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Diazepam Rectal Gel


5.5.2018 | Cameron Keat

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.

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. 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. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators.

Table 3 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 recommended dose of Diazepam rectal gel is 0.2-0.5 mg/kg depending on age. The Diazepam rectal gel dose should be individualized for maximum beneficial effect. See the dosing table for specific recommendations.

Interference With Cognitive and Motor Performance : Because benzodiazepines have the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that Diazepam rectal gel therapy does not affect them adversely.

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Diazepam Rectal Gel

6.2 Labor and Delivery.

DEA Controlled Substance Schedule C-IV TABLE OF CONTENTS.

6.6 Caution in Renally Impaired Patients.

Chronic use (even at therapeutic doses) may lead to the development of physical dependence: discontinuation of the therapy may result in withdrawal or rebound phenomena.

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 approximay 2-5% of patients.

Metabolites of Diazepam rectal gel are excreted by the kidneys; to avoid their excess accumulation, caution should be exercised in the administration of the drug to patients with impaired renal function.

Table 3: 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.

The more severe withdrawal symptoms have usually been limited to those patients who had received excessive doses over an extended period of time. These withdrawal symptoms may consist of tremor, abdominal and muscle cramps, vomiting, sweating, headache, muscle pain, extreme anxiety, tension, restlessness, confusion and irritability. In severe cases, the following symptoms may occur: derealization, depersonalization, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations or epileptic seizures. Withdrawal symptoms, similar in character to those noted with barbiturates and alcohol have occurred following abrupt discontinuance of diazepam. Consequently, after extended therapy, abrupt discontinuation should generally be avoided and a gradual dosage tapering schedule followed. Generally milder withdrawal symptoms (e.g., dysphoria and insomnia) have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic levels for several months.

6.7 Caution in Hepatically Impaired Patients.

Rebound Anxiety : A transient syndrome whereby the symptoms that led to treatment with diazepam recur in an enhanced form. It may be accompanied by other reactions including mood changes, anxiety, and restlessness. This may occur upon discontinuation of treatment.

In elderly patients Diazepam rectal gel should be used with caution due to an increase in halflife with a corresponding decrease in the clearance of free diazepam. It is also recommended that the dosage be decreased to reduce the likelihood of ataxia or oversedation.

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

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

Diazepam is contraindicated in patients with a known hypersensitivity to this drug and, because of lack of sufficient clinical experience, in children under 6 months of age. It may be used in patients with open angle glaucoma who are receiving appropriate therapy, but is contraindicated in acute narrow angle glaucoma.

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

Withdrawal symptoms of the barbiturate type have occurred after the discontinuation of regular use of benzodiazepines (see DRUG ABUSE AND DEPENDENCE section). Chronic Use.

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.

Other adverse events most commonly associated with discontinuation and occurring in two patients were hypoventilation and rash. Approximay 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. Adverse events occurring in one patient were asthenia, hyperkinesia, incoordination, vasodilatation and urticaria. These events were judged to be related to diazepam rectal gel.

Prescribers should advise caregivers that they expect to be informed immediay if a patient develops any new findings which are not typical of the patient’s characteristic seizure episode.

Information to be Communicated by the Prescriber to the Caregiver.

The safety of this strategy has been established in clinical trials. 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.

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

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.

There may also be non-teratogenic risks associated with the use of benzodiazepines during pregnancy. In addition, children born to mothers receiving benzodiazepines on a regular basis late in pregnancy may be at some risk of experiencing withdrawal symptoms during the postnatal period. There have been reports of neonatal flaccidity, respiratory and feeding difficulties, and hypothermia in children born to mothers who have been receiving benzodiazepines late in pregnancy. An increased risk of congenital malformations and other developmental abnormalities associated with the use of benzodiazepine drugs during pregnancy has been suggested.

Diazepam rectal gel should be used with caution in patients with compromised respiratory function related to a concurrent disease process (e.g., asthma, pneumonia) or neurologic damage. WARNINGS General.

6.8 Use in Patients with Compromised Respiratory Function.

Therefore, diazepam rectal gel is not recommended for use in children under six months of age. Withdrawal Symptoms. Prolonged CNS depression has been observed in neonates treated with diazepam.

Abuse and dependence of benzodiazepines have been reported. The risk is more pronounced in patients on long-term therapy. Once physical dependence to benzodiazepines has developed, termination of treatment will be accompanied by withdrawal symptoms. 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. Diazepam is subject to Schedule IV control under the Controlled Substances Act of 1970.

Because diazepam and its metabolites may be present in human breast milk for prolonged periods of time after acute use of Diazepam rectal gel, patients should be advised not to breast-feed for an appropriate period of time after receiving treatment with Diazepam rectal gel. 6.4 Pediatric Use.

Evidence to support the use of diazepam rectal gel was adduced in two controlled trials 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 acuy. 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.

The majority of adverse events were mild to moderate in severity and transient in nature. Diazepam rectal gel adverse event data were collected from double-blind, placebo-controlled studies and open-label studies.

The structural formula is as follows:. It is a colorless to light yellow crystalline compound, insoluble in water. The chemical name of diazepam is 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one. Diazepam is a benzodiazepine derivative. The empirical formula is C 16 H 13 ClN 2 O and the molecular weight is 284.75.

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. CNS Depression.

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.

Advice Regarding the Use of Diazepam rectal gel in Women of Childbearing Potential : In general, the use of Diazepam rectal gel in women of childbearing potential, and more specifically during known pregnancy, should be considered only when the clinical situation warrants the risk to the fetus.

It is believed that diazepam enhances the actions of GABA by causing GABA to bind more tightly to the GABAA receptor. 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. 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. 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 (GABAA). Excessive depolarization of neurons is implicated in the generation and spread of seizures.

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.

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. 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.

6.1 Usage in Pregnancy Pregnancy Category D.

Adverse Event Incidence in Controlled Clinical Trials.

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.

Until additional information is available, Diazepam rectal gel is not recommended for obstetrical use. In humans, measurable amounts of diazepam have been found in maternal and cord blood, indicating placental transfer of the drug. 6.3 Nursing Mothers.

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 compley returned to their level of baseline functioning.

Treatment Frequency. 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.

No clinical studies have been conducted with diazepam rectal gel in pregnant women. Data from several sources raise concerns about the use of diazepam during pregnancy.

PRECAUTIONS. Tonic status epilepticus has been precipitated in patients treated with IV diazepam for petit mal status or petit mal variant status.

The successful and safe use of Diazepam rectal gel depends in large measure on the competence and performance of the caregiver. Prescribers should routinely discuss the steps in the Patient/Caregiver Package Insert (see Patient/Caregiver Insert printed at the end of the product labeling and also included in the product carton). Prescribers are strongly advised to take all reasonable steps to ensure that caregivers fully understand their role and obligations vis a vis the administration of Diazepam rectal gel to individuals in their care.

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.

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.

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. 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.

Clinical studies have not been conducted to establish the efficacy and safety of Diazepam rectal gel in children under two years of age. 6.5 Geriatric Use. The controlled trials demonstrating the effectiveness of Diazepam rectal gel included children two years of age and older.

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

Table 1: Usual Diazepam Rectal Gel Dosage.

The Diastat 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.

Diazepam rectal gel is clear to slightly yellow and has a pH between 6.5 - 7.2. 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 rectal delivery system is a non-sterile diazepam gel provided in a prefilled, unit-dose, rectal delivery system.

The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Patients 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. In general, the use of diazepam in women of childbearing potential, and more specifically during known pregnancy, should be considered only when the clinical situation warrants the risk to the fetus.

Table 2: Recommended Dosage Based on Weight and Age.

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

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.

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.

Therefore, Diazepam rectal gel should be used with caution in patients with liver disease. Concomitant liver disease is known to decrease the clearance of diazepam.

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