Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

STRENSIQ (BLA-125513)

(ASFOTASE ALFA)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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07/10/2024 (SUPPL-33)

Approved Drug Label (PDF)

Boxed Warning

Newly added section:

WARNING: HYPERSENSITIVITY REACTIONS INCLUDING ANAPHYLAXIS

Patients treated with enzyme replacement therapies have experienced life- threatening hypersensitivity reactions, including anaphylaxis. Anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy.

Initiate STRENSIQ under the supervision of a healthcare provider with appropriate medical monitoring and support measures. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue STRENSIQ and immediately initiate appropriate medical treatment, including use of epinephrine. Inform patients of the symptoms of life-threatening hypersensitivity reactions, including anaphylaxis and to seek immediate medical care should symptoms occur [see Warnings and Precautions (5.1)].

5 Warnings and Precautions

5.1 Hypersensitivity Reactions Including Anaphylaxis

Additions and/or revisions underlined:

Life-threatening hypersensitivity reactions, including anaphylaxis, have been reported in patients treated with enzyme replacement therapies, including STRENSIQ.

…

Anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy. Initiate STRENSIQ under the supervision of a healthcare provider with appropriate medical monitoring and support measures. If a severe hypersensitivity reaction (e.g., anaphylaxis) occurs, discontinue STRENSIQ and immediately initiate appropriate medical treatment, including use of epinephrine.

…

Inform patients of the symptoms of life-threatening hypersensitivity reactions, including anaphylaxis and to seek immediate medical care should symptoms occur.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Hypersensitivity Reactions Including Anaphylaxis

Life-threatening hypersensitivity reactions, including anaphylaxis may occur with STRENSIQ treatment.
Anaphylaxis has occurred during the early course of enzyme replacement therapy and after extended duration of therapy.
Symptoms of life-threatening hypersensitivity reactions, including anaphylaxis and to seek immediate medical care should symptoms occur [see Warnings and Precautions (5.1)].
…

06/12/2020 (SUPPL-18)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Hypersensitivity Reactions

(Additions and/or revisions underlined)

Hypersensitivity reactions, including anaphylaxis, have been reported in STRENSIQ- treated patients. Signs and symptoms consistent with anaphylaxis included difficulty breathing, choking sensation, nausea, periorbital edema, and dizziness. These reactions have occurred within minutes after subcutaneous administration of STRENSIQ and have been observed more than 1 year after treatment initiation. Other hypersensitivity reactions have also been reported in STRENSIQ-treated patients, including vomiting, fever, headache, flushing, irritability, chills, erythema, rash, pruritus and oral hypoesthesia.

5.3 Ectopic Calcifications

(Additions and/or revisions underlined)

Patients with HPP are at increased risk for developing ectopic calcifications. Events of ectopic calcification, including ophthalmic (conjunctival and corneal) and renal (nephrocalcinosis, nephrolithiasis), have been reported in the clinical trial experience with 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.

5.4 Possible Immune-Mediated Clinical Effects

(Newly added subsection)

In clinical trials, most STRENSIQ-treated patients developed anti-asfotase alfa antibodies and neutralizing antibodies which resulted in reduced systemic exposure of asfotase alfa. In postmarketing reports, some STRENSIQ-treated patientswith initial therapeutic response subsequently developed recurrence and worsening in disease-associated laboratory and radiographic biomarkers (some in association with neutralizing antibodies) suggesting possible immune-mediated effects on STRENSIQ’s pharmacologic action resulting in disease progression. The effect of anti-asfotase alfa antibody formation on the long-term efficacy of STRENSIQ is unknown. There are no marketed anti-asfotase alfa antibody tests. If patients experience progression of HPP symptoms or worsening of disease-associated laboratory and imaging biomarkers after a period of initial therapeutic response to STRENSIQ, consider obtaining anti-asfotase alfa antibody testing by contacting STRENSIQ Medical Information at Alexion at 1-888-765-4747 or by email at medinfo@alexion.com. Close clinical follow up is recommended.

6 Adverse Reactions

(Additions and/or revisions underlined)

The following adverse reactions are described below and elsewhere in the labeling:

Hypersensitivity Reactions
Lipodystrophy
Ectopic Calcifications
Possible Immune-Mediated Clinical Effects

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

Less Common Adverse Reactions

Adverse reactions that occurred at rates less than 1% included:

Hypocalcemia
Renal Stones
Chronic hepatitis
Decreased vitamin B6
Long-Term Safety

In long-term extension trials reflecting a median exposure to STRENSIQ of 142 weeks (range 0.1 weeks to 392 weeks) in 112 patients with perinatal/infantile- (n = 89), juvenile- (n = 22), and adult-onset (n = 1) HPP (age at enrolment = 1 day to 66.5 years), the most common adverse reactions were similar to those reported in Table 4.

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of the antibodies in the studies described below with the incidence of antibodies in other studies or to other asfotase alpha products may be misleading.

During clinical trials, anti-asfotase alfa antibodies have been detected in patients receiving treatment with STRENSIQ using an electrochemiluminescent (ECL) immunoassay. Antibody positive samples were tested to determine the presence of neutralizing antibodies based on in vitro inhibition of the catalytic activity of STRENSIQ.

Among STRENSIQ-treated patients with hypophosphatasia (HPP) in clinical studies who had post-baseline antibody data available, 97/109 (89%) tested positive for anti-asfotase alfa antibodies at some time point during STRENSIQ treatment. Among those 97 patients, 55 (57%) also tested positive for neutralizing antibodies at some time point during STRENSIQ treatment. No correlation was observed between the anti-asfotase alfa antibody titers and the neutralizing antibody (% inhibition) values. Formation of anti- asfotase alfa antibody resulted in a reduced systemic exposure of asfotase alfa.

6.3 Postmarketing Experience

(Newly added subsection)

The following adverse reactions have been identified during post-approval use of STRENSIQ. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Some STRENSIQ-treated patients with initial therapeutic response to STRENSIQ subsequently developed worsening in disease-associated laboratory and radiographic biomarkers (some in association with neutralizing antibodies) suggesting possible immune-mediated effects on STRENSIQ’s pharmacologic action resulting in disease progression.

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions underlined)

The safety and effectiveness of STRENSIQ for the treatment of perinatal/infantile- and juvenile-onset HPP have been established in pediatric patients. Use of STRENSIQ for this indication is based on 4 prospective, open-label clinical trials conducted in 89 pediatric patients with perinatal/infantile-onset or juvenile-onset HPP.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise the patient or caregiver to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Advise patients or caregivers of the following:

Preparation

When preparing a volume for injection greater than 1 mL, split the volume equally between two syringes, and administer two injections. When administering the two injections, use two separate injection sites.
Take the unopened STRENSIQ vial(s) out of the refrigerator 15 to 30 minutes before injecting to allow the liquid to reach room temperature.
Inspect the solution in the vial(s) for particulate matter and discoloration.
Assemble injection supplies. Administer STRENSIQ using sterile disposable syringes and injection needles. The syringes should be of small enough volume that the prescribed dose can be withdrawn from the vial with reasonable accuracy. Always use a new syringe and needle.
Remove vial cap, aseptically prepare the vial and insert the syringe into the vial to withdraw the prescribed dose for administration.
Remove any air bubbles in the syringe and verify the correct dose.

STRENSIQ vials are for one time use only. Discard any unused product.

Administration

Administer STRENSIQ within 3 hours upon removal of the vial(s) from refrigeration.
Rotate the injection site to reduce the risk of lipohypertrophy and injection site atrophy.
Do NOT administer injections in areas that are reddened, inflamed, or swollen.

Inject STRENSIQ subcutaneously into the determined site and properly dispose of the syringe and needle.

Hypersensitivity Reactions

Reactions related to administration and injection may occur during and after STRENSIQ treatment. Inform patients and/or caregivers of the signs and symptoms of hypersensitivity reactions and have them seek immediate medical care should signs and symptoms occur.

Lipodystrophy

Lipohypertrophy (enlargement or thickening of tissue) and localized atrophy (depression in the skin) have been reported at injection sites after several months. Follow proper injection technique and rotate injection sites.

Possible Immune-Mediated Clinical Effects

Anti-drug antibodies may develop during treatment which may interfere with STRENSIQ’s pharmacologic action. Inform patients or their caregivers to contact their healthcare provider if they experience worsening symptoms of HPP (e.g., increased respiratory support, increased difficulty walking, new fractures).

01/26/2018 (SUPPL-3)

Approved Drug Label (PDF)

7 Drug Interactions

7.1 Drug Interference with Laboratory Tests

(Newly added subsection)

Laboratory Tests Utilizing Alkaline Phosphatase as a Detection Reagent

Studies have shown that there is analytical interference between asfotase alfa and laboratory tests that utilize an alkaline phosphatase (ALP)-conjugated test system, rendering 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.

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.

Do not rely on serum ALP measurements for clinical decision making in patients treated with STRENSIQ.

10/18/2016 (SUPPL-2)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Hypersensitivity Reactions (addition underlined)

Hypersensitivity reactions, including anaphylaxis, have been reported in STRENSIQ- treated patients. Signs and symptoms consistent with anaphylaxis included difficulty breathing, choking sensation, nausea, periorbital edema, and dizziness. These reactions have occurred within minutes after subcutaneous administration of STRENSIQ and can occur in patients on treatment for more than one year. Other hypersensitivity reactions have also been reported in STRENSIQ-treated patients, including vomiting, fever, headache, flushing, irritability, chills, skin erythema, rash, pruritus and oral hypoesthesia.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Patient Information

STRENSIQ may cause serious side effects, including: (addition underlined)

choking sensation