BOTOX® (onabotulinumtoxinA) for injection

BOTOX® (onabotulinumtoxinA) for injection

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BOTOX® (onabotulinumtoxinA) for injection

OnabotulinumtoxinA is a sterile, vacuum-dried purified botulinum toxin type A, produced from fermentation of Hall strain Clostridium botulinum type A, and intended for intramuscular, intradetrusor and intradermal use. It is purified from the culture solution by dialysis and a series of acid precipitations to a complex consisting of the neurotoxin, and several accessory proteins. The complex is dissolved in sterile sodium chloride solution containing Albumin Human and is sterile filtered (0.2 microns) prior to filling and vacuum-drying.

The primary release procedure for BOTOX uses a cell-based potency assay to determine the potency relative to a reference standard. The assay is specific to Allergan’s products BOTOX and BOTOX Cosmetic. One Unit of BOTOX corresponds to the calculated median intraperitoneal lethal dose (LD50) in mice. Due to specific details of this assay such as the vehicle, dilution scheme, and laboratory protocols, Units of biological activity of BOTOX cannot be compared to nor converted into Units of any other botulinum toxin or any toxin assessed with any other specific assay method. The specific activity of BOTOX is approximately 20 Units/nanogram of neurotoxin protein complex.

Each vial of BOTOX (onabotulinumtoxinA) for injection contains either 50 Units of Clostridium botulinum type A neurotoxin complex, 0.25 mg of Albumin Human, and 0.45 mg of sodium chloride; 100 Units of Clostridium botulinum type A neurotoxin complex, 0.5 mg of Albumin Human, and 0.9 mg of sodium chloride; or 200 Units of Clostridium botulinum type A neurotoxin complex, 1 mg of Albumin Human, and 1.8 mg of sodium chloride in a sterile, vacuum-dried form without a preservative.

Indications and usage

BOTOX is an acetylcholine release inhibitor and a neuromuscular blocking agent indicated for:

  • Treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and frequency, in adults who have an inadequate response to or are intolerant of an anticholinergic medication
  • Treatment of urinary incontinence due to detrusor overactivity associated with a neurologic condition [e.g., spinal cord injury (SCI), multiple sclerosis (MS)] in adults who have an inadequate response to or are intolerant of an anticholinergic medication
  • Treatment of neurogenic detrusor overactivity (NDO) in pediatric patients 5 years of age and older who have an inadequate response to or are intolerant of anticholinergic medication.
  • Prophylaxis of headaches in adult patients with chronic migraine (≥15 days per month with headache lasting 4 hours a day or longer)
  • Treatment of spasticity in patients 2 years of age and older
  • Treatment of cervical dystonia in adult patients, to reduce the severity of abnormal head position and neck pain
  • Treatment of severe axillary hyperhidrosis that is inadequately managed by topical agents in adult patients
  • Treatment of blepharospasm associated with dystonia in patients 12 years of age and older
  • Treatment of strabismus in patients 12 years of age and older

Limitations of Use

Safety and effectiveness of BOTOX have not been established for:

  • Prophylaxis of episodic migraine (14 headache days or fewer per month)
  • Treatment of hyperhidrosis in body areas other than axillary

Mechanism of Action

BOTOX blocks neuromuscular transmission by binding to acceptor sites on motor or autonomic nerve terminals, entering the nerve terminals, and inhibiting the release of acetylcholine. This inhibition occurs as the neurotoxin cleaves SNAP-25, a protein integral to the successful docking and release of acetylcholine from vesicles situated within nerve endings. When injected intramuscularly at therapeutic doses, BOTOX produces partial chemical denervation of the muscle resulting in a localized reduction in muscle activity. In addition, the muscle may atrophy, axonal sprouting may occur, and extrajunctional acetylcholine receptors may develop. There is evidence that reinnervation of the muscle may occur, thus slowly reversing muscle denervation produced by BOTOX.

When injected intradermally, BOTOX produces temporary chemical denervation of the sweat gland resulting in local reduction in sweating.

Following intradetrusor injection, BOTOX affects the efferent pathways of detrusor activity via inhibition of acetylcholine release.

Dosage and administration

Follow indication-specific dosage and administration recommendations. In a 3 month interval, do not exceed a total dose of:

  • Adults: 400 Units
  • Pediatrics: the lesser of 10 Units/kg or 340 Units

Overactive Bladder: Recommended total dose 100 Units, as 0.5 mL (5 Units) injections across 20 sites into the detrusor

Adult Detrusor Overactivity associated with a Neurologic Condition: Recommended total dose 200 Units, as 1 mL (~6.7 Units) injections across 30 sites into the detrusor

Pediatric Detrusor Overactivity associated with a Neurologic Condition: 0.5 mL injections across 20 sites into the detrusor

  • Greater than or equal to 34 kg: Recommended total dose is 200 Units
  • Less than 34 kg: Recommended total dose is 6 Units/kg

Chronic Migraine: Recommended total dose 155 Units, as 0.1 mL (5 Units) injections per each site divided across 7 head/neck muscles

Adult Upper Limb Spasticity: Recommended total dose up to 400 Units divided among affected muscles.

Adult Lower Limb Spasticity: Recommended total dose 300 Units to 400 Units divided across ankle and toe muscles

Pediatric Upper Limb Spasticity: Recommended total dose 3 Units/kg to 6 Units/kg (maximum 200 Units) divided among affected muscles

Pediatric Lower Limb Spasticity: Recommended total dose 4 Units/kg to 8 Units/kg (maximum 300 Units) divided among affected muscles

Cervical Dystonia: Base dosing on the patient’s head and neck position, localization of pain, muscle hypertrophy, patient response, and adverse event history; use lower initial dose in botulinum toxin naïve patients

Axillary Hyperhidrosis: 50 Units per axilla

Blepharospasm: 1.25 Units-2.5 Units into each of 3 sites per affected eye

Strabismus: The dose is based on prism diopter correction or previous response to treatment with BOTOX

Contraindications

  • Hypersensitivity to any botulinum toxin preparation or to any of the components in the formulation
  • Infection at the proposed injection site
  • Intradetrusor Injections: Urinary tract infection or urinary retention

Warnings and adverse reactions

Spread of Toxin Effect: Postmarketing safety data from BOTOX and other approved botulinum toxins suggest that botulinum toxin effects may, in some cases, be observed beyond the site of local injection. The symptoms are consistent with the mechanism of action of botulinum toxin and may include asthenia, generalized muscle weakness, diplopia, 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 related to spread of toxin effects. 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, and particularly in those patients who have an underlying condition that would predispose them to these symptoms. In unapproved uses and in approved indications, symptoms consistent with spread of toxin effect have been reported at doses comparable to or lower than doses used to treat cervical dystonia and spasticity. Patients or caregivers should be advised to seek immediate medical care if swallowing, speech or respiratory disorders occur.

Lack of Interchangeability between Botulinum Toxin Products: The potency Units of BOTOX are specific to the preparation and assay method utilized. They are not interchangeable with other preparations of botulinum toxin products and, therefore, units of biological activity of BOTOX cannot be compared to nor converted into units of any other botulinum toxin products assessed with any other specific assay method.

Serious Adverse Reactions with Unapproved Use: Serious adverse reactions, including excessive weakness, dysphagia, and aspiration pneumonia, with some adverse reactions associated with fatal outcomes, have been reported in patients who received BOTOX injections for unapproved uses. In these cases, the adverse reactions were not necessarily related to distant spread of toxin, but may have resulted from the administration of BOTOX to the site of injection and/or adjacent structures.

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Hypersensitivity Reactions: Serious and/or immediate hypersensitivity reactions have been reported. These reactions include anaphylaxis, serum sickness, urticaria, soft tissue edema, and dyspnea. If such a reaction occurs, further injection of BOTOX should be discontinued and appropriate medical therapy immediately instituted. 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.

Increased Risk of Clinically Significant Effects with Pre-Existing Neuromuscular Disorders: Individuals with peripheral motor neuropathic diseases, amyotrophic lateral sclerosis or neuromuscular junction disorders (e.g., myasthenia gravis or Lambert-Eaton syndrome) should be monitored when given botulinum toxin. Patients with known or unrecognized neuromuscular disorders or neuromuscular junction disorders may be at increased risk of clinically significant effects including generalized muscle weakness, diplopia, ptosis, dysphonia, dysarthria, severe dysphagia and respiratory compromise from therapeutic doses of BOTOX

Dysphagia and Breathing Difficulties: Treatment with BOTOX and other botulinum toxin products can result in swallowing or breathing difficulties. Patients with preexisting swallowing or breathing difficulties may be more susceptible to these complications. In most cases, this is a consequence of weakening of muscles in the area of injection that are involved in breathing or oropharyngeal muscles that control swallowing or breathing

Corneal Exposure and Ulceration in Patients Treated with BOTOX for Blepharospasm: 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. 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.

Retrobulbar Hemorrhages in Patients Treated with BOTOX for Strabismus: During the administration of BOTOX for the treatment of strabismus, retrobulbar hemorrhages sufficient to compromise retinal circulation have occurred. It is recommended that appropriate instruments to decompress the orbit be accessible.

Urinary Tract Infections in Patients with Overactive Bladder: BOTOX increases the incidence of urinary tract infection. Clinical trials for overactive bladder excluded patients with more than 2 UTIs in the past 6 months and those taking antibiotics chronically due to recurrent UTIs. Use of BOTOX for the treatment of overactive bladder in such patients and in patients with multiple recurrent UTIs during treatment should only be considered when the benefit is likely to outweigh the potential risk.

Urinary Retention in Adults Treated for Bladder Dysfunction: Due to the risk of urinary retention, treat only patients who are willing and able to initiate catheterization post-treatment, if required, for urinary retention.

Adverse reactions

The most common adverse reactions (≥5% and >placebo, if applicable) are

  • OAB: urinary tract infection, dysuria, urinary retention
  • Adult Detrusor Overactivity associated with a neurologic condition: urinary tract infection, urinary retention
  • Pediatric Detrusor Overactivity associated with a neurologic condition: urinary tract infection, leukocyturia, bacteriuria
  • Chronic Migraine: neck pain, headache
  • Adult Spasticity: pain in extremity
  • Pediatric Spasticity: upper respiratory tract infection
  • Cervical Dystonia: dysphagia, upper respiratory infection, neck pain, headache, increased cough, flu syndrome, back pain, rhinitis
  • Axillary Hyperhidrosis: injection site pain and hemorrhage, non-axillary sweating, pharyngitis, flu syndrome

Drug interactions

Aminoglycosides and Other Agents Interfering with Neuromuscular Transmission: Co-administration of BOTOX and aminoglycosides or other agents interfering with neuromuscular transmission (e.g., curare-like compounds) should only be performed with caution as the effect of the toxin may be potentiated.

Anticholinergic Drugs: Use of anticholinergic drugs after administration of BOTOX may potentiate systemic anticholinergic effects.

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

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

Use in specific populations

Pregnancy: There are no studies or adequate data from postmarketing surveillance on the developmental risk associated with use of BOTOX in pregnant women. In animal studies, administration of BOTOX during pregnancy resulted in adverse effects on fetal growth (decreased fetal weight and skeletal ossification) at clinically relevant doses, which were associated with maternal toxicity

Lactation: There are no data on the presence of BOTOX 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 BOTOX and any potential adverse effects on the breastfed infant from BOTOX or from the underlying maternal conditions.

Pediatric Use

  • Overactive Bladder: Safety and effectiveness in patients below the age of 18 years have not been established.
  • Detrusor Overactivity associated with a Neurologic Condition: The safety and effectiveness of BOTOX for detrusor overactivity associated with a neurologic condition have been established in pediatric patients 5 years of age and older who have an inadequate response to or are intolerant of anticholinergic medication.
  • Prophylaxis of Headaches in Chronic Migraine: Safety and effectiveness in patients below the age of 18 years have not been established.
  • Spasticity: Safety and effectiveness have been established in pediatric patients 2 to 17 years of age
  • Axillary Hyperhidrosis: Safety and effectiveness in patients below the age of 18 years have not been established.
  • Cervical Dystonia: Safety and effectiveness in pediatric patients below the age of 16 years have not been established.
  • Blepharospasm and Strabismus: Safety and effectiveness in pediatric patients below the age of 12 years have not been established.
Overdosage

Excessive doses of BOTOX (onabotulinumtoxinA) for injection may be expected to produce neuromuscular weakness with a variety of symptoms.

Symptoms of overdose are likely not to be present immediately following injection. Should accidental injection or oral ingestion occur or overdose be suspected, the person should be medically supervised for several weeks for signs and symptoms of systemic muscular weakness which could be local, or distant from the site of injection. These patients should be considered for further medical evaluation and appropriate medical therapy immediately instituted, which may include hospitalization.

If the musculature of the oropharynx and esophagus are affected, aspiration may occur which may lead to development of aspiration pneumonia. If the respiratory muscles become paralyzed or sufficiently weakened, intubation and assisted respiration may be necessary until recovery takes place. Supportive care could involve the need for a tracheostomy and/or prolonged mechanical ventilation, in addition to other general supportive care.

In the event of overdose, antitoxin raised against botulinum toxin is available from the Centers for Disease Control and Prevention (CDC) in Atlanta, GA. However, the antitoxin will not reverse any botulinum toxin-induced effects already apparent by the time of antitoxin administration. In the event of suspected or actual cases of botulinum toxin poisoning, please contact your local or state Health Department to process a request for antitoxin through the CDC. If you do not receive a response within 30 minutes, please contact the CDC directly at 1-770-488-7100. More information can be obtained at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5232a8.htm.

Storage and Handling

Unopened vials of BOTOX should be stored in a refrigerator between 2° to 8°C (36º to 46ºF) for up to 36 months. Do not use after the expiration date on the vial. Reconstituted BOTOX may be stored in a refrigerator (2° to 8°C) for up to 24 hours until time of use

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