Consumer medicine information

Maxydol Tablets

Paracetamol + Codeine phosphate hemihydrate + Doxylamine succinate

BRAND INFORMATION

Brand name

Maxydol

Active ingredient

Paracetamol + Codeine phosphate hemihydrate + Doxylamine succinate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Maxydol Tablets.

Maxydol

Maxydol

 Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine.

 1. Why am I using Maxydol?

Maxydol contains the active ingredient paracetamol, codeine phosphate hemihydrate and doxylamine succinate. Maxydol is used for temporary relief of acute moderate pain when other analgesics have proven not to be effective. For more information, see Section 1. Why am I using Maxydol? in the full CMI.

 2. What should I know before I use Maxydol?

Do not use if you have ever had an allergic reaction to Maxydol or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

You may develop addiction, dependence, and tolerance.

For more information, see Section 2. What should I know before I use Maxydol? in the full CMI.

 3. What if I am taking other medicines?

Some medicines may interfere with Maxydol and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

 4. How do I use Maxydol?

The standard dose for adults is 1 or 2 tablets for severe pain, taken every 4 to 6 hours if necessary. More instructions can be found in Section 4. How do I use Maxydol? in the full CMI.

 5. What should I know while using Maxydol?

Things you should do
  • Remind any doctor, dentist or pharmacist when you visit that you are using Maxydol.
  • Talk to your doctor or pharmacist if this medicine is not relieving your pain.
  • Tell your doctor or pharmacist, if you become pregnant while you are taking this medicine.
Things you should not do
  • Do not take more than the recommended dose, unless your doctor tells you to. Do not take more than 8 tablets a day.
  • Do not give this medicine to children under 12 years of age.
  • Do not take this medicine for longer than a few days at a time unless advised to by a doctor.
Driving or using machines
  • This medicine may cause drowsiness or sleepiness in some people. If this happens, do not drive or use operate machinery. Make sure you know how you react to Maxydol tablets before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy.
Drinking alcohol
  • Do not drink alcohol while using the medicine.
Looking after your medicine
  • Keep the tablets in a cool dry place where the temperature stays below 25°C.
  • Keep your tablets in the pack until it is time to take them.

For more information, see Section 5. What should I know while using Maxydol? in the full CMI.

 6. Are there any side effects?

The common side effects include drowsiness or sleepiness, dry mouth, constipation, difficulty breathing, nausea, vomiting, dizziness, stomach pain, skin rashes, sweating and diarrhoea. They are usually mild. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

WARNING:

Limitations of Use

Maxydol should only be used when your doctor decides that other treatment options are not able to effectively manage your pain, or you cannot tolerate them.

Hazardous and Harmful Use

Maxydol poses risks of abuse, misuse and addiction which can lead to overdose and death. Your doctor will monitor you regularly during treatment.

Life Threatening Respiratory Depression

Maxydol can cause life-threatening or fatal breathing problems (slow, shallow, unusual or no breathing), even when used as recommended. These problems can occur at any time during use, but the risk is higher when first starting Maxydol and after a dose increase, if you are older, or have an existing problem with your lungs. Your doctor will monitor you and change the dose as appropriate.

Use of Other Medicines While Using Maxydol

Using Maxydol with other medicines that can make you feel drowsy such as sleeping tablets (e.g. benzodiazepines), other pain relievers, antihistamines, antidepressants, antipsychotics, gabapentinoids (e.g. gabapentin and pregabalin), cannabis and alcohol may result in severe drowsiness, decreased awareness, breathing problems, coma and death. Your doctor will minimise the dose and duration of use; and monitor you for signs and symptoms of breathing difficulties and sedation. You must not drink alcohol while using Maxydol.

Maxydol

Active ingredient(s): Paracetamol, Codeine phosphate hemihydrate and Doxylamine succinate

 Consumer Medicine Information (CMI)

This leaflet provides important information about using Maxydol. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Maxydol.

Where to find information in this leaflet:

1. Why am I using Maxydol?
2. What should I know before I use Maxydol?
3. What if I am taking other medicines?
4. How do I use Maxydol?
5. What should I know while using Maxydol?
6. Are there any side effects?
7. Product details

 1. Why am I using Maxydol?

Maxydol contains the active ingredients paracetamol, codeine phosphate hemihydrate and doxylamine succinate. Paracetamol is an analgesic. It also helps in reducing fever. Codeine phosphate is an analgesic and doxylamine succinate is an antihistamine with calmative effects.

In combination, paracetamol, codeine phosphate and doxylamine produce greater analgesia than any of these drugs alone. Maxydol tablets contain no aspirin.

Maxydol is used to provide effective temporary relief of moderate to severe pain when other analgesics have proven not to be effective and discomfort associated with headache (including tension and migraine), period pain, toothache, muscle pain, backache, rheumatic pain, neuralgia, pain associated with trauma or surgery and other pain where a combined analgesic & calmative action is required.

 2. What should I know before I use Maxydol?

Warnings

Do not use Maxydol if:

  • you are allergic 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.
  • you have had an allergic reaction to other opioid analgesics such as morphine or pethidine
  • you have had an allergic reaction to other antihistamines.
  • you have liver failure
  • you have G6PD deficiency, a human enzyme deficiency
  • you have acute breathing difficulties such as bronchitis, unstable asthma or emphysema
  • you have chronic constipation
  • you have diarrhoea caused by antibiotics or poisoning.

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

Do not take this medicine if you are also taking monoamine oxidase inhibitors, a type of medicine used to treat depression.

Do not take Maxydol tablets if the packaging is torn or shows signs of tampering.

Do not take this medicine if you are CYP2D6 ultra-rapid metaboliser.

Do not take this medicine if your age is 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 and life-threatening adverse reactions

Do not take Maxydol tablets with any other products containing paracetamol, unless advised to do so by a doctor or pharmacist. Taking too much paracetamol may cause serious liver damage.

Do not give Maxydol tablets to a child under 12 years.

Check with your doctor if you have:

  • any allergies to any other medicines or any other substances, such as foods, preservatives or dyes any of the ingredients listed at the end of this leaflet
  • aspirin or any other NSAID medicine
  • a history of drug or alcohol dependence
  • kidney or liver disease
  • heart problems
  • difficulty breathing, wheezing, chronic cough, asthma or other chronic breathing conditions
  • glaucoma a history of drug or alcohol dependence
  • a history of dependence
  • recent surgery on the stomach or intestines
  • head injury or trauma
  • enlarged prostate
  • low blood pressure
  • underactive thyroid
  • epilepsy
  • compromised respiratory function (due to emphysema, kyphoscoliosis or obesity)
  • known analgesic intolerance
  • know you are a CYP 2D6 ultra-rapid metaboliser
  • chronic alcohol use including recent cessation of alcohol intake
  • low glutathione reserves
  • Gilbert's syndrome
  • prostate problems
  • thyroid problems
  • Multiple sclerosis
  • urinary, bowel or gallbladder conditions
  • Addison's disease
  • convulsions, fits or seizures
  • pre-existing opioid dependence
  • chronic constipation

Caution is particularly recommended for use in adolescents and young adults with a history of drug and/or alcohol abuse.

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

  • glaucoma (high pressure in the eyes)
  • stomach or duodenal ulcer, or other stomach problems
  • prostate problems
  • bladder problems

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

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

Do not take Maxydol during the third trimester of pregnancy.

Do not take codeine during labour, especially if the baby is premature. The medicine may produce withdrawal effects in the newborn baby.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

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

It passes into the breast milk and there is a possibility that the baby may be affected.

Addiction

You can become addicted to Maxydol even if you take it exactly as prescribed. Maxydol may become habit forming causing mental and physical dependence. If abused it may become less able to reduce pain.

Dependence

As with all other opioid containing products, your body may become used to you taking Maxydol. Taking it may result in physical dependence. Physical dependence means that you may experience withdrawal symptoms if you stop taking Maxydol suddenly, so it is important to take it exactly as directed by your doctor.

Tolerance

Tolerance to Maxydol may develop, which means that the effect of the medicine may decrease. If this happens, more may be needed to maintain the same effect.

 3. What if I am taking other medicines?

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

Some medicines may interfere with Maxydol and affect how it works. It includes:

  • warfarin, a medicine used to prevent blood clots
  • metoclopramide, a medicine used to control nausea and vomiting
  • medicines used to treat epilepsy or fits
  • chloramphenicol, an antibiotic used to treat ear and eye infections
  • medicines used to help you relax, sleep or relieve anxiety, such as barbiturates, benzodiazepines and sedatives
  • medicines used to relieve stomach cramps or spasms
  • medicines used to prevent travel sickness
  • medicines used to treat Parkinson's disease
  • medicines used to treat high blood pressure
  • medicines for diarrhoea, such as kaolin, pectin and loperamide
  • other pain relief medication
  • monoamine oxidase inhibitors, medicines used to treat depression, if taken within the last 14 days
  • quinidine, a medicine used to treat abnormal or irregular heart beat
  • phenothiazines and antipsychotic agents, medicines used to treat mental disorders
  • medicines used to treat alcohol and/or opioid dependence (e.g. naltrexone, buprenorphine or methadone) or other opioids, used to treat pain or suppress coughs or medicines containing alcohol (ethanol), e.g. some cough syrups
  • Chelating resin
  • Buprenorphine
  • Naltrexone
  • CYP 2D6 inhibitors such as fluoxetine, paroxetine, bupropion, cinacalcet, methadone
  • CYP 3A4 inducers such as rifampin

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

 4. How do I use Maxydol?

How much to take

  • Adults and children over 12 years: Take 1-2 tablets every 4-6 hours as necessary.
  • Do not exceed 8 tablets in a 24-hour period. Do not give to children under 12 years of age.
  • Follow the instructions provided and use written on the medicine's label.
  • Talk to your doctor or pharmacist if you do not understand the instructions on the box.

WARNING:

Keep to the recommended dose.

  • Adults: Do not take this medicine for longer than a few days at a time unless advised to by a doctor.
  • Adolescents and children over 12 years of age: Do not take this medicine for longer than 48 hours at a time unless advised to by a doctor.
  • Maxydol tablets is for minor and temporary ailments and should be used strictly as directed. Prolonged use without medical supervision could be harmful.
  • Codeine may be habit forming if taken frequently and over a long period of time.
  • If you are not sure how long to take Maxydol tablets, talk to your doctor or pharmacist.
  • If your symptoms persist, worsen or new symptoms develop, talk to your pharmacist.

When to take Maxydol

  • Maxydol tablets can be taken with or without food.
  • If you are not sure when to take it, ask your doctor or pharmacist.

How to take it

  • Swallow Maxydol tablets with a glass of water. Maxydol tablets can be taken with or without food.

If you forget to use Maxydol

Maxydol should be used regularly at the same time each day. Do not try to make up for missed doses by taking more than one dose at a time. This may increase the chance of getting an unwanted side effect.

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

Do not take a double dose to make up for the dose you missed.

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

If you use too much Maxydol

If you or someone else receive too much (overdose), and experience one or more of the symptoms below, immediately call triple zero (000) for an ambulance. Keep the person awake by talking to them or gently shaking them every now and then. You should follow the above steps even if someone other than you have accidentally used Maxydol that was prescribed for you. If someone takes an overdose they may experience one or more of the following symptoms:

  • Slow, unusual or difficult breathing
  • Drowsiness, dizziness or unconsciousness
  • Slow or weak heartbeat
  • Nausea or vomiting
  • Convulsions or fits

If you think that you have used too much Maxydol, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention. Large amounts of paracetamol can cause liver damage.

If children taken too much Maxydol tablets they can suffer nightmares, hallucinations, fitting or have difficulty sleeping.

When seeking medical attention, take this leaflet and remaining medicine with you to show the doctor. Also tell them about any other medicines or alcohol which have been taken.

 5. What should I know while using Maxydol?

Things you should do

Do not take more than the recommended dose on the label or for a longer period of time.

If you are over 65 years of age, talk to your pharmacist or doctor about how much to take.

Elderly patients are more likely to have side effects from taking these medicines.

Call your doctor straight away if you:

  • are about to start taking any new medicine
  • symptoms do not improve
  • plan to have surgery that needs a general anaesthetic
  • become pregnant while you are taking this medicine,

Remind any doctor, dentist or pharmacist when you visit that you are using Maxydol.

Things you should not do

  • Do not take more than the recommended dose unless your pharmacist or doctor tells you to.
  • Do not take with other medicines containing paracetamol unless your doctor or pharmacist tells you to.
  • Adults: Do not take for more than a few days at a time unless your doctor tells you to.
  • Children and adolescents (12-17 years): Do not take for longer than 48 hours unless your doctor tells you to.
  • Do not give Maxydol tablets to anyone else, even if they have the same condition as you.
  • Do not use Maxydol tablets to treat any other complaints unless your doctor or pharmacist tells you to.
  • Do not drink alcohol.

Things to be careful of

  • Do not take high doses of the medicine for long periods of time unless your doctor tells you to.
  • Maxydol tablet may be habit forming if taken at high doses for extended periods of time.
  • Too much paracetamol may cause delayed, serious liver damage.
  • Only drink small quantities of alcohol (beer, wine or spirits) while taking paracetamol.
  • Drinking alcohol and taking paracetamol at the same time can cause liver damage. It is not recommended that you drink alcohol while taking Maxydol.
  • Children should not ride bicycles if affected and should be supervised to avoid potential harm.
  • Be careful if you are over 65 and unwell or taking other medicines.
  • Some people may experience side effects such as drowsiness, confusion, dizziness and unsteadiness, which may increase the risk of a fall.
  • About 8% of people are poor metabolisers of codeine and Maxydol tablets may not work as well if you are one of those people.
  • Talk to your doctor or pharmacist if this medicine is not relieving your pain.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Maxydol affects you.

Maxydol tablets may cause drowsiness or sleepiness in some people. If this happens, do not drive or use operate machinery. Make sure you know how you react to Maxydol tablets before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy.

Drinking alcohol

Tell your doctor if you drink alcohol.

Do not take this medicine if you regularly drink large quantities of alcohol.

Do not drink alcohol while taking Maxydol.

Drinking alcohol increases the likelihood of becoming drowsy.

Withdrawal

Continue taking your medicine for as long as your doctor tells you. If you stop having this medicine suddenly, your pain may worsen and you may experience some or all of the following withdrawal symptoms:

  • nervousness, restlessness, agitation, trouble sleeping or anxiety
  • body aches, weakness or stomach cramps
  • loss of appetite, nausea, vomiting or diarrhoea
  • increased heart rate, breathing rate or pupil size
  • watery eyes, runny nose, chills or yawning
  • increased sweating

Looking after your medicine

  • 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 the tablets in a cool dry place where the temperature stays below 25°C.
  • Heat and dampness can destroy some medicines.
  • A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date. If you take it after the expiry date has passed, it may not work as well.

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

 6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
More broad or affecting different parts of the body:
  • drowsiness or sleepiness
  • dry mouth,
  • constipation
  • difficulty breathing
  • nausea
  • vomiting
  • dizziness
  • stomach pain
  • skin rashes
  • Sweating
  • diarrhoea
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
More broad or affecting different parts of the body:
  • 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
  • Hepatitis (symptoms include loss of appetite, itching, yellowing of the skin and eyes, light coloured bowel motions, dark coloured urine)
  • swelling of the face, lips, mouth or throat, which may cause difficulty in swallowing or breathing
  • fainting
  • hives
  • yellowing of the skin and eyes (jaundice)
Allergy related:
  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

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.

 7. Product details

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

What Maxydol contains

Active ingredient
(main ingredient)
  • Paracetamol
  • Codeine phosphate hemihydratye
  • Doxylamine Succinate
Other ingredients
(inactive ingredients)
  • Starch maize
  • Hydroxypropyl cellulose
  • Sodium lauryl sulphate
  • Pregelatinized maize starch
  • Silica - colloidal anhydrous
  • Talc-purified
  • Stearic acid
  • Povidone
  • Magnesium stearate

Do not take this medicine if you are allergic to any of these ingredients.

What Maxydol looks like

Maxydol tablets are white capsule-shaped tablets with a breakline on one side. They are available in blister packs of 20 and 40 tablets. (AUST R 277276)

Who distributes Maxydol

Arrow Pharma Pty Ltd
15 – 17 Chapel Street
Cremorne
Victoria
3121
Email id: drugsafety@cipla.com
Phone no: 1 800 569 074

This leaflet was prepared in October 2020.

Published by MIMS May 2021

BRAND INFORMATION

Brand name

Maxydol

Active ingredient

Paracetamol + Codeine phosphate hemihydrate + Doxylamine succinate

Schedule

S4

 

1 Name of Medicine

Paracetamol, codeine phosphate hemihydrate and doxylamine succinate.

2 Qualitative and Quantitative Composition

Each tablet contains paracetamol 500 mg, codeine phosphate hemihydrate 10 mg, and doxylamine succinate 5.1 mg.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

White, capsule shaped, biconvex tablets with a central break line on one side and plain on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

For the temporary relief of acute moderate pain.

4.2 Dose and Method of Administration

Adults and children over 12 years.

One or two tablets with water every 4-6 hours if necessary. Do not exceed 8 tablets in 24 hours period.
This medicine should not be taken with other medicines containing paracetamol unless advised to do so by a doctor or pharmacist.
Maxydol is contraindicated for use in patients who are:
aged below 12 years;
aged between 12 to 18 years in whom respiratory function might be compromised, including post tonsillectomy and/or adenoidectomy for obstructive sleep apnoea (also see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Paediatric use).

4.3 Contraindications

Maxydol is contraindicated for use in patients who are:
CYP 2D6 ultra-rapid metabolisers (see Section 4.4 Special Warnings and Precautions for Use, CYP2D6 metabolism);
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, obesity and pulmonary disease, due to an increased risk of developing serious and life-threatening adverse reactions (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use);
breastfeeding (see Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation);
using monoamine inhibitors (MAOIs) or have stopped treatment within the last 14 days (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Codeine is contraindicated in the event of impending childbirth or in case of risk of premature birth.
This medicine should not be given to patients with:
known hypersensitivity or idiosyncratic reaction to paracetamol, codeine phosphate hemihydrate or other opiates, doxylamine succinate or to other antihistamines of the ethanolamine class or any of the other ingredients;
severe respiratory disease, acute respiratory disease (e.g. acute asthma, acute exacerbations of chronic obstructive pulmonary disease) and respiratory depression, since codeine may exacerbate the condition;
patients with severe hepatocellular insufficiency;
patients with glucose-6-phosphate-dehydrogenase deficiency;
chronic constipation;
during labour when delivery of a premature infant is anticipated as it may produce codeine withdrawal symptoms in the neonate;
active alcoholism (as this may predispose patients to paracetamol hepatoxicity);
diarrhoea due to pseudomembranous colitis or poisoning (until the causative organism or toxin has been eliminated from the gastrointestinal tract since codeine may slow their elimination, thereby prolonging the diarrhoea);
narrow-angle glaucoma;
stenosing peptic ulcer;
symptomatic prostatic hypertrophy;
bladder neck obstruction;
pyloroduodenal obstruction.

4.4 Special Warnings and Precautions for Use

To avoid the risk of overdose.

Check that paracetamol is absent from the composition of other medicinal products taken concomitantly.

Alcohol.

Avoid alcohol.

Hepatotoxicity.

This medication may be dangerous when used in large amounts or for long periods. In adults, hepatotoxicity may occur after ingestion of a single dose of paracetamol 10 to 15 g; a dose of 25 g or more is potentially fatal (see Section 4.9 Overdose). Hepatic failure is known to occur occasionally with the long term use of paracetamol.
Hepatotoxicity may occur with paracetamol even at therapeutic doses, after short treatment duration and in patients without pre-existing liver dysfunction.

Hypersensitivity reaction.

Patients with known analgesic intolerance or known bronchial asthma must only use Maxydol after having consulted a physician (hypersensitivity reactions including bronchospasm are possible).

Non-steroidal anti-inflammatory drugs (NSAIDs).

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 immediately paracetamol treatment and seek medical advice.

Paracetamol should be used upon medical advice in patients with.

Mild to moderate hepatocellular insufficiency; severe renal insufficiency; chronic alcohol use including recent cessation of alcohol intake; low glutathione reserves; Gilbert's syndrome.
Maxydol should be used with caution in patients with:
decreased respiratory reserve e.g. asthma or chronic obstructive pulmonary disease (COPD);
pre-existing respiratory depression. Maxydol is contraindicated for use in patients with acute respiratory depression (see Section 4.3 Contraindications);
raised intracranial pressure or head injury;
prostatic hypertrophy;
hypotension;
hypothyroidism;
epilepsy.

Codeine must be administered with caution.

Codeine must be administered with caution in certain patients such as those who present with impaired cardiac, hepatic or renal function, hypotension, benign prostatic hyperplasia, urethral stenosis, adrenal insufficiency (Addison's disease), hypothyroidism, multiple sclerosis, chronic colitis ulcerative, gallbladder conditions and diseases that present with reduced respiratory capacity such as emphysema, kyphoscoliosis and severe obesity.

Cholecystectomy.

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.

Convulsive disorders.

Codeine should be used with caution in patients with convulsive disorders.

Analgesic use.

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 after careful risk-benefit assessment and caution in case of.

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.

Doxylamine must be administered with caution in patients with.

Urinary retention; susceptibility to angle closure glaucoma.

Hazardous and harmful use.

Maxydol contains the opioid codeine and is a potential drug of abuse, misuse and addiction. Addiction can occur in patients appropriately prescribed Maxydol 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 Maxydol.
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 Maxydol 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 Maxydol 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 renal and hepatic 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 (see Section 4.2 Dose and Method of Administration). 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 Maxydol with CNS depressant medicines, such as other opioid 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 Maxydol 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 Maxydol.
Codeine may obscure the diagnosis or the course of gastrointestinal diseases.
Prolonged use of codeine may produce physical and psychological dependence.
See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions for additional information.

Alcohol consumption.

Active alcohol consumption (three or more alcoholic drinks daily) and the use of pain relievers containing paracetamol may increase the risk of liver damage or stomach bleeding.

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 non-pharmacological 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 Maxydol 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 Maxydol, 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 Maxydol (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.

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.

CYP2D6 metabolism.

Maxydol 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 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. 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 differs according to racial and ethnic group. The prevalence of ultra-rapid metabolisers is estimated to be 1% in those of Chinese, Japanese and Hispanic descent, 3% in African Americans and 1%-10% in Caucasians. The highest prevalence (16%-28%) occurs in North African, Ethiopian and Arab populations (also see Section 4.4 Special Warnings and Precautions for Use, Pediatric use; Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation).
It should also be used with caution in patients who: have a history of drug abuse; are taking other respiratory depressants or sedatives, including alcohol; have had recent gastrointestinal tract surgery.

Use in hepatic impairment.

This medicine should be used with caution in patients with hepatic impairment.

Use in renal impairment.

This medicine should be used with caution in patients with renal impairment.

Use in the elderly.

Elderly patients may experience paradoxical excitation with doxylamine and are more likely to have central nervous system (CNS) depressive side effects, including confusion, especially respiratory depression. (See Section 4.3 Contraindications).
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 depressant effects of codeine.

Paediatric use.

Children may experience paradoxical excitation with doxylamine.
Maxydol is contraindicated for use in children:
younger than 12 years;
aged between 12 to 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.

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

The following interactions have been noted:
Anticoagulant drugs (warfarin) - dosage may require reduction if paracetamol and anticoagulants are taken for a prolonged period of time.
Paracetamol absorption is increased by substances that increase gastric emptying, e.g. metoclopramide or domperidone.
Paracetamol absorption is decreased by substances that decrease gastric emptying, e.g. propantheline, antidepressants with anticholinergic properties, and narcotic analgesics.
Paracetamol may increase chloramphenicol concentrations entailing the risk of increased toxicity.
When used concurrently with zidovudine, an increased tendency for neutropenia may develop. Combination of Maxydol and zidovudine should be avoided.
The risk of paracetamol toxicity may be increased in patients receiving other potentially hepatotoxic drugs or drugs that induce liver microsomal enzymes such as barbiturates and other antiepileptics (such as phenobarbital, phenytoin, carbamazepine, topiramate), rifampicin and alcohol. 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.
Paracetamol excretion may be affected and plasma concentrations altered when given with probenecid.
Cholestyramine reduces the absorption of paracetamol if given within 1 hour of paracetamol.
CNS depressants - concomitant use of codeine with central nervous system depressants (e.g. barbiturates, chloral hydrate, sedatives, alcohol and centrally acting muscle relaxants) can cause additive CNS depression.
Anticholinergics - concurrent use of codeine with anticholinergic agents may increase the risk of severe constipation and/or urinary retention.
Antihypertensives - hypotensive effects may be potentiated when used concurrently with codeine and lead to orthostatic hypotension.
Antiperistaltic antidiarrhoeals (e.g. kaolin, pectin and loperamide) - concurrent use with codeine may increase the risk of severe constipation and CNS depression.
Metoclopramide - codeine may antagonise the effects of metoclopramide on gastrointestinal activity.
Monoamine oxidase inhibitors (MAOIs) - concurrent administration or use within 14 days of ceasing MAOIs may enhance the potential respiratory depressant effects of codeine, the central nervous effects and other side effects of unpredictable severity. Codeine should not be used within two weeks after the discontinuation of MAOI treatment.
Opioid analgesics - concurrent use of codeine and other opioid receptor antagonists is usually inappropriate as additive CNS depression, respiratory depression and hypotensive effects may occur.
Substances that inhibit CYP2D6 such as quinidine, phenothiazines and antipsychotic agents can interfere with the metabolism of codeine to morphine, reducing the analgesic effect of codeine.
The following interactions with doxylamine have been noted:
Central nervous system (CNS) depressants (alcohol, sedatives, opioid analgesics, hypnotics) - may cause an increase in sedation effects, 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).
Monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) - may prolong and induce respiratory depression and intensify the anticholinergic and CNS depressive effects.
Dexchlorpheniramine when taken with monoamine oxidase inhibitors (MAOIs) may cause a decrease in blood pressure.
Chlorpheniramine when taken concomitantly with phenytoin may cause a decrease in phenytoin elimination.
The concomitant use of benzodiazepines and opioids including alcohol 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, Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol).

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.
Paracetamol may increase the risk of bleeding in patients taking warfarin and other antivitamin K. Patients taking paracetamol and antivitamin K should be monitored for appropriate coagulation and bleeding complications.
Chelating resin can decrease the intestinal absorption of paracetamol and potentially decrease its efficacy if taken simultaneously.
Co-administration of flucloxacillin with paracetamol may lead to metabolic acidosis, particularly in patients presenting risk factors of glutathione depletion, such as sepsis, malnutrition or chronic alcoholism.

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, 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.

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.

No data available.
(Category A)
Paracetamol, codeine and doxylamine have been taken by a large number of pregnant women and women of childbearing age without any proven increase in the frequency of malformations or other direct or indirect harmful effects on the foetus having been observed.
Maxydol 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 precautionary measure, use of Maxydol should be avoided during the third trimester of pregnancy and during labour (see Section 4.3 Contraindications). Maxydol should only be used during pregnancy under medical supervision if the potential benefit justifies the potential risk to the foetus. If administered during pregnancy, morphinomimetic properties of codeine should be taken into account.
Maxydol is contraindicated during labour when delivery of a premature infant is anticipated as it may produce codeine withdrawal symptoms in the neonate.
 Paracetamol, codeine and doxylamine succinate are excreted in breast milk. Codeine may cause respiratory depression in newborn infant.
Maxydol is contraindicated during breastfeeding (also see Section 4.4 Special Warnings and Precautions for Use, CYP2D6 metabolism) due to risk of respiratory depression in the infant. There are no data available on the use of Maxydol during lactation.
Analgesic doses excreted in breast milk are generally low. However, infants of breastfeeding mothers taking codeine may have an increased risk of morphine overdose if the mother is an ultrarapid metaboliser of codeine. Paracetamol, doxylamine and codeine are excreted into human breast milk. Codeine is partially metabolised by cytochrome P4502D6 (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 breastfed infant. Life-threatening adverse events or neonatal death may occur even at therapeutic doses (also see Section 4.4 Special Warnings and Precautions for Use, CYP2D6 metabolism).
Therefore, Maxydol 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.
Breastfeeding mothers should be told how to recognize signs of high morphine levels in themselves and their babies. For example, in a 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

This medicine may cause drowsiness and may increase the effects of alcohol. Drowsiness may continue the following day. Those affected should not drive or operate machinery; alcohol should be avoided.
Both doxylamine succinate and codeine may cause drowsiness in some patients. Codeine may also cause disturbances of visuomotor coordination and visual acuity, and psychomotor impairment impacting the mental and or physical ability required for the performance of potentially dangerous tasks. Thus, patients should not operate vehicles or machinery or engage in activities which require them to be fully alert. Patients should be cautioned to abstain from alcohol.

4.8 Adverse Effects (Undesirable Effects)

Side-effects with Maxydol are infrequent. However, among those reported are: anorexia, drowsiness, depression, dizziness, sweating, anaphylactic shock, angioneurotic oedema, angioedema, difficulty in breathing, drop in blood pressure, gastrointestinal discomfort such as nausea and diarrhoea, dry mouth and, on rare occasions, erythema, urticaria, rash.

Paracetamol.

Side effects of paracetamol are rare and usually mild, although haematological reactions have been reported. Skin rashes and hypersensitivity reactions occur occasionally.
Overdosage with paracetamol if left untreated can result in severe, sometimes fatal liver damage and rarely, acute renal tubular necrosis.
Paracetamol may occasionally cause skin reactions and isolated cases of agranulocytosis and thrombocytopenic purpura have been reported. Changes in blood picture (rarely thrombocytopenia, neutropenia, leukopenia, and, in isolated cases, pancytopenia) may occur.
Bronchospasm 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.

Codeine.

The most common adverse effects associated with codeine are nausea, vomiting, drowsiness, dizziness, pancreatitis and constipation.
Other side effects include: cough suppression, respiratory depression, euphoria, dysphoria, skin rashes, histamine release (hypotension, flushing of the face, tachycardia, breathlessness) and other allergic reactions.
Adverse effects reported relating specifically to the codeine component are: hypersensitivity, confusional state, dysphoria, euphoria, seizure, headache, somnolence, dizziness, hypotension, sedation, miosis, tinnitus, respiratory depression, constipation, vomiting, nausea, dry mouth, pruritus, urinary retention, and fatigue. Long term use also entails the risk of drug dependence. Visuomotor coordination and visual acuity may be adversely affected in a dose-dependent manner at higher doses or in particularly sensitive patients.

Doxylamine.

Central nervous system (CNS) effects.

CNS depressive effects of doxylamine include sedation, dizziness and impaired performance (impaired driving performance, poor work performance, incoordination, reduced motor skills, and impaired information processing). Performance may be impaired in the absence of sedation and may persist the morning after a night-time dose.
CNS stimulatory effects of doxylamine may include anxiety, hallucinations, appetite stimulation, muscle dyskinesias and activation of epileptogenic foci.
High doses of doxylamine may cause nervousness, tremor, insomnia, agitation, and irritability.
Haemolytic anaemia, particularly in patients with underlying glucose-6-phosphate-dehydrogenase deficiency has been reported. Kounis syndrome and bronchospasm have also been reported.
Doxylamine succinate may cause drowsiness in some individuals, as well as paradoxical stimulation, psychomotor impairment, blurred vision, thickened respiratory secretions, gastrointestinal disorders and urinary retention.

Anticholinergic effects.

Side effects of doxylamine associated with cholinergic blockage include dryness of the eyes, mouth and nose, blurred vision, urinary hesitancy and retention, constipation and tachycardia.

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 medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at https://www.tga.gov.au/reporting-problems.

4.9 Overdose

Symptoms.

Toxic symptoms of paracetamol overdose include vomiting, abdominal pain, hypotension, sweating, central stimulation with exhilaration and convulsions in children, drowsiness, respiratory depression, cyanosis and coma. The most serious adverse effect of acute overdosage of paracetamol is a dose dependent, potentially fatal hepatic necrosis.
In adults, hepatotoxicity may occur after ingestion of a single dose of paracetamol 10 to 15 g (20-30 tablets); a dose of 25 g (50 tablets) or more is potentially fatal. Symptoms during the first two days of acute poisoning by paracetamol do not reflect the potential seriousness of the intoxication. Major malfestations of liver failure such as jaundice, hypoglycaemia and metabolic acidosis may take at least three days to develop. Patients may be asymptomatic for several days following the ingestion of large doses of paracetamol and laboratory evidence of hepatotoxicity may be delayed up to one week. Non-fatal damage is usually reversible.
Codeine overdose produces central stimulation with exhilaration followed by vomiting, drowsiness, respiratory depression and coma. In children, convulsions may occur.
Ingestion of large amounts of doxylamine is most commonly associated with impaired consciousness, although seizures and anticholinergic symptoms such as tachycardia and mydriasis have been reported. Rhabdomyolysis has been noted during some cases of doxylamine overdose, with an associated rise in plasma creatine kinase and myoglobinuria.
If an overdose is taken or suspected, immediately contact the Poisons Information Centre (in Australia, call 131 126; in New Zealand call 0800 764 766) for advice, or go to a hospital straight away even if you feel well because of the risk of delayed, serious liver damage with paracetamol.
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.

Paracetamol is a p-aminophenol derivative that exhibits analgesic and antipyretic activity. It does not possess anti-inflammatory activity. Paracetamol is thought to produce analgesia through a central inhibition of prostaglandin synthesis.
Codeine acts centrally. It has an analgesic effect, which is thought to be due mainly to its partial metabolic conversion to morphine. Codeine has about one-sixth the analgesic activity of morphine.
Doxylamine succinate competes with histamine at central and peripheral histamine1-receptor sites, preventing the histamine-receptor interaction and subsequent mediator release.
Doxylamine succinate is a highly lipophilic molecule that readily crosses the blood-brain barrier. Doxylamine succinate is highly selective for histamine1-receptors but has little effect on histamine2 or histamine3 receptors. Also, doxylamine succinate activates 5-hydroxytryptamine (serotonin) and α-adrenergic receptors and blocks cholinergic receptors.
Doxylamine has pronounced sedative effects.
The combination of paracetamol, codeine and doxylamine can be shown to give an enhanced analgesic effect.

Clinical trials.

Systemic reviews comparing paracetamol-codeine combinations versus paracetamol alone concluded that in single-dose studies addition of codeine to paracetamol produced a comparatively small but statistically significant increase in analgesic effect; however, there was an increased incidence of adverse effects with the combination.

5.2 Pharmacokinetic Properties

Absorption.

Paracetamol.

Paracetamol is readily absorbed from the gastrointestinal tract with peak plasma concentrations occurring about 10 to 60 minutes after oral administration.

Codeine.

Codeine and its salts are well absorbed from the gastrointestinal tract and does not interfere with the paracetamol absorption.

Doxylamine.

Doxylamine is also well absorbed from the gastrointestinal tract.

Distribution.

Paracetamol.

Paracetamol is distributed into most body tissues. Plasma protein binding is negligible at usual therapeutic doses but increases with increasing doses.

Codeine.

Peak plasma codeine concentrations occur at about one hour after ingestion of codeine phosphate hemihydrate. The plasma half-life of codeine has been reported to be between 3 to 4 hours after oral administration.

Doxylamine.

Following oral administration peak plasma levels occur after 2-3 hours.

Metabolism.

Paracetamol.

Paracetamol is metabolised extensively in the liver. The metabolites of paracetamol include a minor hydroxylated intermediate which has hepatotoxic activity. This intermediate metabolite is detoxified by conjugation with glutathione, however, it can accumulate following paracetamol overdosage (more than 150 mg/kg or 10 g total paracetamol ingested) and if left untreated can cause irreversible liver damage.
Paracetamol is metabolised differently by premature infants, newborns, infants and young children compared to adults, the sulfate conjugate being predominant.

Codeine.

Codeine is metabolised by O- and N-demethylation in the liver (via the cytochrome P450 system) to morphine (about ten percent of a codeine dose is demethylated to morphine), norcodeine and other metabolites including normorphine and hydrocodone.
About 8% of people metabolise drugs poorly via CYP2D6, and are likely to obtain reduced benefit from codeine due to reduced formation of the active metabolite, morphine.

Doxylamine.

It is metabolised by the liver and has a half-life of about 10 hours in healthy adults. The major metabolic site is the liver and major metabolic pathways are N-demethylation, N-oxidation, hydroxylation, N-acetylation, N-desalkylation and ether cleavage.

Excretion.

Paracetamol.

The elimination half-life varies from about 1 to 3 hours. Excreted in the urine mainly as inactive glucuronide and sulfate conjugates. Less than 5% is excreted unchanged.

Codeine.

Codeine and its metabolites are excreted almost entirely by the kidney, mainly as conjugates with glucuronic acid. Approximately 3% to 16% of a dose is eliminated unchanged in the urine.

Doxylamine.

It is excreted in the urine as unchanged doxylamine (60%) and metabolites (nordoxylamine and dinordoxylamine).

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

No data available.

6 Pharmaceutical Particulars

6.1 List of Excipients

The inactive ingredients are: starch maize, hyprolose, sodium lauryl sulphate, pregelatinised maize starch, silica colloidal anhydrous, talc-purified, stearic acid, povidone and 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

Blister packs of 20 and 40 tablets.

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

Paracetamol.

Appearance is white or almost white crystalline powder. Solubility is sparingly soluble in water, freely soluble in alcohol, very slightly soluble in methylene chloride.

Codeine phosphate hemihydrate.

Appearance is white, or almost white crystalline powder or small, colourless crystals. Solubility is freely soluble in water, slightly soluble or very slightly soluble in ethanol (96%).

Doxylamine succinate.

Appearance is white or creamy-white powder with a characteristic odour. Solubility is very soluble in water and freely soluble in ethanol (96%).

Chemical structure.

Paracetamol.


Chemical name: N-(4-hydroxyphenyl) acetamide.
Molecular formula: C8H9NO2.
MW: 151.2.

CAS number.

103-90-2.

Codeine phosphate hemihydrate.


Chemical name: (5R, 6S)-7, 8-didehydro-4, 5-epoxy-3-methoxy-N-methylmorphinan-6-ol dihydrogen orthophosphate hemihydrate.
Molecular formula: C18H21NO3.H3PO4.½H2O.
MW: 406.4.

CAS number.

41444-62-6.

Doxylamine succinate.


Chemical name: N,N-Dimethyl-2-[α-methyl- α-(2-piridyl) benzyloxy] ethylamine hydrogen succinate.
Molecular formula: C17H22N2O.C4H6O4.
MW 388.5.

CAS number.

562-10-7.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription only medicine.

Summary Table of Changes