PETHIDINE HYDROCHLORIDE 50 MG TABLETS - Summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Pethidine Hydrochloride 50 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 50 mg pethidine hydrochloride.

Excipient(s) with known effect

Each tablet also contains lactose monohydrate and sucrose.

For the full list of excipients, see section 6.1.

Tablet

White to off-white round tablet, diameter 8.0 mm, marked ‘PE 50’ on one side and a break line on the other.

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4.1 Therapeutic indications

1) Obstetric analgesia.

2) Moderate to severe pain.

3) Premedication and analgesia during anaesthesia.

4.2 Posology and method of administration

Posology

Adults:

■ The normal single dose, usually not to be repeated more often than four hourly, is as follows: Orally: 50 – 150 mg.

Elderly and debilitated patients

■ The initial dose should not exceed 50 mg orally as such patients are likely to be particularly sensitive to the central depressant effects of the drug.

Paediatric population:

■ A single dose of 0.5 – 2 mg / kg body weight orally. This dose may be repeated if clinically necessary but it should not be repeated more often than four hourly.

Prior to starting treatment with opioids, a discussion should be held with patients to put in place a strategy for ending treatment with pethidine hydrochloride in order to minimise the risk of addiction and drug withdrawal syndrome (see section 4.4).

Method of Administration

For oral administration.

4.3 Contraindications

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

Not to be given to comatose patients or to patients with respiratory depression, obstructive airways disease or acute asthma. It should not be given to patients who are receiving monoamine oxidase inhibitors or moclobemide, or within two weeks of their withdrawal. For full list of interactions with other medicinal products, see section 4.5. Not to be given to patients with a history of hypersensitivity or idiosyncratic response to the drug or any of its constituents.

Pethidine hydrochloride should be avoided in patients exhibiting acute alcoholism, delirium tremens or convulsive disorders, and paralytic ileus. Pethidine hydrochloride depresses respiratory function and should be avoided in patients with respiratory insufficiency and in patients with head injuries, raised intracranial pressure severe hepatic or renal impairment. Patients with phaechromocytoma should not be treated with pethidine hydrochloride.

Use of pethidine hydrochloride should be avoided in patients with diabetic acidosis where there is a danger of coma.

4.4 Special warnings and precautions for use

Paediatric population

Pethidine has a slower elimination rate and a larger inter-subject variability in neonates and young infants compared to older children and adults, which may lead to dose related reactions such as respiratory depression. If pethidine use is contemplated in neonates or young infants (up to 12 months), any potential benefits of the drug need to be weighed against the relative risk to the patient.

Drug dependence, tolerance and potential for abuse

For all patients, prolonged use of this product may lead to drug dependence (addiction), even at therapeutic doses. The risks are increased in individuals with current or past history of substance misuse disorder (including alcohol misuse) or mental health disorder (e.g., major depression).

Additional support and monitoring may be necessary when prescribing for patients at risk of opioid misuse.

A comprehensive patient history should be taken to document concomitant medications, including over-the-counter medicines and medicines obtained online, and past and present medical and psychiatric conditions.

Patients may find that treatment is less effective with chronic use and express a need to increase the dose to obtain the same level of pain control as initially experienced. Patients may also supplement their treatment with additional pain relievers. These could be signs that the patient is developing tolerance. The risks of developing tolerance should be explained to the patient.

Overuse or misuse may result in overdose and/or death. It is important that patients only use medicines that are prescribed for them at the dose they have been prescribed and do not give this medicine to anyone else.

Patients should be closely monitored for signs of misuse, abuse, or addiction.

The clinical need for analgesic treatment should be reviewed regularly.

Drug withdrawal syndrome

Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with pethidine hydrochloride.

Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. Tapering from a high dose may take weeks to months.

The opioid drug withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other symptoms may also develop including irritability, agitation, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhoea, increased blood pressure, increased respiratory rate or heart rate.

If women take this drug during pregnancy, there is a risk that their newborn infants will experience neonatal withdrawal syndrome.

Hyperalgesia

Hyperalgesia may be diagnosed if the patient on long-term opioid therapy presents with increased pain.

This might be qualitatively and anatomically distinct from pain related to disease progression or to breakthrough pain resulting from development of opioid tolerance. Pain associated with hyperalgesia tends to be more diffuse than the pre-existing pain and less defined in quality. Symptoms of hyperalgesia may resolve with a reduction of opioid dose.

Pethidine hydrochloride should only be given with caution, and in reduced dosage, to neonates and premature infants, elderly or debilitated patients, hypotension, decreased respiratory reserve, biliary tract disorders, hypothyroidism, adrenal cortical insufficiency, shock, prostatic hypertrophy, and supraventricular tachycardia. Use of cough suppressants containing opioid analgesics is not generally recommended in children and should be avoided altogether in those under at least 1 year.

Cross tolerance between narcotic analgesics can occur. In the case of severe continuing pain it may be advisable to try other treatments. A reduction in dose is advisable in cases of renal disease and chronic hepatic disease.

Pethidine hydrochloride tablets contain lactose monohydrate and sucrose. Patients with rare hereditary problems of galactose intolerance, fructose intolerance, the Lapp lactase deficiency, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs

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 “Interaction with other medicinal products and other forms of interaction”).

Serotonin syndrome

Due to the risk of serotonin syndrome, pethidine should not be used in combination with serotonergic products (see section 4.5).

4.5 Interaction with other medicinal products and other forms of interaction

Alcohol: Enhanced sedative and hypotensive effects.

Antidepressants, SSRI and Tricyclic: The use of pethidine hydrochloride should be avoided in patients receiving monoamine oxidase inhibitors (including moclobemide), or within two weeks of their withdrawal. Increased risk of CNS toxicity. Pethidine hydrochloride may increase potential for both selective serotonin re-uptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) to cause convulsions.

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 “Special warnings and precautions for use”).

Anxiolytics and Hypnotics: Sedative effects may be enhanced by simultaneous use of pethidine hydrochloride.

Antipsychotics: Increased risk of convulsions with pethidine hydrochloride.

Carbamazepine: Reduces the effects of pethidine hydrochloride.

Coumarins: Pethidine hydrochloride enhances anticoagulant effects of coumarins.

Digoxin: Risk of digoxin toxicity increased.

Duloxetine: Possible increased serotonergic effects when administered with pethidine hydrochloride.

Selegiline: Caution with pethidine hydrochloride advised by manufacturer of selegiline.

Ciprofloxacin: The manufacturer of ciprofloxacin advises that, if it is used for surgical prophylaxis, opiates should not be used for premedication as this may reduce the plasma concentration of ciprofloxacin.

Cimetidine: The metabolism of pethidine hydrochloride is inhibited (plasma concentrations of pethidine hydrochloride are increased).

Domperidone and metoclopramide: Pethidine hydrochloride antagonises the gastro-intestinal activity of these drugs.

Mexilitine: Pethidine hydrochloride delays the absorption of mexilitine.

Ritonavir: Plasma concentration of pethidine hydrochloride may be increased by ritonavir.

Serotonergic products:

Cases of serotonin syndrome have been reported in patients taking pethidine concomitantly with serotonergic drugs such as selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs), and with St John’s wort (Hypericum perforatum) (see Section 4.4).

4.6 Fertility, pregnancy and lactation

Pregnancy

Regular use during pregnancy may cause drug dependence in the foetus, leading to withdrawal symptoms in the neonate.

If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Administration during labour may depress respiration in the neonate and an antidote for the child should be readily available.

Breast-feeding

Administration to nursing women is not recommended as pethidine may be secreted in breast milk and may cause respiratory depression in the infant.

Fertility

There are insufficient fertility data available to indicate whether pethidine hydrochloride has any effect on fertility.

4.7 Effects on ability to drive and use machines

Pethidine hydrochloride may modify the patient’s reactions to a varying extent, depending on dosage, administration and individual susceptibility. If affected or if you are in any doubt that you may be affected do not drive or operate machinery until any effects have worn off.

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 medicine is likely to affect your ability to drive

Do not drive until you know how the medicine affects you

It is an offence to drive while under the influence of this medicine

However, you would not be committing an offence (called ‘statutory defence’) if:

o The medicine has been prescribed to treat a medical or dental problem and

o You have taken it according to the instructions given by the prescriber and in

the information provided with the medicine and

o It was not affecting your ability to drive safely

4.8 Undesirable effects

Reporting of suspected adverse reactions

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 the Yellow Card Scheme (Tel: Freephone 0808 100 3352 or Website: www.mhra.gov.uk/yellowcard) or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

5   PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Phenylpiperidine derivatives

ATC code: N02A B02

Mechanism of action

Pethidine hydrochloride binds to opioid receptors and exerts its chief pharmacological action on the CNS and the neural elements of the bowel. The analgesic effects of pethidine hydrochloride are detectable about 15 minutes after oral administration, reaching a peak in about 2 hours and subsiding gradually over several hours. In equianalgesic doses pethidine hydrochloride depresses respiration to a similar extent to morphine. Pethidine hydrochloride has a spasmogenic effect on certain smooth muscles similar to that observed for other opioids.

Pharmacodynamic effects

Ambulatory patients given pethidine hydrochloride may experience syncope associated with hypotension but symptoms rapidly clear on lying down. Otherwise in therapeutic doses pethidine hydrochloride has no significant untoward effects on the cardiovascular systems, especially if patients are lying down. Pethidine hydrochloride combines analgesic and antispasmodic properties; it is relatively short acting and has little soporific effect. These properties make pethidine hydrochloride particularly useful for pain relief in labour and as an adjunct to nitrous oxide-oxygen anaesthesia.

5.2 Pharmacokinetic properties

Peak plasma concentrations are normally observed between 1 and 2 hours after oral administration. However, only about 50% of the drug escapes first pass metabolism to enter the circulation. About 60% is protein bound in plasma. The T/2 is ~3 hours after IV administration of pethidine hydrochloride; in patients with cirrhosis this increases to ~6 hours.

Heavy alcohol drinkers have an increased apparent volume of distribution with consequent initially lower pethidine hydrochloride plasma concentrations. Older Patients have higher plasma concentrations and reduced protein binding which may account for the increased response in therapeutic dosages. Pethidine hydrochloride is mainly metabolised in the liver by hydrolysis to pethidinic acid, or by N-demethylation to norpethidine, followed by hydrolysis to norpethidinic acid. Subsequent, partial conjugation with glucuronic acid may also occur.

Paediatric population

A single study of pethidine pharmacokinetics was conducted in 21 infant patients who received a single 1mg/kg dose following surgery or during mechanical ventilation. Vc, Vss and tD □ was shown to vary greatly between infant subjects, but were not demonstrated to correlate with age, gestational age, postconceptional age, weight or body surface area. Clearance was demonstrated to correlate with age, gestational age, postconceptional age, weight and body surface area. Median elimination half-life was demonstrated to be 10.7 hours (range 3.3. to 59.4 hours), median clearance was 8.0 ml/kg/min (range 1.8 to 34.9 ml/kg/min), median volume of the central compartment 2.4 L/kg (range 0.5 to 4.8 L/kg) and median steady-state volume of distribution was 7.2 L/kg (range 3.3 to 11.0 L/kg).

5.3 Preclinical safety data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6.1 List of excipients

Maize starch

Lactose monohydrate

Sucrose

Talc

Magnesium stearate

Acacia

6.2 Incompatibilities

None applicable.

6.3 Shelf life

36 months

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

ALU/ALU blisters. Pack size of 50 tablets.

6.6 Special precautions for disposal No special requirement.