Codeine-containing products are indicated in patients older than 12 years of age for the short-term treatment of acute, moderate pain which is not relieved by paracetamol or ibuprofen alone. Prodein Plus soluble tablet is indicated in the management of symptoms of headache, including migraine, toothache, backache, common cold, influenza, menstrual pain, musculoskeletal pain.

Posology

Adults 1-2 tablets up to four times daily as required to a 8 tablets in 24 hours. The dose should not be repeated more frequently than every 4 hours.
Adolescents aged 16 to18 years of age: 1-2 tablets every 6 hours.Do not exceed 4 doses, equivalent to 8 tablets. Adolescents aged 12 years to 18 years: This medicine is not recommended for use in children aged 12 years to 18 years with compromised respiratory function for the symptomatic treatment of cough and/or cold (see section 4.4). 1 tablet every 6 hours. Do not exceed 4 doses, equivalent to 4 tablets.

Paediatric population

Children aged less than 12 years: This medicine is contraindicated in children below the age of 12 years for the symptomatic treatment of cough and/or cold (see section 4.3). Codeine should not be used in children below the age of 12 years because of the risk of opioid toxicity due to the variable and unpredictable metabolism of codeine to morphine (see sections 4.3 and 4.4).

Elderly patients
Experience has indicated that normal adult dose of paracetamol is usually appropriate. However in frail, immobile, elderly subjects or in elderly patients with renal or hepatic impairment, a reduction in the amount or frequency of dosing may be appropriate.

The maximum daily dose of paracetamol should not exceed 60mg/kg/day (up to a maximum of 2g per day) in the following situations, unless directed by a physician:
• Weight less than 50kg
• Chronic alcoholism
• Dehydration
• Chronic malnutrition
Do not exceed the stated dose.
The duration of treatment should be limited to 3 days and if no effective pain relief is achieved the patients/carers should be advised to seek the views of a physician.
Renal Impairment
It is recommended, when giving paracetamol to patients with renal impairment, to reduce the dose and to increase the minimum interval between each administration to at least 6 hours unless directed otherwise by a physician. See table below:
Glomerular filtration rate
Dose
10-50 ml/min
500mg every 6 hours
<10ml/min
500mg every 8 hours
The restrictions related to the use of paracetamol products in patients with renal impairment are primarily a consequence of the paracetamol content of the drug (see section 4.4).

Hepatic Impairment

In patients with hepatic impairment or Gilbert’s Syndrome, the dose should be reduced or the dosing interval prolonged. The daily dose of paracetamol should not exceed 2g/day unless directed by a physician. The restrictions related to the use of paracetamol products in patients with hepatic impairment are primarily a consequence of the paracetamol content of the drug (see section 4.4).
Method of administration
For oral administration only.
Tablets should be dissolved in at least half a glass of water.

 Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.  Acute asthma;  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)  In women during breastfeeding (see section 4.6)  In patients for whom it is known they are CYP2D6 ultra-rapid metabolisers  In children below the age of 12 years for the symptomatic treatment of cough and/or cold due to an increased risk of developing serious and life-threatening adverse reactions;  In patients with chronic constipation.

Patients who have been diagnosed with liver or kidney impairment must seek medical advice before taking paracetamol or codeine. Underlying liver disease increases the risk of paracetamol-related liver damage. The hazard of overdose is greater in those with non-cirrhotic alcoholic liver disease. Care should be observed in administering the product to any patients whose condition may be exacerbated by opioids, particularly the elderly, who are especially sensitive to their central and gastro-intestinal effects, those on concurrent CNS depressant drugs and those with prostate hypertrophy.

Excessive intake of caffeine (e.g. coffee, tea and some canned drinks) should be avoided while taking this product. Patients with inflammatory or obstructive bowel disorders or acute abdominal conditions should consult a doctor before using this product. Patients with a history of cholecystectomy should consult a doctor before using this product as it may cause acute pancreatitis in some patients. Prodein plus soluble tablet contains codeine whose regular or prolonged use may produce psychological and physical dependence. This product should be used with caution in patients with current or past history of substance abuse or dependence (including drug or alcohol) or mental illness (eg: major depression). Abuse or misuse may result in overdose and/or death (see section 4.9) Prolonged regular use, 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. Prolonged use of any type of painkiller for headaches can make them worse. If this situation is experienced or suspected, medical advice should be obtained and treatment should be discontinued. The diagnosis of 'medication overuse headache' should be suspected in patients who have frequent or daily headaches despite (or because of) the regular use of headache medications. 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. Paracetamol should be administered only with particular caution under the following circumstances: • Glutathione deficiency • Chronic alcoholism • Dehydration • Chronic malnutrition • The elderly • Adults and adolescents weighing less than 50 kg • Renal impairment (GFR ≤50ml/min) • Glucose-6-phosphate dehydrogenase deficiency • Haemolytic anaemia • Concomitant treatment with medicinal products affecting hepatic function • Hepatic impairment • Gilbert’s Syndrome (familial non-haemolytic jaundice)

Patients taking, or who have taken, monoamine oxidase inhibitors (MAOIs) within the preceding two weeks (see section 4.5) should not take this product. Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs Concomitant use of Prodein plus and sedative medicines such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant use with these sedative medicines should be under medical supervision and reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe Prodein plus 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) Do not take with other paracetamol or codeine containing medicines. Immediate medical advice should be sought in the event of overdosage even if the patient feels well because the risk of irreversible liver damage (see section 4.9). Codeine, as with other opioids should be used with caution in patients with hypotension, hypothyroidism, head injury or raised intracranial pressure. 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 metabolizer, 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:

Paediatric population
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. This product should be used only when clearly necessary. Prolonged use without medical supervision may be harmful. Do not take for more than 3 days without consulting a doctor. Do not exceed the stated dose. In general, medicinal products containing paracetamol should be taken for only a few days without the advice of a physician or dentist and not at high doses. If high fever or signs of secondary infection occur or if symptoms persist for longer than 3 days, a physician should be consulted. Prolonged or frequent use is discouraged. Patients should be advised not to take other paracetamol containing products concurrently. Taking multiple daily doses in one administration can severely damage the liver; in such case medical assistance should be sought immediately.

If symptoms persist, consult your doctor. Keep this medicine out of the sight and reach of children. Each effervescent tablet contains 427 mg of sodium, equivalent to 21% of the WHO recommended maximum daily intake for sodium. The maximum daily dose of this product is equivalent to 171% of the WHO recommended maximum daily intake for sodium.The effervescent tablet is considered high in sodium. This should be particularly taken into account for those on a low salt diet.The product should be used with caution in patients with hypertension, oedema or renal insufficiency because of the sodium content. This medicine contains 50mg sorbitol (E 420) per tablet. Sorbitol is a source of fructose. Patients with hereditary fructose intolerance (HFI) should not take/be given this medicinal product.

Paracetamol

The rate of paracetamol absorption may be increased by metoclopramide or domperidone and may be reduced by cholestyramine. Colestyramine should not be administered within one hour of taking paracetamol. 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 use of drugs which induce hepatic microsomal enzymes, such as anticonvulsants and oral contraceptive steroids, may increase the extent of metabolism of paracetamol, resulting in reduced plasma concentrations of the drug and a faster elimination rate. Drugs which induce hepatic microsomal enzymes, such as alcohol and barbiturates, may increase the hepatotoxicity of paracetamol, particularly after overdose. In case of concomitant treatment with probenecid, the dose of paracetamol should be reduced because probenecid reduces the clearance of paracetamol by 50% because it prevents the conjugation of paracetamol with glucuronic acid. Paracetamol may affect the half-life of chloramphenicol. Evidence of a clinically relevant interaction appears to be lacking. Although no routine monitoring is needed, it is important to bear in mind this potential interaction when these two medications are concomitantly administered, especially in malnourished patients.

Phenytoin may reduce the analgesic and antipyretic effects of paracetamol and may increase the
formation of the toxic N-acetyl-p-benzoquinone imine (NAPQI) metabolite of paracetamol
leading to increased risk of hepatotoxicity.
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 risk factors (see section 4.4)
Codeine
Opiate analgesics may interact with monoamine oxidase inhibitors (MAOIs) and result in
serotonin syndrome. Whilst evidence is limited for the interaction with codeine, it is
recommended that the product should not be taken concurrently or within two weeks of stopping
treatment with a MAOI. The effect of CNS depressants (including alcohol) may be potentiated
by codeine.
Codeine may antagonize the effects of metoclopramide and domperidone on gastrointestinal
motility.
Concomitant use of antimuscarinics or medications with antimuscarinic action may result in an
increased risk of severe constipation, which may led to paralytic ileus and or/urinary retention.
Quinidine can inhibit the analgesic effect of codeine.
Codeine may delay the absorption of mexiletine and thus reduce the antiarrhythmic effect of the
latter. Cimetidine inhibits the metabolism of opioid analgesics resulting in increased plasma
concentrations.
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).
Caffeine
Caffeine, a CNS stimulant, has an antagonistic effect towards the action of sedatives and
tranquilisers. Caffeine may enhance the tachycardiac effect of some decongestants.

Pregnancy
Use during pregnancy should be avoided, unless advised by a physician. This includes maternal
use during labour because of the potential for respiratory depression in the neonate.Regular use

of codeine during pregnancy may cause physical dependence in the foetus leading to withdrawal
symptoms in the neonate.
The safety of paracetamol-caffeine-codeine during pregnancy has not been established relative to
the possible adverse effects onfoetal development and should be avoided.In pregnancy a total
daily consumption above 200 mg caffeine per day could possibly increase the risk of
spontaneous abortion and low birth weight.
Breastfeeding
This medicine is contraindicated in women 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 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.
Paracetamol and caffeine are excreted in breast milk but not in a clinically significant amount.
Although significant caffeine toxicity has not been observed in breastfed infants, caffeine may
have a stimulating effect on the infant.
Fertility
There are no data available regarding the influence of paracetamol, codeine and caffeine on
fertility.

Patients should be advised not to drive or operate machinery if affected by drowsiness.

Adverse reactions reported from extensive post-marketing experience are tabulated below by
System Organ Class and frequency. The following convention has been utilised for the
classification of undesirable effects: very common (≥1/10), common (≥1/100, <1/10),
uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), not known
(cannot be estimated from available data).

Caffeine

When the recommended paracetamol-caffeine-codeine dosing regimen is combined with dietary
caffeine intake, the resulting higher dose of caffeine may increase the potential for caffeinerelated
adverse effects such as insomnia, restlessness, anxiety, irritability, headaches,
gastrointestinal disturbances and palpitations.

Codeinev

Adverse reactions identified during post-marketing use are listed below by organ system class.

Overuse of this product, defined as consumption of quantities in excess of the recommended dose, or consumption for a prolonged period of time may lead to physical or psychological dependency. Symptoms of restlessness and irritability may result when treatment is stopped.

Pharmacotherapeutic group: Opioids in combination with non-opioid analgesics, codeine and paracetamol, ATC Code: N02AJ06. Paracetamol is an analgesic and antipyretic. Codeine is a centrally acting weak analgesic. Codeine exerts its effect through μ opioid receptors, although codeine has low affinity for these receptors, and its analgesic effect is due to its conversion to morphine. Codeine, particularly in combination with other analgesics such as paracetamol, has been shown to be effective in acute nociceptive pain.
Caffeine is a potent stimulator of the CNS.

Paracetamol is rapidly and almost completely absorbed from the gastrointestinal tract. It is relatively uniformly distributed throughout most body fluids and exhibits variable protein binding. Excretion is almost completely renal, in the form of conjugated metabolites. Caffeine is absorbed readilyafter oral administration, maximal plasma concentrations are achieved within one hour and the plasma half-life is about 3.5 hours. 65-80% of administered caffeine is excreted in the urine as l-methyluric acid l- methylxanthine.

Codeine phosphate is well absorbed after oral administration and iswidely distributed. About 86% is excreted in the urine in 24 hours; 40 - 70% is free or conjugated codeine, 5 - 15% is free or conjugated morphine, and 10 - 20% is free or conjugated norcodeine.

Codeine and caffeine, individually and in combination, have a well-established safety profile. There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

Conventional studies using the currently accepted standards for the evaluation of toxicity to reproduction and development are not available for paracetamol.

The active ingredients are Paracetamol 500 mg, codeine phosphaste hemoihydrate 8 mg and caffeine anhydrous 30mg.
The other ingredients are sodium bicarbonate, sorbitol, saccharin sodium, anhydrous citric acid, povidone, sodium lauryl sulphate, dimethicone, purified water, sodium carbonate anhydrous and dichloromethane.

N/A

24 months

Store below 30°C.
Keep out of the reach and sight of children.
Protect from light and moisture.

Packs of Prodein Plus Soluble Tablets contain 20 effervescent tablets (5 x 4’s).
Prodein Plus Soluble Tablets packed in 4 ply laminated foil Plain 195mm composed of 4 layer glassine paper 41 gsm, polyethylene film (ldpe) 75 gauge, Aluminium foil 9 microns, Polyethylene film (LDPE) 150 gauge. Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.