DALERON COLD3 Film-coated tablet Ref.[51126] Active ingredients: Demorphan Paracetamol Pseudoephedrine

Patients with mild or moderate hepatic or renal insufficiency should be under medical supervision while taking this medicine.

The medicine is not suitable for patients with heart disease, hypertension, thyroid disease, diabetes or problems with urination due to enlarged prostate, unless otherwise directed by the doctor.

Severe skin reactions

Severe skin reactions, such as acute generalized exanthematous pustulosis (AGEP), may occur with pseudoephedrine-containing products. This acute pustular eruption may occur within the first 2 days of treatment, with fever, and numerous, small, mostly non-follicular pustules arising on a widespread oedematous erythema and mainly localized on the skin folds, trunk, and upper extremities. Patients should be carefully monitored. If signs and symptoms, such as pyrexia, erythema, or many small pustules, are observed, administration of Daleron COLD3 should be discontinued and appropriate measures taken, if needed.

Ischaemic colitis

Some cases of ischaemic colitis have been reported with pseudoephedrine. Pseudoephedrine should be discontinued and medical advice sought if sudden abdominal pain, rectal bleeding or other symptoms of ischaemic colitis develop.

Ischaemic optic neuropathy

Cases of ischaemic optic neuropathy have been reported with pseudoephedrine. Pseudoephedrine should be discontinued if sudden loss of vision or decreased visual acuity such as scotoma occurs.

Cases of dextromethorphan abuse and dependence have been reported. Caution is particularly recommended for adolescents and young adults as well as in patients with a history of drug abuse or abuse of psychoactive substances.

Dextromethorphan is metabolised by hepatic cytochrome P450 2D6. The activity of this enzyme is genetically determined. About 10% of the general population are poor metabolisers of CYP2D6. Poor metabolisers and patients with concomitant use of CYP2D6 inhibitors may experience exaggerated and/or prolonged effects of dextromethorphan. Caution should therefore be exercised in patients who are slow metabolizers of CYP2D6 or use CYP2D6 inhibitors (see also section 4.5).

Caution is advised if paracetamol is administered concomitantly with flucloxacillin due to increased risk of high anion gap metabolic acidosis (HAGMA), particularly in patients with severe renal impairment, sepsis, malnutrition and other sources of glutathione deficiency (e.g. chronic alcoholism), as well as those using maximum daily doses of paracetamol. Close monitoring, including measurement of urinary 5-oxoproline, is recommended.

Serotonin syndrome

Serotonergic effects, including the development of a potentially life-threatening serotonin syndrome, have been reported for dextromethorphan with concomitant administration of serotonergic agents, such as selective serotonin re-uptake inhibitors (SSRIs), drugs which impair the metabolism of serotonin (including monoamine oxidase inhibitors (MAOIs)) and CYP2D6 inhibitors.

Serotonin syndrome may include mental-status changes, autonomic instability, neuromuscular abnormalities, and/or gastrointestinal symptoms.

If serotonin syndrome is suspected, treatment with Daleron COLD3 should be discontinued.

Daleron COLD3 should not be taken longer than necessary. If the symptoms and signs of disease last more than 5 days, the doctor should decide about further use of the medicine.

The medicine should be used with caution in debilitated and exhausted patients and in alcoholics.

Effects on laboratory test results

Daleron COLD3 may interfere with doping test results in athletes.

Excipient

Daleron COLD3 contains quinoline yellow (E104), which may cause allergic reactions. May have an adverse effect on activity and attention in children.

Paracetamol:

• During long-term and regular use, paracetamol potentiates the effects of warfarin and increases the risk of haemorrhage.
• If paracetamol is used concomitantly with cholestyramine, the absorption of paracetamol is reduced (reduced effect of paracetamol).
• Metoclopramide and domperidone increase the absorption of paracetamol.
• Concomitant administration of paracetamol and nonsteroidal anti-inflammatory agents increases the risk of renal impairment.
• During concomitant therapy with paracetamol and chloramphenicol, the half-life of chloramphenicol may be extended (by up to 5 times).
• The likelihood of toxic effects may be increased with concomitant administration of agents, such as antiepileptics, barbiturates and rifampicin, because they induce liver enzymes.
• Salicylamide prolongs paracetamol elimination time, which leads to accumulation of the active substance and thus to increased formation of toxic metabolites.
• Concurrent intake of paracetamol and alcohol may increase the hepatotoxicity of paracetamol.
• Caution should be taken when paracetamol is used concomitantly with flucloxacillin as concurrent intake has been associated with high anion gap metabolic acidosis, especially in patients with risks factors (see section 4.4).

Pseudoephedrine:

• The medicine should not be used concomitantly with MAO inhibitors and two weeks following therapy with MAO inhibitors. Concomitant use may cause severe hypertensive crisis, headache, hyperpyrexia and severe cardiac arrhythmias. As a sympathomimetic, pseudoephedrine stimulates the release of norepinephrine by indirect action, while MAO inhibitors increase the quantity of norepinephrine in adrenergic neurons by inhibiting the breakdown of catecholamines. Concomitant use highly increases the available quantity of norepinephrine and potentiates the activity of the sympathetic nervous system.
• Concomitant administration of pseudoephedrine and methyldopa may lead to disorders in blood pressure regulation, with resultant hypertensive crisis.
• Concomitant use of dihydroergotamine and pseudoephedrine may result in highly increased blood pressure.
• Concomitant use of pseudoephedrine and substances that alkalinise the urine (e.g. sodium hydrogen carbonate) considerably slows the elimination of pseudoephedrine.

Dextromethorphan:

• The medicine should not be used concomitantly with MAO inhibitors and two weeks following therapy with MAO inhibitors. Concomitant use may cause serotonin syndrome (nausea, vomiting, hypertension, muscle cramps, tremor, hyperpyrexia, mental changes, cardiac arrest). Co-administration of MAO inhibitors and dextromethorphan results in changed reuptake and metabolism of catecholamines, and in accumulation of serotonin in the central nervous system.
• Concomitant administration of dextromethorphan and fluoxetine (an antidepressant, a serotonin reuptake inhibitor in cerebral neurons) increases the toxicity of dextromethorphan (nausea, vomiting, visual disturbances, hallucinations) or the risk of serotonin syndrome. Fluoxetine inhibits cytochrome P450IID6 (CYP2D6), an isoenzyme that catalyses the metabolism of dextromethorphan. Concurrent intake of these two agents results in a competitive inhibition of the metabolism of both active substances and in an increase in their serum levels, and consequently in increased toxicity.
• Co-administration of dextromethorphan and haloperidol (a neuroleptic, a dopamine antagonist) increases the toxicity of dextromethorphan. Haloperidol is an inhibitor of cytochrome P450IID6, which catalyses the metabolism of dextromethorphan. If these agents are used concomitantly, the metabolism of dextromethorphan is inhibited and its serum levels increased.
• Dextromethorphan is metabolized by CYP2D6 and has an extensive first-pass metabolism. Concomitant use of potent CYP2D6 enzyme inhibitors can increase the dextromethorphan concentrations in the body to levels multifold higher than normal. This increases the patient’s risk for toxic effects of dextromethorphan (agitation, confusion, tremor, insomnia, diarrhoea and respiratory depression) and development of serotonin syndrome. Potent CYP2D6 enzyme inhibitors include fluoxetine, paroxetine, quinidine and terbinafine. In concomitant use with quinidine, plasma concentrations of dextromethorphan have increased up to 20-fold, which has increased the CNS adverse effects of the agent. Amiodarone, flecainide and propafenone, sertraline, bupropion, methadone, cinacalcet, haloperidol, perphenazine and thioridazine also have similar effects on the metabolism of dextromethorphan. If concomitant use of CYP2D6 inhibitors and dextromethorphan is necessary, the patient should be monitored and the dextromethorphan dose may need to be reduced.

Pregnancy

Preclinical studies in animals have not demonstrated undesirable effects on pregnancy and foetal development. Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero show inconclusive results. Nevertheless, risk cannot be completely excluded therefore the medicine is not recommended for use during pregnancy and lactation.

Breast-feeding

Pseudoephedrine is excreted in breast milk and may cause restlessness and insomnia in the nursing infant.

Fertility

There are no data available on the effect on fertility in humans.

Daleron COLD3 has no or negligible influence on the ability to drive and use machines.

Undesirable effects that may occur during treatment with Daleron COLD3 are classified into the following groups in order of frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Frequency of undesirable effects listed by individual organ systems:

If severe undesirable effects occur, treatment should be discontinued.

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 ADR Reporting Website: www.medicinesauthority.gov.mt/adrportal.

Not applicable.