Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER)
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 (≥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
- In placebo-controlled clinical trials of DYSPORT®, the most common adverse reactions (≥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 (≥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 = 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)
- 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.
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.
USE IN SPECIFIC POPULATIONS
- 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.
- 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).
- 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.
Females and Males of Reproductive Potential
- In rats, DYSPORT produced adverse effects on mating behavior and fertility.
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.
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.
MG has been added; please refer to label.
BOXED WARNING (EDITED)
WARNING: DISTANT SPREAD OF TOXIN EFFECT
- Postmarketing reports indicate that the effects of Dysport and all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. These may include asthenia, generalized muscle weakness, diplopia, blurred vision, ptosis, dysphagia, dysphonia, dysarthria, urinary incontinence and breathing difficulties. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening and there have been reports of death. The risk of symptoms is probably greatest in children treated for spasticity but symptoms can also occur in adults treated for spasticity and other conditions, particularly in those patients who have underlying conditions that would predispose them to these symptoms. In unapproved uses, including spasticity in children, and in approved indications, cases of spread of effect have been reported at doses comparable to or lower than the maximum recommended total dose.
What is the most important information I should know about DYSPORT?
DYSPORT may cause serious side effects that can be life threatening including:
- Problems breathing or swallowing
- Spread of toxin effects
These problems can happen within hours, or days to weeks after an injection of DYSPORT. Call your doctor or .......
Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins and herbal products. Using DYSPORT with certain other medicines may cause serious side effects.
- added..... Do not start any new medicines until you have told your doctor that you have received DYSPORT in the past.