezing or difficulty breathing,
  • swelling of the face, lips, tongue or other parts of the body,
  • rash, itching or hives on the skin.

If you have previously had an allergic reaction to Strensiq, your doctor will discuss with you the next steps and the possibility to restart Strensiq under medical supervision.

Do not use Strensiq after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should be treated with Strensiq, talk to your doctor.

Before you start to use Strensiq

Some known eye-related side-effects have been reported in clinical trials with Strensiq, most likely associated with hypophosphatasia, however, talk to your doctor if you experience any vision problems while being treated with Strensiq.

Early fusion of the bones of the head in children < 5 years of age has been reported in clinical studies of infants with hypophosphatasia, with and without use of Strensiq. Talk to your doctor if you notice any change in the shape of your child’s head.

You may experience a reaction at the injection site (pain, swelling, rash, discolouration) during the injection of Strensiq or during the hours following the injection. If you experience any severe reaction at the injection site, tell your doctor immediately.

Increases of parathyroid hormone (a hormone that controls calcium concentration in your blood) and low calcium levels have been reported in clinical studies with Strensiq. As a consequence, your doctor may ask you to do some blood tests and, depending on the results of the blood test, ask you to take supplements of calcium and oral vitamin D.

Weight gain may occur during your treatment with Strensiq. Your doctor will provide dietary advice as necessary.

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you are pregnant or want to become pregnant. Your doctor can discuss with you the risks and benefits involved.

Tell your doctor if you are breastfeeding. It is not known whether Strensiq passes into breast milk. You should not breast feed while using Strensiq unless you have discussed it with your doctor.

If you have not told your doctor about any of the above, tell them before you start using Strensiq.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you buy without prescription from your pharmacy, supermarket or health food shop.

Some medicines and Strensiq may interfere with each other. They may be affected by Strensiq or may affect how well it works. You may need different amounts of your medicines or may need to take different medicines.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking this medicine.

How to use Strensiq

Follow all directions given to you by your doctor, nurse or pharmacist carefully. They may differ from the information contained in this leaflet.

“How to use Strensiq” will be explained to you by a healthcare professional experienced in the management of patients with metabolic or bone related diseases. After being trained by the doctor or specialized nurse, you can inject Strensiq yourself at home.

Do not inject Strensiq into a vein or muscle. Strensiq is intended for subcutaneous (under the skin) injection.

If you do not understand these instructions, ask your doctor, nurse or pharmacist for help.

How much to use

Your doctor will tell you how much of this medicine (in number of milligrams) you need to inject based on your body weight.

The correct dose will be calculated by your doctor based on a total of 6 milligrams of Strensiq, per kg of body weight, per week.

You will inject either 3 or 6 times a week depending on the recommendation of your doctor.

Your doctor may adjust your dose as your weight changes.

The maximum amount of Strensiq to be injected is 1 mL. If more than 1 mL is required, split the volume equally between two or more syringes, and administer each injection using a separate site.

How to use Strensiq

Please read the following instructions very carefully:

If you are injecting this medicine yourself, you will be shown how to prepare and give the injection by your doctor, pharmacist or nurse.

Do not inject this medicine yourself unless you have received training and you understand the procedure.

You may experience a reaction at the injection site. Please read “Side Effects” very carefully to know what side effects can occur before using this medicine.

When injecting, it is important to change the injection site between different areas of the body to help reduce potential pain and irritation.

Areas with a good amount of fat below the skin (thigh, arm) are the most suitable areas to inject.

How to inject Strensiq:

  1. Before you begin, take your vial(s) of Strensiq out of the refrigerator. It is recommended to administer the medicine WITHIN 3 HOURS after removing the vial (s) from the refrigerator.
Always use a new vial. Each vial is for single use and should only be punctured once.
  1. Wash your hands thoroughly with soap and water.
  2. Place all the items you will need on a clean surface where you will not be disturbed. These should include;
  • vial(s) of Strensiq
  • syringes and needles
  • alcohol swabs (if required)
  • gauze or cotton wool
  • sharps container
  • adhesive bandage
  • injection diary (or other recording means).
  1. Visually check the vial before use. Strensiq should be colourless to slightly yellow in colour. Do not use if it is cloudy, hazy, discoloured or contains particles.
  2. Remove the protective cap from the vial.
  3. Remove the plastic cap covering the syringe needle and draw air into the syringe, equal to the volume of medicine to be injected. The volume per injection should not exceed 1mL. If this is the case, multiple injections should be done at different sites.
  4. Holding the syringe and vial at 45° angle, insert the needle through the sterile rubber top and inject air into the vial.

  1. Turn the vial and syringe upside down. With the needle in the solution, pull the plunger to withdraw the volume of the correct dose into the syringe.

  1. Before removing the needle from the vial, check the syringe for air bubbles.

If bubbles are present, hold the syringe with the needle pointing upwards and gently tap the side of the syringe until the bubbles float to the top.

Once all the bubbles are at the top of the syringe, gently push on the plunger to force the bubbles out of the syringe and back into the vial.
After removing the bubbles, check the dose of medicine in the syringe to be sure you have drawn up the correct amount.
Remove the needle from the vial and make sure the needle does not touch anything.
You are now ready to inject the correct dose.
  1. Choose an injection site. Strensiq should be administered as a subcutaneous injection into the fatty layer just below the skin. This is called the subcutaneous layer and it is just above the muscle. Areas with a substantial amount of fat below the skin (as shown in the diagram) are the most suitable areas to inject.
Your doctor will advise you on the possible injection sites.

It is important to rotate injection sites, as this may help reduce pain and irritation. Do not inject into areas that are reddened, inflamed, swollen or into any areas in which you feel lumps, firm knots, or pain.
  1. Using an alcohol-based (isopropyl alcohol or ethanol) solution wipe or clean the site.
  2. Gently pinch the skin of the chosen injection area between your thumb and index finger.

  1. Holding the syringe like a pencil or a dart, insert the needle into the raised skin so it is at an angle of between 45° and 90° to the skin surface.

For children, or patients who have little subcutaneous fat or thin skin, a 45° angle may be preferable.
  1. While continuing to hold the skin, push the syringe plunger to inject the medicine while counting slowly to 10.

  1. Remove the needle, release the skin fold and gently place a piece of cotton wool or gauze over the injection site for a few seconds.
This will help seal the punctured tissue and prevent any leakage.
Do not rub the injection site after injection.
  1. Dispose of your syringe, needle cap and used vial into your sharps container.
DO NOT re-cap the needle.
  1. Place a small adhesive bandage over the injection site if necessary.
  2. If you need a second injection for your prescribed dose, get another Strensiq vial and repeat steps 4 through 17.
  3. Record all details of the injection in your injection diary or using another means. It is recommended that you note:
  • where you injected
  • the dose injected
  • any injection reactions.

If you have any concerns about injection reactions, preparing or administering your injection, discuss them with your doctor or pharmacist.

If you miss a dose

Do not take a double dose to make up for a forgotten dose. Contact your doctor for advice.

If you use too much (overdose)

If you suspect you have accidentally injected a higher dose of Strensiq than prescribed, please contact your doctor for advice or contact the Poisons Information Centre on 13 11 26.

While you are using Strensiq

Things you must do

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

Tell your doctor or pharmacist if you are traveling. You will need to calculate how many vials you will need for your trip. Take extra in case you are away longer than expected.

Discuss traveling with your medicine with your doctor or pharmacist.

If you become pregnant while using Strensiq, tell your doctor immediately. Your doctor will discuss the benefits and risks of continuing treatment with Strensiq during pregnancy, including participation in a monitoring program.

If you intend to breastfeed whilst using STRENSIQ, consult your doctor. Your doctor will discuss the benefits and risks of continuing treatment with Strensiq whilst breastfeeding, including participation in a monitoring program.

If you are having any blood tests, tell your doctor that you are using this medicine. Some medicines can interfere with the results of some tests.

If you need to undergo laboratory tests (giving blood for testing), tell your doctor that you are treated with Strensiq. Strensiq may cause some tests to show wrongly higher or lowerresults. Therefore another type of test may need to be used if you are treated with Strensiq.

Keep all of your doctor’s appointments so that your progress can be checked. Because your dose is calculated based on your weight, it is important that your doctor can monitor your weight and adjust as needed. Your doctor may do some tests to make sure the medicine is working and to prevent unwanted side effects.

Things you must not do

Do not stop taking your medicine or lower the dosage without checking with your doctor.

Side Effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using Strensiq.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Tell your doctor if you notice any of the following and they worry you:

  • reactions at the injection site during the injection of the medicine or during the hours following the injection (which can lead to redness, discolourations, itching, pain and/or swelling)
  • chills, fever, rash, irritability,
  • skin redness, loose skin, discolouration of the skin, bruising, scarring
  • fatty lumps under the surface of the skin or localised loss of fat tissue
  • small dent or depression of the skin at the injection site
  • pain in hands and feet
  • nausea or feeling sick
  • numbness of the lips/mouth
  • aching muscles, muscle tenderness or weakness not caused by exercise
  • hot flush
  • infection of the skin at injection site
  • headache.

The above list includes the more common side effects of your medicine.

Tell your doctor as soon as possible if you notice any of the following:

  • bruising more easily than normal
  • eye problems, blurred vision.

Tell your doctor or go to the Emergency Department at your nearest hospital if you notice any of the following;

Strensiq contains a protein and proteins can cause allergic reactions in some people. Symptoms of such reactions include;

  • shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin
  • low blood pressure
  • vomiting
  • fast heart rate
  • choking sensation

The above lists include serious side effects that may require medical attention.

Other side effects not listed above may occur in some patients. Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Storing Strensiq

Keep your medicine in the packaging until it is time to use it. If you take the medicine out of the packaging it may not keep well.

Keep your medicine in the refrigerator (2°C to 8°C). Do not put Strensiq in, or near the freezer compartment, and never inject Strensiq that you know, or suspect, has been frozen.

After opening the vial, the product should be used immediately (within 3 hours maximum at room temperature, up to 25°C)

Keep Strensiq where children cannot reach it.

Disposal

Ask your pharmacist what to do with any medicine that is left over.

Product Description

What Strensiq looks like

Strensiq is a clear, colourless to slightly yellow, solution contained in a glass vial.

It is available in packs of 12 vials in the following strengths;

Ingredients

Active ingredient

  • asfotase alfa rch

Other ingredients

  • sodium chloride
  • monobasic sodium phosphate monohydrate
  • dibasic sodium phosphate heptahydrate
  • Water for Injection

Manufacturer

In Australia this product is registered by:

Alexion Pharmaceuticals Australasia Pty Ltd
Suite 401, Level 4, Building A.
20 Rodborough Rd. Frenchs Forest.
NSW 2086.

Medical enquiries: 1800 788 189

Registration numbers;

AUST R 232545

AUST R 232546

AUST R 266984

AUST R 266985

AUST R 266986

This leaflet was prepared in - November 2020

® = Registered Trademark

Published by MIMS December 2020

BRAND INFORMATION

Brand name

Strensiq

Active ingredient

Asfotase alfa

Schedule

S4

 

1 Name of Medicine

Asfotase alfa rch.

2 Qualitative and Quantitative Composition

Strensiq is supplied as a single-use vial containing 40 or 100 mg/mL of asfotase alfa rch.
Asfotase alfa rch is a human recombinant tissue nonspecific alkaline phosphatase (TNSALP)-Fc-deca-aspartate fusion protein with enzymatic activity, produced by recombinant DNA technology using mammalian Chinese Hamster Ovary (CHO) cell culture.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection. Strensiq is a sterile, preservative-free, non-pyrogenic, clear, slightly opalescent or opalescent, colourless to slightly yellow aqueous solution; few small translucent or white particles may be present. For subcutaneous injection.

4 Clinical Particulars

4.1 Therapeutic Indications

Strensiq (asfotase alfa rch) is indicated as enzyme replacement therapy in patients with paediatric onset hypophosphatasia.

4.2 Dose and Method of Administration

Strensiq treatment should be initiated by a physician experienced in the management of patients with metabolic or bone disorders.

Patient monitoring program.

Physicians should enrol consenting patients receiving Strensiq in a monitoring program.

Recommended dose.

The recommended dosage regimen is 2 mg/kg of body weight, administered subcutaneously 3 times per week, or 1 mg/kg of body weight administered 6 times per week. Also see dosing chart (Table 1).
The maximum volume of subcutaneous injection is 1 mL per injection site. If more than 1 mL is required, split the volume equally between two or more syringes and administer each injection using a separate site.
Patients should be regularly reviewed for their response to treatment and appropriate dose, including patients who have progressed to adolescence and adulthood.

Method of administration.

Patients can self-inject only if they have been appropriately trained on administration procedures.
Take the unopened Strensiq vial(s) out of the refrigerator 15 to 30 minutes before injecting to allow the liquid to reach room temperature. Do not warm Strensiq in any other way (for example, do not warm it in a microwave or in hot water).
Strensiq should be administered using sterile disposable syringes and injection needles. The use of two different gauge needles is recommended, a larger bore needle (e.g. 25 gauge) for withdrawal of the medication and a smaller bore needle (e.g. 29 gauge) for the injection. An aseptic technique should be used. The syringes should be of small enough volume that the prescribed dose can be withdrawn from the vial with reasonable accuracy.
Do not administer intravenously or intramuscularly. Strensiq must be administered as subcutaneous injection.
Do not administer injections in areas that are reddened, inflamed, or swollen. Injection sites should be rotated and carefully monitored for signs of potential reactions. Rotate the injection from among the following sites to reduce the risk of lipodystrophy: abdominal area, thigh, deltoid or buttocks (see Section 4.4 Special Warnings and Precautions for Use).

Special populations.

Patients with renal and hepatic impairment.

The safety and efficacy of Strensiq have not been studied in patients with renal or hepatic impairment, and no specific dose regimen can be recommended for these patients.

Adult patients.

Safety and efficacy data in patients > 18 years old are limited.

4.3 Contraindications

Strensiq is contraindicated in patients with known hypersensitivity to asfotase alfa rch, Chinese hamster ovary cell proteins or to any of the excipients of this product.
Severe and life-threatening hypersensitivity to the active substance or to any of the excipients if hypersensitivity is not controllable (see Section 4.4 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

Limited data.

Due to HPP being an ultra-rare (orphan) disease, only limited, Phase II data have been provided in support of the safety and efficacy of Strensiq in the treatment of HPP.

Hypersensitivity.

Hypersensitivity reactions have been reported in Strensiq-treated patients including signs and symptoms consistent with anaphylaxis. Signs and symptoms included difficulty breathing, choking sensation, periorbital oedema and dizziness. The reactions have occurred within minutes after subcutaneous administration of Strensiq. Hypersensitivity reactions have been observed as late as more than one year after treatment initiation. Other hypersensitivity reactions included vomiting, nausea, fever, headache, flushing, irritability, chills, erythema, rash, pruritus and oral hypoesthesia (see Section 4.8 Adverse Effects (Undesirable Effects)).
Other severe allergic type hypersensitivity reactions are possible, including urticaria, difficulty breathing and/or cardiovascular collapse. If severe hypersensitivity reaction occurs, immediate discontinuation of Strensiq 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 Strensiq 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.
Severe or life-threatening hypersensitivity to the active substance or to any of the excipients if hypersensitivity is not controllable (see Section 4.3 Contraindications).

Injection site reactions.

Administration of Strensiq may result in local injection site reactions (including, but not limited to, erythema, rash, discolouration, pruritus, pain, papule, nodule or atrophy) defined as any related adverse event occurring during the injection, or until the end of the injection day (see Section 4.8 Adverse Effects (Undesirable Effects)). These have been generally assessed as non-serious, mild to moderate in severity and self-limiting. Rotation of injection sites may help to minimise these reactions. One patient treated in clinical trials experienced a severe ISR of injection site discolouration which led to the discontinuation of Strensiq.
Strensiq administration should be interrupted in any patient experiencing severe injection reactions and appropriate medical therapy administered.

Lipodystrophy.

Localized lipodystrophy, including lipoatrophy and lipohypertrophy, has been reported at injection sites after several months in patients treated with Strensiq in clinical trials. Patients should be advised to follow proper injection technique and to rotate injection sites (see Section 4.2 Dose and Method of Administration).

Craniosynostosis.

In Strensiq clinical studies, adverse events of craniosynostosis (associated with increased intracranial pressure), including worsening of pre-existing craniosynostosis have been reported in HPP 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 HPP 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 HPP 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 infantile onset HPP patients below 5 years of age.

Ectopic calcification.

Patients with HPP are at increased risk for developing ectopic calcifications.
Ophthalmology examinations and renal ultrasounds are recommended at baseline and periodically during treatment with Strensiq to monitor for signs and symptoms of ophthalmic and renal ectopic calcifications and for changes in vision or renal function.
In clinical trials, events of ectopic calcification including opthalmic (corneal and conjunctival) calcification and nephrocalcinosis have been reported to be at least possibly related to Strensiq. There was insufficient information to determine whether or not the reported events were consistent with the disease or due to Strensiq. No visual changes or changes in renal function were reported resulting from the occurrence of ectopic calcifications.

Serum parathyroid hormone and calcium.

Serum parathyroid hormone concentrations may increase in HPP patients administered Strensiq, most notably during the first 12 weeks of treatment. It is recommended that serum parathyroid hormone and calcium be monitored in patients treated with Strensiq. Supplements of calcium and oral vitamin D may be required.

Disproportionate weight gain.

Patients may display disproportionate weight increase. Dietary supervision is recommended.

Use in hepatic impairment.

Safety and efficacy of Strensiq have not been studied in patients with hepatic impairment.

Use in renal impairment.

Safety and efficacy of Strensiq have not been studied in patients with renal impairment.

Use in the elderly.

Safety and efficacy of Strensiq in patients older than 65 years have not been established. Therefore, there is no information available to determine whether patients aged 65 years and over respond differently from younger patients.

Paediatric use.

The safety and efficacy of Strensiq have been studied in paediatric patients aged between 0-18 years. The posology of Strensiq is based on body weight.

Effects on laboratory tests.

Serum alkaline phosphatase.

High serum ALP measurements detected through clinical laboratory testing are expected in patients receiving Strensiq and reflect circulating concentrations of asfotase alfa rch.
Do not rely on serum ALP measurements for clinical decision making in patients treated with Strensiq.

Laboratory tests utilizing alkaline phosphatase as a detection reagent.

Alkaline phosphatase (ALP) is used as the detection reagent in many routine laboratory assays. Studies have shown that there may be analytical interference between asfotase alfa and laboratory tests that utilize an alkaline phosphatase (ALP)-conjugated test system, rendering potentially erroneous test results in patients treated with Strensiq. ALP-conjugated test systems are utilized to measure substances such as hormones, bacterial antigens and antibodies. Therefore, it is recommended that laboratory assays which do not have ALP-conjugate technology be used when testing samples from patients who are receiving Strensiq.
To avoid erroneous test results for patients treated with Strensiq, inform laboratory personnel that the patient is being treated with Strensiq and discuss the use of a testing platform which does not utilize an ALP-conjugated test system.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No interaction studies have been performed with asfotase alfa rch. Based on its structure and pharmacokinetics, asfotase alfa rch is an unlikely candidate for cytochrome P450 mediated interactions.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No adverse effects on fertility were observed in male and female rats given intravenous doses of asfotase alfa rch at ≤ 50 mg/kg/day, yielding exposures to asfotase alfa rch (based on plasma AUC) up to 19 times higher than that in patients at the recommended human dose of 2 mg/kg SC three times weekly.
(Category C)
There are no available data on Strensiq use in pregnant women. Pregnant and lactating women were excluded from Strensiq clinical trials. Strensiq is not recommended during pregnancy, and in women of childbearing potential not using contraception. Patients should be advised to inform their physician if they become pregnant.
Animal studies are insufficient to conclude that asfotase alfa rch has no effects on the foetal skeleton. In embryofoetal development studies, no adverse effects were observed in pregnant rats and rabbits that received intravenous doses of asfotase alfa rch during organogenesis at doses up to 50 mg/kg/day. These doses resulted in exposures (based on plasma AUC) 18 and 50 times, respectively, the estimated clinical AUC at the recommended human dose of 2 mg/kg SC three times weekly. However, the production of antibodies against asfotase alfa rch in rabbits may have affected the detection of reproductive toxicity.
 There is insufficient information on the excretion of asfotase alfa rch in human milk. A risk to the newborns/ infants cannot be excluded. Breast-feeding should not be commenced whilst on treatment with Strensiq.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

The data described below reflect exposure to Strensiq in 112 patients with perinatal/infantile- (n=89), juvenile-onset (n=22) and adult-onset (n=1) HPP (age at enrolment from 1 day to 66.5 years) treated with Strensiq, most for more than 2 years (range from 1 day to 391.9 weeks [7.5 years]): a majority of patients (69) received at least 120 weeks (2.3 years) of treatment of which 44 patients received 240 weeks (4.6 years) or more of treatment.
The most common adverse reactions were injection site reactions (74%). The majority of these reactions resolved within a week. One patient withdrew from the trial due to an injection site hypersensitivity.
Other common adverse reactions included lipodystrophy, ectopic calcifications and hypersensitivity reactions.
The frequency of injection site reactions, lipodystrophy and ectopic calcification were higher in patients with juvenile-onset HPP as compared to perinatal/infantile-onset HPP patients and was likely due to the increased dosing frequency in older patients.
Table 2 gives the adverse events observed from clinical trials.

Less common adverse reactions.

Adverse reactions that occurred at rates less than 10% included: hypocalcaemia; renal stones; chronic hepatitis; decreased vitamin B6; skin discolouration; skin hyperpigmentation.

Description of selected adverse reactions.

Injection site reactions (ISRs).

ISRs (including injection site atrophy, abscess, erythema, discoloration, pain, pruritus, macule, swelling, contusion, bruising, lipodystrophy (lipoatrophy or lipohypertrophy), induration, reaction, nodule, rash, papule, haematoma, inflammation, urticaria, calcification, warmth, haemorrhage, cellulitis, scar, mass, extravasation, exfoliation and vesicles) are the most common adverse reactions, observed in approximately 74% of the patients in the clinical studies.

Hypersensitivity.

Hypersensitivity reactions (including irritability, pyrexia, rash, pruritus, chills, erythema, nausea, vomiting, flushing, oral hypoesthesia, headache, tachycardia and cough) are very common adverse reactions, observed in approximately 22/112 (19.6%) of the patients in the clinical studies. 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.

Immunogenicity.

As with all therapeutic proteins, there is potential for immunogenicity. Among 109 HPP patients enrolled in the clinical trials, 97/109 (89.0%) tested positive for anti-drug antibodies at some time point after receiving 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. Formation of anti-drug antibodies resulted in reduced systemic exposure of asfotase alfa rch. In clinical trials, the development of antibodies has not been shown to affect clinical efficacy or safety.
No trends in adverse events based on antibody status were observed in completed clinical trials. Furthermore, patients confirmed positive for antibodies have not shown signs of hypersensitivity or tachyphylaxis following subcutaneous administration of Strensiq.
Cases from the post-approval setting suggest that development of inhibitory antibodies may be associated with a decreased clinical response.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

The maximum dose of Strensiq used in clinical trials is 28 mg/kg/week. No dose related toxicity or change in the safety profile has been observed in clinical studies to date; therefore no overdose level has been determined.
For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Hypophosphatasia (HPP) is a rare, serious, and potentially fatal, genetic disorder caused by loss-of-function mutation(s) in the gene encoding TNSALP. In patients with HPP, a deficiency in TNSALP enzymatic activity leads to elevations in several TNSALP substrates, including inorganic pyrophosphate (PPi). Elevated extracellular levels of PPi block hydroxyapatite crystal growth which inhibits bone mineralisation and causes accumulation of unmineralised bone matrix which manifests as rickets and bone deformations in infants and children and as osteomalacia (softening of bones) once growth plates close, along with muscle weakness. Replacement of the TNSALP enzyme upon Strensiq treatment reduces the enzyme substrate levels.
Asfotase alfa rch, a human recombinant TNSALP-Fc-deca-aspartate fusion protein with enzymatic activity, promotes mineralisation of the skeleton in patients with HPP.

Pharmacodynamics.

Perinatal/infantile-and juvenile-onset HPP patients treated with Strensiq had reductions in plasma TNSALP substrates, PPi and pyridoxal 5'-phosphate (PLP) within 6 to 12 weeks of treatment. Reductions in plasma PPi and PLP levels did not correlate with clinical outcomes. In adult patients with paediatric-onset HPP, the pharmacodynamics of Strensiq was consistent with those observed in paediatric patients with perinatal/infantile-onset or juvenile-onset HPP.
Bone biopsy data from perinatal/ infantile onset and juvenile onset HPP patients treated with Strensiq demonstrated decreases in osteoid volume and thickness indicating improved bone mineralization.

Clinical trials.

Due to HPP being an ultra-rare (orphan) disease, only limited, Phase II data have been provided in support of the safety and efficacy of Strensiq in the treatment of HPP.
Four studies were conducted in the clinical development program for Strensiq, in which a total of 111 patients with paediatric-onset HPP were enrolled. Of these 111 patients, 89 had perinatal- or infantile-onset HPP, while 22 had juvenile-onset HPP. In Studies ENB-002-08/ENB-003-08 and ENB-010-10, eligible patients had perinatal- or infantile- onset HPP and were ≤ 3 or ≤ 5 years of age at enrolment, respectively. In Study ENB-006-09/ENB-008-10, eligible patients were required to have perinatal- or infantile- or juvenile-onset disease and be aged between 5 and 12 years at enrolment, while in Study ENB-009-10, eligible patients had perinatal- or infantile- or juvenile-onset and were aged between 13 and 65 years at enrolment. Patient demographics in HPP clinical trials are summarised in Table 3.
Baseline characteristics of patients with paediatric onset HPP evaluated in clinical trials included low ALP and one or more of the following; elevated TNSALP biochemical substrates (PPi and PLP), abnormal bone structure (elevated osteoid indices, reduced bone mineral content, skeletal deformities of rickets such as bowed legs, abnormally shaped chest, below normal Z-score for height) or impaired physical function (gross motor weakness, developmental delay, impaired walking, inability to perform activities of daily living). At baseline, patients less than 5 years of age presented with additional morbidities including nephrocalcinosis, seizures, respiratory compromise (including respiratory failure requiring support) and gross motor delays. In Study ENB-002-08/ENB-003-08, most patients (9/11, 81.8%) presented with significant gross motor delays on the BSID-III (Bayley Scales of Infant and Toddler Development, Third Edition) e.g. gross motor scaled scores of 1, which is 3 SDs below the mean SD for healthy age-matched peers. In Study ENB-009-10, 18/19 (94.7%) patients experienced fractures and 18 patients had bone pain severe enough to limit activity.
Subcutaneous doses of 6 mg/kg/week of Strensiq were administered 3 times a week or 6 times a week. After completion of the initial 24-week treatment period in ENB-002-08 and ENB-006-09, most patients continued to receive Strensiq by enrolling into an extension study.

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

Study ENB-002-08/ENB-003-08 was a 24 week prospective single arm trial in 11 patients aged 3 weeks to 39.5 months, with severe perinatal/infantile-onset HPP; 7/11 (64%) were female and 10/11 (91%) were white. Severe perinatal/infantile-onset HPP was defined as biochemical, medical history and radiographic evidence of HPP as well as the presence of any of the following: respiratory compromise, rachitic chest deformity, vitamin B6-dependent seizures, and/or failure to thrive. Ten of 11 patients completed the 24-week trial and continued treatment in the extension phase. Nine patients have been treated with Strensiq for at least 5 years (60 months) and 4 patients have been treated for more than 7 years (84 months).

Study ENB-010-10.

Study ENB-010-10 was prospective open-label study in 69 patients, aged 1 day to 5 years with perinatal/ infantile-onset HPP; 54/69 (78%) were white. Thirty-eight patients were treated for at least 2 years (24 months) and 6 patients have been treated for at least 5 years (60 months).

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

Study ENB-006-09/ENB-008-10 was a prospective open-label 24 week trial that enrolled 13 patients that included 5 perinatal/ infantile-onset HPP patients and 8 juvenile-onset HPP patients. Twelve of the 13 patients entered the extension study and were treated for at least 6 years (72 months).

Study ENB-009-10.

Study ENB-009-10 was an open-label, randomised study that enrolled 19 patients. Patients were randomly assigned to 1 of 2 Strensiq treatment groups (either 0.3 mg/kg/day or 0.5 mg/kg/day) or to the prospective control group for the 24-week primary treatment period. All patients received Strensiq treatment (0.5 mg/kg/day) in the extended treatment period. After 48 weeks all patients were adjusted to the recommended dose 1.0 mg/kg/day. Fourteen patients completed and 5 discontinued the study. At study completion, the median treatment period was 60 months (range, 24 to 68 months). Four patients had perinatal/infantile-onset HPP, 14 patients had juvenile-onset HPP, and 1 patient had adult-onset HPP. Age was 13 to 66 years at inclusion and was between 17 and 72 years at study completion.

Study results.

Perinatal/infantile-onset HPP.

Skeletal manifestations.

Radiographs from 81 Strensiq-treated perinatal/infantile-onset HPP patients, including 77 patients in ENB-002-08/ENB-003-08 and ENB-010-10, and 4 patients in ENB-006-09/ENB-008-10, were examined to assess HPP-related rickets using the 7-point Radiographic Global Impression of Change (RGI-C) scale. Patients with a minimum RGI-C score of +2 were defined as "responders". Radiologic improvements could be seen by Week 24; at last assessment, 63/81 [78%] treated patients were rated as RGI-C responders. No comparative data were available from historical controls. The mean time interval between the baseline and last RGI-C assessment was 35.7 months (range was 2.5 months to 89.4 months).
Radiographs were also scored using the 10-grade Rickets Severity Scale (RSS), which can be used to quantify the severity of rickets in the wrists and knees of these patients based on the degree of metaphyseal fraying and cupping and the proportion of growth plate affected. A score of 10 represents severe rickets, while a score of 0 represents an absence of rickets. Change in RSS scores were also statistically significant, with progressive improvements (at Week 24, median change in RSS score was -1.5, and at last overall assessment, the median change was -3.0).

Growth.

Height and weight measurements (as measured by Z-scores) were available post-treatment for 82 perinatal/infantile-onset HPP patients, including 78 patients enrolled in Studies ENB-002-08/ENB-003-08 and ENB-010-10, and 4 patients enrolled in ENB-006-09/ENB-008-10 (Table 4).

Survival and ventilation-free survival.

Survival and invasive ventilation-free survival were compared in Strensiq-treated patients with severe perinatal- or infantile-onset HPP (ENB-002-08/ENB/003-08 and ENB-010-10) with a historical cohort of untreated patients with similar clinical characteristics (ENB-011-10), all of whom had a history of rachitic chest deformity, vitamin B6-dependent seizures, and/or failure to thrive (Table 5 and Figure 1).
Overall survival was improved in the cohort of treated patients with severe perinatal- or infantile-onset HPP, compared to the matched historical control group, with 69/78 (88%) treated patients vs. 13/48 (27%) historical controls alive at last contact. In patients who required any form of respiratory support, 23/29 (79%) of the treated patients survived through their last assessment (median age at last assessment was 3.9 years), versus 1 of 20 (5%) of historical controls.

Ventilation support.

The natural history of untreated infant HPP patients suggests higher mortality if ventilation is required. 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 patients completed the studies, and 11 discontinued. 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 to 168 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 to 216 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.
Juvenile-onset HPP.

Skeletal manifestations.

In study ENB-006-09/ENB-008-10, radiographs from 8 Strensiq-treated patients and 32 historical controls were compared to assess HPP-related rickets using the 7-point RGI-C (Radiographic Global Impression of Change) scale. Patients who achieved a RGI-C score of 2 or higher (corresponding to substantial healing of rickets) were classified as being responders to treatment. All 8 treated patients were rated as responders by Month 54 of treatment. The mean duration between the baseline and last RGI-C assessments for control patients was 56 months (range was 8 to 95 months). At last assessment, 2/32 (6%) of control patients were rated as responders.

Gait/mobility.

Gait was assessed using a modified Performance Oriented Mobility Assessment-Gait (MPOMA-G) scale) in 8 Strensiq-treated patients at 6 month intervals out to 36 months. Step length improved by at least 1 point in either foot in 6/8 patients compared to 1/6 (17%) control patients. Mobility was also assessed using the 6 Minute Walk Test (6MWT) in 7 of the 8 patients. At last assessment, all 7 patients had an improvement in distance walked of at least the minimal clinically important difference. The mean increase from baseline for distance walked is 222.4 meters (range from 81 to 297 meters). Mean walking distance reached the normal range after 6 months of treatment and improvements were sustained over 6 years.

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 standard procedure. Histological analysis of biopsies used Osteomeasure software (Osteometrics, USA). Nomenclature, symbols and units followed recommendations of the American Society for Bone and Mineral Research.
At baseline, the mineralisation indices; osteoid thickness, osteoid volume per bone volume and mineralisation lag time were all elevated, relative to a normative sample of healthy individuals, which was consistent with osteomalacia. At Week 24, all 3 parameters had declined significantly from their pre-treatment levels, associated with improved bone mineralisation. The results for 10 patients in the per-protocol set (excludes those patients who received oral vitamin D between baseline and week 24) who underwent biopsy of the trans-iliac bone crest before and after receiving Strensiq are presented in Table 6.

Growth.

Height, weight and head circumference were plotted on growth charts (series of percentile curves that illustrate distribution) available from the Centres for Disease Control and Prevention, USA. These reference data were drawn from a representative sample of healthy children and are not specific for children with special health care needs: they have been used in the absence of growth charts for children with HPP.
For those patients who received Strensiq: 9/13 patients displayed persistent apparent catch-up height-gain as shown by movement over time to a higher percentile on CDC growth charts. Three of the 13 patients did not display apparent catch-up height-gain and 1 patient did not have enough data to permit judgement. Progress through Tanner stages appeared appropriate.
For the time period of observation of historical controls: 1/16 patients displayed apparent catch-up height-gain, 12/16 patients did not display apparent catch-up height-gain and data were inconclusive in 3/16 patients.
Some patients required oral vitamin D supplements during the study (see Section 4.4 Special Warnings and Precautions for Use, Serum parathyroid hormone and calcium).
Adolescent and adult patients with HPP.

Bone biopsy.

A histomorphometric assessment (transiliac crest bone biopsy) was conducted in ENB-009-10. Patients underwent biopsy of the trans-iliac bone crest either as part of a control group or before and after exposure to Strensiq and results are presented in Table 7.

Physical function and growth.

Physical function was evaluated in ENB-009-10 using the 6 minute walk test (ambulation). At Week 24, change from baseline in distance walked in 6 minutes (6MWT) was 35.0 (-2, 182) m for the combined treatment group and -6.5 (-46, 113) m for the control group. The difference between treated and untreated patients did not achieve statistical significance due to patient heterogeneity, low Strensiq dose and/or the small sample size of the study. During the extended treatment period, most patients had sustained or increased improvements.
There was no improvement in height in the overall study population in Study ENB-009-10; however, this was expected given that 6/19 of the patients were adolescents at the time of enrolment.

5.2 Pharmacokinetic Properties

Based on data in 38 HPP patients the pharmacokinetics of asfotase alfa rch exhibited dose proportionality across the dose range of 0.3 mg/kg to 3 mg/kg, administered three times per week, and appeared to be time-independent. Steady state exposure was achieved as early as three weeks after the administration of the first dose. The elimination half-life following subcutaneous administration was approximately 5 days. In adult patients with paediatric-onset HPP, the pharmacokinetics of asfotase alfa rch at doses of 0.5, 2 and 3 mg/kg administered three times per week was consistent with those observed in paediatric patients with paediatric-onset HPP, and thus supported the approved dose of 6 mg/kg per week in treating adult patients with paediatric-onset HPP.
Table 8 summarises the pharmacokinetic parameters following multiple doses in 20 HPP patients after subcutaneous administration of Strensiq at 2 mg/kg three times per week in Study ENB-010-10 (age of less than or equal to 5 years) and Study ENB-006-08/ENB-008-10 (age of greater than 5 to 12 years), indicating the pharmacokinetics were similar between patients in the two age groups.
Based on the results of population pharmacokinetic analysis, body weight was identified to affect asfotase alfa rch clearance and volume of distribution parameters. It is expected that pharmacokinetic exposures will increase with body weight. The impact of immunogenicity on asfotase alfa rch pharmacokinetics varied over time due to the time varying nature of immunogenicity and overall was estimated to decrease pharmacokinetic exposures by less than 20%.
Formation of anti-drug antibodies resulted in reduced systemic exposure of asfotase alfa rch.
The extrinsic factors affecting asfotase alfa rch pharmacokinetic exposures were formulation specific activity and total sialic acid content.

Absorption.

Following weekly SC administrations of Strensiq, the observed median Tmax ranged from 1 to 2 days and the absolute bioavailability ranged from 45.8-98.4%. Following once weekly administration of Strensiq 3 mg/kg IV bolus on Week 1 followed by 2 mg/kg SC on Weeks 2, 3 and 4, the Week 4 mean ± SD observed Cmax and AUCt parameters were 1020 ± 326 U/L and 284,926 ± 79,652 U.h/L, respectively.

Distribution.

Based on population PK analysis, the estimated central and peripheral volumes of distribution (mean) for a patient with body weight 70 kg were 5.66 L (95% CI: 2.76, 11.6) and 44.8 L (95% CI: 33.2, 60.5), respectively. These results indicated that asfotase alfa rch was initially distributed primarily in the intra-vascular space and then distributed to the extra-vascular space, reflecting its ability to partition into tissues, likely including skeletal tissue.

Metabolism.

In vitro or in vivo metabolism studies are not considered relevant since the expected metabolic pathway is the normal catabolic degradation into small peptides and individual amino acids.

Excretion.

The central and peripheral clearance estimates for a patient with body weight 70 kg (and 95% CI) were 15.8 (13.2, 18.9) L/day and 51.99 (44.0, 61.2) L/day respectively. The average elimination half-life of asfotase alfa rch was 2.28 ± 0.58 days with a range of 1.06 to 3.62 days.

Special populations.

Based on the population PK analysis, age and sex were not found to be significant covariates.

Renal and hepatic impairment.

The safety and efficacy of Strensiq in patients with renal or hepatic impairment have not been evaluated and no specific dose regimen can be recommended for these patients.
Significant PK-PD relationships were demonstrated based on the efficacy biomarker data and clinical endpoints in patients with paediatric onset HPP, across the range of perinatal/ infantile and juvenile onset cohorts. These relationships supported the recommendation of the 6 mg/kg/week dose, administered as either 2 mg/kg 3 times weekly or 1 mg/kg 6 times weekly.

5.3 Preclinical Safety Data

Genotoxicity.

No studies have been conducted to assess the genotoxic potential of asfotase alfa rch.

Carcinogenicity.

No studies have been conducted to assess the carcinogenic potential of asfotase alfa rch.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium chloride, dibasic sodium phosphate heptahydrate, monobasic sodium phosphate monohydrate, water for injections.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
Do not use beyond the expiration date (EXP) stamped on the packaging.

6.4 Special Precautions for Storage

Strensiq vials must be stored in a refrigerator (2° to 8°C, Do not freeze) in the original packaging in order to protect from light.
Out of refrigeration, the product should be kept at room temperature and administered within 3 hours.

6.5 Nature and Contents of Container

Strensiq is supplied as packs of 12 single-use glass vials. See Table 9.

6.6 Special Precautions for Disposal

Product is for single use in one patient only. Discard any unused portion left in the vial, as the product contains no preservatives. Unused or expired medicine should be returned to a pharmacy for disposal.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

CAS registry number: 1174277-80-5.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes