Salix Pharmaceuticals, Inc.
Department of Health and Human Services
|Public Health Service |
Food and Drug Administration
|Silver Spring, MD 20993|
TRANSMITTED BY FACSIMILE
Carolyn J. Logan
President and Chief Executive Officer
Salix Pharmaceuticals, Inc.
1700 Perimeter Park Drive
Morrisville, NC 27560
RE: NDA #22-246
METOZOLV™ ODT (metoclopramide hydrochloride) orally disintegrating tablets
Dear Ms. Logan:
The Division of Drug Marketing, Advertising, and Communications (DDMAC) has reviewed a “Now Approved” journal ad (MET 09/05), Sales Aid (MET 09/08), and consumer Co-Pay Backer Card (MCOMET 09/04) for METOZOLV™ ODT (metoclopramide hydrochloride) orally disintegrating tablets (Metozolv ODT) submitted by Salix Pharmaceuticals, Inc. (Salix) under cover of Form FDA-2253, along with a Dry Erase Board obtained at the American Society of Health-System Pharmacists Midyear Clinical Meeting and Exhibition held in Las Vegas, Nevada, on December 6-10, 2009. These pieces are false or misleading because they omit and minimize risk information, broaden the indication of Metozolv ODT, and contain unsubstantiated comparative and other claims. Thus, these pieces misbrand Metozolv ODT in violation of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 352(a) & (n); 321(n), and FDA implementing regulations. See 21 CFR 1.21, 21 CFR 202.1(e)(3)(i); (e)(5); (e)(6)(i) & (e)(7)(viii). These violations are concerning from a public health perspective because they suggest that Metozolv ODT is safer and more effective than has been demonstrated by substantial evidence or substantial clinical experience, and encourage use in circumstances other than those for which the drug has been shown to be safe and effective.
Furthermore, Salix failed to submit some of these materials to FDA under cover of Form FDA-2253 at the time of their initial publication or use, as required by 21 CFR 314.81(b)(3)(i).
According to its FDA-approved product labeling (PI):
METOZOLV ODT is indicated as short-term (4 to 12 weeks) therapy for adults with symptomatic, documented gastroesophageal reflux disease (GERD) who fail to respond to conventional therapy.
METOZOLV ODT is indicated for the relief of symptoms associated with acute and recurrent diabetic gastroparesis (gastric stasis) in adults.
The Important Limitations subsection of the Indications and Usage section of the PI also states, “METOZOLV ODT is indicated for adults only. Therapy should not exceed 12 weeks in duration. The safety and effectiveness in pediatric patients have not been established.”
The PI includes the following boxed warning for Metozolv ODT (bolded emphasis in original):
WARNING: TARDIVE DYSKINESIA
Treatment with metoclopramide can cause tardive dyskinesia, a serious movement disorder that is often irreversible. The risk of developing tardive dyskinesia increases with duration of treatment and total cumulative dose.
Metoclopramide therapy should be discontinued in patients who develop signs or symptoms of tardive dyskinesia. There is no known treatment for tardive dyskinesia. In some patients, symptoms may lessen or resolve after metoclopramide treatment is stopped.
Treatment with metoclopramide for longer than 12 weeks should be avoided in all but rare cases where therapeutic benefit is thought to outweigh the risk of developing tardive dyskinesia…
Metozolv ODT is also associated with a number of other serious risks, as reflected in its PI. For example, Metozolv ODT is contraindicated in patients with intestinal obstruction, hemorrhage, or perforation; pheochromocytoma; epilepsy; and in those taking concomitant medications with extrapyramidal reactions. Serious Warnings and Precautions associated with Metozolv ODT include the following: tardive dyskinesia; acute dystonic reactions, drug induced Parkinsonism and other extrapyramidal symptoms; neuroleptic malignant syndrome; depression; hypertension; and congestive heart failure and ventricular arrhythmia. The PI for Metozolv ODT also includes information pertaining to withdrawal from metoclopramide and common adverse reactions (>2%), including headache, nausea, vomiting, fatigue, and somnolence.
Omission/Minimization of Risk Information
Promotional materials are misleading if they fail to reveal facts that are material in light of representations made by the materials or with respect to consequences that may result from the use of the drug as recommended or suggested by the materials. The Co-Pay Backer Card presents various product benefit claims for Metozolv ODT, but entirely omits risk information for Metozolv ODT. We acknowledge that the statement, “Please see accompanying full Prescribing Information for Metozolv ODT, including BOXED WARNING” (emphasis original) appears in small type on the front and inside panels of the Co-Pay Backer Card. However, this does not mitigate the misleading omission of risk information from the card. Your omission of the serious risk profile of your drug raises severe public health concerns.
Similarly, the Dry Erase Board presents effectiveness claims for Metozolv ODT but omits
important risk information associated with its use. We acknowledge that the text from the
Boxed Warning appears on the front of the Dry Erase Board, while some additional risk
information is printed on the back of the piece. However, as a practical matter, the risk
information printed on the back of the piece is not visible or even accessible to the viewer
since the back of the Dry Erase Board contains two adhesive strips designed to be adhered
to a wall. Furthermore, as is detailed below, the risk presentation contained on the back of
the piece fails to include material information about the risks that are disclosed. Presenting
risk information in this manner is not sufficient to ensure that the claims in the Dry Erase
Board are truthful and non-misleading. As a result, the piece misleadingly suggests that
Metozolv ODT is safer than has been demonstrated by substantial evidence or substantial
Additionally, the Dry Erase Board, “Now Approved” journal ad, and Sales Aid fail to include
relevant risk information about the Warnings & Precautions that are presented in various
locations on the pieces. These pieces contain the following statement:
“METOZOLV ODT should be used with caution in patients showing acute dystonic
reactions, drug-induced Parkinsonism, or other extrapyramidal symptoms; neuroleptic
malignant syndrome; with a prior history of depression; hypertension; congestive heart
failure and ventricular arrhythmia. Patients may experience withdrawal symptoms
after stopping the use of METOZOLV ODT.”
However, they omit important risk information related to these Warnings & Precautions.
Specifically, these pieces fail to reveal that extrapyramidal symptoms (EPS), manifested
primarily as acute dystonic reactions, occur in approximately 1 in 500 patients treated with
the usual adult dosages of 30 to 40 mg/day of metoclopramide, and that drug-induced
Parkinsonism can occur during metoclopramide therapy, more commonly within the first six
months after beginning treatment, but also after longer periods. Furthermore, these pieces
fail to convey that there have been rare reports of an uncommon but potentially fatal
symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS)
associated with metoclopramide, along with the clinical manifestations of NMS and that
management of NMS should include immediate discontinuation of metoclopramide and other
drugs not essential to concurrent therapy. Moreover, these pieces fail to disclose that
depression associated with metoclopramide use has occurred in patients with and without a
history of depression, that intravenously administered metoclopramide has been shown to
release catecholamines, and that since metoclopramide produces a transient increase in
plasma aldosterone, patients with cirrhosis or congestive heart failure may be at risk of
developing fluid retention and volume overload. Finally, these pieces fail to appropriately
convey the adverse reactions, especially those involving the nervous system, that may occur
after stopping the use of Metozolv ODT.
Your failure to reveal material information regarding the risks associated with Metozolv ODT
in an array of both professionally-directed and consumer-directed promotional materials,
including pieces not discussed within this letter, is extremely concerning from a public health
Broadening of Indication
Promotional materials are misleading if they suggest that a drug is useful in a broader range of conditions or patients than has been demonstrated by substantial evidence or substantial clinical experience. The Co-Pay Backer Card includes the claim, “Rapidly melts on your tongue – ideal for all patients, but especially those who have difficulty swallowing” (emphasis added; footnote omitted). The back of the Co-Pay Backer Card presents the following claim about the indication for Metozolv ODT:
o “The first available rapidly disintegrating metoclopramide tablet for simple relief of diabetic gastroparesis and refractory GERD” (footnote omitted).
These presentations suggest that Metozolv ODT is “ideal” for all patients with diabetic gastroparesis and refractory GERD. However, this suggestion is false as Metozolv ODT is not ideal for all such patients, as evidenced by the numerous contraindications and limitations of indications for use described in the PI.
Furthermore, similar claims in the “Now Approved” journal ad (“METOZOLV ODT is a convenient, orally disintegrating metoclopramide tablet for simple relief of diabetic gastroparesis and refractory GERD” (emphasis added, reference omitted)) and the Sales Aid also misleadingly broaden the indication of Metozolv ODT.
Specifically, these claims fail to adequately communicate the full approved indication for the
drug, including limitations for use. As a result, these claims and presentations suggest that
Metozolv ODT is suitable for any patient with diabetic gastroparesis or refractory GERD.
However, the use of Metozolv ODT is only recommended for a limited patient population. As
described in the Background section above, Metozolv ODT is indicated as short-term (4 to 12
weeks) therapy for adults with symptomatic, documented gastroesophageal reflux disease
(GERD) who fail to respond to conventional therapy and for the relief of symptoms associated
with acute and recurrent diabetic gastroparesis (gastric stasis) in adults. We note that further
information about the limitations of the indication is provided near the bottom of the “Now
Approved” journal ad and on page four of the Sales Aid, in single spaced paragraphs in small
type. However, this information, which is not disclosed in conjunction with the above
prominent claims (and is, in the case of the Sales Aid, separated by several pages from the
relevant claim), is not sufficient to mitigate the misleading impression communicated by the
prominent claims in the ad and Sales Aid.
Additionally, the Dry Erase Board includes the claim, “METOZOLV™ ODT…Convenient relief.” in conjunction with a graphic of the gastrointestinal tract, with various common
pathologies indicated on the graphic. The totality of this presentation misleadingly implies that Metozolv ODT is indicated for the listed common pathologies such as Crohn’s Disease, Ulcerative Colitis and SIBO, when this is not the case. We acknowledge that the following statements appear in small type at the bottom of the board:
METOZOLV™ ODT is indicated for short-term therapy in adults with symptomatic, documented gastroesophageal reflux who fail to respond to conventional therapy and for relief of symptoms of diabetic gastroparesis.
All other diseases shown are strictly for educational purposes.
However, these claims do not correct the misleading impression conveyed by the prominent
presentation on the board that Metozolv ODT is effective for the common pathologies noted
on the illustration.
For the reasons discussed above, these promotional pieces misleadingly broaden the
indication of Metozolv ODT by suggesting that the drug is useful in a broader range of
conditions and patients than has been demonstrated by substantial evidence or substantial
Unsubstantiated Comparative Claims
Numerous presentations in the Sales Aid misleadingly suggest that Metozolv ODT is superior
to other treatments. For example, page two of the Sales Aid presents the claims (footnotes
“Only orally disintegrating prokinetic available” and
“Does not require additional liquid that may add to gastric volume”
followed by the prominent claim (emphasis original):
“Use METOZOLV ODT when you consider prescribing a prokinetic”
Furthermore, page three of the Sales Aid includes the following claims, under the headline,
“Patients prefer an orally disintegrating tablet (ODT)”1,2,3,4,5,6,7:
“CONVENIENCE 91% of patients said that the use of orally disintegrating tablets was convenient or very convenient
COMPLIANCE 42% of patients favored the ease of compliance of orally disintegrating tablets versus 7% who favored conventional tablets
PREFERENCE 75% of patients who have difficulty swallowing preferred orally disintegrating tablets to conventional tablets” (emphasis original, footnotes omitted).
Additionally, page four of the Sales Aid includes the claim, “Unique delivery system compared with traditional metoclopramide tablets” (emphasis added).
The totality of these claims and presentations suggest that, as a result of its delivery system,
Metozolv ODT offers a therapeutic advantage over other available treatment options, and
should be prescribers’ drug of choice (and is patients’ drug of choice). We are not aware of
substantial evidence or substantial clinical experience to support these assertions. We
acknowledge that the statement, “Only orally disintegrating prokinetic available” is true.
However, when presented with the totality of the other claims in this piece, this statement
contributes to the misleading impression that Metozolv ODT offers a therapeutic advantage
over other treatment options. We also note that Metozolv ODT should not be prescribers’
initial choice when they consider prescribing a prokinetic for the treatment of symptomatic,
documented gastroesophageal reflux, as, due to the risks associated with its use, it is only
indicated for patients who fail to respond to conventional therapy. Furthermore, the PI
indicates that for patients with severe diabetic gastroparesis, injectable metoclopramide
should be the initial therapy used:
The initial route of administration should be determined by the severity of the presenting symptoms. If only the earliest manifestations of diabetic gastric stasis are present, oral administration of METOZOLV ODT may be initiated. However, if severe symptoms are present, therapy should begin with metoclopramide injection. Administration of metoclopramide injection up to 10 days may be required before symptoms subside, at which time oral administration may be instituted.
Moreover, the articles cited to support the patient preference claims on page three of the
Sales Aid discuss studies that assessed outcomes with ODT formulations in different drug
classes and in different patient populations (e.g., Parkinson’s disease and adults with
dysphagia); none of the references specifically evaluated Metozolv ODT, and therefore they
do not constitute substantial evidence to support the above claims.
Finally, we note that page three of the Sales Aid also includes the claim, “75% of subjects
expressed a preference for the orally disintegrating Zydis® formulation compared with a
conventional tablet” (emphasis original; footnote omitted). This claim is misleading because it
implies that the Zydis technology of Metozolv ODT is preferred over a conventional tablet.
However, the article cited discusses a study that assessed outcomes of this technology with
another drug, famotidine wafer, and did not specifically evaluate the impact of Metozolv ODT
on patient preference and therefore it does not constitute substantial evidence to support this
Unsubstantiated Claims/Omission of Material Facts
The “Now Approved” journal ad includes the following claims (emphasis added, references and footnote omitted8):
“METOZOLV ODT is a convenient, orally disintegrating tablet for simple relief of diabetic gastroparesis and refractory GERD.”
The Sales Aid, Dry Erase Board, and Co-Pay Backer Card also contain similar claims. These
claims are misleading because they suggest that, overall, treatment with Metozolv ODT (and
not just the dosage and administration of the drug) will provide “simple relief” or “convenient
relief” to patients with diabetic gastroparesis or GERD. We are not aware of evidence to
support the implication that the effects of the drug, combined with its risks, translate into
“simple relief” or “convenient relief” for patients. In contrast, Metozolv ODT is associated with
many potentially serious risks that patients need to recognize and report to their healthcare
provider, such as tardive dyskinesia, extrapyramidal symptoms, and neuroleptic malignant
syndrome. In addition, Metozolv ODT may cause drowsiness, dizziness, or otherwise impair
mental alertness or physical abilities required for the performance of hazardous tasks such as
operating machinery or driving a motor vehicle. Other common adverse reactions include
headache, nausea, and restlessness. Furthermore, patients may experience withdrawal
symptoms, including those involving the nervous system, after stopping the use of Metozolv
ODT. These are all factors that negate any claim of “convenience” or “simplicity” of treatment
relief for a patient.
The Sales Aid also presents the claim, “Can be taken anywhere, without liquid” (bolded
emphasis original, underlined emphasis added). This presentation misleadingly omits
important contextual information regarding dosing instructions for the drug, some of which
could impede the convenience of the product for patients. Specifically, the PI states the
following (in pertinent part, emphasis added):
Take on an empty stomach at least 30 minutes before eating since food can decrease the peak concentrations of drug in the bloodstream and/or the time it takes to achieve the maximum drug level in the bloodstream… Do not repeat dose if inadvertently taken with food.
Since the tablet absorbs moisture rapidly, only remove each dose from the packaging just prior to taking. Handle the tablet with dry hands and place on the tongue. If the tablet should break or crumble while handling, discard and remove a new tablet…
METOZOLV ODT is designed to be taken without liquid; however, the effect on the pharmacokinetics of taking METOZOLV ODT with liquid is unknown.
Failure to Submit Under Form FDA-2253
FDA regulations require companies to submit specimens of any labeling or advertising devised for promotion of the drug product at the time of initial dissemination of the labeling and at the time of initial publication of the advertisement for a prescription drug product. A copy of the Dry Erase Board was not submitted to FDA as required by 21 CFR 314.81(b)(3)(i). Furthermore, a copy of the journal ad and Sales Aid were not submitted to FDA at the time of their initial publication as required by 21 CFR 314.81(b)(3)(i). While the journal ad was submitted on FDA-Form 2253 on November 13, 2009, (as MCOMET 09/05), we are aware that this advertisement appeared in the October 2009 issue of Gastroenterology & Endoscopy News (Volume 60, Number 10). Additionally, while the Sales Aid was submitted on FDA-Form 2253 on February 10, 2010, we are also aware that this piece was available at the American Society of Health-System Pharmacists Midyear Clinical Meeting and Exhibition held in Las Vegas, Nevada, on December 6-10, 2009.
Conclusion and Requested Action
For the reasons discussed above, these pieces misbrand Metozolv ODT in violation of the Act, 21 U.S.C. 352(a) & (n); 321(n), and FDA implementing regulations. See 21 CFR 1.21; 21 CFR 202.1(e)(3)(i); (e)(5); (e)(6)(i); & (e)(7)(viii). Furthermore, Salix failed to submit some of these promotional materials under cover of Form FDA-2253 at the time of their initial publication, as required by 21 CFR 314.81(b)(3)(i).
DDMAC requests that Salix immediately cease the dissemination of violative promotional materials for Metozolv ODT such as those described above. Please submit a written response to this letter on or before April 2, 2010, stating whether you intend to comply with this request, listing all promotional materials (with the 2253 submission date) for Metozolv ODT that contain violations such as those described above, and explaining your plan for discontinuing use of such violative materials. Because the violations described above are serious, we request, further, that your submission include a comprehensive plan of action to disseminate truthful, non-misleading, and complete corrective messages about the issues discussed in this letter to the audiences that received the violative promotional materials. Please direct your response to me at the Food and Drug Administration, Center for Drug Evaluation and Research, Division of Drug Marketing, Advertising, and Communications, 5901-B Ammendale Road, Beltsville, MD 20705-1266, or facsimile at 301-847-8444. In all future correspondence regarding this matter, please refer to MACMIS #18382 in addition to the NDA number. We remind you that only written communications are considered official. If you choose to revise your promotional materials, DDMAC is willing to assist you with your revised materials by commenting on your revisions before you use them in promotion.
The violations discussed in this letter do not necessarily constitute an exhaustive list. It is your responsibility to ensure that your promotional materials for Metozolv ODT comply with each applicable requirement of the Act and FDA implementing regulations.
Failure to correct the violations discussed above may result in FDA regulatory action, including seizure or injunction, without further notice.
Thomas W. Abrams, RPh, MBA
Division of Drug Marketing,
Advertising, and Communications
1 de Argila CM, Ponce J, Márquez E, et al. Acceptability of lansoprazole orally disintegrating tablets in patients with gastro-oesophageal reflux disease. Clin Drug Invest. 2007;27:765-770.
2 Nausieda PA, Pfeiffer RF, Tagliati M, Kastenholz KV, DeRoche C, Slevin JT. A multi-center, open-label, sequential study comparing preferences for carbidopa-levodopa orally disintegrating tablets and conventional tablets in subjects with Parkinson’s disease. Clin Ther. 2005;27:58-63.
3 Carnaby-Mann G, Crary M. Pill swallowing by adults with dysphagia. Arch Otolaryngol Head Neck Surg. 2005;131:970-975.
4 Schwartz JI, Yeh KC, Berger ML, et al. Novel oral medication delivery system for famotidine. J Clin Pharmacol. 1995;35:362-367.
5 Dowson A, Bundy M, Salt R, Kilminster S. Patient preference for triptan formulations: a prospective study with zolmitriptan. Headache. 2007;47:1144-1151.
6 Dowson AJ, Almqvist P. Part III: the convenience of, and patient preference for, zolmitriptan orally disintegrating tablet. Curr Med Res Opin. 2005;21:S13-S17.
7 Clarke A, Johnson ES, Mallard N, et al. A new low-dose formulation of selegiline: clinical efficacy, patient preference and selectivity for MAO-B inhibition. J Neural Transm. 2003;110:1257-1271.
8 It is not clear in the piece what reference footnote “1” in the “Now Approved” journal ad refers to, as no references (or footnotes) are listed in the ad itself.