Consumer medicine information

Pexsig

Perhexiline maleate

BRAND INFORMATION

Brand name

Pexsig

Active ingredient

Perhexiline maleate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Pexsig.

What is in this leaflet

This leaflet answers some common questions about Pexsig (perhexiline maleate) tablets. It does not contain all of the available information about Pexsig tablets. It does not replace talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Pexsig tablets against the expected benefits.

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

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

What Pexsig is used for

The name of your medicine is Pexsig and is available in a 100 mg strength tablet.

The active ingredient is called perhexiline maleate. Perhexiline belongs to a group of medicines called anti-anginal agents.

These are used to reduce the frequency of moderate to severe attacks of angina pectoris (severe chest pain caused by heart disease). Pexsig acts by increasing the efficiency of the heart.

Only take Pexsig when your doctor prescribes it for you.

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

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 it

When you must not take it

Do not take Pexsig if you have:

  • Liver disease
  • Kidney disease
  • If you have ever had any unusual or allergic reaction to Pexsig or any of its ingredients.

If you are not sure, talk to your doctor about it.

You should tell your doctor before starting treatment with Pexsig if you:

  • Have diabetes
    If you use insulin or take a certain type of antidiabetic tablet you may need to adjust your dosage during the first few days after starting on Pexsig.
  • Have kidney or liver disease
  • Are taking any medicines (whether prescription or non-prescription)

Your doctor needs to know about other drugs you may be taking, particularly medicines known as beta-blockers and anti-diabetics.

If your doctor wants you to stop taking beta-blockers, you must not stop them suddenly; but should withdraw them gradually over several days.

Tell your doctor if you are pregnant or intend to become pregnant. As there is no experience with the use of Pexsig in pregnant women, your doctor must weigh the potential benefits against the possible risks.

Do not take this medicine if you are breastfeeding.

Do not use it after the expiry date (EXP) printed on the pack.

Do not purchase or take Pexsig if the packing shows signs of tampering.

Do not give Pexsig to children.

Pexsig may cause dizziness or unsteadiness in some patients. If affected, do not drive a vehicle, operate machinery or do anything else that could be dangerous if you are dizzy or faint.

Tell your doctor about any other medicines that you take, including medicines bought without a doctor’s prescription.

There are several medicines, particularly medicines known as beta-blockers (used for heart conditions and high blood pressure) and anti-diabetics (used to treat diabetes), which may affect the way Pexsig works.

Your doctor may still want you to take these other medicines but may need to adjust the dose of them or take other precautions.

You should check with your doctor or pharmacist to see if you are taking any of these types of medicines.

How to take it

How much to take

The dose will be decided by your doctor and will depend on your condition and how you respond to Pexsig.

A common starting dose is one Pexsig tablet taken once or twice a day; your doctor may increase or decrease this dose at intervals, usually 2 to 4 weeks, based on the results obtained.

Generally, the dose should not exceed three Pexsig tablets a day in divided doses. In some cases, a dose of 4 Pexsig tablets per day may be necessary.

Do NOT take more tablets than your doctor has prescribed.

Some patients may require a lower dose than the 100 mg contained in Pexsig tablets; in this case, Pexsig tablets can be broken in half, giving 50 mg in each half tablet.

When should I take it

If your doctor has prescribed you more than one Pexsig tablet per day, you will take them in divided doses as directed by your doctor.

For example, if you have been prescribed two tablets per day, your doctor would probably direct you to take one tablet in the morning and one in the evening.

Follow the directions on the pharmacist’s label on the pack.

Pexsig tablets should be swallowed whole with a glass of water.

How long to take it

Pexsig controls your condition but does not cure it. Therefore, Pexsig should be taken every day for as long as your doctor has prescribed it.

If you forget to take it

If you miss taking your Pexsig dose, take the tablet(s) as soon as you remember and then go back to taking it as you would normally.

However, if it is almost time for your next dose, skip the missed dose and take your next dose. If you are unsure about this, ask your pharmacist or doctor.

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

If you take too much (overdose)

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

While you are taking it

Before you start taking Pexsig, your doctor will examine you and have some blood tests carried out.

While you are taking Pexsig, the doctor will repeat the examinations and tests at regular intervals (at least once a month) in order to see how you are responding and whether your body is tolerating the treatment.

One of these tests is to measure the amount of Pexsig in your blood, so that your doctor may adjust the dose, if necessary.

If the blood tests or the examinations reveal certain results, your doctor may decide that you stop taking this medicine or change the dose.

If your doctor orders any blood tests, the fact that you are taking Pexsig may cause some changes in the results which your doctor may discuss with you.

Remember that this medicine is for you. Only a doctor can prescribe it for you.

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

Side effects

Although most people benefit from taking Pexsig, it may have unwanted effects.

The following unwanted effects have been reported in patients taking this medicine (most unwanted effects usually occur in the first few weeks of treatment and some may disappear in 2 to 4 weeks). More often they go away if the dose is reduced. In some cases, they only go away if the treatment is stopped.

Serious unwanted effects

Immediately contact your doctor, or, if your doctor is not available, go to the nearest casualty department at your nearest hospital, if you develop any of the following symptoms:

  • Muscle weakness
  • Numbness or tingling
  • Weakness
  • Loss of appetite
  • Weight loss.

More common unwanted effects

(reported in 65% of patients)

  • Dizziness or drunken sensation
  • Difficulty in/or changed walking
  • Unsteadiness
  • Nausea
  • Vomiting
  • Headache
  • Lack of appetite and moderate weight loss (2 to 4 Kg)
  • Temporary increases in blood substances from the liver
  • Increases in blood fats
  • Moderate decreases in blood sugar
  • Alterations to the ECG (the electrical record of heart activity).

Less common unwanted effects:

  • Profound weakness
  • Nervousness
  • Weariness and lack of interest
  • Inability to sleep
  • Tremors
  • Numbness
  • Tingling
  • Fainting
  • Disorders of the urinary and sexual organs
  • Changes in sexual drive
  • Flushing or sweating
  • Rash or itchy rash.

Rare, more severe, unwanted effects

  • Inflammation of the nerve roots of the skin and spine, and accompanied by fever (the first signs may be numbness, tingling and/or weakness in the legs with difficulty in walking)
  • Severe lack of sugar in the blood
  • Significant weight loss (more than 10%) and liver disease.

Tell your doctor if you notice any other unwanted effects or are concerned, or troubled in any way, by unwanted effects.

Other unwanted effects not listed above may also occur in some patients.

If you take too much (overdose)

If you accidentally take too many tablets, you will likely have the following symptoms:

  • Nausea
  • Vomiting
  • Unsteady walking
  • Headache.

More severe symptoms, for example, liver damage or irregular or rapid heartbeat, may develop. Damage to the liver could occur.

You should immediately contact your doctor or go to the casualty department of your nearest hospital if you have taken too many Pexsig tablets.

After taking it

Storage

Keep your medicine out of reach of children.

Keep it away from direct sunlight and away from the damp. Store below 30°C.

Do not store them in the bathroom or near the kitchen sink.

Do not leave it in the car or on windowsills

Do not use the tablets after the expiry date shown on the pack.

Disposal

If your doctor tells you to stop taking Pexsig tablets, return any left over to your pharmacist for disposal.

Product description

What it looks like

A white to off-white tablet scored on one side. It is supplied in amber glass bottles containing 100 tablets.

Ingredients

Each Pexsig tablet contains 100 mg of the active ingredient (perhexiline maleate).

Each tablet also contains the following inactive ingredients:

  • Lactose monohydrate
  • Maize starch
  • Sucrose
  • Purified talc.

The tablets do not contain preservatives, gluten or azo dyes.

Sponsor

Aspen Pharma Pty Ltd
34-36 Chandos Street
St Leonards NSW 2065
Australia

Australian Registration Number: AUST R 52182

This leaflet was revised in July 2020.

Published by MIMS September 2020

BRAND INFORMATION

Brand name

Pexsig

Active ingredient

Perhexiline maleate

Schedule

S4

 

1 Name of Medicine

Perhexiline maleate.

2 Qualitative and Quantitative Composition

Pexsig tablets contain perhexiline maleate 100 mg as the active ingredient.
Excipients with known effect include lactose monohydrate and sucrose. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

White to off-white tablet scored on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

To reduce the frequency of moderate to severe attacks of angina pectoris due to coronary artery disease in patients who have not responded to other conventional therapy or in whom such therapy may be contraindicated.

Note.

Because of the serious nature of potential side effects, perhexiline maleate should be reserved for use in patients with intractable angina who are refractory or intolerant to other agents and are not suitable candidates for coronary bypass surgery.

4.2 Dose and Method of Administration

Adults.

Commence therapy with 100 mg daily. Adjust progressively, up or down, at 2 to 4 weekly intervals, based on the results of plasma level monitoring. It is generally advised not to administer more than 300 mg per day, in divided doses, but in certain cases it may be necessary to use 400 mg per day. The maintenance dose must be the minimum dose that is effective and well tolerated.

Geriatric.

As for adults, but see Section 4.3 Contraindications.

Paediatric.

Not recommended for use in children as safety and efficacy in this age group has not been established.

Monitoring of plasma levels.

Plasma perhexiline concentrations should be maintained between 0.15 and 0.60 microgram/mL. Because of perhexiline's slow and variable clearance, the marked intersubject variability in metabolism of the drug and the potential for serious toxicity, regular monitoring of plasma levels of perhexiline is essential commencing at the end of the first week of use. Dosage should not be increased unless the plasma concentrations are subtherapeutic and at least two to four weeks have elapsed since commencement or last increase in dose, of perhexiline. If facilities for determining plasma levels are not available, Pexsig should not be prescribed (see Section 4.3 Contraindications).

Alcohol.

Limited data indicate that oral co-administration of perhexiline did not exacerbate ethanol induced liver damage in rats; no human data are available.

Food.

No information available.

4.3 Contraindications

Pexsig is not recommended in the presence of the following conditions:
A history of porphyria.
Impaired hepatic or renal function.
Known hypersensitivity to the drug.
If facilities for determining plasma levels are not available, Pexsig should not be prescribed.
See Section 4.2 Dose and Method of Administration, Monitoring of plasma levels.

4.4 Special Warnings and Precautions for Use

Diabetes mellitus.

Pexsig should be administered with caution to patients with diabetes mellitus. Hypoglycaemia is most likely to occur in diabetic patients receiving insulin or sulphonylureas; in the majority of such patients, fasting blood sugar levels fall by approximately 30% over the first three days of therapy.

Cardiovascular effects.

The safety and efficacy of perhexiline following myocardial infarction (when clinical and laboratory findings are not stable) have not been established.
Pexsig has an effect on the ventricular conduction systems that may also have the potential of producing or aggravating ventricular conduction disturbances.

Neurological effects.

In several patients on long-term therapy with perhexiline, sensory, motor and autonomic neuropathy has been reported. In some cases of motor nerve dysfunction, biopsies showed denervation atrophy and demyelinisation. In other cases, reduced motor nerve conduction velocity, without clinical signs of peripheral neuropathy, has been reported; this change in motor nerve function was not related to the dose of perhexiline or the duration of therapy. Other patients, in addition, had evidence of autonomic neuropathy (i.e. postural hypotension, abnormal autonomic function tests). Protein concentration in the CSF has sometimes been significantly elevated (also see Section 4.8 Adverse Effects (Undesirable Effects)). Bilateral papilloedema, with fundal haemorrhages and both reversible and permanent impairment of visual acuity, has been reported sometimes.
Treatment with Pexsig should be discontinued in the following instances.
1. Appearance of peripheral neuropathy.
2. Appearance of clinical signs of hepatic disease.
3. Persistent elevations in serum enzymes or abnormalities of specific liver function tests.
3. Persistent or marked hypoglycaemia.
5. Excessive weight loss.
(See Section 4.8 Adverse Effects (Undesirable Effects)).

Investigations.

Hepatotoxicity as manifested by an elevation in serum liver enzymes is a common adverse effect occurring during perhexiline therapy. Serum enzymes (SGPT, SGOT, ALP, LDH) should, therefore, be assessed prior to the commencement of treatment and at least every month thereafter.
During the administration of Pexsig, patients must be regularly examined (at least every month) especially for the appearance of the signs or symptoms described below.
The following clinical and laboratory observations are particularly recommended before and/or during treatment.
1. Tests for signs and symptoms of peripheral neuropathy, such as paraesthesias and muscle weakness.
2. Observation for clinical signs of hepatic involvement (weakness, loss of appetite, loss of weight).
3. Determination of serum enzymes (ALT/SGPT, AST/SGOT, ALP, LDH) and bilirubin.
4. Determination of blood glucose.
5. Determination of weight.
6. Determination of plasma levels of perhexiline (see Section 4.2 Dose and Method of Administration).
If such medical monitoring proves impractical, Pexsig should not be prescribed.

Use in hepatic impairment.

The use of Pexsig in patients with hepatic impairment is not recommended (see Section 4.3 Contraindications).

Use in renal impairment.

The use of Pexsig in patients with renal impairment is not recommended (see Section 4.3 Contraindications).

Use in the elderly.

As for adults - but see Section 4.3 Contraindications.

Paediatric use.

Not recommended for use in children.

Effects on laboratory tests.

There may be changes in the ECG, viz. slight depression of the T-wave and prolongation of the QT interval. A single case of torsades de pointes has been reported.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Insulin and antidiabetic agents, e.g. sulfonylurea.

Because hypoglycaemia has been reported in association with the administration of Pexsig, special attention must be paid with concomitant administration of products that would provoke hypoglycaemia, such as antidiabetics.

Adriamycin.

Perhexiline when administered concomitantly with adriamycin when used in oncology chemotherapy may cause an increase in cell concentration leading to adriamycin toxicity.

Anticoagulants.

In an uncontrolled trial with perhexiline in 46 patients with angina pectoris, (27 receiving perhexiline combined with anticoagulants), 9 developed elevated serum transaminase levels; and 8 of these patients were taking oral anticoagulant drugs, warfarin and phenindione.

Cytochrome P450 2D6 (CYP450 2D6, CYP2D6) inhibitors or substrates.

Interaction with drugs that are either substrates or inhibitors of cytochrome CYP2D6 is possible. Caution should, therefore, be exercised in patients treated with perhexiline where such drugs are to be introduced, as a significant change in perhexiline blood concentration may occur. Perhexiline blood levels should be carefully monitored to ensure blood levels remain below 0.60 microgram/mL (0.6 mg/L) with dosage adjustments as required. Examples of CYP2D6 inhibitors and substrates are given below, however, this list is not meant to be exhaustive.
Beta-adrenergic blocking agents, e.g. propranolol. Because hypoglycaemia has been reported in association with the administration of Pexsig, special attention must be paid with concomitant administration of products that would provoke hypoglycaemia, such as beta-blockers.
SSRIs e.g. fluoxetine, paroxetine and citalopram. Cases of perhexiline toxicity have been reported with selective serotonin (5HT) uptake inhibitors such as fluoxetine, paroxetine and citalopram. These drugs have been shown to compete with perhexiline for the hepatic cytochrome P450 2D6 (CYP450 2D6) enzyme system.
Tricyclic and tetracyclic antidepressants, e.g. clomipramine hydrochloride, mirtazapine.
Antiviral agents, e.g. ritonavir and delavirdine.
Antimalarials, e.g. chloroquine, proguanil and lumefantrine.
Antinauseants, antiemetics, e.g. ondansetron, dolasetron and metoclopramide.
Antiarrhythmics, e.g. amiodarone and quinidine.
Narcotic analgesics, e.g. codeine, methadone, morphine, oxycodone, pethidine and tramadol.
Neuroleptics, e.g. haloperidol, risperidone and chlorpromazine.
Cytotoxic drugs, e.g. tamoxifen, vinblastine, vincristine, vinorelbine, gefitinib and imatinib.
In addition, the following drugs are known substrates or inhibitors of CYP2D6: chlorpheniramine, dextromethorphan, donepezil, ethosuximide, galantamine, tolterodine, celecoxib, cimetidine, terbinafine, bupropion and moclobemide (RIMA).

Note.

Pexsig has been prescribed with the following medications: nitroglycerin, anticoagulants, digitalis, diuretics, hypolipidaemics, antihypertensives, tranquillisers and other products. The safety of concomitant administration with these products has not yet been established, with the exception of nitroglycerin used in controlled clinical experiments. In cases where Pexsig is discontinued and other therapy substituted, account must be taken of the half-life of the compound.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

While no teratogenic effects have been established in animal studies, treatment of male and female rats causes a reduction in fertility and treatment of pregnant rabbits and rats then causes a decrease in foetal weight and an increase in the number of resorptions.
(Category B2)
There is limited experience of the drug's use in pregnant women and the potential benefits must be weighed against possible risks.
Perhexiline has been assigned to Category B2 in the Australian Categorisation of Risk for Medicines in Pregnancy.
The definition of this Category B2 is as follows:
Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human foetus having been observed. Studies in animals are inadequate or may be lacking, but available data show no evidence of an increased occurrence of foetal damage.
 It is not known whether perhexiline maleate is excreted in breast milk and its effect on the newborn infant is unknown. Therefore, it is not recommended for nursing mothers.

4.7 Effects on Ability to Drive and Use Machines

Because of the possibility of dizziness, weakness, syncope or ataxia, caution should be used when driving vehicles or operating machinery.

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

Short term (occurring after as little as 24 hours of therapy).

Nausea, dizziness (usually transient), hypoglycaemia in diabetic patients and torsades de pointes (very rare).

Long term (usually occurring after ≥ 3 months of continuous treatment).

Peripheral neuropathy, hepatitis/cirrhosis, extrapyramidal dysfunction, muscle weakness and ataxia.
Approximately 65% of patients on perhexiline suffer adverse effects and in 7 to 8% of all patients receiving perhexiline, these are sufficiently severe to warrant discontinuing therapy. Most adverse reactions usually occur in the initial weeks of treatment. They can be transient and may disappear spontaneously in two to four weeks. More often, they recede only after the dosage is reduced, but sometimes treatment must be discontinued. In general, the appearance and severity of adverse reactions seem to be dose dependent.
Reported most often are dizziness or a "drunken" sensation, gait disorders, unsteadiness, as well as nausea, vomiting, headache, anorexia and moderate weight loss (2 to 4 kg).
Frequently reported are moderate and generally transient elevations of serum enzymes (AST/SGOT, ALT/SGPT, ALP, LDH) and bilirubin. Increases in total lipids and triglycerides, moderate hypoglycaemia and alterations of the ECG (slight depression of the T-wave and prolongation of the QT interval) have also been noted.
Less frequently reported are profound weakness, nervousness, lassitude, insomnia, tremors, paraesthesias, syncope, genito-urinary disorders, changes in libido, flushing or sweating, rash or urticaria.
Rarely reported are diplopia, abdominal pain, extrapyramidal syndromes and epileptiform seizures.
Occasionally, the following more severe occurrences have been reported in patients being treated with Pexsig.
Sensorimotor polyradiculoneuritis, sometimes of a demyelinisation nature, which can affect the four limbs and may be accompanied by papillitis and an increase in the protein (albumin) content of the cerebrospinal fluid. This polyradiculoneuritis first appears as paraesthesias of the extremities and/or weakness of the legs with difficulty in walking.
Severe hypoglycaemia.
Significant weight loss (more than 10% of initial weight) which can progress to true cachexia. Polyradiculoneuritis, hypoglycaemia and weight loss usually regress with suspension of treatment with Pexsig.
Hepatopathology, including some cases of subacute alcoholic type hepatitis. Some patients have been found to have cirrhosis. The state of the liver before treatment with Pexsig, the influence of concomitant therapy or aetiological factors such as alcohol and viral hepatitis are not known. In rare cases, hepatic damage or hypoglycaemia have led to the death of the patient.
Hypertriglyceridemia.

4.9 Overdose

Symptoms.

Reported symptoms following overdosage are nausea and vomiting. Other symptoms that have not been reported but would be anticipated are ataxia and headache. Hepatic damage and cardiac arrhythmias may possibly occur.

Treatment.

Treatment should be symptomatic and supportive. Acute perhexiline overdose should result in careful monitoring of drug levels, continuous cardiac monitoring and serial blood glucose recordings in diabetic patients. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via a nasogastric tube, once the airway is protected. Adequate urinary output should also be maintained. Dialysis is not indicated because of the high degree of protein and tissue binding.
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.

Perhexiline maleate is an anti-anginal agent. Its mechanism of action as an antianginal agent has not been fully elucidated in humans; however, in vitro studies suggest that perhexiline causes inhibition of myocardial fatty acid catabolism (e.g. by inhibition of carnitine palmitoyltransferase-1: CPT-1) with a concomitant increase in glucose utilisation and consequent oxygen-sparing effect. This is likely to have two consequences: (i) increased myocardial efficiency and (ii) decreased potential for impairment of myocardial function during ischaemia.
The inhibition of CPT-1 is likely to contribute to the anti-ischaemic effects of perhexiline. Animal studies indicate a direct action of the drug on the myocardium, dependent in part on the marked degree of tissue binding. In vitro studies indicate a non-specific depressant effect of perhexiline on all smooth muscle. It also inhibits the spontaneous depolarisation of Purkinje fibres in the dog myocardium and reduces sodium and potassium conductance.
Perhexiline has a cardiac membrane effect similar to that of quinidine and procainamide. Perhexiline, whilst it does not affect resting heart rate, has been shown to reduce exercise induced tachycardia in man. Perhexiline has also been shown to have a mild diuretic effect in man and animals.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

After oral administration, perhexiline maleate is well absorbed (> 80%) from the gastrointestinal tract.

Bioavailability.

Complete data on rate and extent of absorption are not available.

Distribution.

There is a large volume of distribution of perhexiline that is probably related to the marked tissue binding of both perhexiline and its metabolites. Adverse effects related to the central nervous system such as vestibular and cerebellar dysfunction are presumed because it crosses the blood brain barrier. It is not known whether it enters breast milk or crosses the placenta.

Protein binding.

Perhexiline and its metabolites are highly protein bound (> 90%). There is also some degree of binding to red blood cells.

Metabolism.

The full metabolic fate of perhexiline has not been elucidated. The principal metabolites of perhexiline in man are monohydroxyperhexiline (which is excreted, in part, conjugated with glucuronic acid) and dihydroxyperhexiline that accounts for a relatively small proportion of the total metabolites. Two unidentified metabolites have also been found in the faeces. The pharmacological activity of the metabolites is not known.

Excretion.

Perhexiline and its metabolites are cleared from the body via extensive hepatic metabolism to mono- and dihydroxyperhexilines, and are excreted in the bile and urine in a ratio of 1:2.
Hydroxylation of perhexiline is controlled by cytochrome P450 2D6 (CYP450 2D6). Approximately 7% of Caucasians are poor hydroxylators, and usually clear perhexiline at approximately 10% of the rate of normal metabolisers. A few patients are ultrafast hydroxylators and require increased steady-state doses of perhexiline. Even in normal metabolisers, the clearance of perhexiline is readily saturable within the clinical dose range. This results in disproportionate changes in steady-state plasma perhexiline concentration per unit change in daily dose.

Half-life.

Because of its non-linear metabolism, perhexiline cannot strictly be said to have a half-life at perhexiline concentrations normally measured in plasma. It is a relatively long acting drug with marked variation in rate of elimination between individuals. In the majority of patients, the drug behaves as if it has a half-life of two to six days. In a small number of individuals, this may increase to greater than thirty days.

Note.

While long-term studies have not been carried out, it is possible that, with continuing treatment, the metabolism and excretion of perhexiline may be altered. Studies in man have shown that in the first 1 to 2 weeks no unchanged perhexiline is detected in the urine but after that, unaltered drug appears in the urine in all subjects.

Clinical significance of pharmacokinetics.

As a result of the marked variations in clearance, three types of population have been suggested, namely fast, intermediate and slow metabolisers. There is a wide range of variation between individuals in the daily levels of perhexiline (0.29 to 3.8 microgram/mL on a 400 mg per day of perhexiline) and no studies have established the time taken to reach steady-state conditions. However, it is likely that steady-state blood levels will be achieved only after two to four weeks of therapy, and after longer periods in some patients. This time period should be borne in mind when dosage adjustment is being considered.
In view of the above and considering that tissue binding occurs to a marked degree with both perhexiline and its metabolites (the pharmacological activity of the latter is unknown), accumulation with increased toxicity may result and could be a contributing factor in causing neuropathy.

5.3 Preclinical Safety Data

Genotoxicity.

Perhexiline maleate has been tested for genotoxicity in bacterial and mammalian mutation assays. Perhexiline maleate was not mutagenic in experiments with bacteria (six Salmonella typhimurium strains capable of detecting G-C modifications). Weak mutagenic activity was evident in Chinese hamster V79 cells in the presence of metabolic activation. The clastogenic potential of perhexiline maleate has not been investigated.

Carcinogenicity.

No long-term studies in animals to evaluate the carcinogenic potential of perhexiline maleate have been conducted. Perhexiline maleate is a pyridine, and data from experimental studies indicate that pyridines represent a potential cause of cancer in man. Pyridine has been implicated in the formation of liver cancers.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate, maize starch, purified talc and sucrose.

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 in cool dry place below 30°C.

6.5 Nature and Contents of Container

Glass bottles of 100 tablets, fitted with a child-resistant closure.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Perhexiline maleate is 2-(2,2-Dicyclohexylethyl) piperidine maleate. Molecular formula is C19H35N,C4H4O4 and molecular weight of 393.6.
Perhexiline maleate is a fine white crystalline powder. It is slightly soluble in water (0.1% to 1.0% w/w or 1 - 10 mg/g). Soluble in chloroform and methanol.

Chemical structure.


CAS number.

6724-53-4.

7 Medicine Schedule (Poisons Standard)

Prescription only medicine: S4.

Summary Table of Changes