Document: spc-doc_PL 20416-0065 change

• spc-doc_PL 04569-0161
• spc-doc_PL 17907-0010
• spc-doc_PL 20416-0065

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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Dihydrocodeine tablets BP 30mg

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

Dihydrocodeine Tartrate BP 30mg per tablet.

3.    PHARMACEUTICAL FORM

Dihydrocodeine tablets BP 30mg are presented as white normal convex tablets engraved with company logo on one face and A435 on the other face.

4.    CLINICAL PARTICULARS

4.1    Therapeutic Indications

For the relief of moderate to severe pain in conditions where an alert patient is desired, viz, sciatica, osteoarthritis, chronic rheumatoid arthritis, arthritis of the spine, peripheral vascular disease, post-herpetic neuralgia, Paget's disease, malignant disease and post-operative pain.

4.2    Posology and method of administration

Adults:One tablet every 4-6 hours or as recommended by the prescriber.

Children aged 4-12 years: 0.5 to 1.0 mg/kg body-weight every 4-6 hours. A more suitable dosage form is recommended for this age group (e.g. elixir).

Children under 4 years: Not recommended.

Elderly: Dosage should be reduced in the elderly.

Dihydrocodeine tablets are best administered with or after food. The analgesic effect of this product is not materially enhanced by increasing the above dose: in severe cases the interval between doses should be reduced to obtain the requisite analgesic effect.

Route of administration: Oral

4.3 Contraindications

1.    Hypersensitivity to opioid analgesics (including dihydrocodeine) or to any of the excipients.

2.    Acute respiratory depression and obstructive airways disease.

3.    Diarrhoea due to pseudomembranous colitis or poisoning.

4.    Where there is a risk of paralytic ileus.

5.    Raised intracranial pressure or head injury.

6.    Comatose patients

7.    Acute alcoholism

4.4 Special warnings and precautions for use

Dihydrocodeine should be given in reduced doses or with caution to patients with asthma and decreased respiratory reserve. Avoid use during an acute asthma attack. Dihydrocodeine should be avoided, or the dose reduced in patients with hepatic or renal impairment.

Dihydrocodeine should be given in reduced doses or with caution to debilitated patients, adrenocortical insufficiency, prostatic hyperplasia, urethral stricture, hypotension, shock, inflammatory or obstructive bowel disorders, hypothyroidism or convulsive disorders.

However, these conditions should not necessarily be a deterrent to use in palliative care.

Use with caution in those with a history of drug abuse.

Alcohol should be avoided whilst under treatment with dihydrocodeine.

In patients already habituated to a drug such as Pethidine the substitution of dihydrocodeine in equianalgesic doses has lead to the appearance of abstinence symptoms. This suggests that dihydrocodeine despite its effectiveness as an analgesic has a low addiction potential. Nevertheless when dihydrocodeine is prescribed for chronic use the physician should take care to avoid any unnecessary increase in dosage, especially where there is a previous history of drug dependence and abuse.

Avoid abrupt withdrawal after long-term treatment.

Administration of pethidine and possibly other opioid analgesics to patients taking a monoamine oxidase inhibitor (MAOI) has been associated with very severe and sometimes fatal reactions. If the use of dihydrocodeine is considered essential then great care should be taken in patients taking MAOIs or within 14 days of stopping MAOIs. (See section 4.5).

The risk-benefit of continued use should be assessed regularly by the prescriber.

The leaflet will state in a prominent position in the “before taking” section:

•    Do not take for longer than directed by your prescriber.

•    Taking dihydrocodeine regularly for a long time can lead to addiction, which might cause you to feel restless and irritable when you stop the tablets.

•    Taking a painkiller for headaches too often or for too long can make them worse.

The label will state (to be displayed prominently on outer pack - not boxed)

•    Do not take for longer than directed by your prescriber as taking dihydrocodeine regularly for a long time can lead to addiction.

Patients with rare hereditary problems of galactose intolerance, the LAPP lactase deficiency or glucose-galactose malabsorption should not take this medicine as it contains lactose.

4.5 Interaction with other medicinal products and other forms of interaction

Dihydrocodeine may cause the release of histamine; hence this product should not be administered during an asthmatic attack and should be administered with caution in patients with allergic disorders.

Concurrent administration of dihydrocodeine with antidiarrhoeal and antiperistaltics such as difenoxin, atropine, kaolin, pectin, belladonna alkaloids, opium preparations and loperamide, may increase the risk of severe constipation and central nervous system depression.

Concurrent administration of dihydrocodeine with antihypertensive agents especially ganglionic blockers such as guanethidine, diuretics, hypotension producing medication may potentiate the hypotensive effect and increase risk of orthostatic hypotension.

Concomitant administration of dihydrocodeine with other medications with antimuscarinic action may lead to increased risk of severe constipation and may lead to paralytic ileus and/or urinary retention.

Concurrent administration with metoclopramide or domperidone may antagonise the effects of metoclopramide or domperidone on gastrointestinal motility.

The depressant effects of opioid analgesics are enhanced by other CNS depressants such as:

Alcohol - enhanced hypotensive, sedative effect and respiratory depression. Anaesthetics - may increase anaesthetic and sedative effect.

Sedating antihistamines - may enhance the CNS depressive effects when taken with opioids.

Anxiolytics or hypnotics - may enhance CNS depressive effects when taken with opioids.

Tricyclic antidepressants - may enhance CNS depressive effects when taken with opioids.

Antipsychotics - enhanced hypotensive, sedative effect.

MAOIs taken with pethidine have been associated with severe CNS excitation or depression (including hypertension or hypotension). Although this has not been documented with dihydrocodeine, it is possible that a similar interaction may occur and therefore the use of dihydrocodeine should be avoided while the patient is taking MAOIs and for 2 weeks after MAOI discontinuation.

Administration with moclobemide may cause CNS excitation or depression (hypertension or hypotension).

Cimetidine may inhibit the metabolism of dihydrocodeine, resulting in increased plasma concentrations.

Dihydrocodeine may delay absorption of mexiletine.

Cyclizine may counteract the haemodynamic benefits of opioids.

4.6 Fertility, pregnancy and lactation

Dihydrocodeine traverses the placental barrier, regular use during pregnancy and labour may depress neonatal respiration and cause physical dependence in the foetus, leading to withdrawal symptoms, therefore administration should be avoided during the later stages of pregnancy. Gastric stasis and risk of inhalation pneumonia may occur in the mother during labour. Teratogenic effects have not been demonstrated in humans. However studies in mice have shown delayed ossification; and increased resorption has been reported in rats. Therefore risk benefit must be considered when administering during pregnancy.

Dihydrocodeine is excreted in the breast milk in very small amounts which are probably insignificant however as neonates are most susceptible to its effects, especially the respiratory depressant effects, use of this product in nursing mothers is not recommended.

4.7 Effects on ability to drive and use machines

Dihydrocodeine may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery.

May cause drowsiness, paraesthesia, dizziness, vertigo, muscle rigidity, visual disturbances, confusion and hallucinations, if affected, do not drive or operate machinery.

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:

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

-    You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

-    It was not affecting your ability to drive safely.

4.8 Undesirable effects

Regular prolonged use of dihydrocodeine is known to lead to addiction and tolerance. Symptoms of restlessness and irritability may result when treatment is then stopped.

Prolonged use of a painkiller for headaches can make them worse.

Immune system disorders

Allergic reactions such as hives, itching, skin rashes, swelling of face, dyspnoea and difficulty in breathing.

Metabolism and nutrition disorders Anorexia.

Psychiatric disorders

Mental depression, hallucinations, restlessness, confusion, mood changes, euphoria, dysphoria, unusual excitement in children, nightmares

Nervous system disorders

Paraesthesia, convulsions, uncontrolled muscular movements, tremors, dizziness, headache.

Eye disorders

Miosis, visual disturbances.

Ear and labyrinth disorders Vertigo.

Cardiac disorders

Irregularities of cardiac rhythm, bradycardia, tachycardia, palpitations.

Vascular disorders

Postural hypotension, facial flushing.

Larger doses produce hypotension.

Respiratory, thoracic and mediastinal disorders Larger doses produce respiratory depression.

Gastrointestinal disorders

Nausea and vomiting, constipation, dry mouth, stomach cramps, abdominal pain. Hepatobiliary disorders

Biliary spasm which may be associated with alterations in liver enzyme values.

Skin and subcutaneous tissue disorders Urticaria, pruritis, sweating.

Musculoskeletal, connective tissue and bone disorders

Muscle rigidity has been reported after high doses especially respiratory muscles. Renal and urinary disorders

Difficulty with micturition, urinary retention, ureteric spasm, dysuria.

Reproductive system and breast disorders Sexual dysfunction.

General disorders and administration site conditions Oedema, drowsiness, malaise, tiredness.

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 at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

The effects in overdosage will be potentiated by simultaneous ingestion of alcohol and psychotropic drugs.

Symptoms

Central nervous system depression, including respiratory depression, may develop but is unlikely to be severe unless other sedative agents have been co-ingested, including alcohol, or the overdose is very large. Symptoms resulting from overdose are cold, clammy skin, confusion, convulsions, dizziness, drowsiness, asthenia, hypotension, tachycardia, bradycardia, nervousness, restlessness, pin-point pupils, nausea and vomiting are common, slow or troubled breathing and unconsciousness.

Management

This should include general symptomatic and supportive measures including monitoring of vital signs until stable. Consider activated charcoal if an adult presents within one hour of ingestion of more than 350 mg or a child more than 5 mg/kg. Treatment entails, emptying the stomach via induction of emesis or gastric lavage, maintenance of patient airway and institution of assisted or controlled respiration if necessary. Administration of opioid antagonist naloxone 10mcg/kg of body-weight or 400mcg-2mg as a single dose preferably intravenous may be required if coma or respiratory depression is present. Naloxone is a competitive antagonist and has a short half-life so large and repeated doses may be required in a seriously poisoned patient. Observe for at least four hours after ingestion, or eight hours if a sustained release preparation has been taken. It must be borne in mind that naloxone may also antagonise the analgesic action of opioid analgesics and may precipitate withdrawal symptoms in physically dependent patients.

For reversal of post-operative opioid depression, dosage of naloxone must be carefully titrated to avoid interference with post-operative pain or causing other adverse effects; hypertension and tachycardia, sometimes resulting in left ventricular failure and pulmonary oedema has resulted following naloxone administration in these circumstances especially in cardiac patients. Initial doses of as low as 0.5mcg/kg of body-weight have been recommended. Supportive measures such as intravenous fluids and vasopressor drugs may be required.

Patients should be monitored continuously while administrating additional naloxone as needed.

5.1 Pharmacodynamic properties

ATC code N02A A08

Dihydrocodeine tartrate is an analgesic with uses similar to those of morphine but is less potent.

Dihydrocodeine is an opioid (narcotic analgesic) which binds with stereospecific receptors located at many sites within the central nervous system.

It alters processes affecting both the perception and emotional response to pain.

The exact site and mechanism of action is unknown.

However it is thought to affect the release of various neurotransmitters from afferent nerves sensitive to painful stimuli and maybe partially responsible for the analgesic effect.

Multiple subtypes of opioid receptors have been proposed, each responsible for various therapeutic and/or side effects of opioid drugs. Action of dihydrocodeine may therefore depend upon its binding affinity for each type of receptor and on whether it acts as a full agonist or a partial agonist or is inactive at each type of receptor. At least two types of receptors (mu and kappa) are known to be responsible for the analgesic action. Sigma, a third type may not mediate analgesia; action at this receptor may produce the subjective and psychomimetic effects characteristic of other opioid analgesics such as pentazocine, butorphanol and nalbuphine.

Dihydrocodeine also has an antidiarroheal action, it acts locally and probably centrally to alter the intestinal motility.

It has anti-tussive action due to suppression of the cough reflex by a direct action probably in the medulla or pons.

Dihydrocodeine is also a suppressant of the narcotic abstinence syndrome and acts as a substitute for other opioid drugs.

When administered orally it prevents or attenuates the withdrawal symptoms during detoxification. The resulting withdrawal symptoms which may occur when the substituted opioid is discontinued are less severe.

Dihydrocodeine is much less potent as an analgesic as compared with morphine and has only mild sedative effect.

Pharmacokinetic properties

Dihydrocodeine is well absorbed from the gastro-intestinal tract following oral administration and a small quantity is bound to plasma proteins.

Peak levels of plasma dihydrocodeine concentration are attained 1.6 - 1.8 hours following ingestion. After oral administration the bioavailability of the drug is approximately 20%, indicating that the pre-systemic metabolism plays a substantial role in reducing the bioavailability of dihydrocodeine. Dihydrocodeine is excreted in the urine as unchanged drug and metabolites. The mean elimination half-life ranges between 3.5 - 5 hours. Dihydrocodeine is metabolised in the liver by O- and N-demethylation.

5.3 Preclinical Safety Data

Not applicable

6. PHARMACEUTICAL PARTICULARS

6.1.    List of Excipients

Lactose BP Maize starch BP Pregelatinised maize starch BP Sodium starch glycollate BP Stearic acid BP Magnesium stearate BP Potable water

6.2. Incompatibilities

None

6.3. Shelf-Life

3 years

6.4. Special Precautions for Storage

Protect from heat, light and moisture. Keep out of the reach of children.