Diazepam 10 mg/2mL Injection — NDC 11704-600-01 (Billing 11704-0600-01)

WARNINGS Diazepam Autoinjector is to be administered only by the intramuscular (I.M.) route. Risks from Concomitant Use With Opioids Concomitant use of benzodiazepines, including diazepam, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of benzodiazepines and opioids for patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. If a decision is made to prescribe diazepam concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. Advise both patients and caregivers about the risks of respiratory depression and sedation when diazepam is used with opioids (see PRECAUTIONS ).

Abuse, Misuse, and Addiction The use of benzodiazepines, including Diazepam injection, 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, that is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death (see DRUG ABUSE AND DEPENDENCE: Abuse ).

Before prescribing Diazepam injection and throughout treatment, assess each patient's risk for abuse, misuse, and addiction. Use of Diazepam injection, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of Diazepam injection along with monitoring for signs and symptoms of abuse, misuse, and addiction. Do not exceed the recommended dosing frequency; avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug.

If a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate. Dependence and Withdrawal Reactions After Use of Diazepam injection More Frequently Than Recommended For patients using Diazepam injection more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue Diazepam injection (a patient-specific plan should be used to taper the dose). Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use.

Acute Withdrawal Reactions The continued use of benzodiazepines may lead to clinically significant physical dependence. Although Diazepam injection is indicated only for intermittent use (see INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION ), if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction of Diazepam injection, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) (see DRUG ABUSE AND DEPENDENCE: Dependence ) .

Protracted Withdrawal Syndrome In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months (see DRUG ABUSE AND DEPENDENCE: Dependence ). Respiratory and Central Nervous System Depression Extreme care must be used in administering injectable diazepam to the elderly, to very ill patients and to those with limited pulmonary reserve because of the possibility that apnea and/or cardiac arrest may occur. Concomitant use of barbiturates, alcohol, or other central nervous system depressants… [Excerpted — this section continues on DailyMed.]

ADVERSE REACTIONS Side effects most commonly reported were drowsiness, fatigue and ataxia; venous thrombosis and phlebitis at the site of injection. Other adverse reactions less frequently reported include: CNS: confusion, depression, dysarthria, headache, hypoactivity, slurred speech, syncope, tremor, vertigo. G.I.: constipation, nausea.

G.U.: incontinence, changes in libido, urinary retention. Cardiovascular: bradycardia, cardiovascular collapse, hypotension. EENT: blurred vision, diplopia, nystagmus.

Skin: urticaria, skin rash. Other: hiccups, changes in salivation, neutropenia, jaundice. Paradoxical reactions such as acute hyperexcited states, anxiety, hallucinations, increased muscle spasticity, insomnia, rage, sleep disturbances and stimulation have been reported; should these occur, use of the drug should be discontinued.

Minor changes in EEG patterns, usually low-voltage fast activity, have been observed in patients during and after diazepam therapy and are of no known significance. In peroral endoscopic procedures, coughing, depressed respiration, dyspnea, hyperventilation, laryngospasm and pain in throat or chest have been reported. Because of isolated reports of neutropenia and jaundice, periodic blood counts and liver function tests are advisable during long-term therapy.

Drug Interactions 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. Concomitant Use with Other Psychotropic Agents or Anticonvulsant Drugs If diazepam is to be combined with other psychotropic agents or anticonvulsant drugs, 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.

In highly anxious patients with evidence of accompanying depression, particularly those who may have suicidal tendencies, protective measures may be necessary. The usual precautions in treating patients with impaired hepatic function should be observed. Metabolites of diazepam are excreted by the kidney; to avoid their excess accumulation, caution should be exercised in the administration to patients with compromised kidney function.

Concomitant Use with Cimetidine The clearance of diazepam and certain other benzodiazepines can be delayed in association with Tagamet (cimetidine) administration. The clinical significance of this is unclear.

PRECAUTIONS Drug Interactions 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. Concomitant Use with Other Psychotropic Agents or Anticonvulsant Drugs If diazepam is to be combined with other psychotropic agents or anticonvulsant drugs, 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.

In highly anxious patients with evidence of accompanying depression, particularly those who may have suicidal tendencies, protective measures may be necessary. The usual precautions in treating patients with impaired hepatic function should be observed. Metabolites of diazepam are excreted by the kidney; to avoid their excess accumulation, caution should be exercised in the administration to patients with compromised kidney function.

Concomitant Use with Cimetidine The clearance of diazepam and certain other benzodiazepines can be delayed in association with Tagamet (cimetidine) administration. The clinical significance of this is unclear. Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, such as Diazepam injection, during pregnancy.

Healthcare providers are encouraged to recommend that pregnant women taking Diazepam injection enroll in the North American Antiepileptic Drug (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 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 injection during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to Diazepam injection during pregnancy for signs of withdrawal. Manage these neonates accordingly (see WARNINGS: Neonatal Sedation and Withdrawal Syndrome ).

Data Human Data Published data from observational studie… [Excerpted — this section continues on DailyMed.]

DRUG ABUSE AND DEPENDENCE Controlled Substance Diazepam is a schedule IV controlled substance. Abuse Diazepam injection is a benzodiazepine and a CNS depressant with a potential for abuse and addiction. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects.

Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence.

Even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. Abuse and misuse of benzodiazepines may lead to addiction. 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.

Benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders (see WARNINGS: Abuse, Misuse, and Addiction ). The following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo.

The following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. Death is more often associated with polysubstance use (especially benzodiazepines with other CNS depressants such as opioids and alcohol). Dependence Physical Dependence After Use of Diazepam Injection More Frequently Than Recommended Diazepam injection may produce physical dependence if used more frequently than recommended.

Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Although Diazepam injection is indicated only for intermittent use (see INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION ), if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening.

Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use (see WARNINGS: Dependence and Withdrawal Reactions ). For patients using Diazepam injection more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue Diazepam injection (see WARNINGS: Dependence and Withdrawal Reactions ).

Acute Withdrawal Signs and Symptoms Acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, mu… [Excerpted — this section continues on DailyMed.]

Controlled Substance Diazepam is a schedule IV controlled substance.