PEXSIG Tablet Ref.[9639] Active ingredients:

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.

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.

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 (see also section 4.8, Undesirable effects). Bilateral papilloedema, with fundal haemorrhages and both reversible and permanent impairment of visual acuity, has been reported sometimes. 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.

Investigation

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.

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/SGT, 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.

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;
4. persistent or marked hypoglycaemia;
5. excessive weight loss (see section 4.8, Undesirable effects).

Use in Renal Impairment

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

Use in Hepatic Impairment

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

Use in Children

Not recommended for use in children.

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.

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.

Alcohol: No information available.

Food: No information available.

Other Medicines

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 anti-diabetics and beta-blockers.

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 (CY P450 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 μg/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 eg. 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 (CYP 450 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. ondanestron, 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.

Interference with clinical laboratory tests

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

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.

Pregnancy

There is limited experience of the medicine’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 Category B2

Medicines 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.

Lactation

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.

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

Short Term (occurring after as little as 24 hours of therapy): nausea, dizziness (usually transient), hypoglycaemia in diabetic patients and torsade 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 Q.T. 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. Hypertriglyceridemia.

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions https://nzphvc.otago.ac.nz/reporting/.

No data available.