C-IV

Rx only

Oxazepam, USP is the first of a chemical series of compounds known as the 3-hydroxybenzodiazepinones. A therapeutic agent providing versatility and flexibility in control of common emotional disturbances, this product exerts prompt action in a wide variety of disorders associated with anxiety, tension, agitation, and irritability, and anxiety associated with depression. In tolerance and toxicity studies on several animal species, this product reveals significantly greater safety factors than related compounds (chlordiazepoxide and diazepam) and manifests a wide separation of effective doses and doses inducing side effects.

Oxazepam capsules, USP contain 10 mg, 15 mg or 30 mg oxazepam, USP. The following inactive ingredients are contained in these capsules: corn starch, croscarmellose sodium, FD&C Red #40, gelatin, hypromellose, lactose (monohydrate), magnesium stearate, methylparaben, propylparaben, sodium lauryl sulfate, titanium dioxide, and other inert ingredients. The 10 mg capsule also contains D&C Red #28. The 15 mg capsule also contains D&C Yellow #10. The 30 mg capsule also contains D&C Red #28 and FD&C Blue #1.

Oxazepam, USP is 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one. A white crystalline powder with a molecular weight of 286.72, its structural formula is as follows:

Pharmacokinetic testing in 12 volunteers demonstrated that a single 30 mg dose of a capsule, tablet or suspension will result in an equivalent extent of absorption. For the capsule and tablet, peak plasma levels averaged 450 mg/mL and were observed to occur about 3 hours after dosing. The mean elimination half-life for oxazepam was approximately 8.2 hours (range 5.7 to 10.9 hours).

This product has a single, major inactive metabolite in man, a glucuronide excreted in the urine.

Age (less than 80 years old) does not appear to have a clinically significant effect on oxazepam kinetics. A statistically significant increase in elimination half-life in the very elderly (greater than 80 years of age) as compared to younger subjects has been reported, due to a 30% increase in volume of distribution, as well as a 50% reduction in unbound clearance of oxazepam in the very elderly [see PRECAUTIONS: Geriatric Use].

Oxazepam capsules are 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.

Anxiety associated with depression is also responsive to oxazepam therapy.

This product has been found particularly useful in the management of anxiety, tension, agitation and irritability in older patients.

Alcoholics with acute tremulousness, inebriation, or with anxiety associated with alcohol withdrawal are responsive to therapy.

The effectiveness of oxazepam 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.

History of previous hypersensitivity reaction to oxazepam. Oxazepam is not indicated in psychoses.

Risks from Concomitant Use with Opioids: Concomitant use of benzodiazepines, including oxazepam, 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 oxazepam 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 oxazepam than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking oxazepam, 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 oxazepam is used with opioids. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined [see PRECAUTIONS: Drug Interactions].

Abuse, Misuse, and Addiction: The use of benzodiazepines, including oxazepam, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death [see DRUG ABUSE AND DEPENDENCE: Abuse].

Before prescribing oxazepam and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of oxazepam, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of oxazepam 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: To reduce the risk of withdrawal reactions, use a gradual taper to discontinue oxazepam or reduce the dosage (a patient-specific plan should be used to taper the dose) [see DOSAGE AND ADMINISTRATION: Discontinuation or Dosage Reduction of Oxazepam].

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 oxazepam, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of oxazepam after continued use, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) [see DRUG ABUSE AND DEPENDENCE: Dependence].

Protracted Withdrawal Syndrome

In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months [see DRUG ABUSE AND DEPENDENCE: Dependence].

As with other CNS-acting drugs, patients should be cautioned against driving automobiles or operating dangerous machinery until it is known that they do not become drowsy or dizzy on oxazepam therapy.

Patients should be warned that the effects of alcohol or other CNS-depressant drugs may be additive to those of Oxazepam, possibly requiring adjustment of dosage or elimination of such agents.

The necessity for discontinuation of therapy due to undesirable effects has been rare. Transient mild drowsiness is commonly seen in the first few days of therapy. If it persists, the dosage should be reduced. In few instances, dizziness, vertigo, headache and rarely syncope have occurred either alone or together with drowsiness. Mild paradoxical reactions; i.e., excitement, stimulation of affect, have been reported in psychiatric patients; these reactions may be secondary to relief of anxiety and usually appear in the first two weeks of therapy.

Other side effects occurring during oxazepam therapy include rare instances of minor diffuse skin rashes - morbilliform, urticarial, and maculopapular, nausea, lethargy, edema, slurred speech, tremor, and altered libido. Such side effects have been infrequent and are generally controlled with reduction of dosage. A case of an extensive fixed drug eruption also has been reported.

Although rare, leukopenia and hepatic dysfunction including jaundice have been reported during therapy. Periodic blood counts and liver-function tests are advisable.

Ataxia with oxazepam has been reported in rare instances and does not appear to be specifically related to dose or age.

Although the following side reactions have not as yet been reported with oxazepam, they have occurred with related compounds (chlordiazepoxide and diazepam): paradoxical excitation with severe rage reactions, hallucinations, menstrual irregularities, change in EEG pattern, blood dyscrasias including agranulocytosis, blurred vision, diplopia, incontinence, stupor, disorientation, fever and euphoria.

Transient amnesia or memory impairment has been reported in association with the use of benzodiazepines.

To report SUSPECTED ADVERSE EVENTS, contact Actavis at 1-800-432-8534 or FDA at 1-800-FDA-1088 or http://www.fda.gov/ for voluntary reporting of adverse reactions.

Controlled Substance

Oxazepam is a schedule IV controlled substance.

Abuse

Oxazepam 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 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

Oxazepam 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 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 [see WARNINGS: Dependence and Withdrawal Reactions].

To reduce the risk of withdrawal reactions, use a gradual taper to discontinue oxazepam or reduce the dosage [see DOSAGE AND ADMINISTRATION: Discontinuation or Dosage Reduction of Oxazepam and 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 oxazepam 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 oxazepam may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

In the management of overdosage with any drug, it should be borne in mind that multiple agents may have been taken.

Because of the flexibility of this product and the range of emotional disturbances responsive to it, dosage should be individualized for maximum beneficial effects.

This product is not indicated in pediatric patients under 6 years of age. Absolute dosage for pediatric patients 6 to 12 years of age is not established.

Discontinuation or Dosage Reduction of Oxazepam

To reduce the risk of withdrawal reactions, use a gradual taper to discontinue oxazepam or reduce the dosage. If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level. Subsequently decrease the dosage more slowly [see WARNINGS: Dependence and Withdrawal Reactions and DRUG ABUSE AND DEPENDENCE: Dependence].

Oxazepam Capsules, USP are available as follows:

10 mg — Each pink opaque gelatin #4 capsule printed with and 067 in black ink on both cap and body contains 10 mg of Oxazepam, USP. Capsules are supplied in bottles of 100 (NDC 0228-2067-10) and 500 (NDC 0228-2067-50).

15 mg — Each red opaque gelatin #4 capsule printed with and 069 in black ink on both cap and body contains 15 mg of Oxazepam, USP. Capsules are supplied in bottles of 100 (NDC 0228-2069-10) and 500 (NDC 0228-2069-50).

30 mg — Each maroon opaque gelatin #4 capsule printed with and 073 in blue ink on both cap and body contains 30 mg of Oxazepam, USP. Capsules are supplied in bottles of 100 (NDC 0228-2073-10).

Keep tightly closed.

Dispense in a tight, light-resistant container as defined in the USP.

Store at 25ºC (77ºF); excursions permitted to 15ºC to 30ºC (59ºF to 86ºF).

In mice, oxazepam exerts an anticonvulsant (anti-pentylenetetrazol) activity at 50-percent-effective doses of about 0.6 mg/kg orally. (Such anticonvulsant activity of benzodiazepines correlates with their tranquilizing properties.) To produce ataxia (rotabar test) and sedation (abolition of spontaneous motor activity), the 50-percent-effective doses of this product are greater than 5 mg/kg orally. Thus, about ten times the therapeutic (anticonvulsant) dose must be given before ataxia ensues, indicating a wide separation of effective doses and doses inducing side effects.

In evaluation of antianxiety activity of compounds, conflict behavioral tests in rats differentiate continuous response for food in the presence of anxiety-provoking stress (shock) from drug-induced motor incoordination. This product shows significant separation of doses required to relieve anxiety and doses producing sedation or ataxia. Ataxia-producing doses exceed those of related CNS-acting drugs.

Acute oral LD50 in mice is greater than 5000 mg/kg, compared to 800 mg/kg for a related compound (chlordiazepoxide).

Subacute toxicity studies in dogs for four weeks at 480 mg/kg daily showed no specific changes; at 960 mg/kg, two out of eight died with evidence of circulatory collapse. This wide margin of safety is significant compared to chlordiazepoxide HCl, which showed nonspecific changes in six dogs at 80 mg/kg. On chlordiazepoxide, two out of six died with evidence of circulatory collapse at 127 mg/kg, and six out of six died at 200 mg/kg daily. Chronic toxicity studies of oxazepam in dogs at 120 mg/kg/day for 52 weeks produced no toxic manifestation.

Fatty metamorphosis of the liver has been noted in six-week toxicity studies in rats given this product at 0.5% of the diet. Such accumulations of fat are considered reversible, as there is no liver necrosis or fibrosis. Breeding studies in rats through two successive litters did not produce fetal abnormality.

Oxazepam has not been adequately evaluated for mutagenic activity.

In a carcinogenicity study, oxazepam was administered with diet to rats for two years. Male rats receiving 30 times the maximum human dose showed a statistical increase, when compared to controls, in benign thyroid follicular cell tumors, testicular interstitial cell adenomas, and prostatic adenomas. An earlier published study reported that mice fed dietary dosages of 35 or 100 times the human daily dose of oxazepam for 9 months developed a dose-related increase in liver adenomas.1 In an independent analysis of some of the microscopic slides from this mouse study, several of these tumors were classified as liver carcinomas. At this time, there is no evidence that clinical use of oxazepam is associated with tumors.

1. FOX, K.A, LAHCEN, R.B.: Liver-cell Adenomas and Peliosis Hepatis in Mice Associated with Oxazepam. Res. Commun. Chem. Pathol. Pharmacol. 8:481-488, 1974.
   

Manufactured by:
Actavis Elizabeth LLC
Elizabeth, NJ 07207 USA

Distributed by:
Actavis Pharma, Inc.
Parsippany, NJ 07054 USA

Rev. B 1/2021

NDC 0228-2067-10

Oxazepam Capsules, USP 10 mg CIV

PHARMACIST: Dispense the accompanying Medication Guide to each patient.

100 Capsules

Rx only

NDC 0228-2069-10

Oxazepam Capsules, USP 15 mg CIV

PHARMACIST: Dispense the accompanying Medication Guide to each patient.

100 Capsules

Rx only

NDC 0228-2073-10

Oxazepam Capsules, USP 30 mg CIV

PHARMACIST: Dispense the accompanying Medication Guide to each patient.

100 Capsules

Rx only