DIAZEPAM

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, benzoic acid, benzyl alcohol (1.5%), ethyl alcohol (10%), hydroxypropyl methylcellulose, propylene glycol, purified water, and sodium benzoate. Diazepam rectal gel is clear to slightly yellow and has a pH between 6.5-7.5. 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-2 H -1,4-benzodiazepin-2-one. The structural formula is as follows: chemstructure

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.

(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. Calculating Prescribed Dose 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. Age (years) Recommended Dose 2 through 5 0.5 mg/kg 6 through 11 0.3 mg/kg 12 and older 0.2 mg/kg 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. 2 - 5 Years 6 - 11 Years 12+ Years 0.5 mg/kg 0.3 mg/kg 0.2 mg/kg Weight Dose Weight Dose Weight Dose (kg) (mg) (kg) (mg) (kg) (mg) 6 to 10 5 10 to 16 5 14 to 25 5 11 to 15 7.5 17 to 25 7.5 26 to 37 7.5 16 to 20 10 26 to 33 10 38 to 50 10 21 to 25 12.5 34 to 41 12.5 51 to 62 12.5 26 to 30 15 42 to 50 15 63 to 75 15 31 to 35 17.5 51 to 58 17.5 76 to 87 17.5 36 to 44 20 59 to 74 20 88 to 111 20 The rectal delivery system includes a plastic applicator with a flexible, molded tip available in two lengths. The diazepam rectal gel rectal delivery system 10 mg syringe is available with a 4.4 cm tip and the diazepam rectal gel rectal delivery system 20 mg syringe is available with a 6.0 cm tip. Diazepam rectal gel 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 diazepam rectal gel 2.5 mg dose may also be used as a partial replacement dose for patients who may expel a portion of the first dose. Additional 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. Treatment Frequency 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. Pharmacist Instructions pic1 pic2 pic3

Diazepam rectal gel is contraindicated in patients with a known hypersensitivity to diazepam. Diazepam rectal gel may be used in patients with open angle glaucoma who are receiving appropriate therapy but is contraindicated in acute narrow angle glaucoma.

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.