Migraleve Film-coated Tablets

SPC

4.2       Posology and method of administration

Do not take for more than 3 days continuously without medical review. If prescribed do not take for longer than directed.

Adults and the elderly:  Two Migraleve Pink tablets to be swallowed immediately it is known that a migraine attack has started or is imminent.  If further treatment is required, two Migraleve Yellow tablets every 4-6 hours.

Maximum dose:  8 tablets (two Migraleve Pink and six Migraleve Yellow) in 24 hours.

Paediatric population:

Children 12 – 14 years:  One Migraleve Pink tablet to be swallowed immediately it is known that a migraine attack has started or is imminent.  If further treatment is required, one Migraleve Yellow tablet every 4 hours.

Maximum dose:  4 tablets (one Migraleve Pink and three Migraleve Yellow) in 24 hours.

Children aged below 12 years:

Do not give to children under 12 years because of the risk of opioid toxicity due to the variable and unpredictable metabolism of codeine to morphine (see section 4.3 Contra-indications and 4.4 Special Warnings and Precautions for Use)

4.2       Posology and method of administration

Do not take for more than 3 days continuously without medical review. If prescribed do not take for longer than directed.

Adults, children 15 years and over, and the elderly:  Two Migraleve Pink tablets to be swallowed immediately it is known that a migraine attack has started or is imminent.  If further treatment is required, two Migraleve Yellow tablets every 4-6  hours.

Maximum dose:  8 tablets (two Migraleve Pink and six Migraleve Yellow) in 24 hours.

Paediatric population:

Children 12 – 14 years:  One Migraleve Pink tablet to be swallowed immediately it is known that a migraine attack has started or is imminent.  If further treatment is required, one Migraleve Yellow tablet every 4 hours.

Maximum dose:  4 tablets (one Migraleve Pink and three Migraleve Yellow) in 24 hours.

Children aged below 12 years:

Do not give to children under 12 years because of the risk of opioid toxicity due to the variable and unpredictable metabolism of codeine to morphine (see sSection 4.3 Contra-indications and Section 4.4 Special Warnings and Precautions for Use).

The use of this product in children aged less than 12 years of age is not recommended (see Section 4.3 and Section 4.4)

4.3       Contraindications

Hypersensitivity to any of the ingredients.

In all paediatric patients (0-18 years of age) who undergo tonsillectomy and/or adenoidectomy for obstructive sleep apnoea syndrome due to an increased risk of developing serious and life-threatening adverse reactions (see section 4.4 Special Warnings and Precautions for Use).

In women during breastfeeding (see Section 4.6 Fertility, Pregnancy and Lactation).

In patients for whom it’s known they are CY2D6 ultra-rapid metabolisers.

4.3       Contraindications

Hypersensitivity to any of the active substances (Paracetamol, Codeine phosphate and /or Buclizine hydrochloride) or to any of the excipients listed in section 6.1. ingredients.

Codeine-containing products are contraindicated for postoperative pain management Iin all paediatric patients (0-18 years of age) who have undergone tonsillectomy and/or adenoidectomy for obstructive sleep apnoea syndrome due to an increased risk of developing serious and life-threatening adverse reactions (see section Section 4.4 Special Warnings and Precautions for Use).

In women during breastfeeding (see Section 4.6 Fertility, Pregnancy and Lactation).

In patients for whom it’s known they are CY2D6 ultra-rapid metabolisers.

4.4       Special warnings and precautions for use

Migraine should be medically diagnosed.  Because some medicines do not combine, if you are already taking prescribed medicines please consult your doctor.  If symptoms persist consult your doctor.  Migraleve Pink tablets contain potent medicaments and should not be taken continuously for extended periods without the advice of a doctor.  Do not exceed the stated dose.  May cause drowsiness.  Avoid alcoholic drink.  Should be used with caution in patients with severe renal disease or liver dysfunction.

Patients should be advised not to take other paracetamol-containing products concurrently.

Immediate medical advice should be sought in the event of an overdose even if the patient feels well because of the risk of irreversible liver damage.

Prolonged regular use for more than 3 days, except under medical supervision, may lead to physical and psychological dependence (addiction) and result in withdrawal symptoms, such as restlessness and irritability once the drug is stopped.

Codeine is metabolised by the liver enzyme CYP2D6 into morphine, its active metabolite. If a patient has a deficiency or is completely lacking this enzyme an adequate analgesic effect will not be obtained. Estimates indicate that up to 7% of the Caucasian population may have this deficiency. However, if the patient is an extensive or ultra-rapid metaboliser there is an increased risk of developing side effects of opioid toxicity even at commonly prescribed doses. These patients convert codeine into morphine rapidly resulting in higher than expected serum morphine levels.

General symptoms of opioid toxicity include confusion, somnolence, shallow breathing, small pupils, nausea, vomiting, constipation and lack of appetite. In severe cases this may include symptoms of circulatory and respiratory depression, which may be life-threatening and very rarely fatal.

Estimates of prevalence of ultra-rapid metabolisers in different populations are summarized below:

Post-operative use in children

There have been reports in the published literature that codeine given post-operatively in children after tonsillectomy and/or adenoidectomy for obstructive sleep apnoea, led to rare, but life-threatening adverse events including death (see also section 4.3). All children received doses of codeine that were within the appropriate dose range; however there was evidence that these children were either ultra-rapid or extensive metabolisers in their ability to metabolise codeine to morphine.

Children with compromised respiratory function

Codeine is not recommended for use in children in whom respiratory function might be compromised including neuromuscular disorders, severe cardiac or respiratory conditions, upper respiratory or lung infections, multiple trauma or extensive surgical procedures. These factors may worsen symptoms of morphine toxicity.

4.4       Special warnings and precautions for use

Migraine should be medically diagnosed.  Because some medicines do not combine, patients should be advised to tell their doctor if you they are already taking prescribed medicines please consult your doctor.  They should also be advised to consult their doctor Iif symptoms persist. consult your doctor.  Migraleve Pink tablets contain potent medicaments and should not be taken continuously for extended periods without the advice of a doctor. 

Do not exceed the stated dose.

Codeine

Codeine is an opioid agent. Tolerance, psychological and physical dependence may occur with prolonged use and/or high doses (see Section 4.8). Prolonged regular use for more than 3 days, except under medical supervision, may lead to physical and psychological dependence (addiction) and result in withdrawal symptoms, such as restlessness and irritability once the drug is stopped.

Codeine should be used with caution in patients at risk for additive CNS effects (see Section 4.5), convulsive disorders, head injuries, and in conditions in which intracranial pressure is raised.

Codeine should be used with caution in patients with decreased respiratory reserve, bronchial asthma, pulmonary oedema, obstructive airway disease, acute respiratory depression or obstructive bowel disorders and in patients at risk of paralytic ileus.

Use with caution in patients with renal and hepatic impairment.

Do not exceed the stated dose.  May cause drowsiness.  Avoid alcoholic drink.  Should be used with caution in patients with severe renal disease or liver dysfunction.

Patients should be advised not to take other paracetamol-containing products concurrently.

Immediate medical advice should be sought in the event of an overdose even if the patient feels well because of the risk of irreversible liver damage.

4.5       Interaction with other medicaments 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 use of paracetamol with increased risk of bleeding; occasional doses have no significant effect.

4.5       Interaction with other medicaments and other forms of interaction

Codeine

Concomitant use with central nervous system depressants (e.g. barbiturates, chloral hydrate, benzodiazepines, phenthiazines, alcohol and centrally acting muscle relaxants) may cuase additive CNS depression.

Concurrent use with other opioid receptor agonists may cause additive CNS depression, respiratory depression and hypotensive effect.

Codeine analgesia is believed to be dependent upon the cytochrome P450 isoenzyme CYP2D6 catalysed o-demethylation to form the active metabolite morphine although other mechanisms have been cited. An interaction with quinidine, methadone and paroxetine (CYP2D6 inhibitors) leading to decreased plasma concentrations of morphine has been described, which may have the potential to decrease codeine analgesia.

4.6       Fertility, pregnancy and lactation

Although experiments in some animal species gave rise to adverse effects following the administration of buclizine to pregnant animals e.g. foetal abnormalities and maternal deaths, these occurred at doses in excess of 120 times the human daily dose.  Whilst there are no specific reasons for contra-indicating Migraleve Pink during pregnancy, as with all drugs it is recommended that Migraleve Pink be used in pregnancy only when the physician has considered the need in respect of the patients’ welfare. 

Codeine should not be used during breastfeeding (see section 4.3 Contra-indications).

At normal therapeutic doses, codeine and its active metabolites may be present in breast milk at very low doses and are unlikely to adversely affect the breast fed infant.

However if the patient is an ultra rapid metaboliser of CYP2D6, higher levels of the active metabolite, morphine,  may be present in breast milk and on very rare occasions may result in symptoms of opioid toxicity in the infant which may be fatal.

If symptoms of opioid toxicity develop in either the mother or the infant, then all codeine containing medicines should be stopped and alternative non-opioid analgesics prescribed. In severe cases consideration should be given to prescribing naloxone to reverse these effects.

4.6       Fertility, pregnancy and lactation

Pregnancy

This product should not be used during pregnancy unless the potential benefit of treatment to the mother outweighs the possible risks to the developing foetus.

4.8       Undesirable effects

Rare allergic reactions to paracetamol, such as skin rashes, hives or itching.  Codeine may cause constipation. Buclizine hydrochloride may cause drowsiness.

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.

4.8       Undesirable effects

Rare allergic reactions to paracetamol, such as skin rashes, hives or itching.  Codeine may cause constipation. Buclizine hydrochloride may cause drowsiness.

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.

Very rare cases of serious skin reactions have been reported with paracetamol

Adverse reactions identified during clinical trials and post-marketing experience with paracetamol, codeine, buclizine hydrochloride or the combinations of paracetamol/codeine or paracetamol/codeine/buclizine hydrochloride are listed below by System Organ Class (SOC).

The frequencies are defined as according to the following convention:

Very common (≥1/10);

Common (≥1/100 and <1/10);

Uncommon (≥1/1,000 and <1/100);

Rare (≥1/10,000 and <1/1,000); very rare (<1/10,000),

Not known frequency (cannot be estimated from the available data).

ADRs are presented by frequency category based on 1) incidence in adequately designed clinical trials or epidemiology studies, if available, or 2) when incidence is unavailable, frequency category is listed as ‘Not known’.

¹ Adverse events reported by ≥1% of codeine/paracetamol treated subjects in 27 randomised placebo-controlled trials

² Associated with codeine

³ Associated with paracetamol

⁴ Reported following paracetamol use, but not necessarily causally related to the drug

⁵ Associated with buclizine

⁶ Associated with paracetamol / codeine combination

⁷ Low level transaminase elevations may occur in some patients taking therapeutic doses of paracetamol; these elevations are not accompanied with liver failure and usually resolve with continued therapy or discontinuation of paracetamol.

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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail:medsafety@hpra.ie.

4.9       Overdose

Paracetamol

Liver damage is possible in adults who have taken 10g or more of paracetamol.  Ingestion of 5g or more of paracetamol may lead to liver damage if the patient has risk factors (see below).

Risk Factors:

If the patient

Is on long term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St John’s Wort or other drugs that induce liver enzymes.

Or

Regularly consumes ethanol in excess of recommended amounts.

Or

Is likely to be glutathione deplete e.g. eating disorders, cystic fibrosis, HIV infection, starvation, cachexia.

Symptoms of paracetamol overdosage 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, haemorrhage, hypoglycaemia, cerebral oedema, and death.  Acute renal failure with acute tubular necrosis, strongly suggested by loin pain, haematuria and proteinuria, may develop even in the absence of severe liver damage.  Cardiac arrhythmias and pancreatitis have been reported.

Immediate treatment is essential in the management of paracetamol overdose.  Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention.  Symptoms may be limited to nausea or vomiting and may not reflect the severity of overdose or the risk of organ damage.  Management should be in accordance with established treatment guidelines, see BNF overdose section.  Treatment with activated charcoal should be considered if the overdose has been taken within 1 hour.  Plasma paracetamol concentration should be measured at 4 hours or later after ingestion (earlier concentrations are unreliable) but results should not delay initiation of treatment beyond 8 hours after ingestion, as the effectiveness of the antidote declines sharply after this time.  If required the patient should be given intravenous N-acetylcysteine, in line with the established dosage schedule.  If vomiting is not a problem, oral methionine may be a suitable alternative for remote areas, outside hospital.

Codeine

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

Codeine overdose associated with 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.  The pupils may be pin-point in size; nausea and vomiting are common. Hypotension and tachycardia are possible but unlikely.

Management of codeine overdose includes general symptomatic and supportive measures including a clear airway and 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.

Give naloxone 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.

4.9       Overdose

Paracetamol

Please refer to local guidance for the treatment of paracetamol overdose.

Liver damage is possible in adults and adolescents (≥ 12 years of age) who have taken greater than 7.5 to 10g or more of paracetamol over a period of 8 hours or less. Fatalities are infrequent (less than 3-4% of untreated cases) and have rarely been reported with overdoses of less than 15g. 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.

Ingestion of 5g or more of paracetamol may lead to liver damage if the patient has risk factors (see below).

Risk Factors:

If the patient

Is on long term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St John’s Wort or other drugs that induce liver enzymes.

Or

Regularly consumes ethanol in excess of recommended amounts.

Or

Is likely to be glutathione deplete e.g. eating disorders, cystic fibrosis, HIV infection, starvation, cachexia.

Symptoms

Symptoms of paracetamol overdosage in the first 24 hours are pallor, nausea, hyperhidrosis, malaise, vomiting, anorexia and abdominal pain.  Liver damage may not become apparent until 12 to 48 to 72  hours after ingestion.  This may include hepatomegaly, liver tenderness, jaundice, acute hepatic failure and hepatic necrosis. Abnormalities of glucose metabolism and metabolic acidosis may occur. Blood bilirubin, hepatic enzymes, INR, prothrombin time, blood phosphate and blood lactate may be increased.  In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema, and death.  Acute renal failure with acute tubular necrosis, strongly suggested by loin pain, haematuria and proteinuria, may develop even in the absence of severe liver damage.  Cardiac arrhythmias and pancreatitis have been reported.

Management

Immediate treatment is essential in the management of paracetamol overdose.  Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention.  Symptoms may be limited to nausea or vomiting and may not reflect the severity of overdose or the risk of organ damage.  Management should be in accordance with established treatment guidelines, see BNF overdose section.  Treatment with activated charcoal should be considered if the overdose has been taken within 1 hour.  Plasma paracetamol concentration should be measured at 4 hours or later after ingestion (earlier concentrations are unreliable) but results should not delay initiation of treatment with N-acetylcysteine beyond 8 hours after ingestion, as the effectiveness of the antidote declines sharply after this time.  If required the patient should be given intravenous N-acetylcysteine, in line with the established dosage schedule.  If vomiting is not a problem, oral methionine may be a suitable alternative for remote areas, outside hospital.

Codeine

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

Codeine overdose associated with 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.  The pupils may be pin-point in size; nausea and vomiting are common. Hypotension and tachycardia are possible but unlikely. Other risks of codeine overdose include asthenia, cardiorespiratory arrest, cerebral oedema, coma, confusional state, convulsion, drug dependence, fatigue, hypoxia, ileus, renal failure, respiratory failure, stupor, and withdrawal symptoms.

Management of codeine overdose includes general symptomatic and supportive measures including a clear airway and 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.

Give naloxone 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.

Buclizine

Overdose with sedating antihistamines is associated with antimuscarinic, extrapyramidal, and CNS effects. When CNS stimulation predominates over CNS depression, which is more likely in children or the elderly, it causes ataxia, excitement, tremors, psychoses, hallucinations and convulsions; hyperpyrexia may also occur. Deepening coma and cardiorespiratory collapse may follow. In adults, CNS depression is more common with drowsiness, coma, and convulsions, progressing to respiratory failure and cardiovascular collapse.

SPC

4.2       Posology and method of administration

Do not take for more than 3 days continuously without medical review. If prescribed do not take for longer than directed.

Adults and the elderly:  Two Migraleve Pink tablets to be swallowed immediately it is known that a migraine attack has started or is imminent.  If further treatment is required, two Migraleve Yellow tablets every 4-6 hours.

Maximum dose:  8 tablets (two Migraleve Pink and six Migraleve Yellow) in 24 hours.

Paediatric population:

Children 12 – 14 years:  One Migraleve Pink tablet to be swallowed immediately it is known that a migraine attack has started or is imminent.  If further treatment is required, one Migraleve Yellow tablet every 4 hours.

Maximum dose:  4 tablets (one Migraleve Pink and three Migraleve Yellow) in 24 hours.

Children aged below 12 years:

Do not give to children under 12 years because of the risk of opioid toxicity due to the variable and unpredictable metabolism of codeine to morphine (see section 4.3 Contra-indications and 4.4 Special Warnings and Precautions for Use)

4.2       Posology and method of administration

Do not take for more than 3 days continuously without medical review. If prescribed do not take for longer than directed.

Adults, children 15 years and over, and the elderly:  Two Migraleve Pink tablets to be swallowed immediately it is known that a migraine attack has started or is imminent.  If further treatment is required, two Migraleve Yellow tablets every 4-6  hours.

Maximum dose:  8 tablets (two Migraleve Pink and six Migraleve Yellow) in 24 hours.

Paediatric population:

Children 12 – 14 years:  One Migraleve Pink tablet to be swallowed immediately it is known that a migraine attack has started or is imminent.  If further treatment is required, one Migraleve Yellow tablet every 4 hours.

Maximum dose:  4 tablets (one Migraleve Pink and three Migraleve Yellow) in 24 hours.

Children aged below 12 years:

Do not give to children under 12 years because of the risk of opioid toxicity due to the variable and unpredictable metabolism of codeine to morphine (see sSection 4.3 Contra-indications and Section 4.4 Special Warnings and Precautions for Use).

The use of this product in children aged less than 12 years of age is not recommended (see Section 4.3 and Section 4.4)

4.3       Contraindications

Hypersensitivity to any of the ingredients.

In all paediatric patients (0-18 years of age) who undergo tonsillectomy and/or adenoidectomy for obstructive sleep apnoea syndrome due to an increased risk of developing serious and life-threatening adverse reactions (see section 4.4 Special Warnings and Precautions for Use).

In women during breastfeeding (see Section 4.6 Fertility, Pregnancy and Lactation).

In patients for whom it’s known they are CY2D6 ultra-rapid metabolisers.

4.3       Contraindications

Hypersensitivity to any of the active substances (Paracetamol, Codeine phosphate and /or Buclizine hydrochloride) or to any of the excipients listed in section 6.1. ingredients.

Codeine-containing products are contraindicated for postoperative pain management Iin all paediatric patients (0-18 years of age) who have undergone tonsillectomy and/or adenoidectomy for obstructive sleep apnoea syndrome due to an increased risk of developing serious and life-threatening adverse reactions (see section Section 4.4 Special Warnings and Precautions for Use).

In women during breastfeeding (see Section 4.6 Fertility, Pregnancy and Lactation).

In patients for whom it’s known they are CY2D6 ultra-rapid metabolisers.

4.4       Special warnings and precautions for use

Migraine should be medically diagnosed.  Because some medicines do not combine, if you are already taking prescribed medicines please consult your doctor.  If symptoms persist consult your doctor.  Migraleve Pink tablets contain potent medicaments and should not be taken continuously for extended periods without the advice of a doctor.  Do not exceed the stated dose.  May cause drowsiness.  Avoid alcoholic drink.  Should be used with caution in patients with severe renal disease or liver dysfunction.

Patients should be advised not to take other paracetamol-containing products concurrently.

Immediate medical advice should be sought in the event of an overdose even if the patient feels well because of the risk of irreversible liver damage.

Prolonged regular use for more than 3 days, except under medical supervision, may lead to physical and psychological dependence (addiction) and result in withdrawal symptoms, such as restlessness and irritability once the drug is stopped.

Codeine is metabolised by the liver enzyme CYP2D6 into morphine, its active metabolite. If a patient has a deficiency or is completely lacking this enzyme an adequate analgesic effect will not be obtained. Estimates indicate that up to 7% of the Caucasian population may have this deficiency. However, if the patient is an extensive or ultra-rapid metaboliser there is an increased risk of developing side effects of opioid toxicity even at commonly prescribed doses. These patients convert codeine into morphine rapidly resulting in higher than expected serum morphine levels.

General symptoms of opioid toxicity include confusion, somnolence, shallow breathing, small pupils, nausea, vomiting, constipation and lack of appetite. In severe cases this may include symptoms of circulatory and respiratory depression, which may be life-threatening and very rarely fatal.

Estimates of prevalence of ultra-rapid metabolisers in different populations are summarized below:

Post-operative use in children

There have been reports in the published literature that codeine given post-operatively in children after tonsillectomy and/or adenoidectomy for obstructive sleep apnoea, led to rare, but life-threatening adverse events including death (see also section 4.3). All children received doses of codeine that were within the appropriate dose range; however there was evidence that these children were either ultra-rapid or extensive metabolisers in their ability to metabolise codeine to morphine.

Children with compromised respiratory function

Codeine is not recommended for use in children in whom respiratory function might be compromised including neuromuscular disorders, severe cardiac or respiratory conditions, upper respiratory or lung infections, multiple trauma or extensive surgical procedures. These factors may worsen symptoms of morphine toxicity.

4.4       Special warnings and precautions for use

Migraine should be medically diagnosed.  Because some medicines do not combine, patients should be advised to tell their doctor if you they are already taking prescribed medicines please consult your doctor.  They should also be advised to consult their doctor Iif symptoms persist. consult your doctor.  Migraleve Pink tablets contain potent medicaments and should not be taken continuously for extended periods without the advice of a doctor. 

Do not exceed the stated dose.

Codeine

Codeine is an opioid agent. Tolerance, psychological and physical dependence may occur with prolonged use and/or high doses (see Section 4.8). Prolonged regular use for more than 3 days, except under medical supervision, may lead to physical and psychological dependence (addiction) and result in withdrawal symptoms, such as restlessness and irritability once the drug is stopped.

Codeine should be used with caution in patients at risk for additive CNS effects (see Section 4.5), convulsive disorders, head injuries, and in conditions in which intracranial pressure is raised.

Codeine should be used with caution in patients with decreased respiratory reserve, bronchial asthma, pulmonary oedema, obstructive airway disease, acute respiratory depression or obstructive bowel disorders and in patients at risk of paralytic ileus.

Use with caution in patients with renal and hepatic impairment.

Do not exceed the stated dose.  May cause drowsiness.  Avoid alcoholic drink.  Should be used with caution in patients with severe renal disease or liver dysfunction.

Patients should be advised not to take other paracetamol-containing products concurrently.

Immediate medical advice should be sought in the event of an overdose even if the patient feels well because of the risk of irreversible liver damage.

4.5       Interaction with other medicaments 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 use of paracetamol with increased risk of bleeding; occasional doses have no significant effect.

4.5       Interaction with other medicaments and other forms of interaction

Codeine

Concomitant use with central nervous system depressants (e.g. barbiturates, chloral hydrate, benzodiazepines, phenthiazines, alcohol and centrally acting muscle relaxants) may cuase additive CNS depression.

Concurrent use with other opioid receptor agonists may cause additive CNS depression, respiratory depression and hypotensive effect.

Codeine analgesia is believed to be dependent upon the cytochrome P450 isoenzyme CYP2D6 catalysed o-demethylation to form the active metabolite morphine although other mechanisms have been cited. An interaction with quinidine, methadone and paroxetine (CYP2D6 inhibitors) leading to decreased plasma concentrations of morphine has been described, which may have the potential to decrease codeine analgesia.

4.6       Fertility, pregnancy and lactation

Although experiments in some animal species gave rise to adverse effects following the administration of buclizine to pregnant animals e.g. foetal abnormalities and maternal deaths, these occurred at doses in excess of 120 times the human daily dose.  Whilst there are no specific reasons for contra-indicating Migraleve Pink during pregnancy, as with all drugs it is recommended that Migraleve Pink be used in pregnancy only when the physician has considered the need in respect of the patients’ welfare. 

Codeine should not be used during breastfeeding (see section 4.3 Contra-indications).

At normal therapeutic doses, codeine and its active metabolites may be present in breast milk at very low doses and are unlikely to adversely affect the breast fed infant.

However if the patient is an ultra rapid metaboliser of CYP2D6, higher levels of the active metabolite, morphine,  may be present in breast milk and on very rare occasions may result in symptoms of opioid toxicity in the infant which may be fatal.

If symptoms of opioid toxicity develop in either the mother or the infant, then all codeine containing medicines should be stopped and alternative non-opioid analgesics prescribed. In severe cases consideration should be given to prescribing naloxone to reverse these effects.

4.6       Fertility, pregnancy and lactation

Pregnancy

This product should not be used during pregnancy unless the potential benefit of treatment to the mother outweighs the possible risks to the developing foetus.

4.8       Undesirable effects

Rare allergic reactions to paracetamol, such as skin rashes, hives or itching.  Codeine may cause constipation. Buclizine hydrochloride may cause drowsiness.

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.

4.8       Undesirable effects

Rare allergic reactions to paracetamol, such as skin rashes, hives or itching.  Codeine may cause constipation. Buclizine hydrochloride may cause drowsiness.

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.

Very rare cases of serious skin reactions have been reported with paracetamol

Adverse reactions identified during clinical trials and post-marketing experience with paracetamol, codeine, buclizine hydrochloride or the combinations of paracetamol/codeine or paracetamol/codeine/buclizine hydrochloride are listed below by System Organ Class (SOC).

The frequencies are defined as according to the following convention:

Very common (≥1/10);

Common (≥1/100 and <1/10);

Uncommon (≥1/1,000 and <1/100);

Rare (≥1/10,000 and <1/1,000); very rare (<1/10,000),

Not known frequency (cannot be estimated from the available data).

ADRs are presented by frequency category based on 1) incidence in adequately designed clinical trials or epidemiology studies, if available, or 2) when incidence is unavailable, frequency category is listed as ‘Not known’.

¹ Adverse events reported by ≥1% of codeine/paracetamol treated subjects in 27 randomised placebo-controlled trials

² Associated with codeine

³ Associated with paracetamol

⁴ Reported following paracetamol use, but not necessarily causally related to the drug

⁵ Associated with buclizine

⁶ Associated with paracetamol / codeine combination

⁷ Low level transaminase elevations may occur in some patients taking therapeutic doses of paracetamol; these elevations are not accompanied with liver failure and usually resolve with continued therapy or discontinuation of paracetamol.

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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail:medsafety@hpra.ie.

4.9       Overdose

Paracetamol

Liver damage is possible in adults who have taken 10g or more of paracetamol.  Ingestion of 5g or more of paracetamol may lead to liver damage if the patient has risk factors (see below).

Risk Factors:

If the patient

Is on long term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St John’s Wort or other drugs that induce liver enzymes.

Or

Regularly consumes ethanol in excess of recommended amounts.

Or

Is likely to be glutathione deplete e.g. eating disorders, cystic fibrosis, HIV infection, starvation, cachexia.

Symptoms of paracetamol overdosage 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, haemorrhage, hypoglycaemia, cerebral oedema, and death.  Acute renal failure with acute tubular necrosis, strongly suggested by loin pain, haematuria and proteinuria, may develop even in the absence of severe liver damage.  Cardiac arrhythmias and pancreatitis have been reported.

Immediate treatment is essential in the management of paracetamol overdose.  Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention.  Symptoms may be limited to nausea or vomiting and may not reflect the severity of overdose or the risk of organ damage.  Management should be in accordance with established treatment guidelines, see BNF overdose section.  Treatment with activated charcoal should be considered if the overdose has been taken within 1 hour.  Plasma paracetamol concentration should be measured at 4 hours or later after ingestion (earlier concentrations are unreliable) but results should not delay initiation of treatment beyond 8 hours after ingestion, as the effectiveness of the antidote declines sharply after this time.  If required the patient should be given intravenous N-acetylcysteine, in line with the established dosage schedule.  If vomiting is not a problem, oral methionine may be a suitable alternative for remote areas, outside hospital.

Codeine

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

Codeine overdose associated with 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.  The pupils may be pin-point in size; nausea and vomiting are common. Hypotension and tachycardia are possible but unlikely.

Management of codeine overdose includes general symptomatic and supportive measures including a clear airway and 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.

Give naloxone 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.

4.9       Overdose

Paracetamol

Please refer to local guidance for the treatment of paracetamol overdose.

Liver damage is possible in adults and adolescents (≥ 12 years of age) who have taken greater than 7.5 to 10g or more of paracetamol over a period of 8 hours or less. Fatalities are infrequent (less than 3-4% of untreated cases) and have rarely been reported with overdoses of less than 15g. 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.

Ingestion of 5g or more of paracetamol may lead to liver damage if the patient has risk factors (see below).

Risk Factors:

If the patient

Is on long term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St John’s Wort or other drugs that induce liver enzymes.

Or

Regularly consumes ethanol in excess of recommended amounts.

Or

Is likely to be glutathione deplete e.g. eating disorders, cystic fibrosis, HIV infection, starvation, cachexia.

Symptoms

Symptoms of paracetamol overdosage in the first 24 hours are pallor, nausea, hyperhidrosis, malaise, vomiting, anorexia and abdominal pain.  Liver damage may not become apparent until 12 to 48 to 72  hours after ingestion.  This may include hepatomegaly, liver tenderness, jaundice, acute hepatic failure and hepatic necrosis. Abnormalities of glucose metabolism and metabolic acidosis may occur. Blood bilirubin, hepatic enzymes, INR, prothrombin time, blood phosphate and blood lactate may be increased.  In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema, and death.  Acute renal failure with acute tubular necrosis, strongly suggested by loin pain, haematuria and proteinuria, may develop even in the absence of severe liver damage.  Cardiac arrhythmias and pancreatitis have been reported.

Management

Immediate treatment is essential in the management of paracetamol overdose.  Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention.  Symptoms may be limited to nausea or vomiting and may not reflect the severity of overdose or the risk of organ damage.  Management should be in accordance with established treatment guidelines, see BNF overdose section.  Treatment with activated charcoal should be considered if the overdose has been taken within 1 hour.  Plasma paracetamol concentration should be measured at 4 hours or later after ingestion (earlier concentrations are unreliable) but results should not delay initiation of treatment with N-acetylcysteine beyond 8 hours after ingestion, as the effectiveness of the antidote declines sharply after this time.  If required the patient should be given intravenous N-acetylcysteine, in line with the established dosage schedule.  If vomiting is not a problem, oral methionine may be a suitable alternative for remote areas, outside hospital.

Codeine

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

Codeine overdose associated with 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.  The pupils may be pin-point in size; nausea and vomiting are common. Hypotension and tachycardia are possible but unlikely. Other risks of codeine overdose include asthenia, cardiorespiratory arrest, cerebral oedema, coma, confusional state, convulsion, drug dependence, fatigue, hypoxia, ileus, renal failure, respiratory failure, stupor, and withdrawal symptoms.

Management of codeine overdose includes general symptomatic and supportive measures including a clear airway and 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.

Give naloxone 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.

Buclizine

Overdose with sedating antihistamines is associated with antimuscarinic, extrapyramidal, and CNS effects. When CNS stimulation predominates over CNS depression, which is more likely in children or the elderly, it causes ataxia, excitement, tremors, psychoses, hallucinations and convulsions; hyperpyrexia may also occur. Deepening coma and cardiorespiratory collapse may follow. In adults, CNS depression is more common with drowsiness, coma, and convulsions, progressing to respiratory failure and cardiovascular collapse.