Diazepam Injection, USP is a sterile, nonpyrogenic solution intended for intramuscular or intravenous administration. Each milliliter (mL) contains 5 mg diazepam; 40% propylene glycol; 10% alcohol; 5% sodium benzoate and benzoic acid added as buffers; and 1.5% benzyl alcohol added as a preservative. pH 6.6 (6.2 to 6.9). Note: Solution may appear colorless to light yellow.

Diazepam is a benzodiazepine derivative chemically designated as 7-chloro-1,3-dihydro-1-methyl-5- phenyl-2H-1,4-benzodiazepin-2-one. It is a colorless crystalline compound, insoluble in water, with the following molecular structure:

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.

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 is a useful adjunct in status epilepticus and severe recurrent convulsive seizures.

Diazepam is a useful premedication (the I.M. route is preferred) for relief of anxiety and tension in patients who are to undergo surgical procedures. Intravenously, prior to cardioversion for the relief of anxiety and tension and to diminish the patient's recall of the procedure.

Dosage should be individualized for maximum beneficial effect. The usual recommended dose in older children and adults ranges from 2 mg to 20 mg I.M. or I.V., 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 flask. If it is not feasible to administer diazepam directly I.V., 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.

Diazepam Injection, USP 5 mg/mL is supplied as follows:

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

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

October, 2004. HOSPIRA, INC., LAKE FOREST, IL 60045 USA. FDA rev date: 4/30/1999

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 Abuse And Dependence

Diazepam Injection is classified by the Drug Enforcement Administration as a schedule IV controlled substance.

Withdrawal symptoms, similar in character to those noted with barbiturates and alcohol (convulsions, tremor, abdominal and muscle cramps, vomiting and sweating), have occurred following abrupt discontinuance of diazepam. The more severe withdrawal symptoms have usually been limited to those patients who had received excessive doses over an extended period of time. Generally milder withdrawal symptoms (e.g., dysphoria and insomnia) have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic levels for several months. Consequently, after extended therapy, abrupt discontinuation should generally be avoided and a gradual dosage tapering schedule followed. Addiction-prone individuals (such as drug addicts or alcoholics) should be under careful surveillance when receiving diazepam or other psychotropic agents because of the predisposition of such patients to habituation and dependence.

No information provided.

When used intravenously, the following procedures should be undertaken to reduce the possibility of venous thrombosis, phlebitis, local irritation, swelling, and, rarely, vascular impairment; 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 I.V., it may be injected slowly through the infusion tubing as close as possible to the vein insertion.

Extreme care must be used in administering Diazepam Injection, particularly by the I.V. route, 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 increases depression with increased risk of apnea. Resuscitative equipment including that necessary to support respiration should be readily available.

When diazepam is used with a narcotic analgesic, the dosage of the narcotic should be reduced by at least one-third and administered in small increments. In some cases the use of a narcotic may not be necessary.

Diazepam Injection should not be administered to patients in shock, coma, or in acute alcoholic intoxication with depression of vital signs. As is true of most CNS-acting drugs, patients receiving diazepam should be cautioned against engaging inhazardous occupations requiring complete mental alertness, such as operating machinery or driving a motor vehicle.

Tonic status epilepticus has been precipitated in patients treated with I.V. diazepam for petit mal status or petit mal variant status.

Usage in Pregnancy

An increased risk of congenital malformations associated with the use of minor tranquilizers (diazepam, meprobamate and chlordiazepoxide) during the first trimester of pregnancy has been suggested in several studies. Because use of these drugs is rarely a matter of urgency, their use during this period should almost always be avoided. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. Patients should 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.

In humans, measurable amounts of diazepam were found in maternal and cord blood, indicating placental transfer of the drug. Until additional information is available, diazepam injection is not recommended for obstetrical use.

Pediatric Use

Efficacy and safety of parenteral diazepam has not been established in the neonate (30 days or less of age).

Prolonged central nervous system depression has been observed in neonates, apparently due to inability to biotransform diazepam into inactive metabolites.

In pediatric use, in order to obtain maximal clinical effect with the minimum amount of drug and thus to reduce the risk of hazardous side effects, such as apnea or prolonged periods of somnolence, it is recommended that the drug be given slowly over a three-minute period in a dosage not to exceed 0.25 mg/kg. After an interval of 15 to 30 minutes the initial dosage can be safely repeated. If, however, relief of symptoms is not obtained after a third administration, adjunctive therapy appropriate to the condition being treated is recommended.

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

Benzyl alcohol has been reported to be associated with a fatal gasping syndrome in premature infants.

Although seizures may be brought under control promptly, a significant proportion of patients experience a return to seizure activity, presumably due to the short-lived effect of diazepam after I.V. administration. The physician should be prepared to re-administer the drug. However, diazepam is not recommended for maintenance, and once seizures are brought under control, consideration should be given to the administration of agents useful in longer term control of seizures.

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.

Since an increase in cough reflex and laryngospasm may occur with peroral endoscopic procedures, the use of a topical anesthetic agent and the availability of necessary countermeasures are recommended.

Until additional information is available, diazepam injection is not recommended for obstetrical use.

Diazepam injection has produced hypotension or muscular weakness in some patients particularly when used with narcotics, barbiturates or alcohol. Lower doses (usually 2 mg to 5 mg) should be used for elderly and debilitated patients.

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

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 norepinephrine or 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.

Diazepam is contraindicated in patients with a known hypersensitivity to this drug; acute narrow angle glaucoma; and open angle glaucoma unless patients are receiving appropriate therapy.

In animals, diazepam appears to act on parts of the limbic system, the thalamus and hypothalamus, and induces calming effects. Diazepam, unlike chlorpromazine and reserpine, has no demonstrable peripheral autonomic blocking action, nor does it produce extrapyramidal side effects; however, animals treated with diazepam do have a transient ataxia at higher doses. Diazepam was found to have transient cardiovascular depressor effects in dogs. Long-term experiments in rats revealed no disturbances of endocrine function. Injections into animals have produced localized irritation of tissue surrounding injection sites and some thickening of veins after intravenous use.

Animal Pharmacology

Oral LD₅₀ of diazepam is 720 mg/kg in mice and 1240 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 60-228 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.

No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

DIAZEPAM - INJECTION

(dye-AZZ-eh-pam)

COMMON BRAND NAME(S): Valium

USES: Diazepam is used to treat anxiety and muscle spasms. The injection form is used when the medication cannot be taken by mouth. It is also used in patients with alcohol withdrawal to prevent seizures and treat other symptoms (e.g., agitation, anxiety, hallucinations).

This medication is also used for short-term treatment of serious seizures that do not stop (status epilepticus). It is not for ongoing daily use to prevent seizures.

It is also used before surgeries or procedures to cause drowsiness, decrease anxiety, and cause forgetfulness about the procedure or surgery.

This medication belongs to a class of drugs called benzodiazepines, which act on the brain and nerves (central nervous system) to produce a calming effect. It works by enhancing the effects of a certain natural chemical in the body (GABA) that causes calm.

HOW TO USE: Learn all preparation and usage instructions in the product package. Do not mix with other medications in the same syringe/solution. If any of the information is unclear, consult your doctor or pharmacist.

This medication is given by injection into a vein or deep into a muscle by a health care professional. Giving the medication too fast can cause heart problems. If giving this medication into a vein, inject it slowly into a large vein because the medication is very irritating to the vein. Do not inject this medication into an artery or into the skin.

This medication may be available in a vial, ampule, pre-filled syringe, or pre-filled syringe with autoinjector. The autoinjector automatically delivers a dose of 10 milligrams deep into the muscle. It cannot be used when a lower dose is needed. Do not use the autoinjector for injecting into a vein.

The liquid should be clear to pale yellow. Before using this product, check it visually for particles or discoloration. If either is present, do not use the liquid. If you are using a form of this drug that requires preparation, prepare it just before using. Discard any unused solution. If you have questions about the use of this medication, consult the pharmacist.

Dosage is based on your medical condition and response to treatment. You will be closely monitored for several hours after receiving this medication. If your doctor orders you to continue to receive this medication, you should be switched to a form that can be taken by mouth as soon as possible.

This medication may cause dependence, especially if it has been used regularly for an extended time or if it has been used in high doses. In such cases, withdrawal reactions (e.g., shakiness, trouble sleeping, muscle cramps, vomiting, sweating, seizures, mental/mood changes such as anxiety/agitation) may occur if you suddenly stop this drug. To prevent withdrawal reactions when stopping extended, regular treatment with this drug, gradually reduce the dosage as directed. Consult your doctor or pharmacist for more details, and report any withdrawal reactions immediately.

Rarely, abnormal drug-seeking behavior (addiction) is possible with this medication. Do not increase your dose, take it more frequently, or take it for a longer time than prescribed. Properly stop the medication when so directed.

When used for an extended time, this medication may not work as well and may require different dosing. Talk with your doctor if this medication stops working well.

SIDE EFFECTS: Drowsiness, dizziness, nausea, unsteadiness, or pain/burning/redness at the injection site may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: fainting, fast/irregular heartbeat, mental/mood changes (e.g., confusion, depression, strange thoughts), muscle weakness, pain/swelling/signs of infection at the injection site, vision changes (e.g., blurred/double vision).

Tell your doctor immediately if any of these rare but very serious side effects occur: slow/shallow breathing, easy bleeding/bruising, chest pain, loss of consciousness, signs of infection (e.g., fever, persistent sore throat), slurred speech, severe stomach/abdominal pain, unusual tiredness, dark urine, difficulty walking, yellowing eyes/skin.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using diazepam, tell your doctor or pharmacist if you are allergic to it; or to other benzodiazepines (e.g., chlordiazepoxide); or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: breathing trouble during sleep (sleep apnea), severe breathing problems (except in patients who are breathing with help from a machine), certain blood disorder (porphyria), certain eye problem (glaucoma), a certain muscle disease (myasthenia gravis).

Before using this medication, tell your doctor your medical history, especially of: breathing problems (e.g., asthma), brain problems that could affect breathing (e.g., decreased consciousness, head injury), depression, history of drug/alcohol abuse, heart disease, kidney disease, liver disease, mental/mood disorders (e.g., depression), certain type of seizure (petit mal).

This drug may make you dizzy or drowsy. For at least 3 hours after receiving this drug, you should not get out of bed without help. Do not drive, use machinery, or do any activity that requires alertness until the effects of the medication wear off (at least 24 hours). Avoid alcoholic beverages.

Get up slowly to avoid dizziness and lightheadedness when rising from a sitting or lying position. Alcoholic beverages will increase these effects.

Caution is advised when using this drug in children because it may affect children differently, causing restlessness or mental/mood changes (e.g., agitation, hallucinations) instead of calm.

A preservative (benzyl alcohol) that may be found in this product or in the liquid used to mix this product can infrequently cause serious problems (sometimes death) if more than 100 milligrams daily is given to an infant during the first months of life. The risk is greater with low-birth-weight infants. Symptoms include sudden gasping, low blood pressure, or a very slow heartbeat. If you notice any of these symptoms in your newborn, tell the doctor immediately. If possible, a preservative-free product should be used when treating newborns.

Caution is advised when using this drug in the elderly because they may be more sensitive to the effects of the drug, especially confusion and dizziness. This medication may also affect the elderly differently, causing restlessness or mental/mood changes (e.g., agitation, hallucinations) instead of calm.

This medication is not recommended for use during pregnancy. It may harm an unborn baby. If you become pregnant or think you may be pregnant, tell your doctor immediately. Consult your doctor before using this medication.

This drug may pass into breast milk and have undesirable effects on a nursing infant. Therefore, breast-feeding while using this medication is not recommended. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

This drug should not be used with the following medications because very serious interactions may occur: fluvoxamine, sodium oxybate.

If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting this medication.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: kava, phenytoin.

Other medications can affect the removal of diazepam from your body, which may affect how diazepam works. Examples include cimetidine, ketoconazole, omeprazole, among others.

Tell your doctor or pharmacist if you also take drugs that cause drowsiness such as: certain antihistamines (e.g., diphenhydramine), anti-seizure drugs (e.g., carbamazepine), medicine for sleep or anxiety (e.g., alprazolam, zolpidem), muscle relaxants, narcotic pain relievers (e.g., codeine), psychiatric medicines (e.g., chlorpromazine, clozapine, risperidone, amitriptyline, trazodone, MAO inhibitors such as phenelzine). Check the labels on all your medicines (e.g., cough-and-cold products) because they may contain ingredients that may cause drowsiness. Ask your pharmacist about using those products safely.

This medication contains a small amount of alcohol. Tell your doctor if you are taking drugs such as disulfiram or metronidazole that can cause an unpleasant reaction when combined with alcohol.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: extreme drowsiness/dizziness, confusion, slow/shallow breathing, loss of consciousness.

NOTES: Do not share this medication with others. It is against the law.

Laboratory and/or medical tests (e.g., complete blood count, liver function tests) may be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: Not applicable. This medication is not usually given on a regular schedule.

STORAGE: Store vials at room temperature between 68-77 degrees F (20-25 degrees C). Store pre-filled injectors at room temperature at 77 degrees F (25 degrees C). Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. Store away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised August 2008 Copyright(c) 2008 First DataBank, Inc.