ZIPAMOL PLUS 8 MG / 500 MG EFFERVESCENT TABLETS, CO-CODAMOL 8 MG / 500 MG EFFERVESCENT TABLETS - summary of medicine characteristics

Zipamol PLUS 8 mg/500 mg effervescent tablets

Co-codamol 8 mg/500 mg effervescent tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 8 mg/500 mg effervescent tablet contains 500 mg paracetamol and 8 mg codeine phosphate hemihydrate.

Excipient(s) with known effect

Each tablet contains 100 mg of sorbitol (E420).

Each tablet contains 418.59 mg sodium (equivalent to 18.20 mmol).

For the full list of excipients, see section 6.1.

Effervescent tablets

White to off-white, round, flat, bevelled edge tablets, plain on both sides. The diameter of tablet is approximately 25.4 mm.

4.1 Therapeutic indications

For the short-term treatment of acute moderate pain which is not relieved by paracetamol, ibuprofen or aspirin alone such as headaches, migraine, neuralgia, toothache, dysmenorrhoea and rheumatic pain.

Codeine is indicated in patients older than 12 years of age for the treatment of acute moderate pain which is not considered to be relieved by other analgesics such as paracetamol or ibuprofen alone.

4.2 Posology and method of administration

Posology

Do not take continuously for more than 3 days without consulting your doctor.

Two tablets, to be dissolved in a glass of water, every 4 hours when necessary up to a

maximum of 8 tablets in 24 hours.

Children aged 16 to 18 years:

One to two tablets every 6 hours when necessary up to a maximum of four doses in 24 hours.

Children aged 12 to 15 years:

One tablet every 6 hours when necessary to a maximum of four doses in 24 hours.

Paediatric population:

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 section 4.3 and 4.4).

Method of administration

For oral administration.

4.3 Contraindications

Hypersensitivity to paracetamol, codeine phosphate 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

Drug dependence, tolerance and potential for abuse

For all patients, prolonged use of this product may lead to drug dependence (addiction), even at therapeutic doses. The risks are increased in individuals with current or past history of substance misuse disorder (including alcohol misuse) or mental health disorder (e.g., major depression).

Additional support and monitoring may be necessary when prescribing for patients at risk of opioid misuse.

A comprehensive patient history should be taken to document concomitant medications, including over-the-counter medicines and medicines obtained online, and past and present medical and psychiatric conditions.

Patients may find that treatment is less effective with chronic use and express a need to increase the dose to obtain the same level of pain control as initially experienced. Patients may also supplement their treatment with additional pain relievers. These could be signs that the patient is developing tolerance. The risks of developing tolerance should be explained to the patient.

Overuse or misuse may result in overdose and/or death. It is important that patients only use medicines that are prescribed for them at the dose they have been prescribed and do not give this medicine to anyone else.

Patients should be closely monitored for signs of misuse, abuse, or addiction.

The clinical need for analgesic treatment should be reviewed regularly.

Drug withdrawal syndrome

Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with codeine.

Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. Tapering from a high dose may take weeks to months.

The opioid drug withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other

symptoms may also develop including irritability, agitation, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhoea, increased blood pressure, increased respiratory rate or heart rate.

If women take this drug during pregnancy, there is a risk that their newborn infants will experience neonatal withdrawal syndrome.

Hyperalgesia

Hyperalgesia may be diagnosed if the patient on long-term opioid therapy presents with increased pain. This might be qualitatively and anatomically distinct from pain related to disease progression or to breakthrough pain resulting from development of opioid tolerance. Pain associated with hyperalgesia tends to be more diffuse than the pre-existing pain and less defined in quality. Symptoms of hyperalgesia may resolve with a reduction of opioid dose.

Care is advised in the administration of paracetamol to patients with severe renal or severe hepatic impairment. The hazard of overdose is greater in those with non-cirrhotic alcoholic liver disease. Do not exceed the recommended dose.

The recommended dose should not be exceeded. This medicine should not be taken with any other paracetamol-containing products. If symptoms persist, the patient should be advised to consult their doctor. The patient should be advised to see immediate medical advice in the event of an overdose, even if they feel well, because of the risk of delayed, serious liver damage.

Use with caution in patients with convulsive disorders.

The label will state:

Front of pack

Can cause addiction

Contains opioid

For three days use only.

Back of pack

This medicine is used for the short term treatment of acute moderate pain which is not relieved by paracetamol, ibuprofen or aspirin alone such as headache, migraine, neuralgia, toothache, painful menstrual periods and rheumatic pains

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

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

The leaflet will state:

This medicine contains codeine, which is an opioid, which can cause addiction. You can get withdrawal symptoms if you stop taking it suddenly.

Important things you should know about co-codamol

This medicine can only be used for the short term treatment of acute, moderate pain such as headaches, migraine, neuralgia, toothache, painful menstrual periods and rheumatic pain which is not relieved by paracetamol, ibuprofen or aspirin alone.

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

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

Section 1: What co-codamol is and what it is used for

Zipamol PLUS is used in adults and children over 12 years of age for the short term treatment of acute moderate pain caused by headaches, migraine, toothache, neuralgia, period pain and rheumatic pains when other painkillers such as paracetamol, ibuprofen or aspirin alone have not worked. Wait at least 4 hours after you last took other painkillers before taking this medicine.

Section 2: Before you take co-codamol

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

This medicine contains paracetamol. Do not take anything else containing paracetamol while taking this medicine

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

Section 3: How to take co-codamol

Do not take for more than 3 days. If you need to use this medicine for more than 3 days you must speak to your doctor or pharmacist

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: Possible side effects

This will appear at the end of section 4 How do I know if I am addicted?

If you notice any of the following signs whilst taking Zipamol PLUS, it could be a sign that you have become addicted.

You need to take the medicine for longer than advised by your prescriber

You feel you need to use more than the recommended dose

You are using the medicine for reasons other than prescribed

When you stop taking the medicine you feel unwell, and you feel better once taking the medicine again

If you notice any of these signs, it is important you talk to your prescriber

CY2D6 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 summarised below:

Not recommended for children under 12 years of age.

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.

Co-codamol 8/500 effervescent tablets should be used upon medical advice in patients with:

Mild-to-moderate hepatocellular insufficiency

Severe renal insufficiency

Monitoring after prolonged use should include blood count, liver function and renal function.

Sodium

This medicinal product contains 418.59mg sodium (main component of cooking/table salt) per tablet, equivalent to 20.93% of the WHO recommended maximum daily intake of sodium for an adult.

The maximum daily dose of this product is equivalent to 167.44% of the WHO recommended maximum daily intake for sodium.

Co-codamol is considered high in sodium. This should be particularly taken into account for those on a low sodium diet.

Sorbitol

This medicine contains 100mg sorbitol in each tablet. Sorbitol is a source of fructose. If your doctor has told you that you (or your child) have an intolerance to some sugars or if you have been diagnosed with hereditary fructose intolerance (HFI), a rare genetic disorder in which a person cannot break down fructose, talk to your doctor before you (or your child) take or receive this medicine.

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

Patients receiving other narcotic analgesics, antitussive, antihypertensives, antihistamines, antipsychotics, antianxiety agents or other CNS depressants (including alcohol) concomitantly with this codeine containing drug may exhibit additive CNS depression.

4.6 Fertility, pregnancy and lactationPregnancy

Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in the recommended dose. A large amount of data on pregnant women indicate neither malformative, nor feto/neonatal toxicity. Paracetamol can be used during pregnancy if clinically needed however it should be used at the lowest effective dose for the shortest possible time and at the lowest possible frequency.

Codeine can cause respiratory depression and withdrawal syndrome in newborns.

Results of one case control study suggest that there might be an increased risk of malformations of the respiratory tract in the offspring of women who consumed codeine during the first four months of pregnancy. This increase was statistically not significant. Evidence of other malformations is also reported in epidemiological studies on narcotic analgesics, including codeine.

Codeine has been used for many years without apparent ill consequence and animal studies have not shown any hazard.

Patients should follow the advice of their doctor regarding the use of this product.

Regular use during pregnancy may cause drug dependence in the foetus, leading to withdrawal symptoms in the neonate.

If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Administration during labour may depress respiration in the neonate and an antidote for the child should be readily available.

Administration to nursing women is not recommended as codeine may be secreted in breast milk and may cause respiratory depression in the infant.

Paracetamol is excreted in breast milk but not in a clinically significant amount. Available published data do not contraindicate breast feeding.

Codeine should not be used during breastfeeding (see section 4.3). Co-codamol 8/500 Effervescent Tablets are contraindicated during breast-feeding.

At normal therapeutic doses codeine and its active metabolites 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.

4.7 Effects on ability to drive and use machines

Patients should be advised not to drive or operate machinery if affected by dizziness 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 prescribing 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 prescribed to treat a medical or dental problem and

o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

o It was not affecting your ability to drive safely

4.8 Undesirable effects

Regular prolonged use of codeine is known to lead to addiction and tolerance. Symptoms of restlessness and irritability may result when treatment is then stopped.

Prolonged use of a painkiller for headaches can make them worse.

The information below lists reported adverse reactions, ranked using the following frequency classification:

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).

Codeine can produce typical opioid effects including constipation, nausea, vomiting, dizziness, light-headedness, drowsiness, confusion and urinary retention. The frequency and severity are determined

by dosage, duration of treatment and individual sensitivity. Tolerance and dependence can occur, especially with prolonged high dosage of codeine.

There have been very rare occurrences of pancreatitis.

Immune system disorders

Hypersensitivity including skin rash may occur.

Not known: Anaphylactic shock, angioedema

Blood and lymphatic system disorders

Not known: agranulocytosis, thrombocytopenia

Respiratory, thoracic and mediastinal disorders

Not Known: Respiratory depression

Skin and subcutaneous disorders

Very rare cases of serious skin reactions have been reported.

Psychiatric disorders

Not Known: Confusional state, dysphoria, euphoria

Frequency unknown: Drug dependence (see section 4.4)

Nervous system disorders

Not Known: Seizure, headache, somnolence, dizziness

Eye disorders

Not Known: Miosis

Gastrointestinal disorders

Not Known: Constipation, vomiting, nausea, dry mouth

General disorders and administration site conditions

Uncommon: drug withdrawal syndrome

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 via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Patients should be informed of the signs and symptoms of overdose and to ensure that family and friends are also aware of these signs and to seek immediate medical help if they occur.

Symptoms

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:

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

b. regularly consumes ethanol in excess of recommended amounts or

c. is likely to be glutathione deplete e.g. eating disorders, cystic fibrosis,

HIV infection, starvation, cachexia.

Symptoms of paracetamol over-dosage 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, gastrointestinal bleeding 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 serious hepatic dysfunction beyond 24h from ingestion should be discussed with the NPIS or a liver unit.

Further measures will depend on the severity, nature and course of clinical symptoms of paracetamol intoxication and should follow standard intensive care protocols.

The effects of Codeine over-dosage will be potentiated by simultaneous ingestion of alcohol and psychotropic drugs.

Symptoms

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

Management 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 4 hours after ingestion, or 8 hours if a sustained release preparation has been taken.

The opioid antagonist naloxone hydrochloride is an antidote to respiratory depression and must be administered intravenously.

Patients should be advised to first consult their healthcare professional before taking codeine if they are taking a benzodiazepine.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anilides, Paracetamol combinations

ATC Code: N02B E51

Paracetamol is a well-established analgesic and antipyretic.

Codeine is a centrally weak acting analgesic. Codeine exerts its effect through li 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 Pharmacokinetic properties

Paracetamol is rapidly and almost completely absorbed from the gastrointesti­nal tract.

Concentration in plasma reaches a peak in 30–60 minutes. Plasma half-life is 1–4 hours.

Paracetamol is relatively uniformly distributed throughout most body fluids, plasma protein binding is variable.

Codeine phosphate is well absorbed after oral administration and is widely distributed.

About 86% is excreted in the urine in 24 hours, 40–70% is free or conjugated morphine and 10–20% is free or conjugated Norcodeine.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Citric acid, anhydrous

Sorbitol (E420)

Sodium hydrogen carbonate

Povidone

Simeticone

Sodium carbonate, anhydrous

Saccharin sodium

Macrogol 6000

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

Do not store above 25°C.

Store in the original package in order to protect from moisture.

6.5 Nature and contents of container

Surlyn strip packs: containing : 32 tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

7 MARKETING AUTHORISATION HOLDER

Lambda Therapeutic Limited

Sage House, 319 Pinner Road,

North Harrow, Middlesex,

HA1 4HF, United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 29959/0010

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

09/07/2021