Alprazolam 0.25 mg Tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

Buy It Now

Active ingredient:
Alprazolam
Available from:
Rowex Ltd
ATC code:
N05BA; N05BA12
INN (International Name):
Alprazolam
Dosage:
0.25 milligram(s)
Pharmaceutical form:
Tablet
Prescription type:
Product subject to prescription which may not be renewed (A)
Therapeutic area:
Benzodiazepine derivatives; alprazolam
Authorization status:
Marketed
Authorization number:
PA0711/140/001
Authorization date:
2008-10-17

Package leaflet: Information for the patient

Alprazolam 0.25 mg Tablets

Alprazolam 0.5 mg Tablets

Alprazolam 1 mg Tablets

alprazolam

Read all of this leaflet carefully before you start taking this medicine because it contains important

information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if

their signs of illnes are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not

listed in this leaflet. See section 4.

What is in this leaflet

What Alprazolam is and what it is used for

What you need to know before you take Alprazolam

How to take Alprazolam

Possible side effects

How to store Alprazolam

Content of the pack and other information

1.

What Alprazolam is and what it is used for

Alprazolam is a tranquilliser containing the active substance alprazolam. Alprazolam belongs to one of a

group of medicines called benzodiazepines. Benzodiazepines affect chemical activity in the brain to promote

sleep and to reduce anxiety and worry.

Alprazolam is used to treat anxiety that is severe, disabling or causing the sufferer great distress.

Alprazolam tablets should only be used for short-term treatment of anxiety. The overall duration of treatment

should not be more than 12 weeks including a period where the dose is gradually reduced (this is called dose

‘tapering’).

2.

What you need to know before you take Alprazolam

Do not take Alprazolam if you

are allergic to alprazolam or any of the other ingredients of this medicine (listed in section 6), or

previously had an allergic reaction to another benzodiazepine.

suffer from myasthenia gravis (severe muscle weakness)

have a severe lung disease e.g. bronchitis, emphysema

have "sleep apnoea", where breathing temporarily stops during sleep

have a severe liver disease.

Warnings and precautions

Talk to your doctor or pharmacist before taking Alprazolam

if you have ever suffered any mental illness that requires hospital treatment

if you are under 18 years old

if you have problems with your lungs, kidneys or liver

if you have abused drugs or alcohol in the past or find it difficult to stop taking medicines, drinking or

taking drugs. Your doctor may want to give you special help when you need to stop taking these tablets.

if you notice that the effect of the tablets becomes less after a few weeks of use.

if you are troubled by symptoms that indicate physical and psychological dependence on alprazolam.

You notice psychological dependence by not wanting to stop taking the medicine. Physical dependence

means that withdrawal symptoms occur when the treatment with this medicine is stopped suddenly (see

the section “If you stop taking Alprazolam”).

The risk of dependence increases with higher doses and a longer period of treatment. Therefore, the

duration of treatment must be as short as possible.

if you experience memory loss.

This mostly occurs a few hours after taking the tablet. See section 4 “Possible side effects”.

To reduce the risk patients should ensure that they will be able to have uninterrupted sleep of 7-8 hours.

if you experience psychiatric and “paradoxical” reactions such as

anxiety

irritability

attacks of rage

nightmares

increased insomnia

perceptions of things that do not exist (hallucinations)

severe mental disorders in which control over one’s own behaviour and actions is disturbed

(psychosis)

inappropriate behaviour and other behavioural disturbances.

These conflicting reactions occur more frequently in children and elderly patients. Tell your doctor if

such symptoms occur as the treatment may possibly need to be stopped.

if you suffer from chronic tightness of the chest you should be aware that Alprazolam can aggravate this.

if you suffer from severe depression.

Alprazolam can sometimes cause an excessively lively mood (mania) or an increase in suicidal

tendencies.

if you suffer from psychosis - a severe mental illness which disturbs your behaviour, actions and self-

control, then Alprazolam is not appropriate.

if you have a certain form of suddenly raised eyeball pressure (narrow-angle glaucoma) or if you are at

risk of experience this.

Please tell your doctor if any of the above apply or have previously applied to you.

Children and adolescents

Alprazolam is not recommended for children and adolescents under the age of 18 years.

Other medicines and Alprazolam

Tell your doctor or pharmacist if you are taking or have recently taken or might take any other medicines,

including medicines obtained without a prescription especially medicines listed below, as the effect of

Alprazolam may be stronger when taken at the same time:

Medicines that increase Alprazolam’s sedative effect:

sleep-inducing and tranquillising medicines

medicines used to treat severe mental disorder like schizophrenia (antipsychotics)

medicines used to treat severe depression

any other medicines to treat anxiety or depression

medicines used to treat epilepsy

medicines that are used for anaesthesia

certain medicines used to treat allergies, so called sedative antihistamines.

Concomitant use of Alprazolam and opioids (strong pain killers, medicines for substitution therapy and some

cough medicines) increases the risk of drowsiness, difficulties in breathing (respiratory depression), coma

and may be life-threatening. Because of this, concomitant use should only be considered when other

treatment options are not possible.

However if your doctor does prescribe Alprazolam together with opioids the dose and duration of

concomitant treatment should be limited by your doctor.

Please tell your doctor about all opioid medicines you are taking, and follow your doctor’s dose

recommendation closely. It could be helpful to inform friends or relatives to be aware of the signs and

symptoms stated above. Contact your doctor when experiencing such symptoms.

These painkillers can also increase the euphoria and dependence risk.

Medicines that increase Alprazolam’s effect as a result of suppression of the breakdown of alprazolam in

the liver:

nefazodone, fluvoxamine, fluoxetine, sertraline, medicines used to treat severe depression

cimetidine, a medicine used to treat gastric disorders

certain medicines used to treat AIDS (known as HIV protease inhibitors, e.g. ritonavir, saquinavir,

indinavir)

dextropropoxyphene, a medicine used to treat pain

the oral contraceptive pill

diltiazem, a medicine used to treat high blood pressure and heart disorders

macrolide antibiotics such as erythromycin, medicines used to treat infections

certain medicines used to treat fungal infections, such as ketoconazole and itraconazole.

Medicines that decrease Alprazolam’s effect due to the increased alprazolam breakdown in the liver:

carbamazepine or phenytoin, medicines used to treat epilepsy and other conditions

St John’s wort, a herbal medicine used to treat depression

rifampicin, a medicine to treat tuberculosis.

Medicines whose effects may be increased by Alprazolam:

digoxin, a medicine used to treat heart failure and heart rhythm disturbances

The risk of digoxin poisoning is particularly increased in elderly patients and, where doses exceeding

1 mg Alprazolam are taken daily.

muscle relaxants, such as pancuronium, atracurium

The muscle-relaxant effect may be greater, especially on beginning Alprazolam treatment.

imipramine and desipramine, certain medicines used to treat severe depression

clozapine, a medicine used to treat severe mental disorder (psychosis)

The risk of respiratory and/or cardiac arrest may be higher.

Alprazolam with alcohol

It is important not to drink any alcohol while you are taking Alprazolam, as alcohol increases the effects of

the medicine

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your

doctor or pharmacist for advice before taking this medicine.

Pregnancy

There are no adequate experiences from the use of Alprazolam in pregnant women. Do not take Alprazolam

if you are pregnant or planning to become pregnant, unless your doctor considers it strictly indicated.

Observations in humans have indicated that the substance alprazolam can be harmful to the unborn child. If

you are pregnant or planning a pregnancy, consult your doctor about the possibility to stop the treatment. If

you are taking Alprazolam until birth, let your doctor know as your newborn might have some withdrawal

symptoms when it is born.

Breast-feeding

There is a risk of an effect on the baby. Therefore you should not breast-feed during Alprazolam treatment.

Driving and using machines

Alprazolam can cause side effects such as

drowsiness

memory loss

muscle relaxation and

decreased concentration.

Therefore your ability to react may be affected, particularly if you have had insufficient sleep. These effects

may be increased if you drink alcohol. Do not drive or operate machines during treatment with Alprazolam.

Alprazolam contains lactose, sodium and sodium benzoate

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before

taking this medicine.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially `sodium-free´.

This medicine contains 0.12 mg sodium benzoate in each tablet. Sodium benzoate may increase jaundice

(yellowing of the skin and eyes) in newborn babies (up to 4 weeks old).

3.

How to take Alprazolam

Always take Alprazolam exactly as your doctor has told you. You should check with your doctor or

pharmacist if you are not sure.

Adults

Starting dose: 0.25 - 0.5 mg three times daily.

If the effect is insufficient the dose may be increased by your doctor to a maximum of 3 mg per day

(= 24 hours), divided into several doses.

Elderly, debilitated patients and patients with disturbed kidney function or mild liver dysfunction

Starting dose: 0.25 mg two to three times per day (= 24 hours).

If the effect is insufficient the dose may be increased by your doctor to a maximum of 0.75 mg per day

(= 24 hours), divided into several doses.

There is a reduced clearance of the medicine and an increased sensitivity to the medicine in elderly patients.

Alprazolam must not be taken by patients with severely reduced liver function. See section 2 “What you

need to know before you take Alprazolam.”

Use in children and adolescents

Alprazolam is not recommended for children and adolescents under the age of 18 years.

If you feel that Alprazolam is too strong or not strong enough, ask your doctor or pharmacist for advice.

Method of administration

Alprazolam is intended for oral use. The tablets should be taken at the same time every day with a glass of

water. The tablet can be taken independently of mealtimes

and can be divided into equal doses.

Duration of treatment

Treatment with Alprazolam should be as short as possible. This means that you will not normally be given

Alprazolam for more than 8 to 12 weeks., including the tapering-off period. In some cases your doctor may

decide to extend the duration of treatment. Treatment with Alprazolam should not be for more than 12 weeks

without review of your condition by your doctor. This is because use of benzodiazepines may lead to the

development of physical and psychic dependence upon these products. The risk of dependence increases

with the dose and duration of treatment; but it is also greater in patients with a history of alcohol or drug

abuse. Talk to your doctor if you are worried about this.

If you take more Alprazolam than you should

Please contact your doctor or pharmacist immediately if this occurs. Overdose symptoms can include:

drowsiness

confusion and

lethargy.

In a severe overdose the symptoms can be coordination problems, for example:

drunken gait

reduced muscle tone

lowered blood pressure

suppressed breathing

in rare cases coma

fatal in very rare cases.

If you forget to take Alprazolam

If you have forgotten to take a dose, you can still take it unless it is almost time for your next dose. In this

case follow the normal dosing schedule.

Do not take a double dose of Alprazolam to make up for the forgotten dose.

If you stop taking Alprazolam

If you suddenly stop taking Alprazolam, directly after stopping treatment or several days later withdrawal

symptoms may occur, such as mood changes, insomnia and restlessness. This risk will increase if your dose

is reduced too quickly or, if you suddenly stop the treatment.

Suddenly stopping this medicine is therefore not recommended. Your doctor will gradually reduce the dose.

This should be done by reducing the dose every three days, by a maximum of 0.5 mg. It may be necessary in

some cases to reduce the dose more slowly.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Reasons for stopping Alprazolam treatment immediately

If you get any of these symptoms, see your doctor straight away as treatment will need to be

discontinued. Your doctor will then advise how treatment will be stopped.

Very occasionally treatment with Alprazolam can cause serious behavioural or psychiatric effects - for

example agitation, restlessness, aggressiveness, irritability, violent anger, false beliefs, nightmares and

hallucinations or other inappropriate behaviour.

Sudden wheeziness, difficulty in swallowing or breathing, swelling of eyelids, face or lips, rash or

itching (especially affecting the whole body).

Reasons for seeing your doctor straight away

Tell your doctor straight away if you get the following symptoms as your dose or treatment might need to be

changed:

Memory loss (amnesia).

Yellowing of the skin and whites of the eyes (jaundice).

Dependence and withdrawal symptoms

It is possible to become dependent on medicines like Alprazolam while you are taking them which

increases the likelihood of getting withdrawal symptoms when you stop treatment.

Withdrawal symptoms are more common if you:

- stop treatment suddenly

- have been taking high doses

- have been taking this medicine for a long time

- have a history of alcohol or drug abuse.

This can cause effects such as headaches, muscle pain, extreme anxiety, tension, restlessness, confusion,

mood changes, difficulty sleeping and irritability.

In severe cases of withdrawal you can also get the following symptoms: nausea (feeling sick), vomiting,

sweating, stomach cramps, muscle cramps, a feeling of unreality or detachment, being unusually sensitive to

sound, light or physical contact, numbness and tingling of the feet and hands, hallucinations (seeing or

hearing things which are not there while you are awake), tremor or epileptic fits.

Other side effects that may occur are:

Very common: may affect more than 1 in 10 people

Depression

Sleepiness and drowsiness

Jerky, uncoordinated movements

Inability to remember bits of information

Slurred speech

Dizziness, light-headedness

Headaches

Constipation

Dry mouth

Tiredness

Irritability.

Common: may affect up to 1 in 10 people

Loss of appetite

Confusion and disorientation

Increased or decreased sex drive (men and women) and sexual dysfunction

Nervousness or feeling anxious or agitated

Insomnia (inability to sleep or disturbed sleep)

Problems with balance, and unsteadiness (similar to feeling drunk) especially during the day

Loss of alertness or concentration

Inability to stay awake, feeling sluggish

Shakiness or trembling

Double or blurred vision

Feeling sick

Skin reactions

Change in your weight.

Uncommon: may affect up to 1 in 100 people

Feeling elated or over-excited, which causes unusual behaviour

Hallucination (seeing or hearing things that do not exist)

Feeling agitated or angry

Incontinence

Cramping pain in the lower back and thighs, which may indicate menstrual disorder

Muscle spasms or weakness

Vomiting

Drug dependence

Withdrawal syndrome.

Not known: frequency cannot be estimated from the available data

In women, irregular periods or production of too much prolactin (the hormone that stimulates milk

production)

Feeling hostile or aggressive

Abnormal thoughts

Twisting or jerking movements

Being hyperactive

Stomach upsets

Problems with liver function (this shows up in blood tests), inflammation of the liver (hepatitis)

Imbalance to part of nervous system. Symptoms may include: fast heartbeat and unstable blood pressure

(feeling dizzy, light-headed or faint)

Serious allergic reaction which causes swelling of the face or throat

Swelling of the ankles, feet or fingers

Skin reaction caused by sensitivity to sunlight

Difficulty urinating or bladder control problems

Increased pressure in the eyes, which can also affect your vision

Drug abuse.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed

in this leaflet. You can also report side effects directly via HPRA Pharmacovigilance; website: www.hpra.ie.

By reporting side effects you can help provide more information on the safety of this medicine.

5.

How to store Alprazolam

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the blister and carton after ‘EXP’. The

expiry date refers to the last day of that month.

Do not store above 25°C.

Keep the blister in the outer carton in order to protect from light.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw

away medicines you no longer use. These measures will help protect the environment.

6.

Contents of the pack and other information

What Alprazolam contains

The active substance is alprazolam.

Each tablet contains 0.25 mg of alprazolam.

Each tablet contains 0.5 mg of alprazolam.

Each tablets contains 1 mg of alprazolam.

other

ingredients

sodium

docusate,

sodium

benzoate,

pregelatinised

maize

starch,

microcrystalline cellulose, lactose, magnesium stearate, colloidal anhydrous silica, Erythrosine aluminium

lake (E127) (only for 0.5 mg), Indigo carmine aluminium lake (E132) (only for 1 mg).

What Alprazolam looks like and contents of the pack

0.25 mg tablets:

White, oblong tablet with a score line and debossed "APZM 0.25".

The tablet can be divided into equal halves.

0.5 mg tablets:

Pink, oblong tablet with a score line and debossed "APZM 0.5".

The tablet can be divided into equal halves.

1 mg tablets:

Light blue, oblong tablet with a score line and debossed "APZM 1".

The tablet can be divided into equal halves.

The tablets are packed in in aluminium/PVC blisters which are inserted in a carton.

Pack sizes:

10, 20, 30, 40, 50, 60 or 100 tablets

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturers

Marketing Authorisation Holder

Rowex Ltd., Bantry, Co. Cork, Ireland.

Manufacturers

Dragenopharm Apotheker Püschl GmbH, Göllstr. 1, D-84529 Tittmoning, Germany.

Salutas Pharma GmbH, Otto-von-Guericke-Allee 1, 39179 Barleben, Germany.

Lek Pharmaceuticals d.d., Verovškova 57, 1526 Ljubljana, Slovenia.

Lek Pharmaceuticals d.d., Trimlini 2D, 9220 Lendava, Slovenia.

This medicinal product is authorised in the Member States of the EEA under the following names:

Netherlands

ALPRAZOLAM HEXAL 0,25 MG, TABLETTEN

ALPRAZOLAM HEXAL 0,5 MG, TABLETTEN

ALPRAZOLAM HEXAL 1,0 MG, TABLETTEN

Ireland

Alprazolam 0.25 mg Tablets

Alprazolam 0.5 mg Tablets

Alprazolam 1 mg Tablets

This leaflet was last approved in 02/2020.

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Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Alprazolam 0.25 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 0.25 mg of alprazolam.

Excipient(s) with known effect:

Each tablet contains 92.2 mg of lactose and 0.12 of sodium benzoate.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet.

White, oblong tablet with a score line and debossed APZM 0.25.

The tablets can be divided into equal doses.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Symptomatic treatment of anxiety.

Alprazolam should only be used if the disorder is severe or is causing invalidity, or if the patient is experiencing inordinate

suffering as a result of the disorder.

4.2 Posology and method of administration

Posology

The treatment period should be as short as possible. The patient should be reassessed regularly and the need for continued

treatment should be evaluated, especially in case the patient is symptom free. The total length of treatment should not exceed

8-12 weeks, including the period of gradual dose reduction. Prolonged treatment may be necessary in certain circumstances,

but this should not be done until the patient's condition has been reassessed.

As with all benzodiazepines, physicians should be aware that long-term use might lead to dependence in certain patients.

The optimal dose of alprazolam should be individually determined in accordance with the severity of the symptoms and the

patient's response. The lowest dose which can control symptoms should be used. Dose should be reassessed at intervals of no

more than 4 weeks. The usual dose is stated below. In the few patients who require higher doses, the dose should be increased

cautiously to avoid adverse reactions. When higher dose is required, the evening dose should be increased before the daytime

doses.

Patients who have never previously taken psychotropic medicinal products generally require lower doses than patients who

have either already been treated with tranquillisers, antidepressants or hypnotic medicinal products or those who are chronic

alcoholics. In order to avoid ataxia and over-sedation it is recommended that the lowest effective dose be used.

Adults

Initial dose*: 0.25 mg to 0.5 mg, three times a day

Dose*: 0.5 mg to maximum 3 mg per day in divided doses

Elderly, debilitated patients, or patients with impaired renal or hepatic function disorders

Initial dose*: 0.25 mg, twice or three times a day

Dose*: 0.5 mg to 0.75 mg per day in divided doses: gradually increase the dose if necessary, and if the disease permits.

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* If undesirable effects occur, the dose should be reduced.

Paediatric population

Safety and efficacy of alprazolam have not been established in children and adolescents below the age of 18 years; therefore

use of alprazolam is not recommended.

Method of administration

Oral use

Discontinuation of treatment

The dose should be gradually reduced. It is recommended that the daily dose of alprazolam be reduced at a rate not exceeding

0.5 mg per three days. In some patients, it may indeed be necessary to reduce the dose even more gradually.

4.3 Contraindications

Hypersensitivity to the active substance, benzodiazepines or to any of the excipients listed in section 6.1.

Benzodiazepines are also contraindicated in patients with

Myasthenia gravis

Severe respiratory insufficiency

Sleep apnoea syndrome

Severe hepatic insufficiency

4.4 Special warnings and precautions for use

Risk from concomitant use of opioids:

Concomitant use of alprazolam and opioids may result in sedation, respiratory depression, coma and death. Because of these

risks, concomitant prescribing of sedative medicines such as benzodiazepines or related medicinal products such as alprazolam

with opioids should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to

prescribe alprazolam concomitantly with opioids, the lowest effective dose should be used, and the duration of treatment

should be as short as possible (see also general dose recommendation in section 4.2).

The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is

strongly recommended to inform patients and their caregivers (where applicable) to be aware of these symptoms (see section

4.5).

Tolerance

The hypnotic effect can diminish following repeated use over a period of several weeks.

Dependence

Chronic use of benzodiazepines can lead to the development of physical and mental dependence. The risk of dependence is

greater as the dose and length of treatment increase. There is also an increased risk in patients with a history of drug and

alcohol abuse. Furthermore, pharmacodependency may occur at therapeutic doses and/or in patients with no individualised

risk factor. There is an increased risk of pharmacodependency with the combined use of several benzodiazepines regardless of

the anxiolytic or hypnotic indication. Cases of abuse have also been reported.

Patients receiving alprazolam should be monitored accordingly (see sections 4.2, 4.8 and 4.9).

If there is physical dependence, the suspension of treatment is accompanied by withdrawal symptoms. These may consist of

headache and muscle pain, severe anxiety and tension, sleep disorders, restlessness, confusion and irritability. In severe cases

the following symptoms occur: depersonalisation, derealisation, hyperacusis, loss of sensation and tingling sensations in the

limbs, hypersensitivity to light, sound and touch, hallucinations and epileptic seizures. Withdrawal symptoms can appear

several days after the end of treatment.

Rebound insomnia, anxiety and tension

When treatment with Alprazolam is suspended, a transient syndrome can occur in which the symptoms that prompted

treatment with a benzodiazepine (or benzodiazepine-like substance) in the first place recur with greater intensity than before.

The syndrome can be accompanied by other reactions including mood swings, anxiety or sleep disturbances, insomnia and

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restlessness. Since the risk of withdrawal symptoms/rebound symptoms is greater following rapid dose reduction or the abrupt

suspension of treatment, it is recommended that the dose be reduced gradually (tapering off).

It is suggested that the daily dose of alprazolam be decreased by no more than 0.5 mg every three days. Some patients may

require even slower dose reduction.

Duration of treatment

The duration of treatment should be as short as possible (see 4.2) and should not exceed 8-12 weeks, including the so called

tapering off period of gradual dose reduction. Prolongation of the duration of treatment should only be considered after

re-evaluation of the condition of the patient.

It may be important to inform the patient at the start of treatment that the course of treatment will be limited and to explain

clearly how doses will be gradually reduced.

It is important to prepare patients for the occurrence of rebound symptoms in order to avoid as much as possible unease

about the occurrence of such symptoms during the cessation of therapy. In the case of benzodiazepines with a short half-life

time, there are indications that withdrawal symptoms can occur within the dose interval, especially when a high dose is

involved. If benzodiazepines with long half-life times are used, it is important to point out that it is prudent not to switch to

benzodiazepines with short half-life times because of the withdrawal symptoms that may occur.

Amnesia

As with other benzodiazepines, Alprazolam can cause anterograde amnesia. This usually occurs several hours after the product

has been taken (see also 4.8). To reduce the risk patients should ensure that they will be able to have uninterrupted sleep of

7-8 hours.

Psychiatric and paradoxical reactions

Reactions like restlessness, agitation, irritability, aggressiveness, delusion, fits of rage, nightmares, aggravated insomnia,

hallucinations, psychoses, inappropriate behaviour, oneiroid delirium and other behavioural disorders occur, when using

benzodiazepines. Should this occur, use of the medicinal product should be terminated. Paradoxical reactions occur more often

in children and elderly patients.

Specific patient groups

Alprazolam should not be used in patients less than 18 years of age because safety and efficacy has not been established.

The elderly and/or debilitated patients should be treated preferably with a lower than usual dose (see 4.2) to preclude the

development of ataxia or oversedation. Use Alprazolam with caution in elderly patients as there is a risk of falls secondary to

the myorelexant effects of benzodiazopines.

In patients with chronic respiratory insufficiency a lower dose should be used, given the possibility of respiratory depression.

Caution is recommended when treating patients with impaired renal function or mild to moderate hepatic insufficiency.

Benzodiazepines are contraindicated for the treatment of patients with severe hepatic disorders, since benzodiazepines can

promote the development of encephalopathy.

Benzodiazepines are not effective for the primary treatment of psychoses.

In a few cases manic episodes were reported in patients with latent depression.

Benzodiazepines are not recommended for the primary treatment of psychotic illness.

Benzodiazepines are not effective for the primary treatment of severe depression and should not be used alone for the

treatment of anxiety associated with severe depression, since suicide could occur in such patients. When administering to

severely depressed and suicidal patients it is necessary to take suitable precautions and to prescribe appropriate amounts.

Due to possible anticholinergic undesirable effects benzodiazepines should be used with great caution in patients with acute

narrow angle glaucoma or in those patients that may be predisposed.

Benzodiazepines should also be used with the greatest caution in patients with a history of alcohol and drug abuse.

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Alprazolam contains lactose, sodium and sodium benzoate

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption

should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

This medicinal product contains 0.12 mg sodium benzoate in each tablet. Sodium benzoate may increase jaundice (yellowing

of the skin and eyes) in newborn babies (up to 4 weeks old).

4.5 Interaction with other medicinal products and other forms of interactions

Pharmacodynamic interactions

Psychotropic medicinal products:

Alprazolam should be used with caution when combined with other CNS depressants. Enhancement of the central depressive

effect may occur in case of concomitant use with antipsychotics (neuroleptics), anxiolytics/sedatives, some antidepressant

agents, anticonvulsants, sedative H1-antihistamines.

Opioids:

The concomitant use of sedative medicines such as benzodiazepines or related active substances such as alprazolam with

opioids increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The

dose and duration of concomitant use should be limited (see section 4.4).

Special care should be made with medicinal products depressing respiratory function such as opioids (analgesics, antitussives,

substitutive treatments), notably in elderly people.

In the case of opioid analgesics enhancement of the euphoria may also occur leading to an increase in psychic dependence.

Alcohol:

Combination with alcohol potentates the sedative effect of alprazolam. This will affect patients' ability to drive and use

machines.Intake of alcohol should be avoided during treatment with alprazolam.

Clozapine:

With clozapine there is an increased risk of respiratory and/or cardiac arrest.

Muscle relaxants:

One should be prepared for an increase of the muscle relaxing effect (risk of falls) when alprazolam is used during therapy with

a muscle relaxant, especially during the beginning of treatment with alprazolam.

Pharmacokinetic interactions

Since alprazolam is metabolised by certain hepatic enzymes (especially CYP3A4), its effect is enhanced by medicinal products

that inhibit these enzymes. Alprazolam should therefore be used with caution in patients taking these medicinal products and a

reduction of dose may be necessary when such medicinal products are concomitantly used.

CYP3A4 inhibitors

Caution is recommended when alprazolam is co-administered with fluoxetine, propoxyphene, oral contraceptives, sertraline or

diltiazem.

The co-administration of alprazolam with strong CYP3A4 inhibitors like azole antifungals (ketoconazole, itraconazole,

posaconazole, voriconazole), protease inhibitors or some macrolides (erythromycin, clarithromycin, telithromycin) should be

made with caution and a substantial dose reduction considered.

Itraconazole, a potent CYP3A4-inhibitor, increases AUC and prolongs the elimination half-life for alprazolam. In a study where

healthy volunteers were given itraconazole 200 mg/day and 0.8 mg alprazolam, the AUC was increased two-three fold, and the

elimination half-life was prolonged to about 40 hours. Alterations have also been seen on psychomotor function affected by

alprazolam. Itraconazole may enhance the CNS-depressant effects of alprazolam and withdrawal of itraconazole may attenuate

the therapeutic efficacy of alprazolam.

Nefazodone, fluvoxamine and cimetidine: Caution is required when using these agents (CYP3A4 inhibitors) and alprazolam

concurrently and a possible reduction of the alprazolam dose should be considered.

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Nefazodone inhibits CYP3A4 mediated oxidation of alprazolam, which results in a doubling of the plasma concentration of

alprazolam and risk of intensified CNS effects. In combination, it is therefore recommended to reduce the alprazolam dose to

one half of the dose.

Fluvoxamine treatment extends the half-life for alprazolam from 20 hours to 34 hours and doubles the alprazolam

concentration in plasma. When used in combination, half of the dose of alprazolam is recommended.

Cimetidine reduces the clearance of alprazolam which may possibly intensify the effect. The clinical significance of the

interaction has not yet been determined.

CYP3A4 inducers

A reduced effect of alprazolam might occur in patients taking CYP3A4 inducers like rifampicin, phenytoin, carbamazepine or St

John's wort. The plasma alprazolam concentrations in the elimination phase are dependent on certain hepatic enzymes (in

particular CYP3A4) for the metabolism and are reduced by medicinal products that induce these enzymes. When St. John's

wort therapy or treatment with other CYP3A4 inducing agents is suddenly stopped, overdose symptoms of alprazolam may

occur.

Interactions involving HIV protease inhibitors (e.g. ritonavir) and alprazolam are complex and time dependent. Short term, 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.

The effect of alprazolam on the pharmacokinetics of other medicinal products:

Digoxin:

Increase of digoxin plasma levels has been reported with concomitant use of 1 mg alprazolam daily, particularly in the elderly.

Therefore, patients receiving alprazolam and digoxin concurrently should be closely monitored for signs and symptoms of

digoxin toxicity.

Imipramine and desipramine:

It has been reported that concurrent administration of alprazolam (at doses of up to 4 mg/day) with imipramine and

desipramine caused the steady state plasma levels of these substances to increase by 31% and 20% respectively. It is not yet

known whether these changes are of clinical significance.

Warfarin:

It could not be determined whether there was any effect on prothrombin times and warfarin plasma levels.

No interaction was found with propranolol and disulfiram.

4.6 Fertility, pregnancy and lactation

Pregnancy

The data concerning teratogenicity and effects on postnatal development and behavior following benzodiazepine treatment

are inconsistent. A large amount of data based on cohort studies indicate that first trimester exposure to benzodiazepine is not

associated with an increase in the risk of major malformation. However, some early case-control epidemiological studies have

found an increased risk of oral clefts. The data indicated that the risk of having an infant with an oral cleft after maternal

benzodiazepine exposure is less than 2/1000 compared with an expected rate for such defects of approximately 1/1000 in the

general population.

Benzodiazepine treatment at high dose, during the second and/or the third trimester of pregnancy, has revealed a decrease of

foetal active movements and a variability of foetal cardiac rhythm.

When treatment has to be administered for medical reasons during the last part of pregnancy, even at low doses, floppy infant

syndrome such as axial hypotonia, sucking troubles leading to a poor weight gain may be observed. These signs are reversible

but they may last from 1 up to 3 weeks, according to the half life of the product. At high doses, respiratory depression or

apnea and hypothermia in newborn may appear. Moreover, neonatal withdrawal symptoms with hyperexcitability, agitation

and tremor may be observed a few days after birth, even if no floppy infant syndrome is observed. The apparition of

withdrawal symptoms after birth depends on the half life of the substance.

Alprazolam should not be used during pregnancy unless the clinical condition of the woman requires treatment with

alprazolam. 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.The therapeutic indications and posology should be strictly respected.

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If alprazolam treatment is necessary during last part of pregnancy, high doses should be avoided and withdrawal symptoms

and/or floppy infant syndrome should be monitored in newborn.

Breast-feeding

Alprazolam passes into breast milk. Accordingly, women are advised not to breastfeed while they are using Alprazolam.

Fertility

No data are available regarding effects of alprazolam on fertility.

4.7 Effects on ability to drive and use machines

Alprazolam has major influence on the ability to drive and use machines. Persons whose functioning involves the ability to

carry out keen and continuous observations, alertness so as to make the right decisions and full control over the use of limbs,

should be warned that their abilities to are affected by sedation, amnesia, reduced concentration and muscular weakness. If a

patient does not get enough sleep the risk of reduced alertness increases.

Patients should be warned of this hazard and advised not to drive or operate machinery during treatment. These effects are

potentiated by alcohol (see section 4.5)

4.8 Undesirable effects

Adverse reactions have been ranked under headings of frequency using the following convention:

Very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥1/10000, < 1/1000); very rare (<

1/10000); not known (cannot be estimated from the available data).

MedDRA

System Organ Class

Frequency

Undesirable Effects

Endocrine disorders

Not known

Hyperprolactinaemia*

Metabolism and nutrition disorders

Common

Decreased appetite

Psychiatric disorders

Very common

Depression

Common

Confusional state, disorientation, libido decreased,

anxiety, insomnia, nervousness, libido increased*

Uncommon

Mania* (see section 4.4), hallucination*, anger*,

agitation*, dependence

Not known

Hypomania*, aggression*, hostility*, thinking

abnormal*, psychomotor hyperactivity*, drug abuse

Nervous system disorders

Very common

Sedation, somnolence, ataxia, memory impairment,

dysarthria, dizziness, headache

Common

Balance disorder, coordination abnormal,

disturbance in attention, hypersomnia, lethargy,

tremor

Uncommon

Amnesia

Not Known

Autonomic nervous system imbalance*, dystonia*

Eye disorders

Common

Vision blurred

Gastrointestinal disorders

Very common

Constipation, dry mouth

Common

Nausea

Uncommon

Vomiting

Not known

Gastrointestinal disorder*

Hepatobiliary disorders

Not known

Hepatitis*, hepatic function abnormal*, jaundice*

Skin and subcutaneous tissue disorders

Common

Dermatitis*

Not Known

Angioedema*, photosensitivity reaction*

Musculoskeletal and connective tissue disorders

Uncommon

Musculoskeletal weakness

Renal and urinary disorders

Uncommon

Incontinence*

Not known

Urinary retention*

Reproductive system and breast disorders

Common

Sexual dysfunction*

Uncommon

Menstruation irregular*

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General disorders and administration site conditions

Very common

Fatigue, irritability

Uncommon

Withdrawal syndrome

Not Known

Oedema peripheral*

Investigations

Common

Weight increased, weight decreased

Not known

Intraocular pressure increased*

*ADR identified post-marketing

Withdrawal symptoms have occurred following rapid decrease or abrupt discontinuance of benzodiazepines including

alprazolam. These can range from mild dysphoria and insomnia to a major syndrome, which may include abdominal and

muscle cramps, vomiting, sweating, tremor and convulsions. In addition, withdrawal seizures have occurred upon rapid

decrease or abrupt discontinuation of therapy with alprazolam.

Side effects like drowsiness, sedation, decreased attention, confusion, fatigue, headache, double vision, dizziness, muscle

weakness, ataxia, and blurred vision may occur, especially at the beginning of treatment. These symptoms are generally

reduced with repeated administration.

Amnesia

Anterograde amnesia can occur even at therapeutic doses and the risk increases at higher doses. Amnesia may be

accompanied by inappropriate behaviour (see also section 4.4).

Depression

Previously unnoticed depressions may become apparent, in susceptible individuals, during benzodiazepine use.

Psychiatric and "paradoxical" reactions

Reactions such as restlessness, agitation, irritability, aggression, delusions, fits of rage, nightmares, hallucinations, psychoses,

inappropriate behaviour and other behavioural disorders. Such paradoxical reactions are more likely to occur in children and

elderly patients. In case of paradoxical reactions treatment should be stopped.

Dependence

Use of this substance (even at therapeutic doses) can result in the development of physical dependence. Suspension of

treatment can therefore lead to withdrawal symptoms and rebound symptoms (see also section 4.4 ). Cases of psychological

dependence can also occur. Instances of abuse have been reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via HPRA Pharmacovigilance; website: www.hpra.ie.

4.9 Overdose

General information about toxicity

As with other benzodiazepines, overdose should not present a threat to life unless combined with other CNS depressants

(including alcohol). In the management of overdose with any medicinal product it should be born in mind that multiple agents

may have been taken. Treatment should be adjusted accordingly.

Symptoms

An overdose usually takes the form of a depression of central nervous system activity, varying from drowsiness to coma. In

mild cases of overdosing the symptoms consist of drowsiness, mental confusion and lethargy. In more severe cases ataxia,

hypotonia, hypotension, respiratory depression, in rare cases coma and in very rare cases death.

Management

Soon after ingestion it is advisable to stimulate vomiting if the patient is conscious, or, alternatively, if the patient is

subconscious, to perform gastric lavage while protecting the airway by intubation. If emptying of the stomach does not result

in an improvement of the patient's condition, activated charcoal should be administered and, if necessary, be left behind in the

stomach in combination with a laxative. When the amount taken is known to be large, this still may be effective after a long

time forced diuresis or haemodialysis is of no value.

Flumazenil can be useful as an antidote.

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For individuals in coma, treatment is largely symptomatic. Measures should be taken to avoid possible complications such as

asphyxia due to patients swallowing their tongue or aspiration of the stomach contents. The intravenous administration of

liquids can be useful in preventing dehydration.

Especially when combined with other sedatives, supporting the vital functions, in particular respiration, is important.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Psycholeptics; benzodiazepine derivates

ATC code: N05BA12

Mechanism of action

Alprazolam, like other benzodiazepines, has a high affinity for the benzodiazepine binding site in the brain. It facilitates the

inhibitory neurotransmitter action of gamma-aminobutyric acid which mediates both pre- and post-synaptic inhibition in the

central nervous system (CNS).

Alprazolam is an anxiolytic medicinal product. Like other benzodiazepines, in addition to its anxiolytic properties, Alprazolam

has sedative, hypnotic, muscle-weakening and anticonvulsive properties.

5.2 Pharmacokinetic properties

Absorption

Alprazolam is rapidly absorbed following oral administration. After oral administration, bioavailability is 80% or more.

Maximum plasma levels are reached one to two hours after oral administration.

Distribution

Following a single administration, the plasma levels are directly proportional to the administered dose. The maximum plasma

levels observed following a dose of 0.5 mg to 3 mg are 8 to 37 ng/ml. Following several administrations of 1.5 mg to 10

mg/day, the average steady-state level was 18.3 to 100 ng/ml.

In vitro, 70% of alprazolam is bound to serum proteins.

Biotransformation

The most important metabolites of alprazolam present in urine are alpha-hydroxy-alprazolam and a benzophenone derivative.

The major metabolites in plasma are alpha-hydroxy-alprazolam and 4-hydroxy-alprazolam.Alprazolam is mainly metabolised

by CYP3A4.

The benzophenone derivative is virtually inactive. The biological activity of alpha-hydroxy-alprazolam is comparable with that

of alprazolam, while 4-hydroxy-alprazolam is about 10 x less active. The plasma levels of these metabolites are low. Their

half-lives appear to be of the same order of magnitude as that of alprazolam. The metabolites therefore make only a limited

contribution to the biological activity of Alprazolam.

Elimination

The average half-life of alprazolam is between 12 and 15 hours. Repeated doses may lead to accumulation and this should be

borne in mind in elderly patients and those with impaired renal or hepatic function.

Alprazolam and its metabolites are mainly excreted via the urine.

Elderly

In elderly men the mean elimination half-life can be prolonged (approximately 16 h).

Hepatic impairment

The mean elimination half-life is increased with impaired liver function (approximately 19 h).

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based in conventional studies on genotoxicity and carcinogenic potential.

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In rats administered alprazolam for 24 months a tendency for dose-related increase in number of cataracts and in corneal

vascularisation was evident in females and males, respectively. The lesions did not appear until after 11 months of treatment.

In a repeated dose toxicity study (12 months) with high doses p.o. convulsions were observed in dogs, some of which were

lethal. Relevance for men is not clear.

There was no evidence of carcinogenic potential as revealed by carcinogenicity studies conducted in rats and mice.

Alprazolam administered to rats and rabbits at high doses caused an increase in birth defects and foetal death.

Prenatal exposure of mice and rats to benzodiazepines, including alprazolam, has been associated with behavioural changes in

the offspring. The possible significance of these changes to the human situation is unclear.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Docusate sodium

Sodium benzoate (E211)

Starch, pregelatinised (maize starch)

Cellulose, microcrystalline

Lactose monohydrate

Magnesium stearate

Silica, colloidal anhydrous

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

Do not store above 25°C.

Keep the blister in the outer carton in order to protect from light.

6.5 Nature and contents of container

The tablets are packed in aluminium/PVC blisters which are inserted in a carton.

Pack sizes:

10, 20, 30, 40, 50, 60, 100 tablets

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Rowex Ltd

Newtown

Bantry

Co. Cork

Ireland

8 MARKETING AUTHORISATION NUMBER

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PA0711/140/001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 17th October 2008

Date of last renewal: 23rd December 2010

10 DATE OF REVISION OF THE TEXT

July 2020

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