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Botox cosmetic® prodoct monograph

PrBOTOX COSMETIC®
OnabotulinumtoxinA for injection Ph. Eur.
Clostridium botulinum type A neurotoxin complex (900kD)
Sterile vacuum-dried concentrate powder for solution for injection
100 and 200 Allergan units per vial
Neuromuscular Paralytic Agent
Table of Contents
PART I: HEALTH PROFESSIONAL INFORMATION . 3
SUMMARY PRODUCT INFORMATION . 3 INDICATIONS AND CLINICAL USE . 3 CONTRAINDICATIONS . 3 WARNINGS AND PRECAUTIONS . 4 ADVERSE REACTIONS . 8 DOSAGE AND ADMINISTRATION . 11 OVERDOSAGE . 14 ACTION AND CLINICAL PHARMACOLOGY . 15 STORAGE AND STABILITY . 16 SPECIAL HANDLING INSTRUCTIONS . 16 DOSAGE FORMS, COMPOSITION AND PACKAGING . 16 PART II: SCIENTIFIC INFORMATION . 18
PHARMACEUTICAL INFORMATION . 18 CLINICAL TRIALS . 18 DETAILED PHARMACOLOGY . 20 TOXICOLOGY . 21 REFERENCES . 24 PART III: CONSUMER INFORMATION . 26
BOTOX COSMETIC®
OnabotulinumtoxinA for injection Ph. Eur
Clostridium botulinum type A neurotoxin complex (900kD)
PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION
Administration
Dosage Form / Strength
Clinically Relevant Nonmedicinal Ingredients
powder for solution for injection; 100 For a complete listing see Dosage Forms, and 200 Allergan units per vial Composition and Packaging section.
INDICATIONS AND CLINICAL USE
BOTOX COSMETIC® (onabotulinumtoxinA for injection) is indicated:
 for the treatment of upper facial rhytides, including forehead, lateral
Geriatrics (> 65 years of age):
Studies specifically designed to determine the dose in elderly patients have not
been performed. Dosages for the elderly are as for other adults. Initial dosing
should begin at the lowest recommended dose for the specific indication.
Pediatrics (< 18 years of age):
Use of BOTOX COSMETIC® is not recommended in children.
CONTRAINDICATIONS
BOTOX COSMETIC® is contraindicated in:
 patients who are hypersensitive to any botulinum toxin type A or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph.  the presence of infection at the proposed injection site(s). WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions
 The term “Allergan unit” upon which dosing is based, is a specific measurement of toxin activity that is unique to Allergan’s formulation of botulinum toxin type A. Therefore, the “Allergan units” used to describe BOTOX COSMETIC® activity are different from those used to describe that of other botulinum toxin preparations and the units representing BOTOX COSMETIC® activity are not interchangeable with other products.  BOTOX COSMETIC® should only be given by physicians with the appropriate qualifications and experience in the treatment and the use of required equipment.  Follow the recommended dosage and frequency of administration for BOTOX COSMETIC® (See WARNINGS AND PRECAUTIONS, General
and DOSAGE AND ADMINISTRATION).

General
BOTOX® and BOTOX COSMETIC® contain the same active ingredient in the
same formulation. Therefore adverse events observed with the use of BOTOX®
also have the potential to be associated with the use of BOTOX COSMETIC®.
Use BOTOX COSMETIC® only as directed.
Do not use dosage recommendations and potency Units applied to other
botulinum toxin products when using BOTOX COSMETIC®.
The safe and effective use of BOTOX COSMETIC® (onabotulinumtoxinA for
injection) depends upon proper storage of the product, selection of the correct
dose, and proper reconstitution and administration techniques.
Physicians administering BOTOX COSMETIC® should be familiar with the
relevant anatomy of the area involved and any alterations to the anatomy due to
prior surgical procedures. Care should be taken when injecting in or near
vulnerable anatomic structures. Serious adverse events including fatal outcomes
have been reported in patients who had received BOTOX® injected directly into
salivary glands, the oro-lingual-pharyngeal region, esophagus and stomach. Some
patients had pre-existing dysphagia or significant debility. Pneumothorax
associated with injection procedure has been reported following the
administration of BOTOX® near the thorax. Caution is warranted when injecting
in proximity to the lung, particularly the apices.
Caution should be used when BOTOX COSMETIC® 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.
Muscle weakness remote to the site of injection and other serious adverse effects (e.g. dysphagia when injected into the neck region) have been very rarely reported in the cosmetic application. Patients or caregivers should be advised to seek immediate medical care if swallowing, speech or respiratory disorders arise. Patients with a history of underlying neurologic disorders, dysphagia and/or aspiration should be treated with extreme caution. The botulinum toxin product should be used under specialist supervision in these patients and should only be used if the benefit of treatment is considered to outweigh the risk. Injection intervals of BOTOX COSMETIC® should be no more frequent than every two months. Indication specific dosage and administration recommendations should be followed. If combined with non-cosmetic indications, the maximum cumulative dose should generally not exceed 6 Units/kg, up to a maximum of 360 Units, in a 3 month interval. The primary release procedure for BOTOX COSMETIC® uses a cell-based potency assay to determine the potency relative to a reference standard. The assay is specific to Allergan’s product BOTOX COSMETIC®. One Allergan Unit (U) of BOTOX COSMETIC ® 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 COSMETIC® 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 COSMETIC® is approximately 20
Units/nanogram of neurotoxin protein complex.
This product contains human serum 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.
Carcinogenesis and Mutagenesis
Studies in animals have not been performed to evaluate the carcinogenic potential
of BOTOX COSMETIC®. BOTOX COSMETIC® was not mutagenic in in vitro
and in vivo mutagenicity studies. (See TOXICOLOGY Section for more
information.)
Cardiovascular
There have been rare reports following administration of botulinum toxin of
adverse events involving the cardiovascular system, including arrhythmia and
myocardial infarction, some with fatal outcomes. Some of these patients had risk
factors including preexisting cardiovascular disease. The exact relationship of
these events to BOTOX COSMETIC®/BOTOX® is unknown.
Immune

Formation of neutralizing antibodies to botulinum toxin type A may reduce the
effectiveness of BOTOX COSMETIC® treatment by inactivating the biological
activity of the toxin. The critical factors for neutralizing antibody formation have
not been well characterized. The results from some studies suggest that BOTOX®
injections at more frequent intervals or at higher doses may lead to greater
incidence of antibody formation. When appropriate, the potential for antibody
formation may be minimized by injecting with the lowest effective dose given at
the longest feasible intervals between injections.
As with all biologic products, an anaphylactic reaction may occur. Necessary
precautions should be taken and epinephrine should be available.
Serious and/or immediate hypersensitivity reactions such as anaphylaxis and
serum sickness have been rarely reported, as well as other manifestations of
hypersensitivity including urticaria, soft tissue edema, and dyspnea. Some of
these reactions have been reported following the use of BOTOX COSMETIC®
either alone or in conjunction with other products associated with similar
reactions. If such a reaction occurs, further injection should be discontinued and
appropriate medical therapy immediately instituted. One fatal case of anaphylaxis
has been reported in which the patient died after being injected with BOTOX
COSMETIC® diluted with 5 ml of 1% lidocaine. The causal role of BOTOX
COSMETIC® , lidocaine, or both cannot be reliably determined.

Neurologic

Extreme caution should be exercised when administering BOTOX COSMETIC®
to individuals with peripheral motor neuropathic diseases (e.g., amyotrophic
lateral sclerosis, or motor neuropathy) or neuromuscular junction disorders (e.g.,
myasthenia gravis or Lambert-Eaton syndrome). Patients with neuromuscular
junction disorders may be at increased risk of clinically significant systemic
effects including severe dysphagia and respiratory compromise from typical doses
of BOTOX COSMETIC®. There have been rare cases of administration of a
botulinum toxin to patients with known or unrecognized neuromuscular junction
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. When exposed
to very high doses, patients with neurologic disorders, e.g., pediatric cerebral

palsy or adult spasticity, may also be at increased risk of clinically significant
systemic effects.
Ophthalmologic

In order to reduce the complications of ptosis, avoid injection near the levator
palpebrae superioris, particularly in patients with larger brow-depressor
complexes. Medial corrugator injections should be placed at least 1 cm above the
bony supraorbital ridge. To reduce the occurrence of diplopia, injections of the
lateral canthal lines should be outside the bony orbit, not medial to the vertical
line through the lateral canthus. To reduce the occurrence of lip ptosis, injections
should be above the insertion of the zygomaticus muscles.
Skin
As is expected for any injection procedure, localized pain, inflammation,
paresthesia, hypoaesthesia, tenderness, swelling/edema, erythema, localized
infection, bleeding and/or bruising have been associated with the injection.
Needle-related pain and/or anxiety have resulted in vasovagal responses,
including transient symptomatic hypotension and syncope. Care should be taken
when injecting near vulnerable anatomic structures.
Special Populations
Pregnant Women: There are no adequate and well-controlled studies of BOTOX
COSMETIC® administration in pregnant women. Studies in animals have shown
reproductive toxicity. The potential risk for humans is unknown. BOTOX
COSMETIC® should not be used during pregnancy
. 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.
Nursing Women: 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 COSMETIC® is administered to a nursing woman.
Pediatrics (2-18 years of age): Use of BOTOX COSMETIC® is not
recommended in children.
Geriatrics (> 65 years of age): Studies specifically designed to determine the
dose in elderly patients have not been performed. Dosages for the elderly are as
for other adults. Initial dosing should begin at the lowest recommended dose for
the specific indication.
Monitoring and Laboratory Tests
There are no specific requirements for laboratory test monitoring when patients
are treated with BOTOX COSMETIC®.
ADVERSE REACTIONS

Adverse Drug Reaction Overview
In general, adverse reactions occur within the first few days following injection
and while generally transient may have duration of several months or, in rare
cases, longer.
Local muscle weakness represents the expected pharmacological action of
botulinum toxin in muscle tissue. However, weakness of adjacent muscles
associated with local diffusion and/or injection technique has been reported.
Muscle weakness remote to the site of injection and other serious adverse effects
(e.g. dysphagia when injected into the neck region) have been very rarely reported
in the cosmetic application.
As is expected for any injection procedure, localized pain, inflammation,
paresthesia, hypoaesthesia, tenderness, swelling/oedema, erythema, localized
infection, bleeding and/or bruising have been associated with the injection.
Needle-related pain and/or anxiety have resulted in vasovagal responses,
including transient symptomatic hypotension and syncope.
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. Safety was evaluated in two multicenter, double-blind, placebo-controlled, parallel group studies of identical design for the treatment of glabellar lines (N=535; 405 in the BOTOX COSMETIC®-treated group and 130 in the placebo-treated group). The most frequently reported treatment-related adverse events were headache (9.4% in the BOTOX COSMETIC®-treated group and 15.4% in the placebo-treated group) and blepharoptosis (3.2% in the BOTOX COSMETIC®-treated group and 0% in the placebo-treated group). Blepharoptosis is consistent with the pharmacologic action of BOTOX COSMETIC®, and may be technique related. Adverse events that were reported as treatment-related and were reported in 1-3%
of BOTOX COSMETIC®-treated patients are listed in decreasing order of
incidence: injection site pain/burning/stinging (2.5%), face pain (2.2%), erythema
(1.7%), local muscle weakness (1.7%), injection site edema (1.5%), ecchymosis
(1.0%), skin tightness (1.0%), paresthesia (1.0%) and nausea (1.0%). Most
adverse events reported were of mild-to-moderate severity and all were transient.
In a multicenter, open-label, repeat injection study, 318 patients who had
participated in one of the two double-blind studies and who had glabellar line
severity of at least mild severity at maximum frown received 2 additional
treatments of BOTOX COSMETIC®. In this study, adverse events were
comparable in type, incidence, severity, and causality to those reported in the two
placebo-controlled, double-blind studies.
In clinical studies where BOTOX COSMETIC® was administered for the
treatment of forehead or periorbital wrinkles, treatment-related adverse events
have been consistent with those for glabellar lines. Adverse events that were
reported as treatment-related after treatment of horizontal forehead lines with 16
U of BOTOX COSMETIC® include: headache (20%), bruising (10%), eyelid
swelling (15%), and aching or itching forehead (10%). Injecting well above the
brow reduces the risk of ptosis.
Treatment-related adverse events associated with treatment of periorbital wrinkles
include mild bruising (4-25%) and headache (5.6%); these events occurred at a
similar rate on the placebo-treated side. In addition, eyelid droop or shape change,
and pain have been reported. Rare cases of diplopia and an asymmetric smile due
to injection of zygomaticus major have been reported. These complications can
be avoided with adherence to the recommended injection location (see
WARNINGS AND PRECAUTIONS AND DOSAGE AND
ADMINISTRATION SECTIONS)
.
Abnormal Hematologic and Clinical Chemistry Findings
No specific trends in abnormal hematologic or clinical chemistry findings have
been reported.
Post-Market Adverse Drug Reactions
BOTOX® and BOTOX COSMETIC® contain the same active ingredient in the
same formulation. Therefore, adverse events observed with the use of BOTOX
COSMETIC® also have the potential to be associated with the use of BOTOX®.
Adverse events after treatment with botulinum toxin include rare spontaneous
reports of death, sometimes associated with anaphylaxis, dysphagia, respiratory
compromise, pneumonia, and/or other significant debility. There have also been
rare 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 pre-existing cardiovascular disease. New onset
or recurrent seizures have also been reported, typically in patients who are
predisposed to experiencing these events. The exact relationship of these events to
the botulinum toxin injection has not been established.
The following other adverse events have been reported since the drug has been
marketed: denervation/muscle atrophy; respiratory depression and/or respiratory
failure (non-Cosmetic indications); dyspnea; aspiration pneumonia (non-Cosmetic
indications); dysarthia; dry mouth; strabismus; peripheral neuropathy; abdominal
pain; diarrhea; nausea; vomiting; pyrexia; anorexia; vision blurred; visual
disturbance; hypoacusis; tinnitus; vertigo; facial palsy; facial paresis; brachial
plexopathy; radiculopathy; syncope; hypoaesthesia; malaise; myalgia; myasthenia
gravis; paraesthesia; allergic reaction; skin rash (including erythema multiforme,
urticarial, dermatitis psoriasiform, and psoriasiforme eruption); pruritus;
hyperhidrosis; alopecia, including madarosis.
These reactions are reported voluntarily from a population of uncertain size. The
exact relationship of these events to botulinum toxin is unknown.

DRUG INTERACTIONS

Overview
No specific interactions have been reported.
Drug-Drug Interactions
Table 1: Established or Potential Drug-Drug Interactions
Proper name of drug
Clinical comment
The effect of botulinum toxin may be potentiated by aminoglycoside antibiotics or spectinomycin, or other drugs that interfere with neuromuscular transmission (e.g. tubocuraine-type muscle relaxants). Caution should be exercised when aminoglycosides (e.g. streptomycin, tobramycin, neomycin, gentamycin, netilmicin, kanamycin, tetracyclines, lincomycin or any other drugs that interfere with neuromuscular transmission. T Unknown The effect of administering different botulinum neurotoxin serotypes at the same time or within several months of each other is unknown. Excessive weakness may be exacerbated by administration of another botulinum toxin prior to the resolution of the effects of a previously administered botulinum toxin. Legend: C = Case Study; CT = Clinical Trial; T = Theoretical
Drug-Food Interactions
Interactions with food have not been established.

Drug-Herb Interactions
Interactions with herbal products have not been established.

Drug-Laboratory Interactions
Interactions with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION
Dosing Considerations

For Intramuscular Use Only
BOTOX COSMETIC® (onabotulinumtoxinA for injection) should only be
given by physicians with the appropriate qualifications and experience in
the treatment and the use of required equipment.
The term “Allergan unit” upon which dosing is based, is a specific measurement of toxin activity that is unique to Allergan’s formulation of botulinum toxin type A. Therefore, the “Allergan units” used to describe BOTOX COSMETIC® activity are different from those used to describe that of other botulinum toxin preparations and the units representing BOTOX COSMETIC® activity are not interchangeable with other products. The use of one vial for more than one patient is not recommended because the product and diluent do not contain a preservative. Treatment should be initiated at the lowest recommended dose. This dose can be gradually increased in subsequent treatments to the maximum recommended dose, if needed. Injection intervals of BOTOX COSMETIC® should be no more frequent than every two months. Indication specific dosage and administration recommendations should be followed. In treating adult patients, if combined with non-cosmetic indications, the maximum cumulative dose should generally not exceed 6 Units/kg, up to a maximum of 360 Units, in a 3 month interval. Recommended Dose and Dosage Adjustment
BOTOX COSMETIC® is reconstituted only with 0.9% sterile non-preserved
saline. Dilutions resulting in 4.0 U - 7.0 U per 0.1 mL are generally
recommended.
Glabellar lines: 4 U should be administered intramuscularly using a 30 gauge
needle in each of 5 sites, 2 in each corrugator muscle and 1 in the procerus muscle
for a total dose of 20 U.
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.
Forehead lines: 2-6 U should be injected intramuscularly at each of 4 injection
sites in the frontalis muscle, every 1-2 cm along either side of a deep forehead
crease, 2-3 cm above the eyebrows, for a total dose of up to 24 U.
Lateral canthus lines: Generally, 2-6 U should be injected bilaterally at each of 1-
3 injection sites at a 2-3 mm depth, lateral to the lateral orbital rim, where most
lines are seen when a smile is forced. Injection should be at least 1 cm outside the
bony orbit, not medial to the vertical line through the lateral canthus, and not
close to the inferior margin of the zygoma.
An injection of BOTOX COSMETIC® is prepared by drawing into a sterile 1.0
mL tuberculin 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 may be attached to the electromyographic injection
needle, preferably a 1.5 inch, 27 gauge needle. Injection volume in excess of the
intended dose is expelled through the needle into an appropriate waste container
to assure patency 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 COSMETIC®.
Lack of Response:
There are several potential explanations for a lack or diminished response to an
individual treatment with BOTOX COSMETIC®. These may include inadequate
dose selection, selection of inappropriate muscles for injection, muscles
inaccessible to injection, underlying structural abnormalities such as muscle
contractures or bone disorders, change in pattern of muscle involvement, patient
perception of benefit compared with initial results, inappropriate storage or
reconstitution, as well as neutralizing antibodies to botulinum toxin. A
neutralizing antibody is defined as an antibody that inactivates the biological
activity of the toxin. However, there have been patients who continued to
respond to therapy and demonstrated presence of neutralizing antibodies; the
proportion of patients which lose their response to botulinum toxin therapy and have demonstrable levels of neutralizing antibodies is small. The critical factors for neutralizing antibody production are the frequency and dose of injection. To reduce the potential for neutralizing antibody formation, it is recommended that injection intervals of BOTOX COSMETIC® should be no more frequent than two months. More frequent injections should not be required, as BOTOX COSMETIC® treatment reduces the severity of the facial lines for up to 120 days. A suggested course of action when patients do not respond to BOTOX COSMETIC® injections is: 1) wait the usual treatment interval; 2) consider reasons for lack of response listed above; 3) more than one treatment course should be considered before classification of a patient as a non-responder; 4) test patient serum for neutralizing antibody presence.
Missed Dose
Missed doses may be administered as soon as is practical.
Administration
An injection of BOTOX COSMETIC® is prepared by drawing into a sterile 1.0
mL tuberculin syringe an amount of the properly diluted toxin (see Dilution
Table, below) slightly greater than the intended dose. Air bubbles in the syringe
barrel are expelled and the syringe may be attached to the electromyographic
injection needle, preferably a 1.5 inch, 27 gauge needle. Injection volume in
excess of the intended dose is expelled through the needle into an appropriate
waste container to assure patency 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 COSMETIC® .
Reconstitution:
Parenteral Products:

To reconstitute vacuum-dried BOTOX COSMETIC®, use sterile normal saline
without a preservative; 0.9% Sodium Chloride Injection is the only recommended
diluent. Draw up the proper amount of diluent in the appropriate size syringe.
Since BOTOX COSMETIC® 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 time of reconstitution on the
space on the label. BOTOX COSMETIC® should be administered within twenty-
four hours after reconstitution.
During this time period, reconstituted BOTOX COSMETIC® should be stored in a refrigerator (2o to 8o C). Reconstituted BOTOX COSMETIC® should be clear, colorless and free of particulate matter. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration and whenever the solution and the container permit. Table 2: Dilution
Resulting dose:
Quantity of Diluent Added (0.9% Sodium Chloride for Injection)
Units per 0.1 mL
100 U Vial
200 U Vial
Note: These dilutions are calculated for an injection volume of 0.1mL. A decrease or increase in the BOTOX
COSMETIC dose is also possible by administering a smaller or larger injection volume (i.e. 0.05mL (50%
decrease in dose) to 0.15mL (50% increase in dose)).
OVERDOSAGE

For management of a suspected drug overdose, contact your regional Poison Control Centre. In the event of overdosage or injection error, additional information may be obtained by contacting Allergan, Inc. at (800) 433-8871. Overdose of BOTOX COSMETIC® is a relative term and depends upon dose, site of injection, and underlying tissue properties. Signs and symptoms of overdose are not apparent immediately post-injection. Should accidental injection or oral ingestion occur, or overdose be suspected, the person should be medically monitored for up to several weeks for progressive signs or symptoms of muscular weakness distant from the site of injection that may include ptosis, diplopia, swallowing and speech disorders, generalized weakness or respiratory failure. These patients should be considered for further medical evaluation and appropriate medical therapy immediately instituted, which may include hospitalization. ACTION AND CLINICAL PHARMACOLOGY
Mechanism of Action
BOTOX COSMETIC® (onabotulinumtoxinA for injection) is a sterile, vacuum-
dried form of purified botulinum neurotoxin type A complex, produced from a
culture of the Hall strain of Clostridium botulinum grown in a medium containing
N-Z amine, glucose and yeast extract. It is purified to a crystalline complex
consisting of the neurotoxin, a non-toxic protein and four major hemagglutinin
proteins.

BOTOX COSMETIC® 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 COSMETIC® produces partial chemical denervation of the muscle
resulting in localized muscle paralysis. When chemically denervated, 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 reversing muscle weakness produced by localized injection of
BOTOX COSMETIC®.
The primary release procedure for BOTOX COSMETIC® uses a cell-based
potency assay to determine the potency relative to a reference standard. The
assay is specific to Allergan’s product BOTOX COSMETIC®. One Allergan Unit
(U) of BOTOX COSMETIC® corresponds to the calculated median
intraperitoneal lethal dose (LD50) in mice. Due to specific method details such as
the vehicle, dilution scheme and laboratory protocols, Units of biological activity
of BOTOX COSMETIC® cannot be compared to or converted into units of any
other botulinum toxin activity. The specific activity of BOTOX COSMETIC® is
approximately 20 Units/nanogram of neurotoxin protein complex.
Pharmacodynamics

No formal pharmacodynamic studies have been conducted with BOTOX
COSMETIC®
(onabotulinumtoxinA) for injection.
Pharmacokinetics

It is believed that little systemic distribution of therapeutic doses of BOTOX
COSMETIC® occurs. BOTOX COSMETIC® is not expected to be presented in
the peripheral blood at measurable levels following IM or intradermal injection at
the recommended doses. The recommended quantities of neurotoxin administered
at each treatment session are not expected to result in systemic, overt distant
clinical effects, i.e. muscle weakness, in patients without other neuromuscular
dysfunction. However, clinical studies using single fiber electromyographic
techniques have shown subtle electrophysiologic findings consistent with
neuromuscular inhibition (i.e. “jitter”) in muscles distant to the injection site, but
these were unaccompanied by any clinical signs or symptoms of neuromuscular
inhibition from the effects of botulinum toxin.

STORAGE AND STABILITY

 Store the vacuum-dried product either in a refrigerator at 2o - 8oC, or in a
 Administer BOTOX COSMETIC® within 24 hours after the vial is removed  During these 24 hours, reconstituted BOTOX COSMETIC® should be stored  Reconstituted BOTOX COSMETIC® should be clear, colorless and free of  Do not freeze reconstituted BOTOX COSMETIC®.  At the time of use, product acceptability should be confirmed relative to the expiration date indicated on the product vial and outer box.

SPECIAL HANDLING INSTRUCTIONS

All vials, including expired vials, or equipment used with the drug should be
disposed of carefully as is done with all medical waste.
DOSAGE FORMS, COMPOSITION AND PACKAGING
BOTOX COSMETIC® is available in 100 and 200 unit (U) sterile vials of
Clostridium botulinum toxin type A in a vacuum-dried form without a
preservative. One Allergan unit (U) corresponds to the calculated median lethal
dose (LD50) in mice using reconstituted BOTOX COSMETIC® and injected
The quantities of the ingredients in each vial are listed below: INGREDIENTS
100 Allergan U Vial
200 Allergan U Vial
Clostridium botulinum toxin type A PART II: SCIENTIFIC INFORMATION
PHARMACEUTICAL INFORMATION
Drug Substance
Proper name: OnabotulinumtoxinA for injection
Molecular formula: The amino acid composition of the neurotoxin complex
(based on the average of three independent assays) is as follows:
Asx1442Thr485Ser531Glx719Pro237Gly395Ala341Val390Cys103Met84Ile644Leu718Tyr499Ph
e356Lys486His47Arg241Trp115 where Asx represents a mixture of Asn and Asp, and Glx represents a mixture of Gln and Glu. Molecular mass: 900kD Structural formula: The Purified Neurotoxin Complex is a 900 kD complex composed of a 150 kD neurotoxin, a 130 kD non-toxic, non-hemagglutinating protein, and various hemagglutinins ranging between 14 and 48 kD. The 150 kD neurotoxin is produced as a single-chain polypeptide. The polypeptide is activated by the proteolytic enzymes of C. botulinum during fermentation in a process known as nicking, which converts the single-chain polypeptide into a di-chain polypeptide comprised of a 97 kD heavy chain linked by a disulfide bond to a 53 kD light chain. The complete amino acid sequence of the neurotoxin was derived from a cloned DNA sequence. The neurotoxin, before nicking, consists of 1296 amino acids (1295 after the Met at the N-terminus is cleaved. Ten amino acid residues, from Leu438 - Lys447, are removed during nicking. The primary release procedure for BOTOX COSMETIC® uses a cell-based potency assay to determine the potency relative to a reference standard. The assay is specific to Allergan’s product BOTOX COSMETIC®. One Allergan unit (U) of BOTOX COSMETIC® 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 COSMETIC® 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 COSMETIC® is approximately 20
Units/nanogram of neurotoxin protein complex.

CLINICAL TRIALS

In a clinical study, the safety and efficacy of BOTOX COSMETIC®
(onabotulinumtoxinA for injection) was compared with placebo for the treatment
of glabellar lines. BOTOX COSMETIC® was administered to 203 subjects as a
single treatment of intramuscular injections at 5 sites, 2 in each corrugator muscle
and 1 in the procerus muscle. Each injection was 0.1 mL (4 U), for a total of 0.5 mL (20 U). The following was concluded: · >80% of subjects responded to treatment as rated by investigators and >90% by self-assessment. For both primary efficacy variables, the investigator’s rating of glabellar line severity at maximum frown and the subject’s global assessment of change of appearance of glabellar lines, there was a statistically and clinically significant higher responder rate with BOTOX COSMETIC® than with placebo at all timepoints from day 7 through day 120 (p<0.001). For the investigator’s rating of glabellar line severity at rest, there was a significantly higher responder rate with BOTOX COSMETIC® than with placebo at all timepoints. Subgroup analyses of the primary efficacy variables by age group (≤50 years and ≥51 years) and by investigator gave results similar to those for the overall study population. Subjects rated their impression of improvement even more highly than did the investigators, particularly later in the study. By day 120, 44.1% of subjects rated their appearance as at least moderately improved. COSMETIC® was shown in this study to be well-tolerated, with no treatment-related serious adverse events. The safety and efficacy of BOTOX COSMETIC® for the treatment of horizontal forehead lines has been described in published investigator clinical studies. BOTOX COSMETIC® was administered to 59 subjects as a single treatment of intramuscular injections at injection doses into the frontalis of 8, 16 and 24 U. The following was concluded: · Approximately 90% of subjects responded to treatment as rated by investigators and up to 75-80% by self-assessment. · There was a reduction in horizontal rhytide severity in all three BOTOX COSMETIC® treatment groups at both contraction and repose. · There was a significant dose-response trend for rate of improvement at maximum brow elevation: 53% in the 24 U group versus 15% in the 8 U group at 16 weeks, by a trained observer. · There was a significant dose-response trend for rate of relapse to baseline: 35% in the 24 U group versus 75% in the 8 U group at 16 weeks, by a trained observer. · BOTOX COSMETIC® was shown in this study to be well-tolerated, with no treatment-related serious adverse events. The most common treatment-related adverse events were headache, local pain and swelling resulting from injection. In another published investigator clinical study, the safety and efficacy of BOTOX COSMETIC® was compared with placebo for the treatment of lateral canthal lines (crow’s feet). BOTOX COSMETIC® was administered to 60 subjects in orbicularis oculi muscle as a single injection treatment at one of 3 doses (6, 12 and 18 U total) on one side, and placebo contralaterally. In a second study of lateral canthal lines, BOTOX COSMETIC® (5-15 U) was injected on each side in 80 subjects. The following was concluded: · BOTOX COSMETIC® was associated with significantly higher success rates than placebo at all dose levels, as determined by both trained observers and patients. · At four weeks post-injection, 89-95% patients on the BOTOX COSMETIC®- treated side were considered by investigators as treatment responders, and 60-80% of patients felt they had treatment success, compared to approximately 5-15% and 15-45%, respectively on the placebo-treated side. · No clear dose-response relationship was observed. · Benefits of the second injection lasted longer than the first. The success rate of a second injection reached 100% for the 12 and 18 U groups, and approximately 80% of patients were considered treatment successes at 16 weeks, for all groups. · Patient surveys revealed high satisfaction with BOTOX COSMETIC® treatments; 89% described themselves as satisfied or very satisfied; 93% indicated they would undergo treatment again. COSMETIC® was well tolerated. No serious or severe adverse events were reported. The most common adverse event related to treatment was bruising; the incidence was similar on the placebo-treated side.
DETAILED PHARMACOLOGY

BOTOX COSMETIC® (onabotulinumtoxinA for injection) blocks neuromuscular
transmission by binding to acceptor sites on motor 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 COSMETIC® produces
partial chemical denervation of the muscle resulting in localized reduction in
muscle activity and possible muscle atrophy. When chemically denervated,
axonal sprouting may occur, and extrajunctional aceylcholine receptors may
develop. There is evidence that reinneration of the muscle may occur, thus
reversing muscle denervation produced by localized injection of BOTOX
COSMETIC®.
TOXICOLOGY
Mutagenicity Studies:
BOTOX COSMETIC® (onabotulinumtoxinA for injection) was not mutagenic in
the in vitro Ames microbial mutagen test with or without metabolic activation at
a maximum concentration of 42.9 U/plate using tester strains of Salmonella
typhimurium
and Escherichia coli. No increases in the average mutant
frequencies were seen in in vitro evaluations of BOTOX COSMETIC® at dosages
as high as 43.0 U/plate (approximately 100,000 times the maximum anticipated
clinical dose, based upon 360 U/60 kg person) with and without metabolic S9
activation in AS52/XPRT mammalian cells. No chromosomal aberrations were
produced in in vitro evaluations of BOTOX COSMETIC® in Chinese hamster
ovary cells at dosages as high as 43.0 U/kg with and without metabolic activation.
No clastogenic effects were observed in in vivo micronucleus evaluations of
BOTOX COSMETIC® in mice at doses as high as six to seven times the
maximum anticipated human dose.
Fertility and Reproductive Toxicity:
A fertility and reproductive toxicity study with BOTOX COSMETIC® was
evaluated in rats. No effects on reproduction were observed following
intramuscular injection of BOTOX COSMETIC® at dosages of 4 U/kg
(approximately 2/3 of the maximum recommended human dose) in male rats and
at dosages of 8 U/kg in female rats. Higher dosages (8 and 16 U/kg) were
associated with dose-dependent reductions in fertility in male rats, and the
cohabitation period was slightly increased at dosages of 16 U/kg. Altered estrous
cycling (prolonged diestrus) and interrelated reductions in fertility occurred in the
female rats dosed with 16 U/kg.

Teratogenic Effects:
The teratogenic effects of BOTOX COSMETIC® were evaluated in mice, rats and
rabbits. No teratogenic effects were observed when presumed pregnant mice
were injected intramuscularly with doses of 4 U/kg (approximately 2/3 of the
maximum recommended human dose) and 8 U/kg on days 5 and 13 of gestation;
however, dosages of 16 U/kg induced a slightly lower fetal body weight. No
teratogenic effects were observed in rats when injected intramuscularly with doses
of 16 U/kg on days 6 and 13 of gestation, and 2 U/kg/day on days 6 through 15 of
gestation. In rabbits, daily injections at dosages of 0.5 U/kg/day (days 6 through
18 of gestation) and 4 and 6 U/kg (days 6 and 13 of gestation) caused death and
abortions among surviving animals. External malformations were observed in the fetus in one 0.125 U/kg/day and one 2 U/kg dosage. The rabbit appears to be a more sensitive species to BOTOX COSMETIC®. Reproductive and Developmental Effects: The reproductive and developmental effects of BOTOX COSMETIC® were evaluated in rats at dose levels of 4, 8 and 16 U/kg. Muscle atrophy at the injected site, reduced body weight gains and reduced absolute feed consumption were observed following intramuscular injection of BOTOX COSMETIC® at dosages of 4 U/kg and higher on days 5 and 13 of presumed gestation, and day 7 of lactation. No effects on maternal reproductive performance were observed at the highest dose tested, 16 U/kg (approximately three times the maximum recommended human dose). No adverse effects on development of the pups was observed at 4 U/kg; however, higher dosages were associated with reduced pup body weight and/or pup viability at birth. Animal Toxicology Studies: There were no observable toxic effects in rats that received a single intravenous or intramuscular injection of 5 U/kg of BOTOX COSMETIC®, and in monkeys that received 8 U/kg intramuscularly. In a one year study where monkeys received seven intramuscular injections (once every two months), there were no observable toxic effects at a BOTOX COSMETIC® dosage level of 4 U/kg (approximately 2/3 of the maximum recommended human dose). Three out of six female monkeys in the 16 U/kg group were sacrificed in extremis. This probably was a treatment-related effect of high doses of BOTOX COSMETIC®. Local muscle atrophy and degeneration at the injection site (expected pharmacological effects) were observed in all BOTOX COSMETIC® treated monkeys. There was evidence of systemic toxicity in animals treated with 8 U/kg and 16 U/kg. No antibodies were detected in the sera of animals during the study. In a 20 week study where juvenile monkeys received a series of three im injection sessions (each session divided into four sites, distributed bilaterally into the heads of the gastrocnemius muscles, and given at 8 week intervals), the NOEL was at a BOTOX COSMETIC® dosage level of 8 U/kg. Local pharmacologic effects were observed in all BOTOX COSMETIC®-treated animals and included decreases in size and weights of the injected site (gastrocnemius muscles) and microscopic observations of muscle fiber atrophy with occasional involvement of the underlying soleus muscle. Systemic effects included a slight transient decrease in body weight gains in animals receiving 12 U/kg. Antigenicity: Antigenicity studies in rats and guinea pigs showed no effects. In an indirect hemagglutination assay, mice were immunized once per week for two weeks. Both the placebo (human serum albumin) and BOTOX COSMETIC® were antigenic when Complete Freund's Adjuvant (CFA) was used. No antigenicity was detected without the adjuvant. Ocular or dermal irritation: No ocular or dermal irritation was observed in rabbits at concentrations of BOTOX COSMETIC® up to 200 U/mL. REFERENCES
1. Blitzer A, Binder W, Aviv J, Keen M, Brin M. The management of hyperfunctional facial
lines with botulinum toxin- A collaborative study of 210 injection sites in 162 patients. Arch Otolar Head Neck Surg 1997;123:389-392. 2. Carruthers A and Carruthers J. Chapter 20: Botulinum toxin and laser resurfacing for lines around the eyes. In: Management of Facial Lines and Wrinkles. Binder J, Boyd J B and Carruthers A, ed. Lippincott Williams and Wilkens, Philadelphia, 2000. 3. Carruthers A and Carruthers J. Botulinum toxin in the treatment of glabellar frown lines and other facial wrinkles. In: Neurological Disease and Therapy. Therapy with Botulinum Toxin. Jankovic J and Hallett M, ed. New York: Marcel Dekker 1994;25:577-595. 4. Carruthers A and Carruthers J. Botulinum Toxin Type A in the treatment of hyperfunctional facial lines and cosmetic disorders. In: MF Brin, J Jankovic, M Hallett (eds.) Scientific and Therapeutic Aspects of Botulinum Toxin. Pennsylvania: Lippencott Williams and Wilkens, 2002: Chapter 27, p. 287-93. 5. Carruthers A and Carruthers J. Clinical indications and injection technique for the cosmetic use of Botulinum A exotoxin. J Dermatol Surg 1998;24:1189-94. 6. Carruthers A, Carruthers J, and Cohen J. A prospective, double-blind, randomized, parallel- group, dose-ranging study of botulinum toxin type A in female subjects with horizontal forehead rhytides. Dermatol Surg 2003 May;29(5):461-7. 7. Ellis DAF and Tan AKW. Cosmetic upper-facial rejuvenation with botulinum. J 8. Garcia A and Fulton JE Jr. Cosmetic denervation of the muscles of facial expression with botulinum toxin A- Dose-response study. Dermatol Surg 1996;22(1): 39-43. 9. Guerrissi J and Sarkissian P. Local injection into mimetic muscles of botulinum toxin A for the treatment of facial lines. Ann Plastic Surg 1997;39:447-53. 10. Hankins CL, Strimling R and Rogers GS. Botulinum A toxin for glabellar wrinkles: Dose and response. Dermatol Surg 1998;24 (11):1181-3. 11. Keen M, Blitzer A, Aviv J, Binder W, Prystowsky J, Smith H et al. Botulinum toxin A for hyperkinetic facial lines: Results of a double-blind placebo-controlled study. Plast Reconstr Surg 1994a;94:94-9. 12. Keen M, Kopelman JE, Aviv JE, Binder W, Brin M, and Blitzer A. Botulinum toxin A: A novel method to remove periorbital wrinkles. Facial Plast Surg 1994b;10:141-146. 13. Koch RJ, Troell R and Goode R. Contemporary management of the aging brow and 14. Lowe NJ, Maxwell A and Harper H. Botulinum A exotoxin for glabellar folds: A double- blind, placebo-controlled study with an electromyo-graphic injection technique. Am Acad Dermatol 1996;35:569-72. 15. Lowe NJ, Lask Gary, Yamauchi Paul and Moore Donna. Bilateral, double-blind, randomized comparison of 3 doses of botulinum toxin type A and placebo in patients with crow’s feet. J Am Acad Dermatol 2002 Dec;47(6):834-40. 16. Niamtu J. 3rd Botulinum toxin A: A review of 1,085 oral and maxillofacial patient treatments. (1998-2001) J Oral Maxillofac Surg 2003;61(3):317-24. PART III: CONSUMER INFORMATION
BOTOX COSMETIC®
(onabotulinumtoxinA for injection)
BOTOX COSMETIC® is for intramuscular use only. This leaflet is part III of a three-part "Product BOTOX COSMETIC® should only be given by a Monograph" published when BOTOX COSMETIC®
physician with the appropriate qualifications and was approved for sale in Canada and is designed experience in the treatment and the use of required specifically for Consumers. This leaflet is a summary and will not tell you everything about BOTOX
COSMETIC®. Contact your doctor or pharmacist if
Seek immediate medical attention if swallowing, Tell your doctor if you experience any difficulties in ABOUT THIS MEDICATION
BOTOX COSMETIC®, as
it could be related to the dosage. Difficulty in swallowing food, ranging from very mild to severe, can BOTOX COSMETIC® is used to treat upper facial persist for 2-3 weeks after injection, or longer. lines, including forehead, crow’s feet, and frown lines. Tell your doctor if you are taking other medicines, including any you have bought at your pharmacy,  you are allergic or sensitive to any of the INTERACTIONS WITH THIS MEDICATION
you have an infection in the muscles where it would normally be injected. you have any muscle disorders in other parts of BOTOX COSMETIC® may be increased
your body, including myasthenia gravis, Eaton by aminoglycoside antibiotics (e.g. streptomycin, tobramycin, neomycin, gentamicin, netilmicin, kanamycin, amikacin), spectinomycin, polymyxins, tetracyclines, lincomycin or any other drugs that interfere with neuromuscular transmission. OnabotulinumtoxinA for injection is a sterile, form of purified botulinum neurotoxin type A complex PROPER USE OF THIS MEDICATION
What the important nonmedicinal ingredients are: Overdose:
WARNINGS AND PRECAUTIONS
In case of drug overdose, contact a health care practitioner, hospital emergency department or regional Poison Control Centre immediately, even if BOTOX COSMETIC® talk to
you have myasthenia gravis or Eaton Lambert Syndrome, amyotrophic lateral sclerosis or another SIDE EFFECTS AND WHAT TO DO ABOUT THEM
General
Pain, tenderness and/or bruising at the site of injection.
• you have an infection at a proposed injection site. Malaise (generally feeling unwell), lasting up to six • you are scheduled to have surgery using a general weeks after injection with BOTOX COSMETIC®. Weakness and rarely, changes in the way the heart • you are taking or are likely to take antibiotics, beats, chest pain, skin rash and allergic reaction (symptoms: shortness of breath, wheezing or difficulty • you are pregnant or become pregnant while taking breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin). COSMETIC® given to rabbits during pregnancy have caused abortion or fetal malformations. The following events have been reported rarely (<0.1%) • you are nursing. It is not known whether this drug since BOTOX COSMETIC® has been marketed: skin
is excreted in human milk, but many drugs are rash, itching, allergic reaction (including anaphylaxis), dysphagia, respiratory compromise, seizures, and facial
paralysis. There have also been rare reports after
botulinum toxin treatment 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.
This is not a complete list of side effects. For any
unexpected effects while taking
BOTOX
COSMETIC®
, contact your doctor or pharmacist.
REPORTING SUSPECTED SIDE EFFECTS

You can report any suspected adverse reactions
associated with the use of health products to the
Canada Vigilance Program by one of the following 3
ways:
-------------------------------------------------------------------

Report online at
www.healthcanada.gc.ca/medeffect
Call toll-free at 1-866-234-2345
Complete a Canada Vigilance Reporting
Form and:
- Fax toll-free to 1-866-678-6789, or
- Mail to:
Canada Vigilance Program
Health Canada
Postal Locator 0701D
Ottawa, Ontario

Postage paid labels, Canada Vigilance Reporting Form
and the adverse reaction reporting guidelines are available
on the MedEffect™ Canada Web site at
www.healthcanada.gc.ca/medeffect.
NOTE: Should you require information related to
the management of side effects, contact your health
professional. The Canada Vigilance Program does
not provide medical advice.

MORE INFORMATION
This document plus the full product monograph, prepared for health professionals can be found by contacting the sponsor, Allergan at: 1-877-255-3746 or www.allergan.ca This leaflet was prepared by Allergan Last revised: May 23, 2013 2013 Allergan Inc., Markham, ON L6G 0B5 ®Marks owned by Allergan Inc. All rights reserved.

Source: http://www.allergan.ca/assets/pdf/ca_botox_cosm_pm.pdf

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