Paracetamol

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Acetaminophen
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Paracetamol
others[1]
Other namesN-acetyl-para-aminophenol (APAP), acetaminophen (USAN US)
AHFS/Drugs.comMonograph
MedlinePlusa681004
License data
Pregnancy
category
intravenous (IV)
Drug classAnalgesics and antipyretics
ATC code
Legal status
Legal status
  • AU: S4 (Rx), OTC, and unscheduled
  • CA: OTC / Rx-only[4]
  • UK:
    General sales list
    (GSL, OTC)
  • US: WARNING[3]OTC / Rx-only
Intravenous – 8 minutes[8]
Elimination half-life1.9–2.5 hours[6]
ExcretionUrine[6]
Identifiers
  • N-(4-hydroxyphenyl)ethanamide
JSmol)
Density1.263 g/cm3
Melting point169 °C (336 °F) [10][11]
Solubility in water
  • 7.21 g/kg (0 °C)[12]
  • 8.21 g/kg (5 °C)[12]
  • 9.44 g/kg (10 °C)[12]
  • 10.97 g/kg (15 °C)[12]
  • 12.78 g/kg (20 °C)[12]
  • ~14 mg/ml (20 °C)
    • CC(=O)Nc1ccc(O)cc1
    • InChI=1S/C8H9NO2/c1-6(10)9-7-2-4-8(11)5-3-7/h2-5,11H,1H3,(H,9,10) checkY
    • Key:RZVAJINKPMORJF-UHFFFAOYSA-N checkY
      (verify)

    Paracetamol (acetaminophen

    Panadol
    .

    At a standard dose, paracetamol slightly decreases body temperature;

    surgical pain, but it is inferior to ibuprofen.[25] The paracetamol/ibuprofen combination provides further increase in potency and is superior to either drug alone.[25][26] The pain relief paracetamol provides in osteoarthritis is small and clinically insignificant.[15][27][28] The evidence in its favor for the use in low back pain, cancer pain, and neuropathic pain is insufficient.[15][29][27][30][31][32]

    In the short term, paracetamol is safe and effective when used as directed.

    non-steroidal anti-inflammatory drugs (NSAID) for long term use.[35] Paracetamol is also often used in patients who cannot tolerate NSAIDs like ibuprofen.[36][37] Chronic consumption of paracetamol may result in a drop in hemoglobin level, indicating possible gastrointestinal bleeding,[38] and abnormal liver function tests. The recommended maximum daily dose for an adult is three to four grams.[39][40][27] Higher doses may lead to toxicity, including liver failure.[41] Paracetamol poisoning is the foremost cause of acute liver failure in the Western world, and accounts for most drug overdoses in the United States, the United Kingdom, Australia, and New Zealand.[42][43][44]

    Paracetamol was first made in 1878 by

    others.[50] In 2021, it was the 113th most commonly prescribed medication in the United States, with more than 5 million prescriptions.[51][52]

    Medical uses

    Fever

    Paracetamol is a drug of choice for reducing fever. However, there has been a lack of research on its antipyretic properties, particularly in adults.[14] The most recent review on paracetamol and management of fever in the general practice (2008) argued that its benefits are unclear.[14] In addition, when used for the common cold, paracetamol may relieve a stuffed or runny nose, but not other cold symptoms such as a sore throat, malaise, sneezing, or cough; however, these data are of poor quality.[53]

    For patients in critical care, paracetamol decreased body temperature by only 0.2–0.3 °C more than control interventions; there was no difference in mortality.[16] It did not change the outcome in febrile patients with stroke.[54] The results are contradictory for paracetamol use in sepsis: higher mortality, lower mortality, and no change in mortality were all reported.[16] Paracetamol offered no benefit in the treatment of dengue fever and was accompanied by a higher rate of liver enzyme elevation: a sign of a potential liver damage.[55] Overall, there is no support for a routine administration of antipyretic drugs, including paracetamol, to hospitalized patients with fever and infection.[20]

    The efficacy of paracetamol in children with fever is unclear.

    febrile seizures and should not be used for that purpose.[57][58] It appears that 0.2 °C decrease of the body temperature in children after a standard dose of paracetamol is of questionable value, particularly in emergency situations.[14] Based on this, some physicians advocate using higher doses that may decrease the temperature by as much as 0.7 °C.[17] Meta-analyses showed that paracetamol is less effective than ibuprofen in children (marginally less effective, according to another analysis[59]), including children younger than 2 years old,[60] with equivalent safety.[18] Exacerbation of asthma occurs with similar frequency for both medications.[61] Giving paracetamol and ibuprofen together at the same time to children under 5 is not recommended, however doses may be alternated if required.[57]

    Pain

    Paracetamol is used for the relief of mild to moderate pain such as headache, muscle aches, minor arthritis pain, toothache as well as pain caused by cold, flu, sprains, and dysmenorrhea.[62] It is recommended, in particular, for acute mild to moderate pain, since the evidence for the treatment of chronic pain is insufficient.[15]

    Musculoskeletal pain

    The benefits of paracetamol in musculoskeletal conditions, such as osteoarthritis and backache, are uncertain.[15]

    It appears to provide only small and not clinically important benefits in

    EULAR for hand osteoarthritis.[63] Similarly, the ESCEO algorithm for the treatment of knee osteoarthritis recommends limiting the use of paracetamol to short-term rescue analgesia only.[64]

    Paracetamol is ineffective for acute low back pain.[15][29] No randomized clinical trials evaluated its use for chronic or radicular back pain, and the evidence in favor of paracetamol is lacking.[27][30][29]

    Headaches

    Paracetamol is effective for acute migraine:[21] 39% of people experience pain relief at one hour compared with 20% in the control group.[65] The aspirin/paracetamol/caffeine combination also "has strong evidence of effectiveness and can be used as a first-line treatment for migraine".[23] Paracetamol on its own only slightly alleviates episodic tension headache in those who have them frequently.[22] However, the aspirin/paracetamol/caffeine combination is superior to both paracetamol alone and placebo and offers meaningful relief of tension headache: 2 hours after administering the medication, 29% of those who took the combination were pain-free as compared with 21% on paracetamol and 18% on placebo.[66] The German, Austrian, and Swiss headache societies and the German Society of Neurology recommend this combination as a "highlighted" one for self-medication of tension headache, with paracetamol/caffeine combination being a "remedy of first choice", and paracetamol a "remedy of second choice".[24]

    Dental and other post-surgical pain

    Pain after a dental surgery provides a reliable model for the action of analgesics on other kinds of acute pain.

    non-steroidal anti-inflammatory drugs (NSAIDs) ibuprofen, naproxen or diclofenac are clearly more efficacious than the paracetamol/codeine combination which is frequently prescribed for dental pain.[68] The combinations of paracetamol and NSAIDs ibuprofen or diclofenac are promising, possibly offering better pain control than either paracetamol or the NSAID alone.[25][26][69][70] Additionally, the paracetamol/ibuprofen combination may be superior to paracetamol/codeine and ibuprofen/codeine combinations.[26]

    A meta-analysis of general post-surgical pain, which included dental and other surgery, showed the paracetamol/codeine combination to be more effective than paracetamol alone: it provided significant pain relief to as much as 53% of the participants, while the placebo helped only 7%.[71]

    Other pain

    Paracetamol fails to relieve procedural pain in

    non-steroidal anti-inflammatory drugs (NSAIDs).[74]

    The studies to support or refute the use of paracetamol for cancer pain and for neuropathic pain are lacking.[31][32] There is limited evidence in favor of the use of the intravenous form of paracetamol for acute pain control in the emergency department.[75] The combination of paracetamol with caffeine is superior to paracetamol alone for the treatment of acute pain.[76]

    Patent ductus arteriosus

    Paracetamol helps ductal closure in

    indomethacin, but results in less frequent gastrointestinal bleeding than ibuprofen.[77] Its use for extremely low birth weight and gestational age infants however requires further study.[77]

    Adverse effects

    Gastrointestinal adverse effects such as nausea and

    Rechallenge tests and an analysis of American but not French pharmacovigilance databases indicated a risk of these reactions.[79][80]

    In clinical trials for osteoarthritis, the number of participants reporting adverse effects was similar for those on paracetamol and on placebo. However, the abnormal liver function tests (meaning there was some inflammation or damage to the liver) were almost four times more likely in those on paracetamol, although the clinical importance of this effect is uncertain.[81] After 13 weeks of paracetamol therapy for knee pain, a drop in hemoglobin level indicating gastrointestinal bleeding was observed in 20% of participants, this rate being similar to ibuprofen group.[38]

    Due to the absence of controlled studies, most of the information about the long-term safety of paracetamol comes from observational studies.[37] These indicate a consistent pattern of increased mortality as well as cardiovascular (stroke, myocardial infarction), gastrointestinal (ulcers, bleeding) and renal adverse effects with increased dose of paracetamol.[38][37][82] Use of paracetamol is associated with 1.9 times higher risk of peptic ulcer.[37] Those who take it regularly at a higher dose (more than 2–3 g daily) are at much higher risk (3.6–3.7 times) of gastrointestinal bleeding and other bleeding events.[83] Meta-analyses suggest that paracetamol may increase the risk of kidney impairment by 23%[84] and kidney cancer by 28%.[82] Paracetamol is particularly dangerous to the liver in overdose, but even without overdose those who take this drug may develop acute liver failure requiring liver transplantation more frequently than the users of nonsteroidal anti-inflammatory drugs.[36] Paracetamol slightly but significantly increases blood pressure and heart rate.[37] The majority of observational studies suggests that, used chronically, it may increase the risk of developing hypertension, as confirmed in a prospective randomized confirmed trial.[85] The risk is higher with the higher dose.[83]

    The association between paracetamol use and asthma in children has been a matter of controversy.[86] However, the most recent research suggests that there is no association,[87] and that the frequency of asthma exacerbations in children after paracetamol is the same as after another frequently used pain killer ibuprofen.[61]

    Use in pregnancy

    Paracetamol safety in pregnancy has been under increased scrutiny. There appears to be no link between paracetamol use in the first trimester and adverse pregnancy outcomes or

    birth defects. However, indications exist of a possible increase of asthma and developmental and reproductive disorders in the offspring of women with prolonged use of paracetamol during pregnancy.[83]

    Paracetamol use by the mother during pregnancy is associated with an increased risk of childhood

    autism spectrum disorder, attention deficit hyperactivity disorder, hyperactivity symptoms, and conduct disorder, with the association being lower in a meta-analysis where a larger demographic was used, but it is unclear whether this is a causal relationship and there was potential bias in the findings.[83][90][91] There is also an argument that the large number, consistency, and the robust designs of the studies provide a strong evidence in favor of paracetamol causing the increased risk of these neurodevelopmental disorders.[92][93] In animal experiments, paracetamol disrupts fetal testosterone production, and several epidemiological studies linked cryptorchidism with mother's paracetamol use for more than two weeks in the second trimester. On the other hand, several studies did not find any association.[83]

    The consensus recommendation appears to be to avoid prolonged use of paracetamol in pregnancy and use it only when necessary, at the lowest effective dosage and for the shortest time.[83][94][95]

    Overdose

    Overdose of paracetamol is caused by taking more than the recommended maximum daily dose of paracetamol for healthy adults (three or four grams),[39][40] and can cause potentially fatal liver damage.[96][97] A single dose should not exceed 1000 mg, and doses should be taken no sooner than four hours apart.[39] While a majority of adult overdoses are linked to suicide attempts, many cases are accidental, often due to the use of more than one paracetamol-containing product over an extended period.[98]

    Paracetamol toxicity is the foremost cause of acute liver failure in the Western world, and accounts for most drug overdoses in the United States, the United Kingdom, Australia, and New Zealand.[42][99][43][44][when?] Paracetamol overdose results in more calls to poison control centers in the US than overdose of any other pharmacological substance.[100] According to the FDA, in the United States, "56,000 emergency room visits, 26,000 hospitalizations, and 458 deaths per year [were] related to acetaminophen-associated overdoses during the 1990s. Within these estimates, unintentional acetaminophen overdose accounted for nearly 25% of the emergency department visits, 10% of the hospitalizations, and 25% of the deaths."[101][needs update
    ]

    Overdoses are frequently related to high-dose

    opioids, as these opioids are most often combined with paracetamol.[102] The overdose risk may be heightened by frequent consumption of alcohol.[103]

    Untreated paracetamol overdose results in a lengthy, painful illness. Signs and symptoms of paracetamol toxicity may initially be absent or

    non-specific symptoms. The first symptoms of overdose usually begin several hours after ingestion, with nausea, vomiting, sweating, and pain as acute liver failure starts.[104] People who take overdoses of paracetamol do not fall asleep or lose consciousness, although most people who attempt suicide with paracetamol wrongly believe that they will be rendered unconscious by the drug.[105][106]

    Treatment is aimed at removing the paracetamol from the body and replenishing

    liver transplant is often required if damage to the liver becomes severe.[42][107]

    NAC was usually given following a treatment nomogram (one for people with risk factors, and one for those without), but the use of the nomogram is no longer recommended as evidence to support the use of risk factors was poor and inconsistent, and many of the risk factors are imprecise and difficult to determine with sufficient certainty in clinical practice.[108][109] Toxicity of paracetamol is due to its quinone metabolite NAPQI and NAC also helps in neutralizing it.[106] Kidney failure is also a possible side effect.[103]

    Interactions

    propantheline and morphine lengthen tmax and decrease Cmax.[110][111] The interaction with morphine may result in patients failing to achieve the therapeutic concentration of paracetamol; the clinical significance of interactions with metoclopramide and propantheline is unclear.[111]

    There have been suspicions that

    St John's wort.[112] On the other hand, the anti-tuberculosis drug isoniazid cuts the formation of NAPQI by 70%.[111]

    Ranitidine increased paracetamol area under the curve (AUC) 1.6-fold. AUC increases are also observed with nizatidine and cisapride. The effect is explained by these drugs inhibiting glucuronidation of paracetamol.[111]

    Paracetamol raises plasma concentrations of ethinylestradiol by 22% by inhibiting its sulfation.[111] Paracetamol increases INR during warfarin therapy and should be limited to no more than 2 g per week.[113][114][115]

    Pharmacology

    Pharmacodynamics

    Paracetamol appears to exert its effects through two mechanisms: the inhibition of

    N-arachidonoylphenolamine (AM404).[116]

    Supporting the first mechanism, pharmacologically and in its side effects, paracetamol is close to classical

    peroxides is low. Under these conditions, COX-2 is the predominant form of cyclooxygenase, which explains the apparent COX-2 selectivity of paracetamol. Under the conditions of inflammation, the concentration of peroxides is high, which counteracts the reducing effect of paracetamol. Accordingly, the anti-inflammatory action of paracetamol is slight.[116][117] The anti-inflammatory action of paracetamol (via COX inhibition) has also been found to primarily target the central nervous system
    and not peripheral areas of the body, explaining the lack of side effects associated with conventional NSAIDs such as gastric bleeding.

    The second mechanism centers on the paracetamol metabolite

    CB2, an inhibitor of endocannabinoid transporter, and a potent activator of TRPV1 receptor.[116] This and other research indicate that cannabinoid system and TRPV1 may play an important role in the analgesic effect of paracetamol.[116][119]

    In 2018, Suemaru et al. found that, in mice, paracetamol exerts anticonvulsant effect by activation of TRPV1 receptors[120] and decrease in neuronal excitability by hyperpolarization of neurons.[121] The exact mechanism of the anticonvulsant effect of acetaminophen is not clear. According to Suemaru et al., acetaminophen and its active metabolite AM404 show a dose-dependent anticonvulsant activity against pentylenetetrazol-induced seizures in mice.[120]

    Pharmacokinetics

    After being taken by mouth, paracetamol is rapidly absorbed from the small intestine, while absorption from the stomach is negligible. Thus, the rate of absorption depends on stomach emptying. Food slows the stomach emptying and absorption, but the total amount absorbed stays the same.[122] In the same subjects, the peak plasma concentration of paracetamol was reached after 20 minutes when fasting versus 90 minutes when fed. High carbohydrate (but not high protein or high fat) food decreases paracetamol peak plasma concentration by four times. Even in the fasting state, the rate of absorption of paracetamol is variable and depends on the formulation, with maximum plasma concentration being reached after 20 minutes to 1.5 hours.[6]

    Paracetamol's bioavailability is dose-dependent: it increases from 63% for 500 mg dose to 89% for 1000 mg dose.[6] Its plasma terminal elimination half-life is 1.9–2.5 hours,[6] and volume of distribution is roughly 50 L.[123] Protein binding is negligible, except under the conditions of overdose, when it may reach 15–21%.[6] The concentration in serum after a typical dose of paracetamol usually peaks below 30 μg/mL (200 μmol/L).[124] After 4 hours, the concentration is usually less than 10 μg/mL (66 μmol/L).[124]

    Important pathways of paracetamol metabolism

    Paracetamol is

    UGT1A1 and UGT1A6 accounts for 50–70% of the drug metabolism. Additional 25–35% of paracetamol is converted to sulfate by sulfation enzymes SULT1A1, SULT1A3, and SULT1E1.[125]

    A minor metabolic pathway (5–15%) of

    mitochondria proteins of the liver cells causing oxidative stress and toxicity.[125]

    Yet another minor but important direction of metabolism is deacetylation of 1–2% of paracetamol to form

    fatty acid amide hydrolase into AM404, a compound that may be partially responsible for the analgesic action of paracetamol.[123]

    Chemistry

    Synthesis

    Classical methods

    Classical methods for the production of paracetamol

    The classical methods for the production of paracetamol involve the

    absolute ethanol or ethyl acetate to produce a 91% yield of 4-aminophenol.[126][127][128]

    Celanese synthesis

    An alternative industrial synthesis developed at

    ketoxime, and finally the acid-catalyzed Beckmann rearrangement of the cetoxime to the para-acetylaminophenol product.[126][129]

    Celanese method for the preparation of paracetamol

    Reactions

    Paracetamol crystals (crystallized from an aqueous solution) under a microscope

    4-Aminophenol may be obtained by the amide hydrolysis of paracetamol. This reaction is also used to determine paracetamol in urine samples: After hydrolysis with hydrochloric acid, 4-aminophenol reacts in ammonia solution with a phenol derivate, e.g. salicylic acid, to form an indophenol dye under oxidization by air.[130]

    History

    Bernard Brodie
    demonstrated that acetanilide and phenacetin are both metabolized to paracetamol, which is a better-tolerated analgesic.

    Antifebrin by Cahn & Hepp in 1886.[131] But its unacceptable toxic effects—the most alarming being cyanosis due to methemoglobinemia, an increase of hemoglobin in its ferric [Fe3+] state, called methemoglobin, which cannot bind oxygen, and thus decreases overall carriage of oxygen to tissue—prompted the search for less toxic aniline derivatives.[132] Some reports state that Cahn & Hepp or a French chemist called Charles Gerhardt first synthesized paracetamol in 1852.[46][47]

    Harmon Northrop Morse synthesized paracetamol at Johns Hopkins University via the reduction of p-nitrophenol with tin in glacial acetic acid in 1877,[133][134] but it was not until 1887 that clinical pharmacologist Joseph von Mering tried paracetamol on humans.[132] In 1893, von Mering published a paper reporting on the clinical results of paracetamol with phenacetin, another aniline derivative.[135] Von Mering claimed that, unlike phenacetin, paracetamol had a slight tendency to produce methemoglobinemia. Paracetamol was then quickly discarded in favor of phenacetin. The sales of phenacetin established Bayer as a leading pharmaceutical company.[136]

    Von Mering's claims remained essentially unchallenged for half a century, until two teams of researchers from the United States analyzed the metabolism of acetanilide and phenacetin.

    Bernard Brodie, Julius Axelrod and Frederick Flinn confirmed that paracetamol was the major metabolite of acetanilide in humans, and established that it was just as efficacious an analgesic as its precursor.[138][139][140] They also suggested that methemoglobinemia is produced in humans mainly by another metabolite, phenylhydroxylamine. A follow-up paper by Brodie and Axelrod in 1949 established that phenacetin was also metabolized to paracetamol.[141] This led to a "rediscovery" of paracetamol.[132]

    Paracetamol was first marketed in the United States in 1950 under the name Triagesic, a combination of paracetamol,

    Sterling-Winthrop Co. as Panadol, available only by prescription, and promoted as preferable to aspirin since it was safe for children and people with ulcers.[143][144] In 1963, paracetamol was added to the British Pharmacopoeia, and has gained popularity since then as an analgesic agent with few side-effects and little interaction with other pharmaceutical agents.[143][134]

    Concerns about paracetamol's safety delayed its widespread acceptance until the 1970s, but in the 1980s paracetamol sales exceeded those of aspirin in many countries, including the United Kingdom. This was accompanied by the commercial demise of phenacetin, blamed as the cause of

    In June 2009, an FDA advisory committee recommended that new restrictions be placed on paracetamol use in the United States to help protect people from the potential toxic effects. The maximum single adult dosage would be decreased from 1000 mg to 650 mg, while combinations of paracetamol and other products would be prohibited. Committee members were particularly concerned by the fact that the then-present maximum dosages of paracetamol had been shown to produce alterations in liver function.[148]

    In January 2011, the FDA asked manufacturers of prescription combination products containing paracetamol to limit its amount to no more than 325 mg per tablet or capsule and began requiring manufacturers to update the labels of all prescription combination paracetamol products to warn of the potential risk of severe liver damage.[149][150][151][152][153] Manufacturers had three years to limit the amount of paracetamol in their prescription drug products to 325 mg per dosage unit.[150][152]

    In November 2011, the Medicines and Healthcare products Regulatory Agency revised UK dosing of liquid paracetamol for children.[154]

    In September 2013, "Use Only as Directed", an episode of the radio program This American Life[155] highlighted deaths from paracetamol overdose. This report was followed by two reports by ProPublica alleging that the "FDA has long been aware of studies showing the risks of acetaminophen. So has the maker of Tylenol, McNeil Consumer Healthcare, a division of Johnson & Johnson"[156] and "McNeil, the maker of Tylenol, ... has repeatedly opposed safety warnings, dosage restrictions and other measures meant to safeguard users of the drug."[157]

    During the COVID-19 pandemic it was considered by some in the scientific community that it was an effective analgesic medication to treat symptoms of COVID-19, but this was found to be unsubstantiated.[158][159][160][161]

    Society and culture

    Naming

    Paracetamol is the Australian Approved Name[162] and British Approved Name[163] as well as the international nonproprietary name used by the WHO and in many other countries; acetaminophen is the United States Adopted Name[163] and Japanese Accepted Name and also the name generally used in Canada,[163] Venezuela, Colombia, and Iran.[163][164] Both paracetamol and acetaminophen are contractions of para-acetylaminophenol, a chemical name for the compound. The word "acetaminophen" is a shortened form of N-acetyl aminophenol, and was coined and first marketed by McNeil Laboratories in 1955.[165] The word "paracetamol" is a shortened form of para-acetyl-amino-phenol,[166] and was coined by Frederick Stearns & Co in 1956.[167] The initialism APAP used by dispensing pharmacists in the United States comes from the alternative chemical name [N-]acetyl-para-aminophenol.[168]

    Available forms

    Tylenol 500 mg capsules
    Panadol 500 mg tablets
    For comparison: The pure drug is a colourless crystalline powder.

    Paracetamol is available in oral, suppository, and

    intravenous forms.[169] Intravenous paracetamol is sold under the brand name Ofirmev in the United States.[170]

    In some formulations, paracetamol is combined with the

    propoxyphene napsylate.[176] A combination of paracetamol, codeine, and the doxylamine succinate is also available.[177]

    Paracetamol is sometimes combined with

    is added to this combination.

    Veterinary use

    Cats

    Paracetamol is extremely toxic to cats, which lack the necessary

    N-acetylcysteine is recommended.[187]

    Dogs

    Paracetamol has been reported to be as effective as aspirin in the treatment of musculoskeletal pain in dogs.[188] A paracetamol–codeine product (brand name Pardale-V)[189] licensed for use in dogs is available for purchase under supervision of a vet, pharmacist or other qualified person.[189] It should be administered to dogs only on veterinary advice and with extreme caution.[189]

    The main effect of toxicity in dogs is liver damage, and GI ulceration has been reported.[187][190][191][192] N-acetylcysteine treatment is efficacious in dogs when administered within two hours of paracetamol ingestion.[187][188]

    Snakes

    Aerial bait cartridges consisting of dead mice with 80 mg paracetamol tablets

    Paracetamol is lethal to snakes[193] and has been suggested as a chemical control program for the invasive brown tree snake (Boiga irregularis) in Guam.[194][195] Doses of 80 mg are inserted into dead mice that are scattered by helicopter[196] as lethal bait to be consumed by the snakes.

    Notes

    1. ^ Commonly called "acetaminophen" in the US, Canada, Japan, and South Korea.

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