onabotulinumtoxinA (Botox, Botox Cosmetic, botulinum toxin)
Dosing and uses of Botox, Botox Cosmetic (onabotulinumtoxinA)
Adult dosage forms and strengths
injectable, powder for reconstitution
- 50 units/vial
- 100 units/vial
- 200 units/vial
Blepharospasm
1.25-2.5 units injected into medial and lateral pretarsal orbicularis oculi of upper lid and lateral pretarsal orbicularis oculi of lower lid; not to exceed 200 units in 30 days
May increase dose 2-fold if response to initial treatment dose does not last longer than 2 months
Little benefit obtained from injecting >5 units per site
Tolerance may develop if treatment given more than every 3 months; effect not usually permanent
Strabismus
1.25-5 units IM; <25 units per injection
Vertical muscles, and horizontal strabismus of <20 prism diopters: 1.25-2.5 units in any one muscle
Persistent VI nerve palsy of >1 month of duration: 1.25-2.5 units in the medial rectus muscle
Horizontal strabismus of 20-50 prism diopters: 2.5-5 units in any one muscle
Incomplete paralysis of target muscle: May increase dose 2-fold if patient experience incomplete paralysis of the target
Primary Axillary Hyperhidrosis
50 units injected intradermally to each axilla evenly distributed in multiple sites approximately 1-2 cm apart
Upper and Lower Limb Spasticity
Indicated for the treatment of upper and lower limb spasticity in adults to decrease the severity of increased muscle stiffness
Select dose based on muscles affected, severity of muscle activity, prior response to treatment, and adverse event history (EMG guidance recommended)
Do not exceed a cumulative dose of 400 units in 3-month interval when treating adults for 1 or more indications
Upper limb spasticity
- Selected muscles: Elbow flexors (biceps), wrist flexors (flexor carpi radialis and flexor carpi ulnaris), finger flexors (flexor digitorum profundus and flexor digitorum sublimis), and thumb flexors (adductor pollicis and flexor pollicis longus)
- In clinical trials, doses ranging from 75 units to 400 units were divided among selected muscles to treat upper limb spasticity at a given treatment session
- Recommended dose per muscle for upper limb spasticity
- Biceps brachii: 100-200 units divided in 4 sites
- Flexor carpi radialis: 12.5-50 units in 1 site
- Flexor carpi ulnaris: 12.5-50 units in 1 site
- Flexor digitorum profundus: 30-50 units in 1 site
- Flexor digitorum sublimis: 30-50 units in 1 site
- Adductor pollicis: 20 units in 1 site
- Flexor pollicis longus: 20 units in 1 site
Lower limb spasticity
- Selected muscles: Gastrocnemius, soleus, tibialis posterior, flexor hallucis longus, and flexor digitorum longus
- Recommended dose for treating lower limb spasticity is 300 units to 400 units divided among 5 muscles
- Recommended dose per muscle for lower limb spasticity
- Gastrocnemius medial head: 75 units divided in 3 sites
- Gastrocnemius lateral head: 75 units divided in 3 sites
- Soleus: 75 units divided in 3 sites
- Tibialis Posterior: 75 units divided in 3 sites
- Flexor hallucis longus: 50 units divided in 2 sites
- Flexor digitorum longus: 50 units divided in 2 sites
Chronic Migraine
Indicated for prophylactic treatment of headaches in adults with chronic migraine, a distinct and severe neurological disorder characterized by patients with migraine history who suffer from headaches on 15 or more days/month. Headaches typically last 4 h/day or longer
Recommended total dose 155 units, as 0.1 mL (5 units) IM injections per each site divided across 7 head/neck muscles q12wk
Recommended dose per muscle site (totaling 155 units)
- Frontalis: 20 units divided in 4 sites
- Corrugator: 10 units divided in 2 sites
- Procerus: 5 units in 1 site
- Occipitalis: 30 units divided in 6 sites
- Temporalis: 40 untied divided in 8 sites
- Trapezius: 30 units divided in 6 sites
- Cervical paraspinal muscle group: 20 units divided in 4 sites
Detrusor Overactivity
Indicated for urinary incontinence caused by detrusor overactivity in patients with neurologic conditions (eg, spinal cord injury, multiple sclerosis) in adults who have an inadequate response to or are intolerant to anticholinergic medication
200 units (divided into 30 intradetrusor injections) administered using cystoscopy
Duration of effect may last up to 10 months; may repeat procedure when effect of previous injection diminishes, but no sooner than 12 weeks from the prior bladder injection
Overactive Bladder
Indicated for adults with overactive bladder symptoms (urge incontinence, urgency, frequency) who cannot use or do not adequately respond to anticholinergic medication
100 units (divided into 20 intradetrusor injections of 5 units each) administered using cystoscopy
Requirements for repeating procedure
- 12 weeks have elapsed since prior treatment
- Post-void residual urine volume >200 mL
- At least 2 reported urinary incontinence episodes over 3 days
Botox Cosmetic
Glabellar lines: Inject 4 units (0.1 mL) into each of 5 sites, 2 in each corrugator muscle and 1 in procerus muscle for a total dose of 20 units
Canthal lines: Inject 4 units (0.1 mL) into 3 sites per side (6 total injection points) in the lateral orbicularis oculi muscle for a total of 24 units/0.6 mL (12 units per side)
Duration of activity is approximately 3-4 months
More frequent dosing not recommended
Indications (Botox Cosmetic)
- Indicated for temporary improvement in the appearance of moderate-to-severe:
- -glabellar lines (ie, frown lines) associated with corrugators and/or procerus muscle activity
- -lateral canthal lines (ie, crow’s feet) associated with orbicularis oculi activity
Dosing considerations (Botox Cosmetic)
- Treatment for both glabellar and lateral canthal lines can be given at the same time
- Do not exceed a cumulative dose of 360 units per 3 months when treating patients for 1 or more indication
Dosing Considerations
Lower initial dose if no prior botulinum toxin treatment
Adjust dose based on response
When treating adult patients for 1 or more indications, the maximum cumulative dose should generally not exceed 360 Units in a 3 month intervaL
Bladder dysfunction indications: Administer prophylactic antibiotics (except aminoglycosides) beginning 1-3 days pretreatment and continue 1-3 days post treatment to reduce risk for procedure-releated UTI
Administration
Blepharospasm: Use sterile, 27- or 30-gauge needle without EMG guidance to inject into the medial & lateral pretarsal orbicularis oculi of upper lid and into the lateral pretarsal orbicularis oculi of lower lid
Axillary Hyperhidrosis: Standard staining techniques (eg, Minor's iodine starch test) are used to identify the hyperhidrotic area to be injected; patients should shave their underarms and refrain from using over the counter deodorants/antiperspirants for 24 hours prior to such staining tests
Strabismus: Inject into extraocular muscles
Pediatric dosage forms and strengths
injectable solution
- 100 units
<12 Years
Safety and efficacy not established
≥12 Years
Blepharospasm
- 1.25-2.5 units IM; < 200 units in 30 days
- May increase dose 2-fold if response to initial treatment dose does not last longer than 2 months
- Little benefit obtained from injecting >5 units per site
Strabismus
- 1.25-5 units IM; <25 units per injection
- Vertical muscles, and horizontal strabismus of <20 prism diopters: 1.25-2.5 units in any one muscle
- Persistent VI nerve palsy of >1 month of duration: 1.25-2.5 units in the medial rectus muscle
- Horizontal strabismus of 20-50 prism diopters: 2.5-5 units in any one muscle
- Incomplete paralysis of target muscle: May increase dose 2-fold if response to initial treatment dose
Primary axillary hyperhidrosis
- Safety and efficacy not established
Chronic migraine
- <18: Safety and efficacy not established
Muscle Contractures (Orphan)
Treatment of dynamic muscle contractures in pediatric cerebral palsy patients
Orphan indication sponsor
- Allergan, Inc; 2525 Dupont Drive, P.O. Box 19534; Irvine, CA 92713
Botox, Botox Cosmetic (onabotulinumtoxinA) adverse (side) effects
>10%
Dysphagia (19-74% )
Ptosis of eyelid (1-20.8% )
Dry eyes (6.3-19% )
Urinary retention with intradetrusor injections (17%)
Influenza-like symptoms (2-16% )
Upper respiratory infection (12% )
Headache (3-11% )
Neck pain (3-11% )
1-10%
Injection site pain (3% to 10% ),
Sweating symptom, non-axillary (3% to 10% )
Backache (2-10% )
Fever (2-10% )
Chronic migraine
- Migraine (4%)
- Musculoskeletal stiffness (4%)
- Muscular weakness (4%)
- Myalgia (3%)
- Musculoskeletal pain (3%)
- Facial paresis (2%)
- Muscle spasms (2%)
- Hypertension (2%)
Frequency not defined
Cardiac dysrhythmia
Myocardial infarction
Seizure
Dry mouth
Dyspepsia
Anaphylaxis
Respiratory depression
Lagophthalmus
Treatment of upper limb spasticity
- Fatigue
- Nausea
- Muscle weakness
- Pain in the arms
- Bronchitis
Warnings
Black box warnings
Effects of all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects
These symptoms 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 death have been reported
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 adults, and in approved indications, cases of spread of effect have been reported at doses comparable to those used to treat cervical dystonia and at lower doses
Contraindications
Hypersensitivity
Neuromuscular disease
Infection at the proposed injection site
Intradetrusor injection: Urinary tract infection or urinary retention (post-void residual >200 mL)
Cautions
Avoid injections near the levator palpebrae superioris minimize the risk of ptosis, especially in individuals with larger brow-depressor complexes
Risk of respiratory compromise & death esp in children treated for cerebral palsy-associated spasticity
Effects of the botulinum toxin may spread from the area of injection to other areas of the body, causing symptoms similar to those of botulism - watch for dyspnea, dysphagia or speech impairment
The different botulinum toxin products are not interchangeable
Pre-existing neuromuscular disorders
Only consider for treatment of urinary incontinence for patients willing and able to initiate catheterization post-treatment, if required (due to risk of urinary retention); patients with diabetes mellitus more likely to develop urinary retention than non-diabetics
Increased risk for UTI; do not use for treatment of urinary incontinence with present UTI, routine catheterization, or if patient is unable to empty bladder without assistance
Use with caution in patients with compromised respiratory function
Corneal exposure and ulceration due to reduced blinking may occur when treating blepharospasm
Retrobulbar hemorrhages and compromised retinal circulation may occur when treating strabismus
Bronchitis and upper respiratory tract infections in patients treated for upper limb spasticity reported
Serious adverse reactions, including excessive weakness, dysphagia, and aspiration pneumonia, with some adverse reactions associated with fatal outcomes, reported in patients who received injections for unapproved uses
Tailor dosing in initial and sequential treatment sessions to the individual based on the size, number and location of muscles involved, severity of spasticity, presence of local muscle weakness, patient’s response to previous treatment, or adverse event history with this therapy
Pregnancy and lactation
Pregnancy category: C
Lactation: Not known if excreted in breast milk; effect on nursing infant not known
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Botox, Botox Cosmetic (onabotulinumtoxinA)
Mechanism of action
Neurotoxin from Clostridium botulinum; prevents ACh release from presynaptic membrane, causing temporary calming of muscle contractions by blocking the transmission of nerve impulses
Pharmacokinetics
Metabolism: unknown
Excretion: unknown
Minimal levels in circulation after IM injection
Onset of action
- Blepharospasm: 3-4 days
- Strabismus: 1-2 days
- Cervical Dystonia: 2 weeks
- Detrusor overactivity: 2 weeks
Duration
- Blepharospasm: 3-4 months
- Strabismus: 1-2 days
- Cervical Dystonia: 3-4 months
- Detrusor overactivity: 42-48 weeks
Administration
IM Administration
Blepharospasm: use sterile, 27- or 30-gauge needle without EMG guidance to inject into the medial & lateral pretarsal orbicularis oculi of upper lid and into the lateral pretarsal orbicularis oculi of lower lid
Axillary Hyperhidrosis: standard staining techniques (eg, Minor's iodine starch test) are used to identify the hyperhidrotic area to be injected; pts should shave their underarms & refrain from using OTC deodorants/antiperspirants for 24 hr prior to such staining tests
Strabismus: Inject into extraocular muscles
IM Preparation
Vacuum dried powder for reconstitution only with sterile, non-preserved 0.9% Sodium Chloride Injection USP prior to injection
Chronic migraine: The recommended dilution is 200 Units/4 mL or 100 Units/2 mL, with a final concentration of 5 Units per 0.1 mL
Storage
Administer within 24 hours following reconstitution
Store reconstituted solution in refrigerator (2-8°C)
Store unreconstituted powder in refrigerator (2-8°C)
