Consumer medicine information

Paxam

Clonazepam

BRAND INFORMATION

Brand name

Paxam

Active ingredient

Clonazepam

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Paxam.

What is in this leaflet

This leaflet answers some common questions about PAXAM. It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

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

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

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

What PAXAM is used for

PAXAM is used to treat epilepsy in adults and children aged 2 years and over.

PAXAM contains the active ingredient clonazepam, which belongs to a group of medicines called benzodiazepines. These medicines are thought to work by their action on brain chemicals.

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

The use of benzodiazepines may lead to dependence on the medicine. If you have any concerns, you should discuss this with your doctor.

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

Before you take PAXAM

When you must not take it

Do not take PAXAM if you have an allergy to:

  • any medicine containing clonazepam or other benzodiazepines
  • any of the ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not take PAXAM if you have:

  • severe and chronic lung disease
  • severe liver disease
  • an addiction to drugs or alcohol

Do not take this medicine if you have galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption. People with these rare hereditary problems should not take this medicine as it contains lactose.

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 have allergies to any other medicines, foods, dyes or preservatives.

Tell your doctor if you have or have had any of the following medical conditions:

  • liver problems
  • kidney problems
  • lung problems
  • high or low blood pressure
  • glaucoma, a condition characterised by an increased pressure in the eye
  • myasthenia gravis, a condition characterised by severe muscle weakness
  • depression, psychosis, schizophrenia
  • spinal or cerebellar ataxia, condition of clumsiness or in coordination of the muscles
  • history of addiction or drug dependence
  • porphyria, a rare hereditary disorder which affects blood pigment
  • sleep apnoea, a condition where you stop breathing when you're asleep; PAXAM is not recommended for use in patients with sleep apnoea due to possible additive effects on respiratory depression.

Tell your doctor if you are pregnant or plan to become pregnant. It is not known whether PAXAM is safe to use during pregnancy. There have been reports of unwanted effects occurring in the newborn with the use of medicines of this class when used during pregnancy.

Your doctor will discuss with you the risks and benefits involved.

Tell your doctor if you are breastfeeding or plan to breastfeed. The active ingredient in PAXAM passes into breast milk and may cause drowsiness and feeding difficulties in the baby.

Tell your doctor if you drink alcohol. Alcohol may change the effects of PAXAM and may even cause you to have an epileptic seizure.

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

Taking other medicines

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

Some medicines and PAXAM may interfere with each other. These include:

  • other medicines for epilepsy, such as phenytoin, carbamazepine, sodium valproate
  • sleeping tablets, sedatives, muscle relaxants
  • medicines for depression such as tricyclic antidepressants, monoamine oxidase inhibitors
  • medicines for mental illness
  • antihistamines, medicines for allergies or colds
  • pain relievers
  • anaesthetics
  • cimetidine, a medicine used to treat reflux and stomach ulcers
  • disulfiram, a medicine used to deter alcohol consumption
  • lithium, a medicine used to treat mood swings and some types of depression.
  • fluconazole, an antifungal medication used for a number of fungal infections

These medicines may be affected by PAXAM or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

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

How to take PAXAM

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

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

How much to take

Take PAXAM exactly as directed by your doctor. Your doctor will tell you how many tablets you need to take each day and when to take them. The dose may depend on your age, your medical condition and whether or not you are taking any other medicines.

PAXAM is usually started using a low dose. Your doctor may gradually increase this dose to the lowest amount needed to control your condition depending on how well you respond to and tolerate the medicine.

The usual adult maintenance dose is between 4 mg and 8 mg a day.

Children, the elderly and people with liver or kidney problems may need smaller doses.

How to take it

Swallow the tablets with a glass of water. PAXAM tablets can be broken in half or quarters if your doctor has prescribed half or quarter of a tablet.

When to take it

PAXAM is usually taken twice a day (in the morning and evening). However, depending on your dose, your doctor may recommend you take it three or four times a day.

PAXAM can be taken with or without food.

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

How long to take it

Continue taking your medicine for as long as your doctor recommends. This medicine helps to control your condition but does not cure it. It is important to keep taking your medicine even if you feel well.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

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

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

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

If you take too much (overdose)

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 that you or anyone else may have taken too much PAXAM. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Symptoms of an overdose may include feeling drowsy, tired, confused, dizzy, having difficulty breathing, feeling weak or become unconscious.

While you are taking PAXAM

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking PAXAM.

Tell any other doctors, dentists and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, including dental surgery, tell the surgeon, anaesthetist or dentist that you are taking this medicine. It may affect other medicines used during surgery.

If you become pregnant while taking this medicine, tell your doctor immediately.

Tell your doctor if you feel that this medicine is not helping your condition. If you continue to have seizures (fits) your doctor may need to adjust or review your treatment.

Tell your doctor if, for any reason, you have not taken PAXAM exactly as prescribed. Otherwise, your doctor may adjust your treatment unnecessarily.

Keep all of your doctor's appointments so that your progress can be checked. Your doctor may ask you to have regular blood tests to check your blood count, kidney and liver function.

Things you must not do

Do not take PAXAM to treat any other complaints unless your doctor tells you to.

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

Do not stop taking your medicine or lower the dosage without checking with your doctor. Stopping this medicine suddenly may make your epilepsy worse and cause some unwanted effects. Your doctor will tell you how to gradually reduce the amount of PAXAM you are taking before stopping completely.

Do not drink alcohol while you are taking PAXAM. Combining this medicine and alcohol can make you more sleepy or dizzy. Alcohol can also affect how well PAXAM works and may even cause more seizures (fits).

Be careful driving or operating machinery until you know how PAXAM affects you. This medicine may cause drowsiness, dizziness or affect alertness in some people.

These effects may continue the following day.

If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Children should not ride a bike, climb trees or do anything else that could be dangerous if they are feeling drowsy or sleepy.

Do not take Paxam for a longer time than your doctor has prescribed.

Things to be careful of

If PAXAM is being given to a young child, you should be especially careful that they are breathing freely.

PAXAM may increase the amount of saliva and fluid in the airways.

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 PAXAM.

This medicine helps most people with their epilepsy, 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.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

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

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

  • drowsiness, tiredness
  • dizziness, light-headedness
  • unsteadiness when walking
  • muscle weakness
  • slurred speech
  • loss of memory, inattentiveness, confusion, lack of concentration, slowed reactions
  • increased saliva
  • chest congestion
  • headaches, hangover feeling in the morning
  • unpleasant dreams

The above list includes the more common side effects of your medicine. They may disappear with continued treatment.

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

  • behaviour changes such as aggression, agitation, irritability, depression, restlessness, nervousness, hostility, anxiety, sudden feelings of rage
  • severe sleep disturbances, nightmares, vivid dreams
  • hallucinations or delusions
  • bleeding or bruising more easily than normal
  • signs of frequent infections such as fever, severe chills, sore throat, mouth ulcers.

The above list includes serious side effects which may require medical attention. Some of these side effects are rare.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at the nearest hospital:

  • swelling of the face, lips, mouth, throat or neck, which may cause difficulty swallowing or breathing
  • fainting
  • more fits than usual
  • difficulty breathing, shortness of breath
  • chest pain
  • thoughts of self-harm

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

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 PAXAM

Storage

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

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

Do not store PAXAM or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

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

Disposal

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

Product description

What it looks like

PAXAM is available in 2 strengths:

  • PAXAM 0.5 - round, peach coloured tablet marked "CN" over "0.5" on one side and cross scored on the other.
  • PAXAM 2 - round, white tablet marked "CN" over "2" on one side and cross scored on the other.

Each bottle contains 100 tablets.

Ingredients

PAXAM contains either 0.5 mg or 2 mg of clonazepam as the active ingredient.

The tablets also contain the following inactive ingredients:

  • lactose monohydrate
  • maize starch
  • microcrystalline cellulose
  • magnesium stearate
  • sunset yellow FCF aluminium lake [PAXAM 0.5 tablet only].

PAXAM also contains galactose and sulfites.

PAXAM tablets do not contain gluten.

Manufacturer

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

Australian registration numbers:

PAXAM 0.5 - AUST R 54846

PAXAM 2 - AUST R 54847

This leaflet was prepared in July 2023.

paxam_cmi\Jul23/00

Published by MIMS September 2023

BRAND INFORMATION

Brand name

Paxam

Active ingredient

Clonazepam

Schedule

S4

 

1 Name of Medicine

Clonazepam.

2 Qualitative and Quantitative Composition

Each tablet contains 0.5 mg or 2 mg of clonazepam as the active ingredient.

Excipients of known effect.

Lactose monohydrate, galactose and sulfites.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Paxam 0.5.

Flat bevelled edged, peach coloured, marked CN over 0.5 on one side, cross scored on the reverse.

Paxam 2.

Flat bevelled edged, white tablet, marked CN over 2 on one side, cross scored on the reverse.

4 Clinical Particulars

4.1 Therapeutic Indications

Most types of epilepsy in children, especially absences (petit mal), myoclonic seizures and tonic-clonic fits, whether due to primary generalised epilepsy, or to secondary generalisation of partial epilepsy.
In adults, all varieties of generalised epilepsy (including myoclonic, akinetic, tonic and tonic-clonic seizures), and in partial epilepsy (including psychomotor seizures).

4.2 Dose and Method of Administration

Dosage of clonazepam is essentially individualised and depends in the first instance on the age of the patient. It will be determined in each patient according to clinical response and tolerance. In order to minimise initial adverse effects, it is essential to commence with low doses and increase the daily dose progressively until a maintenance dose suited to the individual patient has been reached. Some degree of tolerance may be observed to both the adverse and therapeutic effects. If epilepsy is not adequately controlled at the maximum recommended dosage level, alternative or combination therapy should be considered (see Section 4.4 Special Warnings and Precautions for Use).
Before adding clonazepam to an existing anticonvulsant regimen, it should be considered that the use of multiple anticonvulsants may result in an increase of undesirable effects.
As with all antiepileptic agents, treatment with clonazepam must not be stopped abruptly, but must be reduced in a stepwise fashion (see Section 4.4 Special Warnings and Precautions for Use).

Dosage for initiation of therapy.

Children.

2 to 5 years: 0.5 mg/day (half a 0.5 mg tablet morning and evening); 6 to 12 years: 0.75 mg/day (half a 0.5 mg tablet in the morning, one 0.5 mg tablet in the evening).

Adults.

1 mg/day (one 0.5 mg tablet morning and evening). See Table 1.
The daily quota should, if possible, be divided into three or four doses spread over the day.
The maintenance dose should be attained after 2 to 4 weeks of treatment. To obtain optimum adjustment of the dose in children, the 0.5 mg tablets should be used.

Use in the elderly.

Elderly patients are usually more sensitive to the effects of benzodiazepines. Particular care should be taken during up-titration in elderly patients. The lowest possible dose should be used in the elderly. The maintenance dose will usually be in the lower range of adult dosage (see Section 4.4 Special Warnings and Precautions for Use).

Impaired hepatic function.

Patients with severe hepatic impairment should not be treated with clonazepam (see Section 4.3 Contraindications). Patients with mild to moderate hepatic impairment should be given the lowest dose possible.

Impaired renal function.

The safety and efficacy of clonazepam in patients with renal impairment has not been studied. Based on pharmacokinetic considerations no dose adjustment is required in these patients, however the pharmacodynamics of the probable accumulated clonazepam metabolites may necessitate dosage review in these patients (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special populations).

4.3 Contraindications

Clonazepam is contraindicated in patients with:
known hypersensitivity to benzodiazepines;
known hypersensitivity to any of the excipients in Paxam;
chronic obstructive airways disease with incipient respiratory failure;
dependence on drugs of abuse and CNS depressants including alcohol;
severe hepatic impairment as benzodiazepines may precipitate hepatic encephalopathy.

4.4 Special Warnings and Precautions for Use

Some loss of effect may occur during the course of clonazepam treatment.

Lactose intolerance.

Since Paxam contains lactose, patients with rare hereditary problems of galactose intolerance (the Lapp lactase deficiency or glucose-galactose malabsorption) should not take this medicine.

Porphyria.

Clonazepam should be used with care in patients with porphyria because it may have a porphyrogenic effect.

Concomitant use of alcohol and CNS depressants.

The concomitant use of clonazepam with alcohol and/or CNS depressants has the potential to increase the clinical effects of clonazepam; possibly including severe sedation that could result in coma or death, clinically relevant respiratory and/or cardiovascular depression (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 4.9 Overdose).
Since alcohol can provoke epileptic seizures irrespective of therapy and may potentiate the CNS depressant effects of clonazepam, it is imperative that patients should abstain from drinking alcohol while under treatment with clonazepam. 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 Paxam.
Paxam should be used with particular care in patients with ataxia; in the event of acute intoxication with alcohol or drugs, other anti-epileptic medicines, hypnotics, analgesics, neuroleptic agents, antidepressants or lithium; or if the patient suffers from sleep apnoea.
As up to 70% of clonazepam metabolites are excreted via the kidneys, the pharmacodynamics of clonazepam and its metabolites might be altered.

Hypotension.

Although hypotension has occurred rarely, Paxam 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.

Amnesia.

Transient amnesia or memory impairment has been reported in association with the use of benzodiazepines. The risk increases with higher doses.

Sleep apnoea.

Benzodiazepines are not recommended for use in patients with sleep apnoea due to possible additive effects on respiratory depression. Sleep apnoea appears to be more common in patients with epilepsy and the relationship between sleep apnoea, seizure occurrence and post-ictal hypoxia needs to be considered in light of benzodiazepine-induced sedation and respiratory depression. Therefore, clonazepam should only be used in epileptic patients with sleep apnoea when the expected benefit exceeds the potential risk.

Myasthenia gravis.

As with any substance with CNS depressant and/or muscle relaxant properties, clonazepam could increase the muscle weakness in myasthenia gravis and should be used with caution in this condition.

Acute narrow-angle glaucoma.

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

Psychiatric and paradoxical reactions.

Paradoxical reactions such as restlessness, agitation, irritability, aggressiveness, nervousness, hostility, anxiety, delusion, sleep disturbances, nightmares, hallucinations, psychoses, vivid dreams, acute rage, stimulation or excitement, inappropriate behaviour and other adverse behavioural effects may occur. Should such reactions occur Paxam should be discontinued.

Impaired respiratory function.

Caution in the use of Paxam is recommended in patients with respiratory depression. In patients with chronic obstructive pulmonary disease (COPD), benzodiazepines can cause increased arterial carbon dioxide tension and decreased oxygen tension. The dosage of Paxam must be carefully adjusted to individual requirements in patients with pre-existing disease of the respiratory system.

Depression, psychosis and schizophrenia.

Paxam is not recommended as primary therapy in patients with depression and/or 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. Patients with a history of depression and/or suicide attempts should be kept under close supervision.

Epilepsy.

The dosage of Paxam must be carefully adjusted to individual requirements in patients undergoing treatment with other centrally acting medications or anticonvulsant (antiepileptic) agents (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
When clonazepam is administered to persons with convulsive disorders, an increase in the frequency and/or severity of grand mal seizures may occur, necessitating increased anticonvulsant medication. Abrupt withdrawal of benzodiazepines in persons with convulsive disorders may be associated with a temporary increase in the frequency and/or severity of seizures. When in the judgement of the clinician, the need for dosage reduction or discontinuation arises, this should be done gradually.

Abuse.

Caution must be exercised in administering Paxam to individuals known to be addiction prone or those whose history suggests they may increase the dosage on their own initiative. It is desirable to limit repeat prescription without adequate medical supervision.

Dependence.

The use of benzodiazepines may lead to development of physical and psychological dependence, as defined by the presence of a withdrawal syndrome on discontinuation of the medicine. The risk of dependence increases with dose and duration of treatment. It is also greater in patients with a medical history of alcohol and/or drug abuse. Abuse has been reported in poly-drug users. 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.
Withdrawal symptoms similar in character to those noted with barbiturates and alcohol have occurred following abrupt discontinuation of benzodiazepines. These symptoms range from insomnia, anxiety, agitation, sleep disturbances, headaches, diarrhoea, irritability, dysphoria, palpitations, panic attacks, vertigo, myoclonus, akinesia, hypersensitivity to light, sound and touch, abnormal body sensations (e.g. feeling of motion, metallic taste), depersonalisation, derealisation, delusional beliefs, hyperreflexia and loss of short-term memory, to a major syndrome which may include convulsions, tremor, abdominal and muscle cramps, confusional state, delirium, hallucinations, hyperthermia, psychosis, vomiting and sweating. Such manifestations of withdrawal, especially the more serious ones, are more common in patients who have received excessive doses over a prolonged period. However, withdrawal symptoms have been reported following abrupt discontinuation of benzodiazepines taken continuously at therapeutic levels. Accordingly, Paxam should be terminated by tapering the dose to minimise the occurrence of withdrawal symptoms. Patients should be advised to consult with their physician before either increasing the dose or abruptly discontinuing the medication.
Rebound phenomena have been described in the context of benzodiazepine use. Rebound insomnia and anxiety mean an increase in the severity of these symptoms beyond pre-treatment levels following cessation of benzodiazepines. Rebound phenomena, in general, possibly reflect re-emergence of pre-existing symptoms combined with withdrawal symptoms described earlier. Some patients prescribed benzodiazepines with very short half-lives (in the order of 2 - 4 hours) may experience relatively mild rebound symptoms in between their regular doses. Withdrawal/rebound symptoms may follow high doses for relatively short periods.

Use in hepatic impairment.

Benzodiazepines may have a contributory role in precipitating episodes of hepatic encephalopathy in severe hepatic impairment (see Section 4.3 Contraindications). Special caution should be exercised when administering clonazepam to patients with mild to moderate hepatic impairment. In patients in whom benzodiazepine therapy for periods longer than 4 weeks is deemed necessary, periodic liver function tests are recommended.
Following the prolonged use of clonazepam 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 4 weeks to 4 months have been suggested. As with other benzodiazepines, when treatment is suddenly withdrawn, a temporary increase in sleep disturbance can occur after the use of clonazepam (see Dependence below).
Only a small minority of patients with the common seizure types achieves a lasting remission with clonazepam. Tolerance to the anticonvulsant effect of clonazepam may occur after 4 weeks to 6 months of continuous treatment of patients, leading to increased seizure frequency. Increasing the dose in this situation is rarely worthwhile. If seizures are no longer being adequately controlled, the medicine should be discontinued, and alternative treatment implemented.

Use in renal impairment and blood dyscrasias.

Patients with impaired renal function should use benzodiazepine medication with caution and dosage reduction may be advisable. In rare instances, patients on benzodiazepines have developed blood dyscrasias, and some have had elevations of liver enzymes. In patients in whom benzodiazepine therapy for periods longer than 4 weeks is deemed necessary, periodic blood counts are recommended.

Use in the elderly.

There have been reports of falls and fractures in benzodiazepine users. The risk is increased in those taking concomitant sedatives (including alcoholic beverages) and in the elderly.
Elderly or debilitated patients may be particularly susceptible to the pharmacologic effects of benzodiazepines such as giddiness, ataxia and confusion, which may increase the risk of a fall.
Elderly patients, patients with pre-existing disease of the respiratory system (e.g. chronic obstructive lung disease), liver or kidney disease, or those who are receiving treatment with other centrally acting medications or anticonvulsant agents, require very careful dosage adjustment.

Paediatric use.

Salivary and bronchial hypersecretion can occur in infants and small children, and supervision is required to ensure that airways remain free, especially on commencing therapy or in the event of respiratory infection.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Clonazepam can be administered concurrently with one or more other anti-epileptic medicines, in which case the dosage of each medicine must be adjusted to achieve the optimum effect. Interactions have been reported between some benzodiazepines and other 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 other anticonvulsant is performed more frequently.

Pharmacokinetic interactions.

The anti-epileptic medicines phenytoin, phenobarbital (phenobarbitone), carbamazepine, lamotrigine and valproate may increase the clearance of clonazepam, thereby decreasing the plasma concentrations of the latter during combined treatment.

Phenytoin.

The effect of clonazepam on phenytoin plasma levels is not clear as the latter may increase or decrease according to study reports depending on dosing and patient factors.

Carbamazepine.

Levels may be lowered by clonazepam.
Clonazepam itself does not appear to induce the enzymes responsible for its own metabolism. The enzymes involved in the metabolism of clonazepam have not been clearly identified but include CYP3A4. Inhibitors of CYP3A4 (e.g. fluconazole) may impair the metabolism of clonazepam and lead to exaggerated concentration and effects.
The selective serotonin reuptake inhibitors (SSRIs) sertraline and fluoxetine do not significantly affect the pharmacokinetics of clonazepam when administered concomitantly.

Pharmacodynamic interactions.

Benzodiazepines, including clonazepam, produce additive CNS depressant effects when co-administered with other medications which themselves produce CNS depression, e.g. other anticonvulsant (anti-epileptic) agents, lithium, barbiturates, sedatives, tricyclic antidepressants, non-selective MAO inhibitors, phenothiazines and other antipsychotics, skeletal muscle relaxants, antihistamines, narcotic analgesics and anaesthetics. This is especially true in the presence of alcohol (see Section 4.4 Special Warnings and Precautions for Use).
Clonazepam undergoes oxidative metabolism and, consequently, may interact with disulfiram or cimetidine resulting in increased plasma levels of clonazepam. Patients should be observed closely for evidence of enhanced benzodiazepine response during concomitant treatment with either disulfiram or cimetidine; some patients may require a reduction in benzodiazepine dosage.
The anticholinergic effects of atropine and similar medicines, antihistamines and antidepressants may be potentiated.
Minor EEG changes, usually low voltage fast activity, of no known clinical significance, has been reported with benzodiazepine administration.
Some specific interactions noted with clonazepam are:

Alcohol.

Epileptic patients should not under any circumstances consume alcohol while being treated with clonazepam, since alcohol may alter the effect of the medicine, reduce the efficacy of treatment or produce unexpected side effects (see Section 4.4 Special Warnings and Precautions for Use).

Sodium valproate.

Reports of sodium valproate causing petit mal status epilepticus with clonazepam exist.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Dietary administration of clonazepam to male and female rats was associated with a reduced pregnancy rate and impaired pup survival at doses of 60 mg/m2/day or greater (4-fold the maximal recommended human dose [MRHD]); the no effect dose was 6 mg/m2/day (less than clinical exposure).
(Category B3)
The risk of a mother with epilepsy and taking anticonvulsants giving birth to a baby with an abnormality is about three times that of the normal population. Some of this risk is due to the anticonvulsant medicines taken. Mothers taking more than one anticonvulsant medicine might have a higher risk of having a baby with a malformation than mothers taking one medicine.
Overall the risk of having an abnormal child is far outweighed by the dangers to the mother and foetus of uncontrolled convulsions. It is, therefore, recommended that:
women on anticonvulsant medicines receive pre-pregnancy counselling with regard to the risk of foetal abnormalities;
anticonvulsants should be continued during pregnancy and monotherapy should be used if possible at the lowest effective dose;
folic acid supplement (5 mg daily) should be commenced four weeks prior to and continue for twelve weeks after conception;
specialist prenatal diagnosis including detailed mid-trimester ultrasound should be offered.
Clonazepam is a benzodiazepine. These medicines cross the placenta and appear in the foetus and may, after continuous administration during a large part of pregnancy, give rise to hypotonia, reduced respiratory function and hypothermia in the newborn child. Withdrawal symptoms in newborn infants have occasionally been reported with this class of medicines.
Oral administration of clonazepam during the period of organogenesis has elicited a low, non-dose-related incidence of a similar pattern of malformations in rabbits (cleft palate, open eyelids, fused sternebrae, limb defects) and mice (exencephaly, central nervous system defects) at doses less than MRHD. These effects were not observed in rats at oral doses more than 20-fold MRHD. The clinical significance of these findings is unknown.
Withdrawal symptoms in newborn infants have been reported with benzodiazepines.
Studies in animals have shown evidence of an increased occurrence of foetal damage, the significance of which is considered uncertain in humans.
 Paxam must not be given to breastfeeding women. Clonazepam is excreted in human breast milk, and may cause drowsiness and feeding difficulties in the infant.
If there is a compelling reason for use of clonazepam, breast feeding should be discontinued.

4.7 Effects on Ability to Drive and Use Machines

As with all patients taking CNS depressant medications, patients receiving Paxam should be warned not to operate dangerous machinery or motor vehicles until it is known that they do not become drowsy or dizzy from clonazepam therapy. Abilities may be impaired on the day following use (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.8 Adverse Effects (Undesirable Effects)

Adverse effects to clonazepam occur in about 50% of patients, depending on dose and they are usually referable to its sedative and muscle relaxant effects and are also usually transitory (however, they can continue in up to 10% of patients and may result in withdrawal of the medicine) (see Table 2). Adverse effects can, to a certain extent, be avoided by a low initial dose, which is gradually increased in the absence of side effects.

More common adverse effects.

Drowsiness or somnolence (50%), ataxia (30%), behaviour problems (25%), hypersalivation (10%), fatigue (8%), muscle weakness (5%), vertigo (5%) and light-headedness, tiredness, sleepiness, lassitude and dizziness.
These effects are generally temporary and usually disappear during treatment either spontaneously or by dose reduction.

Less common adverse effects.

Agitation (1.5%), excitability (0.7%), irritability (1.5%), aggressive behaviour (1.4%), disturbances of concentration, depression (1%), confusion (1.9%), bronchial hypersecretion (1.4%), slowed reactions and antero-grade amnesia, restlessness and disorientation have been observed.
With certain forms of epilepsy, an increase in the frequency of seizures during long-term treatment is possible.
Even if taken as directed, clonazepam can slow reactions to such an extent that the ability to drive a vehicle or operate machinery is seriously impaired. The effect is increased if the patient has also taken alcohol (see Section 4.4 Special Warnings and Precautions for Use; Section 4.7 Effects on Ability to Drive and Use Machines).
Other adverse events which have been reported and may be related to clonazepam administration are presented in 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.

4.9 Overdose

Symptoms.

Overdosage of benzodiazepines is usually manifested by degrees of central nervous system depression ranging from drowsiness to coma. In mild cases, symptoms include drowsiness, mental confusion and lethargy. In more serious cases, symptoms may include ataxia, dysarthria, nystagmus, hypotonia, hypotension, respiratory depression, coma, and very rarely, death. Coma may be more protracted and cyclical, particularly in elderly patients. Increased frequency of seizures may occur in patients at supratherapeutic plasma concentrations. Benzodiazepine respiratory depressant effects are more serious in patients with respiratory disease.
Benzodiazepines increase the effects of other central nervous system depressants, including alcohol. When combined with other CNS depressants, the effects of overdosage are likely to be severe and may prove fatal.

Treatment.

Treatment of overdose is symptomatic; institute supportive measures as indicated by the patient's clinical state. If the overdosage is known to be small, observation of the patient and monitoring of their vital signs only may be appropriate. In adults or children who have taken an overdose of benzodiazepines within 1 - 2 hours, consider activated charcoal with airway protection if indicated.
If CNS depression is severe consider the use of flumazenil (Anexate), a benzodiazepine antagonist. This should only be administered under closely monitored conditions. It has a short half-life (about an hour), therefore, patients administered flumazenil will require monitoring after its effects have worn off. Flumazenil may precipitate seizures and is to be used with extreme caution in the presence of medicines that reduce seizure threshold (e.g. tricyclic antidepressants) and epileptic patients who have been treated with benzodiazepines. Refer to the prescribing information for flumazenil (Anexate), for further information on the correct use of this medicine.
Haemoperfusion and haemodialysis are not useful in benzodiazepine intoxication.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Clonazepam is an anticonvulsant, which exhibits several pharmacological properties characteristic of the benzodiazepine class of medicines.
The exact site and mode of action of the anticonvulsant action of clonazepam is unknown.
Benzodiazepines enhance the polysynaptic inhibitory processes at all levels of the central nervous system. Clonazepam is more effective in blocking spread of electrical activity in the lesion itself.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption and bioavailability.

Clonazepam is rapidly and almost completely (82 - 98%) absorbed after oral administration, with peak serum levels being reached between 2 to 3 hours. The absorption half-life is 24 min. With continuous therapy, accumulation occurs, and although values differ in different reports, the therapeutic serum level appears to be between 10 and 80 nanogram/mL. In one study with increase in dosage to 5 mg/day, the average level of clonazepam after 15 days was 54 nanogram/mL. A steady state is usually reached within 2 to 3 weeks.
Plasma concentrations of clonazepam at steady states for once daily dosage regimens are 3-fold higher than those after single oral doses. Following multiple oral doses of 2 mg three times daily, steady-state pre-dose plasma concentrations of clonazepam ranged from 30 - 80 nanogram/mL. The plasma concentration-dose relationship of clonazepam is linear.
The absolute bioavailability is 90%.

Distribution.

Clonazepam enters the cerebral tissues rapidly.
The distribution half-life is approximately between 0.5 - 1 hour. The apparent volume of distribution (3 L/kg) suggests concentration in some tissues.
The plasma protein binding of clonazepam ranges from 82 - 86%.

Metabolism.

Clonazepam is metabolised in the liver. The metabolic pathways include hydroxylation, reduction of the nitro groups to an amine and addition of acetate to the amino grouping. Clonazepam is extensively metabolised by reduction to 7-amino-clonazepam and by N-acetylation to 7-acetamido-clonazepam. Hydroxylation at the C-3 position also occurs. Hepatic cytochrome P-450 3A4 is implicated in the nitroreduction of clonazepam to pharmacologically inactive metabolites.

Excretion.

The mean elimination half-life is 39.0 ± 8.3 hours. The mean clearance ± SD is 55.1 ± 8.2 mL/min following a single dose of 2 mg clonazepam given intravenously.
50 - 70% of the dose is excreted in the urine and 10 - 30% in the faeces as metabolites. The urinary excretion of unchanged clonazepam is usually less than 2% of the administered dose. The metabolites are present in urine both as free and conjugated (glucuronide and sulphate) compounds.

Clinical significance of pharmacokinetics.

With chronic dosing, accumulation occurs. However, there is a wide variation in therapeutic plasma levels and a correlation between adverse effects with plasma levels or the rate of increase in plasma concentration of clonazepam and its metabolites has not been established. Consequently, monitoring of plasma levels, as is often done with some anticonvulsants, would be valuable.
It should be emphasised that because of the effect of clonazepam on plasma levels of other anticonvulsants administered concomitantly (and vice versa) the patient should be monitored carefully in the initial stages for clinical response and occurrence of side effects.

Pharmacokinetics in special populations.

Renal impairment.

Renal impairment does not affect the pharmacokinetics of clonazepam. Therefore, based on pharmacokinetic considerations, no dosage adjustment may be required in patients with renal impairment. The pharmacodynamics of probable accumulated clonazepam metabolites may necessitate dosage review in these patients.

Hepatic impairment.

The influence of hepatic disease on clonazepam pharmacokinetics has not been investigated. However, due to the sole hepatic metabolism of clonazepam, the pharmacokinetics of clonazepam are expected to be affected on theoretical grounds.

Elderly patients.

The pharmacokinetics of clonazepam in the elderly has not been established.

Neonates.

Although the elimination half-life (41.9 ± 29.8 hours) and clearance values in neonates pre-treated with phenobarbital are the same order of magnitude as those reported in non-pretreated adults, post-natal age does, however, affect the clearance of clonazepam under normal conditions.

5.3 Preclinical Safety Data

Genotoxicity.

Clonazepam and five of its metabolites were negative in bacterial gene mutation assays. Chromosomal damage assays have not been conducted with clonazepam.

Carcinogenicity.

No 2-year carcinogenicity studies have been conducted with clonazepam. An 18-month chronic study in rats showed no treatment-related histopathological changes at dietary doses up to 1800 mg/m2/day (greater than 100-fold MRHD).

6 Pharmaceutical Particulars

6.1 List of Excipients

Paxam 0.5 tablets contain lactose monohydrate, microcrystalline cellulose, maize starch and magnesium stearate and sunset yellow FCF aluminium lake.
Paxam 2 tablets contain lactose monohydrate, microcrystalline cellulose, maize starch and magnesium stearate.

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

Container type: bottle (HDPE).
Pack sizes: 100, 200 tablets.
Some strengths, pack sizes and/or pack types may not be marketed.

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.

6.7 Physicochemical Properties

Chemical structure.


Clonazepam is a light yellow powder which is practically insoluble in water.
Chemical name: 5-(2-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one.
Molecular formula: C15H10ClN3O3.
Molecular weight: 315.7.

CAS number.

1622-61-3.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

Summary Table of Changes