Dose Modification

Where dose modification is necessary for the treatment of cervical dystonia, uncontrolled open-label studies suggest that dose adjustment can be made in 250 Unit steps according to the individual patient's response, with re-treatment every 12 weeks or longer, as necessary, based on return of clinical symptoms. Uncontrolled, open-label studies also suggest that the total dose administered in a single treatment should be between 250 Units and 1000 Units. Re-treatment, if needed, should not occur in intervals of less than 12 weeks. Doses above 1000 Units have not been systematically evaluated.

Injection Technique

Glabellar facial lines arise from the activity of the lateral corrugator and vertical procerus muscles. These can be readily identified by palpating the tensed muscle mass while having the patient frown. The corrugator depresses the skin creating a "furrowed" vertical line surrounded by tensed muscle (i.e., frown lines). The location, size, and use of the muscles vary markedly among individuals. Physicians administering DYSPORT must understand the relevant neuromuscular and/or orbital anatomy of the area involved and any alterations to the anatomy due to prior surgical procedures.

Risk of ptosis can be mitigated by careful examination of the upper lid for separation or weakness of the levator palpebrae muscle (true ptosis), identification of lash ptosis, and evaluation of the range of lid excursion while manually depressing the frontalis to assess compensation.

In order to reduce the complication of ptosis, the following steps should be taken:

• Avoid injection near the levator palpebrae superioris, particularly in patients with larger brow depressor complexes.
• Medial corrugator injections should be placed at least 1 centimeter above the bony supraorbital ridge.
• Ensure the injected volume/dose is accurate and where feasible kept to a minimum.
• Do not inject toxin closer than 1 centimeter above the central eyebrow.

To inject DYSPORT, advance the needle through the skin into the underlying muscle while applying finger pressure on the superior medial orbital rim. Inject patients with a total of 50 Units in five equally divided aliquots. Using an appropriately sized needle, inject 10 Units of DYSPORT into each of five sites, two in each corrugator muscle, and one in the procerus muscle (see Figure 1).

Figure 1

Upper Limb Spasticity

In the clinical trial that assessed the efficacy and safety of DYSPORT for treatment of upper limb spasticity in adults [see Clinical Studies (14.3)], doses of 500 Units and 1000 Units were divided among selected muscles at a given treatment session (see Table 3 and Figure 2).

Figure 2: Muscles for Injection for Upper Limb Spasticity in Adults

Repeat DYSPORT treatment should be administered when the effect of a previous injection has diminished, but no sooner than 12 weeks after the previous injection. A majority of patients in clinical studies were retreated between 12-16 weeks; however some patients had a longer duration of response (i.e., 20 weeks). The degree and pattern of muscle spasticity at the time of re-injection may necessitate alterations in the dose of DYSPORT and muscles to be injected. Clinical improvement may be expected one week after administration of DYSPORT.

Lower Limb Spasticity

In the clinical trial that assessed the efficacy and safety of DYSPORT for treatment of lower limb spasticity in adults [see Clinical Studies (14.3)], doses of 1000 Units and 1500 Units were divided among selected muscles at a given treatment session (see Table 4 and Figure 3).

Figure 3: Muscles for Injection for Lower Limb Spasticity in Adults

Repeat DYSPORT treatment should be administered when the effect of a previous injection has diminished, but no sooner than 12 weeks after the previous injection. A majority of patients in clinical studies were retreated between 12-16 weeks. The degree and pattern of muscle spasticity at the time of re-injection may necessitate alterations in the dose of DYSPORT and muscles to be injected.

Upper Limb Spasticity in Pediatric Patients 2 Years of Age and Older

In the clinical trial that assessed the efficacy and safety of DYSPORT for treatment of upper limb spasticity in pediatric patients 2 years of age or older with a weight of at least 10 kg [see Clinical Studies (14.4)], doses of 8 Units/kg or 16 Units/kg were divided among selected muscles of the target upper limb at a given treatment session (see Table 5 and Figure 4).

Table 5 describes the recommended Units/kg dose of DYSPORT per muscle. The maximum recommended total dose of DYSPORT administered for treatment of upper limb spasticity must not exceed 16 Units/kg or 640 Units, whichever is lower.

Figure 4: Muscles for Injection for Upper Limb Spasticity in Pediatric Patients

Repeat DYSPORT treatment should be administered when the effect of a previous injection has diminished but no sooner than 16 weeks after the previous injection. A majority of patients in the clinical study were retreated between 16-28 weeks; however, some patients had a longer duration of response (i.e., 34 weeks or more). The degree and pattern of muscle spasticity at the time of re-injection may necessitate alterations in the dose of DYSPORT and muscles to be injected.

Lower Limb Spasticity in Pediatric Patients 2 Years of Age and Older In the clinical trial that assessed the efficacy and safety of DYSPORT for treatment of lower limb spasticity in pediatric patients 2 years of age or older [see Clinical Studies (14.4)], doses of 10 Units/kg to 15 Units/kg were divided among selected muscles of the target lower limb at a given treatment session (see Table 6 and Figure 5).

Table 6 describes the recommended Units/kg dose of DYSPORT per muscle of the Gastrocnemius-Soleus Complex (GSC). The recommended total DYSPORT dose per treatment session is 10 Units/kg to 15 Units/kg for unilateral lower limb injections or 20 Units/kg to 30 Units/kg for bilateral lower limb injections. However, the total dose of DYSPORT administered in a 3-month interval must not exceed 15 Units/kg for unilateral lower limb injections, 30 Units/kg for bilateral lower limb injections, or 1000 units, whichever is lower. The total dose administered should be divided between the affected spastic muscles of the lower limb(s). When possible, the dose should be distributed across more than 1 injection site in any single muscle (see Table 6).

Figure 5: Muscles for Injection for Lower Limb Spasticity in Pediatric Patients

Although actual location of the injection sites can be determined by palpation, the use of injection guiding technique (e.g., electromyography or electrical stimulation, or ultrasound) is recommended to target the injection sites.

Repeat DYSPORT treatment should be administered when the effect of a previous injection has diminished but no sooner than 12 weeks after the previous injection. A majority of patients in the clinical studies were retreated between 16-22 weeks, however; some had a longer duration of response. The degree and pattern of muscle spasticity and overall clinical benefit at the time of re-injection may necessitate alterations in the dose of DYSPORT and muscles to be injected.

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.

Cervical Dystonia

The data described below reflect exposure to DYSPORT in 446 cervical dystonia patients in 7 studies. Of these, two studies were randomized, double-blind, single treatment, placebo-controlled studies with subsequent optional open-label treatment in which dose optimization (250 to 1000 Units per treatment) over the course of 5 treatment cycles was allowed [see Clinical Studies (14.1)].

The population was almost entirely Caucasian (99%) with a median age of 51 years (range 18–82 years). Most patients (87%) were less than 65 years of age; 58.4% were women.

Glabellar Lines

In placebo-controlled clinical trials of DYSPORT, the most common adverse reactions (≥2%) following injection of DYSPORT were nasopharyngitis, headache, injection site pain, injection site reaction, upper respiratory tract infection, eyelid edema, eyelid ptosis, sinusitis, nausea, and blood present in urine.

Table 9 reflects exposure to DYSPORT in 398 patients 19 to 75 years of age who were evaluated in the randomized, placebo-controlled clinical studies that assessed the use of DYSPORT for the temporary improvement in the appearance of glabellar lines [see Clinical Studies (14.2)]. Adverse reactions of any cause occurred in 48% of the DYSPORT-treated patients and 33% of the placebo-treated patients.

In the clinical trials safety database, where some patients received up to twelve treatments with DYSPORT, adverse reactions were reported for 57% (1425/2491) of patients. The most frequently reported of these adverse reactions were headache, nasopharyngitis, injection site pain, sinusitis, URI, injection site bruising, and injection site reaction (numbness, discomfort, erythema, tenderness, tingling, itching, stinging, warmth, irritation, tightness, swelling).

Adverse reactions that occurred after repeated injections in 2–3% of the population included bronchitis, influenza, pharyngolaryngeal pain, cough, contact dermatitis, injection site swelling, and injection site discomfort.

The incidence of eyelid ptosis did not increase in the long-term safety studies with multiple re-treatments at intervals ≥ three months. The majority of the reports of eyelid ptosis were mild to moderate in severity and resolved over several weeks [see Dosage and Administration (2.4)].

Spasticity in Adults

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 [see Clinical Studies (14.4)]. The most commonly observed adverse reactions (≥10% of patients) were: upper respiratory tract infection and pharyngitis.

Additional adverse reactions occurring below 3% and considered to be drug related include: myalgia, pain in extremity, fatigue, influenza-like illness, injection site eczema, injection site bruising, injection site rash, injection site pain, and injection site swelling.

Lower Limb Spasticity in Pediatric Patients

Table 13 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 [see Clinical Studies (14.4)]. The most commonly observed adverse reactions (≥10% of patients) were: upper respiratory tract infection, nasopharyngitis, influenza, pharyngitis, cough and pyrexia.

Cervical Dystonia

About 3% of subjects developed antibodies (binding or neutralizing) over time with DYSPORT treatment.

Glabellar Lines

Testing for antibodies to DYSPORT was performed for 1554 subjects who had up to nine cycles of treatment. Two subjects (0.13%) tested positive for binding antibodies at baseline. Three additional subjects tested positive for binding antibodies after receiving DYSPORT treatment. None of the subjects tested positive for neutralizing antibodies.

Spasticity in Adults

Spasticity in Pediatric Patients 2 Years of Age and Older

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 (see Data).

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

Risk Summary

There are no data on the presence of DYSPORT in human or animal milk, the effects on the breastfed infant, 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.

Infertility

In rats, DYSPORT produced adverse effects on mating behavior and fertility [see Nonclinical Toxicology (13.1)].

Cervical Dystonia

Safety and effectiveness in pediatric patients have not been established [see Boxed Warning and Warnings and Precautions (5.2)].

Glabellar Lines

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

Spasticity

Safety and effectiveness have been established in pediatric patients 2 years of age and older [see Warnings and Precautions (5.1), Adverse Reactions (6.1), and Clinical Studies (14.4)]. 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 and 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 [see Boxed Warning, Warnings and Precautions (5.2) and Adverse Reactions (6.1)].

Safety and effectiveness in pediatric patients below the age of 2 years have not been established [see Boxed Warning and Warnings and Precautions (5.2)].

Cervical Dystonia

There were insufficient numbers of patients aged 65 years and over in the clinical studies to determine whether they respond differently than younger patients. In general, elderly patients should be observed to evaluate their tolerability of DYSPORT, due to the greater frequency of concomitant disease and other drug therapy [see Dosage and Administration (2.3)].

Glabellar Lines

Of the total number of subjects in the placebo-controlled clinical studies of DYSPORT, 8 (1%) were 65 years and over. Efficacy was not observed in subjects aged 65 years and over [see Clinical Studies (14.2)]. For the entire safety database of geriatric subjects, although there was no increase in the incidence of eyelid ptosis, geriatric subjects did have an increase in the number of ocular adverse reactions compared to younger subjects (11% vs. 5%) [see Dosage and Administration (2.4)].

Adult Spasticity

Carcinogenesis

Studies to evaluate the carcinogenic potential of DYSPORT have not been conducted.

Mutagenesis

Genotoxicity studies have not been conducted for DYSPORT.

Impairment of Fertility

In a fertility and early embryonic development study in rats in which either males (2.9, 7.2, 14.5 or 29 Units/kg) or females (7.4, 19.7, 39.4 or 78.8 Units/kg) received weekly intramuscular injections prior to and after mating, dose-related increases in pre-implantation loss and reduced numbers of corpora lutea were noted in treated females. Failure to mate was observed in males that received the high dose. The no-effect dose for effects on fertility was 7.4 Units/kg in females and 14.5 Units/kg in males (approximately one-half and equal to, respectively, the maximum recommended human dose of 1000 Units on a body weight basis).

Study GL-1

Study GL-1 was a single-dose, double-blind, multicenter, randomized, placebo-controlled study in which 158 previously untreated subjects received either placebo or 50 Units of DYSPORT, administered in five aliquots of 10 Units (see Figure 1). Subjects were followed for 180 days. The mean age was 43 years; most of the subjects were women (85%), and predominantly Caucasian (49%) or Hispanic (47%). At Day 30, 55% of DYSPORT-treated subjects achieved treatment success: a composite 2 grade improvement of glabellar line severity at maximum frown (see Table 16).

In study GL-1, the reduction of glabellar line severity at maximum frown was greater at Day 30 in the DYSPORT group compared to the placebo group as assessed by both Investigators and subjects (see Table 17).

Study GL-2

Study GL-2 was a repeat-dose, double-blind, multicenter, placebo-controlled, randomized study. The study was initiated with two or three open-label treatment cycles of 50 Units of DYSPORT administered in five aliquots of 10 Units DYSPORT (see Figure 1). After the open-label treatments, subjects were randomized to receive either placebo or 50 Units of DYSPORT. Subjects could have received up to four treatments through the course of the study. Efficacy was assessed in the final randomized treatment cycle. The study enrolled 311 subjects into the first treatment cycle and 142 subjects were randomized into the final treatment cycle. Overall, the mean age was 47 years; most of the subjects were women (86%) and predominantly Caucasian (80%).

At Day 30, 52% of DYSPORT-treated subjects achieved treatment success: a composite 2 grade improvement of glabellar line severity at maximum frown (see Table 16).

The proportion of responders in the final treatment cycle was comparable to the proportion of responders in all prior treatment cycles.

After the final repeat treatment with DYSPORT, the reduction of glabellar line severity at maximum frown was greater at Day 30 in the DYSPORT group compared to the placebo group as assessed by both Investigators and subjects (see Table 18).

Study GL-3

Study GL-3 was a single-dose, double-blind, multicenter, randomized, placebo-controlled study in which 300 previously untreated subjects received either placebo or 50 Units of DYSPORT, administered in five aliquots of 10 Units (see Figure 1). Subjects were followed for 150 days. The mean age was 44 years; most of the subjects were women (87%), and predominantly Caucasian (75%) or Hispanic (18%).

At Day 30, 60% of DYSPORT-treated subjects achieved treatment success: a composite 2 grade improvement of glabellar line severity at maximum frown (see Table 16).

In study GL-3, the reduction of glabellar line severity at maximum frown was greater at Day 30 in the DYSPORT group compared to the placebo group as assessed by both Investigators and subjects (see Table 19).

Geriatric Subjects

In GL1, GL2, and GL3, there were 8 subjects aged 65 and older who were randomized to DYSPORT 50 Units in 5 equal aliquots of 10 Units (4) or placebo (4). None of the geriatric DYSPORT subjects were a treatment success at maximum frown at Day 30.

Upper Limb Spasticity

The efficacy and safety of DYSPORT for the treatment of upper limb spasticity in adults was evaluated in a randomized, multicenter, double-blind, placebo-controlled study that included 238 patients (159 DYSPORT and 79 placebo) with upper limb spasticity (Modified Ashworth Scale (MAS) score ≥2 in the primary targeted muscle group for toxin-naive patients or MAS score ≥3 in the primary targeted muscle group for toxin non-naive patients at least 4 months after the last botulinum toxin injection, of any serotype) who were at least 6 months post-stroke or post-traumatic brain injury. The median age of the patients in this study was 55 years (range 18 to 78 years), 64% were male, and 86% were Caucasian.

DYSPORT 500 Units (N=80), DYSPORT 1000 Units (N=79), or placebo (N=79) was injected intramuscularly into the affected upper limb muscles. After injection of the primary targeted muscle groups (PTMG), the remainder of the dose was injected into at least two additional upper limb muscles determined by the patient's individual presentation. Table 20 provides the mean and range of DYSPORT doses injected and the number of injections into specific muscles of the upper limb.

The co-primary efficacy variables were muscle tone assessed by the MAS at the primary targeted muscle group at Week 4 and the Physician Global Assessment (PGA; ranges from –4 = markedly worse to +4= markedly improved) at Week 4 (see Table 21).

Lower Limb Spasticity

The efficacy of DYSPORT for the treatment of lower limb spasticity was evaluated in a randomized, multicenter, double-blind, placebo-controlled study that included 381 patients (253 DYSPORT and 128 placebo). Patients had lower limb spasticity (Modified Ashworth Scale (MAS) score ≥2 in the affected ankle joint for toxin-naive patients, or MAS score ≥3 in the affected ankle joint for toxin non-naive patients) and were at least 6 months post-stroke or post-traumatic brain injury.

Table 22 provides the median DYSPORT doses injected and the number of injections into specific muscles of the lower limb as reported in the double-blind study. In the study, the gastrocnemius and soleus muscles, and at least one additional lower limb muscle were injected, according to the clinical presentation.

The primary efficacy variable was muscle tone assessed by the MAS at the ankle joint at Week 4. The first secondary endpoint was the Physician Global Assessment at Week 4 (see Table 23).

Upper Limb Spasticity in Pediatric Patients

The efficacy of DYSPORT for the treatment of upper limb spasticity in pediatric patients 2 to 17 years of age was evaluated in a double-blind, low-dose controlled, multicenter study (NCT02106351). A total of 208 patients with spasticity because of cerebral palsy who were toxin naive or non-naive (66% had prior treatment with a botulinum toxin), weighed at least 10 kgs, and had a baseline Modified Ashworth Score (MAS) of grade 2 or greater (99% patients) at the primary targeted muscle groups (PTMG) were enrolled in the modified Intention to Treat population (mITT). Patients received DYSPORT 16 Units/kg (n=70), DYSPORT 8 Units/kg (n=69), or DYSPORT 2 Units/kg (n=69) injected into the upper limb. The elbow flexors and wrist flexors respectively were the PTMG in 57% and in 43% of patients. The median age of the patients in this study was 9 years (range 2 to 17 years; 57% were between 2 and 9 years of age); 60% of patients were male, and 75% were White.

The primary efficacy endpoint was the mean change from baseline in MAS in the PTMG at Week 6 (see Table 24). The secondary efficacy endpoint was the mean Physician Global Assessment (PGA) score assessed at Week 6 (Table 25). Although PGA scores numerically favored DYSPORT treatment over the low-dose control, the difference was not statistically significant.

Lower Limb Spasticity in Pediatric Patients

The efficacy of DYSPORT for the treatment of lower limb spasticity in patients 2 to 17 years of age was evaluated in a double-blind, placebo-controlled, multicenter study . A total of 235 patients with cerebral palsy causing dynamic equinus foot deformity who were toxin-naive or non-naive and had a Modified Ashworth Score (MAS) of grade 2 or greater at the ankle plantar flexors were enrolled. Patients received DYSPORT 10 Units/kg/leg (n=79), DYSPORT 15 Units/kg/leg (n=79) or placebo (n=77) injected into the gastrocnemius and soleus muscles (see Table 27). Forty-one percent of patients (n=66) were treated bilaterally and received a total lower limb DYSPORT dose of either 20 Units/kg (n=37) or 30 Units/kg (n=29). The median age of the patients in this study was 5 years (range 2 to 17 years); 60% of patients were male, and 73% were Caucasian.

The primary efficacy endpoint was the mean change from baseline in MAS in ankle plantar flexor at Week 4; a co-primary endpoint was the mean Physician's Global Assessment (PGA) score at Week 4 (see Table 26).

Cervical Dystonia, Spasticity in Adults and Pediatric Patients

500 Unit Vial

Each vial contains 500 Units of freeze-dried abobotulinumtoxinA.
Box containing 1 vial—NDC 15054-0500-1
Box containing 2 vials—NDC 15054-0500-2

300 Unit Vial

Each vial contains 300 Units of freeze-dried abobotulinumtoxinA.
Box containing 1 vial—NDC 15054-0530-6

Glabellar Lines

Each vial contains 300 Units of freeze-dried abobotulinumtoxinA.
Box containing 1 vial— NDC 0299-5962-30