Valium

DESCRIPTION

Valium (diazepam) is a benzodiazepine derivative. The chemical name of diazepam is 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin- 2-one. It is a colorless to light yellow crystalline compound, insoluble in water. The empirical formula is C₁₆H₁₃ClN₂O and the molecular weight is 284.75. The structural formula is as follows:

Valium is available for oral administration as tablets containing 2 mg, 5 mg or 10 mg diazepam. In addition to the active ingredient diazepam, each tablet contains the following inactive ingredients: anhydrous lactose, corn starch, pregelatinized starch and calcium stearate with the following dyes: 5-mg tablets contain FD&C Yellow No. 6 and D&C Yellow No. 10; 10-mg tablets contain FD&C Blue No. 1. Valium 2-mg tablets contain no dye.

INDICATIONS

Valium 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, Valium may be useful in the symptomatic relief of acute agitation, tremor, impending or acute delirium tremens and hallucinosis.

Valium 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 Valium may be used adjunctively in convulsive disorders, although it has not proved useful as the sole therapy.

The effectiveness of Valium 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 AND 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 DOSE:
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 pediatric patients 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 Valium

为了减少戒断反应的风险,使用gradual taper to discontinue Valium 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警告:Dependence And Withdrawal ReactionsandDrug Abuse And Dependence:Dependence）.

HOW SUPPLIED

For oral administration, Valium is supplied as round, flat-faced scored tablets with V-shaped perforation and beveled edges. Valium is available as follows: 2 mg, white -bottles of 100 (NDC0140 - 0004-01); 5 mg, yellow -bottles of 100 (NDC0140 - 0005-01) and 500 (NDC0140 - 000514); 10 mg, blue -bottles of 100 (NDC0140 - 0006-01) and 500 (NDC0140 - 0006-14).

Engraved on tablets:

2 mg - 2 VALIUM^®(front)
ROCHE (twice on scored side)

5 mg - 5 VALIUM^®(front)
ROCHE (twice on scored side)

10 mg - 10 VALIUM^®(front)
ROCHE (twice on scored side)

Storage

Store at room temperature 59° to 86°F (15° to 30°C). Dispense in tight, light-resistant containers as defined in USP/NF.

Distributed by: Waylis Therapuetics LLC., Wixom, MI 48393. Revised: Jan 2023

SIDE EFFECTS

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,gastrointestinaldisturbances

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 musclespasticity, insomnia, sleep disturbances, and nightmares. Inappropriate behavior and other adverse behavioral effects have been reported when usingbenzodiazepines. 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 inlibido, urinary retention

Skin and Appendages:skin reactions

Laboratories:elevated transaminases and alkaline phosphatase

Other:changes in salivation, includingdry mouth, hypersalivation.

Antegradeamnesiamay 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 Valium therapy and are of no known significance.

Because of isolated reports ofneutropeniaandjaundice, 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 ofrespiratory depressionbecause of actions at different receptor sites in the CNS that controlrespiration. Benzodiazepines interact at GABAA sites and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsenopioid-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 Valium is to be combined with other centrally acting agents, careful consideration should be given to thepharmacologyof the agents employed particularly with compounds that may potentiate or be potentiated by the action of Valium, such as phenothiazines, antipsychotics, anxiolytics/sedatives, hypnotics, anticonvulsants,narcoticanalgesics, anesthetics,sedativeantihistamines, narcotics, barbiturates, MAO inhibitors and otherantidepressants.

Alcohol

Concomitant use with alcohol is not recommended due to enhancement of the sedative effect.

Antacids

安定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.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

In studies in which mice and rats were administered diazepam in the diet at a dose of 75 mg/kg/day (approximately 6 and 12 times, respectively, the maximum recommended human dose [MRHD=1 mg/kg/day] on a mg/m²basis) 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/m²basis) 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/m²basis).

Drug Abuse And Dependence

Controlled Substance

第四安定安定,包含一个时间表控制substance.

Abuse

Valium 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警告:Abuse,Misuse, andAddiction）.

The following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia,anorexia、焦虑、侵略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

Valium may produce physical dependence from continued therapy. 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. Abrupt discontinuation or rapid dosage reduction of benzodiazepines or administration of flumazenil, a benzodiazepineantagonist, 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), those who have had longer durations of use (see警告:Dependence And Withdrawal Reactions）.

为了减少戒断反应的风险,使用gradual taper to discontinue Valium or reduce the dosage (seeDOSAGE AND ADMINISTRATION:Discontinuation Or Dosage Reduction Of Valiumand警告:Dependence And Withdrawal Reactions）.

Acute Withdrawal Signs And Symptoms

Acute withdrawal signs and symptoms associated with benzodiazepines have included abnormalinvoluntarymovements, 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 benzodiazepine is characterized by anxiety, cognitive impairment, depression, insomnia,formication, motor symptoms (e.g., weakness, tremor, muscle twitches),paresthesia, andtinnitusthat persists beyond 4 to 6 weeks after initial benzodiazepine withdrawal. Protractedwithdrawal symptomsmay 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; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

Tolerance

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

警告

Risks From Concomitant Use With Opioids

Concomitant use of benzodiazepines, including Valium, 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 Valium 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 opioidanalgesic, prescribe a lower initial dose of Valium than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking Valium, 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 Valium 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 (seeDRUG INTERACTION）.

滥用,滥用和成瘾

The use of benzodiazepines, including Valium, 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 (seeDrug Abuse And Dependence:Abuse）.

Before prescribing Valium and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of Valium, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of Valium along with monitoring for signs and symptoms of abuse, misuse, and addiction. Prescribe the lowest effective dosage; 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

为了减少戒断反应的风险,使用gradual taper to discontinue Valium or reduce the dosage (a patient-specific plan should be used to taper the dose) (seeDOSAGE AND ADMINISTRATION:Discontinuation Or Dosage Reduction Of Valium）.

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 Valium, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of Valium after continued use, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) (seeDrug 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 (seeDrug Abuse And Dependence:Dependence）.

Valium is not recommended in the treatment of psychotic patients and should not be employed instead of appropriate treatment.

Since Valium has acentral nervous systemdepressant effect, patients should be advised against the simultaneous ingestion of alcohol and other CNS-depressant drugs during Valium therapy.

As with other agents that haveanticonvulsantactivity, when Valium is used as an adjunct in treating convulsive disorders, the possibility of an increase in the frequency and/or severity ofgrand malseizures may require an increase in the dosage of standard anticonvulsant medication. Abrupt withdrawal of Valium in such cases may also be associated with a temporary increase in the frequency and/or severity of seizures.

Neonatal Sedation And Withdrawal Syndrome

Use of Valium 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 theneonate(seePRECAUTIONS:Pregnancy）.Monitor neonates exposed to Valium during pregnancy or labor for signs of sedation and monitor neonates exposed to Valium during pregnancy for signs of withdrawal; manage these neonates accordingly.

PRECAUTIONS

General

If Valium 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 that may potentiate the action of diazepam, such as phenothiazines, narcotics, barbiturates, MAO inhibitors and other antidepressants (seeDrug Interactions）.

The usual precautions are indicated for severely depressed patients or those in whom there is any evidence oflatentdepression or anxiety associated with depression, particularly the recognition that suicidal tendencies may be present and protective measures may be necessary.

Psychiatric and paradoxical reactions are known to occur when using benzodiazepines (seeADVERSE REACTIONS）.Should this occur, use of the drug should be discontinued. These reactions are more likely to occur in children and the elderly.

A lower dose is recommended for patients with chronicrespiratory insufficiency, due to the risk of respiratory depression.

Benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse (seeDrug Abuse And Dependence）.

In debilitated patients, it is recommended that the dosage be limited to the smallest effective amount to preclude the development of ataxia or oversedation (2 mg to 2.5 mg once or twice daily, initially, to be increased gradually as needed and tolerated).

Some loss of response to the effects of benzodiazepines may develop after repeated use of Valium for a prolonged time.

Information For Patients

Advise the patient to read the FDA-approved patient labeling (Medication Guide）.

Risks From Concomitant Use With Opioids

Advise both patients and caregivers about the risks of potentially fatal respiratory depression and sedation when Valium is used with opioids and not to use such drugs concomitantly unless supervised by a health care provider. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined (see警告:Risks From Concomitant Use With OpioidsandPRECAUTIONS:Drug Interactions）.

滥用,滥用和成瘾

告知患者使用安定,即使在再保险commended 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警告:Abuse, Misuse, andAddictionandDrug Abuse And Dependence）.

Withdrawal Reactions

Inform patients that the continued use of Valium may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of Valium 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. Instruct patients that discontinuation or dosage reduction of Valium may require a slow taper (see警告:Dependence And Withdrawal ReactionsandDrug Abuse And Dependence）.

Patients should be advised against the simultaneous ingestion of alcohol and other CNS-depressant drugs during Valium therapy. As is true of most CNS-acting drugs, patients receiving Valium should be cautioned against engaging in hazardous occupations requiring complete mental alertness, such as operating machinery or driving a motor vehicle.

Pregnancy

Advise pregnant females that use of Valium 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警告:Neonatal Sedation And Withdrawal SyndromeandPRECAUTIONS:Pregnancy）.Instruct patients to inform their healthcare provider if they are pregnant.

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Valium during pregnancy (seePRECAUTIONS,Pregnancy）.

Nursing

Advise patients that breastfeeding is not recommended during treatment with Valium (seePRECAUTIONS:Nursing Mothers）.

Pregnancy

Pregnancy Exposure Registry

There is a pregnancy registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including Valium, during pregnancy.

Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/pregnancyregistry/.

Risk Summary

Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/orneonatalwithdrawal (see警告:Neonatal Sedation And Withdrawal SyndromeandClinical Considerations）.可用数据来m published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (seeData）.

安定has been shown to beteratogenicin 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/m²basis). Cleftpalateandencephalopathyare the most common and consistently reported malformations produced in these species by administration of high, maternally toxic doses of diazepam during organogenesis.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk ofbirth 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 Valium during pregnancy and labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to Valium during pregnancy for signs of withdrawal. Manage these neonates accordingly (see警告:Neonatal Sedation And Withdrawal Syndrome）.

Labor or Delivery

Special care must be taken when Valium 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 neonates. With newborn infants it must be remembered that the enzyme system involved in the breakdown of the drug is not yet fully developed (especially in premature infants).

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 ofcongenitalmalformations 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

安定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/m²basis). 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 thatprenatalexposure to diazepam doses similar to those used clinically can produce long-term changes in cellular immune responses, brain neurochemistry, and behavior.

Nursing Mothers

安定is present in breastmilk. There are reports of sedation, poor feeding, and poor weight gain in infants exposed to benzodiazepines through breast milk. Because of the potential for serious adverse reaction, including sedation and withdrawal symptoms in breastfed infants, advise patient that breastfeeding is not recommended during treatment with Valium.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 6 months have not been established.

Geriatric Use

In elderly patients, it is recommended that the dosage be limited to the smallest effective amount to preclude the development of ataxia or oversedation (2 mg to 2.5 mg once or twice daily, initially to be increased gradually as needed and tolerated).

Extensive accumulation of diazepam and its major metabolite, desmethyldiazepam, has been noted following chronic administration of diazepam in healthy elderly male subjects. Metabolites of this drug are known to be substantially excreted by the kidney, and the risk of toxic reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Hepatic Insufficiency

Decreases in clearance and protein binding, and increases in volume of distribution and half-life have been reported in patients withcirrhosis. In such patients, a 2-to 5-fold increase in mean half-life has been reported. Delayed elimination has also been reported for the active metabolite desmethyldiazepam. Benzodiazepines are commonly implicated inhepatic encephalopathy. Increases in half-life have also been reported in hepatic fibrosis and in both acute and chronichepatitis(seeCLINICAL PHARMACOLOGY:Pharmacokinetics In Special Populations:Hepatic Insufficiency）.

OVERDOSE

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警告:Dependence And Withdrawal Reactions）.Markedly abnormal (lowered or elevated) blood pressure, heart rate, orrespiratory rateraise 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 management. Flumazenil, a specific benzodiazepine receptor antagonist, is 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 increaseseizurerisk (e.g., tricyclic and tetracyclic antidepressants) and in patients with longterm benzodiazepine use and physical dependency. The risk of withdrawal seizures with flumazenil use may be increased in patients withepilepsy. 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 the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.

CONTRAINDICATIONS

Valium is 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. Valium is also contraindicated in patients withmyasthenia gravis, severe respiratory insufficiency, severe hepatic insufficiency, andsleep apneasyndrome. It may be used in patients withopen-angle glaucomawho are receiving appropriate therapy, but is contraindicated in acute narrow-angleglaucoma.

CLINICAL PHARMACOLOGY

安定is a benzodiazepine that exerts anxiolytic, sedative, muscle-relaxant, anticonvulsant and amnestic effects. Most of these effects are thought to result from a facilitation of the action of gamma aminobutyric acid (GABA), an inhibitoryneurotransmitterin the central nervous system.

Pharmacokinetics

Absorption

After oral administration >90% of diazepam is absorbed and the average time to achieve peak plasma concentrations is 1 – 1.5 hours with a range of 0.25 to 2.5hours. Absorption is delayed and decreased when administered with a moderate fat meal. In the presence of food mean lag times are approximately 45 minutes as compared with 15 minutes when fasting. There is also an increase in the average time to achieve peak concentrations to about 2.5 hours in the presence of food as compared with 1.25 hours when fasting. This results in an average decrease in Cmax of 20% in addition to a 27% decrease in AUC (range 15% to 50%) when administered with food.

Distribution

安定and its metabolites are highly bound to plasma proteins (diazepam 98%). Diazepam and its metabolites cross the blood-brain and placental barriers and are also found in breast milk in concentrations approximately one tenth of those in maternal plasma (days 3 to 9 post-partum). In young healthy males, the volume of distribution at steady-state is 0.8 to 1.0 L/kg. The decline in the plasma concentration-time profile after oral administration is biphasic. The initial distribution phase has a half-life of approximately 1 hour, although it may range up to >3 hours.

Metabolism

安定is N-demethylated by CYP3A4 and 2C19 to the active metabolite N-desmethyldiazepam and is hydroxylated by CYP3A4 to the active metabolite temazepam. N-desmethyldiazepam and temazepam are both further metabolized to oxazepam. Temazepam and oxazepam are largely eliminated by glucuronidation.

Elimination

初始ph值分布ase is followed by a prolonged terminal elimination phase (half-life up to 48 hours). The terminal elimination half-life of the active metabolite N-desmethyldiazepam is up to 100 hours. Diazepam and its metabolites are excreted mainly in the urine, predominantly as their glucuronide conjugates. The clearance of diazepam is 20 to 30 mL/min in young adults. Diazepam accumulates upon multiple dosing and there is some evidence that the terminal elimination half-life is slightly prolonged.

Pharmacokinetics In Special Populations

Children

In children 3 -8 years old the mean half-life of diazepam has been reported to be 18 hours.

Newborns

In full term infants, elimination half-lives around 30 hours have been reported, with a longer average half-life of 54 hours reported in premature infants of 28 -34 weeks gestational age and 8 -81 days post-partum. In both premature and full term infants the active metabolite desmethyldiazepam shows evidence of continued accumulation compared to children. Longer half-lives in infants may be due to incomplete maturation of metabolic pathways.

Geriatric

Elimination half-life increases by approximately 1 hour for each year of age beginning with a half-life of 20 hours at 20 years of age. This appears to be due to an increase in volume of distribution with age and a decrease in clearance. Consequently, the elderly may have lower peak concentrations, and on multiple dosing higher trough concentrations. It will also take longer to reach steady-state. Conflicting information has been published on changes of plasma protein binding in the elderly. Reported changes in free drug may be due to significant decreases in plasma proteins due to causes other than simplyaging.

Hepatic Insufficiency

在轻度和中度肝硬化,平均半衰期is increased. The average increase has been variously reported from 2-fold to 5-fold, with individual half-lives over 500 hours reported. There is also an increase in volume of distribution, and average clearance decreases by almost half. Mean half-life is also prolonged with hepatic fibrosis to 90 hours (range 66 -104 hours), with chronic active hepatitis to 60 hours (range 26 -76 hours), and with acute viral hepatitis to 74 hours (range 49 -129). In chronic active hepatitis, clearance is decreased by almost half.

PATIENT INFORMATION

安定
(dye-AZ-e-pam) 10 mg Tablets

What is the most important information I should know about diazepam tablets?

安定tablets are a benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma and death.
安定tablets can make you sleepy or dizzy, and can slow your thinking and motor skills.

不t drive, operate heavy machinery, or do other dangerous activities until you know how diazepam tablets affect you.
不t drink alcohol or take other drugs that may make you sleepy or dizzy while taking diazepam tablets without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, diazepam tablets may make your sleepiness or dizziness much worse.

不t take more diazepam tablets than prescribed.

What are diazepam tablets?

• 安定tablets are a prescription medicine used:
• to treat anxiety disorders
• for the short-term relief of the symptoms of anxiety
• to relieve the symptoms of alcohol withdrawal including agitation, shakiness (tremor), sudden and severe mental or nervous system changes (delirium tremens) and seeing or hearing things that others do not see or hear (hallucinations)
• along with other medicines for the relief of muscle spasms
• along with other medicines to treatseizure disorders

安定tablets are a federal controlled substance (C-IV) because it can be abused or lead to dependence. Keep diazepam tablets in a safe place to prevent misuse and abuse. Selling or giving away diazepam tablets may harm others, and is against the law. Tell your healthcare provider if you have abused or been dependent on alcohol, prescription medicines or street drugs.

It is not known if diazepam tablets are safe and effective in children under 6 months of age.

It is not known if diazepam tablets are safe and effective for use longer than 4 months.

不t take diazepam tablets if you:

• are allergic to diazepam or any of the ingredients in diazepam tablets. See the end of this Medication Guide for a complete list of ingredients in diazepam tablets.
• have a disease that can cause muscle weakness called myasthenia gravis
• have severe breathing problems (severe respiratory insufficiency)
• have severe liver problems
• have a sleep problem called sleepapneasyndrome

Before you take diazepam tablets, tell your healthcare provider about all of your medical conditions, including if you:

• have or have had depression, mood problems, or suicidal thoughts or behavior
• have lung disease or breathing problems
• have liver or kidney problems
• are pregnant or plan to become pregnant. Diazepam tablets may harm your unborn baby. You and your healthcare provider should decide if you should take diazepam tablets while you are pregnant.
• 母乳喂养母乳喂养或计划。安定passes into your breast milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take diazepam tablets. Do not breastfeed while taking diazepam tablets.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking diazepam tablets with certain other medicines can cause side effects or affect how well diazepam tablets or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider.

How should I take diazepam tablets?

Take diazepam tablets exactly as your healthcare provider tells you to take them. Your healthcare provider will tell you how many diazepam tablets to take and when to take them.
Talk to your healthcare provider about slowly stopping diazepam tablets to avoid withdrawal symptoms.
If you take too many diazepam tablets, call your healthcare provider or go to the nearest hospital emergency room right away.

What should I avoid while taking diazepam tablets?

安定药片可以使你昏昏欲睡。不t drive a car or operate heavy machinery until you know how diazepam tablets affect you.
You should not drink alcohol while taking diazepam tablets. Drinking alcohol can increase your chances of having serious side effects.

What are the possible side effects of diazepam tablets?

• 安定tablets may cause serious side effects, including:
• See “What is the most important information I should know about diazepam tablets?”
• Seizures. Taking diazepam tablets with other medicines used to treat epilepsy can cause an increase in the number or severity of grand mal seizures.
• Withdrawal symptoms. You may have withdrawal symptoms if you stop taking diazepam tablets suddenly. Withdrawal symptoms can be serious and include seizures. Mild withdrawal symptoms include a depressed mood and trouble sleeping. Talk to your healthcare provider about slowly stopping diazepam tablets to avoid withdrawal symptoms.
• Like other antiepileptic drugs, diazepam tablets may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.

Call your healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:

• thoughts about suicide or dying
• new or worse anxiety
• trouble sleeping (insomnia)
• acting on dangerous impulses
• attempts to commit suicide
• feeling agitated or restless
• new or worse irritability
• an extreme increase in activity and talking (mania)
• new or worse depression
• panic attacks
• acting aggressive, being angry, or violent
• other unusual changes in behavior or mood

我怎么能看隋的早期症状吗cidal thoughts and actions?

Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
Keep all follow-up visits with your healthcare provider as scheduled.

Call your healthcare provider between visits as needed, especially if you are worried about symptoms. Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.

Abuse and dependence. Taking diazepam tablets can cause physical and psychological dependence. Physical and psychological dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical and psychological dependence and drug addiction.

The most common side effects of diazepam tablets include:

• drowsiness
• muscle weakness
• fatigue
• loss of control of body movements (ataxia)

These are not all the possible side effects of diazepam tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Teva Pharmaceuticals USA, Inc. at 1-866-832-8537.

How should I store diazepam tablets?

Store diazepam tablets in a tightly closed container between 68°F to 77°F (20°C to 25°C) and out of the light.
Keep diazepam tablets and all medicines out of the reach of children.

General information about the safe and effective use of diazepam tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use diazepam tablets for a condition for which they were not prescribed. Do not give diazepam tablets to other people, even if they have the same symptoms that you have. They may harm them. You can ask your pharmacist or healthcare provider for information about diazepam tablets that is written for health professionals.

What are the ingredients in diazepam tablets?

Active ingredient: diazepam

Inactive ingredients: anhydrous lactose, colloidalsilicondioxide; colorants: 5 mg only (D&C Yellow No. 10 aluminum lake and FD&C Yellow No. 6); 10 mg only (FD&C Blue No. 1 aluminum lake); magnesium stearate, microcrystalline cellulose, pregelatinized corn starch, and sodium starch glycolate