TRANXENE

Chemically, clorazepate dipotassium USP is a benzodiazepine.

The empirical formula is

C 16 H 11 ClK 2 N 2 O 4; the molecular weight is 408.92; 1 H -1, 4-Benzodiazepine-3-carboxylic acid, 7-chloro-2,3-dihydro-2-oxo-5-phenyl-, potassium salt compound with potassium hydroxide (1:1) and the structural formula may be represented as follows: The compound occurs as a fine, light yellow, practically odorless powder.

It is insoluble in the common organic solvents, but very soluble in water.

Aqueous solutions are unstable, clear, light yellow, and alkaline.

Clorazepate dipotassium tablets

USP contain 3.75 mg, 7.5 mg or 15 mg of clorazepate dipotassium USP.

In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, magnesium oxide heavy, magnesium stearate, microcrystalline cellulose, potassium carbonate anhydrous, potassium chloride, talc and the following coloring agents: 3.75 mg.

Lake and

Lake 7.5 mg.

Barium Lake and

Lake 15 mg.

Use in treatment: anxiety disorders (short term) of alcohol withdrawal symptoms in addicted persons (AAS) as an adjunct drug for the treatment of partial epilepsy seizures.

The treatment is to be treated in the form of a therapeutic product that may cause harmful effects on the infant, so the process must be avoided during the period of treatment.

The effectiveness or safety of the treatment in children under nine years of age is not proven.

Care must be taken when the treatment is used in older persons, because of their increased sensitivity to the side effects that the treatment may cause.

Pharmacologically, clorazepate dipotassium has the characteristics of the benzodiazepines.

It has depressant effects on the central nervous system.

The primary metabolite, nordiazepam, quickly appears in the blood stream.

The serum half-life is about 2 days.

The drug is metabolized in the liver and excreted primarily in the urine.

Studies in healthy men have shown that clorazepate dipotassium has depressant effects on the central nervous system.

Prolonged administration of single daily doses as high as 120 mg was without toxic effects.

Abrupt cessation of high doses was followed in some patients by nervousness, insomnia, irritability, diarrhea, muscle aches, or memory impairment.

Since orally administered clorazepate dipotassium is rapidly decarboxylated to form nordiazepam, there is essentially no circulating parent drug.

Nordiazepam, the primary metabolite, quickly appears in the blood and is eliminated from the plasma with an apparent half-life of about to 50 hours.

Plasma levels of nordiazepam increase proportionally with clorazepate dipotassium dose and show moderate accumulation with repeated administration.

The protein binding of nordiazepam in plasma is high (97 to 98%).

Within 10 days after oral administration of a 15 mg (50 μCi) dose of 14 C-clorazepate dipotassium to two volunteers, 62 to 67% of the radioactivity was excreted in the urine and to 19% was eliminated in the feces.

Both subjects were still excreting measurable amounts of radioactivity in the urine (about 1% of the 14 C-dose) on day ten.

Nordiazepam is further metabolized by hydroxylation.

The major urinary metabolite is conjugated oxazepam (3-hydroxynordiazepam), and smaller amounts of conjugated p-hydroxynordiazepam and nordiazepam are also found in the urine.

The treatment is from the benzodiazepine family, which has a tranquilizing and sleeping effect, where it is associated with its own brain receptors, which stimulates the development of a "gamma amnoborect acid" that has a tranquilizing effect, and helps control the excess neurons in the brain that cause epilepsy.

The treatment may cause mental and physical addiction; treatment is administered only by a specialist prescription and not advised for long periods of time.

The side effect most frequently reported was drowsiness.

Less commonly reported (in descending order of occurrence) were: dizziness, various gastrointestinal complaints, nervousness, blurred vision, dry mouth, headache, and mental confusion.

Other side effects included insomnia, transient skin rashes, fatigue, ataxia, genitourinary complaints, irritability, diplopia, depression, tremor, and slurred speech.

There have been reports of abnormal liver and kidney function tests and of decrease in hematocrit.

Decrease in systolic blood pressure has been observed.

To report SUSPECTED ADVERSE

REACTIONS, contact Taro Pharmaceuticals U.S.A., Inc.fda.gov/medwatch.

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: Dependence and Withdrawal Reactions.

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 management.

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

Consider contacting the Poison

Help line or a medical toxicologist for additional overdosage management recommendations.

Concomitant use of benzodiazepines, including clorazepate dipotassium, 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 clorazepate dipotassium concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation.

In patients already receiving an opioid analgesic, prescribe a lower initial dose of clorazepate dipotassium than indicated in the absence of an opioid and titrate based on clinical response.

If an opioid is initiated in a patient already taking clorazepate dipotassium, 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 clorazepate dipotassium 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.

Abuse, Misuse, and Addiction The use of benzodiazepines, including clorazepate dipotassium, 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.

Before prescribing clorazepate dipotassium and throughout treatment, assess each patient's risk for abuse, misuse, and addiction (e.g., using a standardized screening tool).

Use of clorazepate dipotassium, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of clorazepate dipotassium 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.

To reduce the risk of withdrawal reactions, use a gradual taper to discontinue clorazepate dipotassium or reduce the dosage (a patient-specific plan should be used to taper the dose) See DOSAGE AND ADMINISTRATION: Discontinuation of Dosage Reduction of Clorazepate Dipotassium.

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.

The continued use of benzodiazepines, including clorazepate dipotassium, may lead to clinically significant physical dependence.

Abrupt discontinuation or rapid dosage reduction of clorazepate dipotassium after continued use, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) .

In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months.

Use in Depressive Neuroses or Psychotic Reactions Clorazepate dipotassium tablets are not recommended for use in depressive neuroses or in psychotic reactions.

Because of the lack of sufficient clinical experience, clorazepate dipotassium tablets are not recommended for use in patients less than 9 years of age.

Patients taking clorazepate dipotassium tablets should be cautioned against engaging in hazardous occupations requiring mental alertness, such as operating dangerous machinery including motor vehicles.

Since clorazepate dipotassium has a central nervous system depressant effect, patients should be advised against the simultaneous use of other CNS depressant drugs, and cautioned that the effects of alcohol may be increased.

Antiepileptic drugs (AEDs), including clorazepate dipotassium, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication.

Patients treated with any

AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono - and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo.

In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated.

There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed.

Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed.

The finding of increased risk with

AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication.

The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.

Table 1 shows absolute and relative risk by indication for all evaluated AEDs.

Table 1: Risk by indication for antiepileptic drugs in the pooled analysis Indication Placebo Patients with Events Per 1000 Patients Drug Patients with Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing clorazepate dipotassium tablets or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness.

Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.

Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.

Behaviors of concern should be reported immediately to healthcare providers.

Use of clorazepate dipotassium 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 the neonate.

Monitor neonates exposed to clorazepate dipotassium during pregnancy or labor for signs of sedation and monitor neonates exposed to clorazepate dipotassium during pregnancy for signs of withdrawal; manage these neonates accordingly.

Clorazepate dipotassium tablets are contraindicated in patients with a known hypersensitivity to the drug and in those with acute narrow angle glaucoma.

Clorazepate dipotassium tablets are administered orally in divided doses.

The usual daily dose is 30 mg. The dose should be adjusted gradually within the range of to 60 mg daily in accordance with the response of the patient.

In elderly or debilitated patients it is advisable to initiate treatment at a daily dose of 7.5 to 15 mg. Clorazepate dipotassium tablets may also be administered in a single dose daily at bedtime; the recommended initial dose is 15 mg. After the initial dose, the response of the patient may require adjustment of subsequent dosage.

Lower doses may be indicated in the elderly patient.

Drowsiness may occur at the initiation of treatment and with dosage increment.

For the Symptomatic Relief of Acute Alcohol Withdrawal The following dosage schedule is recommended: 1st 24 hours (Day 1) 30 mg initially; followed by to 60 mg in divided doses 2nd 24 hours (Day 2) 45 to 90 mg in divided doses 3rd 24 hours (Day 3) 22.5 to 45 mg in divided doses Day 4 15 to 30 mg in divided doses Thereafter, gradually reduce the daily dose to 7.5 to 15 mg. Discontinue drug therapy as soon as patient's condition is stable.

The maximum recommended total daily dose is 90 mg. Avoid excessive reductions in the total amount of drug administered on successive days.

In order to minimize drowsiness, the recommended initial dosages and dosage increments should not be exceeded.

The maximum recommended initial dose in patients over 12 years old is 7.5 mg three times a day. Dosage should be increased by no more than 7.5 mg every week and should not exceed 90 mg/day. Children (9 to 12 years) The maximum recommended initial dose is 7.5 mg two times a day. Dosage should be increased by no more than 7.5 mg every week and should not exceed 60 mg/day. Discontinuation or Dosage Reduction of Clorazepate Dipotassium To reduce the risk of withdrawal reactions, use a gradual taper to discontinue clorazepate dipotassium or reduce the dosage.

If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level.

Subsequently decrease the dosage more slowly See WARNINGS and DRUG ABUSE AND DEPENDENCE.

USP are available as tablets containing 3.75 mg, 7.5 mg or 15 mg of clorazepate dipotassium, USP.

The 3.75 mg tablets are round flat beveled edge, pale violet colored slightly mottled tablet.

One side is scored and engraved with "T" above the score and "45" below the score.

Other side is plain.

Bottles of 100 (NDC 51672-4042-1) Bottles of 500 (NDC 51672-4042-2) Bottles of 1,000 (NDC 51672-4042-3) The 7.5 mg tablets are round flat beveled edge, orange colored, slightly mottled tablet.

One side is scored and engraved with "T" above the score and "46" below the score.

Bottles of 100 (NDC 51672-4043-1) Bottles of 500 (NDC 51672-4043-2) Bottles of 1,000 (NDC 51672-4043-3) The 15 mg tablets are round flat beveled edge, pale pink colored, slightly mottled tablet.

One side is scored and engraved with "T" above the score and"47" below the score.

Bottles of 100 (NDC 51672-4044-1) Bottles of 500 (NDC 51672-4044-2) Bottles of 1,000 (NDC 51672-4044-3) Recommended storage Protect from moisture.

Keep bottle tightly closed.

Store at 20° to 25°C (68° to 77°F) .

Dispense in a

USP tight, light-resistant container.

Recommended storage

Protect from moisture.

Keep bottle tightly closed.

Store at 20° to 25°C (68° to 77°F) .

Dispense in a

USP tight, light-resistant container.