Drug Facts
Composition & Profile
Identifiers & Packaging
HOW SUPPLIED Diazepam Oral Solution The 5 mg per 5 mL oral solution is supplied as a (wintergreen-spice flavored) clear, orange-colored solution. NDC 0121-0905-05: 5 mL unit dose cup, in a tray of ten cups. STORAGE Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Dispense in a tight, light-resistant container as defined in the USP/NF.; PACKAGE/LABEL PRINCIPAL DISPLAY PANEL Delivers 5 mL NDC 0121-0905-05 Diazepam Oral Solution C-IV 5 mg per 5 mL SUGAR FREE Usual Dosage: See Insert Rx ONLY Package Not Child-Resistant Pkg. by: PHARMACEUTICALS ASSOCIATES, INC. GREENVILLE, SC 29605 SEE INSERT A0905050221 fpl-label-5mg-per-5ml-os-05A.jpg
- HOW SUPPLIED Diazepam Oral Solution The 5 mg per 5 mL oral solution is supplied as a (wintergreen-spice flavored) clear, orange-colored solution. NDC 0121-0905-05: 5 mL unit dose cup, in a tray of ten cups. STORAGE Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Dispense in a tight, light-resistant container as defined in the USP/NF.
- PACKAGE/LABEL PRINCIPAL DISPLAY PANEL Delivers 5 mL NDC 0121-0905-05 Diazepam Oral Solution C-IV 5 mg per 5 mL SUGAR FREE Usual Dosage: See Insert Rx ONLY Package Not Child-Resistant Pkg. by: PHARMACEUTICALS ASSOCIATES, INC. GREENVILLE, SC 29605 SEE INSERT A0905050221 fpl-label-5mg-per-5ml-os-05A.jpg
Overview
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 crystalline powder, insoluble in water and has a molecular weight of 284.74. Its structural formula is as follows: C 16 H 13 CIN 2 O Each 5 mL of Oral Solution contains: diazepam USP 5 mg Inactive Ingredients The flavored 5 mg/5 mL Oral Solution contains bitterness modifier, citric acid, D&C Yellow No. 10, FD&C Red No. 40, polyethylene glycol, propylene glycol, sodium citrate, sorbitol, water and wintergreen coriander spice blend. Chemical structure
Indications & Usage
INDICATIONS Diazepam is indicated for the management of anxiety disorders or 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. In acute alcohol withdrawal, diazepam may be useful in the symptomatic relief of acute agitation, tremor, impending or acute delirium tremens and hallucinosis. 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; and stiff-man syndrome. Oral diazepam may be used adjunctively in convulsive disorders, although it has not proved useful as the sole therapy. The effectiveness of diazepam in long-term use, that is, more than 4 months, has not been assessed by systematic clinical studies. The physician should periodically reassess the usefulness of the drug for the individual patient.
Dosage & Administration
Dosage should be individualized for maximum beneficial effect. While the usual daily dosages given below will meet the needs of most patients, there will be some who may require higher doses. In such cases dosage should be increased cautiously to avoid adverse effects. Adults: Usual Daily Dosage Management of Anxiety Disorders and Relief of Symptoms of Anxiety. Depending upon severity of symptoms – 2 mg to 10 mg, 2 to 4 times daily. Symptomatic Relief in Acute Alcohol Withdrawal. 10 mg, 3 or 4 times during the first 24 hours, reducing to 5 mg, 3 or 4 times daily as needed. Adjunctively for Relief of Skeletal Muscle Spasm. 2 mg to 10 mg, 3 or 4 times daily. Adjunctively in Convulsive Disorders. 2 mg to 10 mg, 2 to 4 times daily. Geriatric Patients or in the presence of debilitating disease. 2 mg to 2.5 mg, 1 or 2 times daily initially; increase gradually as needed and tolerated. Pediatric Patients: Because of varied responses to CNS-acting drugs, initiate therapy with lowest dose and increase as required. Not for use in children under 6 months. 1 mg to 2.5 mg, 3 or 4 times daily initially; increase gradually as needed and tolerated. Discontinuation or Dosage Reduction of Diazepam To reduce the risk of withdrawal reactions, use a gradual taper to discontinue diazepam or reduce the dosage. If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level. Subsequently decrease the dosage more slowly (see WARNINGS: Dependence and Withdrawal Reactions and DRUG ABUSE AND DEPENDENCE: Dependence).
Warnings & Precautions
WARNINGS 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 these drugs in 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. In patients already receiving an opioid analgesic, prescribe a lower initial dose of diazepam than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking diazepam, prescribe a lower initial dose of the opioid and titrate based upon clinical response. Advise both patients and caregivers about the risks of respiratory depression and sedation when diazepam is used with opioids. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined (see PRECAUTIONS: Drug Interactions). Abuse, Misuse, and Addiction The use of benzodiazepines, including diazepam, 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 (see DRUG ABUSE AND DEPENDENCE: Abuse). Before prescribing diazepam and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of diazepam, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of diazepam along with monitoring for signs and symptoms of abuse, misuse, and addiction. Prescribe the lowest possible dosage for the shortest duration; 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 To reduce the risk of withdrawal reactions, use a gradual taper to discontinue diazepam or reduce the dosage (a patient-specific plan should be used to taper the dose) (see DOSAGE AND ADMINISTRATION: Discontinuation or Dosage Reduction of Diazepam). 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, including diazepam, for several days to weeks may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of diazepam after continued use (for several days to weeks), 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). Diazepam is not recommended in the treatment of psychotic patients and should not be employed instead of appropriate treatment. Since diazepam has a central nervous system depressant effect, patients should be advised against the simultaneous ingestion of alcohol and other CNS-depressant drugs during diazepam therapy. As with other agents that have anticonvulsant activity, when diazepam is used as an adjunct in treating convulsive disorders, the possibility of an increase in the frequency and/or severity of grand mal seizures may require an increase in the dosage of standard anticonvulsant medication. Abrupt withdrawal of diazepam in such cases may also be associated with a temporary increase in the frequency and/or severity of seizures. Pregnancy An increased risk of congenital malformations and other developmental abnormalities associated with the use of benzodiazepine drugs during pregnancy has been suggested. 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. Diazepam has been shown to be teratogenic in mice and hamsters when given orally at daily 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/m 2 basis). Cleft palate and encephalopathy 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 long-term changes in cellular immune responses, brain neurochemistry, and behavior. 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. 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 physicians about the desirability of discontinuing the drug. Labor and Delivery Special care must be taken when diazepam is used during labor and delivery, as high single doses may produce irregularities in the fetal heart rate and hypotonia, poor sucking, hypothermia, and moderate respiratory depression in the neonate. With newborn infants it must be remembered that the enzyme system involved in the breakdown of the drug is not fully developed (especially in premature infants). Nursing Mothers Diazepam passes into breast milk. Breastfeeding is therefore not recommended in patients receiving diazepam.
Boxed Warning
RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation (see WARNINGS AND PRECAUTIONS). The use of benzodiazepines, including diazepam, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing diazepam and throughout treatment, assess each patients risk for abuse, misuse, and addiction (see WARNINGS). The continued use of benzodiazepines, including diazepam, for several days to weeks may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of diazepam after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use a gradual taper to discontinue diazepam or reduce the dosage (see DOSAGE AND ADMINISTRATION and WARNINGS).
Contraindications
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. Diazepam is also contraindicated in patients with myasthenia gravis, severe respiratory insufficiency, severe hepatic insufficiency, and sleep apnea syndrome. It may be used in patients with open angle glaucoma who are receiving appropriate therapy, but is contraindicated in acute narrow angle glaucoma.
Adverse Reactions
Side effects most commonly reported were drowsiness, fatigue, muscle weakness and ataxia. The following have also been reported: Central Nervous System: confusion, depression, dysarthria, headache, slurred speech, tremor, vertigo Gastrointestinal System: constipation, nausea, gastrointestinal disturbances Special Senses: blurred vision, diplopia, dizziness Cardiovascular System: hypotension Psychiatric and Paradoxical Reactions: stimulation, restlessness, acute hyperexcited states, anxiety, agitation, aggressiveness, irritability, rage, hallucinations, psychoses, delusions, increased muscle spasticity, insomnia, sleep disturbances, and nightmares. Inappropriate behavior and other adverse behavioral effects have been reported when using benzodiazepines. Should these occur, use of the drug should be discontinued. They are more likely to occur in children and in the elderly. Urogenital System: incontinence, changes in libido, urinary retention Skin and Appendages: skin reactions Laboratories: elevated transaminases and alkaline phosphatase Other: changes in salivation, including dry mouth, hypersalivation Anterograde amnesia may occur using therapeutic dosages, the risk increasing at higher dosages. Amnestic effects may be associated with inappropriate behavior. 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. Because of isolated reports of neutropenia and jaundice, periodic blood counts and liver function tests are advisable during long-term therapy. Postmarketing Experience Injury, Poisoning and Procedural Complications There have been reports of falls and fractures in benzodiazepine users. The risk is increased in those taking concomitant sedatives (including alcohol), and in the elderly.
Drug Interactions
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 GABAA 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 monitor patients closely for respiratory depression and sedation. Centrally Acting Agents If diazepam is to be combined with other centrally acting agents, careful consideration should be given to the pharmacology of the agents employed particularly with compounds that may potentiate or be potentiated by the action of diazepam, such as phenothiazines, antipsychotics, anxiolytics/sedatives, hypnotics, anticonvulsants, narcotic analgesics, anesthetics, sedative antihistamines, narcotics, barbiturates, MAO inhibitors and other antidepressants. Alcohol Concomitant use with alcohol is not recommended due to enhancement of the sedative effect. Antacids Diazepam peak concentrations are 30% lower when antacids are administered concurrently. However, there is no effect on the extent of absorption. The lower peak concentrations appear due to a slower rate of absorption, with the time required to achieve peak concentrations on average 20 – 25 minutes greater in the presence of antacids. However, this difference was not statistically significant. Compounds Which Inhibit Certain Hepatic Enzymes: There is a potentially relevant interaction between diazepam and compounds which inhibit certain hepatic enzymes (particularly cytochrome P450 3A and 2C19). Data indicate that these compounds influence the pharmacokinetics of diazepam and may lead to increased and prolonged sedation. At present, this reaction is known to occur with cimetidine, ketoconazole, fluvoxamine, fluoxetine, and omeprazole. Phenytoin There have also been reports that the metabolic elimination of phenytoin is decreased by diazepam.
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