Botox Cosmetic (onabotulinumtoxinA)

Dosage of onabotulinumtoxinA should be carefully individualized according to patient response and to the particular condition being treated. When initiating treatment, the lowest recommended dose should be used. Generally, the effective dose when injecting into muscle depends on muscle mass: the larger the muscle, the higher the required dose. However, optimal dosages for a number of conditions in which onabotulinumtoxinA has been used have not been established. If a patient treated with onabotulinumtoxinA fails to respond, clinicians should consider the possibility of an inadequate drug dose, incorrectly reconstituted and/or improperly stored drug solution, and/or misinjection.

The manufacturer states that the maximum cumulative dose of onabotulinumtoxinA (given as Botox(R) and/or Botox(R) Cosmetic) for one or more uses in adults should not exceed 400 units in a 3-month period.

Some clinicians suggest that the interval between onabotulinumtoxinA injections should be as long as 8-12 weeks in patients receiving the drug for noncosmetic indications. In addition, some evidence suggests that the possibility of antibody formation increases with higher doses (exceeding 300 units total dose) and more frequent administration of onabotulinumtoxinA. (See Cautions: Antibody Formation.) However, in the management of hyperkinetic facial lines, some clinicians administer repeat injections of onabotulinumtoxinA 2 weeks after the initial injection if desired results have not been achieved, stating that strict adherence to the manufacturer recommended minimum injection interval of 12 weeks does not appear to be critical with the low doses of onabotulinumtoxinA used for cosmesis (usually less than 100 units total dose).

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There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Neuromuscular Blocking Agents/General Anesthetics (Inhl)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: General anesthetics enhance the pharmacologic effects of nondepolarizing muscle relaxants.

CLINICAL EFFECTS: May see an increase in the neuromuscular blocking effects of the nondepolarizing muscle relaxant including respiratory depression, bradycardia, hypotension, flushing, or muscle weakness.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: It may be necessary to decrease the dose of the nondepolarizing muscle relaxant. Monitor neuromuscular function and adjust the dose of the nondepolarizing muscle relaxant accordingly.

DISCUSSION: Concomitant administration of general anesthetics and nondepolarizing muscle relaxants has been shown to produce synergistic neuromuscular blocking effects of nondepolarizing muscle relaxants.

Neuromuscular Blocking Agents/Misc Antibiotics

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Aminoglycosides, bacitracin, clindamycin, lincomycin, and polymyxins may enhance the pharmacologic effects of neuromuscular blocking agents.

CLINICAL EFFECTS: May see an increase in the pharmacologic effects of neuromuscular blocking agents, including prolonged respiratory depression and apnea.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If it is necessary to administer these drugs concurrently, do so with extreme caution. Monitor neuromuscular function and adjust the dose of the neuromuscular blocking agent accordingly.

DISCUSSION: Concomitant administration of aminoglycosides, bacitracin, clindamycin, lincomycin, and polymixins with neuromuscular blocking agents has been shown to produce synergism of the effects on skeletal muscles. Concurrent administration of these drugs has been associated with prolonged respiratory depression, respiratory paralysis, and fatal apnea. The interaction usually occurs when the antibiotic is given prior to or concurrently with the neuromuscular blocking drug, but it may also occur when given after administration. Any antibiotic dosage or route of administration may produce respiratory depression.

Neuromuscular Blocking Agents/Quinine Derivatives

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Synergistic or additive pharmacologic activity.

CLINICAL EFFECTS: May see an increase in the neuromuscular blocking effects, including profound sedation, respiratory depression, coma, and/or death.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concurrent administration of neuromuscular blocking agents and quinine derivatives during the first several hours of postoperative period. If administered, respiratory support may be needed. If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.

DISCUSSION: Administration of quinidine during the immediate postoperative period has been associated with respiratory paralysis and apnea.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Neuromuscular Blocking Agents/Lincosamides

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Lincosamides appear to augment the neuromuscular blocking effects of nondepolarizing muscle relaxants.

CLINICAL EFFECTS: The effects of nondepolarizing neuromuscular relaxants may be prolonged leading to profound sedation, respiratory depression, coma, and/or death.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor respiratory function of the patient and provide the necessary support. In patients who have received nondepolarizing muscle relaxants, avoid use of lincosamides in the recovery room. If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.

DISCUSSION: Lincomycin has been reported to augment the neuromuscular blocking effect of pancuronium in seven anesthetized patients. The effect was readily antagonized by neostigmine administration. In a case report, clindamycin produced prolonged neuromuscular blockade in a patient who had received pancuronium. Neostigmine was ineffective in antagonizing the blockade.

Neuromuscular Blocking Agents/Polypeptide Antibiotics

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Synergistic pharmacologic activity. Polymyxin B affects neuromuscular transmission by blocking acetylcholine receptors. Its action is thus post-synaptic and the neuromuscular block has no antagonists. Polymyxin B causes neostigmine resistance to d-tubocurarine blockade and calcium resistance to the blockade evoked by aminoglycoside antibiotics (1,2,3,4). A pre-synaptic mechanism may also be involved with decreased release of acetylcholine.

CLINICAL EFFECTS: May see an increase in the neuromuscular blocking effects, including profound sedation, respiratory depression, coma, and/or death.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If it is necessary to administer these drugs concurrently, do so with extreme caution. Monitor neuromuscular function and adjust the dose of the neuromuscular blocking agent accordingly. If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.

DISCUSSION: Concomitant administration of polypeptide antibiotics and neuromuscular blocking agents has been shown to produce synergism of the effects on skeletal muscles. Concurrent administration of these drugs has been associated with prolonged respiratory depression, respiratory paralysis, and apnea. This interaction has been documented with colistimethate, polymyxin B, bacitracin, and vancomycin.

Neuromuscular Blocking Agents/Trimethaphan

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Additive pharmacologic effects.

CLINICAL EFFECTS: May see an increase in the neuromuscular blocking effects, including profound sedation, respiratory depression, coma, and/or death.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If it is necessary to administer these drugs concurrently, do so with extreme caution. Monitor neuromuscular function and adjust the dose of the neuromuscular blocking agent accordingly. If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.

DISCUSSION: Available data indicate that the neuromuscular blocking effects of tubocurarine and trimethaphan may be additive.

Select Neuromuscular Blocking Agents/Hydantoins

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: It has been suggested that phenytoin increases end-plate anticholinesterase activity, resulting in higher acetylcholine concentration at the neuromuscular junction.(1)

CLINICAL EFFECTS: A higher plasma concentration of the neuromuscular blocking agent was required to effect a given level of neuromuscular blockade in patients receiving phenytoin.(2,3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving hydantoin anticonvulsants should be monitored for a decreased response to the neuromuscular blocking agent. The dose of the neuromuscular blocking agent may need to be increased and/or given more frequently.(9)

DISCUSSION: In a study, patients receiving phenytoin were administered metocurine, attained 83% of maximum neuromuscular blockade compared with 98% in the control group.(1) In another study, patients maintained on phenytoin for more than one week had a significantly higher pancuronium requirement than those patients not receiving phenytoin.(1) In two separate case reports, patients maintained on phenytoin demonstrated a resistance to pancuronium and a decreased duration of neuromuscular blockade.(3,4) In a study, patients maintained on phenytoin and receiving vecuronium had a significantly shorter total duration and effect of neuromuscular blockade compared to those patients not receiving phenytoin.(5) In contrast, neither the effect nor duration of atracurium's neuromuscular blockade was affected by phenytoin.(5) Two in vitro studies showed that the neuromuscular blockade of curare and tubocurarine was potentiated by the use of phenytoin.(6,7) Ten children received a bolus dose of vecuronium 0.15mg/Kg while on phenytoin and showed a significantly increased clearance of vecuronium compared to the control group, 15.1 and 9.0 ml/Kg/min, respectively.(8) In a case report, a 58 year-old male previously stabilized on phenytoin (400 mg daily) was given an injection of vecuronium (8 mg) to induce muscle blockade during bowel surgery. While monitoring the effectiveness of vecuronium only 75% twitch height blockade was noted after seven minutes. The medication, due to its short duration and impaired effectiveness, had to be given more frequently throughout the surgery in order to maintain adequate muscle block.(9) A separate case report records a decreased response to pancuronium in a 15 year-old male, previously stabilized on phenytoin (350 mg daily), while undergoing surgery to remove a parietal tumor. Pancuronium (0.7 mg/kg) was given as a relaxant during the surgery and monitored using the train-of-four method. Intermittent doses of pancuronium (0.17 mg/kg) were given for the first hour of surgery without successful blockade apparent by the return of all four twitches within ten minutes of each dose. A second attempt at muscular blockade was made with continuous infusion atracurium (0.26-0.55 mg/kg/hour) for the duration of the surgery. Only 16 minutes after stopping the infusion, all four twitches were visible.(10)

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There are no contraindication contraindications for this drug.

• Amyotrophic lateral sclerosis
• Aspiration pneumonia
• Blepharoptosis
• Blurred vision
• Botulism
• Diplopia
• Dysarthria
• Dysphagia
• Dyspnea
• Eaton-lambert syndrome
• Myasthenia gravis
• Peripheral motor neuropathy
• Respiratory depression
• Urinary incontinence

• Atherosclerotic cardiovascular disease
• Hoarseness
• Polyopia

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More Frequent

• Dysphagia
• Lagophthalmos
• Muscle weakness
• Voice change

Less Frequent

• Diplopia
• Fever
• Infection

Rare or Very Rare

• Acute myocardial infarction
• Acute respiratory distress syndrome
• Anaphylaxis
• Aspiration pneumonia
• Atrioventricular block
• Botulism
• Brachial plexus disorder
• Cardiac arrhythmia
• Corneal ulcer
• Dysarthria
• Dyspnea
• Entropion
• Erythema
• Erythema multiforme
• Hearing loss
• Hematoma
• Hypersensitivity drug reaction
• Keratitis
• Muscle atrophy
• Pneumonia
• Respiratory depression
• Seizure disorder
• Serum sickness
• Urinary incontinence

More Frequent

• Back pain
• Blepharoptosis
• Bronchitis
• Cough
• Dysuria
• Ecchymosis
• Eyelid edema
• Fatigue
• Headache disorder
• Influenza
• Injection site infection
• Injection site sequelae
• Nausea
• Neck pain
• Ocular irritation
• Pharyngitis
• Rhinitis
• Upper respiratory infection
• Urinary retention
• Urinary tract infection
• Xerostomia

Less Frequent

• Pruritus of skin
• Skin rash
• Visual changes

Rare or Very Rare

• Acute abdominal pain
• Alopecia
• Anorexia
• Arthralgia
• Blurred vision
• Chest pain
• Diarrhea
• Dizziness
• Dry eye
• Edema
• Excessive granulation tissue
• Eyes vertical deviation
• Facial palsy
• Flu-like symptoms
• Gait abnormality
• General weakness
• Heavy feeling
• Hematuria
• Hyperhidrosis
• Hypertonia
• Hypoesthesia
• Madarosis of eyelid
• Malaise
• Muscle fasciculation
• Musculoskeletal pain
• Myalgia
• Paresthesia
• Peripheral neuropathy
• Photophobia
• Psoriasiform eruption
• Retrobulbar hemorrhage
• Sinusitis
• Stinging of skin
• Strabismus
• Symptoms of anxiety
• Syncope
• Tinnitus
• Urticaria
• Vertigo
• Vomiting

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There are no adequate and well-controlled studies of onabotulinumtoxinA in pregnant women. The drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus; most clinicians state that the drug should not be used for cosmetic purposes during pregnancy. Abortion, decreased fetal body weight, and fetal malformations (e.g., skeletal ossification) have been observed in animals (e.g., mice, rats, rabbits) given onabotulinumtoxinA during gestation.

At least one woman who received onabotulinumtoxinA during pregnancy reportedly gave birth prematurely, although a causal relationship to the drug was considered unlikely.

Reductions in fetal body weight and/or delayed ossification were observed in pregnant mice and rats receiving IM onabotulinumtoxinA in doses of 4, 8, or 16 units/kg 2 times during the period of organogenesis (gestation days 5 and 13). The reproductive developmental no-observed-effect level (NOEL) following IM injection of 4, 8, or 16 units/kg of onabotulinumtoxinA was 4 units/kg in pregnant mice or rats. These no-effect doses for developmental toxicity are approximately equal to the human dose of 400 units or 4 times the average high human dose (64 units) for glabellar, lateral canthal lines, and forehead lines on a body weight (units/kg) basis.

Reduced fetal weights and decreased fetal skeletal ossification were observed with IM onabotulinumtoxinA doses of 4 or 8 units/kg in pregnant rats or 0.5 units/kg in rabbits during the period of organogenesis. These doses were associated with substantial maternal toxicity, including abortions, early deliveries, and maternal death. In these studies, the developmental NOEL of 1 unit/kg in rats is approximately equal to the human dose of 64 units based on units/kg, and the developmental NOEL of 0.25 units/kg in rabbits is less than the human dose of 400 units based on units/kg.

Data on the presence of onabotulinumtoxinA in human milk, the effects on the breastfed infant, or the effects of the drug on milk production are lacking. The benefits of breastfeeding should be considered along with the mother's clinical need for onabotulinumtoxinA and any potential adverse effects on the breastfed infant from onabotulinumtoxinA or from the underlying maternal condition.

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