Status: approved and marketed worldwide

Organizations involved:

Allergan, Inc. – Manuf.; R&D; Tech.; World mark.

GlaxoSmithKline plc – Japan mark.; China mark.

Oculinum Inc. – R&D; Tech.; Former

Smith-Kittlewell Eye Res. Inst. – R&D; Former

University of Wisconsin. – Manuf. other; R&D; Tech.

U.S. Army – R&D; Tech.; Former

Merz GmbH & Co. KGaA – Patent dispute

Cross ref: See the Botulinum Toxin Products entry above for much background information. See also the other Botulinum Toxin product entries below.

Description: BOTOX Purified Neurotoxin Complex (BOTOX) and BOTOX Cosmetic are sterile lyophilized (freeze-dried) powder formulations of botulinum toxin A complex for intramuscular injection. [Note, as discussed below, there have been two different generations of BOTOX using toxin with different potency derived using different methods]. Botulinum toxin A is purified from cultures of Clostridium botulinum (Hall strain) by a series of acid precipitations, resulting in a heavy 900 kilodalton (900 kDa) crystalline toxin complex consisting of the active high molecular weight botulinum toxin A protein, with disulfide bridges at 429-453 and 1234-1279, and an associated hemagglutinin protein also expressed by C. botulinum (along with some similar proteins lacking hemagglutinating activity). Botulinum toxin A in BOTOX is the largest molecule of all marketed botulinum toxin A products with a uniform weight of 900 kDa.

Botulinum toxin A is among the most potent neurotoxins, with a specific toxicity of about 2.5 U/nanogram (nanogram = 10-9 or one billionth of a gram) of dried powder [see below for explanation of BOTOX units]. The amounts used medically are on the order of 1,000- to 100,000-fold less than the estimated human lethal dose (1-2 µg). Botulinum toxin A has potent anticholinergic-type effects and can be injected into muscles to selectively and reversibly reduce or inactivate muscle contraction and control uncontrollable contractions, twitching, etc. The same underlying mechanism that causes toxic effects is the same mechanism that provides clinical benefits. The toxin acts primarily on the parasympathetic nervous system. The mechanism of botulinum toxin is based on this blocking of neurotransmitter release at peripheral cholinergic nerve terminals.

Two generations or versions of BOTOX have been marketed in the U.S. The original product, manufactured from a batch of purified toxin complex produced by researchers at the University of Wisconsin-Madison in 1979, batch 79-11, was used as the source material for BOTOX until the mid-1990s. A second batch of toxin complex, termed “new bulk toxin,” with higher potency then replaced batch 79-11. The new bulk toxin complex may also have been manufactured by the University of Wisconsin-Madison (or at Allergan facilities). [See the “History” section]. BOTOX, but not BOTOX Cosmetic, has been formulated and marketed in the U.S. using both batch 79-11 and, more recently, new bulk toxin complex. BOTOX Cosmetic is newer and has only been formulated using "new bulk toxin."

The amount of toxin biological activity in old (batch 79-11) and more recent (new bulk toxin) BOTOX vials (100 U) has remained unchanged, but the potency (activity per weight) has changed. New bulk (current) toxin has an average potency of 3.4 x 107 mouse (34 million) LD50 units (U)/mg, compared to 0.6 x 107 U (6 million/mg for 79-11 bulk toxin, i.e., the current product is 5-6 times more potent on a by-weight basis. A 100 U vial of the current BOTOX formulation contains only 4.8 ng of new bulk toxin complex, while the 79-11 batch contained 25 ng of 79-11 toxin complex. The higher potency of new bulk toxin, allowing use of less toxin, is presumed to result in reduced antigenicity. Various chemical, rat and monkey, and clinical studies have shown that the two batches are otherwise comparable. BOTOX (both 79-11 and new bulk toxin batches) contains less than 0.1% nucleic acid impurities by spectrometric analysis. Other analyses, including SDS-PAGE, have shown that the biochemical identity of the new bulk toxin and 79-11 bulk toxin are comparable.

BOTOX is packaged in 6.5 mL vials containing 100 units (U) of toxin at a concentration of 500 ng/mL. Vials also contain Albumin (Human) at a concentration of 0.5 mg/vial to stabilize the protein complex and 0.9 mg sodium chloride. The product contains no preservatives. BOTOX has a shelf life of one year when stored frozen below -5˚C (25˚F). BOTOX is shipped to physicians and health care facilities in insulated containers with dry ice. Note, the product insert/labeling refers to BOTOX as being a “vacuum-dried” powder, but the FDA Summary Basis of Approval (SBA) refers to it as being lyophilized (freeze-dried).

Prior to intramuscular injection, BOTOX is reconstituted with sterile, non-preserved saline. BOTOX may be injected into targeted muscles using a special needle to which an monopolar electro-myelo-graphic electrode is attached, allowing the physician to measure muscle contraction activity (and target injections into excessively contracting muscles to halt their contractions).

BOTOX Cosmetic, like BOTOX, is packaged in vials containing 100 units (U) of Clostridium botulinum type A neurotoxin complex, 0.5 mg of Albumin (Human), and 0.9 mg of sodium chloride in a sterile vacuum-dried form without a preservative. BOTOX Cosmetic is considered and regulated by FDA as a drug, not as a cosmetic. BOTOX Cosmetic is reconstituted with 0.9% sterile, non-preserved saline (100 units in 2.5 mL saline) prior to intramuscular injection. The resulting formulation provies 4.0 U per 0.1 mL and a total treatment dose of 20 U in 0.5 mL. BOTOX Cosmetic is supplied as a single patient use vial. The product and diluent do not contain a preservative. Once reconstituted it can be stored at 2-8°C (refrigerated) and used within four hours.

Nomenclature: Botulinum Toxin A/Allergan [BIO]; Botox Cosmetic [TR]; BOTOX Purified Neurotoxin Complex [TR used since 1992; assigned to Allergan]; Vistabel [TR Europe for BOTOX Cosmetic]; Vistabex [TR Europe for BOTOX Cosmetic]; onabotulinumtoxinA [USAN and FDA new in 2009]; Clostridium botulinum type A neurotoxin complex [INN]; onaclostox [former USAN ]; Botulinum toxin type A [FDA old]; botulinum neurotoxin type A (EC 3.4.24.69) from Clostridium botulinium [CAS]; Clostridium botulinum Type A-1 neurotoxin complex (Allergan strain-900 kDa) [CAS]; 93384-43-1 [CAS RN]; Clostridium botulinum toxin type A, Hall strain [SY]; Toxine botulinique A [SY French]; Oculinum [TR used in U.S. until 1992; used in outside U.S.]; NDC 0023-1145-01 [NDC]

The terms Botox, BTX and BT were originally coined by and tended to be used by clinical investigators, while other synonyms, e.g., Botx, BoTX and BoTx, were coined and tended to be used by researchers. Allergan adopted the trade name BOTOX in 1990 and it was registered as a U.S. trademark in 1992. “BOTOX” is used in product labeling (by Allergan) to refer to product approved/packaged for non-cosmetic indications:, while “BOTOX Cosmetic” refers to product approved/packaged for “cosmetic” indications.

Biological.: Uncomplexed botulinum toxin type A protein (pro-toxin) from fermentation of Clostridium botulinum (Hall strain) has a molecular weight of 150 kDa and is composed of (can be cleaved into) a heavy (100 kDa; amino acids 449-1280) and a light chain (50 kDa; amino acids 1-448) linked by a disulfide bond. The light chain, the biologically active component, is associated with a zinc atom, acts as a zinc-dependent endopeptidase with a tetrahedral zinc binding motif, and resembles thermolysin-like endo-pro-teases.

The mechanism of botulinum toxin A is based on this blocking of neurotransmitter release at peripheral choli-nergic nerve terminals (see the Biological section of the Botulinum Toxin Products entry). A 25 kDa synaptosome-associated protein (SNAP-25) associated with the nerve cell membrane is enzymatically cleaved near its C-terminus (G-n197-Arg198) by the botulinum toxin type A light chain. Synaptosomal vesicle fusion requires the interaction of SNAP-25 and other proteins. Enzymatic break down of SNAP-25 disrupts normal binding of synaptosomal vesicles to the axon terminal membrane, and prevents normal stimulation of muscle contraction by blocking the presynaptic release of acetylcholine at the neuromuscular junction, leading to muscle paralysis due to inability to be activated to contract.

One unit of Allergan’s botulinum toxin A (BOTOX) is equivalent to that amount calculated to be mouse median lethal dose (LD50) of the of the reconstituted toxin by intraperitoneal administration in mice. For medical applications, one unit (U) is considered to be 1 murine LD50. Toxin titers are determined in female, white mice, 18-22 g in weight according to the method of Schantz and Kautter as described in Journal of the Association of Official and Analytical Chemistry, vol. 61, p. 96, (1978). High quality (pharmaceutical) type A toxin complex is generally considered to require a specific toxicity of at least 3 x 107 mouse intraperitoneal 50% lethal doses (LD50) per mg.

Studies in rats (using new bulk toxin) receiving intravenous injections have shown the no-observed-effect level (NOEL) for botulinum toxin A toxicity to be 10 units/kg, with the LD50 estimated to be 54.2 U/kg in male and 7.06 U/kg in female rats. The LD50 for intramuscular injection in rats is reported to be 209.3 U/kg in male and 200.0 U/kg in female rats. The NOEL in cynomolgus monkeys after intramuscular injection is 8 U/kg.

The gene sequence for botulinum toxin A was first reported by Thompson D.E., et al., Centre for Applied Microbiology & Research (CAMR; Porton Down, Salisbury, U.K.), with an EMBL locus of CBBOTAG and accession numbers X52066 and X52088. The gene has 4,292 bases. Note, CAMR manufactures a botulinum type A toxin, Reloxin/Dysport, not approved in the U.S. (See related entry).

History: See the History section of the Botulinum Toxin Products entry. The Hall strain of C. botulinum was originally obtained by Dr. J.H. Mueller, Harvard Univ., and developed at Fort Detrick by screening strains for high toxin production.

High purity, crystalline type A botulinum toxin complex (batch 79-11) was prepared in Nov. 1979 by E.J. Schantz, et al., Food Research Institute/Department of Food Micro-biology and Toxicology, University of Wisconsin-Madison. This was provided to Oculinum Inc. for further manufacture, testing and marketing (after approval) as Oculinum, the predecessor of BOTOX products from Allergan. Batch 79-11 consisted of about 150-200 mg of type A toxin complex. This was sufficient purified toxin complex to provide for manufacture of Oculinum/BOTOX for nearly two decades, and was used for manufacture of approximately 250,000 injections (doses).

Dr. Alan Scott, an ophthalmic surgeon with the Smith-Kittlewell Eye Research Institute (San Francisco, CA), is generally considered responsible for the conception and development of the medical uses of botulinum toxin. In the late 1960s, he searched for a suitable toxin for experimental studies and obtained a supply of botulinum toxin type A from Dr. E.J. Schantz, then at Fort Detrick (U.S. Army Medical Research Institute for Infectious Diseases/USAMRIID). The toxin was used in primate studies using a surgically-induced model for strabismus. Dr. Scott began using botulinum toxin type A for treatment of strabismus in rhesus monkeys in 1973, and subsequently began studies in humans.

The U.S. became a party to the Biological and Toxins Weapons Convention in 1972, and halted research and development of offensive biological warfare capabilities (including botulinum toxins). Dr. Schantz and others, then at the Dept. of Food Science, Univ. of Wisconsin (Madison, WI), continued toxin related research and collaboration with Dr. Scott. During the 1970s, these researchers worked to improve the purity of toxin and methods for its preservation for medical uses. Dr. Scott, then with a company he founded, Oculinum, Inc. (Berkeley, CA), initiated human trials in 1976 under an IND. Manufacturing methods not including meat animal products were developed. Dr. E.A. Johnson joined the Univ. of Wisconsin group in 1985 and several new toxin batches were prepared for laboratory and clinical studies. In 1986, Oculinum initiated pivotal U.S. clinical trials using batch 79-11 material. Oculinum subsequently obtained FDA approval and manufactured and marketed the product under the trade name Oculinum.

By the early 1990s, it was clear that antibodies to botulinum toxin type A complex were developing in some patients, particularly those receiving higher and/or more frequent doses. University of Wisconsin investigators demonstrated that this was due to the antigenicity of detoxified toxin, and it was concluded that a purer product should be produced to reduce antigenicity. Toxin detoxification was found to be the result of lyophilization in the presence of sodium chloride. The investigators developed a lyophilization method using toxin dissolved along with Albumin (Human), with the product reconstituted prior to use with sodium chloride solution (saline), which helps stabilize the molecule. The resulting toxin-albumin solution could be lyophilized with about 95% recovery of toxin, and was completely soluble in saline for injection.

In 1991, the Univ. of Wisconsin transferred certain toxin batches and information to Allergan, which had acquired Oculinum Inc. This may have included lyophilized high purity type A toxin in albumin that became the source for current, second-generation (replacing batch 79-11) batch of botulinum toxin type A, originally termed “new bulk toxin,” now marketed by Allergan. However, due to (or conveniently attributed to) national security concerns, little authoritative information is available about the source of the toxin now in Botox/Botox Cosmetic and other products.

Companies.: BOTOX was originally developed and manufactured by Ocuilnum Inc. Allergan, Inc. licensed exclusive worldwide marketing and development rights from Oculinum in 1988. Allergan acquired the remaining assets of Oculinum in July 1990, including its Berkeley, CA, toxin manufacturing facilities.

In Oct. 2005, Allegan granted GlaxoSmithKline plc exclusive marketing rights for BOTOX in Japan and China

In Jan 2008, Allergan announced it would be closing its manufacturing facility in Arklow, Co Wicklow, Ireland, U.K., which had been used for manufacture of BOTOX. Presumably, toxin for BOTOX products is currently sourced from toxin manufactured by the Univ. of Wisconsin and/or by Allergan facilities in Berkeley, CA.

Manufacture: Crystalline type A botulinum toxin complex was first prepared in 1979 by Dr. E.J. Schantz, et al., Food Research Institute/Department of Food Microbiology and Toxicology, University of Wisconsin (Madison, WI). This group manufactured the first batch/lot of botulinum toxin A complex, referred to as lot 79-11, which was further manufactured and marketed as Oculinum and BOTOX for years, respectively, by Oculinum and Allergan. Allergan in recent years has switched to marketing BOTOX manufactured from a second, new batch/lot of toxin type A (new bulk toxin) with higher specific activity (potency). The original batch (79-11) of toxin complex manufactured by the Univ. of Wisconsin involved production of 150-200 mg of twice crystallized product.

Little substantive information about actual product manufacturing processes, locations, etc., is currently available from Allergan or other sources, apparently due to sensitivity about potential terrorist use or diversion of toxin and public misconceptions about the dangers of the toxin. Information about the methods of purification is considered particularly sensitive.

The toxin is not that difficult to manufacture (e.g., C. botulinum can be cultured from contaminated food), but it is difficult to purify a stable product in large quantity. Some of the methods actually used to achieve high levels of toxin production and for large-scale purification are proprietary (unpublished/unpa-ten-ted).

Various sources have indicated that BOTOX has been manufactured at different locations, e.g., FDA has ascribed manufacturing to Allergan’s Berkeley, California facilities, while product inserts/labeling have reported manufacture in Ireland. With the closure of facilities in Ireland, manufacture is now consolidated in the U.S. Allergan may manufacture BOTOX using stocks of crystal-line toxin complex, perhaps, obtained from the Univ. of Wisconsin, or the product may be fully manufactured in-house at the original Oculinum, now Allergan, facilities in Berkeley, CA. With concerns (a convenient excuse) related to potential terrorism, Allergan does not discuss anything related to BOTOX manufacture.

Manufacture of BOTOX involves fermentation of culture of the Clostridium botulinum (Hall strain) in a defined medium containing NZ (or N-Z) Amine A, yeast extract and glucose. Fermen-tation in sealed 12 L carboys (plastic drums) has been reported by the University of Wisconsin. The Hall strain is used because it produces high toxin titers (106 or more mouse LD50 units/mL at 37˚C) within 24-36 hours. Also, most of this strain’s cells lyse and release toxin into the spent medium within several days of culture, which is generally performed at 37˚C for 3-4 days. Unlike other strains requiring meat for high toxin production, the Hall strain produces high yields in a simplified clear medium of hydrolyzed casein (bovine source), yeast extract, and dextrose.

As reported in U.S. patent 5,512,547 (not specific to BOTOX) by researchers at the University of Wisconsin, cultures of the Hall A strain can be grown statically in 10-20 liter volumes of toxin production medium (TPM) consisting of 2.0% NZ amine or TT (Sheffield Labs.), 1.0% yeast extract (Difco), and 0.5% dextrose, pH 7.37.4, for 5-7 days at 37˚C; and the type A toxin complex can be purified according to Good-nough, M.C. (Characterization and stabilization of Clostridium botulinum toxin for medical use, Ph.D. thesis, Univ. of Wisconsin-Madison), adapted from Tse, et al.,1982.

The toxin is purified from culture fluid supernatant by repeated acid precipitation, washing of the precipitate with water, and extraction of the toxin with sodium chloride solution weakly buffered with phosphate at pH of 6.5-6.8. The final step is crystallization of the purified toxin at 4˚C dissolved in phosphate buffered solution (PBS) at about pH 6.8 with the addition of 4 M ammonium sulfate to bring the concentration to 0.9 M. The toxin has been shown to remain stable and active for many years suspended in this ammonium sulfate solution. The solution contains a crystalline complex (purified neurotoxin complex) consisting of the active high molecular weight botulinum toxin A protein and an associated hemagglutinin protein. The stable purified toxin complex has a concentration of about 2 or more mg protein per mL. This must be diluted to 10,000-20,000 or more times prior to injection for therapeutic use.

The crystalline complex is redissolved in a solution containing saline and Albumin (Human) and sterile filtered (0.2 µm filter) prior to filling and lyophilization. After dissolution, 0.1 ml is placed in vials and lyophilized (freeze-dried) to obtain 100 +/- .30 U of active toxin, 0.5 mg of albumin, and 0.9 mg of sodium chloride per vial. The bulk product is filled into vials and sealed under inert nitrogen atmosphere. At least with the 79-11 batch, considerable loss (up to 90%) of activity during drying resulted in the formation of inactive toxin that can act as a toxoid (inactivated toxin vaccine), potentially inducing neutralizing antibody formation (leading to loss of potency). As reported in the FDA Summary Basis of Approval (SBA) document for the original product from Oculinum, filling and lyophilization were performed by Adria SP, Inc. under contract to Oculinum. Vials of lyophilized product are stored at or below -5˚C.

The final product is tested for potency, sterility, general safety, moisture and pyrogen. Potency is determined by a mouse LD50 assay. Acceptable potency values are 100 units +/- 30% per vial for a two test mean, or 100 units +/- 15% for a four test mean. According to the original SBA, safety and potency testing was performed by Northview Pacific Labs. The absence of pyrogens is tested using the Limulus amebocyte lysate (LAL) assay. A modified general safety test is used where the toxin is first neutralized by mixing with type A botulinum-specific antitoxin. Purity is determined by gel electrophoresis and measurement of nucleic acid content.

Crystalline toxin A complex dissolved in 0.05 M sodium phosphate buffer at pH 6.8 has maximum ultraviolet light absorption at 278 nm. The amount of absorption divided by 1.65, the extinction from 1 mg of toxin, yields the total mg of type A toxin complex in a sample. Absorption of light at 260 nm is used to measure residual nucleic acid content, with the 260/278 nm ratio used as an index of purity of the toxin. The ratio for the most highly purified toxin reported is about 0.5, but ratios around 0.6 are acceptable (indicating nucleic acids about 0.08%-0.1%). Immu-nologic assays are not suitable for botulinum toxin quantization for human use.

FDA class: Biologic PLA

CBER class: Toxoids And Toxins For Immunization

CBER to CDER: Among the products transferred within FDA on June 30, 2003

Approvals: Date = 19891229, first approval; PLA ref. no. 85-0227, ELA ref. no. 85-0226; granted to Oculinum, Inc. for BOTOX manufactured from bulk toxin complex lot no. 79-11 (from the Univ. of Wisconsin); orphan designation (expired 12/1996); Indication = treatment of blepharospasm associated with dystonia in adults (patients 12 years of age and above; treatment of strabismus associated with dystonia in adults (patients 12 years of age and above)

Date = 19911209; BLA approval revoked from Oculinum and granted (resissued) to new owner, Allergan

Date = 20001221; BLA supplement (PLA/ELA later converted to BLA); Indication = treatment of cervical dystonia to reduce the severity of abnormal head position and neck pain

Date = 20020412; BLA supplement for BOTOX Cosmetic, with its own insert/labeling; Indication = for the temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in adult patients < 65 years of age

Date = 0040420; BLA supplement; Indication = treatment of severe primary axillary hyperhidrosis (severe underarm sweating) that is inadequately managed with topical agents.

Date: = 20101015; BLA supplement; Indication = prevent headaches in adult patients with chronic migraine [defined as having a history of migraine and experiencing a headache on most days of the month] Date: = 2010309; BLA supplement; Indication = treat spasms of the elbow, wrist and fingers Date = 20110824; BLA supplement; Indication = for injection for the treatment of urinary incontinence due to detrusor overactivity associated with a neurologic condition (e.g. spinal cord injury (SCI), multiple sclerosis (MS)) in adults who have an inadequate response to or are intolerant of an anticholinergic medication.

Date = 20130118; BLA supplement; Indication = for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency and frequency in adults who have had an inadequate response to or are intolerant of an anticholinergic medication. indications: [full text of the "Indications and Usage” section of BOTOX insert/labeling, Jan. 2013]:

indicated for:
• Treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and frequency, in adults who have an inadequate response to or are intolerant of an anticholinergic medication
• Treatment of urinary incontinence due to detrusor overactivity associated with a neurologic condition [e.g., spinal cord injury (SCI),
multiple sclerosis (MS)] in adults who have an inadequate response to or are intolerant of an anticholinergic medication
• Prophylaxis of headaches in adult patients with chronic migraine (≥15 days per month with headache lasting 4 hours a day or longer)
• Treatment of upper limb spasticity in adult patients
• Treatment of cervical dystonia in adult patients, to reduce the severity of abnormal head position and neck pain
• Treatment of severe axillary hyperhidrosis that is inadequately managed by topical agents in adult patients
• Treatment of blepharospasm associated with dystonia in patients ≥12 years of age
• Treatment of strabismus in patients ≥12 years of age
Important limitations: Safety and effectiveness of BOTOX have not been established for:
• Prophylaxis of episodic migraine (14 headache days or fewer per month).
• Treatment of upper limb spasticity in pediatric patients, and for the treatment of lower limb spasticity in adult and pediatric patients.
• Treatment of hyperhidrosis in body areas other than axillary.

indications: [full text of “Cosmetic indications: and Usage” section of product insert/labeling for BOTOX Cosmetic, Jun 2012]:

BOTOX® Cosmetic is indicated for the temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in adult patients ≤ 65 years of age.

Status: The original FDA approval of BOTOX was not made on the basis of controlled clinical trials. Rather, Oculinum requested and was granted “a waiver of the requirement for adequate and well controlled studies to substantiate certain labeling statements.” The FDA recognized that botulinum toxin had been used experimentally for strabismus since 1977, that there was considerable literature describing botulinum toxin use for blepharospasm and strabismus, and that, “Based on over 4,000 patients treated for strabismus, and a similar number treated for blepharospasm, a description of the safety and efficacy of the drug can be provided. Most of the data in these studies were derived from ‘open’ studies where that data were collected from many investigators.”

The Vaccines and Related Biological Products Advisory Committee, FDA, reviewed the product at its Oct. 1982 and July 1986 meetings. The 1982 meeting mainly considered use in large muscles and the 1986 meeting considered use for the approved non-cosmetic indications:. [Note, botulinum toxin type B (MyoBloc) was approved for the same cervical dystonia indications: on the same day as BOTOX].

Prior to approval of BOTOX Cosmetic, BOTOX was extensively promoted and advertised (not by Allergan) for off-label (unapproved) uses, particularly as a wrinkle remedy, with some physicians/clinics even offering this on a walk-in basis. BOTOX can reduce the appearance of wrinkles, e.g., glabellar (frown) lines, by selectively weakening facial muscles. In a Nov. 18, 1994, Federal Register notice, FDA denounced the promotion of such unapproved use as “an egregious example of promoting a potentially toxic biologic for cosmetic purposes.” However, this practice persisted (and persists), with some physicians/clinics advertising walk-in and shopping mall clinics and BOTOX parties for group cosmetic toxin administration.

Even after the approval of BOTOX Cosmetic, much of current use of both BOTOX products is for off-label indications:, e.g., use in other facial muscles than those specifically approved, for non-axillary hyperhidrosis, a wide variety of spasmodic neuromuscular conditions and pain relief, migraine headaches, etc. See the Botulinum Toxin Products entry for a listing of some of botulinum toxin’s many off-label uses.

Note, the FDA Summary Basis of Approval (SBA) document for the original approval cites the crystalline botulinum toxin type A complex (type A toxin complexed with hemagglutinin) as “source material,” with BOTOX manufactured from this by Oculi-num (now Allergan). Apparently, from FDA’s perspective, starting with this bulk toxin, manufacture of BOTOX by Oculinum/Allergan largely involves dilution and formulation of the toxin complex with albumin and saline, filing of vials, lyophilization, and packaging. The University of Wisconsin facilities which manufactured the 79-11 botulinum toxin type A complex were, from available documents, apparently not part of the FDA product/establishment licensing process. This suggests that the University of Wisconsin or another source could be the source of the “new batch” botulinum toxin type A complex used for manufacture of the current product; or Allergan may have manufactured its own botulinum toxin source material. Current FDA and company materials are unclear regarding the manufacturing site(s) for BOTOX, with some sources indicating manufacture in Berkeley, CA, and earlier materials indicating in Ireland.

BOTOX was approved in the European Union in June 2003.

With the post 9/11 concerns about bioterrorism and biological warfare, e.g., Iraq, North Korea, and other countries, and potentially terrorist groups, have been presumed to have manufactured or investigated manufacture of botulinum toxin for offensive use. Since 9/11/2001, even less substantive information related to BOTOX and its manufacture is available from Allergan, FDA, and other sources.

In June 2003, CBER/FDA issued its second official Warning Letter to Allergan concerning alleged misrepresentation of the product in three journal advertisements. The first Warning Letter was issued in April 2001, with other untitled letters issued in Nov. 2000; Feb. 2000, April 2001 and Sept. 2002; with Review Memoranda issued in Dec. 1998 and Sept. 2000. In the most recent Warning Letter, FDA cited Allergan’s misbranding of BOTOX Cosmetic as “America’s most popular cosmetic treatment,” with BOTOX being a biologic and therapeutic, not a cosmetic. FDA objected to the ads promoting BOTOX to reduce frown lines [while it is only approved for glabellar lines (vertical frown lines between the eyebrows)]. FDA also cited Allergan for minimizing the risks from BOTOX by including the phrase “if any occur” at the end of its fair balance (warning) statement, even though almost 50% of BOTOX patients experience some form of adverse event. Allergan received and responded to similar allegations in prior FDA letters.

On March 13, 2006, Vistabel (BOTOX Cosmetic) received approval in the U.K. for the temporary improvement in the appearance of moderate to severe glabellar lines in adult women and men aged 65 and younger, when the severity of these lines has a psychological impact for the patient. Vistabel was the first and only botulinum toxin type A licensed for cosmetic use in the U.K.

In March 2006, Allergan reported, “Since 1989, BOTOX has been approved for 20 indications: in more than 75 countries."

In Jan. 2008, FDA received a "citizen's petition" from Public Citizen, representing 100,000 consumers nationwide, seeking FDA to require Allergan and Solstice Neurosciences to issue a warning letter to physicians regarding Botox and Myobloc, respectively. This letter would alert physicians to serious problems, including hospitalizations and deaths, resulting from the spread of the toxin from the site of injection to other parts of the body. The petition also requested black box warnings in the product label and a MedGuide for patients, to be dispensed by doctors at the time the drug is injected.

Public Citizen had done its own analysis of the FDA Adverse Event database (AERS) for Botox and Myobloc (excluding foreign reports) and found 180 adverse event cases submitted by the manufacturers relating to these conditions, including 16 deaths. Four of these deaths occurred in children less than 18 years of age. Allergan responded, "There are no safety issues raised in the petition that are not already addressed in the labeling for BOTOX."

In Jan 2008, a week after the Public Citizen filing in the U.S., Health Canada reported it was reviewing safety information on Botox.

The European Union (EU) had posted a series of warnings concerning botulinum toxin on its Web site alerting physicians in its member states about the need to monitor for signs of botulinum toxin adverse events. The U.K. and Germany amplified the EU warning with “Dear Doctor Letters,” but no similar official warnings been required by FDA. P.

In Feb. 2008, FDA issued "Early Communication about an Ongoing Safety Review Botox and Botox Cosmetic (Botulinum toxin Type A) and Myobloc (Botulinum toxin Type B)."

In May 2008, Allergan received a subpoena for documents related to the promotion of Botox from the U.S. Attorney's Office for the Northern District of Georgia, broadly requesting documents regarding promotional, educational and other activities. The inquiry involved questions regarding alleged off-label promotion for the treatment of headache.

In May 2009, Allergan received a complete response letter regarding its sBLA to treat upper limb spasticity in post-stroke adults. The FDA did not request additional pre-approval clinical studies. However, the FDA identified items that must be completed before the sBLA can be considered for approval.

In July 2010, the UK regulators became the first country to issue approval for the use of Botox for preventive treatment for chronic migraine. MHRH approved Botox for adults who have headaches for at least 15 days per month with migraine on at least eight of these days.

In April 2011, Allergan Inc. was ordered by a Virginia federal jury trial to pay $212 million to a 67-year-old man with permanent brain damage after being injected with Botox to treat cramps and tremors in his hand in 2007. The jury awarded $12 million in compensatory damages and $200 million in punitive damages, citing that Allergan failed to warn him that injections could trigger an autoimmune reaction leading to brain damage. Allergan presumably appealed the verdict.

In Sept. 2010, Allergan plead guilty and paid $600 million to resolve its criminal and civil liability arising from the company's unlawful promotion of Botox Therapeutic, for uses not approved as safe and effective by FDA. The resolution included a criminal fine and forfeiture totaling $375 million and a civil settlement with the federal government and the states of $225 million. The U.S. Attorney for the Northern District of Georgia, had charged Allergan with off-label promotion of Botox for headache, pain, spasticity and juvenile cerebral palsy - none of which were approved by the FDA; and Allergan made it a top corporate priority to maximize sales of Botox for such off-label uses. It was alleged that Allergan exploited its on-label cervical dystonia (CD) indication to grow off-label pain and headache (HA) sales. In 2003, Allergan developed the "CD/HA Initiative" as a "rescue strategy" in the event of negative results from its clinical trials to ensure continued expansion into the pain and headache markets. As part of this initiative, Allergan claimed that cervical dystonia was "underdiagnosed" and that doctors could diagnose cervical dystonia based on headache and pain symptoms, even when the doctor "doesn't see any cervical dystonia." In 2003, Allergan doubled the size of its reimbursement team to assist doctors in obtaining payment for off-label Botox® injections. Allergan held workshops to teach doctors and their office staffs how to bill for off-label uses, conducted detailed audits of doctors' billing records to demonstrate how they could make money by injecting Botox®, and operated the Botox® Reimbursement Hotline, which provided a wide array of free on-demand services to doctors for off-label uses. Allergan also lobbied government health care programs to expand coverage for off-label uses, directed physician workshops and dinners focused on off-label uses, paid doctors to attend "advisory boards" promoting off-label uses, and created a purportedly independent online neurotoxin education organization to stimulate increased use of Botox for off-label indications:. Allergan agreed to plead guilty to a criminal misdemeanor for misbranding Botox in violation of the FDCA. Under the plea agreement, the company will pay a criminal fine of $375 million, which includes forfeiting assets of $25 million. Allergan has also executed a Corporate Integrity Agreement (CIA) with the Department of Health and Human Services, Office of Inspector General (HHS-OIG). The 5-year CIA requires, among other things, that the board of directors (or a committee of the board) annually review the company's compliance program and pass a resolution that it has implemented an effective compliance program; that certain senior executives annually certify that their departments or functional areas are compliant with federal health care program requirements; that Allergan send doctors a letter notifying them about the settlement; and that the company post on its website information about payments to doctors, such as honoraria, travel, or lodging. Allergan is subject to exclusion from federal health care programs, including Medicare and Medicaid, for a material breach of the CIA and subject to monetary penalties for less significant breaches.

In fall 2011, EMA/EU approved Botox for the management of urinary incontinence in adults with neurogenic detrusor overactivity resulting from neurogenic bladder due to spinal cord injury (SCI) or multiple sclerosis.

Tech. transfer: Allergan has received a number of U.S. and other patents concerning botulinum toxin, nearly all for particular uses/indications:. No U.S. patents in recent decades appear to directly/primarily cover manufacturing methods or botulinum toxins as compositions-of-matter.

U.S. 5,512,547, “Pharmaceutical composition of botulinum neurotoxin and method of preparation,” assigned to the Univ. of Wisconsin (perhaps, licensed by Allergan), claims botulinum neurotoxins with higher specific toxicity and increased stability at higher temperatures than previously available preparations stabilized with albumin and trehalose. Other U.S. patents assigned to the Univ. of Wisconsin include 5,756,468 concerning stabilized lyophilized formulations including trehalose. [BOTOX contains human albumin but not trehalose].

In Oct. 2006, the U.K. High Court of Justice revoked Allergan’s botulinum toxin patent EP-B1 1 366 770 (in the U.K. only) after Merz, which manufactures and markets Xeomin (see related entry below) argued the patent lacked novelty and was obvious. Particularly cited was claim 1, “Use of the neurotoxin component of Botulinium toxin for the manufacture of a medicament for the treatment of pain associated with muscle activity or contracture,” and claim 5, “Use according to any one of the preceding claims, wherein the neurotoxin component of Botulinium type A, B, C, D, E, F or G..” EP-B1 1 366 770 was granted in 2005 by the European Patent Office for a variety of European member states, including Germany and Great Britain. This patent, applied for in 2003, was a second generation divisional patent, the original having been filed in 1994. By the revoked patent’s priority date, two formulations of botulinium toxins were commercially available (BOTOX and Dysport). Merz also charged that the granted patent disclosed additional matter to that was not contained within the original application, since the original application referred only to the use of botulinium toxin to treat various disorders, while the specification of the later patent referred to the use of the neurotoxin component stripped of NAPs (toxin A-binding protein). Allergan argued that since the original application referred to the neurotoxin component in the technical background to the invention, the matter had been sufficiently disclosed, both explicitly and implicitly, by the original application. The presiding judge noted, “In this case, the skilled addressee would have viewed Claim 1 as covering use of the neurotoxic component regardless of whether it formed part of the toxin complex. Accordingly the original application disclosed only the use of the botulinum toxin - not the neurotoxic component stripped of the NAPs” [which would have covered Xeomin from Merz], and “the original application contained no explicit or implicit disclosure of the use of the neurotoxic component of the stripped botulinium toxin.” Allergan appealed this ruling.

Trials: The FDA approval for axillary hyperhydrosis (excessive underarm sweating) was based on the results of two Phase III clinical studies (one in the U.S. and one in Europe). In the U.S. study, 322 patients received either 50 or 75 units of BOTOX per underarm or placebo, and were evaluated at one week after treatment and then every four weeks (through 52 weeks). The primary efficacy evaluation was patient assessment of hyperhidrosis severity using the 4-point Hyperhidrosis Disease Severity Scale (HDSS), which assesses the severity of primary axillary hyperhidrosis and how it affects a patient’s daily activities. Quantity of underarm sweat production also was significantly decreased. Significantly more patients receiving BOTOX vs. placebo achieved at least a 2-grade improvement from baseline in HDSS. To achieve these results, 1-2 BOTOX treatments were sufficient for in responding patients. Median duration of response was 6.5 months, or 201 days. [Repeat injections with BOTOX for hyperhidrosis should be administered when the clinical effect of a previous injection diminishes].

In July 2004, the husband and wife team of Drs. J. and A. Carruthers, University of British Columbia, among the pioneers of BOTOX usage, reported results from a retrospective review of safety data, beginning with their discovery of cosmetic applications for BOTOX in 1987. The study demonstrated that treatment with BOTOX for facial aesthetic procedures is safe and well-tolerated, when used for multiple treatment sessions over extended periods of time and when administered by a trained and qualified physician. Among 853 treatment sessions over periods extending up to nine years, there were no adverse events in 99% of treatment sessions recorded, no adverse events were rated as serious or severe, and all adverse events were temporary.

In May 2005, the first placebo-controlled study evaluating BOTOX as a treatment for urinary incontinence in patients with the neurogenic form of overactive bladder (OAB) showed that BOTOX produced a rapid and sustained reduction in the number of daily incontinence episodes patients experience, and markedly improved patients’ quality of life. OAB is the most common cause of urinary incontinence (loss of bladder control) in adults and is estimated to affect between 13-33 million people in the U.S. alone. OAB with urinary incontinence (“wet” OAB) affects approximately 12 million Americans. Neurogenic OAB (i.e., secondary to another neurologic condition or injury) affects a smaller proportion of the “wet” OAB population in the U.S. However, this condition affects 50% of patients with multiple sclerosis, 40% of acute stroke patients, 10-15% of patients 1-year post-stroke, and is commonly associated with patients suffering from complete spinal cord injury. For many patients, urinary incontinence associated with OAB can cause severe medical and psychosocial disability.

In April 2005, results from a double-blind, placebo-controlled, U.S. Phase II trial of Botox in 355 patients for treatment of chronic daily migraine headaches were published in Headache. Botox missed the primary endpoint. Botox treatment resulted in a mean decrease of 6.7 days from baseline in the number of headache-free days for a 30-day period measured at day 180 compared to a mean decrease of 5.2 days for placebo (p = 0.30; missing the primary endpoint). The trial met the secondary endpoint, with a significantly higher percentage of Botox patients having a decrease from baseline of ≥50% in the frequency of headache days per 30-day period at day 180 (32.7% vs. 15%, p = 0.027). Based on this and associated widespread publicity, there likely has been increased use of Botox for treatment of migraine not responding to conventional treatments.

In Oct. 2004, results were reported by a UCLA School of Medicine investigator from a randomized, double-blinded study in 30 patients comparing the safety and efficacy of Botox Cosmetic and Dysport in the treatment of glabellar lines (the vertical “frown lines” between the brows). Patients were significantly more satisfied with their appearance after treatment with Botox Cosmetic (20 units) than with Dysport (50 units, reported to be the optimal dose for this formulation). At week 12, 64% of patients treated with BOTOX Cosmetic reported experiencing a 50% or greater improvement in glabellar line severity, compared to 33%of Dysport-treated patients. The study also showed that the effects of treatment with BOTOX Cosmetic lasted longer than those of Dysport, based on objective physician ratings of glabellar line severity. Both treatments were well-tolerated.

In Oct. 2005, it was reported that repeated treatments with BOTOX over one year after a stroke can improve muscle tone and reduce pain in the arms and hands, making it easier for patients to dress themselves and perform personal hygiene. The study included 279 stroke patients with wrist, hand or elbow spasticity. This was the first long-term study to evaluate repeated treatment with BOTOX for post-stroke spasticity, a muscle tightness that inhibits movement. The study showed that the treatment is safe and well-tolerated in post-stroke patients and may represent a significant advantage over many oral anti-spasticity medications. Positive results from the same investigators using a single injection were reported in the Aug. 2002 issue of the New England Journal of Medicine.

In March 2006, already defensively preparing for competition from Reloxin/Dysport (see entry below) for cosmetic indications:, Allergan reported results from a study comparing the efficacy and tolerability of BOTOX Cosmetic with Reloxin/Dysport for treatment of moderate to severe glabellar lines. BOTOX Cosmetic lasted longer and patients were more satisfied with their appearance than patients treated with Dysport. The principal investigator remarked, “This study suggests that Dysport may need to be used at higher doses than the currently recommended dose of 50 units for the treatment of glabellar lines to achieve duration of effect and patient satisfaction comparable to BOTOX Cosmetic.”

In the August 2006 issue of Mayo Clinic Proceedings, it was reported that BOTOX may be useful in the prevention of scar formation after trauma (another potential major market). Researchers reported that injecting BOTOX into forehead wounds during the early phase of healing in patients with head wounds inhibited the formation of scar tissue and improved the eventual appearance of wounds after they healed. This method apparently works by preventing muscular movement wrinkling the wound site, providing a flat surface for healing during the first two to three months after the wound occurs. Muscles may repeatedly distort wounds in the healing phase, which can result in inflammation that produces a thicker or wider scar. A Phase III is planned to determine the best dosage and look at the potential of the approach in different wound types. BOTOX (or other botulinum toxin therapeutics) may be particularly valuable for those with facial wounds, and for those who are already scarred. In this later case, the scar tissue could be removed surgically, and botulinum toxin could be injected into the surgical lesion to encourage it to heal in a more cosmetically-appealing way. BOTOX could also help avoid subsequent cosmetic operations to improve the appearance of scars in some patients.

In Oct. 2006, final results were reported from a large, open-label study showing that repeated treatment with BOTOX safely reduces upper limb (wrist, finger and/or arm) spasticity following stroke, and is associated with significant improvements in patients’ ability to function in their daily lives. Significant decreases were also noted in the amount of assistance required by caregivers. A reduction was noted in both hours of care provided each week as well as the number of days that caregivers missed work to care for the patient. The study included 279 stroke patients with wrist, hand or elbow spasticity six months or more after their stroke. BOTOX injections were given to block overactive nerves that trigger excessive muscle contractions or “tone.” Treatment effects were measured using standard, validated scales and questionnaires completed by patients, physicians and caregivers. At week six of the study, muscle tone in the wrist, fingers, thumb, and elbow was markedly decreased from baseline, and the improvement was sustained throughout the one-year study.     

In May 2007, several clinical reports suggesting new indications: for BOTOX and botulinum toxins were reported. Investigators from Wake Forest University Baptist Medical Center reported results from a multi-center study showing that repeated treatment with Botox over one year is well tolerated and results in a significant decrease in spasticity, pain frequency and average pain intensity in upper limbs following stroke. And, a small study showed that about 75% of men suffering from benign prostatic hyperplasia (BPH) experienced partial symptom relief following direct injection of BOTOX into the prostate.

In the June 2007 issue of The Journal of Urology BOTOX was shown in a randomized, double-blind, placebo-controlled conducted by Guy’s Hospital and King’s College London School of Medicine to significantly improve idiopathic detrusor overactivity (IDO) in patients with symptoms of overactive bladder, including improved quality of life, with benefits persisting for at least 24 weeks.

In Sept. 2008, top-line results were reported from two Phase III trials of BOTOX for the prophylactic treatment of headache in adults suffering from chronic migraine - i.e., headaches and/or migraines that occur on 15 or more days each month. This could be another major market for the product. Patients were randomly assigned to treatment with BOTOX or placebo injections every 12 weeks. BOTOX (or placebo) was injected at fixed-sites in varying locations (including the forehead, temples and potentially extending into the neck muscles) depending on where the patient experiences their chronic migraine pain and the severity of their symptoms. The primary analysis was performed at week 24 following two treatment cycles. The two major efficacy endpoints were change from baseline in the number of headache episodes and number of headache days occurring in the 28 day-period preceding the week 24 time point. In Allergan's discussions with the FDA concerning the design of the Phase III clinical trials, the Agency considered number of headache days the preferred efficacy measure for the potential indication. In the first trial, Allergan prospectively used the number of headache episodes as the primary endpoint for evaluation, and mumber of headache days was the major secondary endpoint. Results from the first trial indicated that although both the BOTOX and placebo treatment groups showed a statistically significant improvement from baseline, there was no significant difference in the reduction of number of headache episodes between patients receiving BOTOX and placebo. However, the study showed a decrease in number of headache days, the FDA's preferred efficacy measure, that was significantly greater in patients receiving BOTOX vs. patients receiving placebo (p=0.006). The decrease in number of migraine/probable migraine days was also found to be significantly greater in patients treated with BOTOX vs. patients receiving placebo (p=0.002).

Based on the data from the first Phase III migraine trial, the primary endpoint for the second study was prospectively changed to number of headache days, with number of headache episodes changed to a secondary endpoint, before the data were unmasked. In this study, the primary endpoint and key secondary endpoints showed statistically significant benefit of BOTOX treatment over placebo injections. Patients treated with BOTOX demonstrated a significantly greater decrease in both number of headache days (p <0.001) and number of headache episodes (p=0.003). Similar to the first Phase III trial, the second study also showed a decrease in number of migraine/probable migraine days that was significantly greater in patients treated with BOTOX vs. placebo (p less than 0.001). In both Phase III clinical trials, BOTOX treatments were well tolerated in patients suffering from chronic migraine. Also, quality of life was evaluated using the validated Headache Impact Test (HIT6), and patients receiving BOTOX treatments scored statistically significantly higher improvement in quality of life vs. patients receiving placebo injections (p <0.001 in both studies).

Medical: The neuromuscular blocking effect of botulinum toxin A can be used to alleviate muscle spasm due to excessive neural activity of central origin or to weaken a muscle for therapeutic or cosmetic purposes. Hyperactivity of muscles, regardless of the underlying cause, is characterized by excessive release of acetylcholine at the neuromuscular junctions, so BOTOX is effective for reducing hyperactivity irrespective of its cause.

Minute quantities of botulinum neurotoxin type A are injected directly into selected muscles. BOTOX injection generally provides significant but variable symptomatic relief (muscle deener-vation) lasting for weeks to months. Repeated injections can be used to sustain benefit over longer periods of time.

Botulinum toxin produces its therapeutic effect by a long-term blockade that leads to changes very similar to those produced by surgical denervation. These changes include muscle paralysis, atrophy, and electromyographic abnormalities. In most situations, the clinical effects of botulinum toxin are of limited duration, i.e., reversible, although this may require months. In animals and humans, recovery is accompanied by sprouting of new nerve terminals. The affected nerve terminals never recover. The formation of neuromuscular junctions adjacent to these sprouts parallels the return of neuromuscular activity.

BOTOX (and BOTOX Cosmetic) is supplied with a specific activity of 2.5 U/nanogram, and a vial contains only 100 U. Botox is reconstituted (diluted) with non-preserved sodium chloride 0.9% (saline), with the volume used for reconstitution depending on the desired strength. About 0.1 mL of diluted toxin is usually injected, although from 0.05 to 0.15 mL may be administered to achieve lower or higher doses. Typical side effects of BOTOX include bruising, swelling, brief pain at the injection site, and headaches, but these symptoms generally go away within a few days.

BOTOX Cosmetic is approved for treating brow furrows (glabellar lines; vertical frown lines or creases between the eyebrows). It is generally injected using a 30 gauge needle, 0.1 mL into each of 5 sites, 2 in each of the 2 corrugator muscles and 1 in the procerus muscle, for a total dose of 20 U. BOTOX Cosmetic is reconstituted with 0.9% sterile, non-preserved saline (100 units in 2.5 mL saline) prior to intramuscular injection. The resulting formulation is 4.0 U per 0.1 mL, a total of 20 U per 0.5 mL. The duration of activity for treatment of glabellar lines is approximately 3-4 months.

Note, with only about 20 U of the 100 U vial commonly used (for its approved glabellar lines indication), there is considerable incentive for a vial of BOTOX Cosmetic to be used for treatment of multiple persons. This is one of the reasons for “BOTOX parties,” allowing multiple patients to receive simultaneous treatment with a potential reduction in cost to the patients, and increased profit for the physician.

Antibodies to botulinum toxin type A complex develop in some patients, and these can interfere with treatment efficacy. Botulinum toxin type B (MyoBloc) may be used as an alternative to BOTOX in patients with interfering antibodies.

Botox treatment of hyperhydrosis requires 20 or more site-specific injections at the sites of excessive sweating, e.g., armpits. Although these injections are painful, treatment for hyperhydrosis generally lasts for up to one year, much longer than for other indications:.

In June 2004, results from a systematic review and meta-analysis of clinical trials conducted over the prior 15 years with BOTOX were published (Current Medical Research and Opinion, vol. 20, no. 7). The study found that BOTOX has a favorable safety and tolerability profile across a broad spectrum of indications:, ranging from serious and disabling neurologic conditions to cosmetic use.

To treat chronic migraines, Botox is given approximately every 12 weeks as multiple injections around the head and neck to try to dull future headache symptoms. Botox has not been shown to work for the treatment of migraine headaches that occur 14 days or less per month, or for other forms of headache.

See the Dysport entry below regarding a trial that compared migration characteristics of BOTOX and Dysport.

Market: Total BOTOX product sales were $1.7663 billion in 2012; $1.775 billion in 2011; $1.414 billion in 2010; $1.309 billion in 2009; and in 2008 were $1.311 billion. Total BOTOX product sales in 2006 have been reported to be $900-$950 million, split roughly 57% to 43% (approx. 50-50) for therapeutic versus cosmetic uses. Total Botox products sales were $831 million in 2005, ~$704 million in 2004; $563.9 million in 2003, $439.7 million in 2002, and $309.5 million in 2001.

In its 2012 annual report, Allergan noted, "Therapeutic sales in 2012 accounted for approximately 52% of BOTOX® global sales and increased approximately 13% in U.S. Dollars, with accelerating demand stemming from indications for chronic migraine, upper limb spasticity as well as other movement disorders, and neurogenic or spastic bladder, the first of the urology regulatory approvals. Aesthetic global sales accounted for approximately 48% of BOTOX® global sales in 2012 and grew approximately 8% in U.S. Dollars."

BOTOX products are Allergan’s most important products, accounting for a substantial portion of its total sales. In early 2012, Allergam reported that almost 49% of Botox sales over the past three years were for cosmetic purposes. Allergan reported that during 2003, therapeutic sales accounted for ~60% of total sales and cosmetic sales accounted for ~40% of total sales.

In 2012, Botox use continues to divided evenly between therapeutic and cosmetic uses.

The 2010 approval of Botox for migraines may eventually add up to $1 billion in additiional revenue. FDA approved Botox for use in people who have at least 15 headache days per month. Allergan estimates that 3.2 million Americans have chronic migraines.     

The 2008 Average Wholesale Price (AWP) for both BOTOX and BOTOX Cosmetic is $630/100 U vial ($606.80 in 2007, $582.50 in 2005, $560.00 in 2004) (Red Book, 2008). BOTOX products are preferentially sold directly to physicians trained in their use and to certain pharmacies, rather than sold through retail pharmacies, national resellers, or other middlemen.

The patient’s cost for a facial Botox Cosmetic treatment is usually at least several hundred to $500, while a full upper facial treatment may cost $500-$800. Technically (legally), each vial is for use by a single patient. However, many, if not most, physicians, particularly those administering it to multiple patients in a short period, e.g., at parties or in a large practice, often (re)use a vial to treat multiple patients (allowing reduced costs and increased profits).

The approval for axillary hyperhydrosis further expanded the market for BOTOX. Hyperhidrosis affects an estimated 500,000 to 2 million persons in the U.S. However, most affected persons do not seek treatment, and BOTOX will generally be used only after trying other treatments.

At the start of 2003, with the implementation of the outpatient prospective payment system (OPPS) by the Center for Medicaid and Medicare Services (CMS), hospital outpatient reimbursement for hospitals was reduced to $252/vial for BOTOX, much less than the $419 invoice price for hospitals, and less than the $288 federal supply schedule rate (which is supposed to be the absolute lowest price offered to any purchaser). Some hospitals have been refusing to treat Medicare patients with BOTOX, even for serious disorders, e.g., cervical dystonia (and they, surely, would refuse to subsidize use of BOTOX Cosmetic).

BOTOX is increasingly being used off-label (unapproved use) for treatment of refractory migraine headaches. This requires use of 70 to 100 units about every 10-12 weeks, so treatment is relatively costly. Currently, BOTOX is primarily used by tertiary headache centers in those failing to respond to conventional treatments.

In June 2004, Allergan was awarded $1.5 million in a trademark infringement and unfair competition suit against Mira Life Group Inc. (Los Angeles, CA), which had named its anti-wrinkle cosmetic product as "MiraBotex."

Chronic migraine, an off-label use and potential new indication for BOTOX, is estimated to affect between 1.2 and 3.6 million people in the U.S.

The Aug. 2011 approval to prevent overactive bladder in patients with neurological problems, including spinal cord injury and multiple sclerosis, was expected to add only about $50 million to Botox annual sales. At the time, clinical trials were underway for urinary incontinence, perhaps a $400 million market.

In May 2012, the National Institute for Health and Clinical Excellence (NICE), U.K., published new draft guidance in which it endorsed the use of Botox (botulinum toxin type A) to prevent chronic headaches in patients with migraine. NICE concluded that the most likely cost effectiveness estimate for Botox was £18,900 per QALY (quality-adjusted life year) gained, falling well below the £20,000-£30,000 range considered to represent value for money for the NHS. However, in April 2011 the Scottish Medicines Consortium refused to recommend the use of Botox for migraine prevention for the NHS in Scotland, because of "weaknesses in the clinical data that limit the ability to assess its likely clinical effectiveness in the target treatment population".

Competition: BOTOX competes, to some extent, in the U.S. with Botulinum Toxin Type B (MyoBloc; see entry below), particularly for the indication, cervical dystonia, for which they are both approved, and also for various off-label indications:. However, BOTOX holds a commanding market share, and MyoBloc is largely a second-tier product.

Although not strictly competing with Botox Cosmetic and with totally different mechanisms, various dermal fillers compete with Botox Cosmetic for treatment of facial wrinkles/folds (with many of these products, like Botox Cosmetic, often used off-label). This includes a number of collagen- and hyaluronic acid-based fillers. For example, in March 2003, FDA granted approval to a skin furrow filler which claims to compete against BOTOX Cosmetic for wrinkle treatment, CosmoDerm (see related entry) from Advanced Tissue Sciences Inc. and Inamed Corp., involving human collagen injected under the skin as a dermal filler. In Dec. 2003, FDA approved Restylane (bacterial--derived hyaluronic acid; see related entry) from Medicis Pharmaceutical Corp. (and Q-Med) for correction of moderate to severe facial wrinkles and folds, e.g., nasolabial folds (folds near the nose and mouth). In Oct. 2006, FDA approved Artefill (polymethyl methacrylate microspheres suspended in a bovine collagen; marketed as Artecoll outside the U.S.) from Artes Medical Inc. for filling in wrinkles except those in and around the lips.

Ongoing: Allergan is conducting clinical trials with BOTOX for a variety of new indications. With its universal ability to relax muscles, there are an estimated 100 potential indications for BOTOX (and other comparable botulinum toxin products).

Ref.: Summary Basis of Approval (SBA), PLA ref. no. 85-0226, FDA, undated; Botulinum Toxin: Chemistry, Pharmacology, Toxicity, and Immunology, by Brin, M.E., in Spasticity: Etiology, Evaluation, Management, and the Role of Botulinum Toxin Type A, special issue of Muscle & Nerve, Supplement 6/1997, p. S146-58, 1977; Materials Safety Data Sheet (MSDS), Allergan, Inc., 4 pages, Jan. 17, 2000; Botulinum Toxin: The Story of its Development for the Treatment of Human Disease, by E.J. Schanz and E.A. Johnson, Perspectives in Biology and Medicine, vol. 40, no. 4, p. 317-27, Spring, 1997; Properties and Use of Botulinum Toxin and Other Microbial Neurotoxins in Medicine, by E.A. Schantz and E.A. Johnson, Microbiological Reviews, vol. 56, no. 1, p. 80-99, March 1992; Clinical Use of Botulinum Toxin. NIH Consensus Statement, Nov. 1990; Botulinum Toxin: A Poison That Can Heal, FDA Consumer Magazine (Dec. 1995).