Consumer medicine information

GenRx Alprazolam [9009]

Alprazolam

BRAND INFORMATION

Brand name

GenRx Alprazolam

Active ingredient

Alprazolam

Schedule

S8

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using GenRx Alprazolam [9009].

What is in this leaflet

Read this leaflet carefully before taking your medicine. This leaflet answers some common questions about alprazolam. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the last page.  More recent information on this medicine may be available.

Ask your doctor or pharmacist:

  • if there is anything you do not understand in this leaflet,
  • if you are worried about taking your medicine, or
  • to obtain the most up-to-date information.

You can also download the most up to date leaflet from www.apotex.com.au.

All medicines have risks and benefits. Your doctor has weighed the risks of you using this medicine against the benefits he/she expects it will have for you.

Pharmaceutical companies cannot give you medical advice or an individual diagnosis.

Keep this leaflet with your medicine. You may want to read it again.

What this medicine is used for

The name of your medicine is GenRx Alprazolam. It contains the active ingredient alprazolam.

It is used to treat:

  • anxiety
  • panic attacks.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed this medicine for another reason.

This medicine is available only with a doctor's prescription.

How it works

Alprazolam belongs to a group of medicines called benzodiazepines. They are thought to work by their action on brain chemicals.

In general, benzodiazepines such as alprazolam should be taken for short periods only (for example, 2 to 4 weeks). Continuous long-term use is not recommended unless advised by your doctor. The use of benzodiazepines may lead to dependence on the medicine.

Use in children

This medicine should not be used in children.

Before you take this medicine

When you must not take it

Do not take this medicine if:

  • You have or have had any of the following:
    - severe muscle weakness known as myasthenia gravis
    - severe and chronic lung disease.
  • You are intolerant to lactose - these tablets contain lactose.
  • You are hypersensitive to, or have had an allergic reaction to, alprazolam, benzodiazepines or any of the ingredients listed at the end of this leaflet.
    Symptoms of an allergic reaction may include: cough, shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin; fainting; or hay fever-like symptoms.
    If you think you are having an allergic reaction, do not take any more of the medicine and contact your doctor immediately or go to the Accident and Emergency department at the nearest hospital.
  • The expiry date (EXP) printed on the pack has passed.
  • The packaging is torn, shows signs of tampering or it does not look quite right.

Before you start to take it

Before you start taking this medicine, tell your doctor if:

  1. You have allergies to:
  • any other medicines
  • any other substances, such as foods, preservatives or dyes.
  1. You have or have had any medical conditions, especially the following:
  • depression, psychosis or schizophrenia
  • fits or convulsions
  • liver, kidney or lung disease
  • glaucoma (high pressure in the eye)
  • low blood pressure.
  1. You have a history of alcohol or drug abuse, or find it difficult to stop taking medicines, drugs or drinking alcohol.
  2. You have a history of behavioural or mental conditions, with or without current medical treatment. These may increase your chance of behavioural side effects.
  3. You are currently pregnant or you plan to become pregnant. Do not take this medicine whilst pregnant until you and your doctor have discussed the risks and benefits involved.
  4. You are currently breastfeeding or you plan to breastfeed. Do not take this medicine whilst breastfeeding until you and your doctor have discussed the risks and benefits involved.
  5. You are planning to have surgery or an anaesthetic.
  6. You are currently receiving or are planning to receive dental treatment.
  7. You are taking or are planning to take any other medicines. This includes vitamins and supplements that are available from your pharmacy, supermarket or health food shop.

Taking other medicines

Some medicines may interact with alprazolam. These include:

  • sedatives (medicines used to produce calmness) or tranquilisers
  • sleeping tablets
  • medicines for depression
  • medicines used to treat certain mental and emotional conditions, such as antipsychotics
  • medicines for allergies, such as hay fever, e.g. antihistamines or cold tablets
  • pain relievers especially strong pain relievers, e.g. containing codeine or opioids (codeine-like medicines)
  • muscle relaxants
  • medicines to control fits or seizures
  • cimetidine (a medicine used to treat reflux and ulcers)
  • disulfiram (a medicine used in the treatment of alcoholism)
  • antibiotics, such as erythromycin
  • antifungals, such as ketoconazole and itraconazole
  • oral contraceptives (birth control pill)
  • HIV protease inhibitors, medicines used to treat HIV infection
  • lithium (a medicine used to treat mood swings and some types of depression)
  • medicines used to treat high blood pressure
  • digoxin (a medicine used to control heart beats).

If you are taking any of these you may need a different dose or you may need to take different medicines.

Other medicines not listed above may also interact with alprazolam.

How to take this medicine

Follow carefully all directions given to you by your doctor. Their instructions may be different to the information in this leaflet.

How much to take

Your doctor will tell you how much of this medicine you should take. This will depend on your condition and whether you are taking any other medicines.

Do not stop taking your medicine or change your dosage without first checking with your doctor.

How to take it

Swallow the tablets with a full glass of water.

When to take it

Take this medicine at the same time each day. Taking it at the same time each day will have the best effect and will also help you remember when to take it.

Alprazolam can be taken immediately after meals or on an empty stomach. However, side effects such as sleepiness or drowsiness may be reduced if you take your medicine immediately after meals.

How long to take it

Continue taking your medicine for as long as your doctor tells you.

Do not take alprazolam for longer than your doctor tells you. Usually your medicine should be used for short periods only (for example, 2-4 weeks). Continuous long-term use is not recommended unless advised by your doctor. The use of benzodiazepines may lead to dependence on the medicine.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to. Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for missed doses. This may increase the chance of you experiencing side effects.

If you are unsure about whether to take your next dose, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

If you think that you or anyone else may have taken too much of this medicine, immediately telephone your doctor or the Poisons Information Centre (Tel: 13 11 26 in Australia) for advice. Alternatively, go to the Accident and Emergency department at your nearest hospital.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking this medicine

Things you must do

Tell your doctor that you are taking this medicine if:

  • you are about to be started on any new medicine
  • you are pregnant or are planning to become pregnant
  • you are breastfeeding or are planning to breastfeed
  • you are about to have any blood tests
  • you are going to have surgery or an anaesthetic or are going into hospital.

Your doctor may occasionally do tests to make sure the medicine is working and to prevent side effects. Go to your doctor regularly for a check-up.

Always discuss with your doctor any problems or difficulties during or after taking your medicine.

If you are being treated for anxiety, be sure to discuss with your doctor any problems you may have and how you feel, especially if your anxiety attacks are getting worse or more frequent. This will help your doctor to determine the best treatment for you.

Tell your doctor if, for any reason, you have not taken your medicine exactly as prescribed. Otherwise your doctor may think that it was not effective and change your treatment unnecessarily.

Tell any other doctors, dentists and pharmacists who are treating you that you take this medicine.

Things you must not do

  • Give this medicine to anyone else, even if their symptoms seem similar to yours.
  • Take your medicine to treat any other condition unless your doctor tells you to.
  • Stop taking your medicine, or change the dosage, without first checking with your doctor

Do not suddenly stop taking your medicine if you suffer from epilepsy. Stopping your medicine suddenly may make your epilepsy worse. Do not take your medicine to treat any other complaints unless your doctor tells you to.

Things to be careful of

Be careful when driving or operating machinery until you know how this medicine affects you.

This medicine may cause drowsiness or dizziness in some people and therefore may affect alertness.

Even if you take your medicine at night, you may still be drowsy or dizzy the next day.

Be careful when drinking alcohol while taking alprazolam. Taking your medicine with alcohol can make you more sleepy, dizzy or lightheaded. Your doctor may suggest that you avoid alcohol or reduce the amount of alcohol you drink while you are taking your medicine.

Be careful if you are elderly, unwell or taking other medicines. Some people may experience side effects such as drowsiness, confusion, dizziness and unsteadiness, which may increase the risk of a fall.

Possible side effects

Tell your doctor as soon as possible if you do not feel well while you are taking alprazolam or if you have any questions or concerns.

Do not be alarmed by the following lists of side effects. You may not experience any of them. All medicines can have side effects. Sometimes they are serious but most of the time they are not.

Tell your doctor if you notice any of the following:

  • drowsiness, tiredness, excessive sleepiness
  • dizziness, lightheadedness
  • clumsiness, unsteadiness
  • disoriented
  • slurred speech
  • lack of appetite
  • nausea (feeling sick)
  • constipation
  • dry mouth
  • change in sex drive
  • headache
  • blurred vision
  • insomnia
  • weight changes.

Tell your doctor as soon as possible if you notice any of the following.

These may be serious side effects and you may need medical attention:

  • loss of alertness or concentration, memory loss
  • nervousness or feeling anxious
  • shakiness or tremor, muscle weakness or spasms
  • swellings of hands, ankles or feet
  • depression
  • hypomania, with symptoms such as heightened energy ("wired"), lowered inhibitions and euphoria.

If you experience any of the following, stop taking your medicine and contact your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

These are very serious side effects and you may need urgent medical attention or hospitalisation. These side effects are usually very rare:

  • aggressive behaviour, hostility, agitation, violent anger, hallucinations
  • yellowing of the skin and whites of the eyes.

Other side effects not listed above may occur in some patients.

Allergic reactions

If you think you are having an allergic reaction to alprazolam, do not take any more of this medicine and tell your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

Symptoms of an allergic reaction may include some or all of the following:

  • cough, shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue, throat or other parts of the body
  • rash, itching or hives on the skin
  • fainting
  • hay fever-like symptoms.

Storage and disposal

Storage

Keep your medicine in their original packaging until it is time to take them.

If you take the tablets out of their original packaging they may not keep well.

Keep your medicine in a cool dry place where the temperature is below 25°C.

Do not store your medicine, or any other medicine, in the bathroom or near a sink.

Do not leave your medicine on a window sill or in the car on hot days.

Heat and dampness can destroy some medicines.

Keep your medicine where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking alprazolam or your medicine has passed its expiry date, ask your pharmacist what to do with any medicine that is left over.

Product description

What the tablets look like

The 1 mg tablets are blue, oval biconvex tablets, scored and engraved "APO" over "1" on one side, other side plain.

They are available in blister packs of 50 tablets and in bottles of 50 tablets.

The 2 mg tablets are white, rectangular flat-faced on one side tablets, engraved "APO 2" with centre partial bisect and two bisects on upper side, deep centre bisect with sloped faces toward two bisects on lower side.

They are available in bottles of 50 tablets.

Ingredients

The active ingredient is alprazolam.

Each tablet contains 1 mg or 2 mg of alprazolam.

The tablets also contain the following inactive ingredients:

  • cellulose - microcrystalline
  • lactose
  • croscarmellose sodium
  • magnesium stearate
  • indigo carmine CI 73015 (only contained in the 1 mg tablets).

The tablets are gluten-free, sucrose-free, tartrazine-free and free of any other azo dyes.

Australian Registration Numbers

GenRx Alprazolam 1 mg tablets - blisters - AUST R 79802.

GenRx Alprazolam 1 mg tablets - bottles - AUST R 80935 (not marketed).

GenRx Alprazolam 2 mg tablets - bottles - AUST R 80934.

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113

This leaflet was last updated in:
October 2015.

Published by MIMS November 2017

BRAND INFORMATION

Brand name

GenRx Alprazolam

Active ingredient

Alprazolam

Schedule

S8

 

Name of the medicine

Alprazolam.

Excipients.

Lactose, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. 1 mg tablets also contain indigo carmine aluminium lake.

Description

Chemical name: 8-chloro-1- methyl-6-phenyl-4H-s triazolo (4,3-α) (1,4) benzodiazepine. MW: 308.76. CAS: 28981-97-7. Alprazolam is a white crystalline powder, soluble in methanol or ethanol but with no appreciable solubility in water.

Pharmacology

Pharmacological action.

Alprazolam is an antianxiety, benzodiazepine derivative chemically and pharmacologically related to other drugs of this class.
Pharmacological properties of alprazolam in animals appear similar to those of other benzodiazepines, that is, it produces significant anxiolytic, muscle relaxant, sleep promoting and anticonvulsant effects in appropriate animal models.
The exact site and mechanism of action of benzodiazepines is unknown. It is known that they act within the central nervous system as selective depressants.
Clinical studies in healthy volunteers with alprazolam doses up to 4 mg/day, and in patients with panic disorder at doses up to 10 mg/day, produce only effects which can be considered to be extensions of its pharmacological activity. No clinically significant effects on the cardiovascular or respiratory systems were observed. Alprazolam doses up to 10 mg/day do not clinically affect laboratory parameters or vital signs.
Sleep laboratory studies in humans showed that alprazolam decreased sleep latency, increased duration of sleep and decreased the number of nocturnal awakenings. Alprazolam produced small decreases in both stages 3-4 and REM sleep.

Pharmacokinetics.

Absorption.

Following oral administration to fasting subjects, alprazolam is rapidly absorbed with nearly complete bioavailability. Alprazolam exhibits linear kinetics; after single dose administration of 0.5-3.0 mg plasma levels of 8.0-40 nanogram/mL were observed; during multiple dose administration of 1.5-10 mg/day in divided doses, steady-state plasma levels of 18.3-100 nanogram/mL were observed. Plasma levels of drug reach steady state within seven days after starting or altering dosage size. The steady-state level is 3-4 times that achieved with a single dose.
Peak plasma levels showed a two to threefold variation within individual treatment groups. The plasma half-life of alprazolam after single doses in healthy subjects has ranged from 6-25 hours. The mean half-life of individual treatment groups ranged only from 10-14 hours.

Distribution.

In vitro alprazolam is bound (80%) to human serum protein. Serum albumin accounts for the majority of the binding.

Metabolism.

Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4 (CYP3A4), to two major metabolites in the plasma: 4-hydroxyalprazolam and α-hydroxyalprazolam. A benzophenone derived from alprazolam is also found in humans. Their half-lives appear to be similar to that of alprazolam. The plasma concentrations of 4-hydroxyalprazolam and α-hydroxyalprazolam, relative to unchanged alprazolam concentration, were always less than 4%. The reported relative potencies in benzodiazepine receptor binding experiments and in animal models of induced seizure inhibition are 0.20 and 0.66, respectively, for 4-hydroxyalprazolam and α-hydroxyalprazolam. Such low concentrations and the lesser potencies of 4-hydroxyalprazolam and α-hydroxyalprazolam suggest that they are unlikely to contribute much to the pharmacological effects of alprazolam. The benzophenone metabolite is essentially inactive.

Excretion.

Alprazolam and its metabolites are excreted primarily in the urine. In addition to alprazolam, the major drug related materials excreted in urine are α-hydroxyalprazolam, and a benzophenone analogue. About 50% of the dose is excreted within 24 hours and 94% after 72 hours. With chronic dosing, the apparent elimination half-life increases by about 50%, possibly because of compartmentalisation effects.

Special populations.

Changes in the absorption, distribution, metabolism and excretion of benzodiazepines have been reported in a variety of disease states including alcoholism, impaired hepatic function and impaired renal function. Changes have also been demonstrated in the elderly (see Precautions).

Race.

Maximal concentrations and half-life of alprazolam are approximately 15 and 25% higher in Asians compared to Caucasians.

Cigarette smoking.

Alprazolam concentrations may be reduced by up to 50% in smokers compared to nonsmokers.

Indications

Alprazolam is indicated for the following.

Anxiety.

The short-term symptomatic treatment of anxiety including treatment of anxious patients with some symptoms of depression.

Panic disorder.

The treatment of panic disorder with or without some phobic avoidance, and for blocking or attenuation of panic attacks and phobias in patients who have agoraphobia with panic attacks.

Panic disorder.

The diagnostic criteria for panic disorder in DSM-III-R are the following.
(i) The panic attacks (discrete periods of intense fear or discomfort), at least initially, are unexpected. Later in the course of this disturbance, certain situations (e.g. driving a car or being in a crowded place) may become associated with having a panic attack. These panic attacks are not triggered by situations in which the person is the focus of others' attention (as in social phobia).
(ii) The diagnosis requires four such attacks within a four week period, or one or more attacks followed by at least a month of persistent fear of having another attack.
(iii) The panic attacks must be characterised by at least four of the following symptoms: dyspnoea or smothering sensations; dizziness, unsteady feelings or faintness; palpitations or tachycardia; trembling or shaking; sweating; choking; nausea or abdominal distress; depersonalisation or derealisation; paraesthesiae; flushes (hot flashes) or chills; chest pain or discomfort; fear of dying, fear of going crazy or of doing something uncontrolled.

Note.

Attacks involving four or more symptoms are panic attacks; attacks involving fewer than four are limited symptom attacks.
(iv) At least some of the panic attack symptoms must develop suddenly and increase in intensity within ten minutes of the beginning of the first symptom noticed in the attack.
(v) The panic attack must not be attributable to some known organic factor, e.g. amphetamine or caffeine, intoxication, hyperthyroidism.
The efficacy of alprazolam in conditions where the above criteria are not met has not been established. The risk versus benefits of alprazolam use in milder disorders, which do not meet the above criteria, has not been evaluated. Although current evidence supports the long-term clinical effectiveness of alprazolam in panic disorder, the continuing use of alprazolam needs to be weighed against the difficulties that can occur with dependence and discontinuation.
The results of a long-term study in patients taking alprazolam, that is, beyond 3 months, suggest that many patients continue to benefit from alprazolam therapy and that alprazolam efficacy is maintained for up to 8 months.
The physician should periodically reassess the usefulness of alprazolam for each patient.
A comparative study of alprazolam and placebo in the treatment of panic attacks in patients with panic disorder involved 543 patients over an 8 week period. Alprazolam was significantly more effective than placebo in reducing the total number of panic attacks (p < 0.0001); at week 4, 46.8% of alprazolam patients had achieved zero total panic attacks when compared to 27.1% of placebo patients.
Panic disorders are often severe, chronic illnesses that cause a high level of work and social disability, increased substance abuse, and potentially increased morbidity and mortality.
Psychological and social factors are important in the pathogenesis of panic attacks, either acting alone, or in combination with biological factors. Prolonged pharmacological therapy may be used as an adjunct to psychosocial therapy in the treatment of patients with panic disorders.

Contraindications

Hypersensitivity to benzodiazepines, alprazolam or to any component of the product's formulation (see Excipients).
Myasthenia gravis.
Chronic obstructive airways disease with incipient respiratory failure.

Precautions

Effects on ability to drive and use of machines.

As with all patients taking central nervous system (CNS) depressant medication, patients receiving alprazolam should be warned not to operate dangerous machinery or motor vehicles until it is known that they do not become drowsy or dizzy from alprazolam therapy. Abilities may be impaired on the day following use. Patients should be advised that their tolerance for alcohol and other CNS depressants will be diminished and that these medications should either be eliminated or given in reduced dosage in the presence of alprazolam.
Following the prolonged use of alprazolam at therapeutic doses, withdrawal from the medication should be gradual. An individualised withdrawal timetable needs to be planned for each patient in whom dependence is known or suspected (periods from four weeks to four months have been suggested). As with other benzodiazepines, when treatment is suddenly withdrawn a temporary increase in sleep disturbance can occur after use of alprazolam (see Withdrawal and dependence).
In general, benzodiazepines should be prescribed for short periods only (e.g. 2-4 weeks). With the exception of the use of alprazolam for the treatment of panic disorder (see Indications), continuous long-term use of alprazolam is not recommended. There is evidence that tolerance develops to the sedative effects of benzodiazepines. After as little as one week of therapy with recommended doses, withdrawal symptoms can appear following cessation of treatment, e.g. rebound anxiety following the cessation of an anxiolytic benzodiazepine (see Withdrawal and dependence).

Depression, psychosis and schizophrenia.

Alprazolam is not recommended as primary therapy in patients with depression and psychosis. In such conditions, psychiatric assessment and supervision are necessary if benzodiazepines are indicated. Benzodiazepines may increase depression in some patients and may contribute to deterioration in severely disturbed schizophrenics with confusion and withdrawal. Suicidal tendencies may be present or uncovered and protective measures may be required.
Panic related disorders have been associated with depression, and an increased frequency of suicide amongst untreated patients has been reported. Therefore, the precautions exercised when using any psychotropic drug in depressed or potentially suicidal patients should be applied when using higher doses of alprazolam in patients with panic related disorders.
Episodes of hypomania and mania have been reported in association with the use of alprazolam in patients with depression.

Psychiatric and paradoxical reactions.

In many of the spontaneous case reports of adverse behavioural effects, patients were receiving other CNS drugs concomitantly and/or were described as having underlying psychiatric conditions. Patients who have borderline personality disorder, a prior history of violent or aggressive behaviour, or alcohol or substance abuse may be at risk for such events.
Paradoxical reactions such as acute rage, stimulation or excitement may occur in rare instances; should such reactions occur, alprazolam should be discontinued.

Hypotension.

Although hypotension has occurred rarely, benzodiazepines should be administered with care to patients in whom a drop in blood pressure may lead to cardiac or cerebral complications. This is particularly important in elderly patients.

Epilepsy.

Abrupt withdrawal of benzodiazepines in persons with convulsive disorders may be associated with a temporary increase in the frequency and/or severity of seizures.
Patients with convulsive disorder should not be abruptly withdrawn from alprazolam.

Use in impaired renal/ hepatic function.

Patients with impaired renal or hepatic function should use benzodiazepine medication with caution and a reduction in dosage, or a decision not to prescribe, may be necessary in such patients. In rare instances some patients taking benzodiazepines have developed blood dyscrasias, and some have had elevations of liver enzymes. As with other benzodiazepines, periodic blood counts and liver function tests are recommended.

Impaired respiratory function.

Caution in the use of alprazolam is recommended in patients with respiratory depression. In patients with chronic obstructive pulmonary disease, benzodiazepines can cause increased arterial carbon dioxide tension and decreased oxygen tension.

Acute narrow angle glaucoma.

Caution should be used in the treatment of patients with acute narrow angle glaucoma (because of atropine-like side effects).

Amnesia.

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

Abuse.

Physical and psychological dependence have occurred with recommended doses of benzodiazepines. As with all benzodiazepines, the risk of dependence increases with higher doses and long-term use and is further increased in patients with a history of alcoholism or drug abuse. Caution must, therefore, be exercised in administering alprazolam to individuals known to be addiction prone, or those whose history suggests they may increase the dosage on their own initiative. In such patients it is, therefore, desirable to limit repeat prescriptions without adequate medical supervision. Such individuals should be under careful surveillance when receiving benzodiazepines because of their predisposition to habituation and dependence.

Withdrawal and dependence.

The use of benzodiazepines may lead to dependence as defined by the presence of a withdrawal syndrome on discontinuation of the drug. Tolerance as defined by a need to increase the dose in order to achieve the same therapeutic effect seldom occurs in patients receiving the recommended dose under medical supervision. Tolerance to sedation may occur with benzodiazepines, especially in those with drug seeking behaviour.
The result of withdrawal symptoms is a direct consequence of physical dependence to alprazolam. Signs and symptoms of withdrawal are similar in character to those noted with barbiturates and alcohol and are more prominent after a rapid decrease of dosage or abrupt discontinuation. These symptoms range from insomnia, anxiety, dysphoria, palpitations, panic attacks, vertigo, myoclonus, akinesia, hypersensitivity to light, sound and touch, abnormal body sensations (e.g. feelings of motion, metallic taste), depersonalisation, derealisation, delusional beliefs, hyper-reflexia and loss of short-term memory, to a major syndrome which may include convulsions, tremor, abdominal and muscle cramps, confusional state, delirium, hallucinations, hyperthermia, psychosis, vomiting and sweating. Such manifestations of withdrawal, especially the more serious ones, are more common in patients who have received excessive doses over a prolonged period. However, withdrawal symptoms have been reported following abrupt discontinuation of benzodiazepines taken continuously at therapeutic levels.
Signs and symptoms of withdrawal are more prominent after a rapid decrease of dosage or abrupt discontinuation of benzodiazepines. Hence, abrupt discontinuation of therapy with alprazolam should be avoided. It is recommended that all patients on alprazolam who require a dosage reduction be gradually tapered under close supervision (see Discontinuation therapy) to minimise the incidence or severity of withdrawal problems. It is important to advise patients not to increase the dose of, or abruptly discontinue, their medication without first consulting a physician.
The discontinuation of therapy with alprazolam may not only result in withdrawal symptoms, but also in relapse of the anxiety and panic symptoms of the original disorder and a rebound effect. The term relapse refers to the return of symptoms characteristic of the original disorder, at levels approximately equal to those seen at baseline before active treatment was initiated. Rebound phenomena refers to the return of symptoms characteristic of the original disorder, at levels greater than originally seen at baseline.
In general rebound phenomena reflect the re-emergence of pre-existing conditions combined with withdrawal symptoms described earlier. Withdrawal/ rebound phenomena may follow high doses of benzodiazepines for relatively short periods of time.
In a large database comprised of both controlled and uncontrolled studies in which 641 patients received alprazolam for the treatment of panic disorder, discontinuation emergent symptoms which occurred at a rate of over 5% in patients treated with alprazolam and at a greater rate than the placebo treated group were as shown in Table 1.
From the studies cited, it has not been determined whether these symptoms are clearly related to the dose and duration of therapy with alprazolam in patients with panic disorder.
These discontinuation emergent symptoms do not appear to differ from those associated with other benzodiazepines.
In two controlled trials of six to eight weeks duration where the ability of patients to discontinue medication was measured, 71%-93% of alprazolam treated patients tapered completely off therapy compared to 89%-96% of placebo treated patients. In a controlled clinical trial of 3-12 months duration involving 144 patients, where the ability of patients to discontinue medication was measured, it was found that the majority of alprazolam treated patients (66.9%) were able to taper dose to zero. A minority of patients were unable to successfully stop alprazolam after long-term therapy.

Use in pregnancy.

(Category C)
The safety of alprazolam for use in pregnancy has not been established. Benzodiazepines can potentially cause foetal harm when administered to pregnant women. If alprazolam is used during pregnancy, or if the patient becomes pregnant while taking alprazolam, the patient should be apprised of the potential hazard to the foetus. Because of experience with other members of the benzodiazepine class, alprazolam is assumed to be capable of causing an increased risk of congenital abnormalities when administered to a pregnant woman during the first trimester. Because use of these drugs is rarely a matter of urgency, their use during the first trimester should almost always be avoided. The data concerning teratogenicity and effects in postnatal development and behaviour following benzodiazepine treatment are inconsistent. There is evidence from some early studies with other members of the benzodiazepine class that in utero exposure may be associated with malformations. Later studies with the benzodiazepine class of drugs have provided no clear evidence of any type of defect.
Infants exposed to benzodiazepines during the late third trimester of pregnancy or during labour have been reported to exhibit either the floppy infant syndrome or neonatal withdrawal symptoms. Benzodiazepines cross the placenta and may cause hypotonia, respiratory depression and hypothermia in the newborn infant. Continuous treatment during pregnancy and administration of high doses in connection with delivery should be avoided.
The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. Patients should be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their physicians about the desirability of discontinuing the drug.

Use in lactation.

Benzodiazepines, including alprazolam, are known to be excreted in human milk. Benzodiazepines generally show increased toxicity in neonates and their excretion in breast milk may cause drowsiness, lethargy, weight loss, hypotonia and/or feeding difficulties in the infant. Therefore, unless there are compelling circumstances to the contrary, alprazolam is not recommended for use while breastfeeding.

Paediatric use.

The safety and efficacy of alprazolam in children has not been established.

Use in the elderly.

Such patients may be particularly susceptible to the sedative effects of benzodiazepines and associated giddiness, ataxia and confusion, which may increase the possibility of a fall. For elderly or debilitated patients the dosage should be limited to the smallest effective amount to preclude such effects.

Interactions

The benzodiazepines, including alprazolam, produce additive CNS depressant effects when coadministered with drugs such as barbiturates, alcohol, sedatives, tricyclic antidepressants, nonselective MAO inhibitors and other antipsychotics, skeletal muscle relaxants, antihistamines, narcotic analgesics and anaesthetics (see Precautions).
Pharmacokinetic interactions can occur when alprazolam is administered along with drugs that interfere with its metabolism. Compounds which inhibit certain hepatic enzymes (particularly CYP3A4) may increase the concentration of alprazolam and enhance its activity. Data from clinical studies with alprazolam, in vitro studies with alprazolam and clinical studies with drugs metabolised similarly to alprazolam, provide evidence for varying degrees of interaction and possible interaction with alprazolam for a number of drugs. Based on the degree of interaction and the type of data available, the following recommendations are made.
The coadministration of alprazolam with ketoconazole, itraconazole or other azole antifungals is not recommended. Ketoconazole and itraconazole are potent CYP3A inhibitors and have been shown in vivo to increase plasma alprazolam concentrations.
Caution and consideration of dose reduction is recommended when alprazolam is coadministered with fluvoxamine and cimetidine.
Caution is recommended when alprazolam is coadministered with fluoxetine, propoxyphene, and oral contraceptives. Oral contraceptives may increase the elimination half-life of alprazolam; a 20% increase in the alprazolam steady-state plasma concentration may be expected in women taking alprazolam and oral contraceptives concurrently.
Caution is recommended when alprazolam is coadministered with diltiazem, isoniazid, macrolide antibiotics such as erythromycin and clarithromycin, grapefruit juice, ergotamine, cyclosporin, amiodarone and nifedipine.
Interactions involving HIV protease inhibitors (e.g. ritonavir) and alprazolam are complex and time dependent. Low doses of ritonavir resulted in a large impairment of alprazolam clearance, prolonged its elimination half-life and enhanced clinical effects. However, upon extended exposure to ritonavir, CYP3A induction offset this inhibition. This interaction will require a dose adjustment or discontinuation of alprazolam.
Increased digoxin concentrations have been reported when alprazolam was given, especially in the elderly (over 65 years of age). Patients who receive alprazolam and digoxin should therefore be monitored for signs and symptoms related to digoxin toxicity.
Alprazolam may also interact with disulfiram resulting in increased plasma levels of alprazolam.
Interactions have been reported between some benzodiazepines and anticonvulsants, with changes in the serum concentration of the benzodiazepine or the anticonvulsant. It is recommended that patients be observed for altered responses when benzodiazepines and anticonvulsants are prescribed together and that serum level monitoring of the anticonvulsant be performed more frequently.
Minor EEG changes, usually low voltage fast activity, of no known clinical significance, has been reported with benzodiazepine administration.
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 alprazolam in doses up to 4 mg/day. The clinical significance of these changes is unknown.
Alprazolam causes a small decrease (7%) in lithium clearance. Caution should be exercised with the close monitoring of lithium concentrations to avoid toxicity.
Alprazolam did not affect the prothrombin times or plasma warfarin levels in male volunteers administered sodium warfarin orally.

Adverse Effects

Adverse effects, if they occur, are generally observed at the beginning of therapy and usually disappear upon continued medication or decreased dosage.
In patients treated for anxiety and anxiety associated with depression, the most common adverse effects to alprazolam were drowsiness and lightheadedness/ dizziness. Common adverse effects include disorientation, libido decreased, balance disorder, hypersomnia, lethargy, constipation, dry mouth, and nausea. Less common adverse reactions were blurred vision, headache, depression, insomnia, nervousness/ anxiety, tremor, change in weight, memory impairment/ amnesia, coordination disorders, various gastrointestinal symptoms and autonomic manifestations. As with other benzodiazepines, reactions such as stimulation, agitation, concentration difficulties, confusion, hallucinations or other adverse behavioural effects have been reported with alprazolam. Increased intraocular pressure has been rarely reported.
In addition, the following adverse events have been reported in association with the use of anxiolytic benzodiazepines including alprazolam: dystonia, irritability, anorexia, fatigue, slurred speech, jaundice, musculoskeletal weakness, changes in libido, menstrual irregularities, incontinence, urinary retention, abnormal liver function and hyperprolactinaemia.
The most common adverse effects in patients with panic related disorders were sedation/ drowsiness; fatigue, ataxia/ impaired coordination and slurred speech. Less common adverse effects were altered mood, GI symptoms, dermatitis, memory problems, sexual dysfunction, intellectual impairment and confusion.
Rarely, jaundice or abnormal liver function tests occur during alprazolam therapy, with recovery of function after cessation of use.
Episodes of hypomania, mania and other adverse behavioural effects may occur in rare instances with the use of alprazolam, and may necessitate the discontinuation of therapy. Such discontinuation should follow the recommended daily dosage reduction regimen (see Dosage and Administration).

Postmarketing experience.

The following additional adverse effects have been reported and are listed by MedDRA system organ class.

Endocrine disorders.

Uncommon: hyperprolactinaemia.

Psychiatric disorders.

Uncommon: hypomania, mania, hallucinations, anger, aggression, hostility, agitation, libido disorder, thinking abnormal, psychomotor hyperactivity.

Nervous system disorder.

Uncommon: dystonia. Not known: automatic nervous system imbalance.

Gastrointestinal disorder.

Uncommon: gastrointestinal disorder.

Hepatobiliary disorders.

Uncommon: hepatitis, hepatic function abnormal, jaundice.

Skin and subcutaneous tissue disorders.

Uncommon: dermatitis. Not known: angioedema, photosensitivity reaction.

Renal urinary disorders.

Uncommon: incontinence, urinary retention.

Reproductive system and breast disorders.

Uncommon: sexual dysfunction, menstruation irregular.

General disorders and administration site conditions.

Not known: oedema peripheral.

Investigations.

Uncommon: intraocular pressure increased.

Dosage and Administration

The optimum dosage of alprazolam should be individualised, based upon the severity of the symptoms and individual patient response. The daily dosage (see Table 2) will meet the needs of most patients. In the few patients who require higher doses, dosage should be increased cautiously to avoid adverse effects.
When higher dosage is required, the evening dose should be increased before the daytime doses. In general, patients who have not previously received psychotropic medication will require lower doses than those previously treated with minor tranquillizers, antidepressants or hypnotics or those with a history of chronic alcoholism.
It is recommended that the general principle of using the lowest effective dosage be followed to preclude the development of oversedation or ataxia. In patients who experience early morning anxiety and emergence of anxiety symptoms, it is recommended that the same total daily dose be given divided as more frequent administration.
Patients should be periodically assessed and dosage adjustments made, as appropriate.
Administration of alprazolam immediately after meals does not affect the extent of alprazolam absorption compared to administration on an empty stomach. Food does, however, delay the onset of absorption and decrease the rate of absorption of alprazolam. As a direct consequence, side effects, such as somnolence, are less pronounced.

Discontinuation therapy.

The dosage should be reduced slowly in keeping with good medical practice. It is suggested that the daily dosage of alprazolam be decreased by 0.25 to 0.5 mg every three days. It is important that this rate of dosage reduction does not exceed 0.5 mg every 3 days in order to minimise any possible withdrawal symptoms. Some patients may require an even slower dosage reduction (see Precautions).

Overdosage

Overdosage of benzodiazepines is usually manifested by an extension of their pharmacological activity, including respiratory depression and central nervous system depression (ranging from drowsiness to coma). In mild cases, symptoms may include drowsiness, mental confusion and lethargy, impaired coordination, diminished reflexes, slurred speech, dilated pupils, absent bowel sounds and tachycardia. In more serious cases, symptoms may include ataxia, hypotonia, hypotension, hypothermia, rhabdomyolysis, atrioventricular block, coma and very rarely death. Serious sequelae occur when alprazolam is taken with other drugs and/or alcohol is concomitantly ingested. Deep coma, marked hypotension and respiratory depression may indicate other drugs have been ingested as well. In terms of duration, most obtunded patients become arousable within 12-36 hours following an acute overdose.

Treatment.

In the management of overdosage it should be borne in mind that multiple agents may have been taken. Treatment of overdosage is primarily supportive of respiratory and cardiovascular function. Following overdosage with alprazolam, activated charcoal should be given to reduce absorption. Activated charcoal is most effective when administered within 1 hour of ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via nasogastric tube once the airway is protected.
The benzodiazepine antagonist flumazenil may be useful in hospitalised patients for the reversal of CNS actions of benzodiazepines. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for resedation, respiratory depression and other residual benzodiazepine effects for an appropriate period after treatment. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. Consult the flumazenil product information prior to usage.
Haemoperfusion, forced diuresis and haemodialysis are generally not useful in benzodiazepine intoxication. Ipecac induced emesis is not recommended due to the potential for CNS depression.
For information on the management of overdose, contact the Poisons Information Centre on 131 126 (Australia).

Presentation

Tablets, 1 mg (blue, oval, biconvex, scored, marked APO/1, plain on reverse): 50's (PVC/ PVCD/ aluminium foil blister pack, AUST R 79802; white opaque, round HDPE bottle with CRC lift and peel cap*, AUST R 80935); 2 mg (white, rectangular, flat faced on one side, marked APO 2, with centre partial bisect and two bisects on upper side, deep centre bisect with sloped faces toward two bisects on lower side): 50's (white opaque, round HDPE bottle with CRC lift and peel cap, AUST R 80934).
*Not currently marketed in Australia.
GenRx Alprazolam tablets are intended for oral administration.

Storage

Store below 25°C.

Poison Schedule

S8.