INDICATIONS AND USAGE Diazepam rectal gel is intended for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern in patients with epilepsy 2 years of age and older.

WARNINGS General Diazepam rectal gel should only be administered by caregivers who in the opinion of the prescribing physician 1) are able to distinguish 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) understand explicitly which seizure manifestations may or may not be treated with diazepam rectal gel, and 4) are able to monitor the clinical response and recognize when that response is such that immediate professional medical evaluation is required.

Risks from Concomitant Use with Opioids Concomitant use of benzodiazepines, including diazepam rectal gel and diazepam rectal gel rectal delivery system, and opioids may result in profound sedation, respiratory depression, coma, and death.

Because of these risks, reserve concomitant prescribing of benzodiazepines and opioids for patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone.

If a decision is made to prescribe diazepam rectal gel or diazepam rectal gel rectal delivery system concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation.

Advise both patients and caregivers about the risks of respiratory depression and sedation when diazepam rectal gel or diazepam rectal gel rectal delivery system is used with opioids (see PRECAUTIONS ).

Abuse, Misuse, and Addiction The use of benzodiazepines, including diazepam rectal gel, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death.

Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death (see DRUG ABUSE AND DEPENDENCE: Abuse ).

Before prescribing diazepam rectal gel and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction.

Use of diazepam rectal gel, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of diazepam rectal gel along with monitoring for signs and symptoms of abuse, misuse, and addiction.

Do not exceed the recommended dosing frequency; avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug.

If a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate.

Dependence and Withdrawal Reactions After Use of Diazepam Rectal Gel More Frequently Than Recommended For patients using diazepam rectal gel more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue diazepam rectal gel (a patient-specific plan should be used to taper the dose).

Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use.

Acute Withdrawal Reactions The continued use of benzodiazepines may lead to clinically significant physical dependence.

Although diazepam rectal gel is indicated only for intermittent use (see INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION ), if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction of diazepam rectal gel, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) (see DRUG ABUSE AND DEPENDENCE : Dependence ) .

Protracted Withdrawal Syndrome In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months (see DRUG ABUSE AND DEPENDENCE : Dependence ).

CNS Depression Because diazepam rectal gel produces CNS depression, patients receiving this drug who are otherwise capable and qualified to do so should be cautioned against engaging in hazardous occupations requiring mental alertness, such as operating machinery, driving a motor vehicle, or riding a bicycle until they have completely returned to their level of baseline functioning.

Although diazepam rectal gel is indicated for use solely on an intermittent basis, the potential for a synergistic CNS-depressant effect when used simultaneously with alcohol or other CNS depressants must be considered by the prescribing physician, and appropriate recommendations made to the patient and/or caregiver.

Prolonged CNS depression has been observed in neonates treated with diazepam.

Therefore, diazepam rectal gel is not recommended for use in children under six months of age.

Neonatal Sedation and Withdrawal Syndrome Use of diazepam rectal gel late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate (see PRECAUTIONS: Pregnancy).

Monitor neonates exposed to diazepam rectal gel during pregnancy or labor for signs of sedation and monitor neonates exposed to diazepam rectal gel during pregnancy for signs of withdrawal; manage these neonates accordingly.

Chronic Use Diazepam rectal gel is not recommended for chronic, daily use as an anticonvulsant because of the potential for development of tolerance to diazepam.

Chronic daily use of diazepam may increase the frequency and/or severity of tonic clonic seizures, requiring an increase in the dosage of standard anticonvulsant 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.

ADVERSE REACTIONS 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.

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, 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 Diazepam Rectal Gel Placebo Body System COSTART Term N = 101 % N = 104 % Body As A Whole Headache 5% 4% Cardiovascular Vasodilatation 2% 0% Digestive Diarrhea 4% <1% Nervous Ataxia 3% <1% Dizziness 3% 2% Euphoria 3% 0% Incoordination 3% 0% Somnolence 23% 8% Respiratory Asthma 2% 0% Skin and Appendages Rash 3% 0% 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.

Other Adverse Events Observed During All Clinical Trials 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.

To report SUSPECTED ADVERSE REACTIONS, contact Oceanside Pharmaceuticals at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.