Consumer medicine information

Kalma [8760]

Alprazolam

BRAND INFORMATION

Brand name

Kalma

Active ingredient

Alprazolam

Schedule

S8

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Kalma [8760].

What is in this leaflet

This leaflet answers some common questions about Kalma.

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 Kalma against the benefits this medicine is expected to have for you.

If you have any concerns about taking this medicine, talk to your doctor or pharmacist.

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

What this medicine is used for

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

It is used to treat:

  • anxiety.
  • panic attacks.

Ask your doctor if you have any questions about why Kalma has been prescribed for you. Your doctor, however, may have prescribed Kalma for another reason.

Kalma is available only with a doctor's prescription.

How it works

Kalma 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 alprazolam are 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.

If you take Kalma for too long, it may become habit-forming. Benzodiazepines may lead to physical or psychological dependence. If you have any concerns, you should discuss this with your doctor.

Before you take this medicine

When you must not take it

Do not take this medicine if:

  • You are allergic to alprazolam, benzodiazepines or any of the ingredients listed at the end of this leaflet.
    Some of the symptoms of an allergic reaction may include skin rash, itching or hives, swelling of the face, lips or tongue which may cause difficulty in swallowing or breathing, wheezing or shortness of breath.
  • You have had any of the following:
    - severe and chronic lung disease
    - myasthenia gravis, a condition which causes severe muscle weakness.
  • You are pregnant.
    Kalma may affect your unborn baby if you take it during pregnancy.
    Your doctor will discuss the risks and benefits of taking this medicine during pregnancy.
  • You are breastfeeding.
    Kalma passes into the breast milk and may cause drowsiness, weight loss and feeding difficulties in the infant.

Do not give this medicine to a child unless advised by the child's doctor. The safety and effectiveness of Kalma in children have not been established.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

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 have, any medical conditions, especially the following:

  • depression, psychosis or schizophrenia
  • borderline personality disorder (BPD)
  • post-traumatic stress disorder (PTSD)
  • epilepsy (fits or convulsions)
  • liver, kidney or lung problems
  • glaucoma (increased eye pressure)
  • hypotension (low blood pressure)

Tell your doctor if you are pregnant or planning to become pregnant or are breastfeeding. Your doctor can discuss with you the risks and benefits involved.

Tell your doctor if you have a history of alcohol or drug abuse, or find it difficult to stop taking medicines, drugs or drinking alcohol. Your doctor may want to give you extra support when you need to stop taking this medicine.

Tell your doctor if you plan to have surgery.

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

Taking other medicines

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

Some medicines may be affected by Kalma or may affect how well Kalma works. You may need different amounts of your medicines, or you may need to take different medicines. Your doctor will advise you.

Tell your doctor or pharmacist if you are taking any of the following:

  • other sleeping tablets, sedatives (medicines used to produce calmness) or tranquillisers
  • muscle relaxants
  • medicines for depression
  • lithium, a medicine used to treat mood swings and some types of depression
  • medicines used to treat epilepsy (fits and seizures) such as barbiturates
  • some medicines used to treat high blood pressure
  • antihistamines, medicines for allergies, hay fever or colds, some pain relievers, especially strong pain relievers such as codeine, morphine or propoxyphene
  • disulfiram, a medicine used in the treatment of alcohol dependence
  • cimetidine, a medicine commonly used to treat reflux and ulcers.
  • some antibiotics such as erythromycin or clarithromycin
  • oral contraceptives (birth control pill)
  • HIV protease inhibitors, medicines used to treat HIV infection
  • some antifungals, medicines used to treat fungal infections, such as ketoconazole or itraconazole

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

How to take this medicine

How much to take

Follow all directions given to you by your doctor and pharmacist carefully. They may differ from the information contained in this leaflet.

The dose varies from patient to patient.

Your doctor will tell you how much to take. Take Kalma exactly as directed by your doctor. Your doctor will decide the right dose for you.

Elderly patients and people with liver or kidney problems may need smaller doses.

If you do not understand the instructions on the bottle, ask your doctor or pharmacist for help.

How to take it

Swallow the tablets with a full glass of water.

Kalma 0.25 mg, 0.5 mg and 1 mg tablets can be divided in half along the scoreline if your doctor has prescribed half a tablet. Kalma 2 tablets can also be quartered.

When to take it

Take your tablet at about the same time each day.

Your doctor will tell you how many times a day you should take your medicine but taking it at the same time each day will have the best effect. It will also help you remember to take it.

Kalma can be taken with or without food.

However, taking the tablets immediately after food may reduce the sleepiness or drowsiness you may experience with this medicine.

How long to take it

Do not take Kalma for longer than your doctor has directed.

In general, benzodiazepines such as alprazolam are 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.

Continue taking your medicine for as long as your doctor tells you to and always see your doctor before you stop taking it. Your dose will need to be reduced gradually to prevent unwanted side effects.

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.

If you are not sure what to do, ask your doctor or pharmacist.

If you have any questions about this, check with your doctor or pharmacist.

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

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think you or anyone else may have taken too much Kalma.

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

Tell the doctor, nurse or pharmacist about any alcohol or other medicines which you have taken.

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

While you are taking this medicine

Things you must do

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

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

  • you become pregnant while taking this medicine.
  • you plan to have surgery, including dental surgery.
  • you are about to have any blood tests.
  • you have to have any clinical tests such as an EEG (electroencephalogram).

Alprazolam may affect the results of some tests.

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

If you feel this medicine is not helping your condition, tell your doctor.

Visit your doctor regularly so they can check on your progress and determine whether you need to keep taking this medicine.

Always discuss with your doctor any problems or difficulties during or after taking Kalma. If you are being treated for anxiety, be sure to tell your doctor how you feel, especially if your anxiety attacks are getting worse or more frequent. This will help your doctor determine the best treatment for you.

Do not run out of your medicine.

It is important that you take your medicine as prescribed.

Things you must not do

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

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

Do not drive or operate machinery until you know how Kalma affects you. This medicine may cause drowsiness, dizziness or lightheadedness in some people. If any of these occur, do not drive, operate machinery or do anything else that could be dangerous.

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

Do not take Kalma for longer than your doctor has prescribed.

This medicine should be taken for short periods only (for example 2 to 4 weeks), unless advised otherwise by your doctor.

Do not increase your dose, without first checking with your doctor. If your symptoms have returned even though you are taking the same dose, you should speak to your doctor, who will determine whether a dose adjustment is required.

Do not stop taking this medicine, or change the dose, without checking with your doctor. Stopping this medicine suddenly may make your condition worse and cause other unwanted effects such as trouble sleeping, irritability and nervousness. Your doctor may want you to gradually reduce the amount of Kalma you are taking before stopping completely.

Do not suddenly stop taking Kalma if you suffer from epilepsy. Stopping this medicine suddenly may make your epilepsy worse.

Things to be careful of

Be careful when drinking alcohol while taking this medicine. Your doctor may suggest you avoid alcohol or reduce the amount of alcohol you drink. Combining Kalma and alcohol can make you more sleepy, dizzy or lightheaded. Also, your tolerance to alcohol may be lower than usual.

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 Kalma.

This medicine helps most people with anxiety or panic attacks, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

It can be difficult to tell whether side effects are the result of taking this medicine, effects of your condition or side effects of other medicines you may be taking. For this reason it is important to tell your doctor of any change in your condition.

If you are over 65 years of age you may have an increased chance of getting side effects.

Do not be alarmed by the 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 or pharmacist if you notice any of the following and they worry you:

  • drowsiness, tiredness
  • dizziness, lightheadedness, confusion
  • unsteadiness, clumsiness
  • slurred speech
  • blurred vision
  • headache
  • loss of appetite
  • nausea (feeling sick)
  • constipation
  • dry mouth
  • stomach upsets
  • changes in sex drive
  • urinary problems
  • menstrual irregularities.

The above list includes the more common side effects. They are usually mild and do not last very long.

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

  • loss of alertness or concentration, memory loss
  • abnormal thinking
  • nervousness or feeling anxious
  • shakiness or tremor, muscle weakness
  • involuntary movements
  • swelling of hands, ankles or feet
  • yellowing of the skin and whites of the eyes.

The above list serious side effects that may require medical attention. Serious side effects are not common.

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

  • aggressive behaviour, hostility, agitation, violent anger, hallucinations
  • allergic reactions such as swelling of the face, lips or tongue which may cause difficulty in swallowing or breathing; skin rash, hives or itching.

The above list includes serious side effects which may require medical attention. Serious side effects are rare.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

After taking this medicine

Storage

Keep your tablets in the bottle until it is time to take them. If you take the tablets out of the bottle they may not keep well.

Keep your tablets in a cool dry place, protected from light, where the temperature stays below 25°C.

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

Do not leave your medicine in the car or on window sills.

Heat and dampness can destroy some medicines.

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

Disposal

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

Product description

What it looks like

Kalma 0.25 tablets are white, oval, scored tablets, marked AL|0.25 and G

Available in bottles of 10 and 50 tablets.

Kalma 0.5 tablets are pale pink, oval, scored tablets, marked AL|0.5 and G.

Available in bottles of 10 and 50 tablets.

Kalma 1 tablets are pale blue, oval, scored tablets, marked AL|1.0 and G

Available in bottles of 10 and 50 tablets.

Kalma 2 tablets are white, oblong, triple scored tablets, marked |A|L| and |G|2|.

Available in bottles of 50 tablets.

Ingredients

The active ingredient in Kalma is alprazolam.

Each tablet contains 0.25 mg, 0.5 mg, 1 mg or 2 mg of alprazolam.

The tablets also contain the following inactive ingredients:

  • lactose monohydrate
  • sodium benzoate (211)
  • maize starch
  • magnesium stearate
  • sodium starch glycollate
  • microcrystalline cellulose
  • colloidal anhydrous silica
  • povidone
  • docusate sodium
  • indigo carmine CI 73015 (132) (Kalma 0.5 mg and Kalma 1 mg only)
  • erythrosine CI 45430 (127) (Kalma 0.5 mg only).

Kalma also contains sugars (as lactose and benzoates).

The tablets are gluten free.

Sponsor

Alphapharm Pty Ltd
Level 1, 30 The Bond
30 - 34 Hickson Road
Millers Point NSW 2000
www.mylan.com.au

Australian Registration Numbers

Kalma 0.25 - AUST R 46835

Kalma 0.5 - AUST R 46837

Kalma 1 - AUST R 46839

Kalma 2 - AUST R 63993

This leaflet was prepared in June 2019.

Kalma_cmi\Jun19/00

Published by MIMS September 2019

BRAND INFORMATION

Brand name

Kalma

Active ingredient

Alprazolam

Schedule

S8

 

1 Name of Medicine

Active ingredient: alprazolam.

6.7 Physicochemical Properties

Chemical name: 8-chloro-1-methyl- 6- phenyl-4H-S-triazolo(4,3-α)(1,4)- benzodiazepine.
Molecular formula: 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.


CAS number.

CAS Registry no.: 28981-97-7.

2 Qualitative and Quantitative Composition

Kalma tablets contain alprazolam, an anti-anxiety, benzodiazepine derivative chemically and pharmacologically related to other drugs of this class.
Each Kalma 0.25 tablet contains 0.25 mg of alprazolam; each Kalma 0.5 tablet contains 0.5 mg of alprazolam; each Kalma 1 tablet contains 1 mg of alprazolam; each Kalma 2 tablet contains 2 mg of alprazolam.
Kalma also contains sugars (as lactose and benzoates).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Kalma 0.25.

Alprazolam 0.25 mg tablet: white, oval, marked AL/0.25 on one side, G on reverse.

Kalma 0.5.

Alprazolam 0.5 mg tablet: pale pink, oval, marked AL/0.5 on one side, G on reverse.

Kalma 1.

Alprazolam 1 mg tablet: pale blue, oval, marked AL/1.0 on one side, G on reverse.

Kalma 2.

Alprazolam 2 mg tablet: white, oblong, triple scored, marked /A/L/ on one side, /G/2/ on reverse.

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 CNS as selective depressants.

Clinical trials.

Clinical studies in healthy volunteers with 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 humans showed that alprazolam decreased sleep latency, increased duration of sleep and decreased the number of nocturnal awakenings. Alprazolam produced small decreases in both stages 3 to 4 and rapid eye movement (REM) sleep.

5.2 Pharmacokinetic Properties

Absorption.

Following oral administration to fasting subjects, alprazolam is rapidly absorbed with almost complete bioavailability. Alprazolam exhibits linear kinetics; after single dose administration of 0.5 to 3 mg, plasma levels of 8 to 40 nanogram/mL were observed; during multiple dose administration of 1.5 to 10 mg/day in divided doses, steady-state plasma levels of 18.3 to 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 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 unchanged alprazolam concentration were always less than 4%. The reported relative potencies in benzodiazepine receptor binding experiments and in animal models of induced seizure inhibition are 0.20 and 0.66, respectively, for 4-hydroxyalprazolam and α-hydroxyalprazolam. Such low concentrations and the lesser potencies of 4-hydroxyalprazolam and α-hydroxyalprazolam suggest that they are unlikely to contribute much to the pharmacological effects of alprazolam. The benzophenone metabolite is essentially inactive.

Excretion.

Alprazolam and its metabolites are excreted primarily in the urine. In addition to alprazolam, the major drug related materials excreted in urine are α-hydroxyalprazolam, and a benzophenone analogue. About 50 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

Anxiety.

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.
The diagnostic criteria for panic disorder in DSM-III-R are as follows:
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).
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.
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.
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.
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 (i.e. beyond three months) suggest that many patients continue to benefit from alprazolam therapy and that alprazolam efficacy is maintained for up to eight 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 eight 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

Kalma is contraindicated in:
Known hypersensitivity to benzodiazepines;
Chronic obstructive airways disease with incipient respiratory failure;
Myasthenia gravis.

4.4 Special Warnings and Precautions for Use

Identified precautions. 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 patients or potentially suicidal patients should be applied when using higher doses of alprazolam in patients with panic related disorders. Episodes of hypomania and mania have been reported in association with the use of alprazolam in patients with depression.

Psychiatric and paradoxical reactions.

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

Hypotension.

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

Epilepsy.

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

Impaired respiratory function.

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

Acute narrow angle glaucoma.

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

Amnesia.

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

Abuse.

Physical and psychological dependence have occurred with recommended doses of benzodiazepines. As with all benzodiazepines, the risk of dependence increases with higher doses and long-term use and is further increased in patients with a history of alcoholism or drug abuse. Caution must, therefore, be exercised in administering Kalma 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 prescription 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 recommended doses 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 Kalma tablets. 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 states, 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 Kalma tablets who require a dosage reduction be gradually tapered under close supervision (see Section 4.2 Dose and Method of Administration, 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 doctor.
The discontinuation of therapy with Kalma tablets may not only result in withdrawal symptoms, but also in relapse of the anxiety and panic symptoms of the original disorder and a rebound effect. The term relapse refers to the return of symptoms characteristic of the original disorder, at levels approximately equal to those seen at baseline before active treatment was initiated. Rebound phenomena 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 comprising both controlled and uncontrolled studies in which 641 patients received alprazolam tablets for the treatment of panic disorder, discontinuation emergent symptoms which occurred at a rate of over 5% in patients treated with alprazolam tablets and at a greater rate than the placebo treated group were as 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 of alprazolam tablets 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, in which the ability of patients to discontinue medication was measured, 71 to 93% of alprazolam treated patients tapered completely off therapy compared to 89 to 96% of placebo treated patients.
In a controlled clinical trial of three to twelve months duration involving 144 patients, in which 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.
Instances of irritability, hostility and intrusive thoughts have been reported during discontinuance of alprazolam in patients with post-traumatic stress disorder.

Use in renal and hepatic impairment.

Patients with impaired renal or hepatic function should use benzodiazepine medication with caution and dosage reduction 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 Kalma in children have 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 other medications which themselves produce CNS depression, e.g. barbiturates, alcohol, sedatives, tricyclic antidepressants, nonselective MAO inhibitors, phenothiazines and other antipsychotics, skeletal muscle relaxants, antihistamines or 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 metabolized 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 such as erythromycin and clarithromycin, grapefruit juice, ergotamine, cyclosporine, amiodarone and nifedipine.
Interactions involving HIV protease inhibitors (e.g. ritonavir) and alprazolam are complex and time dependent. Low doses of ritonavir resulted in a large impairment of alprazolam clearance, prolonged its elimination half-life and enhanced clinical effects. However, upon extended exposure to ritonavir, CYP3A induction offset this inhibition. This interaction will require a dose adjustment or discontinuation of alprazolam.
Increased digoxin concentrations have been reported whem alprazolam was given, especially in the elderly (> 65 years of age). Patients who receive alprazolam and digoxin should therefore be monitored for signs and symptoms related to digoxin toxicity.
Alprazolam may also interact with disulfiram resulting in increased plasma levels of alprazolam.
Interactions have been reported between some benzodiazepines and anticonvulsants, with changes in the serum concentration of the benzodiazepine or 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 tablets 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 the 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 woman during the first trimester. Because use of these drugs is rarely a matter of urgency, their use during the first trimester should almost always be avoided. The data concerning teratogenicity and effects in postnatal development and behaviour following benzodiazepine treatment are inconsistent. There is evidence from some early studies with other members of the benzodiazepine class that in utero exposure may be associated with malformations. Later studies with the benzodiazepine class of drugs have provided no clear evidence of any type of defect.
Infants exposed to benzodiazepines during the late third trimester of pregnancy or during labour have been reported to exhibit either the floppy infant syndrome or neonatal withdrawal symptoms. Benzodiazepines cross the placenta and may cause hypotonia, respiratory depression and hypothermia in the newborn infant. Continuous treatment during pregnancy and administration of high doses in connection with delivery should be avoided.
The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. Patients should be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their physicians about the desirability of discontinuing the drug.
Benzodiazepines, including alprazolam, are known to be excreted in human 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, Kalma is not recommended for use in breastfeeding, unless there are compelling circumstances to the contrary.

4.8 Adverse Effects (Undesirable Effects)

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. Common adverse effects include disorientation, libido decreased, balance disorder, hypersomnia, lethargy, constipation, dry mouth and nausea. Less common adverse reactions were blurred vision, headache, depression, insomnia, nervousness/ anxiety, tremor, change in weight, memory impairment/ amnesia, coordination disorders, various gastrointestinal symptoms, and autonomic manifestations. As with other benzodiazepines, reactions such as stimulation, agitation, concentration difficulties, confusion, hallucinations or other adverse behavioural effects have been reported with alprazolam. Increased intraocular pressure has been rarely reported.
In addition, the following adverse events have been reported in association with the use of anxiolytic benzodiazepines including alprazolam: dystonia, irritability, anorexia, fatigue, slurred speech, jaundice, musculoskeletal weakness, changes in libido, menstrual irregularities, incontinence, urinary retention, abnormal hepatic 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, gastrointestinal 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).

Post-marketing experience.

The following additional adverse effects have been reported. See Table 3.

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.

4.2 Dose and Method of Administration

The optimum dosage of Kalma should be individualised, based upon the severity of the symptoms and individual patient response. The daily dosage shown in 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 tranquillizers, antidepressants, or hypnotics or those with a history of chronic alcoholism. It is recommended that the general principle of using the lowest effective dosage be followed to preclude the development of oversedation or ataxia.
In patients who experience early morning anxiety and emergence of anxiety symptoms, it is recommended that the same total daily dose be given divided as more frequent administration.
Patients should be periodically reassessed and dosage adjustments made, as appropriate.
Administration of Kalma 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 Kalma 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 three 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

As with all patients taking CNS depressant medications, patients receiving Kalma should be warned not to operate dangerous machinery or motor vehicles until it is known that they do not become drowsy or dizzy from Kalma 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 Kalma.
Following the prolonged use of Kalma 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 of sleep disturbance can occur after use of Kalma (see Section 4.4 Special Warnings and Precautions for Use, Withdrawal and dependence).
In general, benzodiazepines should be prescribed for short periods only (e.g. 2 to 4 weeks). With the exception of the use of Kalma for the treatment of panic disorder (see Section 4.1 Therapeutic Indications), continuous long-term use of Kalma is not recommended. There is evidence that tolerance develops to the sedative effects of benzodiazepines. After as little as one week of therapy, withdrawal symptoms can appear following the cessation of recommended doses e.g. rebound insomnia following cessation of an anxiolytic benzodiazepine (see Section 4.4 Special Warnings and Precautions for Use, Withdrawal and dependence).

4.9 Overdose

Symptoms.

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 and lethargy, impaired coordination, diminished reflexes, slurred speech, dilated pupils, absent bowel sounds and tachycardia. In more serious cases, symptoms may include ataxia, hypotonia, hypotension, hypothermia, rhabdomyolysis, atrioventricular block, coma and, very rarely, death. Serious sequelae occur when alprazolam is taken with other drugs and/or ethanol is concomitantly ingested. Deep coma, marked hypotension and respiratory depression may indicate other drugs have been ingested as well. In terms of duration, most obtunded patients become arousable within 12 to 36 hours following an acute overdose.

Treatment.

In the management of overdosage, it should be borne in mind that multiple agents may have been taken. Treatment of overdosage is primarily supportive of respiratory and cardiovascular function. Following overdosage with Kalma tablets, activated charcoal should be given to reduce absorption. Activated charcoal is most effective when administered within 1 hour of ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via nasogastric tube once the airway is protected.
The benzodiazepine antagonist flumazenil may be useful in hospitalised patients for the reversal of CNS actions of benzodiazepines. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for resedation, respiratory depression and other residual benzodiazepine effects for an appropriate period after treatment. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. 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.
Contact the Poisons Information Centre on 131126 (Australia) for advice on the management of overdosage.

7 Medicine Schedule (Poisons Standard)

S8.

6 Pharmaceutical Particulars

6.1 List of Excipients

Kalma 0.25, Kalma 0.5, Kalma 1 and Kalma 2 tablets also contain lactose monohydrate, microcrystalline cellulose, maize starch, sodium benzoate, docusate sodium, povidone, colloidal anhydrous silica, sodium starch glycollate, magnesium stearate. Kalma 0.5 tablets also contain erythrosine CI 45430 (Kalma 0.5 only) and indigo carmine CI 73015 (Kalma 0.5 and Kalma 1 only).

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 below 25°C.

6.5 Nature and Contents of Container

Kalma 0.25.

Available in bottle packs (HDPE) of 10 and 50 tablets.

Kalma 0.5.

Available in bottle packs (HDPE) of 10 and 50 tablets.

Kalma 1.

Available in bottle packs (HDPE) of 10 and 50 tablets.

Kalma 2.

Available in bottle packs (HDPE) of 50 tablets.
Not all strengths and/or pack sizes may be available.

6.6 Special Precautions for Disposal

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

Summary Table of Changes