Consumer medicine information

Mevadol Forte

Paracetamol; Codeine phosphate hemihydrate; Doxylamine succinate

BRAND INFORMATION

Brand name

Mevadol Forte

Active ingredient

Paracetamol; Codeine phosphate hemihydrate; Doxylamine succinate

Schedule

What is in this leaflet

This leaflet answers some common questions about Mevadol Forte. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Mevadol Forte against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Mevadol Forte is used for

Mevadol Forte contains three active ingredients,

Paracetamol,
Codeine phosphate hemihydrate, and
Doxylamine succinate.

Paracetamol is an analgesic (pain-relieving medicine) and antipyretic (lowers body temperature). Codeine phosphate hemihydrate is a potent analgesic that helps to relieve pain. The body must convert codeine into morphine before it can provide pain relief. Doxylamine succinate is an antihistamine which can help to relieve tension and nausea associated with pain. This may be especially useful in the treatment of tension headache, migraine and period pain.

Mevadol Forte is used for the short-term management of severe pain for which other treatment options have failed, are not recommended, not tolerated or are otherwise inappropriate to provide sufficient management of pain. This may include toothache or dental pain, pain from injury or surgery and headache pain.

It is suitable for people who cannot take aspirin for pain relief.

Mevadol Forte is available only with a doctor’s prescription.

It belongs to a group of medicines called analgesics containing opioids.

This medicine works by Paracetamol and codeine acting together to stop the pain messages from getting through to the brain.

Ask your doctor or pharmacist if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is available only with a doctor's prescription.

Before you take Mevadol Forte

When you must not take it

Do not take this medicine if you have an allergy to paracetamol, codeine phosphate hemihydrate, doxylamine succinate or any of the ingredients listed at the end of this leaflet.

Always check the ingredients to make sure you can use this medicine.

Do not take this medicine if you have or have had any of the following conditions:

Severe and/or acute respiratory diseases,
such as bronchitis, acute asthma, emphysema, acute chronic obstructive pulmonary disease (COPD).
Other problems with breathing such as, shallow breathing, difficulty breathing, or slow breathing.
Glucose-6-phosphate-dehydrogenase deficiency (an enzyme deficiency that may lead to anaemia)
you very rapidly metabolise codeine into morphine.
Known intolerance to paracetamol.
Severe liver disease or liver failure

Do not take this medicine if you have diarrhoea caused by antibiotics or poisoning.

Do not take this medicine if you are in the third trimester of pregnancy or in labour, especially if the baby is premature.

Do not take this medicine if you are breastfeeding or planning to breastfeed.

Do not take Mevadol Forte if you have a history of drug dependence, including alcohol dependence.

Do not take Mevadol Forte if you are already taking Monoamine Oxidase Inhibitors (MAOIs) such as selegiline or moclobemide, or within 14 days of stopping MAOIs.

Do not take Mevadol Forte if you have experienced allergy (generalised rash or shortness of breath) to morphine or oxycodone.

Do not take Mevadol Forte if the person going to take the tablets is under 12 years.

Do not take Mevadol Forte if you are aged between 12 and 18 years of age and have had your tonsils or adenoids removed to treat sleep apnoea.

Some of the symptoms of an allergic reaction may include:

wheezing, difficulty breathing, or shallow breathing
swelling of the face, lips, tongue or other parts of the body
rash, itching or hives on the skin

Do not take Mevadol Forte if you are aged below 18 years of age and have had your tonsils or adenoids removed to treat sleep apnoea.

Mevadol Forte is not recommended for children under 12 years. Safety and effectiveness in children younger than 12 years have not been established.

Check with your doctor if you are pregnant or intend to become pregnant

Do not take Mevadol Forte during the third trimester of pregnancy. It may affect your developing baby if you take it during pregnancy.

Do not take Mevadol Forte during labour, especially if the baby is premature. This medicine contains codeine, which may produce withdrawal effects in the newborn baby.

Do not take Mevadol Forte if you are breastfeeding or planning to breastfeed. Mevadol Forte passes into breast milk and there is a possibility your baby may be affected.

Do not take Mevadol Forte after the expiry date (EXP) printed on the pack. If you take this medicine after the expiry date has passed, it may not work as well.

Do not take Mevadol Forte if the packaging is torn, shows signs of tampering, or if it doesn’t look quite right. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking Mevadol Forte, contact your doctor or pharmacist.

Before you start to take it

Tell your doctor or pharmacist if you have allergies to:

any other medicines
aspirin or any other non-steroidal anti-inflammatory drugs NSAID
any other substances, such as foods, preservatives or dyes

Tell your doctor or pharmacist if you have or have had any of the following medical conditions:

Liver problems
Gilbert’s syndrome
Kidney problems
Heart problems
Low blood pressure
Lung problems, difficulty breathing, wheezing, chronic cough, asthma, or other chronic breathing conditions
Intolerance to pain relieving medicine
Chronic constipation
Chronic alcohol use including recent cessation of alcohol intake
Opioid dependence
A history of drug and/or alcohol abuse. Caution is particularly recommended for use in adolescents and young adults with a history of drug and/or alcohol abuse.
Low level of glutathione
Recent stomach, intestine or urinary tract surgery
Gall bladder problems or your gall bladder has been removed
Multiple sclerosis
Obstructive and inflammatory bowel disease or other bowel problems
Prostate problems
Retaining urine
Problems passing urine
Underactive thyroid
Adrenal gland problems such as Addison’s disease
Head injury
Fits or seizures
Brain tumour, stroke or other problems with the brain

Tell your doctor or pharmacist if you take any medicines for any other condition.

Tell your pharmacist or doctor if you are pregnant or plan to become pregnant or are breastfeeding. Your pharmacist or doctor will discuss the benefits and possible risks of taking the medicine during pregnancy or during breastfeeding.

If you have not told your doctor or pharmacist about any of the above, tell them before you start taking Mevadol Forte.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Tell your doctor or pharmacist if you are taking any other medicines, which contain paracetamol, codeine or doxylamine.

Do not take Mevadol Forte with Monoamine Oxidase inhibitors (MAOIs), such as selegiline or moclobemide, or within 14 days of stopping MAOIs.

Some medicines can interfere with Mevadol Forte including:

medicine causing sleepiness or drowsiness, such as sedatives or tranquilisers
Benzodiazepines (medicines used as sedatives or to treat anxiety). The use of opioids and benzodiazepines together may increase the risk of drowsiness, difficulties in breathing, coma and may be life-threatening.
Medicines containing alcohol (ethanol), e.g. some cough syrups
Cough suppressants or antitussives
Medicines used to treat alcohol and/or opioid dependence (e.g. naltrexone or buprenorphine)
Medicines used to treat depression
Phenothiazines and antipsychotic agents (medicines used to treat mental disorders)
Some types of antihistamines
Aspirin or any other non-steriodal anti-inflammatory drugs (NSAID)
Gabapentinoids (medicines used for epilepsy or neuropathic pain)
Cannabis
Medicines used to stop or prevent vomiting (antiemetics), such as metoclopramide or domperidone
Medicines used to thin the blood, such as warfarin
Medicines used to treat diarrhoea, such as Kaolin or loperamide
Propantheline (medicine used to treat stomach ulcers)
Medicine used to treat epilepsy or fits, such as phenytoin
Other pain relief medication
Medicines used to treat high blood pressure
Colestyramine (medicine used to treat bile problems and/or high cholesterol)
Chelating resin
Chloramphenicol, an antibiotic used to treat ear and eye infections
Neuromuscular blocking agents such as cisatracurium (medicines used during surgical procedures)
Flucloxacillin, zidovudine or rifampicin, drugs used to treat infections.

These medicines may be affected by Mevadol Forte or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist may have more information on medicines to be careful with or avoid while taking Mevadol Forte.

Medicines that may decrease the effect of Mevadol Forte include:

Medicines that inhibit the liver enzyme, CYP 2D6 inhibitors such as fluoxetine, paroxetine, buproprion, cinacalcet, and methadone.
Medicines that increase the activity of the liver enzyme, CYP 3A4 inducers such as rifampicin

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Mevadol Forte.

How to take Mevadol Forte

How much to take

The usual adult dose is one or two tablets every 4 to 6 hours as needed for relief. Do not exceed 8 tablets in a 24 hour period.

Mevadol Forte is not recommended for children under 12 years of age.

Follow all directions given to you by your doctor or pharmacist carefully. Their directions may differ from the information contained in this leaflet.

How to take it

Swallow the prescribed dose of Mevadol Forte whole with a glass of water. It can be taken with or without food.

If you do not understand the instructions on the box/bottle, ask your doctor or pharmacist for help.

When to take it

Take your medicine at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

It does not matter if you take this medicine before or after food.

How long to take it

Continue taking your medicine for as long as your doctor tells you.

If you forget to take it

If it is almost time to take your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

Remember to wait 4 to 6 hours between doses.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much of Mevadol Forte. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Symptoms of an overdose may include at early stage of. nausea, vomiting, anorexia, pallor, abdominal pain and sweating and general malaise. Three to five days later symptoms seen may be jaundice, fever and abnormal bleeding.

While you are using Mevadol Forte

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking this medicine.

Tell any other doctors, dentists, and pharmacists who are treating you that you are taking Mevadol Forte.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

If you become pregnant while taking this medicine, tell your doctor immediately.

If you are about to have any blood tests, tell your doctor that you are taking this medicine. It may interfere with the results of some tests.

Keep all of your doctor's appointments so that your progress can be checked.

Your doctor may do some liver tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

Call your doctor straight away if you:

Feel you need to take the medicine for longer periods of time.
Feel you need to take more than the prescribed dose
Feel very unwell when you stop taking the medicine but feel better when you start taking the medicine again.

Things you must not do

Do not give Mevadol Forte to anyone else, even if they have the same condition as you.

Do not take Mevadol Forte to treat any other complaints unless your doctor or pharmacist tells you to.

Do not stop taking your medicine or lower the dosage without checking with your doctor. If you stop taking it suddenly, your condition may worsen or you may have unwanted withdrawal side effects. If possible, your doctor will gradually reduce the amount you take each day before stopping the medicine completely.

Things to be careful of

Be careful driving or operating machinery until you know how Mevadol Forte affects you. Mevadol Forte may cause drowsiness, dizziness, affect eyesight or hand-eye coordination in some people. Make sure you know how you react to Mevadol Forte before you drive a car, operate machinery, or do anything else that could be dangerous if you are drowsy. If drowsiness occurs do not drive or operate machinery.

Drinking alcohol

Tell your doctor if you drink alcohol Alcohol and codeine taken together may increase the risk of sedation, respiratory problems, coma or may be life-threatening.

Do not drink alcohol while you are taking Mevadol Forte.

Mevadol Forte may be dangerous if you take large amounts over a long period of time.

Do not take high doses of the medicine for long periods of time unless your doctor tells you to. This medicine contains codeine, which may be habit forming.

If you feel light-headed, dizzy or faint when getting out of bed or standing up, get up slowly. Standing up slowly, especially when you get up from bed or chairs, will help your body get used to the change in position and blood pressure. If this problem continues or gets worse, talk to your doctor.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Mevadol Forte.

This medicine helps most people with relief of severe pain, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are minor and temporary. You may need medical attention if you get some of the side effects.

If you are over 65 years of age you may have an increased chance of getting side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

Less serious side effects

Skin rash
Constipation
Nausea
Vomiting
Drowsiness
Blurred vision
Sweating
Increased sensitivity to pain or increased levels of pain.

These are the more common side effects of Mevadol Forte. They are usually mild

Tell your doctor as soon as possible if you notice any of the following:

Serious side effects

Shortness of breath
Irregular heartbeat
Mouth ulcers, fever and sore throat
Bleeding, bruising more easily
Unusual or extreme mood swings
Headache
Dizziness, light-headedness
Flushing of the face
Painful red areas with blisters and peeling layers of skin which may be accompanied by fever and/or chills
Severe blisters and bleeding in the lips, eyes, mouth, nose and genitals
Stomach pain
Slow and shallow breathing
Hepatitis (symptoms include loss of appetite, itching, yellowing of the skin and eye, light coloured bowel motions, dark coloured urine)

The above list includes serious side effects that may require medical attention. These side effects are rare.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

Wheezing, difficulty breathing, or shallow breathing
Swelling of the face, lips, tongue and other parts of the body
Rash, itching or hives on the skin

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are very rare.

Other side effects not listed above may occur in some patients. Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems.

By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

Storage of Mevadol Forte

Storage

Keep your tablets in the pack until it is time to take them. If you take the tablets out of the pack they will not keep well.

Keep your tablets in a cool dry place where the temperature stays below 25°C.

Do not store Mevadol Forte or any other medicine in the bathroom or near a sink.

Do not leave it in the car on hot days or on window sills. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor or pharmacist tells you to stop taking Mevadol Forte or the tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Do not use this medicine after the expiry date.

Product description

What it looks like

Mevadol Forte is a round, white to off-white uncoated tablet with ‘PCD’ on either side of the break-line on one side and plain on the other side.

Mevadol Forte is available in a carton containing 2 blister packs of 10 tablets each.

Ingredients

Paracetamol 450mg
Codeine phosphate hemihydrate 30mg
Doxylamine succinate 5 mg
Microcrystalline cellulose
Sodium starch glycollate
Hypromellose
Purified Talc
Magnesium stearate

Mevadol Forte does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Supplier

This medicine is supplied in Australia by:

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113

Australian Registration Number
AUST R 310164

This leaflet was prepared in
September 2020

Published by MIMS September 2021

BRAND INFORMATION

Brand name

Mevadol Forte

Active ingredient

Paracetamol; Codeine phosphate hemihydrate; Doxylamine succinate

Schedule

1 Name of Medicine

Paracetamol, codeine phosphate hemihydrate and doxylamine succinate.

2 Qualitative and Quantitative Composition

Each tablet contains paracetamol 450 mg, codeine phosphate hemihydrate 30 mg, doxylamine succinate 5 mg.
For the full list of excipients, also see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Mevadol Forte is a combination oral tablet that contains paracetamol 450 mg, codeine phosphate hemihydrate 30 mg, doxylamine succinate 5 mg.
It is a round, white to off-white uncoated tablet with 'PCD' debossed on either side of a break-line on one side and plain on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Mevadol Forte is indicated for the short-term management of severe pain for which other treatment options have failed, are contraindicated, not tolerated or are otherwise inappropriate to provide sufficient management of pain.

4.2 Dose and Method of Administration

Adults and children 12 years of age and older.

One or two tablets every 4 to 6 hours as needed for relief. Do not exceed 8 tablets in a 24-hour period.
Mevadol Forte is contraindicated for use in patients who are:
younger than 12 years;
aged between 12-18 years in whom respiratory function might be compromised, including post tonsillectomy and/or adenoidectomy for obstructive sleep apnoea. (See Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Paediatric use.)

4.3 Contraindications

Mevadol Forte should not be given to patients with a known hypersensitivity to paracetamol, codeine, doxylamine succinate or any of the excipients listed (see Section 6.1 List of Excipients).
Mevadol Forte must not be used in patients with known glucose-6-phosphate-dehydrogenase deficiency, severe respiratory disease, acute respiratory disease and respiratory depression/insufficiency for example acute asthma and acute exacerbations of chronic obstructive pulmonary disease, since codeine may exacerbate the condition.
Concomitant treatment with monoamine inhibitors (MAOIs) or treatment within 14 days of stopping MAOIs is contraindicated.
Paracetamol should not be used in patients with a history of intolerance to the drug.
Paracetamol should not be used in patients with severe hepatocellular insufficiency.
Due to codeine's structural similarity to morphine and oxycodone, patients experiencing systemic allergy (generalised rash, shortness of breath) to these drugs should not receive codeine.
Codeine is contraindicated in patients with diarrhoea caused by poisoning, until the toxic substance has been eliminated from the gastrointestinal tract, or diarrhoea associated with pseudomembranous colitis caused by antibiotic administration, since codeine may slow the elimination of the toxic material or antibiotic.
Codeine is contraindicated in the event of impending childbirth or in case of risk of premature birth (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).
Mevadol Forte is contraindicated during breast-feeding (see Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation).
Mevadol Forte is contraindicated for use in patients who are:
younger than 12 years (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use);
aged between 12-18 years in whom respiratory function might be compromised, including post tonsillectomy and/or adenoidectomy for obstructive sleep apnoea, due to an increased risk of developing serious life-threatening adverse reactions (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use).
Mevadol Forte is contraindicated for use in patients who are CYP2D6 ultra-rapid metabolisers (see Section 4.4 Special Warnings and Precautions for Use, CYP2D6 metabolism).

4.4 Special Warnings and Precautions for Use

Hepatotoxicity may occur with paracetamol even at therapeutic doses, after short treatment duration and in patients without pre-existing liver dysfunction. In view of the increased risk of hepatotoxicity, the benefit should be weighed against the risk when administering Mevadol Forte to patients with viral hepatitis or pre-existing hepatic disease. In such patients, hepatic function determinations may be required at periodic intervals during high dose or long-term therapy.
It has been reported that paracetamol may produce symptoms of acute toxicity in adults following the ingestion of more than 15 g.
Hepatotoxicity may develop after the ingestion of a single dose of 10 to 15 g (200 to 250 mg/kg) and a dose of more than 25 g of paracetamol is potentially fatal. Patients may be asymptomatic for several days following ingestion of large doses of paracetamol, and laboratory evidence of hepatotoxicity may be delayed for up to one week. Non-fatal hepatic damage is usually reversible. There have been reports of kidney damage, disturbances in clotting mechanisms, metabolic acidosis, hypoglycaemia, agranulocytosis, thrombocytopenia, methaemoglobinaemia and myocardial necrosis.
To avoid the risk of overdose, check that paracetamol is absent from the composition of other medicinal products taken concomitantly.
Caution is advised in patients with underlying sensitivity to aspirin and/or to non-steroidal anti-inflammatory drugs (NSAIDs).

Severe cutaneous adverse reactions (SCARs).

Life-threatening cutaneous reactions Stevens Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) have been reported with the use of paracetamol. If symptoms or signs of SJS and TEN (e.g. progressive skin rash often with blisters or mucosal lesions) occur, patients should stop paracetamol treatment immediately and seek medical advice.

Paracetamol should be used with caution in patients with.

Mild-to-moderate hepatocellular insufficiency; severe renal insufficiency and sepsis; chronic alcohol use including recent cessation of alcohol intake; malnutrition and other sources of low glutathione reserves; glucose-6-phosphate-dehydrogenase deficiency; Gilbert's syndrome.
Cases of high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis have been reported in patients with severe illness and/or pre-disposing factors (see above) who were treated with paracetamol at therapeutic dose for a prolonged period or combination of paracetamol and flucloxacillin. Symptoms of HAGMA may include serious breathing difficulties with deep rapid breathing, drowsiness, nausea and vomiting. Prompt discontinuation of paracetamol and close monitoring is recommended if symptoms of HAGMA appear. The measurement of urinary 5-oxoproline may be useful to identify pyroglutamic acidosis as underlying cause of HAGMA in patients with multiple risk factors.
Codeine should be used with caution in patients with CNS depression or decreased respiratory reserve, for example in emphysema, kyphoscoliosis, hypoxia, hypercapnia or even severe obesity, cor pulmonale or chronic obstructive pulmonary disease. Codeine should be administered with caution in patients with impaired cardiac, hepatic or renal function, hypotension, benign prostatic hyperplasia, urethral stenosis, chronic colitis ulcerative, gall bladder conditions, multiple sclerosis, hypothyroidism, adrenocortical insufficiency (e.g. Addison's disease), shock, myxedema, acute alcohol intoxication or delirium tremens, since codeine may exacerbate the symptoms or increase the risk of respiratory and/or CNS depression.
Codeine should be administered with great caution in patients with head injury, brain tumour or increased intracranial pressure since codeine may increase the risk of respiratory depression and further elevate intracranial pressure. In addition, codeine can produce side effects such as confusion, miosis, vomiting.
These are important signs in following the clinical course of patients with head injuries.
Extensive use of analgesics to relieve headaches or migraines, especially at high doses, may induce headaches that must not be treated with increased doses of the drug. In such cases the analgesic should not continue to be taken without medical advice.
Monitoring after prolonged use should include blood count, liver function and renal function.
Codeine should only be used with careful risk-benefit assessment and great caution in case of:
opioid dependence;
chronic constipation;
conditions with elevated intracranial pressure and head trauma. Codeine can increase the pressure of cerebrospinal fluid and may increase the respiratory depressant effect. Like other narcotics, it causes adverse reactions that can obscure the clinical course of patients with head injury;
impaired consciousness;
compromised respiratory function (due to emphysema, kyphoscoliosis, severe obesity) and chronic obstructive airway disease.
Paracetamol should not be used in patients with active alcoholism as chronic excessive alcohol ingestion predisposes patients to paracetamol hepatotoxicity.
Codeine should be administered with caution in patients with acute abdominal conditions since codeine may obscure the diagnosis or the course of the disease. Codeine should be administered with caution in patients with severe inflammatory bowel disease (risk of toxic megacolon may be increased, especially with repeated dosing). Mevadol Forte should also be used with caution in patients who have had recent gastrointestinal tract surgery.
Patients who have had a cholecystectomy should be treated with caution. The contraction of the sphincter of Oddi can cause symptoms resembling those of myocardial infarction or intensify the symptoms in patients with pancreatitis.
Codeine should be administered with caution in patients with a history of convulsive disorders (convulsions may be induced or exacerbated by codeine).
Codeine should be administered with caution in patients with prostatic hypertrophy, urethral structure or recent urinary tract surgery since codeine may cause urinary retention.
Codeine should be used with caution in elderly or debilitated patients because of the danger of respiratory or cardiac depression.
Patients with known analgesic intolerance or known bronchial asthma must only use Mevadol Forte after having consulted a physician (hypersensitivity reactions including bronchospasm are possible).

Hazardous and harmful use.

Mevadol Forte contains the opioid codeine and is a potential drug of abuse, misuse and addiction. Addiction can occur in patients appropriately prescribed Mevadol Forte at recommended doses.
The risk of addiction is increased in patients with a personal or family history of substance abuse (including alcohol and prescription and illicit drugs) or mental illness. The risk also increases the longer the drug is used and with higher doses. Patients should be assessed for their risks for opioid abuse or addiction prior to being prescribed Mevadol Forte.
There have been reports of drug abuse with codeine, including cases in children and adolescents. Caution is particularly recommended for use in children, adolescents, young adults and in patients with a history of drug and/or alcohol abuse. See Section 4.4 Special Warnings and Precautions for Use, Paediatric use.
All patients receiving opioids should be routinely monitored for signs of misuse and abuse. Opioids are sought by people with addiction and may be subject to diversion. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the safe storage and proper disposal of any unused drug (see Section 6.4 Special Precautions for Storage; Section 6.6 Special Precautions for Disposal). Caution patients that abuse of oral or transdermal forms of opioids by parenteral administration can result in serious adverse events, which may be fatal.
Patients should be advised not to share Mevadol Forte with anyone else.

Respiratory depression.

Serious, life-threatening or fatal respiratory depression can occur with the use of opioids even when used as recommended. It can occur at any time during the use of Mevadol Forte but the risk is greatest during initiation of therapy or following an increase in dose. Patients should be monitored closely for respiratory depression at these times.
The risk of life-threatening respiratory depression is also higher in elderly, frail, or debilitated patients, in patients with hepatic and renal impairment (see Use in hepatic impairment, Use in renal impairment) and in patients with existing impairment of respiratory function (e.g. chronic obstructive pulmonary disease; asthma). Opioids should be used with caution and with close monitoring in these patients. The use of opioids is contraindicated in patients with severe respiratory disease, acute respiratory disease and respiratory depression (see Section 4.3 Contraindications).
The risk of respiratory depression is greater with the use of high doses of opioids, especially high potency and modified release formulations, and in opioid naïve patients. Initiation of opioid treatment should be at the lower end of the dosage recommendations with careful titration of doses to achieve effective pain relief. Careful calculation of equianalgesic doses is required when changing opioids or switching from immediate release to modified release formulations, together with consideration of pharmacological differences between opioids. Consider starting the new opioid at a reduced dose to account for individual variation in response.

Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol.

Concomitant use of opioids and benzodiazepines or other CNS depressants, including alcohol, may result in sedation, respiratory depression, coma and death. Because of these risks concomitant prescribing of Mevadol Forte with CNS depressant medicines, such as other opioids analgesics, benzodiazepines, gabapentinoids, cannabis, sedatives, hypnotics, tricyclic antidepressants, antipsychotics, antihistamines, centrally-active anti-emetics and other CNS depressants, should be reserved for patients for whom other treatment options are not possible. If a decision is made to prescribe Mevadol Forte concomitantly with any of the medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible. Patients should be followed closely for signs and symptoms of respiratory depression and sedation. Patients and their caregivers should be made aware of these symptoms. Patients and their caregivers should also be informed of the potential harms of consuming alcohol while taking Mevadol Forte.

Risk from concomitant use of opioids and gabapentinoids.

Concomitant use of opioids including codeine, with gabapentinoids (gabapentin and pregabalin) may result in respiratory depression, hypotension, profound sedation, coma or death. Concomitant use with gabapentinoids is not recommended.

Use of opioids in chronic (long-term) non-cancer pain (CNCP).

Opioid analgesics have an established role in the treatment of acute pain, cancer pain and palliative and end-of-life care. Current evidence does not generally support opioid analgesics in improving pain and function for most patients with chronic non-cancer pain. The development of tolerance and physical dependence and risks of adverse effects, including hazardous and harmful use, increase with the length of time a patient takes an opioid. The use of opioids for long-term treatment of CNCP is not recommended.
The use of an opioid to treat CNCP should only be considered after maximised nonpharmacological and non-opioid treatments have been tried and found ineffective, not tolerated or otherwise inadequate to provide sufficient management of pain. Opioids should only be prescribed as a component of comprehensive multidisciplinary and multimodal pain management.
Opioid therapy for CNCP should be initiated as a trial in accordance with clinical guidelines and after a comprehensive biopsychosocial assessment has established a cause for the pain and the appropriateness of opioid therapy for the patient (see Hazardous and harmful use, above). The expected outcome of therapy (pain reduction rather than complete abolition of pain, improved function and quality of life) should be discussed with the patient before commencing opioid treatment, with agreement to discontinue treatment if these objectives are not met.
Owing to the varied response to opioids between individuals, it is recommended that all patients be started at the lowest appropriate dose and titrated to achieve an adequate level of analgesia and functional improvement with minimum adverse reactions. Immediate-release products should not be used to treat chronic pain, but may be used for a short period in opioid-naïve patients to develop a level of tolerance before switching to a modified-release formulation. Careful and regular assessment and monitoring is required to establish the clinical need for ongoing treatment. Discontinue opioid therapy if there is no improvement of pain and/or function during the trial period or if there is any evidence of misuse or abuse. Treatment should only continue if the trial has demonstrated that the pain is opioid responsive and there has been functional improvement. The patient's condition should be reviewed regularly and the dose tapered off slowly if opioid treatment is no longer appropriate (see Ceasing opioids).

Tolerance, dependence and withdrawal.

Neuroadaptation of the opioid receptors to repeated administration of opioids can produce tolerance and physical dependence. Tolerance is the need for increasing doses to maintain analgesia. Tolerance may occur to both the desired and undesired effects of the opioid.
Physical dependence, which can occur after several days to weeks of continued opioid usage, results in withdrawal symptoms if the opioid is ceased abruptly or the dose is significantly reduced. Withdrawal symptoms can also occur following the administration of an opioid antagonist (e.g. naloxone) or partial agonist (e.g. buprenorphine). Withdrawal can result in some or all of the following symptoms: dysphoria, restlessness/agitation, lacrimation, rhinorrhoea, yawning, sweating, chills, myalgia, mydriasis, irritability, anxiety, increasing pain, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhoea, increased blood pressure, increased respiratory rate and increased heart rate.
When discontinuing Mevadol Forte in a person who may be physically-dependent, the drug should not be ceased abruptly but withdrawn by tapering the dose gradually (see Ceasing opioids; see Section 4.2 Dose and Method of Administration).

Accidental ingestion/exposure.

Accidental ingestion or exposure of Mevadol Forte, especially by children, can result in a fatal overdose of codeine. Patients and their caregivers should be given information on safe storage and disposal of unused Mevadol Forte (see Section 6.4 Special Precautions for Storage; Section 6.6 Special Precautions for Disposal).

Hyperalgesia.

Hyperalgesia may occur with the use of opioids, particularly at high doses. Hyperalgesia may manifest as an unexplained increase in pain, increased levels of pain with increasing opioid dosages or diffuse sensitivity not associated with the original pain. Hyperalgesia should not be confused with tolerance (see Tolerance, dependence and withdrawal). If opioid induced hyperalgesia is suspected, the dose should be reduced and tapered off if possible. A change to a different opioid may be required.

Opioid-induced hyperalgesia or allodynia.

Opioid-induced hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain (hyperalgesia), or an increase in sensitivity to pain (allodynia). This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect.
Symptoms of OIH include increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). The pain experienced may be at the same location of the underlying pain or be more generalised or widespread in nature. These symptoms may suggest the occurrence of OIH only if there is no evidence of underlying disease progression, opioid tolerane, opioid withdrawal, or addictive behaviour.
If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation (safely switching the patient to a difference opioid moiety).

Ceasing opioids.

Abrupt discontinuation or rapid decreasing of the dose in a person physically dependent on an opioid may result in serious withdrawal symptoms and uncontrolled pain (see Tolerance, dependence and withdrawal). Such symptoms may lead the patient to seek other sources of licit or illicit opioids. Opioids should not be ceased abruptly in a patient who is physically dependent but withdrawn by tapering the dose slowly. Factors to take into account when deciding how to discontinue or decrease therapy include the dose and duration of the opioid the patient has been taking, the type of pain being treated and the physical and psychological attributes of the patient. A multimodal approach to pain management should be in place before initiating an opioid analgesic taper. During tapering, patients require regular review and support to manage any increase in pain, psychological distress and withdrawal symptoms.
There are no standard tapering schedules suitable for all patients and an individualised plan is necessary. In general, tapering should involve a dose reduction of no more than 10 percent to 25 percent every 2 to 4 weeks (see Section 4.2 Dose and Method of Administration). If the patient is experiencing increased pain or serious withdrawal symptoms, it may be necessary to go back to the previous dose until stable before proceeding with a more gradual taper.
When ceasing opioids in a patient who has a suspected opioid use disorder, the need for medication assisted treatment and/or referral to a specialist should be considered.
Doxylamine must be administered with caution in patients with: urinary retention; susceptibility to angle closure glaucoma; benign prostatic hyperplasia.

CYP2D6 metabolism.

Mevadol Forte is contraindicated for use in patients who are CYP2D6 ultra-rapid metabolisers.
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. 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. Children are particularly susceptible due to their immature airway anatomy. Deaths have been reported in children with rapid metabolism who were given codeine for analgesia post adenotonsillectomy. Morphine can also be ingested by infants through breast milk, causing risk of respiratory depression to infants of rapid metaboliser mothers who take codeine.
The prevalence of codeine ultra-rapid metabolism by CYP2D6 in children is not known but is assumed to be similar to that reported in adults. The prevalence of ultra-rapid metabolisers is estimated to be 1% in those of Chinese, Japanese and Hispanic decent, 3% in African Americans and 1%-10% in Caucasians. The highest prevalence (16%-28%) occurs in North African, Ethiopian and Arab populations.
(See Section 4.4 Special Warnings and Precautions for Use, Paediatric use; Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation.) This medication may be dangerous when used in large amounts or for long periods.

Use in hepatic impairment.

Mevadol Forte should be administered with caution to patients with hepatic dysfunction, viral hepatitis, and to patients taking other drugs which affect the liver.

Use in renal impairment.

Mevadol Forte should be administered with caution to patients with renal dysfunction.

Use in the elderly.

Elderly people may be more sensitive to the effects of this medicinal product. The elderly are more likely to have hypertrophy, prostatic obstruction and age-related renal impairment, and may be more susceptible to the undesirable effects due to opioid-induced urinary retention and the respiratory effects of opioid analgesics. Dose reduction may be required.

Paediatric use.

Mevadol Forte is contraindicated for use in children:
younger than 12 years;
aged between 12-18 years in whom respiratory function might be compromised, including post tonsillectomy and/or adenoidectomy for obstructive sleep apnoea. Respiratory depression and death have occurred in some children who received codeine following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolisers of codeine due to a CYP2D6 polymorphism. (See Section 4.4 Special Warnings and Precautions for Use, CYP2D6 metabolism.)

Effects on laboratory tests.

Plasma amylase and lipase activity.

Codeine may cause increased biliary tract pressure, thus increasing plasma amylase and/or lipase concentrations.

Gastric emptying studies.

Gastric emptying is delayed by codeine so gastric emptying studies will not be valid.

Uric acid and blood glucose.

Intake of paracetamol may affect the laboratory determination of uric acid by phosphotungstic acid and of blood glucose by glucose oxidase-peroxidase.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Salicylates and NSAIDs.

Prolonged concurrent use of paracetamol and salicylates or non-steroidal anti-inflammatory drugs may increase the risk of adverse renal effects.

Coumarins.

Paracetamol may increase the risk of bleeding in patients taking warfarin and other coumarin derivatives (antivitamin K). Monitoring of coagulation and bleeding complications is required.

Chloramphenicol.

Paracetamol may slow down the excretion of chloramphenicol, entailing the risk of increased toxicity.

Diflunisal.

Diflunisal may increase the plasma concentrations of paracetamol by 50%.

Anticholinergics.

Concomitant use of codeine and anticholinergic agents may increase the risk of severe constipation and/or urinary retention. Drugs which decrease gastric emptying may decrease the absorption of paracetamol.

Cholestyramine.

Cholestyramine reduces the absorption of paracetamol if given within one hour of paracetamol administration.

Chelating resin.

Chelating resin can decrease the intestinal absorption of paracetamol and potentially decrease its efficacy if taken simultaneously. In general, there must be an interval of more than 2 hours between taking the resin and taking paracetamol, if possible.

Propantheline.

Decreases gastric emptying which may decrease the absorption of paracetamol.

Rifampicin.

Concomitant use may increase the likelihood of paracetamol toxicity (see Hepatotoxic drugs and liver microsomal enzyme inducers below).

Flucloxacillin.

Co-administration of flucloxacillin with paracetamol may lead high anion gap to metabolic acidosis due to pyroglutamic acidosis, particularly in patients presenting risk factors of glutathione depletion such as sepsis, malnutrition or chronic alcoholism.

Alcohol.

Codeine may potentiate the effects of alcohol and increase the likelihood of paracetamol toxicity (see Hepatotoxic drugs and liver microsomal enzyme inducers below). The concomitant use of alcohol and opioids increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. Concomitant use with alcohol is not recommended (see Section 4.4 Special Warnings and Precautions for Use).

Metoclopramide.

Codeine may antagonise the effects of metoclopramide on gastrointestinal motility. Paracetamol absorption is increased by drugs which increase gastric emptying.

Domperidone.

The absorption rate of paracetamol may be increased by domperidone.

Opioid analgesics.

Concurrent use of codeine and other opioid agonists is usually inappropriate as additive CNS depression, respiratory depressant and hypotensive effects may occur. Narcotic analgesics may decrease gastric emptying and therefore decrease the absorption of paracetamol.

Morphinic agonists-antagonists.

Concomitant use of codeine with a partial agonist (e.g. buprenorphine) or antagonist (e.g. naltrexone) can precipitate or delay codeine effects.

Hepatotoxic drugs and liver microsomal enzyme inducers.

The risk of paracetamol toxicity may be increased in patients receiving other potentially hepatotoxic drugs or drugs that induce liver microsomal enzymes, such as antiepileptics (e.g. phenobarbital, phenytoin, carbamazepine, topiramate), alcohol, barbiturates and rifampicin. The induced metabolism results in an elevated production of the hepatotoxic oxidative metabolite of paracetamol. Hepatotoxicity will occur if this metabolite exceeds the normal glutathione binding capacity.

Zidovudine.

When used concurrently with zidovudine an increased tendency for neutropenia may develop. Combination of Mevadol Forte and zidovudine should be avoided.

Antiperistaltic antidiarrhoeals (including kaolin, pectin, loperamide).

Concurrent use of these agents with codeine may increase the risk of severe constipation and CNS depression.

Tranquillisers, sedatives, hypnotics, general anaesthetics and CNS depressants.

Codeine may potentiate the effects of these drugs. Concomitant use of tranquillisers or sedatives may enhance the potential respiratory depressant effects of codeine. (See Section 4.4 Special Warnings and Precautions for Use, Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol.)

Gabapentinoids and opioids.

The concomitant use of opioids with gabapentinoids (gabapentin and pregabalin) increases the risk of the respiratory depression, hypotension, profound sedation, coma or dealth because of additive CNS depressant effect.

Benzodiazepines.

The concomitant use of benzodiazepines and opioids increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. Limit dosage and duration of concomitant use of benzodiazepines and opioids (see Section 4.4 Special Warnings and Precautions for Use).

Monoamine oxidase inhibitors.

Non-selective MAOIs intensify the effects of opioid drugs, which can cause anxiety, confusion and significant respiratory depression and can potentiate the central nervous effects and other side effects of unpredictable severity. Severe and sometimes fatal reactions have occurred in patients concurrently administered MAO inhibitors and pethidine. Codeine should not be given to patients taking non-selective MAOIs or within 14 weeks of stopping such treatment. As it is unknown whether there is an interaction between the selective MAOIs (Reversible Inhibitors of Monoamine Oxidase A) and codeine, caution is advised with this drug combination.

Tricyclic antidepressants.

A codeine-induced respiratory depression can be potentiated by tricyclic antidepressants. (See Section 4.4 Special Warnings and Precautions for Use, Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol.)

Antihypertensives.

Hypotensive effects of antihypertensive agents may be potentiated when used concurrently with codeine and may lead to orthostatic hypotension.

Neuromuscular blocking agents.

Codeine may enhance the effects of neuromuscular blocking agents resulting in increased respiratory depression.
Patients receiving other narcotic analgesics, antitussives, antihypertensives, antihistamines, antipsychotics, antianxiety agents, gabapentinoids, cannabis, centrally-active anti-emetics or other CNS depressants (including alcohol) concomitantly with Mevadol Forte may experience additive CNS depression (see Section 4.4 Special Warnings and Precautions for Use, Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol).

CYP2D6 inhibitors.

Codeine is metabolized by the liver enzyme CYP2D6 to its active metabolite morphine. Medicines that inhibit CYP2D6 activity may reduce the analgesic effect of codeine. Patients taking codeine and moderate to strong CYP2D6 inhibitors (such as quinidine, fluoxetine, paroxetine, bupropion, cinacalcet, methadone) should be adequately monitored for reduced efficacy and withdrawal signs and symptoms. If necessary, an adjustment of the treatment should be considered. If necessary, an adjustment of the treatment should be considered.

CYP3A4 inducers.

Medicines that induce CYP3A4 activity may reduce the analgesic effect of codeine. Patients taking codeine and CYP3A4 inducers (such as rifampin) should be adequately monitored for reduced efficacy and withdrawal signs and symptoms. If necessary, an adjustment of the treatment should be considered.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

See Section 5.3 Preclinical Safety Data.
(Category A)
There have been no observations of an increase in the frequency of malformations or other direct or indirect harmful effects on the foetus in pregnant women and women of child-bearing age who have taken those drugs found in Mevadol Forte.
However, prolonged high-dose use of codeine prior to delivery may prolong codeine withdrawal symptoms in the neonate.
Regular use during pregnancy may cause physical dependence in the foetus, leading to withdrawal symptoms in the neonate. Administration of codeine during labour may cause respiratory depression in the newborn infant. Codeine may cause respiratory depression and withdrawal syndrome in neonates born to mothers who use codeine during the third trimester of pregnancy. As a precautionary measure, use of Mevadol Forte should be avoided during the third trimester of pregnancy and during labour. Codeine is contraindicated in the event of impending childbirth or in case of risk of premature birth (see Section 4.3 Contraindications). Mevadol Forte should only be used during pregnancy under medical supervision if the potential benefit justifies the potential risk to the foetus. If administered during pregnancy, the morphinomimetic properties of codeine should be taken into account.
Mevadol Forte is contraindicated during breast-feeding (see Section 4.4 Special Warnings and Precautions for Use, CYP2D6 metabolism) due to risk of respiratory depression in the infant. Codeine, doxylamine and paracetamol are excreted in breast milk. Analgesic doses excreted in breast milk are generally low. However, codeine is partially metabolized by cytochrome P450 2D6 (CYP2D6) into morphine, which is excreted into breast milk. If nursing mothers are CYP2D6 ultra-rapid metabolisers, higher levels of morphine may be present in their breast milk. This may result in symptoms of opioid toxicity in both mother and the breast-fed infant. Life-threatening adverse events or neonatal death may occur even at therapeutic doses (see Section 4.4 Special Warnings and Precautions for Use, CYP2D6 metabolism).
Therefore, Mevadol Forte is contraindicated for use during breastfeeding. However, in circumstances where a breastfeeding mother requires codeine therapy, breastfeeding should be suspended and alternative arrangements should be made for feeding the infant for any period during codeine treatment.
Breast-feeding mothers should be told how to recognise signs of high morphine levels in themselves and their babies. For example, in the mother, symptoms include extreme sleepiness and trouble caring for the baby. In the baby, symptoms include signs of increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties or limpness. Medical advice should be sought immediately.

4.7 Effects on Ability to Drive and Use Machines

Mevadol Forte may cause drowsiness, disturbances of visuomotor coordination and visual acuity and/or dizziness. Due to the preparation's sedative action, psychomotor impairment impacting the mental and/or physical abilities required for the performance of potentially hazardous activities may occur. Patients treated with this medicine should not drive, operate machinery or drink alcohol whilst taking this medication.

4.8 Adverse Effects (Undesirable Effects)

Reports of adverse reactions are rare. Although the following reactions have been reported when paracetamol and codeine have been administered:

Haematologic.

Less frequent to rare - agranulocytosis, anaemia, thrombocytopenia.

Genitourinary.

Less frequent to rare - renal failure, uraemia, urinary retention or hesitance.

Hypersensitive.

Less frequent to rare - skin rashes and other allergic reactions, histamine release (hypotension, flushing of the face, tachycardia, breathlessness).

Gastrointestinal.

Common - constipation, nausea, vomiting.

Neurological.

Common - drowsiness, dizziness.
Less frequent to rare - euphoria, dysphoria. At higher doses codeine may cause respiratory depression.

Hepatic.

Very rare - pancreatitis.

Metabolism and nutrition system disorders.

Not known - high anion gap metabolic acidosis due to pyroglutamic acidosis, in patients with pre-disposing factors for glutathione depletion (see Section 4.4 Special Warnings and Precautions for Use).
Paracetamol has also been associated with dyspepsia, sweating, erythema, urticaria, anaphylactic shock, angioneurotic oedema, angioedema, leukopenia, neutropenia and pancytopenia. Bronchospasms may be triggered in patients having a tendency of analgesic asthma. Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), acute generalised exanthematous pustulosis, fixed drug eruption and cytolytic hepatitis, which may lead to acute hepatic failure, have also been reported. Large doses may produce hepatotoxicity.
Prolonged administration of high doses may result in drug dependence.
Haemolytic anaemia in patients with underlying glucose 6-phosphate-dehydrogenase deficiency has been reported. Kounis syndrome and bronchospasm have also been reported.
Codeine can cause confusional state, dysphoria, seizure, headache, somnolence, sedation, miosis, tinnitus, dry mouth, pruritus, fatigue and hypotension. Visuomotor coordination and visual acuity may be adversely affected in a dose-dependent manner at higher doses or in particular sensitive patients. Long term use also entails the risk of drug dependence.
The following have been reported in relation to doxylamine: somnolence, paradoxical stimulation, psychomotor impairment, blurred vision, thickened respiratory mucus, gastrointestinal disorders and urinary retention.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at http://www.tga.gov.au/reporting-problems and contact Arrotex Medical Information enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.9 Overdose

Elderly persons, small children, patients with liver disorders, chronic alcohol consumption or chronic malnutrition, as well as patients concomitantly treated with enzyme-inducing drugs, are at an increased risk of intoxication, including fatal outcome.
The intake of too high a dose of paracetamol can lead to impairment of liver function due to necrosis of liver cells, and this condition may progress to hepatic coma and may be fatal. Independently of these liver lesions, kidney damage as a result of necrosis of the renal tubules has also been reported.

Symptoms and signs of poisoning.

The early stage of acute poisoning is typically characterized by nausea, vomiting, anorexia, pallor, abdominal pain, sweating and general malaise. This is usually followed by a 24 to 48-hour period in which the patient feels better; the symptoms however do not disappear altogether. The following stage is characterized by rapid increase in the size of the liver; serum transaminases and bilirubin rise, prothrombin time increases abnormally; urine excretion decreases and a slight increase in nitrogenous substances may develop. Three to five days after poisoning, the clinical features most typically encountered are commonly jaundice, fever, foetor hepaticus, abnormal bleeding tendency, hypoglycaemia, etc., as well as all stages of hepatic encephalopathy.
Nausea, vomiting, anorexia, pallor and abdominal pain generally appear during the first 24 hours of overdosage with paracetamol. Overdosage with paracetamol may cause hepatic cytolysis, which can lead to hepatocellular insufficiency, gastrointestinal bleeding, metabolic acidosis, encephalopathy, disseminated intravascular coagulation, coma and death. Increased levels of hepatic transaminases, lactate dehydrogenase and bilirubin with a reduction in prothrombin level can appear 12 to 48 hours after acute overdosage. It can also lead to pancreatitis, acute renal failure and pancytopenia.
Reactions associated with doxylamine succinate overdosage may vary from central nervous depression to stimulation. Stimulation is particularly likely in children. Atropine-like signs and symptoms, which include dry mouth, fixed dilated pupils, flushing and gastrointestinal symptoms, may also occur. Severe rhabdomyolysis after doxylamine succinate overdose has been reported in humans.
In an evaluation of codeine intoxication in children, symptoms ranked by decreasing order of frequency included sedation, rash, miosis, vomiting, itching, ataxia and swelling of the skin. Respiratory failure may occur. Blood concentrations of codeine ranged from 1.4 to 5.6 micrograms per mL in eight adults whose deaths were attributed to codeine overdosage.
The ingestion of very high doses of codeine can cause initial excitation, anxiety, insomnia (followed by drowsiness in certain cases), areflexia progressing to stupor or coma, headache, miosis, alterations in blood pressure, arrhythmias, dry mouth, hypersensitivity reactions, cold clammy skin, bradycardia, tachycardia, convulsions, gastrointestinal disorders, nausea, vomiting and respiratory depression.
Severe intoxication can lead to apnoea, circulatory collapse, cardiac arrest and death.

Treatment of poisoning.

Despite lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention.
Consists primarily of management of paracetamol toxicity; naloxone hydrochloride is the treatment of choice for codeine intoxication and must be administered intravenously. In cases of overdosage, methods of reducing the absorption of ingested drug are important. Prompt administration of 50 g activated charcoal and 500 mL iced mannitol 20% by mouth may reduce absorption.
Determinations of the plasma concentration of paracetamol are recommended. Plasma concentrations of paracetamol should be measured at 4 hours or later after ingestion (earlier concentrations are unreliable).
If the history suggests that 15 g paracetamol or more has been ingested, administer one of the following antidotes:

Acetylcysteine 20% IV.

Administer 20% acetylcysteine immediately without waiting for positive urine test or plasma level results: initial dose 150 mg/kg over 15 minutes, followed by continuous infusion of 50 mg/kg in 500 mL 5% glucose over 4 hours and 100 mg/kg in 1 L 5% glucose over 16 hours; or

Oral methionine.

2.5 g methionine immediately followed by three further doses of 2.5 g at four hourly intervals. For a 3-year-old child, 1 g methionine 4-hourly for four doses has been used.
If more than ten hours have elapsed since the overdosage was taken, the antidote may be ineffective.
In general, treatment for codeine overdose should be symptomatic. Re-establish adequate respiratory exchange by ensuring a clear airway and using mechanical ventilation. When treatment for paracetamol toxicity has been initiated naloxone 400 microgram may be administered SC, IM or IV; IV may be repeated at intervals of 2 to 3 minutes if necessary. Assisted respiration may be required.
Further measures will depend on the severity, nature and course of clinical symptoms of intoxication and should follow standard intensive care protocols.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Codeine is a potent analgesic. Paracetamol is an analgesic and antipyretic. Doxylamine succinate has calmative and antinauseant properties, which can be useful in relieving tension and nausea associated with pain.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Metabolism.

Patients who metabolise drugs poorly via CYP2D6 are likely to obtain reduced benefit from codeine due to reduced formation of the active metabolite.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

Toxicity studies in animals have shown that high doses of paracetamol cause testicular atrophy and inhibition of spermatogenesis; the relevance of this finding to use in humans is not known.

6 Pharmaceutical Particulars

6.1 List of Excipients

Microcrystalline cellulose, sodium starch glycollate, hypromellose, purified talc, magnesium stearate.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Al/ PVC/ PVDC Amber or Clear Blister Pack containing 10 tablets. Two Blister Packs in a carton of 20 tablets. AUST R 310164.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Paracetamol.

C₈H₉NO₂.

Codeine phosphate hemihydrate.

C₁₈H₂₄NO₇P.½H₂O.

Doxylamine succinate.

C₂₁H₂₈N₂O₅.

CAS number.

Paracetamol: 103-90-2.
Codeine phosphate hemihydrate: 41444-62-6.
Doxylamine succinate: 562-10-7.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine (Schedule 4).

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Consumer medicine information

Mevadol Forte

Paracetamol; Codeine phosphate hemihydrate; Doxylamine succinate

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BRAND INFORMATION

Mevadol Forte Tablets