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BOTOX® Vacuum-dried Injection
BOTOX® Vacuum-dried Injection
SCHEDULING STATUS:
Schedule 4
PROPRIETARY NAME
(and dosage form):
BOTOX® Vacuum-dried Injection
COMPOSITION:
BOTOX® (Botulinum Toxin TypeA) is a sterile, vacuum-dried form of purified botulinum toxin type A, produced from a culture of Clostridium botulinum. It is purified from the culture solution by a series of acid precipitations to a crystalline complex consisting of the active high molecular weight toxin protein and associated non-toxic proteins (some with heamaglutininating properties). The crystalline complex is re-dissolved in a solution containing saline and albumin and sterile filtered (0,2microns) prior to vacuum-drying. BOTOX® is to be reconstituted with sterile non-preserved saline prior to injection.
BOTOX® (Botulinum Toxin Type A) is available in two vial sizes: 50units and 100units (U).
One Allergan unit (U) of Botulinum Toxin Type A corresponds to the calculated median lethal intraperitoneal dose (LD/50) in mice of the reconstituted BOTOX® injected.
Botulinum toxin units are not interchangeable from one product to another. Doses recommended in Allergan Units are different from other botulinum toxin preparations.
Other ingredients
Human albumin and sodium chloride.
PHARMACOLOGICAL CLASSIFICATION
A. 30.4 Biologicals. Other.
PHARMACOLOGICAL ACTION
Pharmacodynamics
BOTOX® (Botulinum Toxin Type A) blocks neuromuscular conduction by binding to receptor sites on motor nerve terminals, entering the nerve terminals and inhibiting the release of acetylcholine. When injected intramuscularly at therapeutic doses, BOTOX® produces a localised chemical denervation resulting in muscle paralysis. When the muscle is chemically denervated, it atrophies and may develop extrajunctional acetylcholine receptors.
There is evidence that the nerve can sprout and re-innervate the muscle, with the weakness caused by BOTOX® injection thus being reversible.
Recovery after intramuscular injection takes place normally within 12weeks of injection as nerve terminals sprout and reconnect with the endplates. After intradermal injection, where the target is the eccrine sweat glands the effect lasted for about 4 to 7months after the first injection in patients treated with 50U per axilla.
When injected into extraocular eye muscle, the medicine induces a period of paralysis lasting from 2 to 20weeks. Injection into the peri-ocular muscles reduces excessive contractions and unwanted muscle spasm.
The paralytic effect on muscles injected with BOTOX® is useful in reducing the excessive, abnormal contractions due to blepharospasm. When used for the treatment of strabismus it is postulated that the administration of BOTOX® affects muscle pairs by inducing an atrophic lengthening of the injected muscle and a corresponding shortening of the muscle's antagonist. Following peri-ocular injection of BOTOX®, distant muscles show electrophysiologic changes but no clinical weakness or other clinical changes for a period of several weeks or months, parallel to the duration of local clinical paralysis.
Pharmacokinetics
The molecular weight is about 150000Daltons, and the molecule is constructed of a heavy chain protein, about 100000Daltons, and a lighter chain protein, about 50000Daltons, held together by one or more disulfide bonds.
Upon extraction from bacterial culture, the Botulinum Toxin Type A is recovered as a para-crystal composed of the above neurotoxin, together with other simple proteins which have weak haemaglutination properties, altogether having a molecular weight of about 900000Daltons. As such, the molecule is quite stable. It is this crystalline toxin haemaglutinin which is utilised as the basis of this product. (The pure neurotoxin appears to be substantially less stable). The Botulinum Toxin Type A is mixed in saline with human albumin to protect and stabilise the diluted Botulinum Toxin Type A, and this solution is vacuum-dried.
Specific receptors on the terminal non-myelinated portion of the motor nerves are sites of attachment of the heavy chain. This is then internalised, and it appears that the light and heavy chain separate, the light chain acting to interfere with calcium metabolism essential to the impulse triggered release of transmitter, acetylcholine. Several proteins with neurological blocking properties (including botulinum and tetanus toxins), share this dichain mechanism of heavy chain as the attachment molecule, and light chain as the active blocking agent within the nerve terminal. While some minimal transport of the botulinum molecule within the nerve terminal has been shown, widespread transport of it up through the cell body and transneuronally does not occur, as with tetanus.
INDICATIONS
BOTOX® is indicated for the treatment and/or management of:
Glabellar lines (50U per vial)
Moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in people less than or equal to 65years of age.
Primary hyperhidrosis of the axillae
Persistent severe primary hyperhidrosis of the axillae, which interferes with the activities of daily living and is resistant to topical treatment.
Focal spasticity in paediatric cerebral palsy patients
Focal spasticity associated with dynamic equinus foot deformity due to spasticity in paediatric cerebral palsy patients, two years of age or older by specialists trained in the procedure.
Strabismus, blepharospasm and hemifacial spasm
Selected cases of strabismus and blepharospasm associated with dystonia, including benign essential blepharospasm or VII nerve disorders (hemifacial spasm), in patients 12years of age and older.
The efficacy of BOTOX® in deviations over 50prism diopters, in restrictive strabismus, in Duane's syndrome with lateral rectus weakness and in secondary strabismus caused by prior surgical over-recession of the antagonist is doubtful, or multiple injections over time may be required. BOTOX® is ineffective in chronic paralytic strabismus except to reduce antagonist contracture in conjunction with surgical repair.
CONTRA-INDICATIONS
BOTOX® is contraindicated in individuals with known hypersensitivity to Botulinum Toxin Type A orany ingredient in the formulation.
The safety and effectiveness of BOTOX® in the treatment of blepharospasm, hemifacial spasm and associated focal dystonias in children (under 12years) have not been demonstrated.
BOTOX® is also contra-indicated in the presence of infection or inflammation at the proposed injection site(s) or when there are generalised disorders of muscle activity (e.g. myasthenia gravis), Eaton Lambert Syndrome or disorders that produce peripheral neuromuscular dysfunction.
BOTOX® should not be used in the presence of inflammation at the proposed injection site(s) or when excessive weakness or atrophy is present in the target muscle. Caution should be exercised when BOTOX® is used for treatment of patients with amyotropic lateral sclerosis or disorders that produce peripheral neuromuscular dysfunction.
WARNINGS
General
The recommended dosages and frequencies of administration for BOTOX® should not be exceeded.
This product contains a small amount of albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries a remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) is also considered remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.
Neutralising antibodies
A neutralising antibody is defined as an antibody that inactivates the biological activity of BOTOX®. The proportion of patients which lose their response to BOTOX® therapy and have demonstrable levels of neutralising antibodies has not been studied well.
The critical factors for neutralising antibody production include the frequency and dose of injection. To reduce the potential for neutralising antibody formation, it is recommended that injection intervals of BOTOX® should be no more frequent than three months.
Adrenaline and other precautions as necessary should be available should an anaphylactic reaction occur. In the treatment of some indications with BOTOX®, there have been reports of death, sometimes associated with dysphagia, pneumonia and/or other significant debility. Patients or caregivers should be advised to seek immediate medical care if swallowing, speech or respiratory disorders arise.
BOTOX® should only be given by physicians with appropriate qualifications, and expertise in the treatment and the use of the required equipment. |
Focal spasticity in paediatric cerebral palsy patients
The use of BOTOX® in cerebral palsy is restricted to specialists trained in the procedure and with access to adequate resuscitating facilities.
Primary hyperhidrosis of the axillae
Avoid symptomatic treatment of hyperhidrosis without ascertaining the diagnosis and/or providing treatment of the potential underlying disease.
INTERACTIONS
The effect of botulinum toxin may be potentiated by aminoglycoside antibiotics or any other drugs that interfere with neuromuscular transmission. Caution should be exercised when BOTOX® is used in patients taking aminoglycosides (e.g. streptomycin, tobramycin, neomycin, gentamicin, netilmicin, kanamycin, amikacin), polymyxins, tetracyclines, linomycin or any other medicine that interfere with neuromuscular transmission (see Side-effects and Special Precautions).
PREGNANCY AND LACTATION
Safety of BOTOX® when administered during pregnancy or lactation has not been established. No information is available on the passage of the toxin into breast milk.
DOSAGE AND DIRECTIONS FOR USE
Please note that dosage and directions for use is specific to each individual indication.
BOTOX® is for single patient use only.
FOR SUBCUTANEOUS, INTRADERMAL OR INTRAMUSCULAR USE
Once opened and reconstituted, use within twenty four hours and discard remaining solution, as the product and diluent do not contain a preservative. Reconstituted BOTOX® should not be frozen.
Optimum dose levels and number of injection sites per muscle have not been established. Individual treatment regimens should therefore be drawn up by the physician. Optimum dose levels should be determined by titration.
The recommended injection volumes per muscle site range from 0.05 –0.1mL (blepharospasm, hemifacial spasm) to 0.1 –0.5mL (cerebral palsy). The recommended injection volume for intradermal injection in axillary hyperhidrosis is 0.1 –0.2mL.
Dilution technique
To reconstitute vacuum-dried BOTOX® use sterile normal saline without a preservative; 0,9% sodium chloride injection is the recommended diluent. Draw up the proper amount of diluent in the appropriate size syringe.
Since BOTOX® is denatured by bubbling or similar violent agitation; inject the diluent into the vial gently. Discard the vial if a vacuum does not pull the diluent into the vial. Record the date and the time of reconstitution on the space on the label. BOTOX® should be administered within 24hours after reconstitution.
During this time period, reconstituted BOTOX® should be stored in a refrigerator (2° to 8°C).
Reconstituted BOTOX® should be clear, colourless and free of particulate matter. Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration and whenever the solution and the container permit.
DILUTION TABLE (50Units per vial)
Diluent Added
(0,9% Sodium Chloride Injection) |
Resulting dose
(in Units per 0,1mL) |
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1,25mL |
4,0U |
DILUTION TABLE (100Units per vial)
Diluent Added
(0,9% Sodium Chloride Injection) |
Resulting dose
(in Units per 0,1mL) |
0,5mL
1,0mL
2,0mL
2,5mL
4,0mL
8,0mL |
20,0U
10,0U
5,0U
4,0U
2,5U
1,25U |
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Note: |
These dilutions are calculated for an injection volume of 0,1mL. A decrease or increase in the BOTOX® dose is also possible by administering a smaller or larger injection volume - from 0,05mL (50% decrease in dose) to 0,15mL (50% increase in dose). |
An injection of BOTOX® is prepared by drawing into a sterile 1,0mL syringe an amount of the properly diluted toxin (see Dilution Table) slightly greater than the intended dose. Air bubbles in the syringe barrel are expelled and the syringe is attached to the electro-myographic injection needle, preferably a 27gauge needle. Injection volume in excess of the intended dose is expelled through the needle into an appropriate waste container to assure potency of the needle and to confirm that there is no syringe-needle leakage. A new, sterile needle and syringe should be used to enter the vial on each occasion for dilution or removal of BOTOX®.
Glabellar lines (50U per vial)
Reconstituted BOTOX® (50U/1,25mL) is injected using a 30gauge/0,30mm needle.
0,1mL (4U) should be administered in each of 5 sites, 2 in each corrugator muscle and 1 in the procerus muscle for a total dose of 20U.
{ILLUSTRATED here - Please see original Package Insert for illustration}
In order to reduce the complication of ptosis, injection near the levator palpebrae superioris should be avoided, particularly in patients with larger brow-depressor complexes. Medial corrugator injections should be placed at least 1 cm above the bony supraorbital ridge.
Primary hyperhidrosis of the axillae
Reconstituted BOTOX® (100U/4,0mL) is injected using a 30 gauge needle. 50U of BOTOX® is injected intradermally, evenly distributed in multiple sites approximately 1 to 2cm apart within the hyperhidrotic area of the axilla. The hyperhidrotic area may be defined by using standard staining techniques, e.g. Minor´s iodine-starch test.
Clinical improvement generally occurs within the first week after injection. Repeat injections of BOTOX® should be administered when the effects from previous injections subside. Treatment response has been reported to persist for 4 to 7months.
Focal spasticity in paediatric cerebral palsy patients
Diluted BOTOX® is injected using a sterile 23 –26 gauge/0,60 –0,45 mm needle. It is administered into each of two sites in the medial and lateral heads of the affected gastrocnemius muscle. In hemiplegia, the recommended total dose is 4U/kg body weight in the affected limb. In diplegia, the recommended total dose is 6U/kg body weight divided between the affected limbs. The total dose should not exceed 200U.
Clinical improvement generally occurs within the first two weeks after injection. Repeat doses should be administered when the clinical effect of a previous injection diminishes but not more frequently than every three months. It may be possible to adapt the dosage regimen to obtain an interval of at least six months between treatment sessions.
Strabismus
To prepare the eye for BOTOX® injection, it is recommended that several drops of a local anaesthetic and an ocular decongestant be given several minutes prior to injection.
Note:The volume of BOTOX® injected for treatment of strabismus should be between 0,05mL to 0,15mL per muscle.
BOTOX® is intended for injection into extraocular muscles utilizing the electrical activity recorded from the tip of the injection needle as a guide to placement within the target muscle. Injection without surgical exposure of the muscle to be treated or electromyographic guidance should not be attempted. Physicians should be familiar with electromyographic technique.
The initial listed doses of the diluted BOTOX® (see Dilution Table) typically create paralysis of injected muscles beginning one to two days after injection and increasing in intensity during the first week. The paralysis lasts for 2 to 6weeks and gradually resolves over a similar time period. Overcorrections lasting over 6months have been rare. About one half of patients will require subsequent doses because of inadequate paralytic response of the muscle to the initial dose or because of mechanical factors such as large deviations or restrictions, or because of the lack of binocular motor fusion to stabilize the alignment.
Initial doses in units (abbreviated as U). Use the lower listed doses for treatment of small deviations. Use the larger doses only for large deviations.
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For vertical muscles, and for horizontal strabismus of less than 20 prism diopters: 1,25U to 2,5U in any one muscle. |
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For horizontal strabismus of 20 prism diopters to 50 prism diopters: 2,5U to 5,0U in any one muscle. |
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For persistent VI nerve palsy of one month or longer duration: 1,25U to 2,5U in the medial rectus muscle. |
Subsequent doses for residual or recurrent strabismus.
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It is recommended that patients be re-examined 7 to 14 days after each injection to assess the effect of that dose. |
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Patients experiencing adequate paralysis of the target muscle that require subsequent injections should receive a dose comparable to the initial dose. |
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Subsequent doses for patients experiencing incomplete paralysis of the target muscle may be increased up to twice the size of the previously administered dose. |
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Subsequent injections should not be administered until the effects of the previous dose have dissipated as evidenced by substantial function in the injected and adjacent muscles. |
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The maximum recommended dose as a single injection for any one muscle is 25U. |
Blepharospasm and hemifacial spasm
For blepharospasm, diluted BOTOX® (see Dilution Table) is injected using a sterile, 27 - 30gauge/ 0,40 –0,30mm needle without electromyographic guidance. 1,25U to 2,5U (0,05mL to 0,1mL volume at each site) injected into the medial and lateral pre-tarsal orbicularis oculi of the upper lid and into the lateral pre-tarsal orbicularis oculi of the lower lid is the initial recommended dose.
Additional sites in the brow area, the lateral orbicularis and in the upper facial area may also be injected if spasms here interfere with vision. Avoiding injection near levator palpebrae superioris may reduce the complication of ptosis. Avoiding medial lower lid injections, and thereby reducing diffusion into the inferior oblique, may reduce the complication of diplopia. The following diagrams indicate the possible injection sites:
{ILLUSTRATED here - Please see original Package Insert for illustration}
In general, the initial effect of the injections is seen within three days and reaches a peak at one to two weeks post-treatment. Each treatment lasts approximately three months, following which the procedure can be repeated at not less than three month intervals. At repeat treatment sessions, the dose may be increased up to two-fold if the response from the initial treatment is considered insufficient- usually defined as an effect that does not last longer than two months. However, there appears to be little benefit obtainable from injection more than 5,0U per site. The initial dose should not exceed 25U per eye. No additional benefit is conferred by treating more frequently than every three months.
In the management of blepharospasm total dosing should not exceed 100U every 12 weeks.
Patients with hemifacial spasm or VIIth nerve disorders should be treated as for unilateral blepharospasm, with other affected facial muscles being injected as needed.
SIDE-EFFECTS AND SPECIAL PRECAUTIONS
General
Patients can be expected to experience an adverse reaction after treatment with BOTOX® at the rates of 35% for blepharospasm and 17% for paediatric cerebral palsy and 11% for hyperhidrosis of the axillae.
Adverse reactions usually occur within the first few days following injection.
Local muscle weakness represents the expected pharmacological action of botulinum toxin in muscle tissue.
Localised pain, tenderness and/or bruising may be associated with the injection. Fever and flu have also been reported after injections with botulinum toxin.
Adverse reactions –frequency by indication
For each indication the frequency of adverse reactions arising from clinical experience is given as follows: Very common (>1/10); Common (>1/100, <1/10); Uncommon (>1/1 000, <1/100); Rare (>1/10 000, <1/1 000); Very rare (<1/10 000).
Glabellar lines:
Common: Headache, blepharoptosis, injection site pain/burning/stinging. Blepharoptosis is consistent with the pharmacological action;
Uncommon: Face pain, erythema, local muscle weakness, injection site edema, ecchymosis, skin tightness, paresthesia and nausea.
Primary hyperhidrosis of the axillae
Common: Non-axillary sweating, injection site reactions, pain, vasodilatation (hot flushes)
Uncommon: Weakness of the arms, pruritus, myalgia, joint disorder and arm pain.
Focal spasticity in paediatric cerebral palsy patients
Very common: Viral infection, ear infection
Common: Localised pain, falling, leg pain, leg (local) weakness and general weakness. Myalgia, muscle weakness, urinary incontinence, somnolence, gait abnormality, malaise, rash, tingling, leg cramps, fever, knee pain, ankle pain, pain at the injection site post-treatment and lethargy.
Strabismus
Very common: Ptosis and vertical deviation
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.
Extraocular muscles adjacent to the injection site are often affected, causing ptosis or vertical deviation, especially with higher doses of BOTOX®. The incidence of ptosis was much less after inferior rectus injection and much greater after superior rectus injection.
The incidence rates of these side-effects persisting for over 6 months in an enlarged series of injections of horizontal muscles were much reduced. In these patients, the injection procedure itself may cause scleral perforations. Vitreous haemorrhage may occur. Retinal detachment or visual loss has not been reported, but retrobulbar haemorrhages may occur. Decompression of the orbit to restore retinal circulation may be required. Pupillary change consistent with ciliary ganglion damage (Adies pupil) has occurred. Anterior segment ischaemia after receiving BOTOX® injection into the medial rectus muscle under direct visualization for esotropia, may develop.
Blepharospasm and hemifacial spasm
Very common: Ptosis
Common: Superficial punctuate keratitis, lagophthalmos, dry eye, irritation, photophobia, lacrimation.
Uncommon: Keratitis, ectropion, diplopia, dizziness, diffuse skin rash/dermatitis, entropion, facial weakness, facial droop, tiredness, visual disturbance, blurring of vision.
Rare: Eyelid swelling
Very rare: Angle closure glaucoma, corneal ulceration.
Ecchymosis occurs easily in the soft eyelid tissues. This can be prevented by applying pressure at the injection site immediately after the injection.
Sedentary patients should be cautioned to resume activity slowly and carefully following administration of BOTOX®.
Additional information
The following have also been reported since the drug has been marketed; skin rash (including erythema multiforme, urticaria and psoriaform eruption), pruritus, allergic/anaphylactic reaction, and facial paralysis.
There have also been reports of adverse events involving the cardiovascular system, including arrhythmia and myocardial infarction, some with fatal outcomes. Some of these patients had risk factors including cardiovascular disease.
A case of peripheral neuropathy has been reported in a large adult male after receivingfour setsof BOTOX® injections, totaling 1 800U (for neck and back spasm, and severe pain) over an 11 week period.
Special precautions
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 anatomy and any alterations to the anatomy due to prior surgical procedures and standard electromyographic techniques.
Clinical fluctuations during the repeated use of BOTOX® (as with botulinum toxins) may be a result of different vial reconstitution procedures, injection intervals, muscles injected and slightly differing potency values given by the biological test method used.
Caution should be used when BOTOX® is used in the presence of excessive weakness or if atrophy is present in the target muscle.
During the administration of BOTOX® for the treatment of strabismus, retrobulbar haemorrhages sufficient to compromise retinal circulation have occurred from needle penetration 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. 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. 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.
Because of the anticholinergic activity of BOTOX® caution should be exercised when treating patients at risk for angle closure glaucoma.
Patients should be warned about possible disturbance of vision following injection of BOTOX®. Presence of antibodies to Botulinum Toxin Type A may reduce the effectiveness of BOTOX® therapy. For this reason, the dose of BOTOX® for strabismus and blepharospasm should be kept as low as possible, in any case below 200U in a one month period.
Paediatric use
Safety and efficacy in the treatment of blepharospasm, hemifacial spasm and associated focal dystonias, in children below the age of 12have not been established. (See Contra-indications).
Similarly, safety and efficacy in the management of focal axillary hyperhidrosis has not been established in persons under 18years of age.
KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
The recommended dosages and frequencies of administration for BOTOX® should not be exceeded. Should accidental injection or oral ingestion occur, the person should be medically supervised for several days on an office or outpatient basis for signs or symptoms of systemic weakness or muscle paralysis.
Patients with botulism may present with symptoms of ptosis, diplopia, swallowing and speech disorders, cranial nerve findings, generalised weakness, or paresis of the respiratory muscles.
Overdose with BOTOX® depends upon the dose, site of injection, and underlying tissue properties. Local weakness may be tolerated and may resolve spontaneously without intervention. However, dysphagia may result in loss of airway and aspiration pneumonia.
Treatment is symptomatic and supportive.
IDENTIFICATION
Clear glass vial containing a small white vacuum-dried powder cake.
Reconstituted BOTOX® should be clear, colourless and free of particulate matter.
PRESENTATION
BOTOX® (Botulinum Toxin Type A) is available in two vial size: 50units or 100units. The clear glass vials are sealed with rubber closures and aluminium seals. As an identifier the 50unit vial is fitted with a red coloured cap and the 100unit vial with a purple cap.
STORAGE INSTRUCTIONS
Store the vacuum-dried product in a refrigerator between 2 - 8°C, or a freezer at or below -5°C. Administer BOTOX® within twenty-four (24)hours after the vial is removed from the freezer and reconstituted. During these twenty-four (24)hours, reconstituted BOTOX® should be stored in a refrigerator (2° to 8°C). Reconstituted BOTOX® should be clear, colourless and free of particulate matter.
Since the product does not contain a preservative, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24hours at +2°C to +8°C.
All vials, including expired vials, or equipment used with the medicine should be disposed of carefully as is done with all medical waste.
KEEP OUT OF REACH OF CHILDREN.
REGISTRATION NUMBER
27/30.4/0164
NAME AND BUSINESS ADDRESS OF THE APPLICANT
Allergan Pharmaceuticals (Pty) Ltd.
Mount Royal Industrial Park
657 James Crescent
Halfway House
South Africa
DATE OF PUBLICATION OF PACKAGE INSERT
5 May 2005
New addition to this site: January 2008
Source: Pharmaceutical Industry |
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