What is paracetamol

Paracetamol also known as acetaminophen, is a pain reliever and a fever reducer medicine. Paracetamol (acetaminophen) is a commonly used medicine to relieve mild or moderate pain, such as muscle aches, arthritis, backaches, menstrual periods, toothaches, colds, sore throats or sprains, reactions to vaccinations (shots) and reduce a high temperature (fever) caused by illnesses such as colds and flu.

Paracetamol may also be used to relieve the pain of osteoarthritis (arthritis caused by the breakdown of the lining of the joints). Paracetamol is in a class of medications called analgesics (pain relievers) and antipyretics (fever reducers). Paracetamol works by changing the way the body senses pain and by cooling the body.

Paracetamol is often recommended as one of the first treatments for pain, as it’s safe for most people to take and side effects are rare. Paracetamol is a common active ingredient to treat pain and reduce fever; it is included in many prescription and over-the-counter (OTC) products.

Paracetamol has weak anti-inflammatory properties and is used as a common analgesic, but may cause liver, blood cell, and kidney damage.

Paracetamol is a widely used nonprescription analgesic and antipyretic medication for mild-to-moderate pain and fever. Harmless at low doses, paracetamol has direct hepatotoxic potential when taken as an overdose and can cause acute liver injury and death from acute liver failure. Even in therapeutic doses, paracetamol can cause transient serum aminotransferase elevations (liver enzymes).

Paracetamol can cause unusual results with certain lab tests for glucose (sugar) in the urine. Tell any doctor who treats you that you are using paracetamol.

You can take paracetamol for:

• mild to moderate pain, for example backache, headache, migraine, muscle strains, period pain, toothache and aches and pains due to colds and flu
• fever (high temperature)
• osteoarthritis and other painful, non-inflammatory conditions.

An overdose of paracetamol can damage your liver or cause death.

• Adults and teenagers who weigh at least 110 pounds should not take more than 1000 milligrams (mg) at one time, or more than 4000 mg in 24 hours.
• Children younger than 12 years old should not take more than 5 doses in 24 hours, using only the number of milligrams per dose that is recommended for the child’s weight and age. Use exactly as directed on the label.

Avoid also using other medicines that contain paracetamol (sometimes abbreviated as APAP), or you could have a fatal overdose.

• You should not use paracetamol if you have severe liver disease.

Is it okay to drink alcohol when I’m taking paracetamol?

Drinking a small amount of alcohol is unlikely to be harmful if you are taking paracetamol.

Paracetamol and pregnancy

Paracetamol is considered the first choice of painkiller if you are pregnant since it has been taken by large numbers of pregnant women without any adverse effect on the mother or baby.

However, if you take paracetamol when pregnant, make sure you take it for the shortest possible time.

Can I take paracetamol if I’m breastfeeding?

Paracetamol is the first choice of painkiller if you are breastfeeding.

It appears in breast milk in very small amounts which are unlikely to harm your baby.

If you take paracetamol when breastfeeding, make sure you take it for the shortest possible time.

How does paracetamol work?

Paracetamol is a p-aminophenol derivative, an odorless compound with a slightly bitter taste with analgesic and antipyretic activities that seems to work by blocking chemical messengers in the brain that tell you that you have pain. Although the exact mechanism through which acetaminophen exert its effects has yet to be fully determined, acetaminophen may inhibit the nitric oxide (NO) pathway mediated by a variety of neurotransmitter receptors including N-methyl-D-aspartate (NMDA) and substance P, resulting in elevation of the pain threshold. The antipyretic activity may result from inhibition of prostaglandin synthesis and release in the central nervous system (CNS) and prostaglandin-mediated effects on the heat-regulating body temperature center in the anterior hypothalamus.

Paracetamol is a widely used analgesic drug. It interacts with various enzyme families including cytochrome P450 (CYP), cyclooxygenase (COX), and nitric oxide synthase (NOS), and this interplay may produce reactive oxygen species (ROS) ¹. The effects of paracetamol (acetaminophen) on prostacyclin, thromboxane, nitric oxide (NO), and oxidative stress in four male subjects who received a single 3 g oral dose of paracetamol was investigated. Thromboxane and prostacyclin synthesis was assessed by measuring their major urinary metabolites 2,3-dinor-thromboxane B2 and 2,3-dinor-6-ketoprostaglandin F1 a, respectively. Endothelial NO synthesis was assessed by measuring nitrite in plasma. Urinary 15(S)-8-iso-prostaglanding F2 a was measured to assess oxidative stress. Plasma oleic acid oxide (cis-EpOA) was measured as a marker of cytochrome P450 activity. Upon paracetamol administration, prostacyclin synthesis was strongly inhibited, while NO synthesis increased and thromboxane synthesis remained almost unchanged. Paracetamol may shift the COX-dependent vasodilatation/vasoconstriction balance at the cost of vasodilatation. This effect may be antagonized by increasing endothelial NO synthesis. High-dosed paracetamol did not increase oxidative stress. At pharmacologically relevant concentrations, paracetamol did not affect NO synthesis/bioavailability by recombinant human endothelial NOS or inducible NOS in rat hepatocytes. It was concluded that paracetamol (acetaminophen) does not increase oxidative stress in humans ¹.

Is paracetamol ibuprofen?

No. Ibuprofen belongs to one of a group of painkillers called non-steroidal anti-inflammatory drugs (NSAIDs). Ibuprofen is better for reducing inflammation (redness and swelling), including teething and toothache.

Whereas paracetamol is usually best for most types of pain, including headache and stomach ache.

Paracetamol and ibuprofen are similar strengths, but they work in different ways. So paracetamol is better for some types of pain than ibuprofen.

Do not give ibuprofen and paracetamol together, though. Instead, if you’ve given paracetamol to your child and they’re still feverish or in pain when the next dose is due, you could try ibuprofen instead.

Don’t take more than the maximum daily dose of either medicine. See your doctor if you’ve tried both ibuprofen and paracetamol and they haven’t helped.

Who can take paracetamol

Most people can take paracetamol safely, including:

• pregnant women
• breastfeeding women
• children over 2 months of age – lower doses are recommended for young children

If you’re not sure whether you can take paracetamol, check the leaflet that comes with it or ask your pharmacist or doctor for advice.

Always get advice before taking paracetamol if you:

• have liver or kidney problems
• have problems with alcohol, such as long-term alcohol misuse
• are very underweight
• are taking other medications

Don’t take paracetamol if you’ve had an allergic reaction to acetaminophen (paracetamol) in the past.

Before taking paracetamol

• tell your doctor and pharmacist if you are allergic to paracetamol, any other medications, or any of the ingredients in the product. Ask your pharmacist or check the label on the package for a list of ingredients.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, or herbal products you are taking or plan to take. Be sure to mention anticoagulants (‘blood thinners’) such as warfarin (Coumadin); isoniazid (INH); certain medications for seizures including carbamazepine (Tegretol), phenobarbital, and phenytoin (Dilantin); medications for pain, fever, coughs, and colds; and phenothiazines (medications for mental illness and nausea). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you have ever developed a rash after taking paracetamol.
• tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking paracetamol, call your doctor.
  if you drink three or more alcoholic beverages every day, do not take paracetamol. Ask your doctor or pharmacist about the safe use of alcoholic beverages while taking paracetamol.
• you should know that combination paracetamol products for cough and colds that contain nasal decongestants, antihistamines, cough suppressants, and expectorants should not be used in children younger than 2 years of age. Use of these medications in young children can cause serious and life-threatening effects or death. In children 2 through 11 years of age, combination cough and cold products should be used carefully and only according to the directions on the label.
• if you have phenylketonuria (PKU, an inherited condition in which a special diet must be followed to prevent mental retardation), you should know that some brands of acetaminophen chewable tablets may be sweetened with aspartame. a source of phenylalanine.

Figure 1. Paracetamol structure

Paracetamol vs acetaminophen

Paracetamol is acetaminophen.

Who can and can’t take paracetamol

Children can take paracetamol as:

• a liquid syrup – from the age of 3 months (2 months if they have a fever after a vaccination)
• suppository – from the age of 3 months (2 months if they have a fever after a vaccination)
• tablets – from the age of 6 years (500mg so they may need to be broken)
• soluble tablets – from the age of 12 years

Check with your doctor or pharmacist if your child:

• is small for their age as a lower dose may be better
• has had liver or kidney problems
• takes medicine for epilepsy
• takes medicine for tuberculosis (TB)

Giving paracetamol with other painkillers

The only safe painkiller to give children alongside paracetamol is ibuprofen.

• Do not give paracetamol and ibuprofen together, though. Instead, if you’ve given them paracetamol and they’re still feverish or in pain when the next dose is due, you could try ibuprofen instead.
• Don’t take more than the maximum daily dose of either medicine. See your doctor if you’ve tried both paracetamol and ibuprofen and they haven’t helped. Do not give ibuprofen to your child if they have asthma, unless your doctor has said it’s okay.
• Don’t give your child another medicine with paracetamol in it. If they take 2 different medicines that contain paracetamol, there’s a risk of overdose. Paracetamol is an ingredient in lots of medicines that you can buy from the supermarket or pharmacy.
• Never give aspirin to a child under the age of 16 (unless prescribed by a doctor).

Never give aspirin to a child under the age of 16 (unless prescribed by a doctor).

Paracetamol for Children Uses

Temporarily:

• reduces fever
• relieves minor aches and pains due to:
• the common cold
• flu
• headache
• sore throat
• toothache

Paracetamol for Children Warnings

Liver warning

This product contains acetaminophen. Severe liver damage may occur if your child takes:

• more than 5 doses in 24 hours, which is the maximum daily amount
• with other drugs containing paracetamol

Allergy alert

Paracetamol may cause severe skin reactions. Symptoms may include:

• skin reddening
• blisters
• rash

If a skin reaction occurs, stop use and seek medical help right away.

Sore throat warning

• If sore throat is severe, persists for more than 2 days, is accompanied or followed by fever, headache, rash, nausea, or vomiting, consult a doctor promptly.

Do NOT use

• with any other drug containing paracetamol (prescription or nonprescription). If you are not sure whether a drug contains paracetamol, ask a doctor or pharmacist.
• if your child is allergic to paracetamol or any of the inactive ingredients in this product

Ask a doctor before use if your child has liver disease

Ask a doctor or pharmacist before use if your child is taking the blood thinning drug warfarin. Long-term use of paracetamol may increase the effect of warfarin, which can increase the risk of bleeding. However, this is unlikely to happen with the occasional use of paracetamol.

When using paracetamol, do not exceed recommended dose.

Stop use and ask a doctor if:

• pain gets worse or lasts more than 5 days
• fever gets worse or lasts more than 3 days
• new symptoms occur
• redness or swelling is present

These could be signs of a serious condition.

Keep out of reach of children.

Overdose warning: In case of overdose, get medical help or contact a Poison Control Center right away.

Is there any food or drink they need to avoid?

Your child can eat and drink normally while taking paracetamol.

You can give your child paracetamol on an empty stomach.

What if my child vomits?

• If your child vomits less than 30 minutes after having a dose of paracetamol tablets or syrup, give them the same dose again.
• If your child vomits more than 30 minutes after a dose of tablets or syrup, you do NOT need to give them another dose. Wait until the next normal dose.

If your child is finding it hard to keep tablets or syrup down, ask your doctor if acetaminophen (paracetamol) suppositories are an option. If they vomit straight after a suppository, you don’t need to give them another dose as the suppository will still work.

What if they take too much?

Giving your child too much paracetamol by accident can be dangerous. The effects of an overdose may not be obvious, but they can be serious and need treatment.

If you think you may have given your child an extra dose of paracetamol by mistake, wait at least 24 hours before giving them any more.

If you think you may have given your child more than the recommended total daily dose of paracetamol, seek advice immediately, even if your child feels well. Go to your nearest hospital emergency department and seek urgent medical attention.

If you need to take your child to hospital, take the paracetamol packet or leaflet inside it plus any remaining medicine with them.

Paracetamol for adults

Paracetamol is a common painkiller used to treat aches and pain. It can also be used to reduce fever 100.4 °F (38 °C) or above.

It’s also available combined with other painkillers and anti-sickness medicines. It’s an ingredient in a wide range of cold and flu remedies.

Key facts

• Paracetamol takes up to an hour to work.
• The usual dose of paracetamol is one or two 500mg tablets at a time.
• Don’t take paracetamol with other medicines containing paracetamol.
• Paracetamol is safe to take in pregnancy and while breastfeeding, at recommended doses.
• Paracetamol is widely available as tablets and capsules. For people who find it difficult to swallow tablets or capsules, paracetamol is also available as soluble tablets that dissolve in water to make a drink and as a syrup.

Who can and can’t take paracetamol

Most people can take paracetamol safely, including pregnant and breastfeeding women.

However, some people need to take extra care with paracetamol.

Check with your doctor or pharmacist if you:

• have had an allergic reaction to acetaminophen (paracetamol) or any other medicines in the past
• have liver or kidney problems
• regularly drink more than the maximum recommended amount of alcohol (14 units a week)
• take medicine for epilepsy
• take medicine for tuberculosis (TB)
• take the blood-thinner warfarin and you may need to take paracetamol on a regular basis.

Paracetamol for Adults Uses

• Temporarily relieves minor aches and pains due to:
  • the common cold
  • headache
  • backache
  • minor pain of arthritis
  • toothache
  • muscular aches
  • premenstrual and menstrual cramps
• Temporarily reduces fever

Paracetamol for Adults Warnings

Liver warning

This product contains paracetamol. Severe liver damage may occur if you take

• more than 4,000 mg of paracetamol in 24 hours
• with other drugs containing paracetamol
• 3 or more alcoholic drinks every day while using this product

Allergy alert

Paracetamol may cause severe skin reactions. Symptoms may include:

• skin reddening
• blisters
• rash

If a skin reaction occurs, stop use and seek medical help right away.

Do NOT use

• with any other drug containing paracetamol (prescription or nonprescription). If you are not sure whether a drug contains paracetamol, ask a doctor or pharmacist.
• if you are allergic to paracetamol or any of the inactive ingredients in this product

Ask a doctor before use if you have liver disease

Ask a doctor or pharmacist before use if you are taking the blood thinning drug warfarin. Long-term use of paracetamol may increase the effect of warfarin, which can increase the risk of bleeding. However, this is unlikely to happen with the occasional use of paracetamol.

Stop use and ask a doctor if:

• pain gets worse or lasts more than 10 days
• fever gets worse or lasts more than 3 days
• new symptoms occur
• redness or swelling is present

These could be signs of a serious condition.

If pregnant or breast-feeding, ask a health professional before use.

Keep out of reach of children.

Overdose warning: In case of overdose, get medical help or contact a Poison Control Center right away.

How many paracetamol can I take?

The usual dose for adults is one or two 500mg paracetamol tablets up to 4 times in 24 hours.

Always leave at least 4 hours between doses.

Overdosing on paracetamol can cause serious side effects. Don’t be tempted to increase the dose or take a double dose if your pain is very bad.

• The total maximum dose of paracetamol for an adult is eight 500mg tablets in 24 hours. Wait at least 4 hours between doses.

Adult dose (over-16s only)

• Total maximum dose of paracetamol for an adult is eight 500mg tablets in 24 hours
  • take one to two 500mg caplets while symptoms last, wait 4-6 hours
  • take one to two 500mg caplets while symptoms last, wait 4-6 hours
  • take one to two 500mg caplets while symptoms last, wait 4-6 hours
  • take one to two 500mg caplets while symptoms last, wait 4-6 hours
• do NOT take more than 6 caplets in 24 hours, unless directed by a doctor
• do NOT take for more than 10 days unless directed by a doctor

Paracetamol max dose (over-16s only)

• 8 x 500 mg = 4,000 mg in 24 hours

What if I take too much?

Taking one or 2 extra tablets by accident is unlikely to be harmful. Wait at least 24 hours before you take any more paracetamol.

Taking more than 2 extra paracetamol tablets can be dangerous and may need treatment.

If you have taken more than the recommended total daily dose of paracetamol, seek advice immediately, even if you feel well. Go to your nearest hospital emergency department and seek urgent medical attention.

If you need to go to hospital, take the paracetamol packet or leaflet inside it plus any remaining medicine with you.

What if I forget to take it?

If you take paracetamol regularly and miss a dose, take it as soon as you remember. If it’s close to the time for your next dose when you remember, then skip the missed dose.

Never take double doses of paracetamol. Never take extra doses to catch up.

If you forget doses often, it may help to set an alarm to remind you. You could also ask your pharmacist for advice on other ways to help you remember to take your medicine.

Taking paracetamol with other painkillers

It’s safe to take paracetamol with other types of painkiller that don’t contain paracetamol, such as ibuprofen, aspirin and codeine.

Don’t take paracetamol alongside other medicines that contain paracetamol. If you take 2 different medicines that contain paracetamol, there’s a risk of overdose.

Pharmacy remedies that contain paracetamol include some:

• migraine remedies
• cough and cold products

Paracetamol may also be combined with other painkillers in medicines that have been prescribed by your doctor, such as:

• co-codamol (paracetamol and codeine)
• co-dydramol (paracetamol and dihydrocodeine)
• tramacet (paracetamol and tramadol)

Paracetamol uses

Paracetamol is used to relieve mild to moderate pain from headaches, muscle aches, menstrual periods, colds and sore throats, toothaches, backaches, and reactions to vaccinations (shots), and to reduce fever. paracetamol may also be used to relieve the pain of osteoarthritis (arthritis caused by the breakdown of the lining of the joints). paracetamol is in a class of medications called analgesics (pain relievers) and antipyretics (fever reducers). Paracetamol works by changing the way the body senses pain and by cooling the body.

Paracetamol dosage

Applies to the following strengths paracetamol: 160 mg; 80 mg/0.8 mL; 160 mg/5 mL; 500 mg; 650 mg; 80 mg; 325 mg; 500 mg/15 mL; 120 mg; 120 mg/5 mL; 80 mg/5 mL; 10 mg/mL; 650 mg/25 mL; 80 mg/mL; 500 mg/5 mL; 48 mg/mL.

Measure liquid paracetamol with the dosing syringe provided, or with a special dose-measuring spoon or medicine cup. If you do not have a dose-measuring device, ask your pharmacist for one.

Paracetamol made for infants is available in two different dose concentrations, and each concentration comes with its own medicine dropper or oral syringe. These dosing devices are not equal between the different concentrations. Using the wrong device may cause you to give your child an overdose of paracetamol. Never mix and match dosing devices between infant formulations of paracetamol.

You may need to shake the liquid before each use. Follow the directions on the medicine label.

The chewable tablet must be chewed thoroughly before you swallow it.

Make sure your hands are dry when handling the paracetamol disintegrating tablet. Place the tablet on your tongue. It will begin to dissolve right away. Do not swallow the tablet whole. Allow it to dissolve in your mouth without chewing.

To use the paracetamol effervescent granules, dissolve one packet of the granules in at least 4 ounces of water. Stir this mixture and drink all of it right away. To make sure you get the entire dose, add a little more water to the same glass, swirl gently and drink right away.

Usual Adult Dose for Fever

Doses may be given as a single or repeated dose as follows:

Oral:

Immediate-release: 325 mg to 1 g orally every 4 to 6 hours
Minimum Dosing Interval: every 4 hours
Maximum Single Dose: 1000 mg
Maximum Dose: 4 g per 24 hours

Extended-Release: 1300 mg orally every 8 hours
Maximum dose: 3900 mg per 24 hours

Rectal:

650 mg rectally every 4 to 6 hours
Maximum dose: 3900 mg per 24 hours

Parenteral:

Weight 50 kg or greater: 1000 mg IV every 6 hours OR 650 mg IV every 4 hours

Maximum Single Dose: 1000 mg
Minimum Dosing Interval: every 4 hours
Maximum Dose: 4000 mg per 24 hours

Weight less than 50 kg: 15 mg/kg IV every 6 hours OR 12.5 mg/kg IV every 4 hours

Maximum Single Dose: 15 mg/kg
Minimum Dosing Interval: every 4 hours
Maximum Dose: 75 mg/kg per 24 hours

Comments:

• Maximum daily dose is based on all routes of administration and all products containing paracetamol.
• Maximum daily dose and dosing recommendations may differ by product; some manufacturers have decreased the maximum daily dose to protect consumers from inadvertent overdoses.
• For IV administration, verify the dose in mg and mL to ensure the dose is correct; verify that infusion pumps are properly programmed

Uses:

• For the management of mild to moderate pain and the management of moderate to severe pain with adjunctive opioid analgesics.
• For the reduction of fever.

Usual Adult Dose for Pain

Doses may be given as a single or repeated dose as follows:

Oral:

Immediate-release: 325 mg to 1 g orally every 4 to 6 hours
Minimum Dosing Interval: every 4 hours
Maximum Single Dose: 1000 mg
Maximum Dose: 4 g per 24 hours

Extended-Release: 1300 mg orally every 8 hours
Maximum dose: 3900 mg per 24 hours

Rectal:

650 mg rectally every 4 to 6 hours
Maximum dose: 3900 mg per 24 hours

Parenteral:

Weight 50 kg or greater: 1000 mg IV every 6 hours OR 650 mg IV every 4 hours

Maximum Single Dose: 1000 mg
Minimum Dosing Interval: every 4 hours
Maximum Dose: 4000 mg per 24 hours

Weight less than 50 kg: 15 mg/kg IV every 6 hours OR 12.5 mg/kg IV every 4 hours

Maximum Single Dose: 15 mg/kg
Minimum Dosing Interval: every 4 hours
Maximum Dose: 75 mg/kg per 24 hours

Comments:

• Maximum daily dose is based on all routes of administration and all products containing paracetamol.
• Maximum daily dose and dosing recommendations may differ by product; some manufacturers have decreased the maximum daily dose to protect consumers from inadvertent overdoses.
• For IV administration, verify the dose in mg and mL to ensure the dose is correct; verify that infusion pumps are properly programmed

Uses:

• For the management of mild to moderate pain and the management of moderate to severe pain with adjunctive opioid analgesics.
• For the reduction of fever.

Usual Pediatric Dose for Pain

Doses may be given as a single or repeated dose as follows:

ORAL:

10 to 15 mg/kg orally every 4 to 6 hours as needed not to exceed 5 doses in 24 hours
-Alternatively, use weight first, then age:
2.7 to 5.3 kg (0 to 3 months): 40 mg orally every 4 hours as needed not to exceed 5 doses in 24 hours
5.4 to 8.1 kg (4 to 11 months): 80 mg orally every 4 hours as needed not to exceed 5 doses in 24 hours
8.2 to 10.8 kg (12 to 23 months): 120 mg orally every 4 hours as needed not to exceed 5 doses in 24 hours
10.9 to 16.3 kg (2 to 3 years): 160 mg orally every 4 hours as needed not to exceed 5 doses in 24 hours
16.4 to 21.7 kg (4 to 5 years): 240 mg orally every 4 hours as needed not to exceed 5 doses in 24 hours
21.8 to 27.2 kg (6 to 8 years): 320 mg orally every 4 hours as needed not to exceed 5 doses in 24 hours
27.3 to 32.6 kg (9 to 10 years): 400 mg orally every 4 hours as needed not to exceed 5 doses in 24 hours
32.7 to 43.2 kg (11 to 12 years): 480 mg orally every 4 hours as needed not to exceed 5 doses in 24 hours

12 years or older:

Immediate-release: 325 mg to 1 g orally every 4 to 6 hours
Minimum Dosing Interval: every 4 hours
Maximum Single Dose: 1000 mg
Maximum Dose: 4 g per 24 hours

Extended-Release: 1300 mg orally every 8 hours
Maximum dose: 3900 mg per 24 hours

RECTAL:

6 to 11 months: 80 mg rectally every 6 hours up to a maximum of 4 doses in 24 hours
12 to 36 months: 80 mg rectally every 4 to 6 hours up to a maximum of 5 doses in 24 hours
3 to 6 years: 120 mg rectally every 4 to 6 hours up to a maximum of 5 doses in 24 hours
6 to 12 years: 325 mg rectally every 4 to 6 hours up to a maximum of 5 doses in 24 hours
12 years or older: 650 mg rectally every 4 to 6 hours up to a maximum of 6 doses in 24 hours

PARENTERAL:

2 to 12 years: 12.5 mg/kg IV every 4 hours OR 15 mg/kg IV every 6 hours
Maximum Single Dose: 15 mg/kg; not to exceed 750 mg
Minimum Dosing Interval: every 4 hours
Maximum Daily Dose: 75 mg/kg in 24 hours; not to exceed 3750 mg

13 years or older; weight less than 50 kg: 12.5 mg/kg IV every 4 hours OR 15 mg/kg IV every 6 hours
Maximum Single Dose: 15 mg/kg; not to exceed 750 mg
Minimum Dosing Interval: every 4 hours
Maximum Daily Dose: 75 mg/kg in 24 hours; not to exceed 3750 mg

13 years or older; weight 50 kg or greater: 650 mg IV every 4 hours OR 1000 mg IV every 6 hours
Maximum Single Dose: 1000 mg
Minimum Dosing Interval: every 4 hours
Maximum Daily Dose: 4000 mg in 24 hours

Comments:

• Maximum daily dose is based on all routes of administration and all products containing paracetamol.
• Maximum daily dose and dosing recommendations may differ by product; some manufacturers have decreased the maximum daily dose to protect consumers from inadvertent overdoses.
• For IV administration, verify the dose in mg and mL to ensure the dose is correct; verify that infusion pumps are properly programmed.

Uses:

For the management of mild to moderate pain and for the management of moderate to severe pain when used with adjunctive opioid analgesics.

Usual Pediatric Dose for Fever

Doses may be given as a single or repeated dose as follows:

ORAL:

10 to 15 mg/kg orally every 4 to 6 hours as needed not to exceed 5 doses in 24 hours
-Alternatively, use weight first, then age:
2.7 to 5.3 kg (0 to 3 months): 40 mg orally every 4 hours as needed not to exceed 5 doses in 24 hours
5.4 to 8.1 kg (4 to 11 months): 80 mg orally every 4 hours as needed not to exceed 5 doses in 24 hours
8.2 to 10.8 kg (12 to 23 months): 120 mg orally every 4 hours as needed not to exceed 5 doses in 24 hours
10.9 to 16.3 kg (2 to 3 years): 160 mg orally every 4 hours as needed not to exceed 5 doses in 24 hours
16.4 to 21.7 kg (4 to 5 years): 240 mg orally every 4 hours as needed not to exceed 5 doses in 24 hours
21.8 to 27.2 kg (6 to 8 years): 320 mg orally every 4 hours as needed not to exceed 5 doses in 24 hours
27.3 to 32.6 kg (9 to 10 years): 400 mg orally every 4 hours as needed not to exceed 5 doses in 24 hours
32.7 to 43.2 kg (11 to 12 years): 480 mg orally every 4 hours as needed not to exceed 5 doses in 24 hours

12 years or older:

Immediate-release: 325 mg to 1 g orally every 4 to 6 hours
Minimum Dosing Interval: every 4 hours
Maximum Single Dose: 1000 mg
Maximum Dose: 4 g per 24 hours

RECTAL:

6 to 11 months: 80 mg rectally every 6 hours up to a maximum of 4 doses in 24 hours
12 to 36 months: 80 mg rectally every 4 to 6 hours up to a maximum of 5 doses in 24 hours
3 to 6 years: 120 mg rectally every 4 to 6 hours up to a maximum of 5 doses in 24 hours
6 to 12 years: 325 mg rectally every 4 to 6 hours up to a maximum of 5 doses in 24 hours
12 years or older: 650 mg rectally every 4 to 6 hours up to a maximum of 6 doses in 24 hours

PARENTERAL:

Neonates (premature neonates born at least 32 weeks gestational age up to 28 days chronological age): 12.5 mg/kg IV every 6 hours
Minimum Dosing Interval: 6 hours
Maximum Daily Dose: 50 mg/kg/day

Infants (29 days to 2 years old): 15 mg/kg every 6 hours
Minimum Dosing Interval: 6 hours
Maximum Daily Dose: 60 mg/kg/day

2 to 12 years: 12.5 mg/kg IV every 4 hours OR 15 mg/kg IV every 6 hours
Maximum Single Dose: 15 mg/kg; not to exceed 750 mg
Minimum Dosing Interval: every 4 hours
Maximum Daily Dose: 75 mg/kg in 24 hours; not to exceed 3750 mg

13 years or older; weight less than 50 kg: 12.5 mg/kg IV every 4 hours OR 15 mg/kg IV every 6 hours
Maximum Single Dose: 15 mg/kg; not to exceed 750 mg
Minimum Dosing Interval: every 4 hours
Maximum Daily Dose: 75 mg/kg in 24 hours; not to exceed 3750 mg

13 years or older; weight 50 kg or greater: 650 mg IV every 4 hours OR 1000 mg IV every 6 hours
Maximum Single Dose: 1000 mg
Minimum Dosing Interval: every 4 hours
Maximum Daily Dose: 4000 mg in 24 hours

Comments:

-Maximum daily dose is based on all routes of administration and all products containing paracetamol.
-Maximum daily dose and dosing recommendations may differ by product; some manufacturers have decreased the maximum daily dose to protect consumers from inadvertent overdoses.
-For IV administration, verify the dose in mg and mL to ensure the dose is correct; verify that infusion pumps are properly programmed.

Use: For the reduction of fever.

Renal Dose Adjustments

Severe renal impairment (Creatinine Clearance less than 30 mL/min): Longer dosing intervals and a reduced total daily dose may be warranted

Liver Dose Adjustments

Parenteral:

Severe hepatic impairment, severe active hepatic disease: Use is contraindicated
Mild to moderate hepatic impairment, mild to moderate active hepatic disease: Use with caution; a reduced total daily dose may be warranted

Over the counter products must contain labeling that states:

This product contains paracetamol. Severe liver damage may occur if:

• Adult takes more than maximum daily dose in 24 hours
• Child takes more than 5 doses in 24 hours
• More than 3 alcoholic drinks are consumed per day while using this product.

Dose Adjustments

Use caution in patients with alcoholism, chronic malnutrition, severe hypovolemia (e.g. due to dehydration or blood loss); A reduced daily dose may be warranted.

Suspected Overdose:

• If an overdose is suspected, obtain a serum drug level as soon as possible, but no sooner than 4 hours after oral ingestion.
• Liver function studies should be obtained and repeated at 24-hour intervals.
• The antidote, N-acetylcysteine (NAC) should be administered as soon as possible according to NAC protocols.

How should paracetamol be used?

Paracetamol comes as a tablet, chewable tablet, capsule, suspension or solution (liquid), extended-release (long-acting) tablet, and orally disintegrating tablet (tablet that dissolves quickly in the mouth), to take by mouth, with or without food. Paracetamol also comes as a suppository to use rectally. Paracetamol is available without a prescription, but your doctor may prescribe paracetamol to treat certain conditions. Follow the directions on the package or prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand.

If you are giving paracetamol to your child, read the package label carefully to make sure that it is the right product for the age of the child. Do not give children paracetamol products that are made for adults. Some products for adults and older children may contain too much paracetamol for a younger child. Check the package label to find out how much medication the child needs. If you know how much your child weighs, give the dose that matches that weight on the chart. If you don’t know your child’s weight, give the dose that matches your child’s age. Ask your child’s doctor if you don’t know how much medication to give your child.

Paracetamol comes in combination with other medications to treat cough and cold symptoms. Ask your doctor or pharmacist for advice on which product is best for your symptoms. Check nonprescription cough and cold product labels carefully before using two or more products at the same time. These products may contain the same active ingredient(s) and taking them together could cause you to receive an overdose. This is especially important if you will be giving cough and cold medications to a child.

Swallow the extended-release paracetamol tablets whole; do not split, chew, crush, or dissolve them.

Place the orally disintegrating tablet (‘Meltaways’) in your mouth and allow to dissolve or chew it before swallowing.

Shake the suspension well before each use to mix the medication evenly. Always use the measuring cup or syringe provided by the manufacturer to measure each dose of the solution or suspension. Do not switch dosing devices between different products; always use the device that comes in the product packaging.

Taking paracetamol with other medicines, food and alcohol

Paracetamol can react unpredictably with certain other medications. This can affect how well either medicine works and might increase the risk of side effects.

It may not be safe to take paracetamol at the same time as:

• other products containing paracetamol – including combination products where paracetamol is one of the ingredients
• carbamazepine – used to treat epilepsy and some types of pain
• colestyramine – used to reduce itchiness caused by primary biliary cirrhosis (a type of liver disease)
• imatinib and busulfan – used to treat certain types of cancer
• ketoconazole – a type of antifungal medicine
• lixisenatide – used to treat type 2 diabetes
• metoclopramide – used to relieve nausea and vomiting
• phenobarbital, phenytoin and primidone – used to control seizures
• warfarin – used to prevent blood clots

Check the leaflet that comes with your medicine to see if it can be taken with paracetamol. Ask a pharmacist or doctor if you’re not sure.

There are no known problems caused by taking paracetamol with any specific foods or by drinking moderate amounts of alcohol while taking paracetamol.

Paracetamol side effects

Paracetamol may cause side effects, but side effects from paracetamol are rare, but can include:

• an allergic reaction, which can cause a rash and swelling
• flushing, low blood pressure and a fast heartbeat – this can sometimes happen when paracetamol is given in hospital into a vein in your arm
• blood disorders, such as thrombocytopenia (low number of platelet cells) and leukopenia (low number of white blood cells)
• liver and kidney damage if you take too much (overdose) – this can be fatal in severe cases

Speak to a pharmacist or doctor if you develop any troublesome side effects that you think could be caused by paracetamol.

Some side effects of paracetamol can be serious. If you experience any of the following symptoms, stop taking paracetamol and call your doctor immediately or get emergency medical attention:

• getting a skin rash that may include itchy, red, swollen, blistered or peeling skin
• rash
• hives
• itching
• swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs
• hoarseness
• difficulty breathing or swallowing

Paracetamol may cause other side effects. Call your doctor if you have any unusual problems while you are taking this medication.

Human Exposure and Toxicity

Nausea, vomiting, and abdominal pain usually occur within 2-3 hours after ingestion of toxic doses of the drug paracetamol. In severe poisoning, central nervous system (CNS) stimulation, excitement, and delirium may occur initially. This may be followed by CNS depression, stupor, hypothermia, marked prostration, rapid shallow breathing, rapid weak irregular pulse, low blood pressure, and circulatory failure. When an individual has ingested a toxic dose of paracetamol, the individual should be hospitalized for several days of observation, even if there are no apparent ill effects, because maximum liver damage and/or cardiotoxic effects usually do not become apparent until 2-4 days after ingestion of the drug. Other symptoms of acute poisoning include cerebral edema and nonspecific myocardial depression. Vascular collapse results from the relative hypoxia and from a central depressant action that occurs only with massive doses. Shock may develop if vasodilation is marked. Fatal seizures may occur. Coma usually precedes death, which may occur suddenly or may be delayed for several days. Biopsy of the liver reveals centralobular necrosis with sparing of the periportal area. There have been reports of acute myocardial necrosis and pericarditis in individuals with paracetamol poisoning. Hypoglycemia, which can progress to coma have been reported in patients ingesting toxic doses of paracetamol. Low prothrombin levels and thrombocytopenia have been reported in patients with paracetamol poisoning. Skin reactions of an erythematous or urticarial nature which may be accompanied by fever and oral mucosal lesions also have been reported. For use anytime during pregnancy, 781 exposures were recorded, and possible associations with congenital dislocation of the hip (eight cases) and clubfoot (six cases) were found. There is inadequate evidence in humans for the carcinogenicity of paracetamol.

Evidence for Carcinogenicity

There is inadequate evidence in humans for the carcinogenicity of paracetamol. There is inadequate evidence in experimental animals for the carcinogenicity of paracetamol ². Overall evaluation: Paracetamol is not classifiable as to its carcinogenicity to humans (Group 3) ².

Animal Toxicity Studies

Concern has been raised over chemical-induced disruption of ovary development during fetal life resulting in long-lasting consequences only manifesting themselves much later during adulthood. A growing body of evidence suggests that prenatal exposure to the mild analgesic acetaminophen/paracetamol can cause such a scenario ³. In a review of three recent reports that collectively indicate that prenatal exposure in a period of 13.5 days post coitum in both rats and mouse can result in reduced female reproductive health. The combined data show that the exposure results in the reduction of primordial follicles, irregular menstrual cycle, premature absence of corpus luteum, as well as reduced fertility, resembling premature ovarian insufficiency syndrome in humans that is linked to premature menopause ³. This could especially affect the Western parts of the world, where the age for childbirth is continuously being increased and paracetamol is recommended during pregnancy for pain and fever ³. The study authors highlight an urgent need for more studies to verify these data including both experimental and epidemiological approaches ³.

There is inadequate evidence in experimental animals for the carcinogenicity of paracetamol. In rats fasted 24 hours and given a single dose of paracetamol (2 g/kg) by gavage, liver necrosis around the central vein was noted at 9-12 hours and was much more extensive at 24 hours after treatment. In mice after dietary exposure to paracetamol up to 6400 mg/kg daily for 13 weeks hepatotoxicity, organ weight changes and deaths were observed. Cats are particularly susceptible to paracetamol intoxication, developing more diffuse liver changes, while hepatic centrilobular lesions found in dogs. High doses of paracetamol caused testicular atrophy and delay in spermiogenesis in mice. Furthermore, reductions in the fertility and neonatal survival in mice were seen in the F0 generation and decreases in F1 pup weights were found at paracetamol dose 1430 mg/kg. Paracetamol was not mutagenic in Salmonella typhimurium assay with or without metabolic activation in six strains: TA1535, TA1537, TA1538, TA100, TA97 and TA98. In vitro and animal data indicate that small quantities of paracetamol are metabolized by a cytochrome P-450 microsomal enzyme to a reactive intermediate metabolite (N-acetyl-p-benzoquinoneimine, N-acetylimidoquinone, NAPQI) which is further metabolized via conjugation with glutathione and ultimately excreted in urine as a mercapturic acid. It has been suggested that this intermediate metabolite is responsible forparacetamol-induced liver necrosis in cases of overdose. Excipients found in liquid formulations of paracetamol may decrease its liver toxicity.

Ecotoxicity Studies

Daphnia magna was the most susceptible among the test organisms to the environmental effects of paracetamol. Paracetamol has recently been identified as a promising snake toxicant to reduce brown tree snake populations on Guam, while posing only the minimal risks to non-target rodents, cats, pigs and birds.

Paracetamol poisoning

Paracetamol toxicity may result from a single toxic dose, from repeated ingestion of large doses of paracetamol (e.g., 7.5-10 g daily for 1-2 days), or from chronic ingestion of the drug ⁴. Dose-dependent, hepatic necrosis is the most serious acute toxic effect associated with overdosage and is potentially fatal ⁴.

A case report of oral paracetamol toxicity in a term newborn infant successfully treated with a 20 hr intravenous N-acetylcysteine infusion protocol without any adverse effects. This case report supports the use of N-acetylcysteine to treat neonatal paracetamol toxicity ⁵.

A 3.5 yr old girl with an upper respiratory infection died of an paracetamol overdose ⁶. When the child’s temperature remained elevated after treatment with 120 mg every 4 hr for 3 doses, dosage was increased to 720 mg every 3 hr. Over the next 24 hr the patient received 5.04 g ⁶.

A 63 yr old man with acute psittacosis had severe hepatic damage after ingesting about 10 g paracetamol over a 48 hr period. Transaminase levels showed striking elevation, with a serum glutamic-oxaloacetic transaminase level of over 15000 iu/L, and decreased rapidly, consistent with toxic insult. The liver showed severe central necrosis at autopsy ⁷.

An 18-year-old woman, gravida 1, presented at 33 weeks’ gestation with signs and symptoms consistent with acute fatty liver of pregnancy and fetal death. Markedly elevated transaminases prompted a search for other etiologies, and paracetamol toxicity was diagnosed. Liver biopsy revealed acute fatty liver of pregnancy and toxin-induced injury consistent with paracetamol use. The patient’s condition deteriorated, resulting in fulminant hepatic failure and requiring postpartum orthotopic liver transplantation. The combination of acute fatty liver of pregnancy and paracetamol toxicity resulted in acute liver failure ⁸.

A case involving a 22-year-old woman in her 31st week of pregnancy who consumed a 15 g dose of paracetamol, followed by a 50 g dose 1 week later is reported ⁹. Fetal distress was observed 16 hours after the second overdose, as evidenced by complete lack of fetal movements and breathing, a marked decrease in fetal heart rate beat-to-beat variability with no accelerations, and a falling baseline rate. Because of the fetal condition, labor was induced (cesarean section was excluded because of the mothers incipient hepatic failure). Eighty-four hours after the overdose, a 2198 g female infant was delivered with an Apgar scores at 1 and 5 min of 9 and 10, respectively. Except for hypoglycemia, mild respiratory disease, and mild jaundice, the newborn did well. Liver enzymes were always within normal range, and the jaundice was compatible with immaturity. Paracetamol was not detected in the cord blood. Follow-up examinations of the infant at 6 weeks and again at 6 months were normal. Protection against serious or permanent liver damage was probably afforded by the prompt administration of iv N-acetylcysteine ⁹.

Nausea, vomiting, and abdominal pain usually occur within 2-3 hours after ingestion of toxic doses of the drug. Unlike aspirin, paracetamol does not usually cause acid/base changes in toxic doses ⁴. In severe poisoning, CNS stimulation, excitement, and delirium may occur initially. This may be followed by CNS (central nervous system) depression; stupor; hypothermia; marked prostration; rapid, shallow breathing; rapid, weak, irregular pulse; low blood pressure; and circulatory failure. Vascular collapse results from the relative hypoxia and from a central depressant action that occurs only with massive doses. Shock may develop if vasodilation is marked. Fatal asphyxial seizures may occur. Coma usually precedes death, which may occur suddenly or may be delayed for several days ⁴.

Paracetamol toxicity usually involves 4 phases ⁴:

1. Anorexia, nausea, vomiting, malaise, and diaphoresis (which inappropriately may prompt administration of additional paracetamol);
2. Resolution of phase-1 manifestations and replacement with right upper quadrant pain or tenderness, liver enlargement, elevated bilirubin and hepatic enzyme concentrations, prolongation of prothrombin time, and occasionally oliguria;
3. Anorexia, nausea, vomiting, and malaise recur (usually 3-5 days after initial symptom onset) and signs of hepatic failure (e.g., jaundice, hypoglycemia, coagulopathy, encephalopathy) and possibly renal failure and cardiomyopathy develop; and
4. Recovery or progression to fatal complete liver failure.

Three hundred and seven cases of liver injury associated with paracetamol use were reported to the US Food and Drug Administration (FDA) from January 1998 to July 2001 ¹⁰. Sixty percent of these adverse events were categorized as severe life-threatening injury with liver failure (category 4); 40% of patients died. Review of these case reports indicates that use of higher than recommended daily dosages of paracetamol results in adverse hepatotoxic effects more often than use of recommended dosages ¹⁰.

The Rocky Mountain Poison and Drug Center ⁹ reported the results of a nationwide study on paracetamol overdose during pregnancy involving 113 women. Of the 60 cases that had appropriate laboratory and pregnancy outcome data, 19 occurred in the 1st trimester, 22 during the 2nd trimester, and 19 during the 3rd trimester. In those cases with a potentially toxic serum level of paracetamol, early treatment with N-acetylcysteine was statistically associated with an improved pregnancy outcome by lessening the incidence of spontaneous abortion and fetal death ⁹. Only one congenital anomaly was observed in the series and that involved a 3rd trimester overdose with nontoxic maternal paracetamol serum levels ⁹.

Very high levels of paracetamol can cause lactic acidosis and altered mental status by uncertain mechanisms, probably involving mitochondrial dysfunctin ¹¹. Symptoms of acute paracetamol poisoning both metabolic acidosis and metabolic alkalosis have been noted; cerebral edema & nonspecific myocardial depression have also occurred ¹². Biopsy of the liver reveals centralobular necrosis with sparing of the periportal area ¹².

Low prothrombin levels have been reported in patients with paracetamol poisoning and in one patient fatal GI hemorrhage was attributed to hypoprothrombinemia. Thrombocytopenia also has been reported. Toxic doses of p-aminophenol derivatives may produce skin reactions of an erythematous or urticarial nature which may be accompanied by fever and oral mucosal lesions ¹³.

Eighty-eight patients with paracetamol-induced acute liver failure were recruited ¹⁴. Control groups included patients with non-paracetamol-induced acute liver failure (n = 13), nonhepatic multiple organ failure (n = 28), chronic liver disease (n = 19), and healthy controls (n = 11). Total and caspase-cleaved cytokeratin-18 (M65 and M30) measured at admission and sequentially on days 3, 7, and 10 following admission. Levels were also determined from hepatic vein, portal vein, and systemic arterial blood in seven patients undergoing transplantation. Protein arrays of liver homogenates from patients with paracetamol-induced acute liver failure were assessed for apoptosis-associated proteins, and histological assessment of liver tissue was performed. Admission M30 levels were significantly elevated in paracetamol-induced acute liver failure and non-paracetamol induced acute liver failure patients compared with multiple organ failure, chronic liver disease, and healthy controls. Admission M30 levels correlated with outcome with area under receiver operating characteristic of 0.755. Peak levels in patients with acute liver failure were seen at admission then fell significantly but did not normalize over 10 days. A negative gradient of M30 from the portal to hepatic vein was demonstrated in patients with paracetamol-induced acute liver failure at the time of liver transplant. Analysis of protein array data demonstrated lower apoptosis-associated protein and higher catalase concentrations in paracetamol-induced acute liver failure compared with controls. Explant histological analysis revealed evidence of cellular proliferation with an absence of histological evidence of apoptosis. Hepatocellular apoptosis occurs in the early phases of human paracetamol-induced acute liver failure, peaking on day 1 of hospital admission, and correlates strongly with poor outcome. Hepatic regenerative/tissue repair responses prevail during the later stages of acute liver failure where elevated levels of M30 are likely to reflect epithelial cell death in extrahepatic organs ¹⁴.

The U.S. Food and Drug Administration (FDA) is informing the public that paracetamol has been associated with a risk of rare but serious skin reactions. These skin reactions, known as Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP), can be fatal ¹⁵. Reddening of the skin, rash, blisters, and detachment of the upper surface of the skin can occur with the use of drug products that contain paracetamol. These reactions can occur with first-time use of paracetamol or at any time while it is being taken. … Anyone who develops a skin rash or reaction while using paracetamol or any other pain reliever/fever reducer should stop the drug and seek medical attention right away. Anyone who has experienced a serious skin reaction with paracetamol should not take the drug again and should contact their health care professional to discuss alternative pain relievers/fever reducers. Health care professionals should be aware of this rare risk and consider paracetamol, along with other drugs already known to have such an association, when assessing patients with potentially drug-induced skin reactions.

Paracetamol overdose

In case of overdose, call the poison control helpline at 1-800-222-1222. Information is also available online at https://www.poisonhelp.org/help. If the victim has collapsed, had a seizure, has trouble breathing, or can’t be awakened, immediately call your local emergency services number.

This is a free and confidential service. All local poison control centers in the United States use this national number. You should call if you have any questions about poisoning or poison prevention. You can call 24 hours a day, 7 days a week.

Can you overdose on paracetamol?

Yes. Taking too much paracetamol, known as an overdose, can be very dangerous.

If you’ve taken more than the recommended maximum dose, go to your nearest accident and emergency (A&E) department as soon as possible.

It can be helpful to take any remaining medicine and the box or leaflet with you to a hospital accident and emergency department if you can.

Some people feel sick, vomit or have abdominal (tummy) pain after taking too much paracetamol, but often there are no obvious symptoms at first.

• Go to a hospital accident and emergency department even if you’re feeling well.

When an individual has ingested a toxic dose of acetaminophen, the individual should be hospitalized for several days of observation, even if there are no apparent ill effects, because maximum liver damage usually does not become apparent until 2-4 days after ingestion of the drug ¹³. Transient azotemia and renal tubular necrosis have been reported in patients with acetaminophen poisoning; renal failure is often associated with fatality. There have been reports of acute myocardial necrosis and pericarditis in individuals with acetaminophen poisoning. Maximum cardiotoxic effects of these drugs appear to be delayed in a manner similar to hepatotoxic effects. Hypoglycemia, which can progress to coma, and metabolic acidosis have been reported in patients ingesting toxic doses of acetaminophen and cerebral edema occurred in one patient ¹³.

In acute paracetamol overdosage, dose-dependent, potentially fatal hepatic necrosis is the most serious adverse effect. Renal tubular necrosis, hypoglycemic coma, and thrombocytopenia may also occur. Plasma paracetamol levels > 300 ug/mL at 4 hours after oral ingestion were associated with hepatic damage in 90% of patients; minimal hepatic damage is anticipated if plasma levels at 4 hours are < 150 ug/mL or < 37.5 ug/mL at 12 hours after ingestion. Early symptoms following a potentially hepatotoxic overdose may include: nausea, vomiting, diaphoresis, and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion ¹⁶.

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