Diazepam Rectal Gel

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.

Diazepam is a benzodiazepine (ben-zoe-dye-AZE-eh-peen). Diazepam affects chemicals in the brain that may become unbalanced and cause seizure.

Diazepam rectal is used to treat occasionally increased seizures (cluster seizures) in people with epilepsy who also routinely take other anti-convulsants. Diazepam rectal is not for long-term daily use to prevent seizures.

Diazepam rectal may also be used for purposes not listed in this medication guide.

You should not receive this medication if you are allergic to diazepam (Valium), or if you have untreated or uncontrolled narrow-angle glaucoma.

To make sure diazepam is safe for you, tell your doctor if you have:

• glaucoma;
• asthma, pneumonia, emphysema, bronchitis, chronic obstructive pulmonary disease (COPD), or other breathing disorder;
• liver or kidney disease;
• a history of depression or suicidal thoughts or behavior;
• a history of drug or alcohol addiction; or
• if you are allergic to other benzodiazepines, such as alprazolam (Xanax), chlordiazepoxide (Librium), clorazepate (Tranxene), lorazepam (Ativan), or oxazepam (Serax).

FDA pregnancy category D. Do not start or stop taking diazepam during pregnancy without your doctor's advice. Diazepam may cause harm to an unborn baby, but having a seizure during pregnancy could harm both mother and baby. Tell your doctor right away if you become pregnant while taking diazepam for seizures.

Diazepam can pass into breast milk and may harm a nursing baby. You should not breast-feed while using this medicine.

The sedative effects of diazepam rectal may last longer in older adults. Accidental falls are common in elderly patients who take benzodiazepines. Use caution to avoid falling or accidental injury while you are using diazepam rectal.

Do not give this medication to a child younger than 6 months old.

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

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.

Drug Abuse And Dependence

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.

Read the entire FDA prescribing information for Diazepam Rectal Gel (Diazepam Rectal Gel)

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• Avoid driving and doing other tasks or actions that call for you to be alert or have clear eyesight until you see how diazepam rectal gel affects you.
• Avoid drinking alcohol while taking this medicine.
• Talk with your doctor before you use other drugs and natural products that slow your actions.
• If you are 65 or older, use diazepam rectal gel with care. You could have more side effects.
• This medicine is not meant for regular, daily use. Talk with the doctor.
• Use with care in children. Talk with the doctor.
• This medicine may cause harm to the unborn baby if you take it while you are pregnant. If you are pregnant or you get pregnant while taking this medicine, call your doctor right away.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Feeling sleepy.
• Feeling tired or weak.
• Muscle weakness.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

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.

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.

Pregnancy Risks

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.

Animal Findings: Diazepam has been shown to be teratogenic in mice and hamsters when given orally at single doses of 100 mg/kg or greater (approximately eight times the maximum recommended human dose [MRHD=1 mg/kg/day] or greater on a mg/m2 basis). Cleft palate and exencephaly are the most common and consistently 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 longterm changes in cellular immune responses, brain neurochemistry, and behavior.

General Concerns and Considerations About Anticonvulsants: Reports suggest an association between the use of anticonvulsant 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 phenobarbital, 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 defects 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 factors or the epileptic condition itself, may be more important than drug therapy in leading to birth defects. The great majority of mothers on anticonvulsant medication deliver normal 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 attendant 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 cannot 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 benzodiazepine drugs has been suggested in several studies.

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 difficulties, and hypothermia in children born to mothers who have been receiving benzodiazepines late in 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.

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.

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 benzodiazepine class, Diazepam Rectal Gel is assumed to be capable of causing an increased risk of congenital abnormalities when administered 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 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.

Withdrawal Symptoms

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

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.

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.

Diazepam is used to treat anxiety, alcohol withdrawal, muscle spasms, and certain types of seizures.

This drug can interfere with your judgment, thinking, and motor skills. You shouldn’t drink alcohol or use other drugs that can also slow down your brain’s activity while you’re on diazepam. You also shouldn’t drive, operate machinery, or do other tasks that require alertness until you know how this drug affects you.

Diazepam is available in several different forms, including oral tablet, oral solution, and rectal gel.

Diazepam can be habit-forming. It can lead to dependence and tolerance, meaning that you’ll need more of the drug for it to work. Keep it in a safe place, and never give it to anyone else because it may harm them. Selling or giving away this medication is against the law.

You shouldn’t stop taking diazepam without talking to your doctor first. Stopping this drug can cause severe withdrawal symptoms. Your risk may be higher if you’ve been on diazepam for a long time.

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• Drug administration See Details

What is diazepam?

Diazepam is a controlled substance drug. It is available in these forms: oral tablet, oral solution, oral solution concentrate, and rectal gel.

Diazepam is available in its generic form. Generic drugs usually cost less. In some cases they may not be available in every strength or form as the brand. Talk to your healthcare provider to see if the generic will work for you.

This drug may be used as part of a combination therapy. That means you need to take it with other drugs.

Why it's used

Diazepam rectal gel is used for short-term control of breakthrough seizures. It’s used in people with severe epilepsy who are already on other drugs to treat seizures.

How it works

Diazepam belongs to a class of drugs called benzodiazepines. A class of drugs refers to medications that work similarly. They have a similar chemical structure and are often used to treat similar conditions.

More Details

Most Common Side Effects

The most common side effects that occur with diazepam include:

• drowsiness

• dizziness

• headache

• abdominal pain

• nervousness

• dilation of your blood vessels

• diarrhea

• inability to control muscle movements (ataxia)

• a feeling of intense excitement or happiness (euphoria)

• loss of coordination

• asthma

• runny or stuffy nose

• skin rash

• lack of energy

If these effects are mild, they may go away within a few days or a couple of weeks. If they’re more severe or don’t go away, talk to your doctor or pharmacist.

Serious Side Effects

If you experience any of these serious side effects, call your doctor right away. If your symptoms are potentially life threatening or if you think you’re experiencing a medical emergency, call 9-1-1.

Serious side effects that can occur with diazepam include:

• Worsening of seizures. Symptoms can include:

  • increase in frequency
  • increase in severity

• Changes in the brain or how you think. Symptoms can include:

  • depression
  • confusion
  • feelings of the room spinning (vertigo)
  • slowed or slurred speech
  • double or blurred vision
  • thoughts of suicide
  • memory loss

• Unexpected reactions. Symptoms can include:

  • extreme excitement
  • anxiety
  • hallucinations
  • increased muscle spasms
  • trouble sleeping
  • agitation

• Liver problems. Symptoms can include:

  • yellowing of your skin or whites of your eyes (jaundice)

• Bladder problems. Symptoms can include:

  • inability to urinate
  • inability to hold urine

• Increase or decrease in sex drive.

• Withdrawal. Symptoms can include:

  • tremor
  • abdominal or muscle cramps
  • sweating
  • convulsions