Precautions and considerations when taking paracetamol

Precautions for use

Paracetamol is intended to be used only as recommended on the medication label or as directed by a medical doctor. Taking quantities of paracetamol that are higher than is recommended (or directed by a medical doctor) is not advisable. No more than 4 000mg (or 4 grams) of paracetamol should be taken in a 24-hour period (this applies to adults). ⁽¹⁾ Should the recommended dosage not be sufficient in treating pain or fever, a medical consultation is advised. A person should never increase the dosage in order to treat such symptoms without the guidance of a medical doctor. He or she will be able to advise on the frequency of dosages that are regarded as safe within a 24-hour period or recommend alternative therapies which may be more appropriate.

A person should consult a medical doctor if symptoms persist and the use of paracetamol does not appear to be adequately treating a condition. A physician will need to evaluate all relevant possibilities of a diagnosable condition which may require a different course of treatment altogether.

Although widely available over-the-counter, many paracetamol products now come with an overdosage warning. Excessive paracetamol use can result in severe damage to the liver. If extensive enough, this damage may be irreversible and in rare cases, require organ transplantation. Worst case scenario – accidental overdosage can also result in enough toxicity to cause a fatality (often due to acute liver failure).

Dosing is normally measured in milligrams (mg) and can sometimes be confused with millilitres. For individuals weighing less that 50kg (110.2lb), dosages are recommended according to weight. Toxicity is mainly associated with misuse of the medication (exceeding maximum daily dosages) or simultaneously taking more than one product (whether prescription or over-the-counter) that contains the active ingredient, acetaminophen. It is important to note that some medication leaflets (label) may abbreviate the name of this active ingredient as follows:

• AC
• APAP
• Acetaminoph
• Acetaminop
• Acetamin
• Acetam

If in doubt about any particular medication which may contain this ingredient, it is best to chat with a medical professional or pharmacist beforehand.

People who may be at higher risk of side-effects should also be cautious when taking paracetamol, even at the recommended dosage allowances. Those with diagnosed liver damage or cirrhosis, liver disease, a history of alcoholism or who consume three or more alcoholic beverages a day should consult their medical doctor before taking paracetamol containing medications (for any reason). A doctor will assess whether lower dosages may be safe based on an individual’s overall condition. In some instances, a doctor may recommend that no more than 2 000mg (or 2 grams) may be taken within a 24-hour period, as necessary.

Individuals with allergies or sensitivities to paracetamol (or any of the other inactive ingredients), as well as who may already be taking blood thinning medications (like aspirin or warfarin) should also consult their medical doctor before taking any acetaminophen containing drugs. Alternatives may be required to avoid unwanted side-effects, like allergic reactions or increased risk of bleeding.

Women who are pregnant or nursing (breastfeeding) an infant must also ensure that their physician is aware of any therapeutic use of paracetamol (before -taking it) to ensure that dosages which are deemed safe are taken.

Interactions

Paracetamol can adversely interact with other substances in the body. Thus, certain precautions should be kept in mind when taking this medication concurrently with other substances or medications. Individuals with certain medical conditions should also be cautious about taking paracetamol.

Interactions are typically classed in the following ways in order to categorise severity:

• Major: Interactions classed in this category are considered highly significant. Clinical interactions may be severe and thus, these combinations should be avoided altogether. The risk of interaction possibility is high, outweighing any benefit.
• Moderate:Interactions are regarded as moderately significant, meaning that combinations may be clinically notable. It is generally best to avoid these combinations as a result. In certain circumstances, combinations of medications may be used with careful monitoring by a medical doctor.
• Minor:Interactions between medications may be minor and not clinically significant. Risk may be minimised by using alternate medication combinations or implementing a therapy plan that circumvents any potential interaction risk.

Here we break down various known interactions with paracetamol as they relate to other medications, substances and medical conditions…

1. Medication interactions

Notable medications known to interact adversely (when coadministration with paracetamol)

Substances and medications (coadministration)	Category: Major interaction
Amyl nitrite Sodium nitrite Sodium thiosulfate	Amyl nitrate is often used as an antihypertensive medication, treating chest pain (angina) and other heart conditions. The substance may also be used for the treatment of cyanide poisoning. The substance combines with cyanide in order to form cyanmethemoglobin which is non-toxic. The medication functions as a vasodilator (i.e. it widens the blood vessels) and is available via prescription. The medication is used as an inhalant which has resulted in some illegal usage by individuals aiming to benefit from the drug’s psychoactive effects. Sodium nitrate and sodium thiosulfate are also substances aimed at treating angina (chest pain). All of these substances can result in the development of methemoglobinemia – a condition wherein the body’s red blood cells contain methaemoglobin (an oxygen-carrying metalloprotein haemoglobin) at levels exceeding 1%. The oxygen-carrying capacity of these red blood cells is reduced as a result, which means that vital organ tissues do not receive as much as is needed for healthy function. Signs of the condition include a grey discolouration of the skin, nail beds and mouth, headache, dizziness or light-headedness, nausea, fatigue, confusion, anxiety, a rapid heartbeat, shortness of breath, and shallow or rapid breathing. Prompt medical attention will be required if such side-effects occur. Combining these substances with paracetamol can increase a person’s risk of developing methemoglobinemia, which can occur within hours. Should it be necessary for these substances to be used with paracetamol, careful medical monitoring will be required.
Epinephrine Prilocaine Prilocaine topical Lidocaine	Epinephrine (or adrenalin) is used to treat superficial bleeding, anaphylaxis and cardiac arrest. Prilocaine and lidocaine are medications with local anaesthetic properties (including topical applications used to numb skin tissues). These substances can also result in the development of methemoglobinemia (described above). Taken concurrently with paracetamol, risk for this condition can increase considerably. Individuals with anaemia or glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency) are generally at higher risk for the development of methemoglobinemia, and thus should be extra cautious when using paracetamol. It is advisable to only use these substances with the express permission of a medical professional who can carefully monitor a person’s condition and the potential interaction risks.
Ethanol	The combination of ethanol (alcohol) and paracetamol can result in adverse reactions affecting the liver. Indications can include the development of body chills, fever, joint swelling or pain, weakness, fatigue, skin rash (and itching), nausea, vomiting, loss of appetite, unusual bruising or bleeding, abdominal pain, dark coloured urine, light coloured stools (faeces) or a yellowing of the skin and whites of the eyes (jaundice). Medications containing ethanol may be recommended by a medical doctor for use simultaneously with paracetamol but will be prescribed with adjusted dosages (usually much lower), that are deemed safer to take.  Medical monitoring may also be required.
Leflunomide	An immune-suppressive drug, leflunomide functions as a disease-modifying anti-rheumatic which helps to control moderate to severe symptoms of rheumatic arthritis and psoriatic arthritis. A side-effect risk of this substance is adverse liver reactions, which can be further enhanced with the combined use of paracetamol. Combined usage will require careful medical monitoring if required. If used together, a medical doctor is likely to warn against the use of alcohol as well which can further increase the risk of damage to the liver.
Lomitapide Mipomersen	These substances function as lipid-lowering agents prescribed in the treatment of the genetic disorder, familial hypercholesterolemia (inherited high cholesterol). This condition is caused by a chromosomal defect which results in the inability for the body to remove LDL (low-density lipoprotein) cholesterol (‘bad cholesterol’) from the bloodstream. Levels are thus high, placing a person at risk of cardiovascular problems. Lomitapide and mipomersen use can result in an increased risk of liver damage, and especially so when used concurrently with paracetamol. Alternative combinations are likely to be recommended as required. A medical doctor will assess use according to a risk management plan in order to determine safety. If used together, medical monitoring will be recommended, and alcohol usage advised to be avoided where possible.
Teriflunomide	This medication functions as the active metabolite of leflunomide and belongs to a class of medications known as immunomodulatory agents. This substance is generally prescribed for the treatment of relapsing forms of multiple sclerosis (MS). A side-effect risk of this medication is also liver function problems or damage, which can be further exacerbated by concurrent use of paracetamol. A doctor will assess a person’s condition accordingly and determine whether controlled use may provide enough benefit to outweigh risk before recommending concurrent use. If these substances are used, medical monitoring will be required. Alcohol use will be discouraged.

Moderate interaction medications and other substances (coadministration with paracetamol)

Substances and medications (coadministration)		Category: Moderate interaction
Aminophylline Amobarbital Bedaquiline Black cohosh Brentuximab Butabarbital Butalbital Carbamazepine Clofarabine Daclizumab Efavirenz Ephedrine Epirubicin Ethotoin Fosphenytoin guaifenesin Idelalisib Imatinib Interferon beta-1a Interferon beta-1b	Isoniazid Mephenytoin Mephobarbital Methohexital Methotrexate Naltrexone Peginterferon beta-1a Pentobarbital Phenobarbital Phenobarbital Phenytoin Potassium iodide Primidone Secobarbital Secobarbital Sulfinpyrazone Thioguanine Thiopental Trabectedin	Liver dysfunction Additional paracetamol in the system may be altered by these substances resulting in an increased risk of liver dysfunction. Indications of liver problems include body chills, fever, joint pain and swelling, body weakness, fatigue, itching of the skin, rash, nausea, vomiting, loss of appetite, unusual bleeding or bruising and a yellowing of the skin and whites of the eyes. These substances may be taken together, but if signs of liver dysfunction develop, a doctor may recommend dosage adjustments (or alternate medications) and periodic testing of the organ to ensure that irreversible damage does not occur.
Anagrelide Deferasirox Glycerol phenylbutyrate Vemurafenib		Elevated blood levels of paracetamol When taken with paracetamol, these substances can elevate blood levels of paracetamol. A doctor may recommend the combination along with frequent consultations for monitoring purposes to ensure that the therapeutic effect is safely met.
Hydroxyprogesterone		Reduced blood levels of paracetamol When taken concurrently this medication may reduce the blood levels of paracetamol and thereby decrease the therapeutic effect.
Busulfan		Elevated effects of other co-administered medications A medication used for the treatment of cancer (chemotherapy), Busulfan may not be recommended for use along with paracetamol. Acetaminophen can increase the levels of busulfan in the blood and contribute to a decrease in normal metabolism. Side-effects of busulfan can include fever, body chills, persistent cough, congestion, bleeding, bruising, stomach or back pain, nausea, vomiting, diarrhoea, decreased appetite, breathing troubles and seizures. Dosage adjustments may be closely monitored should a physician agree that the two may be used simultaneously. Appropriate testing may be required if symptoms induced by interactions occur.
Charcoal		Reduced absorption of paracetamol The use of charcoal products (including activated charcoal) can reduce the absorption capability of paracetamol in the gastrointestinal tract, inhibiting normal circulation and thereby decreasing the therapeutic effect. Activated charcoal is sometimes used in clinical setting to treat an overdose of paracetamol.
Dapsone Dapsone topical		Methemoglobinemia development When taken concurrently with paracetamol, the risk of developing methemoglobinemia may increase. Medical monitoring of use may be required should symptomatic indications develop.
Codeine		Breathing problems Codeine and paracetamol combination products can result in breathing problems. Such reactions are most typical within the initial 24 to 72 hours following treatment commencement or if a dosage is increased. Vulnerable individuals include those who have a history of breathing troubles (such as slowed breathing) or are asthmatic. Individuals with lung conditions, such as COPD (chronic obstructive pulmonary disorder) or others which cause increased pressure on the brain may be advised to avoid codeine and paracetamol combination medications as well. This combination is also not recommended for the treatment of pain or cough in children under the age of 12. Prolonged use of paracetamol and codeine can also be habit forming.

Minor interaction medications and other substances (coadministration use with paracetamol)

Minor interactions may or may not occur when certain combinations of medications are taken concurrently. Short term usage at recommended dosages generally does not induce severe reactions. Adverse interactions that may occur are transient or are not considered clinically significant. If troublesome, a patient can consult their physician for guidance in better managing discomforts while taking the medication combinations.
Adverse interactions can include reduced or delayed gastrointestinal absorption and emptying, increased therapeutic effects of paracetamol (if taken at higher than recommended dosages), decreased therapeutic effects of paracetamol or increased effects of co-administered medications.

Some medications that may have a minor interaction effect include:

• Acetazolamide
• Albiglutide
• Antithrombin alfa
• Antithrombin III
• Argatroban
• Bemiparin
• Bivalirudin
• Cholestyramine
• Clonazepam
• Colestipol
• Dalteparin
• Diazepam
• Disulfiram
• Enoxaparin
• Ethosuximide
• Felbamate
• Fondaparinux
• Gabapentin and Gabapentin enacarbil
• Heparin
• Lacosamide
• Lamotrigine
• Lepirudin
• Levetiracetam
• Liraglutide
• Lorazepam
• Methsuximide
• Metoclopramide
• Metronidazole
• Oxcarbazepine
• Oxybutynin, Oxybutynin topical and Oxybutynin transdermal
• Phenindione
• Protamine
• Rifabutin
• Rifampin
• Rufinamide
• Ruxolitinib
• Sultiame
• Tiagabine
• Tinzaparin
• Topiramate
• Valproic acid
• Zonisamide

3. Interactions associated with medical conditions

The use of paracetamol is contraindicated or cautioned in the following instances:

Risk category	Medical condition	What happens…
Major	Alcoholism (chronic alcohol abuse – 3 or more alcoholic beverages consumed daily)	Hepatoxicity increases with the use of paracetamol. Severe injury to the liver and acute liver failure can occur with these combined substances in the bloodstream. In some instances, this may be life-threatening, and a transplant may be required. If paracetamol is used at strict dosages, a patient will be carefully monitored by a medical professional for signs of liver dysfunction. Care will be taken to avoid additional over-the-counter medications which may contain paracetamol, and thereby reduce the risk of overdosage and adverse effects on the liver.
Major	Liver disease	Paracetamol is mainly metabolised by the liver. Small quantities may be converted to metabolites (an intermediate end product of metabolism) which can also contribute to hepatoxicity effects or methemoglobinemia (a condition wherein methaemoglobin is present in the blood, leading to lower oxygen levels and the impairment of bodily function). Individuals with existing liver dysfunction are high-risk for additional hepatoxicity, causing severe injury to the organ. Severe instances may be life-threatening or result in death due to complete liver failure. If paracetamol is used, it will be under the supervision of a medical professional who will administer strict dosages and implement liver function testing as required. No alcohol consumption will be permitted.
Moderate	Phenylketonuria (Pku)	An inherited medical condition wherein the amino acid, phenylalanine accumulates in the body, caution is advised in individuals with Phenylketonuria. Chewable or effervescent paracetamol (including oral forms and combination varieties) may contain artificial sweetener (such as aspartame). Through ingestion, this can be converted phenylalanine in the gastrointestinal tract and thereby contribute to accumulation control difficulties in the body.

3. Dietary factors / food interactions

The rate of absorption for paracetamol may reduce slightly when taken with food. This should not, however, cause any major discomfort or upset.

The main concern regarding paracetamol is the concurrent consumption of alcohol. This may result in damage to the liver, increasing the toxicity of paracetamol. Alcohol accelerates the metabolism of paracetamol and increases the production of metabolites, enhancing toxic effects.

4. Paracetamol use during pregnancy and in breastfeeding / nursing moms

The use of paracetamol during pregnancy is not uncommon. It is one of the few medications, taken at fairly low dosages, that is generally acceptable for the relief of mild to moderate pain and fever during any stage of pregnancy. General guidelines do encourage any dosages taken to be over a short period only, in order to minimise foetal exposure risk . The use of paracetamol is not discouraged during pregnancy as fever and pain-related symptoms of infection, for instance, could result in unwanted complications, so the use of this medication as needed may be directed by a medical professional in order to avoid these.

Whether or not the use of paracetamol has a direct harmful effect on a developing foetus remains relatively unclear. Low, short-term dosages are not thought to greatly impact a developing baby. No major congenital defects or malformations (external, visceral or skeletal) have been reported with paracetamol use during pregnancy. Miscarriage and stillbirth complications are also not typical following maternal use at recommended or lower dosages. Maternal overdose may result in foetal death or spontaneous abortion of a baby, however.

It is thought that the compounds in paracetamol are capable of crossing the placenta during pregnancy, meaning that an unborn baby may be exposed to the drug to some degree.

Some small studies have made associations between the effects of paracetamol exposure on an unborn baby and maternal use during pregnancy. Future studies may focus on the potential trimester specific effects. For now, associations have potentially linked maternal use of paracetamol during pregnancy to the development of asthma, allergies, neurodevelopmental problems (specifically gross motor development and communication), autism spectrum disorder (and specifically hyperkinetic disorder), lower IQ, attention impairment, behavioural troubles and reduced male reproduction. An increased risk for ADHD (attention deficit / hyperactivity disorder) and ADHD-like behaviours has also been associated with exposure to paracetamol. ⁽²⁾

Paracetamol may only be used during labour and the delivery of the baby if necessary and an attending physician can attribute a favourable benefit-risk assessment while a pregnant woman is in his or her care.

As in pregnancy, the use of paracetamol (at low dosages) in nursing mothers is also not frowned upon, but only really encouraged as is necessary. Small amounts of the medication can be secreted in breast milk and thus passed on to an infant while he/she is being breast fed. The amount is not believed to be high enough to result in any clinically relevant adverse effects on a young child (estimated at between 1 and 2% of the orally taken dosage ⁽³⁾), although caution is still advised as no significant clinical studies have been conducted to either prove or disprove concerns over exposure during breastfeeding.

It is advisable for nursing mothers to only take paracetamol as needed for a short period of time. 

References:

^{1. Medline Plus. April 2017. Acetaminophen: https://medlineplus.gov/druginfo/meds/a681004.html [Accessed 05.07.2018]}

^{2. US National Library of Medicine - National Institutes of Health. March 2016. Use of acetaminophen (paracetamol) during pregnancy and the risk of attention-deficit/hyperactivity disorder in the offspring: https://www.ncbi.nlm.nih.gov/pubmed/27046315 [Accessed 05.07.2018]}

^{3. FDA (U.S. Food and Drug Administration). Acetaminophen - drug label: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/204767s000lbl.pdf  [Accessed 05.07.2018]}