Diazepam rectal gel rectal delivery system is a non-sterile diazepam gel provided in a prefilled, unit-dose, rectal delivery system. Diazepam rectal gel contains 5 mg/mL diazepam, propylene glycol, ethyl alcohol (10%), hydroxypropyl methylcellulose, sodium benzoate, benzyl alcohol (1.5%), benzoic acid and water. Diazepam rectal gel is clear to slightly yellow and has a pH between 6.5-7.2.

Diazepam, the active ingredient of diazepam rectal gel, is a benzodiazepine anticonvulsant with the chemical name 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one. The structural formula is as follows:

Diazepam rectal gel is a gel formulation of diazepam intended for rectal administration in the management of selected, refractory, patients with epilepsy, on stable regimens of AEDs, who require intermittent use of diazepam to control bouts of increased seizure activity.

Evidence to support the use of diazepam rectal gel was adduced in two controlled trials (see CLINICAL PHARMACOLOGY, CLINICAL STUDIES subsection) that enrolled patients with partial onset or generalized convulsive seizures who were identified jointly by their caregivers and physicians as suffering intermittent and periodic episodes of markedly increased seizure activity, sometimes heralded by nonconvulsive symptoms, that for the individual patient were characteristic 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 episodes of seizure activity was based on historical information.

(see also Patient/Caregiver Package Insert)

This section is intended primarily for the prescriber; however, the prescriber should also be aware of the dosing information and directions for use provided in the patient package insert.

A decision to prescribe Diazepam rectal gel involves more than the diagnosis and the selection of the correct dose for the patient.

First, the prescriber must be convinced from historical reports and/or personal observations that the patient exhibits the characteristic identifiable seizure cluster that can be distinguished from the patient's usual seizure activity by the caregiver who will be responsible for administering Diazepam rectal gel.

Second, because Diazepam rectal gel is only intended for adjunctive use, the prescriber must ensure that the patient is receiving an optimal regimen of standard anti-epileptic drug treatment and is, nevertheless, continuing to experience these characteristic episodes.

Third, because a non-health professional will be obliged to identify episodes suitable for treatment, make the decision to administer treatment upon that identification, administer the drug, monitor the patient, and assess the adequacy of the response to treatment, a major component of the prescribing process involves the necessary instruction of this individual.

Fourth, the prescriber and caregiver must have a common understanding of what is and is not an episode of seizures that is appropriate for treatment, the timing of administration in relation to the onset of the episode, the mechanics of administering the drug, how and what to observe following administration, and what would constitute an outcome requiring immediate and direct medical attention.

The Diazepam rectal gel dose should be individualized for maximum beneficial effect. The recommended dose of Diazepam rectal gel is 0.2-0.5 mg/kg depending on age. See the dosing table for specific recommendations.

Because Diazepam rectal gel is provided as unit doses of 2.5, 5, 7.5, 10, 12.5, 15, 17.5, and 20 mg, the prescribed dose is obtained by rounding upward to the next available dose. The following table provides acceptable weight ranges for each dose and age category, such that patients will receive between 90% and 180% of the calculated recommended dose. The safety of this strategy has been established in clinical trials.

The rectal delivery system includes a plastic applicator with a flexible, molded tip available in two lengths. The Diastat^γ' AcuDialγ" 10 mg syringe is available with a 4.4 cm tip and the Diastat^γ' AcuDialγ" 20 mg syringe is available with a 6.0 cm tip. Diastat^γ' 2.5 mg is also available with a 4.4 cm tip.

In elderly and debilitated patients, it is recommended that the dosage be adjusted downward to reduce the likelihood of ataxia or oversedation.

The prescribed dose of Diazepam rectal gel should be adjusted by the physician periodically to reflect changes in the patient's age or weight.

The Diastat^γ' 2.5 mg dose may also be used as a partial replacement dose for patients who may expel a portion of the first dose.

The prescriber may wish to prescribe a second dose of Diazepam rectal gel. A second dose, when required, may be given 4-12 hours after the first dose.

It is recommended that Diazepam rectal gel be used to treat no more than five episodes per month and no more than one episode every five days.

Diazepam rectal gel rectal delivery system is a non-sterile, prefilled, unit dose, rectal delivery system. The rectal delivery system includes a plastic applicator with a flexible, molded tip available in two lengths, designated for convenience as 10 mg Delivery System and 20 mg Delivery System. The available doses from 20 mg delivery system are 10 mg, 12.5 mg, 15 mg, 17.5 mg and 20 mg. The available doses from 10 mg delivery system are 5 mg, 7.5 mg and 10 mg. The Diazepam rectal gel delivery system is available in the following three presentations:

Diastat^γ' Rectal Tip Size NDC

2.5 mg Twin Pack 4.4 cm NDC 66490-650-20

Diastat^γ' AcuDialγ" Rectal Tip Size NDC

10 mg Delivery System Twin Pack4.4 cm NDC 0187-0658-20

20 mg Delivery System Twin Pack6.0 cm NDC 0187-0659-20

Each Twin Pack contains two diazepam rectal gel delivery systems, two packets of lubricating jelly, and administration and disposal Instructions available on the bottom of the package. Diastat^γ' AcuDialγ" is also packed with Instructions for Caregivers upon receipt from pharmacy.

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).

· Remove the syringe from the case.

· Confirm the dose prescribed by your doctor is visible and if known, is correct.

FOR EACH SYRINGE:

· Confirm that the prescribed dose is visible in the dose display window.

· Confirm that the green "READY" band is visible.

· Return the syringe to the case.

The instructions are also available on the bottom of each drug product package.

CAUTION: Federal law prohibits the transfer of this drug to any person other than the patient for whom it was prescribed.

Diazepam rectal gel 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 Diazepam rectal gel died seven to 15 weeks following treatment; neither of these deaths was deemed related to Diazepam rectal gel.

The most frequent adverse event reported to be related to Diazepam rectal gel 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 Diazepam rectal gel in clinical trials of epilepsy discontinued treatment because of an adverse event. The adverse event most frequently associated with discontinuation (occurring in three patients) was somnolence. Other adverse events most commonly associated with discontinuation and occurring in two patients were hypoventilation and rash. Adverse events occurring in one patient were asthenia, hyperkinesia, incoordination, vasodilatation and urticaria. These events were judged to be related to diazepam rectal gel.

In the two domestic double-blind, placebo-controlled, parallel-group studies, the proportion of patients who discontinued treatment because of adverse events was 2% for the group treated with Diazepam rectal gel, versus 2% for the placebo group. In the Diazepam rectal gel group, the adverse events considered the primary 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 placebo was lack of effect.

Table 1 lists 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 Diazepam rectal gel group. Adverse events were usually mild or moderate in intensity.

The prescriber should be aware that these figures, obtained when Diazepam rectal gel 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 prevailing during clinical studies. Similarly, the cited frequencies 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 population 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 Diazepam rectal
gel Group

Other events reported by 1% or more of patients treated in controlled trials but equally or more frequent in the placebo group than in the Diazepam rectal gel group were abdominal pain, pain, nervousness, and rhinitis. Other events reported by fewer than 1% of patients were infection, anorexia, vomiting, anemia, lymphadenopathy, grand mal convulsion, hyperkinesia, cough increased, pruritus, sweating, mydriasis, and urinary tract infection.

The pattern of adverse events was similar for different age, race and gender groups.

Diazepam rectal gel has been administered to 573 patients with epilepsy during all clinical trials, only some of which were placebo-controlled. During these trials, all adverse events were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse events, similar types of events were grouped into a smaller number of standardized categories using modified COSTART dictionary terminology. These categories are used in the listing below. All of the events listed below occurred in at least 1% of the 573 individuals exposed to Diazepam rectal gel.

All reported events are included except those already listed above, events unlikely to be drug-related, and those too general to be informative. Events are included without regard to determination of a causal relationship to diazepam.

BODY AS A WHOLE: Asthenia

CARDIOVASCULAR: Hypotension, vasodilatation

NERVOUS: Agitation, confusion, convulsion, dysarthria, emotional lability, speech disorder, thinking abnormal, vertigo

RESPIRATORY: Hiccup

The following infrequent adverse events were not seen with Diazepam rectal gel but have been reported previously with diazepam use: depression, slurred speech, syncope, constipation, changes in libido, urinary retention, bradycardia, cardiovascular collapse, nystagmus, urticaria, neutropenia and jaundice.

Paradoxical reactions such as acute hyperexcited states, anxiety, hallucinations, increased muscle spasticity, insomnia, rage, sleep disturbances and stimulation have been reported with diazepam; should these occur, use of Diazepam rectal gel should be discontinued.

Diazepam is a Schedule IV controlled substance and can produce drug dependence. It is recommended that patients be treated with Diazepam rectal gel no more frequently than every five days and no more than five times per month.

Addiction-prone individuals (such as drug addicts or alcoholics) should be under careful surveillance when receiving diazepam or other psychotropic agents because of the predisposition of such patients to habituation and dependence.

Abrupt discontinuation of diazepam following chronic regular use has resulted in withdrawal symptoms, similar in character to those noted with barbiturates and alcohol (convulsions, tremor, abdominal and muscle cramps, vomiting and sweating). The more severe withdrawal symptoms have usually been limited to those patients who had received excessive doses over an extended period of time. Generally milder withdrawal symptoms (e.g., dysphoria and insomnia) have been reported following abrupt discontinuation of benzodiazepines taken continuously at therapeutic levels for several months.

If Diazepam rectal gel is to be combined with other psychotropic agents or other CNS-depressants, careful consideration should be given to the pharmacology of the agents to be employed particularly with known compounds which may potentiate the action of diazepam, such as phenothiazines, narcotics, barbiturates, MAO inhibitors and other antidepressants.

The clearance of diazepam and certain other benzodiazepines can be delayed in association with cimetidine administration. The clinical significance of this is unclear.

Valproate may potentiate the CNS-depressant effects of diazepam.

There have been no clinical studies or reports in literature to evaluate the interaction of rectally administered diazepam with other drugs. As with all drugs, the potential for interaction by a variety of mechanisms is a possibility.

Effect of Other Drugs on Diazepam Metabolism: In vitro studies using human liver preparations suggest that CYP2C19 and CYP3A4 are the principal isozymes involved in the initial oxidative metabolism of diazepam. Therefore, potential interactions may occur when diazepam is given concurrently with agents that affect CYP2C19 and CYP3A4 activity. Potential inhibitors of CYP2C19 (e.g., cimetidine, quinidine, and tranylcypromine) and CYP3A4 (e.g., ketoconazole, troleandomycin, and clotrimazole) could decrease the rate of diazepam elimination, while inducers of CYP2C19 (e.g., rifampin) and CYP3A4 (e.g., carbamazepine, phenytoin, dexamethasone and phenobarbital) could increase the rate of elimination of diazepam.

Effect of Diazepam on the Metabolism of Other Drugs: There are no reports as to which isozymes could be inhibited or induced by diazepam. But, based on the fact that diazepam is a substrate for CYP2C19 and CYP3A4, it is possible that diazepam may interfere with the metabolism of drugs which are substrates for CYP2C19, (e.g., omeprazole, propranolol, and imipramine) and CYP3A4 (e.g. cyclosporine, paclitaxel, terfenadine, theophylline, and warfarin) leading to a potential drug-drug interaction.

Although the precise mechanism by which diazepam exerts its antiseizure effects is unknown, animal and in vitro studies suggest that diazepam acts to suppress seizures through an interaction with g-aminobutyric acid (GABA) receptors of the A-type (GABA_A). GABA, the major inhibitory neurotransmitter in the central nervous system, acts at this receptor to open the membrane channel allowing chloride ions to flow into neurons. Entry of chloride ions causes an inhibitory potential that reduces the ability of neurons to depolarize to the threshold potential necessary to produce action potentials. Excessive depolarization of neurons is implicated 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 GABA_A receptor.

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.

Diazepam rectal gel is well absorbed following rectal administration, reaching peak plasma concentrations in 1.5 hours. The absolute bioavailability of Diazepam rectal gel relative to Valium^γ' injectable is 90%. The volume of distribution of Diazepam rectal gel is calculated to be approximately 1 L/kg. The mean elimination half-life of diazepam and desmethyldiazepam following administration of a 15 mg dose of Diazepam rectal gel was found to be about 46 hours (CV=43%) and 71 hours (CV=37%), respectively.

Both diazepam and its major active metabolite desmethyldiazepam bind extensively to plasma proteins (95-98%).

FIGURE 1: Plasma Concentrations of Diazepam and Desmethyldiazepam Following Diastat or IV Diazepam

Metabolism and Elimination: It has been reported in the literature that diazepam is extensively metabolized to one major active metabolite (desmethyldiazepam) and two minor active metabolites, 3-hydroxydiazepam (temazepam) and 3-hydroxy-N-diazepam (oxazepam) in plasma. At therapeutic doses, desmethyldiazepam is found in plasma at concentrations equivalent to those of diazepam while oxazepam and temazepam are not usually detectable. The metabolism of diazepam is primarily hepatic and involves demethylation (involving primarily CYP2C19 and CYP3A4) and 3-hydroxylation (involving primarily CYP3A4), followed by glucuronidation. 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.

Hepatic Impairment: No pharmacokinetic studies were conducted with diazepam rectal gel in hepatically impaired subjects. Literature 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 been studied in renally impaired subjects (see PRECAUTIONS section).

Pediatrics: No pharmacokinetic studies were conducted with diazepam rectal gel in the pediatric population. However, literature 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; approximately 15-21 hours) and adolescents (12 to 16 years; about 18-20 hours) (see PRECAUTIONS section).

Elderly: A study of single dose IV administration of diazepam (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 100 hours at 95 years (healthy elderly) with a corresponding decrease 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 diazepam rectal gel, indicated that neither gender nor cigarette smoking had any effect on the pharmacokinetics of diazepam.

The effectiveness of diazepam rectal gel has been established in two adequate and well controlled clinical studies in children and adults exhibiting the seizure pattern described below under INDICATIONS AND USAGE.

A randomized, double-blind study compared sequential doses of diazepam rectal gel and placebo in 91 patients (47 children, 44 adults) exhibiting the appropriate seizure profile. The first dose was given at the onset of an identified episode. Children 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 were seizure frequency during the period of observation and a global assessment that took into account the severity and nature of the seizures as well as their frequency.

The median seizure frequency for the diazepam rectal gel treated group 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). All three categories of the global assessment (seizure frequency, seizure severity, and "overall") were also found to be statistically significant in favor of Diazepam rectal gel (p < 0.0001). The following histogram displays the results for the "overall" category of the global assessment.

FIGURE 2: Caregiver Overall Global Assessment of the Efficacy of Diastat

Patients treated with Diazepam rectal gel experienced prolonged time-to-next-seizure compared to placebo (p = 0.0002) as shown in the following graph.

FIGURE 3: Kaplan-Meier Survival Analysis of Time-to-Next-Seizure - First Study

In addition, 62% of patients treated with diazepam rectal gel were seizure-free during the observation period compared to 20% of placebo patients.

Analysis of response by gender and age revealed no substantial differences between treatment in either of these subgroups. Analysis of response by race was considered unreliable, due to the small percentage of non-Caucasians.

A second double-blind study compared single doses of diazepam rectal gel 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 primary outcome in this study was seizure frequency. The median seizure frequency for the diazepam rectal gel-treated group was zero seizures per 12 hours, compared to a median seizure frequency of 2.0 seizures per 12 hours for the placebo group, a difference that was statistically significant (p < 0.03). Patients treated with diazepam rectal gel experienced prolonged time-to-next-seizure compared to placebo (p = 0.0072) as shown in the following graph.

FIGURE 4: Kaplan-Meier Survival Analysis of Time-to-Next-Seizure - Second Study

In addition, 55% of patients treated with diazepam rectal gel were seizure-free during the observation period compared to 34% of patients receiving placebo. Overall, caregivers judged diazepam rectal gel to be more effective than placebo (p = 0.018), based on a 10 centimeter visual analog scale. In addition, investigators also evaluated the effectiveness of diazepam rectal gel and judged diazepam rectal gel to be more effective than placebo (p < 0.001).

An analysis of response by gender revealed a statistically significant difference between treatments in females but not in males in this study, and the difference between the 2 genders in response to the treatments reached borderline statistical significance. Analysis of response by race was considered unreliable, due to the small percentage of non-Caucasians.

I M P O R T A N T

Read first before using
To the caregiver using Diastat^γ':

Please do not give DIASTAT^γ' until:

1. You have thoroughly read these instructions

2. Reviewed administration steps with the doctor

3.Understand the directions

1. You have confirmed:

· Prescribed dose is visible and if known, is correct

· green "ready" band is visible

2. You have thoroughly read these instructions

3. Reviewed administration steps with the doctor

4. Understand the directions

Please do not administer DIASTAT until you feel comfortable with how to use DIASTAT. The doctor will tell you exactly when to use DIASTAT. When you use DIASTAT correctly and safely you will help bring seizures under control. Be sure to discuss every aspect of your role with the doctor. If you are not comfortable, then discuss your role with the doctor again.

You must be able to tell the difference between cluster and ordinary seizures.

You must be comfortable and satisfied that you are able to give DIASTAT.

You need to agree with the doctor on the exact conditions when to treat with DIASTAT.

You must know how and for how long you should check the person after giving DIASTAT.

You need to know how soon seizures should stop or decrease in frequency after giving DIASTAT.

You need to know what you should do if the seizures do not stop or there is a change in the person's breathing, behavior or condition that alarms you.

If you have any questions or feel unsure about using the treatment, CALL THE DOCTOR before using DIASTAT.

For information on Diastat^γ'and Diastat^γ' AcuDialγ":
Call 1-877-361-2719 or Visit www.diastat.com

Epilepsy Foundation (EF). You can reach EF
by calling 1-800-EFA-1000 or www.efa.org

ADMINISTRATION AND DISPOSAL INSTRUCTIONS

When to treat. Based on the doctor's directions or prescription

______________________________________________________________

______________________________________________________________

DIASTAT should be used with caution:

· In people with respiratory (breathing) difficulties (e.g., asthma or pneumonia)

· In the elderly

· In women of child bearing potential, pregnancy and nursing mothers

Discuss beforehand with the doctor any additional steps you may need to take if there is leakage of
DIASTAT or a bowel movement.

Patient's DIASTAT dosage is: ________ mg

Patient's resting breathing rate ________ Patient's current weight ________

Confirm current weight is still the same as when DIASTAT was prescribed ____________________________

Check expiration date and always remove cap before using. Be sure seal pin is removed with the cap.

TREATMENT1

*******************************************************************

Important things to tell the doctor.

Stay with the person for 4 hours and make notes on the following:

· Changes in resting breathing rate ____________________________________________

· Changes in color_________________________________________________________

· Possible side effects from treatment__________________________________________

TREATMENT 2

*****************************************************************

Important things to tell the doctor.

Stay with the person for 4 hours and make notes on the following:

·Changes in resting breathing rate_____________________________________________

·Changes in color__________________________________________________________

·Possible side effects from treatment___________________________________________

Put person on their side where they can't fall.

Get medicine.

Get syringe.
Note:Seal Pin is attached to the cap.

Push up with thumb and pull to
remove cap from syringe. Be sure
Seal Pin is removed with the cap.

Lubricate rectal tip
with lubricating jelly.

Turn person
on side facing you.

Bend upper leg forward
to expose rectum.

Separate buttocks to
expose rectum.

Gently insert syringe tip into rectum.
Note:Rim should be snug against
rectal opening.

Keep person on side
facing you, note time given
and continue to observe.

·Seizure(s) continues 15 minutes after giving DIASTAT or per the doctor's instructions:______________________________

·Seizure behavior is different from other episodes.

·You are alarmed by the frequency or severity of the seizure(s).

·You are alarmed by the color or breathing of the person.

·The person is having unusual or serious problems.

Local Emergency Number:
__________________________________
(please be sure to note if your area has 911)

Doctor's Number:
__________________________________
Information for Emergency Squad:

Time DIASTAT given:___________________

Dose: _________________________________

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

DIAZEPAM - RECTAL

(dye-AZZ-eh-pam)

COMMON BRAND NAME(S): Diastat

USES: This medication is used to treat episodes of increased seizures (e.g., acute repetitive seizures, breakthrough seizures) in people who are already taking medications to control their seizures. This product is only recommended for short-term treatment of seizure attacks. It is not for ongoing daily use to prevent seizures. Uncontrolled seizures can turn into serious (possibly fatal) seizures that do not stop (status epilepticus).

Diazepam belongs to a class of medications called benzodiazepines which produce a calming effect on the brain and nerves (central nervous system). It is thought to work by increasing the effect of a certain natural chemical (GABA) in the brain.

HOW TO USE: Read the Patient/Caregiver Information Leaflet provided by your pharmacist before you use this product and each time you get a refill. If you have questions, consult your doctor or pharmacist.

This drug is given rectally by a caregiver trained to recognize the symptoms of your seizures and to correctly give the product. You and your caregivers must follow all instructions from your doctor and pharmacist exactly. Review all the instructions on how to give this medication in the product package. If you have any questions or feel unsure about using this medication, call the doctor or pharmacist before using this product. Get emergency help if the person is having a seizure and you do not feel comfortable using this product.

Before using, check the syringe for the correct dose. Your pharmacist should set the correct dose and lock the syringe in the "ready" position before giving you the product. Before leaving the pharmacy, look at each syringe. The dose should be in the display window on the side. You should see a green band with the word "ready" at the bottom of the syringe barrel. Look to make sure you have the correct syringe tip (e.g., smaller tip for a child) and that there are no cracks around the syringe tip. Return the product to the pharmacist if there is a problem or if you have any questions

Cracks can cause the medication to leak out and not provide the correct amount of medication. If you see a crack, use a different syringe. Cracks can appear over time, so keep checking your syringes to make sure you have good ones ready to use. Also check the expiration date on the package, and refill your prescription before the medication expires.

The dosage is based on age, weight, medical condition, and response to therapy. Be sure you understand when this medication should be used, how to use it, and how to check for side effects/seizure control. In some cases, a second dose may be prescribed and given 4 to 12 hours after the first dose. Usually, this medication should not be used to treat more than 5 episodes per month and no more than one episode every 5 days. If seizures continue after using this product as prescribed (e.g., no change 15 minutes after dose is given), or if there is a change in the person's breathing, behavior, or condition that alarms you, get emergency help right away.

This medication should not be used regularly. This medication may cause dependence when it has been used regularly for a long time (more than a few weeks) or if it has been used in high doses. In such cases, if you suddenly stop this drug, withdrawal reactions may occur. Such reactions can include increased seizures. Report any such reactions to your doctor immediately. When stopping extended, regular treatment with this drug, gradually reducing the dosage as directed will help prevent withdrawal reactions. Consult your doctor or pharmacist for more details.

Though it is very unlikely to occur, this medication can also result in abnormal drug-seeking behavior (addiction/habit forming). Do not increase your dose, take it more frequently, or use it for a longer time than prescribed.

Dispose of this medication properly. Follow the directions in the Patient Information Leaflet. Do not reuse the syringe.

Do not stop taking your regular seizure control medications when you are given this drug.

SIDE EFFECTS: Drowsiness, dizziness, diarrhea, and unsteadiness may occur. If these persist or worsen, notify your doctor promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects. This medication stays in the body for a long time. Be sure to watch for reactions for at least 4 hours after giving the medication.

Seek immediate medical attention if any of these unlikely but very serious side effects occur: slow/shallow/difficult breathing, mental/mood changes (e.g., anxiety, restlessness, hallucinations, sleep problems), slurred speech, trouble walking.

A serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction include: rash, itching, swelling, dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using this product, tell your doctor or pharmacist if you are allergic to it; or to other benzodiazepines (e.g., oxazepam, temazepam); or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: a certain eye problem (narrow-angle glaucoma), a certain muscle disease (myasthenia gravis), breathing trouble during sleep (sleep apnea).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: breathing problems (e.g., asthma, pneumonia), brain problems that could affect breathing (e.g., decreased consciousness, head injury), a certain eye problem (wide-angle glaucoma), kidney disease, liver disease, history of drug/alcohol abuse.

This drug may make you dizzy or drowsy; use caution while engaging in activities requiring alertness such as driving, riding a bicycle, or using machinery. Avoid alcoholic beverages.

To minimize dizziness and lightheadedness, get up slowly when rising from a sitting or lying position.

Caution is advised when using this drug in the elderly because they may be more sensitive to the effects of this drug, especially the drowsiness effect.

This medication is not recommended for use during pregnancy. If you become pregnant or think you may be pregnant, inform your doctor immediately. Consult your doctor for more details.

This drug may pass into breast milk. Because of the possible harm to the infant, breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop or change the dosage of any medicine before checking with them first.

This drug should not be used with the following medications because a very serious interaction may occur: sodium oxybate, fluvoxamine.

If you are currently using either of these medications, tell your doctor or pharmacist before using diazepam.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: cimetidine, clozapine, MAO inhibitors such as furazolidone, isocarboxazid, linezolid, moclobemide, phenelzine, procarbazine, selegiline, tranylcypromine.

Tell your doctor or pharmacist if you also take drugs that cause drowsiness such as: antidepressants (e.g., amitriptyline, nefazodone), certain antihistamines (e.g., diphenhydramine), anti-seizure drugs (e.g., carbamazepine, phenobarbital, valproate), medicine for sleep or anxiety (e.g., alprazolam, kava, zolpidem), muscle relaxants, narcotic pain relievers (e.g., codeine), psychiatric medicines (e.g., chlorpromazine, risperidone).

This medication contains a small amount of alcohol. Tell your doctor if you are taking drugs such as disulfiram or metronidazole that can can cause an unpleasant reaction when combined with alcohol.

Avoid alcohol when using this medication because it may increase side effects such as difficulty breathing and drowsiness.

Check the labels on all your medicines (e.g., cough-and-cold products) because they may contain drowsiness-causing ingredients. Ask your pharmacist about the safe use of those products.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly. Symptoms of overdose may include confusion, slow reflexes, clumsiness, deep sleep, and loss of consciousness.

NOTES: Do not share this medication with others. It is against the law.

MISSED DOSE: Not applicable.

STORAGE: Store at room temperature at 77 degrees F (25 degrees C) away from light and moisture. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For enrollment information call MedicAlert at 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised August 2008 Copyright(c) 2008 First DataBank, Inc.