The recommended dosage and frequency of administration for BOTOX^® should not be exceeded. Risks resulting from administration at higher dosages are not known.

Serious and/or immediate hypersensitivity reactions have been rarely reported. These reactions include anaphylaxis, urticaria, soft tissue edema, and dyspnea. One fatal case of anaphylaxis has been reported in which lidocaine was used as the diluent, and consequently the causal agent cannot be reliably determined. If such a reaction occurs further injection of BOTOX^® should be discontinued and appropriate medical therapy immediately instituted.

Individuals with peripheral motor neuropathic diseases (e.g., amyotrophic lateral sclerosis, or motor neuropathy) or neuromuscular junctional disorders (e.g., myasthenia gravis or Lambert-Eaton syndrome) should only receive BOTOX^® with caution. Patients with neuromuscular disorders may be at increased risk of clinically significant systemic effects including severe dysphagia and respiratory compromise from typical doses of BOTOX^®. Published medical literature has reported rare cases of administration of a botulinum toxin to patients with known or unrecognized neuromuscular disorders where the patients have shown extreme sensitivity to the systemic effects of typical clinical doses. In some of these cases, dysphagia has lasted several months and required placement of a gastric feeding tube.

Dysphagia is a commonly reported adverse event following treatment of cervical dystonia patients with all botulinum toxins. In these patients, there are reports of rare cases of dysphagia severe enough to warrant the insertion of a gastric feeding tube. There are also rare case reports where subsequent to the finding of dysphagia a patient developed aspiration pneumonia and died.

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. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.

The safe and effective use of BOTOX^® depends upon proper storage of the product, selection of the correct dose, and proper reconstitution and administration techniques. Physicians administering BOTOX^® must understand the relevant neuromuscular and/or orbital anatomy of the area involved and any alterations to the anatomy due to prior surgical procedures. An understanding of standard electromyographic techniques is also required for treatment of strabismus and may be useful for the treatment of cervical dystonia.

Caution should be used when BOTOX^® treatment is used in the presence of inflammation at the proposed injection site(s) or when excessive weakness or atrophy is present in the target muscle(s).

Patients with smaller neck muscle mass and patients who require bilateral injections into the sternoclei-domastoid muscle have been reported to be at greater risk for dysphagia. Limiting the dose injected into the sternocleidomastoid muscle may reduce the occurrence of dysphagia. Injections into the levator scapulae may be associated with an increased risk of upper respiratory infection and dysphagia.

Patients should be evaluated for potential causes of secondary hyperhidrosis (e.g. hyperthyroidism) to avoid symptomatic treatment of hyperhidrosis without the diagnosis and/or treatment of the underlying disease. The safety and effectiveness of BOTOX^® for hyperhidrosis in other body areas have not been established. Weakness of hand muscles and blepharoptosis may occur in patients who receive BOTOX^® for palmar hyperhidrosis and facial hyperhidrosis, respectively.

Reduced blinking from BOTOX^® injection of the orbicularis muscle can lead to corneal exposure, persistent epithelial defect and corneal ulceration, especially in patients with VII nerve disorders. One case of corneal perforation in an aphakic eye requiring corneal grafting has occurred because of this effect. Careful testing of corneal sensation in eyes previously operated upon, avoidance of injection into the lower lid area to avoid ectropion, and vigorous treatment of any epithelial defect should be employed. This may require protective drops, ointment, therapeutic soft contact lenses, or closure of the eye by patching or other means.

During the administration of BOTOX^® for the treatment of strabismus, retrobulbar hemorrhages sufficient to compromise retinal circulation have occurred from needle penetrations into the orbit. It is recommended that appropriate instruments to decompress the orbit be accessible. Ocular (globe) penetrations by needles have also occurred. An ophthalmoscope to diagnose this condition should be available. Inducing paralysis in one or more extraocular muscles may produce spatial disorientation, double vision or past pointing. Covering the affected eye may alleviate these symptoms.

Patients or caregivers should be advised to seek immediate medical attention if swallowing, speech or respiratory disorders arise.

Patients with cervical dystonia should be informed of the possibility of experiencing dysphagia, which is typically mild to moderate, but could be severe. Rare consequences of severe dysphagia include aspiration, dyspnea, pneumonia, and the need to reestablish an airway.

As with any treatment with the potential to allow previously sedentary patients to resume activities, the sedentary patient should be cautioned to resume activity gradually following the administration of BOTOX^®.

Pregnancy Category C

When pregnant mice and rats were injected intramuscularly during the period of organogenesis, the developmental NOEL of BOTOX^® was 4 U/kg. Higher doses (8 or 16 U/kg) were associated with reductions in fetal body weights and/or delayed ossification which may be reversible.

In a range finding study in rabbits, daily injection of 0.125 U/kg/day (days 6 to 18 of gestation) and 2 U/kg (days 6 and 13 of gestation) produced severe maternal toxicity, abortions and/or fetal malformations. Higher doses resulted in death of the dams. The rabbit appears to be a very sensitive species to BOTOX^®.

There are no adequate and well-controlled studies of BOTOX^® in pregnant women. Because animal reproductive studies are not always predictive of human response, BOTOX^® should be administered during pregnancy only if the potential benefit justifies the potential risk to the fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risks, including abortion or fetal malformations which have been observed in rabbits.

Long term studies in animals have not been performed to evaluate carcinogenic potential of BOTOX^®.

The reproductive NOELfollowing intramuscular injection of 0, 4, 8, and 16 U/kg was 4 U/kg in male rats and 8 U/kg in female rats. Higher doses were associated with dose-dependent reductions in fertility in male rats (where limb weakness resulted in the inability to mate), and an altered estrous cycle in female rats. There were no adverse effects on the viability of the embryos.

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when BOTOX^® is administered to a nursing woman.

Safety and effectiveness in children below the age of 12 have not been established for blepharospasm or strabismus, or below the age of 16 for cervical dystonia or 18 for hyperhidrosis.

Clinical studies of BOTOX^® did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. There were too few patients over the age of 75 to enable any comparisons. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

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