DIAZEPAM injection, solution

Diazepam by

Drug Labeling and Warnings

Diazepam by is a Prescription medication manufactured, distributed, or labeled by Dr. Reddy's Laboratories Inc, Dr. Reddy’s Laboratories Limited FTO-9. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

Drug Interactions

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 mµ 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.

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.

Diazepam injection has produced hypotension or muscular weakness in some patients particularly when used with narcotics, barbiturates, or alcohol.

The clearance of diazepam and certain other benzodiazepines can be delayed in association with cimetidine administration. The clinical significance of this is unclear.

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: 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 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 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 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 inhibition 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 to 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 injection and any potential adverse effects on the breastfed infant from diazepam injection or from the underlying maternal condition.

Clinical Considerations

Infants exposed to diazepam injection through breast milk should be monitored for sedation, poor feeding and poor weight gain.

  • 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 [including respiratory depressing (seeWARNINGS; Pediatric Use)], 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 ABUSE AND DEPENDENCE

    Controlled Substance

    Diazepam injection is a schedule IV controlled substance.

    Abuse

    Diazepam is a benzodiazepine and a CNS depressant with a potential for abuse and addiction. Abuse is the intentional, nontherapeutic 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 More Frequently than Recommended
    Diazepam 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 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 (seeWARNINGS: Dependence and Withdrawal Reactions ).

    For patients using diazepam more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue diazepam (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, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures, and suicidality.

    Protracted Withdrawal Syndrome

    Protracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond 4 to 6 weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months. As a result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used.

    Tolerance

    Tolerance to diazepam may develop after use more frequently than recommended. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).

    Tolerance to therapeutic effect of benzodiazepines may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

  • OVERDOSAGE

    Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma. In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur. In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal (see Warnings: Abuse, Misuse, and Addiction). Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage.

    In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway maintenance. Flumazenil, a specific benzodiazepine receptor antagonist indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with long- term benzodiazepine use and physical dependency. The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy. Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus). If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage. See the flumazenil injection Prescribing Information.

    Consider contacting a poison center (1-800-222-1222), poisoncontrol.org, or a medical toxicologist for additional overdosage management recommendations.

  • 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 should be injected deeply into the muscle.
    Intravenous Use: For the treatment of status epilepticus in children, the solution should be injected slowly, taking one minute for administration (See     WARNINGS, particularly for use in children). For other indications, 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.

    INDICATION

    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 reaction 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 to10 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 :

    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 (intravenous 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.

    Children 3 months up to 17 years of age with status epilepticus:

    First dose:
    0.2 mg/kg (maximum 8 mg) by slow intravenous push (one minute in duration).

    Second dose (if necessary;
    5 minutes after the first dose):
    0.1 mg/kg (maximum 4 mg) by slow intravenous push (one minute in duration).

    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.

    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.

  • HOW SUPPLIED

    Diazepam Injection, USP 10 mg/2 mL is a clear, colorless to slightly yellow solution supplied in 2 mL Prefilled Sterile Single-dose Syringe with Luer Lock.

    Unit of Sale

    Concentration

    Each

    NDC: 43598-106-10

    Carton of 10

    10 mg/2 mL

    (5 mg/mL)

    NDC: 43598-106-11

    Prefilled, Single-dose syringe with Luer Lock 

    Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature.]

    Protect from light.

  • ANIMAL PHARMACOLOGY

    Oral LD50 of diazepam is 720 mg/kg in mice and 1,240 mg/kg in rats. Intraperitoneal administration of 400 mg/kg to a monkey resulted in death on the sixth day.

    Reproduction Studies:

    A series of rat reproduction studies was performed with diazepam in oral doses of 1, 10, 80, and 100 mg/kg given for periods ranging from 60 to 228 days prior to mating. At 100 mg/kg there was a decrease in the number of pregnancies and surviving offspring in these rats. These effects may be attributable to prolonged sedative activity, resulting in lack of interest in mating and lessened maternal nursing and care of the young. Neonatal survival of rats at doses lower than 100 mg/kg was within normal limits. Several neonates, both controls and experimentals, in these rat reproduction studies showed skeletal or other defects. Further studies in rats at doses up to and including 80 mg/kg/day did not reveal significant teratological effects on the offspring. Rabbits were maintained on doses of 1, 2, 5, and 8 mg/kg from day 6 through day 18 of gestation. No adverse effects on reproduction and no teratological changes were noted.

    CAUTION: Federal (USA) law prohibits dispensing without prescription.

    To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories Inc., at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

    Distributed by:

    Dr. Reddy’s Laboratories Inc.,

    Princeton, NJ 08540

    Made in India

    Issued: 06/2024

  • PACKAGE LABEL PRINCIPAL DISPLAY PANEL SECTION

    Diazepam Injection, USP CIV 10 mg/2 mL(5 mg/mL) - Prefilled Syringe Label

    vial

  • PRINCIPAL DISPLAY PANEL

    Diazepam Injection, USP CIV 10 mg/2 mL(5 mg/mL) - Carton Label

    carton

  • INGREDIENTS AND APPEARANCE
    DIAZEPAM 
    diazepam injection, solution
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 43598-106
    Route of AdministrationINTRAMUSCULAR, INTRAVENOUSDEA ScheduleCIV    
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    DIAZEPAM (UNII: Q3JTX2Q7TU) (DIAZEPAM - UNII:Q3JTX2Q7TU) DIAZEPAM10 mg  in 2 mL
    Inactive Ingredients
    Ingredient NameStrength
    PROPYLENE GLYCOL (UNII: 6DC9Q167V3)  
    ALCOHOL (UNII: 3K9958V90M)  
    SODIUM BENZOATE (UNII: OJ245FE5EU)  
    BENZYL ALCOHOL (UNII: LKG8494WBH)  
    BENZOIC ACID (UNII: 8SKN0B0MIM)  
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 43598-106-1010 in 1 CARTON08/07/2024
    1NDC: 43598-106-112 mL in 1 SYRINGE, GLASS; Type 2: Prefilled Drug Delivery Device/System (syringe, patch, etc.)
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA21842208/07/2024
    Labeler - Dr. Reddy's Laboratories Inc (802315887)
    Establishment
    NameAddressID/FEIBusiness Operations
    Dr. Reddy’s Laboratories Limited FTO-9650446243analysis(43598-106) , manufacture(43598-106)
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