Azo-P

Anxiety Disorders

Azo-P Tablets (Azo-P) are indicated for the management of anxiety disorder (a condition corresponding most closely to the APA Diagnostic and Statistical Manual [DSM-IIIR] diagnosis of generalized anxiety disorder) or the short-term relief of symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic.

Generalized anxiety disorder is characterized by unrealistic or excessive anxiety and worry (apprehensive expectation) about two or more life circumstances, for a period of 6 months or longer, during which the person has been bothered more days than not by these concerns. At least 6 of the following 18 symptoms are often present in these patients: Motor Tension (trembling, twitching, or feeling shaky; muscle tension, aches, or soreness; restlessness; easy fatigability); Autonomic Hyperactivity (shortness of breath or smothering sensations; palpitations or accelerated heart rate; sweating, or cold clammy hands; dry mouth; dizziness or light-headedness; nausea, diarrhea, or other abdominal distress; flushes or chills; frequent urination; trouble swallowing or 'lump in throat'); Vigilance and Scanning (feeling keyed up or on edge; exaggerated startle response; difficulty concentrating or 'mind going blank' because of anxiety; trouble falling or staying asleep; irritability). These symptoms must not be secondary to another psychiatric disorder or caused by some organic factor.

Anxiety associated with depression is responsive to Azo-P.

Panic Disorder

Azo-P is also indicated for the treatment of panic disorder, with or without agoraphobia.

Studies supporting this claim were conducted in patients whose diagnoses corresponded closely to the DSM-III-R/IV criteria for panic disorder.

Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, ie, a discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.

Demonstrations of the effectiveness of Azo-P by systematic clinical study are limited to 4 months duration for anxiety disorder and 4 to 10 weeks duration for panic disorder; however, patients with panic disorder have been treated on an open basis for up to 8 months without apparent loss of benefit. The physician should periodically reassess the usefulness of the drug for the individual patient.

Azo-P (Azo-P) is in a group of drugs called benzodiazepines (ben-zoe-dye-AZE-eh-peens). Azo-P affects chemicals in the brain that may become unbalanced and cause anxiety.

Azo-P is used to treat anxiety disorders, panic disorders, and anxiety caused by depression.

Azo-P may also be used for other purposes not listed in this medication guide.

Azo-P XR tablets may be administered once daily, preferably in the morning. The tablets should be taken intact; they should not be chewed, crushed, or broken.

The suggested total daily dose ranges between 3 to 6 mg/day. Dosage should be individualized for maximum beneficial effect. While the suggested total daily dosages given will meet the needs of most patients, there will be some patients who require doses greater than 6 mg/day. In such cases, dosage should be increased cautiously to avoid adverse effects.

Dosing in Special Populations

In elderly patients, in patients with advanced liver disease, or in patients with debilitating disease, the usual starting dose of Azo-P XR is 0.5 mg once daily. This may be gradually increased if needed and tolerated. The elderly may be especially sensitive to the effects of benzodiazepines.

Dose Titration

Treatment with Azo-P XR may be initiated with a dose of 0.5 mg to 1 mg once daily. Depending on the response, the dose may be increased at intervals of 3 to 4 days in increments of no more than 1 mg/day. Slower titration to the dose levels may be advisable to allow full expression of the pharmacodynamic effect of Azo-P XR.

Generally, therapy should be initiated at a low dose to minimize the risk of adverse responses in patients especially sensitive to the drug. Dose should be advanced until an acceptable therapeutic response (ie, a substantial reduction in or total elimination of panic attacks) is achieved, intolerance occurs, or the maximum recommended dose is attained.

Dose Maintenance

In controlled trials conducted to establish the efficacy of Azo-P XR tablets in panic disorder, doses in the range of 1 to 10 mg/day were used. Most patients showed efficacy in the dose range of 3 to 6 mg/day. Occasional patients required as much as 10 mg/day to achieve a successful response.

The necessary duration of treatment for panic disorder patients responding to Azo-P XR is unknown. However, periodic reassessment is advised. After a period of extended freedom from attacks, a carefully supervised tapered discontinuation may be attempted, but there is evidence that this may often be difficult to accomplish without recurrence of symptoms and/or the manifestation of withdrawal phenomena.

Dose Reduction

Because of the danger of withdrawal, abrupt discontinuation of treatment should be avoided.

In all patients, dosage should be reduced gradually when discontinuing therapy or when decreasing the daily dosage. Although there are no systematically collected data to support a specific discontinuation schedule, it is suggested that the daily dosage be decreased by no more than 0.5 mg every three days. Some patients may require an even slower dosage reduction.

In any case, reduction of dose must be undertaken under close supervision and must be gradual. If significant withdrawal symptoms develop, the previous dosing schedule should be reinstituted and, only after stabilization, should a less rapid schedule of discontinuation be attempted. In a controlled postmarketing discontinuation study of panic disorder patients which compared this recommended taper schedule with a slower taper schedule, no difference was observed between the groups in the proportion of patients who tapered to zero dose; however, the slower schedule was associated with a reduction in symptoms associated with a withdrawal syndrome. It is suggested that the dose be reduced by no more than 0.5 mg every three days, with the understanding that some patients may benefit from an even more gradual discontinuation. Some patients may prove resistant to all discontinuation regimens.

Switch from Azo-P (immediate-release) tablets to Azo-P XR (extended-release) tablets

Patients who are currently being treated with divided doses of Azo-P (immediate-release) tablets, for example 3 to 4 times a day, may be switched to Azo-P XR tablets at the same total daily dose taken once daily. If the therapeutic response after switching is inadequate, the dosage may be titrated as outlined above.

See also:
What is the most important information I should know about Azo-P?

Do not use Azo-P if you are pregnant. It could harm the unborn baby.

Do not use this medication if you are allergic to Azo-P or to other benzodiazepines, such as chlordiazepoxide (Librium), clorazepate (Tranxene), diazepam (Valium), lorazepam (Ativan), or oxazepam (Serax).

Before you take Azo-P, tell your doctor if you have asthma or other breathing problems, glaucoma, kidney or liver disease, a history of alcoholism, or a history of depression, suicidal thoughts, or addiction to drugs or alcohol.

Do not drink alcohol while taking Azo-P. This medication can increase the effects of alcohol.

Azo-P may be habit-forming and should be used only by the person for whom it was prescribed. Keep the medication in a secure place where others cannot get to it.

Use Azo-P as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Azo-P may be taken with or without food. If stomach upset occurs, take with food to reduce stomach irritation.
• Do not remove the blister from the outer pouch until you are ready to take Azo-P. Make sure that your hands are dry when you open the blister pack. Do not push the tablet through the foil. Peel back the foil on the blister pack and place the tablet on your tongue. The tablet dissolves quickly and can be swallowed with saliva. Azo-P may be taken with or without water. Take the tablet immediately after opening the blister pack. Do not store the removed tablet for future use. If you are only taking a half tablet for your dose, throw away the other half. Do not save it for later use.
• If you are taking Azo-P regularly, do not suddenly stop taking it without checking with your doctor. You may have an increased risk of side effects (eg, seizures). If you need to stop Azo-P or add a new medicine, your doctor will gradually lower your dose.
• Eating grapefruit or drinking grapefruit juice may affect the amount of Azo-P in your blood. Talk with your doctor before including grapefruit or grapefruit juice in your diet.
• If you miss a dose of Azo-P and you are using it regularly, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Azo-P.

This medication is used to treat the panic and anxiety symptoms associated with panic disorder. Azo-P belongs to a class of medications 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).

How to use Azo-P

Take this medication by mouth as directed by your doctor, usually once daily in the morning. Do not take with a high-fat meal because doing so can increase the risk of side effects. Do not crush or chew extended-release tablets. Doing so can release all of the drug at once, increasing the risk of side effects. Also, do not split the tablets unless they have a score line and your doctor or pharmacist tells you to do so. Swallow the whole or split tablet without crushing or chewing. Dosage is based on your medical condition, age, and response to treatment. Your dose may be gradually increased until the drug starts working well. Follow your doctor's instructions closely to reduce the risk of side effects.

This medication may cause withdrawal reactions, especially if it has been used regularly for a long time or in high doses. In such cases, withdrawal symptoms (such as seizures) may occur if you suddenly stop using this medication. To prevent withdrawal reactions, your doctor may reduce your dose gradually. Report any withdrawal reactions right away.

Along with its benefits, this medication may rarely cause abnormal drug-seeking behavior (addiction). This risk may be increased if you have abused alcohol or drugs in the past. Take this medication exactly as prescribed to lessen the risk of addiction.

When this medication is used for a long time, it may not work as well. Talk with your doctor if this medication stops working well.

Tell your doctor if your condition persists or worsens.

See also:
What other drugs will affect Azo-P?

The benzodiazepines, including Azo-P, produce additive CNS depressant effects when co-administered with other psychotropic medications, anticonvulsants, antihistaminics, ethanol, and other drugs which themselves produce CNS depression.

The steady state plasma concentrations of imipramine and desipramine have been reported to be increased an average of 31% and 20%, respectively, by the concomitant administration of Azo-P tablets in doses up to 4 mg/day. The clinical significance of these changes is unknown.

Drugs That Inhibit Azo-P Metabolism Via Cytochrome P450 3A: The initial step in Azo-P metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP 3A). Drugs which inhibit this metabolic pathway may have a profound effect on the clearance of Azo-P.

Drugs Demonstrated to be CYP 3A Inhibitors of Possible Clinical Significance on the Basis of Clinical Studies Involving Azo-P (caution is recommended during coadministration with Azo-P):

Drugs and other substances demonstrated to be CYP 3A inhibitors on the basis of clinical studies involving benzodiazepines metabolized similarly to Azo-P or on the basis of in vitro studies with Azo-P or other benzodiazepines (caution is recommended during coadministration with Azo-P): Available data from clinical studies of benzodiazepines other than Azo-P suggest a possible drug interaction with Azo-P for the following: diltiazem, isoniazid, macrolide antibiotics such as erythromycin and clarithromycin, and grapefruit juice. Data from in vitro studies of Azo-P suggest a possible drug interaction with Azo-P for the following: sertraline and paroxetine. Data from in vitro studies of benzodiazepines other than Azo-P suggest a possible drug interaction for the following: ergotamine, cyclosporine, amiodarone, nicardipine, and nifedipine. Caution is recommended during the coadministration of any of these with Azo-P.

See also:
What are the possible side effects of Azo-P?

The information included in the subsection on Adverse Events Observed in Short-Term, Placebo-Controlled Trials with Azo-P extended-release tablets is based on pooled data of five 6- and 8-week placebo-controlled clinical studies in panic disorder.

Adverse event reports were elicited either by general inquiry or by checklist, and were recorded by clinical investigators using terminology of their own choosing. The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment emergent if it occurred for the first time or worsened during therapy following baseline evaluation. In the tables and tabulations that follow, standard MedDRA terminology (version 4.0) was used to classify reported adverse events.

Adverse Events Observed in Short-Term, Placebo-Controlled Trials of Azo-P Extended-Release

Adverse Events Reported as Reasons for Discontinuation of Treatment in Placebo-Controlled Trials

Approximately 17% of the 531 patients who received Azo-P extended-release in placebo-controlled clinical trials for panic disorder had at least one adverse event that led to discontinuation compared to 8% of 349 placebo-treated patients. The most common events leading to discontinuation and considered to be drug-related (i.e., leading to discontinuation in at least 1% of the patients treated with Azo-P extended-release at a rate at least twice that of placebo) are shown in the following table.

Adverse Events Occurring at an Incidence of 1% or More Among Patients Treated with Azo-P Extended-Release

The prescriber should be aware that adverse event incidence cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with event incidence obtained from other clinical investigations involving different treatments, uses, and investigators. The cited values, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in the population studied.

The following table shows the incidence of treatment-emergent adverse events that occurred during 6- to 8-week placebo-controlled trials in 1% or more of patients treated with Azo-P extended-release where the incidence in patients treated with Azo-P extended-release was greater than the incidence in placebo-treated patients. The most commonly observed adverse events in panic disorder patients treated with Azo-P extended-release (incidence of 5% or greater and at least twice the incidence in placebo patients) were: sedation, somnolence, memory impairment, dysarthria, coordination abnormal, ataxia, libido decreased.

Other Adverse Events Observed During the Premarketing Evaluation of Azo-P Extended-Release Tablets

Following is a list of MedDRA terms that reflect treatment-emergent adverse events reported by 531 patients with panic disorder treated with Azo-P extended-release. All potentially important reported events are included except those already listed in the above table or elsewhere in labeling, those events for which a drug cause was remote, those event terms that were so general as to be uninformative, and those events that occurred at rates similar to background rates in the general population. It is important to emphasize that, although the events reported occurred during treatment with Azo-P extended-release, they were not necessarily caused by the drug. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on 1 or more occasions in at least l/l00 patients; infrequent adverse events are those occurring in less than l/100 patients but at least l/1000 patients; rare events are those occurring in fewer than l/1000 patients.

Cardiac disorders: Frequent: palpitation; Infrequent: sinus tachycardia

Ear and Labyrinth disorders: Frequent: Vertigo; Infrequent: tinnitus, ear pain

Eye disorders: Frequent: blurred vision; Infrequent: mydriasis, photophobia

Gastrointestinal disorders: Frequent: diarrhea, vomiting, dyspepsia, abdominal pain; Infrequent: dysphagia, salivary hypersecretion

General disorders and administration site conditions: Frequent: malaise, weakness, chest pains; Infrequent: fall, pyrexia, thirst, feeling hot and cold, edema, feeling jittery, sluggishness, asthenia, feeling drunk, chest tightness, increased energy, feeling of relaxation, hangover, loss of control of legs, rigors

Musculoskeletal and connective tissue disorders: Frequent: back pain, muscle cramps, muscle twitching

Nervous system disorders: Frequent: headache, dizziness, tremor; Infrequent: amnesia, clumsiness, syncope, hypotonia, seizures, depressed level of consciousness, sleep apnea syndrome, sleep talking, stupor

Psychiatric system disorders: Frequent: irritability, insomnia, nervousness, derealization, libido increased, restlessness, agitation, depersonalization, nightmare; Infrequent: abnormal dreams, apathy, aggression, anger, bradyphrenia, euphoric mood, logorrhea, mood swings, dysphonia, hallucination, homicidal ideation, mania, hypomania, impulse control, psychomotor retardation, suicidal ideation

Renal and urinary disorders: Frequent: difficulty in micturition; Infrequent: urinary frequency, urinary incontinence

Respiratory, thoracic, and mediastinal disorders: Frequent: nasal congestion, hyperventilation; Infrequent: choking sensation, epistaxis, rhinorrhea

Skin and subcutaneous tissue disorders: Frequent: sweating increased; Infrequent: clamminess, rash, urticaria

Vascular disorders: Infrequent: hypotension

The categories of adverse events reported in the clinical development program for Azo-P tablets in the treatment of panic disorder differ somewhat from those reported for Azo-P extended-release tablets because the clinical trials with Azo-P tablets and Azo-P extended-release tablets used different standard medical nomenclature for reporting the adverse events. Nevertheless, the types of adverse events reported in the clinical trials with Azo-P tablets were generally the same as those reported in the clinical trials with Azo-P extended-release tablets.

Discontinuation-Emergent Adverse Events Occurring at an Incidence of 5% or More Among Patients Treated with Azo-P Extended-Release

The following table shows the incidence of discontinuation-emergent adverse events that occurred during short-term, placebo-controlled trials in 5% or more of patients treated with Azo-P extended-release where the incidence in patients treated with Azo-P extended-release was two times greater than the incidence in placebo-treated patients.

There have also been reports of withdrawal seizures upon rapid decrease or abrupt discontinuation of Azo-P.

To discontinue treatment in patients taking Azo-P extended-release tablets, the dosage should be reduced slowly in keeping with good medical practice. It is suggested that the daily dosage of Azo-P extended-release tablets be decreased by no more than 0.5 mg every three days. Some patients may benefit from an even slower dosage reduction. In a controlled postmarketing discontinuation study of panic disorder patients which compared this recommended taper schedule with a slower taper schedule, no difference was observed between the groups in the proportion of patients who tapered to zero dose; however, the slower schedule was associated with a reduction in symptoms associated with a withdrawal syndrome.

As with all benzodiazepines, paradoxical reactions such as stimulation, increased muscle spasticity, sleep disturbances, hallucinations, and other adverse behavioral effects such as agitation, rage, irritability, and aggressive or hostile behavior have been reported rarely. In many of the spontaneous case reports of adverse behavioral effects, patients were receiving other CNS drugs concomitantly and/or were described as having underlying psychiatric conditions. Should any of the above events occur, Azo-P should be discontinued. Isolated published reports involving small numbers of patients have suggested that patients who have borderline personality disorder, a prior history of violent or aggressive behavior, or alcohol or substance abuse may be at risk for such events. Instances of irritability, hostility, and intrusive thoughts have been reported during discontinuation of Azo-P in patients with posttraumatic stress disorder.

Post Introduction Reports

Various adverse drug reactions have been reported in association with the use of Azo-P tablets since market introduction. The majority of these reactions were reported through the medical event voluntary reporting system. Because of the spontaneous nature of the reporting of medical events and the lack of controls, a causal relationship to the use of Azo-P tablets cannot be readily determined. Reported events include: gastrointestinal disorder, hypomania, mania, liver enzyme elevations, hepatitis, hepatic failure, Stevens-Johnson syndrome, angioedema, peripheral edema, hyperprolactinemia, gynecomastia, and galactorrhea.

Each extended-release tablet contains alprazolam 500 mcg. It also contains the following components: Lactose monohydrate, microcrystalline cellulose, docusate sodium, sodium benzoate, colloidal anhydrous silica, magnesium stearate, maize starch, F.D.&C. blue no. 2 aluminum lake, F.D. &C. yellow no. 6 aluminum lake, methylhydroxypropylcellulose.

Azo-P tablets contain Azo-P which is a triazolo analog of the1,4 benzodiazepine class of central nervous system active compound.

Azo-P is 8-chloro-1-methyl-6-phenyl-4H-striazolo[-4.3-aχ1,4] benzodiazepine.

Azo-P is a white crystalline powder, soluble in methanol or ethanol but withno appreciable solubility in water at physiological pH.