Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Mercury Pharmaceuticals Limited, Capital House, 85 King William Street, London EC4N 7BL, UK
Pethidine is controlled under the Misuse of Drugs Act 1971 (Schedule 2).
If the intravenous route is being used, pethidine should be given slowly in order to reduce the risk of adverse reactions.
Extreme care is required when administering pethidine to patients with asthma, severe cor pulmonale or reduced respiratory function.
Pethidine should be used with caution or in reduced doses in patients with myasthenia gravis. Pethidine should only be used with caution and in reduced dosage in neonates and premature infants, elderly and debilitated patients and in patients with head injuries, severe hepatic or renal impairment. Renal impairment may result in accumulation of the potentially toxic metabolite norpethidine, particularly with repeat dosing. All of these patient groups may experience increased or prolonged effects of the product.
Pethidine should be used with caution in patients with, hypothyroidism, adrenocortical insufficiency, shock, and supraventricular tachycardia.
Although less spasmogenic than morphine, pethidine may precipitate spasm of the ureter or Sphincter of Oddi. Subsequently it should be used with caution in patients with prostatic hypertrophy and biliary tract disorders including those with pain secondary to gallbladder pathology.
Caution is also required in patients with acute alcoholism, raised intracranial pressure, or history of convulsive disorders, existing hypotension as it may reduce the blood pressure further, myasthenia gravis.
In addition it should be avoided in patients with obstructive or inflammatory bowel disorders due to its effects on the gastrointestinal tract where it may precipitate toxic megacolon.
Repeated administration of pethidine may produce physical and psychological dependence of the morphine type, with the development of withdrawal symptoms on abrupt cessation of therapy or on administration of a narcotic antagonist. Repeated administration may also induce tolerance, with a tendency to increase the dose in order to obtain the desired effect.
Concomitant use of Pethidine and sedative medicines such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe Pethidine concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible.
The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms (see section 4.5).
The concurrent use of MAOIs (including moclobemide) is contra-indicated (see section 4.3) as they may result in CNS excitation or depression.
Very severe reactions including coma, respiratory depression, cyanosis and hypotension have occurred in patients administered monoamine inhibitors (MAOIs). Pethidine should not be administered to patients taking MAOIs or to those who have taken MAOIs within 14 days (see section 4.3). The interaction of pethidine with MAOIs may result in Serotonin syndrome.
The central depressant effects of pethidine may be potentiated by the concurrent use of other central nervous system depressants including anxiolytics and sedatives, hypnotics, barbiturates and tricyclic antidepressants, other analgesics, alcohol and general anaesthetics; respiratory depression, hypotension and profound sedation or coma may result.
Additive effects on CNS depression, respiratory depression and hypotension can occur with concomitant use of opioid agonist analgesics.
Concomitant use of MAO-B inhibitors such as selegiline or rasagiline is contraindicated (see section 4.3) as this may lead to hyperpyrexia and CNS toxicity.
Rasagiline should not be given with pethidine as there is risk of CNS toxicity, its use should be avoided for two weeks after taking rasagiline.
Administration of phenytoin may cause an increase in hepatic metabolism of pethidine and subsequently increased levels of norpethidine (a toxic metabolite).
Severe hypotension may occur when pethidine is administered to patients whose ability to maintain blood pressure has been compromised by a depleted blood volume or by the administration of drugs such as phenothiazine.
Cimetidine inhibits metabolism of pethidine and therefore increases plasma concentration.
Plasma concentrations of pethidine may be decreased by concomitant administration of ritonavir, however levels of norpethidine (a toxic metabolite) may rise. Concomitant administration of ritonavir, isoniazid and pethidine should be avoided (see section 4.3).
Pethidine antagonize effects of domperidone and metoclopramide on gastro-intestinal activity.
The plasma levels of ciprofloxacin may be reduced in the presence of opiate premedicants.
Plasma levels of mexiletine may also be reduced in the presence of opioid analgesics. Use of pethidine in prolonged increasing dosage or concomitantly with anticholinergics may result in neurotoxicity in patients with renal failure, cancer or sickle cell anaemia.
Pethidine when given with duloxetine (SSRIs) may increase serotonergic effects.
Sedative medicines such as benzodiazepines or related drugs: The concomitant use of opioids with sedative medicines such as benzodiazepines or related drugs increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of concomitant use should be limited (see section 4.4).
There is inadequate evidence of safety in human pregnancy, but the drug has been in widely use for many years without apparent ill consequence. Animal studies have not shown any hazard.
As with all drugs during pregnancy care should be taken in assessing the risk to benefit ratio. Administration during labour may cause respiratory depression in the new-born infant.
Pethidine crosses the placenta and is excreted in breast milk. This should be borne in mind when considering its use in patients during pregnancy or breast feeding.
Pethidine may impair the mental and/or physical abilities required for driving or for operating machinery. Patients should be advised accordingly and warned not to drive or to operate machines while taking pethidine as it may cause drowsiness and reduce alertness.
The ability to drive or use machines may be severely affected during and for some time after administration of pethidine. This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:
The information below lists reported adverse reactions, ranked using the following frequency classification:
Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).
Unknown: General hypersensitivity reactions
Unknown: Dependence, confusion, mood altered, mild euphoria, hallucinations, dysphoria, agitation, anxiety, nervousness. Increased risk of delirium in elderly patients.
Unknown: Drowsiness, dizziness, tremor, convulsions, headache, CNS excitation, syncope, lightheadedness, sedation
Unknown: Visual disturbances, dry eye, miosis
Unknown: Vertigo
Unknown: Tachycardia, bradycardia, palpitations
Unknown: Flushing of face, orthostatic hypotension, hypotension1, hypertension, vasodilatation
Unknown: Respiratory depression1
Unknown: Nausea, vomiting, dry mouth, constipation
Unknown: Biliary or Ureteric spasm
Unknown: Sweating, rash, urticaria, pruritis
Unknown: Uncoordinated muscle movements, muscle twitching
Unknown: Difficulty in micturition, renal colic, urinary retention
Unknown: Sexual dysfunction
Unknown: Hypothermia, weakness, injection site reactions including pain, induration and irritation, wheal and flare over the vein with intravenous injection
Unknown: Corneal reflex decreased
1 The most serious adverse effects of pethidine are respiratory depression and hypotension. Rapid intravenous administration of pethidine increases the incidence of these effects and may result in serious respiratory depression and hypotension with tachycardia.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
There was loss of clarity when intravenous solutions of pethidine hydrochloride were mixed with those of aminophylline, amylobarbitone sodium, heparin sodium, methicillin sodium, morphine sulphate, nitrofurantoin sodium, pentobarbitone sodium, phenobarbitone sodium, phenytoin sodium, sodium bicarbonate, sodium iodide, sulphadiazine sodium, sulphafurazole diethanolamine or thiopentone sodium.
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