CO-TIPOL Hard capsule Ref.[108797] Active ingredients: Codeine Codeine and Paracetamol Paracetamol

In order to avoid overdosing, it should be ensured that no other medications containing paracetamol and/or codeine are administered concurrently.

Co‐Tipol should only be used after balancing of risks and benefits in patients

• with opioid dependence,
• with impaired consciousness,
• with conditions associated with increased intracerebral pressure,
• under treatment with MAO inhibitors,
• with chronic obstructive airways disease,

CONTAINS PARACETAMOL.

Do not take with other paracetamol or codeine containing medicines. Paracetamol should be administered with caution under the following circumstances (see section 4.2 where relevant):

• Hepatic impairment
• Chronic alcoholism
• Renal impairment (GFR≤50ml/min)
• Gilbert’s Syndrome (familial non‐haemolytic jaundice)
• Concomitant treatment with medicinal products affecting hepatic function
• Glucose‐6‐phosphate dehydrogenase deficiency
• Haemolytic anaemia
• Glutathione deficiency
• Dehydration
• Chronic malnutrition
• Weight less than 50kg
• Elderly

CYP2D6 metabolism

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 ultrarapid 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.

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

Concomitant use of Co‐Tipol 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 Co‐Tipol 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 4.5).

Severe acute hypersensitivity reactions such as anaphylactic shock have very rarely been seen. Treatment should be discontinued at the earliest signs of hypersensitivity reactions to the use/administration of Co‐Tipol. Measures required to relieve the symptoms should be taken by experienced clinicians.

Severe liver damage may result from exceeding the recommended dose.

If large amounts of paracetamol are taken for extended periods of time or if this medicinal product is not used properly, it may cause headache which should not be treated with increased doses. In such cases, treatment should not be continued without first seeking the advice of a medical practitioner.

In general, the long‐term use of analgesics, above all in combination with pain killers having an anti‐inflammatory and antipyretic action, may lead to permanent damage to the kidney, which might result in renal failure (analgesic nephropathy).

Headache, fatigue, muscular pain, nervousness and vegetative symptoms may occur after abrupt discontinuation of any analgesic not used as directed or taken in large doses over long periods of time. No analgesic should be taken before subsidence of such symptoms, which usually disappear within a few days. A physician should be consulted before resuming treatment.

Co‐Tipol should not be used in high dosage by patients suffering from hypotension and hypovolaemia.

As a component of a fixed dose mixture, codeine exhibits a primary potential of dependence. The prolonged use of large amounts of such products results in the development of tolerance, psychological and physical dependence. Cross‐tolerance to other opioids is induced. Patients with pre‐existing opiate dependence – even those in remission – are likely to suffer a quick relapse. Codeine is regarded as a substitute by heroin addicts. Persons addicted to alcohol and sedatives are also prone to codeine abuse.

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.

Caution:

The prolonged administration of large amounts increases the risk of producing dependence.

Patients receiving large doses and very sensitive persons may develop dose‐related disturbances of visuomotor coordination and impaired visual acuity. Furthermore, respiratory depression and euphoria may occur.

Caution must be exercised in the treatment of patients having undergone cholecystectomy. Myocardial infarction‐like symptoms may occur and symptoms of patients with pancreatitis may become worse as a result of a contraction of the sphincter of Oddi.

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 4.4).

The concomitant use of drugs causing enzyme induction in the liver, such as certain sedative agents and antiepileptics (phenobarbital, phenytoin, carbamazepine, etc.) as well as rifampicin may result in liver damage caused by otherwise safe doses of paracetamol.

The same applies to compounds that may have a toxic action on the liver and to alcohol abuse. When administered in combination with chloramphenicol, Co‐Tipol may substantially slow down the excretion and increase the toxic risk of this compound.

Anticoagulants: The repeated ingestion of paracetamol for more than one week reinforces the response to anticoagulants, while the occasional use of paracetamol has no significant influence on the effect of these drugs.

The absorption of paracetamol may be impaired and the drug may have a slower onset of action, if products delaying stomach emptying (e. g. propantheline) are given simultaneously.

Conversely, the absorption of paracetamol may be enhanced and the drug may have a more rapid onset of action, if the patient concurrently receives drugs accelerating gastric emptying like metoclopramide or domperidone.

Patients who concomitantly receive paracetamol and zidovudine (AZT or retrovir) may be more susceptible to the development of neutropenia.

Ingestion of probenecid inhibits the linkage of paracetamol to glucuronic acid, reducing paracetamol clearance by a factor of about 2. The dose of paracetamol should therefore be reduced if probenecid is given concurrently.

Salicylamides may increase the elimination half‐life of paracetamol.

Cholestyramine reduces the absorption of paracetamol.

Alcohol should be refrained from by patients on Co‐Tipol, since their psychomotor performance may be substantially impaired (overadditive effect of the different ingredients).

Codeine‐induced respiratory depression may be increased in subjects receiving tricyclic antidepressants (imipramine, amitriptyline) or opipramol.

The concomitant use of MAO inhibitors like tranylcypromine may reinforce the action on the central nervous system and produce other side‐effects of unforeseeable severity. That is why Co‐Tipol should not be used within two weeks after the last administration of any MAO inhibitor.

Co‐Tipol increases the effect of analgesics. Its action may be diminished by the simultaneous use of partial opioid agonists and antagonists such as buprenorphine and pentacozine. Cimetidine and other drugs influencing the liver metabolism may increase the effect of Co‐Tipol. Inhibition of morphine degradation resulting in an elevation of plasma levels was seen in patients on morphine treatment. This effect cannot be ruled out for codeine.

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).

Effects on laboratory tests

Uric acid tests using phosphotungstic acid and the determination of blood glucose with glucose oxidase peroxidase may be influenced by paracetamol.

Pregnancy

An association was noted between malformations of the respiratory tract and the use of codeine in the first three months of human pregnancy. Epidemiological studies of narcotic analgesics including codeine have revealed further malformations.

Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero show inconclusive results. If clinically needed, Co‐Tipol should only be used during pregnancy especially in the first three months – if clinical circumstances so indicate and after balancing benefits against risks.

The use of Co‐Tipol is contraindicated in women well advanced in pregnancy or at risk for premature delivery, since codeine can cross the placental barrier and cause respiratory depression in the newborn.

The prolonged use of codeine may give rise to opioid dependence of the foetus. The repeated administration of codeine in the last three months of pregnancy has been reported to cause withdrawal symptoms in the newborn.

Breast-feeding

Co‐Tipol should not be used during breastfeeding (see section 4.3).

At normal therapeutic doses codeine and its active metabolite may be present in breast milk at very low doses and is unlikely to adversely affect the breast fed infant. However, if the patient is an ultrarapid 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.

Even if used properly, the codeine component of Co‐Tipol may modify the patient’s reaction to an extent that his/her ability to drive a car, operate machinery or perform hazardous activities is impaired.

In this section frequencies of undesirable effects are defined as follows: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).

Note:

Patients should be instructed to stop treatment and immediately contact a doctor at the earliest signs of hypersensitivity reactions.

Description of selected adverse reactions

Pulmonary oedema: Patients on large doses may develop pulmonary oedema, especially those with pre‐existing disorders of lung function.

Cardiovascular diseases: Patients taking large amounts tend to develop fall in blood pressure and syncope.

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 national reporting system: HPRA Pharmacovigilance Website: www.hpra.ie

Not applicable.