Reglan & Tardive Dyskinesia Lawyer Blog

Expert Witness For Pliva Discusses Reglan Warning Label

In this report, an expert witness retained by Pliva expresses the opinion that Pliva's metoclopramide warning label was adequate.

9. However, because of how the FDCA was structured, companies that wanted to
market generic versions of drug products approved under NDAs after 1962, such as
Reglan brand of metoclopramide, would have had to duplicate the expensive animal
and clinical studies the innovator did, even though the patent protection had
ended. This situation had the consequence of providing a virtual monopoly for
drugs first approved after 1962, because generic drug manufacturers did not have
the financial resources to perform extensive clinical and animal studies and to
prepare and submit NDAs to the FDA. The Congress remedied this situation in 1984,
when the Hatch-Waxman amendments to the FDCA extended a simplified administrative
process the FDA used for generic versions of older drugs, called an Abbreviated
NDA (ANDA) to generic versions of drugs first approved after 1962. The public
policy arguments for the Hatch-Waxman amendments included the following:

Report Filed In Reglan Lawsuit Alleges Reglan Warnings Were Inadequate

The following report was filed by Bob West, Ph.D., in the Louisiana lawsuit entitled Tarver v. Wyeth. 

United States District Court, W.D. Louisiana.

    TARVER et al,

v.

  WYETH INC et al.

   No. 04CV02036.

  August 20, 2006.

   Summary of Opinions

Robins/Wyeth and other manufacturers of metoclopramide failed to adequately warn
physicians and ultimately patients, of the risks of extrapyramidal symptoms,
specifically tardive dyskinesia with long term (greater than 12 weeks) use of
Reglan/metoclopramide. Furthermore, when a patient takes Reglan/metoclopramide
beyond the recommended period and subsequently develops tardive dyskinesia, then
all of the Reglan/Metoclopramide ingested beyond the recommended period likely
contributed to the development of the tardive dyskinesia.

   History

I am a pharmacologist and toxicologist with over 35 years experience in the drug
and medical device product field. I am a former president of the Drug Information
Association, a world-wide forum to exchange information on drug development among
industry, the FDA and other concerned groups about drug efficacy, safety,
manufacturing controls, pharmacovigilance and regulatory requirements. I have
worked directly and as a consultant in scientific and regulatory affairs for drug
manufacturers, and have knowledge and expertise of the requirements of FDA
regulations and statutes concerning drug labeling and reporting to the FDA. My
training and experience are more fully set forth in the copy of my Curriculum
Vitae which is attached hereto. A list of all publications 1 have authored or
co-authored as well as a list of all cases I have testified in are attached to my
Curriculum Vitae.

    Compensation

My compensation for this study is a $275 per hour; compensation for testimony is
at $325 per hour.

Reglan (metoclopramide) is a dopaminergic antagonist and neuroleptic drug
developed as an antiemetic agent. It is also a prokinetic agent which is
administered in cases of gastric hypomotility such as seen in diabetic neuropathy
and gastroesophageal reflux (GERD). Reglan was marketed outside of the United
States, in France as Primperan in 1964, and in England as Maxilon, as well as
other areas of Europe and Canada. It was approved for marketing in the United
States in 1979 and 1980 for diabetic gastroparesis and in 1982 for intravenous use
as an antiemetic in cancer chemotherapy.

In 1984, Robins obtained approval to market Reglan (metoclopramide) as a short
term therapy for GERD, four to twelve weeks of administration. The labeling under
dosage and administration contains a statement, therapy longer than 12 weeks has
not been evaluated and cannot be recommended. The same statement remains on the
Reglan label until today, while Robins/Wyeth continues to market the product. A
telephone survey, conducted by Robins in 1985, found that 38% of Reglan users took
the drug for between one and two years and another 46% of Reglan users took the
drug for three to six months.

By the time Robins filed an IND with the FDA in 1973, several studies showed that
metoclopramide adversely affected the CNS. Dr. Tibor Bodi of Merck found 3 of 60
subjects developed dystonic phenomenon as did one of the dogs on chronic
administration as reported by Peck. In addition to this information Robins was
also aware of reports in the world medical literature suggesting that long term
metoclopramide therapy presented a significant risk of producing tardive
dyskinesia. As early as 1968, metoclopramide treatment, like treatment with
neuroleptics, caused extrapyramidal symptoms.

The annual report for 1975 of the National Drug Advisory Board in Eire notes that
during the seven year period, 1968 to 1975, there were twenty-eight reports of
side effects with metoclopramide. Most of these cases were dystonia and 30%
occurred in children under the age of 17 years. Other reports in the 1970s noted
the appearance of extrapyramidal symptoms following the use of metoclopramide
(Primperan, Makolon). The Australian Drug Evaluation Committee received
twenty-five reports of adverse reactions to metoclopramide, eighteen concerned the
extrapyramidal symptom. More than half of the patients were under the age of 20.
During the 1980s and prior to the U.S. approval of Reglan for GERD, there were
multiple literature reports on extrapyramidal symptoms, tardive dyskinesia and
Parkinsonian like symptoms involving almost 100 patients. However, the Reglan
Reporter only cites 30 cases since 1964.

Obviously, during this period, Robins was not completely forthcoming with the FDA.
Meetings were held with the FDA Advisory committees, and when asked about the
incidences of these EPS, not all the latest information was provided. Robins
agreed to provide post marketing surveillance as one of its conditions of approval
for the gastroparesis indication. The evidence for this is rather scant.

Additional historic review of the metoclopramide IND reveals irregularities that
make the safety data base ultimately submitted to the FDA for the NDA quite
suspect. According to Dr. Sondervost, Director of Clinical Research at Robins, in
his letter of resignation to E. C. Robins, President (December 15, 1978), he
states that when he took over, he was quite perturbed with the ineffectual
surveillance of the medical program. He found a stack of 250 completely unreviewed
patient data records for another project which thus did not comply with lack of
statutory monitoring requirements. Serious adverse reactions, including patients
that had died, had not been reported by the regulatory staff to the FDA.

He also discusses the status of the oral metoclopramide NDA program and cites
figures of 1500 - 1800 patients who were treated under the IND without
accountability or patient review. Thousands of tablets were sent out with no
accountability. On the basis of the foregoing, one has to question the veracity of
the data base provided to the FDA in the IV/oral metoclopramide submissions. The
authenticity of a significant part of the safety data base is questionable at
best. Obviously, Robins is in violation of both the FDA IND and NDA regulations.

The clinical data base for the original NDA approval for metoclopramide consisted
of two placebo controlled studies representing a meager population of
approximately 100 patients. There were no studies of long duration, e.g. more than
twelve weeks and now twenty years after the original NDA approval for GERD, still
none have been performed.

  Marketing

The Robins market plans for 1982 through 1988 reflect a strategy of promoting
Reglan to treat many commonly treated complaints of the upper GI tract and "to
significantly displace Tagamet and Gaviscon as a first choice prescription therapy
for GERD." They recognized the Reglan patent was about to expire and an
enhancement of the GERD indication could expand market share and allow Robins to
maintain their franchise for Reglan. In the period prior to 1985, this was a
subrosa promotion of an unapproved use and for an extended period of time over and
above the twelve week label indication.

The 1986 market plan for Reglan discusses a patient study which found that of
current users, 46% have taken Reglan for a period of 3 to 6 months, while another
38.1% have been on Reglan for 1-2 years (Plotkin). Thus, to state in the labeling
therapy longer than twelve weeks has not been evaluated and cannot be recommended
begs the issue.

During this period, Robins/Wyeth while "educating physicians," Robins continued to
receive letters inquiring about tardive dyskinesia. They were not completely
forthcoming with the medical community about the continuing reports in the medical
literature. Three days after the August 15, 1984 approval letter for Reglan as a
short term therapy for the GERD indication, Orme published an article in the
British medical literature indicating that metoclopramide should not be used by
the elderly for prolonged periods of time.

21 CFR 202.1(e)(5) requires that an advertisement not present false or misleading
information with respect to side effects, contraindications or effectiveness.
202.1(e)(6)(xi) prohibits a drug manufacturer from using literature, quotations or
references for purposes of "recommending or suggesting conditions of drug use that
are not approved or permitted in the drug package labeling."

Robins violated FDA regulations by its subrosa promotion of an unapproved use of
Reglan. It also permitted its marketing information to control the information it
was providing to the FDA in a timely fashion and only provided incomplete
information on its label. These are violations of FDA regulations, as well as
grossly unsafe, and unethical practices by Robins.

    Adverse Event Reporting Requirements

21 CFR 314.80 controls post-marketing reporting to the FDA of adverse drug
reactions.

Subsection (C)(1)(i) requires 15 day "alert reports" for each drug experience that
is both "serious and unexpected" regardless of source within 15 working days of
initial receipt of the information. (Form 1639 report)

Subsection (c)(1)(ii) requires that the drug company review (at least annually)
the frequency of adverse drug experiences that are both serious and expected
(already listed in the label), regardless of source and report any significant
increase in frequency within 15 days of determining an increase in frequency.

Section 314.81 requires that the drug company in its annual report include a
summary of "significant new information from the previous year that might effect
the safety, effectiveness or labeling of the drug product." The report is also
required to contain a brief description of actions that the applicant has taken or
intends to take as a result of this new information. For example, submit a
labeling supplement, add a warning to the labeling or initiate a new study.

Robins/Wyeth, and other manufacturers of metoclopramide, continued to receive ADRs
and literature reports throughout the 1980s and 1990s bearing upon the
extrapyramidal symptoms and tardive dyskinesia associated with metoclopramide
administration. In addition, the literature reinforced the thesis that
metoclopramide use was long term often in GERD for many years. (Stewart, et al.,
Ganzini, et al., Sewell, et al., Sweet, et al., Miller, et al. and Llau, et al.)
The information obtained via the Med Watch Reports and the ADR tabulations also
reflected the long term use of metoclopramide, e.g., 1-6 years. A visual
inspection of the U.S. sales for 1993-1996 suggests that while sales were
declining, the incidence of ADRs and extrapyramidal symptoms were increasing.

A review of the information provided to the FDA in the annual reports reveals that
Wyeth often provided abstracts of the literature to the Agency without any attempt
to present the complete papers and an analysis of their content. This is
particularly important as a number of these papers, some foreign, pertain to the
incidence of side effects or extrapyramidal symptoms associated with long term
metoclopramide use.

Despite the availability of the Ganzini and Sewell papers, since 1993 and 1994,
there is no evidence that Wyeth made any attempt to critically evaluate these
papers and perform a meta analysis to determine the significance of the data as it
effects the interpretation of ADRs and possible influence on labeling.

Wyeth made no effort to upgrade its data base based on the full interpretation of
the data and the literature thus violating this section of the regulation (Section
314.81).

  Labeling

Reglan was approved for U.S. marketing August 15, 1984 as a short term treatment
for GERD without a tardive dyskinesia warning. In March 1985, the FDA notified
Robins that it was requiring a warning regarding tardive dyskinesia to be added to
the Reglan label. FDA approved the language of the tardive dyskinesia labeling for
Reglan on October 21, 1985. Robins also prepared a "Dear Doctor" letter dated
November 1985 which was supposed to call attention to the revised package insert.
The "Dear Doctor" letter and warning failed to draw attention to the potentially
irreversible tardive dyskinesia risk of long term metoclopramide therapy and that
prolonged use should be avoided.

For the GERD indication, Reglan is to be administered for four to twelve weeks,
but is does not specifically discourage use beyond four to twelve weeks. By
itself, the statement is buried in the rest of the text and does not sufficiently
highlight the impact or meaning of the statement. The indication and warning to
avoid long term use should have been placed in a single distinctive black hox at
the top of the label. Responsible manufacturers use this technique to highlight
important warnings for physicians.

During this period, Robins/Wyeth and later, other manufacturers, were continuing
to market Reglan for GERD with little regard to limiting its duration of use
despite their knowledge from multiple sources that it was being used chronically
(Plotkin, Stewart). Furthermore, literature continued to appear associating
metoclopramide with tardive dyskinesia and extrapyramidal side effects. Ganzini,
et al. found that the excess risk of developing tardive dyskinesia in patients on
long term use of metoclopramide was approximately 13%. They estimated this was
approximately 100 times greater than previously believed based on the information
in the Reglan package insert.

CFR 201.7(iii) states if there are specific conditions that should be met before
the drug is used on a long term basis, the labeling should identify the conditions
and specific indications for each use. Section 201.57(v)(3) Warnings. The labeling
shall be revised to include a warning as soon as there is a reasonable evidence of
an association of a serious hazard with the drug, a causal relationship need not
have been proved. Special problems, e.g., death or serious injury may be placed in
a prominently displaced box. Boxed warning.

CFR 201.57(10) Geriatric Use (c). Evidence from clinical studies and other
reported clinical experience available to the sponsor indicates that use of the
drug in elderly patients is associated with differences in safety or effectiveness
or requires specific monitoring or dosage adjustment then appropriate information
should be added to Contraindications, Warnings - etc. or other sections of the
labeling.

CFR 201.57(9) (ii) Pediatric Use. This subsection of the labeling states that the
manufacturer shall cite any limitations in the pediatric use statement, if there
is a need for specific monitoring and hazards associated with use of the drug in
any subsets of the pediatric population. Furthermore, this should be cited in the
"Contraindications" and "Warnings," "Precautions" and "Dosage" and
"Administration" subsections.

Further, the Reglan/metoclopramide label is misbranded since it does not provide
adequate directions for use or adequate warnings about the appropriate maximum
duration and dose for the labeled indication. (21 USC, para. 352) In addition, the
label is false and misleading since it provides misinformation for the risk of all
EPS from Reglan/metoclopramide being stated to be 1:500 which has little
scientific foundation. In fact, studies published over the twenty year period
since the NDA approval demonstrate the risk of EPS is much higher. Despite this
information, Wyeth and the other manufacturers of Reglan/metoclopramide have
failed to purse appropriate follow-up and conduct their own studies, clinical or
epidemiological regarding the risk of EPS and, in particular, tardive dyskinesia
with long term administration of Reglan/metoclopramide.

CFR 201.57(d). Contraindications states that the contraindication section of the
label shall describe those situations in which the drug should not be used because
the risk of use clearly out ways any possible benefit. These situations include
"continued use of the drug in the face of an unacceptably hazardous adverse
reaction." If a manufacturer has knowledge that the risk of a drug producing a
serious side effect, such as tardive dyskinesia, is substantially increased after
a certain period of dosing, the manufacturers' duty is to state, use past that
time is contraindicated. Wyeth's metoclopramide product in Italy specifically
states in bold print, DO NOT USE FOR LONG TERM USE. Today, there are numerous H2
receptor antagonists and proton pump inhibitors available to treat GERD without
the risk of serious neurological side effects.

CFR 201.57(e). States that the warning section of a label shall describe serious
adverse reactions and potential safety hazards, limitations in use imposed by
them, and steps that should be taken if they occur. Thus, the warning section
should address the hazard of long term use, as well as the need for physicians to
periodically monitor patients on metoclopramide to look for the earliest signs of
EPS and discontinue use.

Section 314.70 deals with Supplements and other changes to an approved
application. Labeling, states that a change in labeling to add or strengthen a
contraindication, warnings, precautions or adverse reactions can be made without
filing a supplement. Both Wyeth and the other manufacturers of
Reglan/metoclopramide should have expanded the warnings to physicians under
314.70(2) with a labeling supplement to strengthen the warnings or precautions.

Robins/Wyeth, for a period of over ten years after obtaining Reglan marketing
approval for GERD, had multiple opportunities to update their labeling by
providing a black box warning, making a more positive statement about limiting
metoclopramide use in GERD, highlighting the higher incidence of extrapyramidal
side effects and adding additional statements about the proper geriatric use. The
only plausible explanation for this inaction is allowing market motives to control
proper medical information and consumer protection. A review of Jolene Linger's
Reglan/Metoclopramide prescriptions from March 1995 to August 2002 and matching
that to the corresponding National Drug Code ("NDC") shows that Mrs. Linger
received Reglan/Metoclopramide in excess of the PDR and package insert information
from the following manufacturers: Wyeth, Inc., ESI Lederle, Inc., Teva
Pharmaceuticals USA, United Research Laboratories, Inc., and Pliva, Inc.

I reserve the right to supplement or amend this report based upon additional
information provided to me as a part of this case or additional discovery taken by
the parties.

Government Report Discusses Metoclopramide Side Effects

This report was filed in the Louisiana Metoclopramide lawsuit entitled Tarver v. Wyeth.

Metoclopramide is a neuroleptic dopamine receptor antagonist, currently marketed
in the U.S. (Reglan(R)) for short-term therapy of gastroesophageal reflux and for
treatment of diabetic gastroparesis. In general, therapy with metoclopramide
tablets should not exceed 12 weeks in duration, as prolonged therapy and
cumulative dose may increase the risk of developing tardive dyskinesia. The aim of
this review is to assist in preparation for a forthcoming advisory committee
meeting on the approvability of Myzan(R), a combination of naproxen and
metoclopramide, for the acute treatment of migraine, by estimating both the use of
metoclopramide in the U.S. as well as the proportion of patients taking
metoclopramide for more than 90 days.

....

Over the ten-year period from 1995 to 2004, there was a two-fold increase in the
number of outpatient prescriptions dispensed for metoclopramide in the U.S. In
1995, the number of prescriptions dispensed for metoclopramide was almost 3.5
million. This number declined to less than 2 million prescriptions dispensed
annually from 1997 to 1999, and then increased abruptly in 2000 and reached over 7
million prescriptions dispensed during 2004. The increase in dispensed
prescriptions beginning in 2000 is likely due to the withdrawal of cisapride, a
treatment for severe nighttime heartburn, from the US. market in March 2000.
Almost 90% of the metoclopramide products dispensed were in an oral tablet dosage
form.

Over one-third of the annual visits in the U.S., in which metoclopramide was
mentioned, were made by patients ages 35-64 years old. Elderly patients (aged 65
years and older) accounted for about a third of the visits in which metoclopramide
was mentioned from 1995-1998, yet their proportions declined steadily in the
subsequent years. As opposed to the elderly population, visits in which
metoclopramide was mentioned in the pediatric population (aged 0-16 years)
increased steadily throughout the ten-year study period and constitute more than
30% of these visits in 2004. Visits in which metoclopramide was mentioned in
patients aged 17- 34 years remained steady. On average, over 55% of the annual
visits in which metoclopramide was mentioned were made by females.

During the last five years, from 2000 through 2004, more than 50% of
metoclopramide uses were for gastroenterology-related diagnoses. "Esophagitis"
(ICD-9 code 530.1) was ranked the most common diagnosis for metoclopramide
mentions, accounting for over 40% of metoclopramide mentions.

Dr. Joseph Lyon prepared the following report for Wyeth in the case of Mcneil v. Wyeth.  He concludes that there is not enough reliable information to determine how likely an individual is to develop tardive dyskinesia or another movement disorder after using Reglan (or Metoclopramide) for a long period of time.

4. To determine what a person's risk of developing a disease such as tardive
dyskinesia after exposure metoclopramide you must have an incidence rate. Any
other measure of the association is of limited worth in determining if exposure to
MCP causes TD. A prevalence rate is determined by multiple factors, all of which
are subject to bias, and unless each of these biases are quantified, the
prevalence rates are of little or no use in determining if there is a causal
connection between the exposure and subsequent development of the disease in
question.

5. The only article I could find in the medical literature that reported an
incidence rate of TD among users of metoclopramide was published by B-E. Wiholm et
al., entitled "Tardive dyskinesia associated with metoclopramide" British Medical
Journal 1984; 288:545-547. This study measured new cases of TD among users of MCP
in Sweden. The cases were reported to an adverse drug reporting system, and the
use of MCP was obtained from prescription data for Sweden. Depending on the
definition of a long term prescription use the authors estimated the incidence of
TD among users of MCP to range from 0.037 cases to 0.050 cases per 100
person-years

6. Using these incidence rates the occurrence of new cases of TD among 100
individuals with long-term use of MCP who were followed up for one year can be
estimated. There would be no new cases of TD (expectation would be of 0.037 to
0.050 case) during a single year. If the group were followed for 10 years its
unlikely any cases would have occurred (expectation of 0.36 to 0.50 cases). It
would require following 100 individual between 20 to 30 years before the first
case would occur.

7. The Wiholm study has been criticized because it Is based on the reporting of
adverse events to diagnose TD, and it possible that an adverse drug reporting
system would underestimate the true incidence of TD. But the estimates can still
be used to approximate the occurrence of new cases of TD among users of MCP. If
the Wiholm study underestimated the incidence of TD associated with MCP use by 10
fold it would still require following 100 people who were taking MCP for 2 to 3
years before the first case of TD occurred.

Expert Witness Discusses Reglan Risks in Texas Reglan Lawsuit

This is the partial deposition of Hal Morgenstern, Ph.D.  In it, he discusses the relative risks of developing tardive dyskinesia after using Reglan or Metoclopramide.

Q. Would you calculate that for me on this piece of paper?

A. I remember that I had to solve for something in this, let's see, okay. There
were 51 metoclopramide and 51 others. Okay. I took -- multiply that times that
divided by that times that.

Q. Would you write that down for me? So your odds ratio is the product of 15 times
42 divided by the product of 36 times 9?

A. As I recall.

Q. And you say o-r with a --

A. Little hat above it.

Q. Thank you. I thought there was a technical term for it.

A. There probably is. Most people just say hat. It means estimate. I'm just used
to doing it.

Q. And why do you say this is an odds ratio estimate?

A. Because I estimated it from the data.

Q. And what I'm getting at is, do you ever calculate odds ratios that are not
estimates?

A. Not from data.

Q. And this gave you 1.94, correct?

A. Uh-huh.

Q. And the confidence interval was .76 to 4.97?

A. Yes, if you're reading from my -- yes.

Q. And that confidence interval includes one, correct?

A. Yes.

Q. And what is the significance of the fact that the confidence interval includes
one?

A. Just means that the 95 percent confidence interval includes the null value.

Q. You chose a 95 percent confidence interval; why?

A. Just standard, I could have chosen anything, most common, some people use 99,
some people use 90.

Q. But 95 percent is the most standard confidence interval used in epidemiology?

MR. PITTLE: Object to the form.

A. I think so.

Q. Now look at the paper on page 1472. Under tardive dyskinesia, it says 29
percent (n=15) of --

A. I'm sorry, where are you?

Q. 29 percent (n=15) of metoclopramide users met the case definition of tardive
dyskinesia compared with 17.6 percent (n=9) of non-users, correct?

FDA Document Discusses Movement Disorders Associated With Metoclopramide

The following document was filed in the Louisiana lawsuit of Tarver v. Wyeth.  It discusses some concerns that the FDA had with metoclopramide and movement disorders.

Regarding the safety of MT100, my main concern relates to the extrapyramidal
adverse events known to be caused by metoclopramide.[FN3] Reglan labeling states
that extrapyramidal symptoms, mainly acute dystonic reactions, occur in
approximately 0.2% of patients receiving oral metoclopramide at doses between 30
to 40 mg per day. Dr. Prohaska notes that during the clinical development program
for MT100, there were two subjects reporting acute dystonic reactions, which
demonstrates the potential for extrapyramidal adverse events even at the dose (16
mg) of metoclopramide contained in MT 00. Akathisia has also been reported with
metoclopramide in the literature,[FN4] and metoclopramide-induced akathisia can
even apparently lead to suicide attempt, as reported in the literature.[FN5]

Expert Witness Report Filed In Lawsuit Regarding Adverse Reactions to Reglan

The following expert report was prepared for Wyeth by Lawrence Schiller, M.D.  in the case of Mcneil v. Wyeth.  The doctor expresses his opinion that certain symptoms were not caused by Reglan.

11. No scientific evidence or literature has ever linked chest pain, cardiac
enlargement, an abnormal E.C.G., a deep cough, mucous build-up on tongue,
excessive perspiration, difficulty in breathing, chronic bronchitis, spitting up
of blood, loss of appetite or weight, or coughing or choking when consuming
liquids to the use of Reglan. The foregoing symptoms complained of by plaintiff
were not caused by her Reglan use.

12. Although there are potential adverse effects associated with the use of
Reglan, the benefits of the medication outweigh those risks associated with its
use. In addition, no safer alternative design for the medication exists. Reglan is
frequently the only medication that can relieve the debilitating symptoms of
gastrointestinal motility conditions, including GERD, diabetic gastroparesis, and
chronic intestinal pseudo-obstruction. Therefore, it is imperative that Reglan be
available for physicians to prescribe, especially since not all patients are
receptive to all treatments.

Expert Witness In Metoclopramide Lawsuit Discusses Tardive Dyskinesia At Length

Dr. Robert Nelson filed the following expert witness report in the case of Swicegood v. Pliva.  In it, he suggests that the manufacturers of Metoclopramide (the generic form of Reglan) have not lived up to their duty to sell a safe product:

There was an understanding by the FDA in the early 1980s that MCP, a dopaminergic agent, had the potential for TD given LT exposure. Initially its use was limited to inpatients and severe DG. However, it was eventually approved for up to 12 weeks treatment of GERD.

The reports of MCP-TD presented in Section X of this report all attribute TD as a consequences of off-label long-term use. Grimes (1982b) and Wiholm (1984) were the first to analyze the signal and publish the problem.

Miller and Jankovic (1989) found the TD emerges, on average, 12 months of exposure and that treatment was continued for an average of 6 months AFTER involuntary movements had started. Sewell (1992a) reviewed the reports in the literature and found 67 cases of MCP-TD with 20 months duration of exposure.

Stewart (1992b) analyzed “inappropriate” long-term use of MCP in the elderly. This descriptive study identified 34 exposed to MCP from 4515 (2898 females; 1617 males) patients who participated in a health screening research program in Florida, 11 (32.4%) were long-term users. The study was initiated because two patients presented to the University hospital with MCP-induced TD within the prior year. Both had taken MCP for longer than 8 years for GERD. Only three of the 34 participants had diabetes mellitus (DM), so GERD or heart-burn-like ailments and not DG was their likely treatment diagnosis. This small study signaled that LT-MCP was a substantial component of MCP use in the elderly.

These published cases and the studies of Stewart, Ganzini, and Sewell made the problem of long-term off-label use visible and highlighted its unique consequences.

To assess risk factors for TD in MCP exposed persons, Schaffer et.al. (2004) reviewed the reports in the FDA Adverse Reaction Reporting System (AERS) through June 2003. They also used the IMS Health data to evaluate MCP prescribing patterns before and after the withdrawal of cisapride from the US marketplace. They extracted a case-series of 87 reports from AERS with TD as the adverse outcome and MCP as an exposure. Each case was re-evaluation for validity of both exposure and outcome. Data regarding prescription utilization (via National Prescription Audit, NPA) and demographics of patients (National Disease & Therapeutic Index, NDTI) treated with MCP, between 1/1992 - 6/2003, were obtained from IMS Health. The mean age for the case-series was 60 years and 2/3 were female. The mean dose was 33 mg/day with mean duration of 753 days (-108 weeks). Most of the known use was for GERD (gastroesophageal reflux disease), or acid reflux, whose main symptom is heartburn. Only 14% of use was for gastroparesis.

The marketing of cisapride for GERD in 1993 had an inverse impact on the sales of MCP, which reversed when cisapride was withdrawn from the market due to QT wave prolongation. Nearly 1/4 of MCP use was in persons, mostly females, over 70 years of age. This descriptive analysis reinforced the fact that a meaningful percentage ( 15-20%) of MCP is used long-term (off-label) in persons (elderly females) who are at the highest risk of TD. The authors reflect on the impact of these prescribing practices given the ‘paucity of evidence that MCP improves the quality of life” and the risk of a life-changing, potentially irreversible neurological disorder.

….

It is my opinion that the defendants have not acted as a reasonable and prudent drug manufacturer and breached their standard of care. Given clear evidence of causality, the well-documented use greater than 12 weeks, and given the strong probability of increased risk for TD conditional on that greater exposure the defendants, should, at a minimum (1) assess the risk of TD beyond 12 weeks of exposure to determine if it is no different than that seen within the approved shorter termed exposure where the benefit-risk balance is considered by the FDA to be acceptable; (2) affirm efficacy beyond 12 weeks for the relevant indication(s) and reestablish that benefit - risk balance with the results from choice #1. The defendants had a responsibility to petition the FDA to update the label and reflect new information. Yet, the defendants have chosen to do neither. As a result, persons continue to be harmed to this day as demonstrated by Kenney (2008). The defendants fell below its standard of care in not reporting to the FDA and treating physicians the data available regarding long term use of metoclopramide. If the defendants would properly inform the FDA and the prescribers about the risk of TD then thousands of injuries from this drug could be prevented. Metoclopramide - as it was marketed and distributed by defendants at the time of Mr. Burnett's ingestion of the drug - was unreasonably dangerous and the information and warnings supplied with the drug were inadequate.”