Syndol Caplets

1. Name Of The Medicinal Product

Syndol Caplets.

2. Qualitative And Quantitative Composition

Paracetamol BP 450.0mg, Codeine Phosphate BP 10.0mg, Doxylamine Succinate NF 5.0mg, Caffeine BP 30.0mg.

3. Pharmaceutical Form

Tablets.

4. Clinical Particulars

4.1 Therapeutic Indications

For the treatment of mild to moderate pain and as an antipyretic. Syndol Caplets are recommended for the symptomatic relief of headache, including muscle contraction or tension headache, migraine, neuralgia, toothache, sore throat, dysmenorrhoea, muscular and rheumatic aches and pains and for post-operative analgesia following surgical or dental procedures.

4.2 Posology And Method Of Administration

For oral administration. Adults and children over 12 years: 1 or 2 tablets every four to six hours as needed for relief. Total dosage over a 24 hour period should not normally exceed 8 tablets. Do not take for more than three days continuously without medical review.

Codeine should be used with caution in the elderly and debilitated patients, as they may be more susceptible to the respiratory depressant effects.

4.3 Contraindications

Hypersensitivity to paracetamol, codeine or other opioid analgesics, or any of the other constituents.

4.4 Special Warnings And Precautions For Use

Do not exceed the stated dose. Do not take concurrently with any other paracetamol or codeine containing compounds. Keep out of the reach of children. Care is advised in the administration of this preparation to patients with impaired kidney or liver function and in those with hypertension, hypothyroidism, adrenocortical insufficiency, prostatic hypertrophy, shock, obstructive bowel disorders, acute abdominal conditions, recent gastrointestinal surgery, gallstones, myasthenia gravis, a history of cardiac arrhythmias or convulsions and in patients with a history of drug abuse or emotional instability.

Codeine may induce faecal impaction, producing incontinence, spurious diarrhoea, abdominal pain and rarely colonic obstruction. Elderly patients may metabolise or eliminate opioid analgesics more slowly than younger adults.

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

If you need to use this medicine for more than three days at a time, see your doctor, pharmacist or healthcare professional. Taking codeine regularly for a long time can lead to addiction, which might cause you to feel restless and irritable when you stop taking 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):

If you need to use this medicine for more than three days at a time, see your doctor or pharmacist. Taking codeine regularly for a long time can lead to addiction. Taking a painkiller for headaches too often or for too long can make them worse.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by cholestyramine. The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular daily use of paracetamol with increased risk of bleeding; occasional doses have no significant effect.

The depressant effects of codeine are enhanced by depressants of the central nervous system such as alcohol, anaesthetics, hypnotics, sedatives, tricyclic antidepressants and phenothiazines. The hypotensive actions of diuretics and anti hypertensive agents may be potentiated when used concurrently with opioid analgesics. Concurrent use of hydroxyzine with codeine may result in increased analgesia as well as increased CNS depressant and hypotensive effects. Concurrent use of codeine with antidiarrhoeal and antiperistaltic agents such as loperamide and kaolin may increase the risk of severe constipation. Concomitant use of antimuscarinics or medications with antimuscarinic action may result in an increased risk of severe constipation that may lead to paralytic ileus and/or urinary retention. The respiratory depressant effect caused by neuromuscular blocking agents may be additive to the central respiratory depressant effects of opioid analgesics. CNS depression or excitation may occur if codeine is given to patients receiving monoamine oxidase inhibitors, or within two weeks of stopping treatment with them. Quinidine can inhibit the analgesic effect of codeine. Codeine may delay the absorption of mexiletine and thus reduce the antiarrhythmic effect of the latter. Codeine may antagonise the gastrointestinal effects of metoclopramide, cisapride and domperidone. Cimetidine inhibits the metabolism of opioid analgesics resulting in increased plasma concentrations. Naloxone antagonises the analgesic, CNS and respiratory depressant effects of opioid analgesics. Naltrexone also blocks the therapeutic effect of opioids.

Incompatibilities: Codeine has been reported to be incompatible with phenobarbitone sodium forming a codeine-phenobarbitone complex, and with potassium iodide, forming crystals of codeine periodide. Acetylation of codeine phosphate by aspirin has occurred in solid dosage forms containing the two drugs, even at low moisture levels.

Interference with laboratory tests: Opioid analgesics interfere with a number of laboratory tests including plasma amylase, lipase, bilirubin, alkaline phosphatase, lactate dehydrogenase, alanine aminotransferase and aspartate aminotransferase. Opioids may also interfere with gastric emptying studies as they delay gastric emptying and with hepatobiliary imaging-using technetium Tc 99m disofenin as opioid treatment may cause constriction of the sphincter of Oddi and increase biliary tract pressure.

4.6 Pregnancy And Lactation

Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in the recommended dosage, but patients should follow the advice of their doctor regarding its use. Codeine crosses the placenta. There is no adequate evidence of safety in human pregnancy and a possible association with respiratory and cardiac malformations has been reported. Regular use during pregnancy may cause physical dependence in the foetus leading to withdrawal symptoms in the neonate. Use during pregnancy should be avoided if possible.

Use of opioid analgesia during labour may cause respiratory depression in the neonate, especially the premature neonate. These agents should not be given during the delivery of a premature baby.

Codeine passes into breast milk in very small amounts that are considered to be compatible with breast feeding.

4.7 Effects On Ability To Drive And Use Machines

Not applicable.

4.8 Undesirable Effects

Doxylamine succinate may cause drowsiness or dizziness in some patients.

Adverse effects of paracetamol are rare but hypersensitivity including skin rash may occur. There have been a few reports of blood dyscrasias including thrombocytopenia and agranulocytosis but these were not necessarily causally related to paracetamol.

The most frequent undesirable effects of codeine are constipation and drowsiness. Less frequent effects are nausea, vomiting, sweating, facial flushing, dry mouth, blurred or double vision, dizziness, orthostatic hypotension, malaise, tiredness, headache, anorexia, vertigo, bradycardia, palpitations, respiratory depression, dyspnoea, allergic reactions (itch, skin rash, facial oedema) and difficulties in micturition (dysuria, increased frequency, decrease in amount). Side effects that occur rarely include convulsions, hallucinations, nightmares, uncontrolled muscle movements, muscle rigidity, mental depression and stomach cramps.

Regular prolonged use of codeine is known to lead to addiction and symptoms of restlessness and irritability may result when treatment is stopped. Prolonged use of a painkiller for headaches can make them worse.

4.9 Overdose

Symptoms of overdose in the first 24 hours are pallor, nausea, vomiting, anorexia, and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, coma and death. Acute renal failure with acute tubular necrosis may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported. Liver damage is possible in adults who have taken 10g or more of paracetamol. It is considered that excess quantities of a toxic metabolite (usually adequately detoxified by glutathione when normal doses of paracetamol are ingested) become irreversibly bound to liver tissue. Immediate treatment is essential in the management of a paracetamol overdose. Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention and any patient who has ingested around 7.5g or more of paracetamol in the preceding 4 hours should undergo gastric lavage. Administration of oral methionine or intravenous N-acetylcysteine which may have a beneficial effect up to at least 48 hours after the overdose, may be required. General supportive measures must be available.

While the dose of codeine phosphate in this preparation is relatively small and therefore less likely to prove a problem, symptoms of overdose include cold clammy skin, confusion, convulsions, dizziness, drowsiness, nervousness or restlessness, miosis, bradycardia, dyspnoea, unconsciousness and weakness. Codeine in large doses may produce respiratory depression, hypotension, circulatory failure and deepening coma. Death may occur from respiratory failure.

Initial treatment includes emptying the stomach by aspiration and lavage. Intensive support therapy may be required to correct respiratory failure and shock. In addition the specific narcotic antagonist, naloxone hydrochloride, may be used rapidly to counteract the severe respiratory depression and coma. A dose of 0.4-2 mg is given intravenously or intramuscularly to adults, this is repeated at intervals of 2-3 minutes; if necessary up to 10mg of naloxone may be given. In children doses of 5-10µg/kg body weight may be given intravenously or intramuscularly. Codeine is not dialysable.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Paracetamol - antipyretic, analgesic; codeine phosphate - analgesic; doxylamine succinate - antihistamine; caffeine - mild stimulant.

5.2 Pharmacokinetic Properties

The pharmacokinetics of paracetamol, codeine phosphate and caffeine are widely published (see Goodman & Gilman's The Pharmacological Basis of Therapeutics, Seventh Edition, pp 693, 505 and 596 respectively). Doxylamine succinate is readily absorbed from the gastrointestinal tract. Following oral administration, the effects start within 15 to 30 minutes and peak within one hour. In humans, 60-80% of doxylamine given has been recovered in urine at 24 hours post-dose.

5.3 Preclinical Safety Data

None stated.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablet Core: Povidone; Croscarmellose Sodium; Corn Starch; Magnesium Stearate; Talc; Purified water.

Coating: Opadry II Yellow (Lactose Monohydrate; Hydroxypropyl Methyl Cellulose (Methocel E15); Polyethylene Glycol 4000; Quinoline Yellow Aluminium Lake (E104); Sunset Yellow Aluminium Lake (E110); Titanium Dioxide)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

60 months.

6.4 Special Precautions For Storage

None stated.

6.5 Nature And Contents Of Container

Blister strips: 250 micron PVC and aluminium foil 20 micron coated with a 15 micron PVC layer.

Blister strips are presented in cardboard cartons.

Pack sizes are 10,20 or 30 tablets.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Seton Products Limited, Tubiton House, Oldham, OL1 3HS

8. Marketing Authorisation Number(S)

PL 11314/0122.

9. Date Of First Authorisation/Renewal Of The Authorisation

16^th January 1999.

10. Date Of Revision Of The Text

October 2006