Consumer medicine information

Alprax

Alprazolam

BRAND INFORMATION

Brand name

Alprax Tablets

Active ingredient

Alprazolam

Schedule

S8

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Alprax.

What is in this leaflet

This leaflet answers some common questions about ALPRAX.

It does not contain all of the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of you taking ALPRAX against the benefits they expect it will have for you.

Talk to your doctor or pharmacist if you have any concerns about taking this medicine.

Keep this leaflet with your medicine.

You may need to read it again.

What ALPRAX is used for

ALPRAX is used to treat:

  • anxiety
  • panic attacks.

Ask your doctor if you have any questions about why it has been prescribed for you.

Your doctor may have prescribed this medicine for another reason.

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

In general, benzodiazepines such as ALPRAX 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.

ALPRAX is not recommended for use in children, as there have been no studies of its effects in children.

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

Before you take it

When you must not take it

Do not take ALPRAX if you are allergic to:

  • medicines containing alprazolam
  • any other benzodiazepine medicine
  • any of the ingredients listed at the end of this leaflet.

Do not take ALPRAX if you have:

  • severe and chronic lung disease
  • severe muscle weakness known as myasthenia gravis.

Do not take it if the expiry date (Exp.) printed on the pack or bottle has passed.

Do not take it if the packaging shows signs of tampering or the tablets do not look quite right.

Before you start to take it

Tell your doctor if you are allergic to any other medicines, foods, dyes or preservatives.

Tell your doctor if you are pregnant or plan to become pregnant.

Your doctor will discuss the risks and benefits of taking ALPRAX during pregnancy.

Tell your doctor if you are breastfeeding or wish to breastfeed.

ALPRAX may pass into the breast milk and cause drowsiness and feeding difficulties in the baby. Your doctor will discuss the risks and benefits of taking this medicine when breastfeeding.

Tell your doctor if you have any medical conditions, especially the following:

  • depression, psychosis or schizophrenia
  • glaucoma (high pressure in the eye)
  • epilepsy (fits or convulsions)
  • liver, kidney or lung disease
  • high or low blood pressure
  • previous problems with addiction to medicine.

If you have not told your doctor about any of the above, tell them before you start taking ALPRAX.

Tell your doctor if you drink alcohol regularly.

Alcohol may increase the effects of ALPRAX.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from a pharmacy, supermarket or health food shop.

Some medicines may be affected by ALPRAX, or may affect how well it works. These include:

  • sleeping tablets, sedatives or tranquillisers
  • medicines for depression
  • lithium, a medicine used to treat mood swings and some types of depression
  • antipsychotics, medicines used to treat certain mental and emotional conditions
  • medicines to control epilepsy and fits
  • antihistamines, medicines used to prevent or relieve the symptoms of allergy (such as hay fever)
  • muscle relaxants
  • some pain relievers
  • cimetidine, a medicine commonly used to treat reflux and ulcers
  • disulfiram, a medicine used in alcohol abuse
  • oral contraceptives
  • some macrolide antibiotics, e.g. erythromycin
  • medicines to treat HIV infection (ritonavir).

Your doctor can tell you what to do if you are taking any of these medicines.

If you are not sure whether you are taking any of these medicines, check with your doctor or pharmacist.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking ALPRAX.

How to take it

How much to take

The dose varies from patient to patient.

Your doctor will tell you how many tablets you need to take each day and when to take them. This depends on your condition and whether or not you are taking any other medicines.

Follow all directions given to you by your doctor and pharmacist carefully.

How to take it

Swallow the tablets with a glass of water.

ALPRAX can be taken with or without food.

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 the missed dose as soon as you remember, and then go back to taking your tablets as you would normally.

Do not take a double dose to make up for the dose you missed.

Ask your doctor or pharmacist if you are not sure what to do.

How long to take it for

Keep taking your medicine for as long as your doctor recommends.

In general, benzodiazepines such as ALPRAX should be taken for short periods only (such as 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 take too much (overdose)

Immediately telephone your doctor, or the Poisons Information Centre (telephone 13 11 26), or go to Accident and Emergency at the nearest hospital, if you think you or anyone else may have taken too much ALPRAX. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

If you take too much, you may feel drowsy, tired, confused, dizzy, have difficulty breathing, feel weak or become unconscious.

While you are taking it

Things you must do

Before starting any new medicine, tell your doctor or pharmacist that you are taking ALPRAX.

Tell all the doctors, dentists and pharmacists who are treating you that you are taking this medicine.

If you become pregnant while taking it, tell your doctor.

Visit your doctor regularly so they can check on your progress.

Your doctor will check your condition to see whether you should continue to take it.

Tell your doctor if you feel that ALPRAX is not helping your condition.

Things you must not do

Do not drive or operate machinery until you know how this medicine affects you.

ALPRAX may cause drowsiness or dizziness in some people. If any of these occur, do not drive, operate machinery or do anything else that could be dangerous.

Do not take it for a longer period than your doctor has prescribed.

Do not stop taking it, or lower the dose, without first checking with your doctor.

Your doctor may want you to gradually reduce the amount of ALPRAX you are taking before stopping completely. This may help reduce the possibility of unwanted side effects.

Do not use it to treat any other conditions unless your doctor tells you to.

Do not give it to anyone else, even if they have the same condition as you.

Things to be careful of

Be careful when drinking alcohol while taking ALPRAX.

Combining this medicine and alcohol can make you more sleepy, dizzy or lightheaded.

Your doctor may suggest that you avoid alcohol or reduce the amount you drink while you are taking ALPRAX.

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.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking ALPRAX.

Like all other medicines, ALPRAX may have unwanted side effects in some people. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Do not be alarmed by this list of possible side effects.

You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following and they worry you:

  • drowsiness, tiredness
  • dizziness, lightheadedness, confusion
  • memory problems
  • unsteadiness, clumsiness
  • slurred speech
  • blurred vision
  • tremor
  • changes in weight
  • impaired sexual function
  • anxiety, irritability and sleep problems after you stop taking ALPRAX.

Tell your doctor immediately or go to Accident and Emergency at the nearest hospital if you notice any of the following:

  • unusual feelings of anger, excitement or overactivity
  • yellowing of the eyes or skin (jaundice).

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice anything that is making you feel unwell.

After taking it

Storage

Keep it 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.

Keep your blister pack of tablets in a cool dry place where the temperature stays below 25°C.

Keep your bottle of tablets in a cool dry place where the temperature stays below 30°C.

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

Do not leave it in the car or on window sills.

Heat and dampness can destroy some medicines.

Disposal

If your doctor tells you to stop taking this medicine, or your tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product description

What it looks like

ALPRAX is available in 4 strengths of tablets:

  • ALPRAX 0.25 blister packs - oval white tablet marked with ‘A | 25’ on one side and plain on the other.
  • ALPRAX 0.5 blister packs – oval pink tablet marked with ‘A | 5’ on one side and plain on the other.
  • ALPRAX 1 blister packs – oval light blue tablet marked with ‘A | 1’ on one side and plain on the other.
  • ALPRAX 2– rectangular white tablet marked with ‘| A | 2 |’ on one side and triple scored on the other. Provided in HDPE bottles with child-resistant caps.

Each pack contains 10 tablets (Alprax 0.5 and 1 only) or 50 tablets. Not all pack sizes are marketed.

Ingredients

The active ingredient in ALPRAX is alprazolam:

  • each ALPRAX 0.25 tablet contains 0.25 mg of alprazolam
  • each ALPRAX 0.5 tablet contains 0.5 mg of alprazolam
  • each ALPRAX 1 tablet contains 1 mg of alprazolam
  • each ALPRAX 2 tablet contains 2 mg of alprazolam.

The tablets also contain:

  • lactose anhydrous
  • microcrystalline cellulose
  • maize starch
  • sodium benzoate
  • docusate sodium
  • povidone
  • colloidal anhydrous silica
  • sodium starch glycollate
  • magnesium stearate
  • pigment blend PB20026 purple (ALPRAX 0.5 only)
  • indigo carmine CI 73015 (132) (ALPRAX 1 only).

ALPRAX tablets are gluten free.

BRAND INFORMATION

Brand name

Alprax Tablets

Active ingredient

Alprazolam

Schedule

S8

 

1 Name of Medicine

Alprazolam.

6.7 Physicochemical Properties

The chemical name for alprazolam is 8-chloro-1-methyl-6-phenyl-4H-s-triazolo (4,3-α)(1,4) benzodiazepine.
C17H13ClN4. Molecular weight: 308.76.
Alprazolam is a white crystalline powder which is soluble in methanol or ethanol but has no appreciable solubility in water.

Chemical structure.

Its structural formula is:

CAS number.

Cas No.: 28981-97-7.

2 Qualitative and Quantitative Composition

Alprax tablets come in four strengths and contain 0.25 mg, 0.5 mg, 1.0 mg or 2.0 mg of alprazolam.
The tablets also contain the following excipients: lactose, microcrystalline cellulose, maize starch, sodium benzoate, docusate sodium, povidone, colloidal anhydrous silica, sodium starch glycollate and magnesium stearate. Alprax 0.5 tablets also contain pigment blend PB-20026 purple and Alprax 1 tablets also contain indigo carmine. The tablets are gluten free.

3 Pharmaceutical Form

Alprax 0.25 (0.25 mg tablet): Oval, white convex tablet marked with “A/25” on one side and plain on the other.
Alprax 0.5 (0.5 mg tablet): Oval, pink convex tablet marked with “A/5” on one side and plain on the other.
Alprax 1 (1 mg tablet): Oval, light blue convex tablet marked with “A/1” on one side and plain on the other.
Alprax 2 (2 mg tablet): Rectangular, white tablet embossed with “/A/2/” on one side and three scorelines on the other.
Note: Not all strengths or presentations may be marketed.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

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 trials.

Clinical studies in healthy volunteers at 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 activities. 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 man 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.

5.2 Pharmacokinetic Properties

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 7 days after starting or altering dosage size. The steady-state level is 3 to 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 to 25 hours. The mean half-life of individual treatment groups ranged only from 10 to 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 metabolised 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 the unchanged alprazolam 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 analog. About 50 percent of the dose is excreted within 24 hours and 94 percent after 72 hours. With chronic dosing, the apparent elimination half-life increases by about 50 percent, 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 Section 4.4 Special Warnings and Precautions for Use).

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.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

No data available.

4 Clinical Particulars

4.1 Therapeutic Indications

Alprazolam is indicated for:

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; paraesthesia; 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, suggests 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 the drug 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.

4.3 Contraindications

Hypersensitivity to benzodiazepines or to any component of the product's formulation (see Section 2 Qualitative and Quantitative Composition); myasthenia gravis; chronic obstructive airways disease with incipient respiratory failure.

4.4 Special Warnings and Precautions for Use

Identified precautions.

As with all patients taking 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 to 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 Section 4.1 Therapeutic Indications), continuous long-term use is not recommended. There is evidence that tolerance develops to the sedative effects of benzodiazepines. After as little as one week 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.

Paradoxical reactions.

Paradoxical reactions such as acute rage, stimulation or excitement may occur in rare instances; should such reactions occur, alprazolam should be discontinued.

Geriatric or debilitated patients.

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.

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.

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. 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, hyperreflexia 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 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 refer 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 are shown in Table 2.
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 to 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 hepatic impairment.

Patients with impaired 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.

Use in renal impairment.

Patients with impaired renal 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.

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.

Paediatric use.

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

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of 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 Section 4.4 Special Warnings and Precautions for Use).
Pharmacokinetic interactions can occur when alprazolam is administered along with drugs that interfere with its metabolism. Compounds which inhibit certain hepatic enzymes (particularly cytochrome P450 3A4) 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 tablets and oral contraceptives concurrently.
Caution is recommended when alprazolam is coadministered with diltiazem, isoniazid, macrolide antibiotics, e.g. erythromycin and clarithromycin, grapefruit juice, ergotamine, cyclosporin, amiodarone and nifedipine.
Interactions involving human immunodeficiency virus (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 offsets this inhibition. This interaction will require a dose adjustment or discontinuation of alprazolam.
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, have 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 tablets did not affect the prothrombin times or plasma warfarin levels in male volunteers administered sodium warfarin orally.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(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 a patient becomes pregnant while taking this drug, 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 women 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 doctors about the desirability of discontinuing the drug.
Benzodiazepines, including alprazolam, are known to be excreted in breast milk. Benzodiazepines generally show increased toxicity in neonates, and the excretion of benzodiazepines 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.

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.
Side 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 reactions to alprazolam were drowsiness and lightheadedness/ dizziness. 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 intra-ocular 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 reactions in patients with panic related disorders were sedation/ drowsiness; fatigue, ataxia/ impaired coordination and slurred speech. Less common adverse reactions 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 Section 4.2 Dose and Method of Administration).

4.2 Dose and Method of 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 1) 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 tranquillisers, 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 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 Section 4.4 Special Warnings and Precautions for Use).

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.9 Overdose

Overdosage of benzodiazepines is usually manifested by an extension of their pharmacologic activity, including respiratory depression and central nervous system depression ranging from drowsiness to coma. In mild cases symptoms may include drowsiness, mental confusion, 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 ethanol are 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 to 36 hours following an acute overdose.

Treatment.

In management of overdosage it should be borne in mind that multiple agents may have been taken. Treatment of overdose 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 one 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. Please 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 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S8.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store bottles below 30°C and blister packs below 25°C.

6.5 Nature and Contents of Container

Alprax 0.25: Provided in HDPE bottles with child resistant caps and aluminium/PVC blister packs of 50 tablets.
Alprax 0.5: Provided in HDPE bottles with child resistant caps and aluminium/PVC/PE/PVDC blister packs of 10 and 50 tablets.
Alprx 1: Provided in HDPE bottles with child resistant caps and aluminium/PVC/PE/PVDC blister packs of 10 and 50 tablets.
Alprax 2: Provided in HDPE bottles of 10, 30 and 50 tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes