Solpadeine Plus Soluble Tablets

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Solpadeine Plus Soluble Tablets.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each t ablet cont ains P aracetamol Ph.Eur. 500 .0 mg , Codeine Phosphate Hemihydrate Ph.Eur. 8.0 mg and Caffeine Ph.Eur. 30.0 mg.

3 PHARMACEUTI CAL FORM

Effervescent tablet.

4 CLI NICAL PARTICULARS

4.1 Therapeutic indications

Codeine is indicated in patients older than 12 years of age for the treatment of acute moderate pain whi ch is not consid ered to be relieved by paracetamol or ibuprofen alone.

Solpadeine Plus Soluble Tablets are recommended for the relief of migraine, headache, back ache, rheum atic pai n, pe riod pains, dental pain, strains & sprains and sciatica.

4.2 Posology and method of administration

Adults (including the elderly)

2 tablets dissolved in at least half a tumbler of water. The dose may be given up to 3 or 4 times a da y if necessary. The dose should not be r epeated more frequently than every 4 hours.

Paediatric population

Children and adolescents aged 12 - 18 years:

2 tablets dissolved in at least half a tumbler of water. The dose may be given up to 3 or 4 times a da y if necessary. The dose should not be r epeated more frequently than every 4 hours.

Children aged less than 12 years:

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).

The duration of treatment should be limited to 3 days and if no e ffective pain relief is achieved the p atients/carers shoul d be ad vised to seek the views of a physician.

4.3 Contraindications

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

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.

4.4 Special warnings and precautions for use

Care is advised in the administration of paracetamol to patients with renal or hepatic impairment. The hazard of overdose is greater in those with noncirrhotic alcoholic liver disease.

Do not exceed the stated dose.

Patients should be advised to consult their doctor if their headaches become persistent.

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

If symptoms persist, consult your doctor.

Keep out of the reach and sight of children.

Patients with 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.

Excessive intake of caffeine (e.g. coffee, tea and some canned drinks) should be avoided while taking this product

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:

Population Prevalenc	e %
African/Ethiopian 29%
African American	3.4% to 6.5%
Asian	1.2% to 2%
Caucasian	3.6% to 6.5%
Greek 6.0%
Hungarian 1.9%
Northern European	1%-2%

Post-operative use in children

There have been reports in the published literature that codeine given postoperatively 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.

The leaflet will state:

Headlines section (to be prominently displayed)

• This medicine is for the short term treatment of acute moderate pain when other painkillers have not worked.

• You should only take this product for a maximum of 3 days at a time. If you need to take it for longer than 3 days you should see your doctor or pharmacist for advice

• This medicine contains codeine which can cause addiction if you take it continuously for more than 3 days. This can give you withdrawal symptoms from the medicine when you stop taking it

• If you take this medicine for headaches for more than 3 days it can make them worse.

Section 1: What the medicine is for:

• Solpadeine Plus Soluble Tablets can be used in patients older than 12 years of age for the short term relief of moderate pain which is not relieved by other painkillers such as paracetamol or ibuprofen alone. They can be used for migraine, headache, dental pain, period pain, strains & sprains, backache, rheumatic pain and sciatica.

Section 2: Before taking

• This medicine contains codeine which can cause addiction if you take it continuously for more than 3 days. This can give you withdrawal symptoms from the medicine when you stop taking it

• If you take a painkiller for headaches for more than 3 days it can make them worse.

Section 3: Dosage

• This medicine should not be taken for more than 3 days. If the pain does not improve after 3 days, talk to your doctor for advice.

• Possible withdrawal effects

This medicine contains codeine and can cause addiction if you take it continuously for more than 3 days. When you stop taking it you may get withdrawal symptoms. You should talk to your doctor or pharmacist if you think you are suffering from withdrawal symptoms.

Section 4: Side effects

• Some people may have side-effects when taking this medicine. If you have any unwanted side-effects you should seek advice from your doctor, pharmacist or other healthcare professional. Also you can help to make sure that medicines remain as safe as possible by reporting any unwanted side-effects via the internet at www.yellowcard.mhra.gov.uk; alternatively you can call Freephone 0808 100 3352 (available between 10am-2pm Monday - Friday) or fill in a paper form available from your local pharmacy.

• How do I know if I am addicted?

If you take the medicine according to the instructions on the pack it is unlikely that you will become addicted to the medicine. However, if the following apply to you it is important that you talk to your doctor:

• You need to take the medicine for longer periods of time

• You need to take more than the recommended dose

• When you stop taking the medicine you feel very unwell but you feel better if you start taking the medicine again

The label will state:

Front of pack

• Can cause addiction

• Use for 3 days only

Back of pack

• Solpadeine Plus Soluble Tablets are for the short term treatment of acute moderate pain when other painkillers have not worked. Wait at least four hours after taking any other painkiller before you take this medicine. For: migraine, headache, dental pain, period pain, backache, rheumatic pain, strains & sprains and sciatica.

• If you need to take this medicine continuously for more than 3 days you should see your doctor or pharmacist

• This medicine contains codeine which can cause addiction if you take continuously for more than 3 days. If you take this medicine for headaches for more than 3 days it can make them worse

4.5 Interaction with other medicinal products and other forms of interaction

Paracetamol

The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by colestyramine. 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.

Codeine

Codeine may antagonize the effects of metoclopramide and domperidone on gastrointestinal motility.

Codeine potentiates the central depressive effects of central nervous system depressants including alcohol, anaesthetics, hypnotics, sedatives, tricyclic antidepressants and phenothiazines.

MAOIs taken with pethidine have been associated with severe CNS excitation or depression (including hypertension or hypotension). Although this has not been documented with codeine, it is possible that a similar interaction may occur and therefore the use of codeine should be avoided while the patient is taking MAOIs and for 2 weeks after MAOI discontinuation.

Opiate analgesics may interact with monoamine oxidase inhibitors (MAOI) and result in serotonin syndrome.

4.6 Fertility, pregnancy and lactation

Pregnancy

Use during pregnancy should be avoided, unless advised by a physician. This includes maternal use d uring labour b ecause of the potential for respir atory depression in the neonate.

The saf ety of p aracetamol-caffeine-codeine du ring p regnancy h as not been established relative to the possible adverse effects of foetal development and should be avoided during pre gnancy due to the possible increased ris k of lower birth wei ght an d spontaneous abortion associated with c affeine consumption.

Lactation

Codeine 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 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.

Although si gnificant c affeine tox icity has not been obs erved in br eastfed infants, caffeine may have a stimulating effect on the infant.

Due to the c affeine content of this product it should not be used if you are pregnant or breastfeeding.

4.7. Effects on Ability to Drive and Use Machines

Patients sh ould be advis ed not to drive or operat e machinery i f affect ed by diz ziness or sedation.

This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When taking this medicine, patients should be told:

• The medicine is likely to affect your ability to drive

• Do not drive until you know how the medicine affects you

• It is an offence to drive while under the influence of this medicine

• However, you would not be committing an offence (called ‘statutory defence’) if:

o The medicine has been taken to treat a medical or dental problem and

o You have taken it according to the information provided with the medicine and

o It was not affecting your ability to drive safely

4.8 Undesirable effects

Adverse events from historical clinical trial data are both infrequent and from small patient exposure. Accordingly, events reported from extensive post-marketing experience at therapeutic/labelled dose and considered attributable are tabulated below by system.

The frequency of these adverse events is not known (cannot be estimated from available data).

Paracetamol

Body System	Undesirable effect
Blood and lymphatic system	Thrombocytopenia
disorders	Agranulocytosis
Immune system disorders	Anaphylaxis Cutaneous hypersensitivity reactions including skin rashes, angiodema and Stevens Johnson syndrome/toxic epidermal necrolysis
Respiratory, thoracic and mediastinal disorders	Bronchospasm*
Hepatobiliary disorders	Hepatic dysfunction

* There have been cases of bronchospasm with paracetamol, but these are more likely in asthmatics sensitive to aspirin or other NSAIDs.

Caffeine

Body System

Undesirable effect

Central nervous system

Nervousness

Dizziness

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 caffeine-related adverse effects such as insomnia, restlessness, anxiety, irritability, headaches, gastrointestinal disturbances and palpitations.

Codeine

Adverse reactions identified during post-marketing use are listed below by MedDRA system organ class. The frequency of these reactions is not known.

Body System	Undesirable effect
Psychiatric disorders	Drug dependency can occur after prolonged use of codeine at higher doses


Gastrointestinal disorder	Constipation, nausea, vomiting, dyspepsia, dry mouth, acute pancreatitis in patients with a history of cholecystectomy
Nervous system disorder	Dizziness, worsening of headache with prolonged use, drowsiness.
Renal and urinary disorders	Difficulty with micturition
Skin and subcutaneous tissue disorder	Pruritus, sweating

4.9 Overdose

Overuse of this product, defined as consumption of quantites 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.

Codeine

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

Symptoms

An overdose of codeine is characterised, in the first phase, by nausea and vomiting. An acute depression of the respiratory centre can cause cyanosis, slower breathing, drowsiness, ataxia and, more rarely, pulmonary oedema. Respiratory pauses, miosis, convulsion, collapse and urine retention. Signs of histamine release have been observed as well.

Management

This should include 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.

Paracetamol

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

Risk Factors:

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

Regularly consumes ethanol in excess of recommended amounts.

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

Symptoms

Symptoms of paracetamol 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, 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). Treatment with N-acetylcysteine may be used up to 24 hours after ingestion of paracetamol, however, the maximum protective effect is obtained up to 8 hours post-ingestion. 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. Management of patients who present with serious hepatic dysfunction beyond 24h from ingestion should be discussed with the NPIS or a liver unit.

Caffeine

Symptoms and signs

Overdose of caffeine may result in epigastric pain, vomiting, diuresis, tachycardia or cardiac arrhythmia, CNS stimulation (insomnia, restlessness, excitement, agitation, jitteriness, tremors and convulsions).

It must be noted that for clinically significant symptoms of caffeine overdose to occur with this product, the amount ingested would be associated with serious paracetamol-related liver toxicity.

Management

Patients should receive general supportive care (e.g. hydration and maintenance of vital signs). The administration of activated charcoal may be beneficial when performed within one hour of the overdose, but can be considered for up to four hours after the overdose. The CNS effects of overdose may be treated with intravenous sedatives.

Summary

Treatment of overdose with Solpadeine Plus Soluble Tablets requires assessment of plasma paracetamol levels for antidote treatment, with signs and symptoms of codeine and caffeine toxicity being managed symptomatically.

Sodium bicarbonate

High doses of sodium bicarbonate would be expected to induce gastrointestinal symptoms including belching and nausea. In addition, high doses of sodium bicarbonate may cause hypernatraemia, electrolytes should be monitored and patients managed accordingly.

5 PHARMACOLOGI CAL PROPERTIES

5.1 P harmacodynamic properties

Paracetamol is a well established analgesic. Caffeine has a stimulating effect on the central nervous system and possesses a weak diuretic action.

Codeine is a centrally acting weak analgesic. Codeine exerts its effect through p 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.

5.2 P harmacokinetic properties

Paracetamol i s rapi dly and al most com pletely absorbed f rom t he gastrointestinal tract.

Concentration of the drug in plasma reaches a peak in 30 - 60 minutes an d the plasma half-life is 1 - 4 hours. P aracetamol is relatively uniformly distributed throughout most body fluids and exhibits variable protein binding. Excretion is almost exclusively renal, in the form of conjugated metabolites.

Codeine phosphate is well absorbed after administration and distributes widely throughout the bod y. 86 % of an o ral dose is ex creted in the urin e within 24 hours, 40 - 70% of this being free or conjugated codeine, 5 - 15% free or conjugated morphine, 10 - 20 % f ree or conj ugated nor codeine, and t race amounts may be free or conjugated normorphine.

Caffeine is rapidly b ut irreg ularly absorbed a fter o ral a dministration, absorption is pH -relat ed. After an oral dos e of 100mg , peak plasma concentrations of 1.5 - 2 pg/ml are attained within 1-2 hours. Plasma half-life = 4 - 10 hours. Caffeine rapidl y distributes throughout the body water, and is approximately 15% bound to plasma prot eins. In 48 hours, 45 % of a do se is excreted in the urine as 1-methylxanthine and 1-methyluric acid.

5.3 Preclinical safety data

There a re no pre cl inical dat a of rel evance to t he prescri ber whi ch are additional to that already included in other sections of the SPC

6 PHARMACEUTI CAL PARTICULARS

6.1 List of excipients

Sodium bicarbonate, sorbitol powder, sacch arin sodium, sodium la uryl sulphate, citric acid, so dium carbonate, pol yvinylpyrrolidone, silicon e fluid 200/350, purified water.

6.2 Incom patibilities

None stated.

6.3 Shelf life

48 months.

6.4 Special precautions for storage

Do not store above 30⁰C

6.5 Nature and contents of container

PPFP or surl yn laminate strips furt her p acked into cardboa rd ca rtons containing 4, 8, 12, 16, 24 or 32 tablets.

6.6 Special precautions for disposal

Not applicable.

7 MARKETING AUTHORISATION HOLDER

Omega Pharma Ltd.

1^st Floor

32 Vauxhall Bridge Road LONDON, SW1V 2SA United Kingdom

8 MARKETI NG AUTHORISATION NUMBER(S)

PL 02855/0080

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

05/03/2009

10. DATE OF REVISION OF THE TEXT

17/04/2015