DIAZEPAM: 38,124 Adverse Event Reports & Safety Profile

DESCRIPTION Each 5 mL of Diazepam Oral Solution contains: diazepam USP ....................................................... 5 mg Each mL of Diazepam Oral Solution (Concentrate) contains: diazepam USP ....................................................... 5 mg alcohol .................................................................. 19% Inactive Ingredients: Diazepam Oral Solution contains polyethylene glycol, propylene glycol, sorbitol solution, sodium citrate dihydrate, bitterness modifier flavor, anhydrous citric acid, peppermint flavor, FD&C Red No. 40, D&C Yellow No. 10, and purified water.

Diazepam Oral

Solution (Concentrate) contains polyethylene glycol, propylene glycol, alcohol (19%), D&C Yellow No. 10, succinic acid, and purified water. Diazepam is a benzodiazepine derivative. Chemically, diazepam is 7-Chloro-1,3-dihydro-1-methyl-5-phenyl-2 H -1,4-benzodiazepin-2-one. It is a white to practically white powder, insoluble in water and has a molecular weight of 284.75. Its structural formula is as follows: image description

INDICATIONS Diazepam is indicated for the management of anxiety disorders for the short-term relief of the symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. Note: Because the autoinjector provides a minimum dose of 10 mg diazepam, it should not be used to treat individuals with mild and moderate degrees of anxiety and anxiety related disorders that would ordinarily be managed with intramuscular doses of less than 10 mg. In acute alcohol withdrawal, diazepam may be useful in the symptomatic relief of acute agitation, tremor, impending or acute delirium tremens and hallucinosis. As an adjunct prior to endoscopic procedures if apprehension, anxiety or acute stress reactions are present, and to diminish the patient's recall of the procedures (See WARNINGS ). Diazepam is a useful adjunct for the relief of skeletal muscle spasm due to reflex spasm to local pathology (such as inflammation of the muscles or joints, or secondary to trauma), spasticity caused by upper motor neuron disorders (such as cerebral palsy and paraplegia); athetosis; stiff man syndrome; and tetanus. Diazepam injection is a useful adjunct in status epilepticus and severe recurrent convulsive seizures. Diazepam is useful premedication for relief of anxiety and tension in patients who are to undergo surgical procedures.

DOSAGE AND ADMINISTRATION Dosage should be individualized for maximum beneficial effect. The usual recommended dose in older children and adults ranges from 2 mg to 20 mg intramuscular or intravenous, depending on the indication and its severity. In some conditions, e.g., tetanus, larger doses may be required. (See dosage for specific indications.) In acute conditions the injection may be repeated within one hour although an interval of 3 to 4 hours is usually satisfactory. Lower doses (usually 2 mg to 5 mg) and slow increase in dosage should be used for elderly or debilitated patients and when other sedative drugs are administered. (See WARNINGS and ADVERSE REACTIONS .) For dosage in infants above the age of 30 days and children, see the specific indications below. When intravenous use is indicated, facilities for respiratory assistance should be readily available. Intramuscular: Diazepam Injection, USP should be injected deeply into the muscle. Intravenous use: (See WARNINGS , particularly for use in children.) The solution should be injected slowly, taking at least one minute for each 5 mg (1 mL) given. Do not use small veins, such as those on the dorsum of the hand or wrist. Extreme care should be taken to avoid intra-arterial administration or extravasation. Do not mix or dilute diazepam with other solutions or drugs in syringe or infusion container. If it is not feasible to administer diazepam directly intravenous, it may be injected slowly through the infusion tubing as close as possible to the vein insertion. Once the acute symptomatology has been properly controlled with diazepam injection, the patient may be placed on oral therapy with diazepam if further treatment is required. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit (see PRECAUTIONS ). NOTE: Solution may appear colorless to light yellow. USUAL ADULT DOSAGE DOSAGE RANGE IN CHILDREN (Intravenous administration should be made slowly)

Moderate Anxiety

Disorders and Symptoms of Anxiety 2 mg to 5 mg, intramuscular or intravenous Repeat in 3 to 4 hours, if necessary.

Severe Anxiety

Disorders and Symptoms of Anxiety 5 mg to 10 mg, intramuscular or intravenous Repeat in 3 to 4 hours, if necessary.

Acute Alcohol

Withdrawal: As an aid in symptomatic relief of acute agitation, tremor, impending or acute delirium tremens and hallucinosis. 10 mg, intramuscular or intravenous initially, then 5 mg to 10 mg in 3 to 4 hours, if necessary.

Endoscopic

Procedures: Adjunctively, if apprehension, anxiety or acute stress reactions are present prior to endoscopic procedures. Dosage of narcotics should be reduced by at least a third and in some cases may be omitted.

See

Precautions for peroral procedures. Titrate intravenous dosage to desired sedative response, such as slurring of speech, with slow administration immediately prior to the procedure.

Generally

10 mg or less is adequate, but up to 20 mg intravenous may be given, particularly when concomitant narcotics are omitted. If intravenous cannot be used, 5 mg to 10 mg intramuscular approximately 30 minutes prior to the procedure.

Muscle

Spasm: Associated with local pathology, cerebral palsy, athetosis, stiff-man syndrome or tetanus. 5 mg to 10 mg, intramuscular or intravenous initially, then 5 mg to 10 mg in 3 to 4 hours, if necessary. For tetanus, larger doses may be required. For tetanus in infants over 30 days of age, 1 mg to 2 mg intramuscular or intravenous, slowly, repeated every 3 to 4 hours as necessary. In children 5 years or older, 5 mg to 10 mg repeated every 3 to 4 hours may be required to control tetanus spasms. Respiratory assistance should be available.

Status

Epilepticus and Severe Recurrent Convulsive Seizures: In the convulsing patient, the intravenous route is by far preferred. This injection should be administered slowly. However, if intravenous administration is impossible, the intramuscular route may be used. 5 mg to 10 mg initially (I.V. preferred). This injection may be repeated if necessary at 10 to 15 minute intervals up to a maximum dose of 30 mg. If necessary, therapy with diazepam may be repeated in 2 to 4 hours; however, residual active metabolites may persist, and readministration should be made with this consideration. Extreme caution must be exercised with individuals with chronic lung disease or unstable cardiovascular status. Infants over 30 days of age and children under 5 years, 0.2 mg to 0.5 mg slowly every 2 to 5 minutes up to a maximum of 5 mg (intravenous preferred).

Children

5 years or older, 1 mg every 2 to 5 minutes up to a maximum of 10 mg (slow intravenous administration preferred). Repeat in 2 to 4 hours if necessary. EEG monitoring of the seizure may be helpful.

Preoperative

Medication: To relieve anxiety and tension. (If atropine, scopolamine or other premedications are desired, they must be administered in separate syringes.) 10 mg, intramuscular (preferred route), before surgery. Cardioversion: To relieve anxiety and tension and to reduce recall of procedure. 5 mg to 15 mg, intravenous, within 5 to 10 minutes prior to the procedure.

Management Of Overdosage

Manifestations of diazepam overdosage include somnolence, confusion, coma, and diminished reflexes. Respiration, pulse and blood pressure should be monitored, as in all cases of drug overdosage, although, in general, these effects have been minimal. General supportive measures should be employed, along with intravenous fluids, and an adequate airway maintained. Hypotension may be combated by the use of Levophed (norepinephrine bitartrate) or Aramine (metaraminol). Dialysis is of limited value. Flumazenil, a specific benzodiazepine receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation, and intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for re-sedation, respiratory depression, and other residual benzodiazepine effects for an appropriate period after treatment. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert including CONTRAINDICATIONS , WARNINGS , and PRECAUTIONS should be consulted prior to use.

CONTRAINDICATIONS Diazepam tablets are contraindicated in patients with a known hypersensitivity to diazepam and, because of lack of sufficient clinical experience, in pediatric patients under 6 months of age. Diazepam tablets are also contraindicated in patients with myasthenia gravis, severe respiratory insufficiency, severe hepatic insufficiency, and sleep apnea syndrome. They may be used in patients with open-angle glaucoma who are receiving appropriate therapy, but are contraindicated in acute narrow-angle glaucoma.

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 COSTART Diazepam Rectal Gel Placebo Body System Term N = 101 N = 104 % % Body As A Whole Cardiovascular Headache Vasodilatation 5% 2% 4% 0% Digestive Nervous Diarrhea Ataxia 4% 3% <1% <1% Dizziness 3% 2% Euphoria Incoordination 3% 3% 0% 0% Somnolence 23% 8% Respiratory Skin and Appendages Asthma Rash 2% 3% 0% 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 Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

AND PRECAUTIONS CNS Depression: Monitor for central nervous system (CNS) depression. May cause an increased CNS-depressant effect when used with alcohol or other CNS depressants. ( 5.4 , 7.2 )

Suicidal

Behavior and Ideation: Monitor patients for suicidal ideation and behavior. ( 5.5 ) Glaucoma: VALTOCO can increase intraocular pressure in patients with glaucoma. VALTOCO may be used in patients with open-angle glaucoma only if they are receiving appropriate therapy. ( 4 , 5.6 )

Neonatal

Sedation and Withdrawal Syndrome: VALTOCO use during pregnancy can result in neonatal sedation and/or neonatal withdrawal. ( 5.7 , 8.1 )

5.1 Risk of Concomitant Use with Opioids Concomitant use of benzodiazepines, including VALTOCO, and opioids may result in profound sedation, respiratory depression, coma, and death <span class="opacity-50 text-xs">[see Drug Interactions (7.1) ]</span>. 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 VALTOCO 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 VALTOCO is used with opioids.

5.2 Abuse, Misuse, and Addiction The use of benzodiazepines, including VALTOCO, 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 <span class="opacity-50 text-xs">[see Drug Abuse and Dependence (9.2) ]</span> . Before prescribing VALTOCO and throughout treatment, assess each patient&apos;s risk for abuse, misuse, and addiction. Use of VALTOCO, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of VALTOCO 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.

5.3 Dependence and Withdrawal Reactions After Use of VALTOCO More Frequently Than Recommended For patients using VALTOCO more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue VALTOCO (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 VALTOCO is indicated only for intermittent use [see Indications and Usage (1) and Dosage and Administration (2) ] , if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction of VALTOCO, 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 (9.3) ].

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 (9.3) ] .

5.4 CNS Depression Benzodiazepines, including VALTOCO, produce CNS depression. Caution patients against engaging in hazardous activities requiring mental alertness (e.g., operating machinery, driving a motor vehicle, or riding a bicycle) until the effects of the drug, such as drowsiness, have subsided, and as their medical condition permits. Although VALTOCO is indicated for use solely on an intermittent basis, the potential for synergistic CNS-depressant effects when used simultaneously with alcohol or other CNS depressants must be considered by the prescriber and appropriate recommendations made to the patient and/or caregiver.

5.5 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including VALTOCO, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed.

Table

3 shows absolute and relative risk by indication for all evaluated AEDs.

Table

3: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events/1000 Patients Drug Patients with Events per 1000 Patients Relative Risk: Incidence of Drug Events in Drug Patients /Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events per 1000 Patients Epilepsy 1.0 3.4 3.5

2.4 Psychiatric 5.7 8.5 1.5

2.9 Other 1.0 1.8 1.9

0.9 Total 2.4 4.3 1.8

1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing VALTOCO or any other AED must balance the risk of suicidal thoughts or behaviors with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

5.6 Glaucoma Benzodiazepines, including VALTOCO, can increase intraocular pressure in patients with glaucoma. VALTOCO may be used in patients with open-angle glaucoma only if they are receiving appropriate therapy. VALTOCO is contraindicated in patients with narrow-angle glaucoma.

5.7 Neonatal Sedation and Withdrawal Syndrome Use of VALTOCO 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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1) ]</span> . Monitor neonates exposed to VALTOCO during pregnancy or labor for signs of sedation and monitor neonates exposed to VALTOCO during pregnancy for signs of withdrawal; manage these neonates accordingly.

5.8 Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preservative VALTOCO is not approved for use in neonates or infants. Serious and fatal adverse reactions including &quot;gasping syndrome&quot; can occur in neonates and low birth weight infants treated with benzyl alcohol-preserved drugs, including VALTOCO. The &quot;gasping syndrome&quot; is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known (VALTOCO contains 10.5 mg of benzyl alcohol per 0.1 mL) <span class="opacity-50 text-xs">[see Use in Specific Populations (8.4) ]</span>.

PRECAUTIONS Information for Patients Risks from Concomitant Use with Opioids: Inform patients and caregivers that potentially fatal additive effects may occur if diazepam rectal gel or diazepam rectal gel rectal delivery system is used with opioids and not to use such drugs concomitantly unless supervised by a health care provider (see WARNINGS and PRECAUTIONS: Drug Interactions ). Abuse, Misuse, and Addiction: Inform patients that the use of diazepam rectal gel more frequently than recommended, even at recommended dosages, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose and death, especially when used in combination with other medications (e.g., opioid analgesics), alcohol, and/or illicit substances. Inform patients about the signs and symptoms of benzodiazepine abuse, misuse, and addiction; to seek medical help if they develop these signs and/or symptoms; and on the proper disposal of unused drug (see WARNINGS: Abuse, Misuse, and Addiction and DRUG ABUSE AND DEPENDENCE ).

Withdrawal

Reactions: Inform patients that use of diazepam rectal gel more frequently than recommended may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of diazepam rectal gel may precipitate acute withdrawal reactions, which can be life-threatening. Inform patients that in some cases, patients taking benzodiazepines have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months (see WARNINGS: Dependence and Withdrawal Reactions and DRUG ABUSE AND DEPENDENCE ). Administration: 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. 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). The successful and safe use of diazepam rectal gel depends in large measure on the competence and performance of the caregiver. Prescribers should advise caregivers that they expect to be informed immediately if a patient develops any new findings which are not typical of the patient’s characteristic seizure episode.

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.

Pregnancy

Advise pregnant females that 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 newborns (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome and PRECAUTIONS: Pregnancy ). Instruct patients to inform their healthcare provider if they are pregnant. Encourage patients to enroll in the North American Antiepileptic Drug (NAAED)

Pregnancy

Registry if they become pregnant while taking diazepam rectal gel. The registry is collecting information about the safety of antiepileptic drugs during pregnancy (see PRECAUTIONS: Pregnancy ).

Lactation

Counsel patients that diazepam, the active ingredient in diazepam rectal gel, is present in breast milk. Instruct patients to inform their healthcare provider if they are breastfeeding or plan to breastfeed. Instruct breastfeeding patients who take diazepam rectal gel to monitor their infants for excessive sedation, poor feeding and poor weight gain, and to seek medical attention if they notice these signs (see PRECAUTIONS: Nursing Mothers ).

Concomitant Medication

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.

Drug Interactions

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 Concomitant Use of Benzodiazepines and Opioids : The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABA A sites, and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and follow patients closely for respiratory depression and sedation.

Other Psychotropic

Agents or Other CNS Depressants: 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. Cimetidine: The clearance of diazepam and certain other benzodiazepines can be delayed in association with cimetidine administration. The clinical significance of this is unclear. Valproate : Valproate may potentiate the CNS-depressant effects of diazepam. 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. Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of rectal diazepam has not been evaluated. In studies in which mice and rats were administered diazepam in the diet at a dose of 75 mg/kg/day (approximately six and 12 times, respectively, the maximum recommended human dose [MRHD=1 mg/kg/day] on a mg/m 2 basis) for 80 and 104 weeks, respectively, an increased incidence of liver tumors was observed in males of both species. The data currently available are inadequate to determine the mutagenic potential of diazepam. Reproduction studies in rats showed decreases in the number of pregnancies and in the number of surviving offspring following administration of an oral dose of 100 mg/kg/day (approximately 16 times the MRHD on a mg/m 2 basis) prior to and during mating and throughout gestation and lactation. No adverse effects on fertility or offspring viability were noted at a dose of 80 mg/kg/day (approximately 13 times the MRHD on a mg/m 2 basis).

Pregnancy Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, such as diazepam rectal gel, during pregnancy. Healthcare providers are encouraged to recommend that pregnant women taking diazepam rectal gel enroll in the NAAED Pregnancy Registry by calling 1-888- 233-2334 or online at http://www.aedpregnancyregistry.org/.

Risk Summary

Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome and PRECAUTIONS: Pregnancy, Clinical Considerations). Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Human Data ). In animal studies, administration of diazepam during the organogenesis period of pregnancy resulted in increased incidences of fetal malformations at doses greater than those used clinically. Data for diazepam and other benzodiazepines suggest the possibility of increased neuronal cell death and long-term effects on neurobehavioral and immunological function based on findings in animals following prenatal or early postnatal exposure at clinically relevant doses (see Animal Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations Fetal/Neonatal

Adverse Reactions Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Monitor neonates exposed to diazepam rectal gel during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to diazepam rectal gel during pregnancy for signs of withdrawal. Manage these neonates accordingly (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome ).

Data Human Data

Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings.

Animal Data

Diazepam has been shown to produce increased incidences of fetal malformations in mice and hamsters when given orally at single doses of 100 mg/kg or greater (approximately 20 times the maximum recommended adult human dose [0.4 mg/kg/day] or greater on a mg/m 2 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. In published animal studies, administration of benzodiazepines or other drugs that enhance GABAergic neurotransmission to neonatal rats has been reported to result in widespread apoptotic neurodegeneration in the developing brain at plasma concentrations relevant for seizure control in humans. The window of vulnerability to these changes in rats (postnatal days 0-14) includes a period of brain development that takes place during the third trimester of pregnancy in humans.

Nursing Mothers Risk Summary

Diazepam is present in breastmilk. There are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk. There are no data on the effects of diazepam on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for diazepam rectal gel and any potential adverse effects on the breastfed infant from diazepam rectal gel or from the underlying maternal condition.

Clinical Considerations

Infants exposed to diazepam rectal gel through breast milk should be monitored for sedation, poor feeding and poor weight gain. 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 breastfeed for an appropriate period of time after receiving treatment with diazepam rectal gel. Caution in Renally Impaired 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. Caution in Hepatically Impaired Patients Concomitant liver disease is known to decrease the clearance of diazepam (see CLINICAL PHARMACOLOGY: Special Populations, Hepatic Impairment ). Therefore, diazepam rectal gel should be used with caution in patients with liver disease. Use in Pediatrics The controlled trials demonstrating the effectiveness of diazepam rectal gel included children two years of age and older. Clinical studies have not been conducted to establish the efficacy and safety of diazepam rectal gel in children under two years of age. Use in Patients with Compromised Respiratory Function 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. Use in Elderly In elderly patients diazepam rectal gel should be used with caution due to an increase in half-life 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.

DRUG INTERACTIONS 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 Concomitant Use of Benzodiazepines and Opioids: The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABA A sites, and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and follow patients closely for respiratory depression and sedation.

Other Psychotropic

Agents or Other CNS Depressants: 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. Cimetidine: The clearance of diazepam and certain other benzodiazepines can be delayed in association with cimetidine administration. The clinical significance of this is unclear. Valproate: Valproate may potentiate the CNS-depressant effects of diazepam. 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. Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of rectal diazepam has not been evaluated. In studies in which mice and rats were administered diazepam in the diet at a dose of 75 mg/kg/day (approximately six and 12 times, respectively, the maximum recommended human dose [MRHD=1 mg/kg/day] on a mg/m2 basis) for 80 and 104 weeks, respectively, an increased incidence of liver tumors was observed in males of both species. The data currently available are inadequate to determine the mutagenic potential of diazepam. Reproduction studies in rats showed decreases in the number of pregnancies and in the number of surviving offspring following administration of an oral dose of 100 mg/kg/day (approximately 16 times the MRHD on a mg/m2 basis) prior to and during mating and throughout gestation and lactation. No adverse effects on fertility or offspring viability were noted at a dose of 80 mg/kg/day (approximately 13 times the MRHD on a mg/m2 basis).

Pregnancy Risk Summary

Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome and PRECAUTIONS: Pregnancy, Clinical Considerations ). Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Human Data ). In animal studies, administration of diazepam during the organogenesis period of pregnancy resulted in increased incidences of fetal malformations at doses greater than those used clinically. Data for diazepam and other benzodiazepines suggest the possibility of increased neuronal cell death and long-term effects on neurobehavioral and immunological function based on findings in animals following prenatal or early postnatal exposure at clinically relevant doses (see Animal Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations Fetal/Neonatal

Adverse Reactions Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Monitor neonates exposed to diazepam rectal gel during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to diazepam rectal gel during pregnancy for signs of withdrawal. Manage these neonates accordingly (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome ).

Data Human Data

Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings.

Animal Data

Diazepam has been shown to produce increased incidences of fetal malformations in mice and hamsters when given orally at single doses of 100 mg/kg or greater (approximately 20 times the maximum recommended adult human dose [0.4 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. In published animal studies, administration of benzodiazepines or other drugs that enhance GABAergic neurotransmission to neonatal rats has been reported to result in widespread apoptotic neurodegeneration in the developing brain at plasma concentrations relevant for seizure control in humans. The window of vulnerability to these changes in rats (postnatal days 0-14) includes a period of brain development that takes place during the third trimester of pregnancy in humans.

Nursing Mothers Risk Summary

Diazepam is present in breastmilk. There are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk. There are no data on the effects of diazepam on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for diazepam rectal gel and any potential adverse effects on the breastfed infant from diazepam rectal gel or from the underlying maternal condition.

Clinical Considerations

Infants exposed to diazepam rectal gel through breast milk should be monitored for sedation, poor feeding and poor weight gain. 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 breastfeed for an appropriate period of time after receiving treatment with diazepam rectal gel. Caution in Renally Impaired 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. Caution in Hepatically Impaired Patients Concomitant liver disease is known to decrease the clearance of diazepam (see CLINICAL PHARMACOLOGY: Special Populations, Hepatic Impairment ). Therefore, diazepam rectal gel should be used with caution in patients with liver disease. Use in Pediatrics The controlled trials demonstrating the effectiveness of diazepam rectal gel included children two years of age and older. Clinical studies have not been conducted to establish the efficacy and safety of diazepam rectal gel in children under two years of age. Use in Patients with Compromised Respiratory Function 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. Use in Elderly In elderly patients diazepam rectal gel should be used with caution due to an increase in half-life 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.