Drug Safety-related Labeling Changes (SrLC)

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DYSPORT (BLA-125274)

(abobotulinumtoxinA)

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

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09/21/2023 (SUPPL-125)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.10 Pre-existing Conditions at the Injection Site

Newly added subsection:

Caution should be exercised when DYSPORT is used where the targeted muscle shows excessive weakness or atrophy.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

• Pre-existing Conditions at the Injection Site [see Warnings and Precautions (5.10)]

 6.3 Postmarketing Experience

Additions and/or revisions underlined:

Because adverse 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.

The following adverse reactions have been identified during post-approval use of DYSPORT: vertigo, photophobia, influenza-like illness, amyotrophy, muscle atrophy, burning sensation, facial paresis, hypoesthesia, erythema, dry eye, and excessive granulation tissue. Hypersensitivity reactions including anaphylaxis have been reported.

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

MEDICATION GUIDE

Additions and/or revisions underlined:

…

What should I tell my doctor before taking DYSPORT?

Tell your doctor about all your medical conditions, including if you:

…

• have weakness in or near your muscles being treated

…

09/25/2019 (SUPPL-115)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(extensive changes to tables; please refer to labeling for complete information)

(additions and/or revisions are underlined)

…

Upper Limb Spasticity in Adults

Table 10 lists the adverse reactions that occurred in greater than or equal to 2% of patients in any DYSPORT dose group and more frequent than placebo in double-blind studies evaluating the treatment of upper limb spasticity in adults. The most common adverse reactions (greater than or equal to 4%) in any DYSPORT dose group was muscular weakness.

…

Upper Limb Spasticity in Pediatric Patients

Table 12 reflects exposure to DYSPORT in 210 patients, 2 to 17 years of age, who were evaluated in a double blind, active-controlled, multicenter study in patients treated for upper limb spasticity. The most commonly observed adverse reactions (greater than or equal to 10% of patients) were: upper respiratory tract infection and pharyngitis.

…

6.2 Immunogenicity

(additions and/or revisions are underlined)

…

Spasticity in Pediatric Patients 2 Years of Age or Older

Upper Limb Spasticity

From 178 subjects treated with DYSPORT for up to 4 treatment cycles and tested for the presence of binding antibodies at baseline and end of study, 7 subjects previously receiving botulinum toxin injections had binding antibodies after treatment.  Among those 7 subjects, 4 subjects (2.3%) developed neutralizing antibodies when tested in the mice bioassay. In the presence of binding and/or neutralizing antibodies to DYSPORT some patients continue to experience clinical benefit.

…

7 Drug Interactions

7.1 Aminoglycosides and Other Agents Interfering with Neuromuscular Transmission

(newly added subsection)

Co-administration of DYSPORT and aminoglycosides or other agents interfering with neuromuscular transmission (e.g., curare-like agents) should only be performed with caution because the effect of the botulinum toxin may be potentiated. If co-administered, observe the patient closely.

7.2 Anticholinergic Drugs

(newly added subsection)

Use of anticholinergic drugs after administration of DYSPORT may potentiate systemic anticholinergic effects such as blurred vision.

7.3 Other Botulinum Neurotoxin Products

(newly added subsection)

The effect of administering botulinum neurotoxin products including DYSPORT, at the same time or within several months of each other is unknown. Excessive weakness may be exacerbated by another administration of botulinum toxin prior to the resolution of the effects of a previously administered botulinum toxin.

7.4 Muscle Relaxants

(newly added subsection)

Excessive weakness may also be exaggerated by administration of a muscle relaxant before or after administration of DYSPORT.

8 Use in Specific Populations

8.1 Pregnancy

(additions and/or revisions are underlined)

Risk Summary

There are no adequate and well-controlled clinical studies with DYSPORT in pregnant women.

DYSPORT should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus.

DYSPORT produced embryo-fetal toxicity in relation to maternal toxicity when given to pregnant rats and rabbits at doses lower than or similar to the maximum recommended human dose (MRHD) of 1000 Units on a body weight (Units/kg) basis.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated populations is unknown.

Data

Animal Data

In a study in which pregnant rats received daily intramuscular injections of DYSPORT (2.2, 6.6, or 22 Units/kg on gestation days 6 through 17 or intermittently 44 Units/kg on gestation days 6 and 12 only) during organogenesis, increased early embryonic death was observed with both schedules at the highest tested doses (22 and 44 Units/kg), which were associated with maternal toxicity. The no- effect dose for embryo-fetal developmental toxicity was 2.2 Units/kg (less than the maximum recommended human dose [MRHD] on a body weight basis).

In a study in which pregnant rabbits received daily intramuscular injections of DYSPORT (0.3, 3.3, or 6.7 Units/kg) on gestation days 6 through 19 or intermittently (13.3 Units/kg on gestation days 6 and 13 only) during organogenesis, no embryofetal data were available at the highest dose administered daily (6.7 Units/kg) because of premature death in all does at that dose. At the lower daily doses or with intermittent dosing, no adverse developmental effects were observed. All doses for which data were available are less than the MRHD on a body weight basis.

In a study in which pregnant rats received 6 weekly intramuscular injections of DYSPORT (4.4, 11.1, 22.2, or 44 Units/kg) beginning on day 6 of gestation and continuing through parturition to weaning, an increase in stillbirths was observed at the highest dose tested, which was maternally toxic. The no-effect dose for pre- and post-natal developmental toxicity was 22.2 Units/kg (similar to the MRHD).

8.4 Pediatric Use

(additions and/or revisions are underlined)

Cervical Dystonia

Safety and effectiveness in pediatric patients have not been established.

Glabellar Lines

DYSPORT is not recommended for use in pediatric patients less than 18 years of age.

Upper Limb Spasticity, Excluding Spasticity Caused by Cerebral Palsy

Safety and effectiveness have been established in pediatric patients 2 years of age and older. The safety and effectiveness of DYSPORT have been established by evidence from adequate and well-controlled studies of DYSPORT in patients 2 years of age and older with upper limb spasticity. A pediatric assessment for DYSPORT demonstrates that DYSPORT is safe and effective in another pediatric population. However, DYSPORT is not approved for such patient population due to marketing exclusivity for another botulinum toxin.

Safety and effectiveness in pediatric patients below the age of 2 years have not been established.

Lower Limb Spasticity in Pediatric Patients

Safety and effectiveness have been established in pediatric patients 2 years of age and older. The safety and effectiveness of DYSPORT have been established by evidence from adequate and well-controlled studies of DYSPORT in patients 2 years of age and older with lower limb spasticity.  The safety and effectiveness of DYSPORT injected into proximal muscles of the lower limb for the treatment of spasticity in pediatric patients has not been established.

Safety and effectiveness in pediatric patients below the age of 2 years have not been established.

Juvenile Animal Data

In a study in which juvenile rats received a single intramuscular injection of DYSPORT (1, 3, or 10 Units/animal) on postnatal day 21, decreased growth and bone length (injected and contralateral limbs), delayed sexual maturation, and decreased fertility were observed at the highest dose tested, which was associated with excessive toxicity during the first week after dosing.

In a study in which juvenile rats received weekly intramuscular injections of DYSPORT (0.1, 0.3, or 1.0 Units/animal) from postnatal day 21 to 13 weeks of age, decreases in bone mineral content in the injected limb, associated with atrophy of injected and adjacent muscles, were observed at the highest dose tested. No adverse effects were observed on neurobehavioral development. However, dose levels were not adjusted for growth of the pups. On a body weight basis, the doses at the end of the dosing period were approximately 15% of those at initiation of dosing. Therefore, the effects of DYSPORT throughout postnatal development were not adequately evaluated.

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

MEDICATION GUIDE

(extensive revisions; please refer to labeling for complete information)

11/05/2018 (SUPPL-112)

Approved Drug Label (PDF)

5 Warnings and Precautions

Newly added subsections:

5.3 Hypersensitivity Reactions

Serious hypersensitivity reactions have been reported with DYSPORT. Hypersensitivity reactions include anaphylaxis, serum sickness, urticaria, soft tissue edema, and dyspnea. If such a serious hypersensitivity reaction occurs, discontinue further injection of DYSPORT and institute appropriate medical therapy immediately.

5.6 Dry Eye with the Treatment of Glabellar Lines

Dry eye has been reported with the use of DYSPORT in the treatment of glabellar lines [see Adverse Reactions (6.2)]. Reduced tear production, reduced blinking, and corneal disorders, may occur with use of botulinum toxins, including DYSPORT.

If symptoms of dry eye (e.g., eye irritation, photophobia, or visual changes) persist, consider referring patient to an ophthalmologist.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

• Hypersensitivity Reactions

• Dry Eye with the Treatment of Glabellar Lines

6.1 Clinical Trials Experience

Following Table 7, additions and/or revisions underlined:

In the clinical trials safety database …

6.2 Postmarketing Experience

Addition of dry eye to the following adverse reactions have been identified during post-approval use of DYSPORT list.

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

PATIENT COUNSELING INFORMATION

Newly added information:

Inform patients that DYSPORT injection may cause eye dryness. Advise patients to report symptoms of eye dryness (e.g., eye pain, eye irritation, photosensitivity, or changes in vision) to their doctor.

06/14/2017 (SUPPL-109)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions are underlined)

DYSPORT is contraindicated in patients with:

• Known hypersensitivity to any botulinum toxin preparation or to any of the components in the formulation. Hypersensitivity reactions have been reported, including anaphylaxis…

5 Warnings and Precautions

5.6 Human Albumin and Transmission of Viral Diseases

(Revised subsection title; Additions and/or revisions are underlined)

This product contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing   processes, it carries an extremely remote risk for transmission of viral diseases and variant Creutzfeldt-Jakob disease (vCJD). There is a theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD), but if that risk actually exists, the risk of transmission would  also be considered extremely remote. No cases of transmission of viral diseases, CJD, or vCJD have ever been identified for licensed albumin or albumin contained in other licensed products.

 

6 Adverse Reactions

(Additions and/or revisions are underlined)

The following serious adverse reactions are discussed below and elsewhere in labeling:

• Human Albumin and Transmission of Viral Diseases

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

Spasticity in Adults

Injection Site Reactions

Injection site reactions (e.g., pain, bruising, haemorrhage, erythema/haematoma etc.) have occurred following administration of DYSPORT in adults treated for spasticity.

 

Less Common Adverse Reactions

…

Lower Limb Spasticity in Adults

The data described below reflect exposure to DYSPORT in 255 adult patient with lower limb spasticity. Of this population, 89% were Caucasian, 66% male, and the median age was 55 years (range 23–77 years). Table 9 lists the adverse reactions that occurred in greater than or equal to 2% of patients in any DYSPORT dose group and more frequent than placebo in the double blind study evaluating the treatment of lower limb spasticity in adults. The most common of these adverse reactions (greater than or equal to 5%) in any DYSPORT dose group were falls, muscular weakness, and pain in extremity.

Table 9: Adverse Reactions Observed in at Least 2% of Patients Treated in the Double-Blind Trial of Adult Patients with Lower Limb Spasticity and Reported More Frequently than with Placebo (Table has been added; please refer to label)

In the efficacy and safety studies of DYSPORT for the treatment of lower limb spasticity in adults, muscular weakness was reported more frequently in women (10%) treated with 1500 units of DYSPORT compared to men (5%). Falls were reported more frequently in patients 65 years of age and over.

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

…

The following adverse reactions have been identified during post-approval use of DYSPORT: vertigo, photophobia, influenza-like illness, amyotrophy, burning sensation, facial paresis, hypoesthesia, erythema, and excessive granulation tissue. Hypersensitivity reactions including anaphylaxis have been reported.

6.3 Immunogenicity

(Additions and/or revisions are underlined)

Spasticity in Adults

…

Lower Limb Spasticity

From 367 subjects treated with DYSPORT and tested for the presence of binding antibodies, 4 subjects were positive at baseline and 2 developed binding antibodies after treatment. No subjects developed neutralizing antibodies. An additional 85 subjects from two separate studies were tested for the presence of neutralizing antibodies only. One subject tested positive for the presence of neutralizing antibodies.

In total, from the 452 subjects treated in with DYSPORT and tested for the presence of neutralizing antibodies, 0.2% developed neutralizing antibodies after treatment.

8 Use in Specific Populations

8.5 Geriatric Use

(Additions and/or revisions are underlined)

Adult Spasticity

Upper Limb Spasticity

Of the total number of subjects in placebo-controlled clinical studies of DYSPORT, 30 percent were aged 65 years and over, while 8 percent were aged 75 years and over…

Lower Limb Spasticity

Of the total number of subjects in placebo controlled clinical studies of DYSPORT, 18% (n = 115) were 65 and over, while 3% (n =20) were 75 and over. Subjects aged 65 years and over who were treated with DYSPORT reported a greater percentage of adverse reactions as compared to younger subjects (46% versus 39%). Fall and asthenia were observed with greater frequency in older subjects, as compared to those younger (10% versus 6% and 4% versus 2%, respectively).

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

MEDICATION GUIDE

(Additions and/or revisions are underlined)

What is DYSPORT?

…

Upper limb spasticity in adults is caused by muscle spasms in the elbow, wrist, and finger muscles. Lower limb spasticity in adults is caused by muscle spasms in the toe and ankle muscles…

Lower limb spasticity in children is caused by muscle spasms in calf muscles…

What are the possible side effects of DYSPORT?

…

The most common side effects of DYSPORT in adults with lower limb spasticity include:

• muscle weakness
• pain in your arms or legs
• fall

12/09/2016 (SUPPL-107)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

Cervical Dystonia

The data described below reflect exposure to DYSPORT® in 446 cervical dystonia patients in 7 studies. Of these, two studies …

07/29/2016 (SUPPL-105)

Approved Drug Label (PDF)

6 Adverse Reactions

The following serious adverse reactions are discussed below and elsewhere in labeling: (additions)

• Distant Spread of Toxin Effect
• Lack of Interchangeability between Botulinum Toxin Products
• Facial Anatomy in the Treatment of Glabellar Lines
• Pre-existing Neuromuscular Disorders
• Human Albumin
• Intradermal Immune Reaction

Clinical Trial Experience

Common Adverse Reactions

• Table 4: Most Common Adverse Reactions ( greater than or equal to 5%) and Greater than Placebo in the Pooled, Double-blind, Placebo-Controlled Phase of Clinical Trials in Patients with Cervical Dystonia replaces Table 1: Most Common TEAEs (>5%) and Greater than Placebo: Double Blind Phase of Clinical Trials (refer to label)
• Table 5: Common Adverse Reactions by Dose in Fixed-dose Study in Patients with Cervical Dystonia replaces Tablet 2: Common TEAEs by Dose in Fixed-dose Study (refer to label)

Less Common Adverse Reactions

Glabellar Lines

• In placebo-controlled clinical trials of DYSPORT®, the most common adverse reactions (greater than or equal to 2%) following injection of DYSPORT® were: addition of nausea, and blood present in urine.
• Table 6: Most Common Adverse Reactions with > 1% Incidence in Pooled, Placebo-Controlled Trials for Glabellar Lines replaces Table 3: Treatment-Emergent Adverse Events with >1% Incidence (refer to label)

Upper Limb Spasticity in Adults (new section)

• Table 7 lists the most frequently reported adverse reactions (greater than or equal to 2%) in any DYSPORT® dose group and more frequent than placebo in double-blind studies evaluating the treatment of upper limb spasticity in adults with DYSPORT®.
• Table 7: Most Common Adverse Reactions Observed in at Least 2% of Patients Treated in Pooled, Double-Blind Trials of Adult Patients with Upper Limb Spasticity Reported More Frequently than with Placebo (new table; please refer to label)

Less Common Adverse Reactions (addition)

• In a pooled analysis of clinical studies, adverse reactions with an incidence of less than 2% reported in DYSPORT® treatment groups included dysphagia 0.5%, gait disturbance 0.5%, hypertonia 0.5%, and sensation of heaviness 0.3%. Injection site reactions (e.g. pain, bruising, haemorrhage, injection site erythema/haematoma etc.) have occurred following administration of DYSPORT®.

Lower Limb Spasticity in Pediatric Patients (addition)

• Table 8 reflects exposure to DYSPORT® in 160 patients, 2 to 17 years of age, who were evaluated in the randomized, placebo controlled clinical study that assessed the use of DYSPORT® for the treatment of unilateral or bilateral lower limb spasticity in pediatric cerebral palsy patients. The most commonly observed adverse reactions (=10% of patients) are: upper respiratory tract infection, nasopharyngitis, influenza, pharyngitis, cough and pyrexia.
• Table 8: Adverse Reactions Observed in greater than or equal to  4% of Patients Treated in the Double-Blind Trial of Pediatric Patients with Lower
• Limb Spasticity and Reported More Frequently than with Placebo (new table; please refer to label)

Immunogenicity

Upper Limb Spasticity

• From 230 subjects treated with DYSPORT® and tested for the presence of binding antibodies, 5 subjects were positive at baseline and 17 developed antibodies after treatment. Among those 17 subjects, 10 subjects developed neutralizing antibodies. An additional 51 subjects from a separate repeat-dose study were tested for the presence of neutralizing antibodies only. None of the subjects tested positive.
• In total, from the 281 subjects treated in the long-term studies and tested for the presence of neutralizing antibodies, 3.6% developed neutralizing antibodies after treatment.
• In the presence of binding and neutralizing antibodies to DYSPORT® some patients continue to experience clinical benefit.

Lower Limb Spasticity in Pediatric Patients

• From 226 subjects treated with DYSPORT® and tested for the presence of binding antibodies, 5 subjects previously receiving botulinum toxins were positive at baseline and 9 patients developed binding antibodies after injections. Among those 9 subjects, 3 subjects developed neutralizing antibodies, while one subject developed neutralizing antibodies from the 5 subjects testing positive for binding antibodies at baseline who previously received botulinum toxin injections.
• From a separate repeat-dose study, 203 subjects were tested for the presence of neutralizing antibodies. Two subjects were positive for neutralizing antibodies at baseline and 5 subjects developed neutralizing antibodies after treatments. In total, from the 429 patients tested for the presence of neutralizing antibodies, 2.1% developed neutralizing antibodies after treatment. In the presence of binding and neutralizing antibodies to DYSPORT®, some patients continued to experience clinical benefit.

Postmarketing Experience

• Because adverse 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.
• The following adverse reactions have been identified during post-approval use of DYSPORT®: addition of hypoesthesia.

8 Use in Specific Populations

Females and Males of Reproductive Potential (PLLR Conversion)

Infertility

• In rats, DYSPORT produced adverse effects on mating behavior and fertility.

Geriatric Use

Upper Limb Spasticity

• Of the total number of subjects in placebo-controlled clinical studies of DYSPORT®, 28.0 percent were aged 65 years and over, while 8.2 percent were aged 75 years and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Lactation (PLLR Conversion)

Risk Summary

• There are no data on the presence of DYSPORT in human or animal milk, the effects on the breastfed child, or the effects on milk production.
• The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for DYSPORT and any potential adverse effects on the breastfed infant from DYSPORT or from the underlying maternal condition.

Pediatric Use

Upper Limb Spasticity

• Safety and effectiveness in pediatric patients have not been established.

Lower Limb Spasticity in Pediatric Patients

• The safety and effectiveness of DYSPORT® injected into proximal muscles of the lower limb for the treatment of spasticity in pediatric patients has not been established.
• Safety and effectiveness in pediatric patients with lower limb spasticity below 2 years of age have not been evaluated.

Juvenile Animal Data

• In a study in which juvenile rats received a single intramuscular injection of DYSPORT (1, 3, or 10 Units/animal) on postnatal day 21, decreased growth and bone length (injected and contralateral limbs), delayed sexual maturation, and decreased fertility were observed at the highest dose tested, which was associated with excessive toxicity during the first week after dosing.
• In a study in which juvenile rats received weekly intramuscular injections of DYSPORT® (0.1, 0.3, or 1.0 Units/animal) from postnatal day 21 to 13 weeks of age, decreases in bone mineral content in the injected limb, associated with atrophy of injected and adjacent muscles, were observed at the highest dose tested. No adverse effects were observed on neurobehavioral development. However, dose levels were not adjusted for growth of the pups. On a body weight basis, the doses at the end of the dosing period were approximately 15% of those at initiation of dosing. Therefore, the effects of Dysport throughout postnatal development were not adequately evaluated.

Pregnancy - PLLR Conversion

Risk Summary

• There are no adequate and well-controlled clinical studies with Dysport in pregnant women. DYSPORT® should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. DYSPORT® produced embryo-fetal toxicity in relation to maternal toxicity when given to pregnant rats and rabbits at doses lower than or similar to the maximum recommended human dose (MRHD) of 1000 Units on a body weight (Units/kg) basis. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated populations is unknown.

Data

• In a study in which pregnant rats received daily intramuscular injections of DYSPORT (2.2, 6.6, or 22 Units/kg on gestation days 6 through 17 or intermittently 44 Units/kg on gestation days 6 and 12 only) during organogenesis, increased early embryonic death was observed with both schedules at the highest tested doses (22 and 44 Units/kg), which were associated with maternal toxicity. The no effect dose for embryo-fetal developmental toxicity was 2.2 Units/kg (less than the maximum recommended human dose [MRHD] on a body weight basis.
• In a study in which pregnant rabbits received daily intramuscular injections of DYSPORT (0.3, 3.3, or 6.7 Units/kg) on gestation days 6 through 19 or intermittently (13.3 Units/kg on gestation days 6 and 13 only) during organogenesis, no embryofetal data were available at the highest dose administered daily (6.7 Units/kg) because of premature death in all does at that dose. At the lower daily doses or with intermittent dosing, no adverse developmental effects were observed. All doses for which data were available are less than the MRHD on a body weight basis.
• In a study in which pregnant rats received 6 weekly intramuscular injections of DYSPORT (4.4, 11.1, 22.2, or 44 Units/kg) beginning on day 6 of gestation and continuing through parturition to weaning, an increase in stillbirths was observed at the highest dose tested, which was maternally toxic. The no-effect dose for pre- and post-natal developmental toxicity was 22.2 Units/kg (similar to the MRHD).

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

MG

Added; please refer to label.