PDR®
`54
`2000
`
`EDITION
`
`YSIC
`DFSK
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`0
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`11
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`Printed on recycled paper (cid:9)
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`ISBN: 1-56363-330-2
`
`AQUESTIVE EXHIBIT 1042 page 0001
`AQUESTIVE EXHIBIT 1042 page 0001
`
`

`

`1012/EISAI (cid:9)
`
`Aricept—Cont.
`
`Postintroduction Reports
`Voluntary reports of adverse events temporally associated
`with ARICEPT® that have been received since market in-
`troduction that are not listed above, and that there is inad-
`equate data to determine the causal relationship with the
`drug include the following: abdominal pain, agitation, cho-
`lecystitis, confusion, convulsions, hallucinations, heart
`block, hemolytic anemia, hyponatremia, pancreatitis, and
`rash.
`OVERDOSAGE
`Because strategies for the •management of overdose are
`continually evolving, it is advisable to contact a Poison
`Control Center to determine the latest recommendations
`for the management of an overdose of any drug.
`As in any case of overdose, general supportive measures
`should be utilized. Overdosage with cholinesterase inhibi-
`tors can result in cholinergic crisis characterized by severe
`nausea, vomiting, salivation, sweating, bradycardia, hypo-
`tension, respiratory depression, collapse and convulsions.
`Increasing muscle weakness is a possibility and may result
`in death if respiratory muscles are involved. Tertiary anti-
`cholinergics such as atropine may be used as an antidote for
`ARICEPT® overdosage. Intravenous atropine sulfate ti-
`trated to effect is recommended: an initial dose of 1.0 to 2.0
`mg IV with subsequent doses based upon clinical response.
`Atypical responses in blood pressure and heart rate have
`been reported with other cholinomimetics when co-adminis-
`tered with quaternary anticholinergics such as gylcopyrro-
`late. It is not known whether ARICEPT® and/or its metab-
`olites can be removed by dialysis (hemodialysis, peritoneal
`dialysis, or hemofiltration).
`Dose-related signs of toxicity in animals included reduced
`spontaneous movement, prone position, staggering gait, lac-
`rimation, clonic convulsions, depressed respiration, saliva-
`tion, miosis, tremors, fasciculation and lower body surface
`temperature.
`DOSAGE AND ADMINISTRATION
`The dosages of ARICEPT® shown to be effective in con-
`trolled clinical trials are 5 mg and 10 mg administered once
`per day.
`The higher dose of 10 mg did not provide a statistically sig-
`nificantly greater clinical benefit than 6 mg. There is a sug-
`gestion, however, based upon order of group mean scores
`and dose trend analyses of data from these clinical trials,
`that a daily dose of 10 mg of ARICEPT® might provide ad-
`ditional benefit for some patients. Accordingly, whether or
`not to employ a dose of 10 mg is a matter of prescriber and
`patient preference.
`Evidence from the controlled trials indicates that the 10 mg
`dose, with a one week titration, is likely to be associated
`with a higher incidence of cholinergic adverse events than
`the 5 mg dose. In open label trials using a 6 week titration,
`the frequency of these same adverse events was similar be-
`tween the 5 mg and 10 mg dose groups. Therefore, because
`steady state is not achieved for 15 days and because the in-
`cidence of untoward effects may be influenced by the rate of
`dose escalation, treatment with a dose of 10 mg should not
`be contemplated until patients have been on a daily dose of
`5 mg for 4 to 6 weeks.
`ARICEPT® should be taken in the evening, just prior to re-
`tiring. ARICEPT® can be taken with or without food.
`HOW SUPPLIED
`ARICEPT® is supplied as film-coated, round tablets con-
`taining either 5 mg or 10 mg of donepezil hydrochloride.
`The 5 mg tablets are white. The strength, in mg (5), is de-
`bossed on one side and ARICEPT is debossed on the other
`side.
`The 10 mg tablets are yellow. The strength, in mg (10), is
`debossed on one side and ARICEPT is debossed on the other
`side.
`5 mg (White) Bottles of 30 (NDC# 62856-245-30)
`Unit Dose Blister Package 100 (10x10)
`(NDC# 62856-245-41)
`10 mg (Yellow) Bottles of 30 (NDC# 62856-246-30)
`Unit Dose Blister Package 100 (10x10)
`(NDC# 62856-246-41)
`Storage: Store at controlled room temperature, 15°C to
`30°C (59°F to 86°F).
`Rx only
`ARICEPT® is a registered trademark of
`Eisai Co., Ltd., Tokyo, Japan
`Manufactured and Marketed by
`Eisai Inc., Teaneck, NJ 07666
`Distributed/Marketed by
`Roerig Division of Pfizer Inc, New York, NY 10017
`®1998 Eisai Inc.
`Revised September, 1998
`200005 (cid:9)
`Shown in Product Identification Guide, page 310
`
`Available to physicians through Eisai Medical Sales Spe-
`cialists and Representatives, free of charge. Most are avail-
`able in Spanish.
`Understanding Alzheimers Disease Brochure
`Managing Alzheimers Disease Brochure
`(both are disease specific brochures)
`Know your Medicine Brochure — English only
`(for patients on Aricept)
`
`26 week patient diary
`(also for patients on Aricept)
`
`Elan Pharma
`800 GATEWAY BOULEVARD
`SOUTH SAN FRANCISCO, CA 94080
`
`For Medical Information Contact:
`(888) NEURO-05
`(888) 638-7605
`To Report Adverse Events Contact:
`(877) ELAN GSS
`(877) 352-6477
`The products below are distributed by Elan Pharma, a busi-
`ness unit of Elan Pharmaceuticals, Inc.
`
`DIASTAT® Rectal Delivery System
`[di 'a-stad
`(diazepam rectal gel!
`Rx only
`
`DESCRIPTION
`Diastat* rectal delivery system is a non-sterile diazepam gel
`provided in a prefilled, unit-dose, rectal delivery system.
`Diastat contains 5 mg/mL diazepam, propylene glycol, ethyl
`alcohol (10%), hydroxypropyl methylcellulose, sodium ben-
`zoate, benzyl alcohol (1.5%), benzoic acid and water. Diastat
`is clear to slightly yellow and has a pH between 6.5-7.2.
`Diazepam, the active ingredient of Diastat, is a benzodiaz-
`epine anticonvulsant with the chemical name 7-chloro-1,3-
`dihydro-1-methy1-5-pheny1-2H-1,4-benzodiazepin-2-one.
`The structural formula is as follows:
`
`CI
`
`* Registered trademark of Elan Pharmaceuticals, Inc.
`
`CLINICAL PHARMACOLOGY
`Mechanism of Action
`Although the precise mechanism by which diazepam exerts
`its antiseizure effects is unknown, animal and in vitro stud-
`ies suggest that diazepam acts to suppress seizures through
`an interaction with -y-aminobutyric acid (GABA) receptors
`of the A-type (GABAA). GABA, the major inhibitory neuro-
`transmitter in the central nervous system, acts at this re-
`ceptor to open the membrane channel allowing chloride ions
`to flow into neurons. Entry of chloride ions causes an inhib-
`itory potential that reduces the ability of neurons to depo-
`larize to the threshold potential necessary to produce action
`potentials. Excessive depolarization of neurons is impli-
`cated in the generation and spread of seizures. It is believed
`that diazepam enhances the actions of GABA by causing
`GABA to bind more tightly to the GABAA receptor.
`Pharmacokinetics
`Pharmacokinetic information of diazepam following rectal
`administration was obtained from studies conducted in
`healthy adult subjects. No pharmacokinetic studies were
`conducted in pediatric patients. Therefore, information from
`the literature is used to define pharmacokinetic labeling in
`the pediatric population.
`Diastat is well absorbed following rectal administration,
`reaching peak plasma concentrations in 1.5 hours. The ab-
`solute bioavailability of Diastat relative to Valium® inject-
`able is 90%. The volume of distribution of Diastat is calcu-
`lated to be approximately 1 L/kg. The mean elimination
`half-life of diazepam and desmethyldiazepam following ad-
`ministration of a 15 mg dose of Diastat was found to be
`about 46 hours (CV=43%) and 71 hours (CV=37%), respec-
`tively. Both diazepam and its major active metabolite des-
`methyldiazepam bind extensively to plasma proteins (95-
`98%).
`[See Figure 1 at top of next page]
`Metabolism and Elimination: It has been reported in the lit-
`erature that diazepam is extensively metabolized to one ma-
`jor active metabolite (desmethyldiazepam) and two minor
`active metabolites, 3-hydroxydiazepam (temazepam) and
`3-hydroxy-N-diazepam (oxazepam) in plasma. At therapeu-
`tic doses, desmethyldiazepam is found in plasma at concen-
`trations equivalent to those of diazepam while oxazepam
`and temazepam are not usually detectable. The metabolism
`of diazepam is primarily hepatic and involves demethyla-
`tion (involving primarily CYP2C19 and CYP3A4) and 3-hy-
`droxylation (involving primarily CYP3A4), followed by glu-
`curonidation. The marked inter-individual variability in the
`clearance of diazepam reported in the literature is probably
`attributable to variability of CYP2C19 (which is known to
`exhibit genetic polymorphism; about 3-5% of Caucasians
`have little or no activity and are "poor metabolizers") and
`CYP3A4. No inhibition was demonstrated in the presence of
`inhibitors selective for CYP2A6, CYP2C9, CYP2D6,
`CYP2E1, or CYP1A2, indicating that these enzymes are not
`significantly involved in metabolism of diazepam.
`
`PHYSICIANS' DESK REFERENCE
`
`Special Populations
`Hepatic Impairment: No pharmacokinetic studies were con
`ducted with Diastat in hepatically impaired subjects. Liter
`ature review indicates that following administration of 0.1
`to 0.15 mg/kg of diazepam intravenously, the half-life of
`diazepam was prolonged by two to five-fold in subjects with
`alcoholic cirrhosis (n=24) compared to age-matched control
`subjects (n=37) with a corresponding decrease in clearance
`by half: however, the exact degree of hepatic impairment in
`these subjects was not characterized in this literature (see
`PRECAUTIONS section).
`Renal Impairment: The pharmacokinetics of diazepam have
`not bean studied in renally impaired subjects (see PRECAU-
`TIONS section).
`Pediatrics: No pharmacokinetic studies were conducted
`with Diastat in the pediatric population. However, litera•
`ture review indicates that following IV administration (0.33
`mg/kg), diazepam has a longer half-life in neonates (birth
`up to one month; approximately 50-95 hours) and infants
`(one month up to two years; about 40-50 hours), whereas it
`has a shorter half-life in children (two to 12 years; approk
`imately 15-21 hours) and adolescents (12 to 16 years; about
`18-20 years) (see PRECAUTIONS section).
`Elderly: A study of single dose IV administration of diaze-
`pam (0.1 mg/kg) indicates that the elimination half-life of
`diazepam increases linearly with age, ranging from about
`15 hours at 18 years (healthy young adults) to about NS
`hours at 95 years (healthy elderly) with a corresponding de•
`crease in clearance of free diazepam (see PRECAUTIONS
`and DOSAGE AND ADMINISTRATION sections).
`Effect of Gender, Race, and Cigarette Smoking: No targeted
`pharmacokinetic studies have been conducted to evaluate
`the effect of gender, race, and cigarette smoking on the
`pharmacokinetics of diazepam. However, covariate analysis
`of a population of treated patients following administration
`of Diastat indicated that neither gender nor cigarette smol
`ing had any effect on the pharmacokinetics of diazepam.
`Clinical Studies
`The effectiveness of Diastat has been established in two ad•
`equate and well-controlled clinical studies in children and
`adults exhibiting the seizure pattern described below under
`INDICATIONS.
`A randomized, double-blind study compared sequential
`doses of Diastat and placebo in 91 patients (47 children, 44
`adults) exhibiting the appropriate seizure profile. The fire(
`dose was given at the onset of an identified episode. Chil•
`dren were dosed again four hours after the first dose and
`were observed for a total of 12 hours. Adults were dosed at
`four and 12 hours after the first dose and were observed for
`a total of 24 hours. Primary outcomes for this study wen
`seizure frequency during the period of observation and
`global assessment that took into account the severity ant
`nature of the seizures as well as their frequency.
`The median seizure frequency for the Diastat treated
`was zero seizures per hour, compared to a median seizure
`frequency of 0.3 seizures per hour 'for the placebo group, a
`difference that was statistically significant (p < 0.0001)M
`three categories of the global assessment (seizure frequeacy,
`seizure severity, and "overall") were also found to be state
`tically significant in favor of Diastat (p < 0.0001). The fal-
`lowing histogram displays the results for the "overall" sate
`gory of the global assessment.
`[See Figure 2 on next page]
`Patients treated with Diastat experienced prolonged time•
`to-next-seizure compared to placebo (p = 0.0002) as shun
`in the following graph.
`[See Figure 3 on next page]
`In addition, 62% of patients treated with Diastat were st
`zure-free during the observation period compared to 201 of
`placebo patients.
`Analysis of response by gender and age revealed no sub-
`stantial differences between treatment in either of these
`subgroups. Analysis of response by race was considered uon
`reliable, due to the small percentage of non-Caucasians.
`A second double-blind study compared single doses of l'fin
`stat and placebo in 114 patients (53 children, 61 adults!.
`The dose was given at the onset of the identified episode and
`patients were observed for a total of 12 hours. The priffouT
`outcome in this study was seizure frequency. The ineden
`seizure frequency for the Diastat-treated group was ram
`seizures per 12 hours, compared to a median seizure fre
`quency of 2.0 seizures per 12 hours for the placebo group 2
`difference that was statistically significant (p < 0.01).
`tients treated with Diastat experienced prolonged timeta
`next-seizure compared to placebo (p = 0.0072) as shown
`the following graph.
`[See Figure 4 at top of page 1014]
`In addition, 55% of patients treated with Diastat were se
`zure-free during the observation period compared to 341 of
`patients receiving placebo. Overall, caregivers judged De
`stat to be more •effective than placebo (p=0.018), based OC I
`10 centimeter visual analog scale. In addition, investigato
`also evaluated the effectiveness of Diastat and judged Die
`stat to be more effective than placebo (p < 0.001).
`An analysis of response by gender revealed a statistegy
`significant difference between treatments in females butut
`in males in this study, and the difference between the 2 SS-
`ders in response to the treatments reached borderline a
`tistical significance. Analysis of response by race was on
`aidered unreliable, due to the small percentage of non-cer
`casions.
`INDICATIONS AND USAGE
`Diastat is a gel formulation of diazepam intended for :+d
`administration in the management of selected, refraet
`patients with epilepsy, on stable regimens of AEDs,
`quire intermittent use of diazepam to control bouts •:it
`creased seizure activity.
`
`monition will be superseded by supplements and subsequent editions
`
`AQUESTIVE EXHIBIT 1042 page 0002
`AQUESTIVE EXHIBIT 1042 page 0002
`
`

`

`FIGURE 1: Plasma Concentrations of Diazepam and
`Dimethyldiazepam Following Diastat or IV Diazepam
`
`600
`
`-.a-Diazepam after 7.6 mg IV
`--....-Dlazeparn after 15 mg Dlastat
`--e-Desmethyl diazepam atter 7.5 mg IV
`--e-Desmethyl diazepam after 15 mg Diastat
`
`1300
`
`200
`
`• 100
`
`0
`
`144 192 240
`
`FIGURE 2: Caregiver Overall Global Assessment of the Efficacy
`of Diastat
`
`Better
`Dlastat Same (cid:9)
`
`13
`
`Worse (cid:9)
`
`4
`
`82
`
`Better
`
`Placebo Same
`
`W orse
`
`a4 (cid:9)
`
`Ei 14 33
`
`1523W3/11351M
`9
`
`-1 59
`
`o
`
`20 (cid:9)
`
`40 (cid:9)
`60 (cid:9)
`Percent of Patients
`
`80
`
`1 0 0
`
`FIGURE 3: Kaplan-Meier Survival Analysis of Time-to-Next-Seizure
`- First Study
`1
`0.9
`
`0.8
`
`0.7
`
`0.6
`
`0.5
`
`0.4 _
`
`0.3
`
`0.2 -
`
`0.1
`
`0
`
`Diastat
`
`Placebo
`
`Probability of No Seizure
`
`0
`
`4
`
`8 (cid:9)
`
`12
`Time (Hours)
`
`16
`
`20
`
`24
`
`culties, and hypothermia in children born to mothers who
`have been receiving benzodiazepines late in pregnancy. In
`addition, children born to mothers receiving benzodiaz-
`epines on a regular basis late in pregnancy may be at some
`risk of experiencing withdrawal symptoms during the post-
`natal period.
`Advice Regarding the Use of Diastat in Women of Child-
`bearing Potential: In general, the use of Diastat in women of
`childbearing potential, and more specifically during known
`pregnancy, should be considered only when the clinical sit-
`uation warrants the risk to the fetus.
`The specific considerations addressed above regarding the
`use of anticonvulsants in epileptic women of childbearing
`potential should be weighed in treating or counseling these
`women.
`Because of experience with other members of the benzodi-
`azepine class, Diastat is assumed to be capable of causing
`an increased risk of congenital abnormalities when admin-
`istered to a pregnant woman during the first trimester. The
`possibility that a woman of childbearing potential may be
`pregnant at the time of institution of therapy should be con-
`sidered. If this drug is used during pregnancy, or if the pa-
`tient becomes pregnant while taking this drug, the patient
`should be apprised of the potential hazard to the fetus. Pa-
`tients should also be advised that if they become pregnant
`during therapy or intend to become pregnant they should
`communicate with their physician about the desirability of
`discontinuing the drug.
`Withdrawal Symptoms
`Withdrawal symptoms of the barbiturate type have oc-
`curred after the discontinuation regular use of benzodiaz-
`epines (see DRUG ABUSE AND DEPENDENCE section).
`
`Chronic Use
`Diastat is not recommended for chronic, daily use as an an-
`ticonvulsant because of the potential for development of tol-
`erance to diazepam. Chronic daily use of diazepam may in-
`crease the frequency and/or severity of tonic clonic seizures,
`requiring an increase in the dosage of standard anticonvul-
`sant medication. In such cases, abrupt withdrawal of
`chronic diazepam may also be associated with a temporary
`increase in the frequency and/or severity of seizures.
`Use in Patients with Petit Mal Status
`Tonic status epilepticus has been precipitated in patients
`treated with IV diazepam for petit mal status or petit mal
`variant status.
`PRECAUTIONS
`Caution in Penally Impaired Patients
`Metabolites of Diastat are excreted by the kidneys; to avoid
`their excess accumulation, caution should be exercised in
`the administration of the drug to patients with impaired re-
`nal function.
`Caution in Hepatically Impaired Patients
`Concomitant liver disease is known to decrease the clear-
`ance of diazepam (see CLINICAL PHARMACOLOGY, Spe-
`cial Populations, Hepatic Impairment). Therefore, Diastat
`should be used with caution in patients with liver disease.
`Use in Pediatrics
`The controlled trials demonstrating the effectiveness of Dia-
`stat included children two years of age and olden Clinical
`studies have not been conducted to establish the efficacy
`and safety of Diastat in children under two years of age.
`
`Continued on next page
`
`Consult 2000 MR® supplements and future editions for revisions
`
`AQUESTIVE EXHIBIT 1042 page 0003
`AQUESTIVE EXHIBIT 1042 page 0003
`
`Evidence to support the use of Diastat was adduced in two
`controlled trials (see CLINICAL PHARMACOLOGY, CLIN-
`ICAL STUDIES subsection) that enrolled patients with par-
`tial onset or generalized convulsive seizures who were iden-
`tified jointly by their caregivers and physicians as suffering
`intermittent and periodic episodes of markedly increased
`seizure activity, sometimes heralded by non-convulsive
`symptoms, that for the individual patient were characteris-
`tic and were deemed by the prescriber to be of a kind for
`which a benzodiazepine would ordinarily be administered
`acutely. Although these clusters or bouts of seizures differed
`among patients, for any individual patient the clusters of
`seizure activity were not only stereotypic but were judged
`by those conducting and participating in these studies to be
`distinguishable from other seizures suffered by that patient.
`The conclusion that a patient experienced such unique epi-
`sodes of seizure activity was based on historical informa-
`tion.
`CONTRAINDICATIONS
`Diastat is contraindicated in patients with a known hyper-
`sensitivity to diazepam. Diastat may be used in patients
`with open angle glaucoma who are receiving appropriate
`therapy but is contraindicated in acute narrow angle glau
`coma.
`WARNINGS
`General
`Diastat should only be administered by caregivers who in
`the opinion of the prescribing physician 1) are able to dis-
`tinguish the distinct cluster of seizures (and/or the events
`presumed to herald their onset) from the patient's ordinary
`seizure activity, 2) have been instructed and judged to be
`competent to administer the treatment rectally, 3) under.
`stand explicitly which seizure manifestations may or may
`not be treated with Diastat, and 4) are able to monitor the
`clinical response and recognize when that response is such
`that immediate professional medical evaluation is re-
`quired.
`CNS Depression
`Because Diastat produces CNS depression, patients receiv-
`ing this drug who are otherwise capable and qualified to do
`so should be cautioned against engaging in hazardous occu-
`pations requiring mental alertness, such as operating ma-
`chinery, driving a motor vehicle, or riding a bicycle until
`they have completely returned to their level of baseline
`functioning.
`Although Diastat is indicated for use solely on an intermit-
`tent basis, the potential for a synergistic CNS-depressant
`effect when used simultaneously with alcohol or other CNS
`depressants must be considered by the prescribing physi-
`cian, and appropriate recommendations made to the patient
`aadlor caregiver.
`Prolonged CNS depression has been observed in neonates
`treated with diazepam. Therefore, Diastat is not recom-
`mended for use in children under six months of age.
`Pregnancy Risks
`No clinical studies have been conducted with Diastat in
`pregnant women. Data from several sources raise concerns
`about the use of diazepam during pregnancy.
`Animal Findings: Diazepam has been shown to be tera-
`togenic in mice and hamsters when given orally at
`single doses of 100 mg/kg or greater (approximately eight
`times the maximum recommended human dose
`IHRHD=1 mg/kg/clay] or greater on a mg/m2 basis). Cleft
`palate and exencephaly are the most common and consis-
`tently reported malformations produced in these species by
`administration of high, maternally-toxic doses of diazepam
`during organogenesis. Rodent studies have indicated that
`prenatal exposure to diazepam doses similar to those used
`clinically can produce long-term changes in cellular immune
`responses, brain neurochemistry, and behavior.
`General Concerns and Considerations About Anticonvul-
`sants: Reports suggest an association between the use of an-
`ticonvulsant drugs by women with epilepsy and an elevated
`incidence of birth defects in children born to these women.
`Data are more extensive with respect to phenytoin and phe-
`nobarbital, but a smaller number of systematic or anecdotal
`reports suggest a possible similar association with the use
`of all known anticonvulsant drugs.
`The reports suggesting an elevated incidence of birth de-
`fects in children of drug-treated epileptic women cannot be
`regarded as adequate to prove a definite cause and effect
`relationship. There are intrinsic methodologic problems in
`obtaining adequate data on drug teratogenicity in humans;
`the possibility also exists that other factors, e.g., genetic fac-
`tors or the epileptic condition itself, may be more important
`than drug therapy in leading to birth defects. The great ma-
`jority of mothers on anticonvulsant medication deliver nor-
`mal infants. It is important to note that anticonvulsant
`drugs should not be discontinued in patients in whom the
`drug is administered to prevent seizures because of the
`strong possibility of precipitating status epilepticus with at-
`tendant hypoxia and threat to life. In individual cases
`where the severity and frequency of the seizure disorder are
`such that the removal of medication does not pose a serious
`threat to the patient, discontinuation of the drug may be
`considered prior to and during pregnancy, although it can-
`not be said with any confidence that even mild seizures do
`not pose some hazards to the developing embryo or fetus.
`General Concerns About Benzodiazepines: An increased
`risk of congenital malformations associated with the use of
`Il benzodiazepine drugs has been suggested in several studies.
`q' There may also be non-teratogenic risks associated with the
`use of benzodiazepines during pregnancy. There have been
`reports of neonatal flaccidity, respiratory and feeding diffi-
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`FIGURE 4: Kaplan-Meier Survival Analysis of Time-to-Next-Seizure
`- Second Study
`
`PHYSICIANS' DESK REFERENCE
`
`1
`
`0.9
`
`0.8
`
`0.7
`
`0.6
`
`0.5
`
`0.4
`
`0.3
`
`0.2
`
`0.1
`
`0
`
`Probability of No Seizure
`
`0
`
`2
`
`4 (cid:9)
`
`6
`Time (Hours)
`
`8
`
`10
`
`12
`
`tion. No adverse effects on fertility or offspring viability
`were noted at a dose of. 80 mg/kg/day (approximately 13
`times the MRHD on a mg/m2 basis).
`Pregnancy—Category D (see WARNINGS section.)
`Labor and Delivery
`In humans, measurable amounts of diazepam have been
`found in maternal and cord blood, indicating placental
`transfer of the drug. Until additional information is avail-
`able, Diastat is not recommended for obstetrical use.
`Nursing Mothers
`Because diazepam and its metabolites may be present in
`human breast milk for prolonged periods of time after acute
`use of Diastat, patients should be advised not to breast-feed
`for an appropriate period of time after receiving treatment
`with Diastat.
`
`ADVERSE REACTIONS
`Diastat adverse event data were collected from double-
`blind, placebo-controlled studies and open-label studies.
`The majority of adverse events were mild to moderate in
`severity and transient in nature.
`Two patients who received Diastat died seven to 15 weeks
`following treatment; neither of these deaths was deemed re-
`lated to Diastat.
`The most frequent adverse event reported to be related to
`Diastat in the two double-blind, placebo-controlled studies
`was somnolence (23%). Less frequent adverse events were
`dizziness, headache, pain, abdominal pain, nervousness,
`vasodilatation, diarrhea, ataxia, euphoria, incoordination,
`asthma, rhinitis, and rash, which occurred in approximately
`2-5% of patients.
`Approximately 1.4% of the 573 patients who received Dia-
`stat in clinical trials of epilepsy discontinued treatment be-
`cause of an adverse event. The adverse event most fre-
`quently associated with discontinuation (occurring in three
`patients) was somnolence. Other adverse events most com-
`monly associated.with discontinuation and occurring in two
`patients were hypoventilation and rash. Adverse events oc-
`curring in one patient were asthenia, hyperkinesia, incoor-
`dination, vasodilatation and urticaria. These events were
`judged to be related to Diastat.
`In the two domestic double-blind, placebo-controlled, paral-
`lel-group studies, the proportion of patients who discontin-
`ued treatment because of adverse events was 2% for the
`group treated with Diastat, versus 2% for the placebo group.
`In the Diastat group, the adverse events considered the pri-
`mary reason for discontinuation were different in the two
`patients who discontinued treatment; one discontinued due
`to rash and one discontinued due to lethargy. The primary
`reason for discontinuation in the patients treated with pla-
`cebo was lack of effect.
`Adverse Event Incidence in Controlled Clinical Trials
`Table 1 lists treatment-emergent signs and symptoms that
`occurred in >1% of patients enrolled in parallel-group, pla-
`cebo-controlled trials and were numerically more common
`in the Diastat group. Adverse events were usually mild or
`moderate in intensity.
`The prescriber should be aware that these figures, obtained
`when Diastat was added to concurrent antiepileptic drug
`therapy, cannot be used to predict the frequency of adverse
`events in the course of usual medical practice when patient
`characteristics and other factors may differ from those pre-
`vailing during clinical studies. Similarly, the cited frequen-
`cies cannot be directly compared with figures obtained from
`other clinical investigations involving different treatments,
`uses, or investigators. An inspection of these frequencies,
`however, does provide the prescribing physician with one
`basis to estimate the relative contribution of drug and non-
`drug factors to the adverse event incidences in the popula-
`tion studied.
`
`TABLE 1: Treatment-Emergent Signs And Symptoms That
`Occurred In >1% Of Patients Enrolled In
`Parallel-Group, Placebo-Controlled Trials And
`Were Numerically More Common In The Diego!
`Group
`
`Body System
`
`COSTART (cid:9)
`Term
`
`Diastat (cid:9) Fiscal)+,
`N = 101 (cid:9) N e 104
`
`•
`
`Body As A Whole
`Cardiovascular
`Digestive
`Nervous
`
`Headache
`Vasodilatation
`Diarrhea
`Ataxia
`Dizziness
`Euphoria
`Incoordination
`Somnolence
`Asthma
`Respiratory
`Skin and Appendages Rash
`
`5%
`2%
`4%
`3%
`3%
`3%
`3%
`23%
`2%
`3%
`
`4%
`0%
`<1%
`<1%
`2%
`0%
`0%
`8%
`0%
`0%
`
`Other events' eported by 1% or more of patients treated In
`controlled trials but equally or more frequent in the placebo
`group than in the Diastat group were abdominal pain, pain
`nervousness, and rhinitis. Other events reported by fewer
`than 1% of patients were infection, anorexia, vomiting, ace•