Ciprofloxacin  is a  fluoroquinolone   antibiotic  used to treat a number of  bacterial infections . [ 5 ]  This includes bone and  joint infections , intra-abdominal infections, certain types of  infectious diarrhea ,  respiratory tract infections , skin infections,  typhoid fever , and  urinary tract infections , among others. [ 5 ]  For some infections it is used in addition to other antibiotics. [ 5 ]  It can be taken by mouth, as eye drops, as ear drops, or intravenously. [ 5 ] [ 6 ]


Common side effects include nausea, vomiting, and diarrhea. [ 5 ]  Severe side effects include an increased risk of  tendon rupture ,  hallucinations , and nerve damage. [ 5 ]  In people with  myasthenia gravis , there is worsening muscle weakness. [ 5 ]  Rates of side effects appear to be higher than some groups of antibiotics such as  cephalosporins  but lower than others such as  clindamycin . [ 7 ]  Studies in other animals raise concerns regarding use in  pregnancy . [ 8 ]  No problems were identified, however, in the children of a small number of women who took the medication. [ 8 ]  It appears to be safe during  breastfeeding . [ 5 ]  It is a second-generation fluoroquinolone with a  broad spectrum of activity  that usually results in the  death of the bacteria . [ 5 ] [ 9 ] [ 10 ]


Ciprofloxacin was patented in 1980 and introduced by Bayer in 1987. [ 11 ] [ 12 ]  It is on the  World Health Organization's List of Essential Medicines . [ 13 ] [ 14 ]  The World Health Organization classifies ciprofloxacin as critically important for human medicine. [ 15 ]  It is available as a  generic medication . [ 5 ] [ 16 ]  In 2022, it was the 181st most commonly prescribed medication in the United States, with more than 2   million prescriptions. [ 17 ] [ 18 ]


Ciprofloxacin is used to treat a wide variety of infections, including  infections of bones and joints ,  endocarditis , bacterial  gastroenteritis ,  malignant otitis externa ,  bubonic plague ,  respiratory tract infections ,  cellulitis ,  urinary tract infections ,  prostatitis ,  anthrax , and  chancroid . [ 5 ]


Ciprofloxacin only treats bacterial infections; it does not treat viral infections such as the  common cold . For certain uses including acute sinusitis, lower respiratory tract infections and uncomplicated  gonorrhea , ciprofloxacin is not considered a first-line agent.


Ciprofloxacin occupies an important role in treatment guidelines issued by major medical societies for the treatment of serious infections, especially those likely to be caused by Gram-negative bacteria, including  Pseudomonas aeruginosa . For example, ciprofloxacin in combination with  metronidazole  is one of several first-line antibiotic regimens recommended by the  Infectious Diseases Society of America  for the treatment of community-acquired abdominal infections in adults. [ 19 ]  It also features prominently in treatment guidelines for acute pyelonephritis, complicated or hospital-acquired urinary tract infection, acute or chronic prostatitis, [ 20 ]  certain types of endocarditis, [ 21 ]  certain skin infections, [ 22 ]  and prosthetic joint infections. [ 23 ]


In other cases, treatment guidelines are more restrictive, recommending in most cases that older, narrower-spectrum drugs be used as first-line therapy for less severe infections to minimize fluoroquinolone-resistance development. For example, the Infectious Diseases Society of America recommends the use of ciprofloxacin and other fluoroquinolones in urinary tract infections be reserved to cases of proven or expected resistance to narrower-spectrum drugs such as  nitrofurantoin  or  trimethoprim/sulfamethoxazole . [ 24 ]  The  European Association of Urology  recommends ciprofloxacin as an alternative regimen for the treatment of uncomplicated urinary tract infections, but cautions that the potential for "adverse events have to be considered". [ 20 ]


Although approved by regulatory authorities for the treatment of respiratory infections, ciprofloxacin is not recommended for respiratory infections by most treatment guidelines due in part to its modest activity against the common respiratory pathogen  Streptococcus pneumoniae . [ 25 ] [ 26 ] [ 27 ]  "Respiratory quinolones" such as  levofloxacin , having greater activity against this pathogen, are recommended as first line agents for the treatment of community-acquired pneumonia in patients with important co-morbidities and in patients requiring hospitalization (Infectious Diseases Society of America 2007). Similarly, ciprofloxacin is not recommended as a first-line treatment for  acute sinusitis . [ 28 ] [ 29 ]


Ciprofloxacin is approved for the treatment of gonorrhea in many countries, but this recommendation is widely regarded as obsolete due to resistance development. [ 30 ] [ 31 ] [ 32 ]


An expert review of published data on experiences with ciprofloxacin use during pregnancy concluded therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (quantity and quality of data=fair), but the data are insufficient to state no risk exists. [ 33 ]  Exposure to quinolones, including levofloxacin, during the first-trimester is not associated with an increased risk of stillbirths, premature births, birth defects, or low birth weight. [ 34 ]


Two small post-marketing epidemiology studies of mostly short-term, first-trimester exposure found that fluoroquinolones did not increase risk of major malformations, spontaneous abortions, premature birth, or low birth weight. [ 35 ] [ 36 ]


Fluoroquinolones have been reported as present in a mother's milk and thus passed on to the nursing child. [ 37 ] [ 38 ]


Oral and intravenous ciprofloxacin are approved by the FDA for use in children for only two indications due to the risk of permanent injury to the musculoskeletal system:


Its spectrum of activity includes most strains of bacterial pathogens responsible for  community-acquired pneumonias ,  bronchitis ,  urinary tract infections , and gastroenteritis. [ 41 ]  Ciprofloxacin is particularly effective against  Gram-negative bacteria  (such as  Escherichia coli ,  Haemophilus influenzae ,  Klebsiella pneumoniae ,  Legionella pneumophila ,  Moraxella catarrhalis ,  Proteus mirabilis , and  Pseudomonas aeruginosa ), but is less effective against  Gram-positive bacteria  (such as methicillin-sensitive  Staphylococcus aureus ,  Streptococcus pneumoniae , and  Enterococcus faecalis ) than newer fluoroquinolones. [ 42 ]


As a result of its widespread use to treat minor infections readily treatable with older, narrower-spectrum antibiotics, many bacteria have developed resistance to this drug, leaving it significantly less effective than it would have been otherwise. [ 43 ] [ 44 ]


Resistance  to ciprofloxacin and other  fluoroquinolones  may evolve rapidly, even during a course of treatment. Numerous  pathogens , including  enterococci ,  Streptococcus pyogenes  , and  Klebsiella pneumoniae  (quinolone-resistant) now exhibit resistance. [ 45 ]  Widespread veterinary usage of fluoroquinolones, particularly in Europe, has been implicated. [ 46 ]  Meanwhile, some  Burkholderia cepacia ,  Clostridium innocuum , and  Enterococcus faecium  strains have developed resistance to ciprofloxacin to varying degrees. [ 47 ]


Fluoroquinolones had become the class of antibiotics most commonly prescribed to adults in 2002. [ 48 ]  Nearly half (42%) of those prescriptions in the US were for conditions not approved by the FDA, such as acute bronchitis, otitis media, and acute upper respiratory tract infection. [ 48 ]


Contraindications include: [ 3 ]


Ciprofloxacin is also considered to be contraindicated in children (except for the indications outlined above), in  pregnancy , to nursing mothers, and in people with  epilepsy  or other  seizure  disorders.


Caution may be required in people with  Marfan syndrome  or  Ehlers-Danlos syndrome . [ 50 ]


Adverse effects can involve the tendons, muscles, joints, nerves, and the central nervous system. [ 51 ] [ 52 ]


Rates of adverse effects appear to be higher than with some groups of antibiotics such as  cephalosporins  but lower than with others such as  clindamycin . [ 7 ]  Compared to other antibiotics some studies find a higher rate of adverse effects [ 53 ] [ 54 ]  while others find no difference. [ 55 ]


In clinical trials most of the adverse events were described as mild or moderate in severity, abated soon after the drug was discontinued, and required no treatment. [ 3 ]  Some adverse effects may be permanent. [ 51 ]  Ciprofloxacin was stopped because of an adverse event in 1% of people treated with the medication by mouth. The most frequently reported drug-related events, from trials of all formulations, all dosages, all drug-therapy durations, and for all indications, were nausea (2.5%), diarrhea (1.6%), abnormal liver function tests (1.3%), vomiting (1%), and rash (1%). Other adverse events occurred at rates of <1%. [ 56 ]


Ciprofloxacin includes a  boxed warning  in the United States due to an increased risk of  tendinitis  and tendon rupture, especially in people who are older than 60 years, people who also use corticosteroids, and people with kidney, lung, or heart transplants. [ 57 ]  Tendon rupture can occur during therapy or even months after discontinuation of the medication. [ 58 ]  One study found that fluoroquinolone use was associated with a 1.9-fold increase in tendon problems. The risk increased to 3.2 in those over 60 years of age and to 6.2 in those over the age of 60 who were also taking corticosteroids. Among the 46,766 quinolone users in the study, 38 (0.08%) cases of Achilles tendon rupture were identified. [ 59 ]


The fluoroquinolones, including ciprofloxacin, are associated with an increased risk of cardiac toxicity, including  QT interval  prolongation,  torsades de pointes , ventricular arrhythmia, and  sudden death . [ 60 ] [ 52 ]


Because Ciprofloxacin is lipophilic, it has the ability to cross the  blood–brain barrier . [ 61 ]  The 2013 FDA label warns of nervous system effects. Ciprofloxacin, like other fluoroquinolones, is known to trigger seizures or lower the seizure threshold, and may cause other central nervous system adverse effects. Headache, dizziness, and insomnia have been reported as occurring fairly commonly in postapproval review articles, along with a much lower incidence of serious CNS adverse effects such as tremors, psychosis, anxiety, hallucinations, paranoia, and suicide attempts, especially at higher doses. [ 7 ]  Like other fluoroquinolones, it is also known to cause peripheral neuropathy that may be irreversible, such as weakness, burning pain, tingling or numbness. [ 62 ]


Fluoroquinolones have already been reported for movement disorders. [ 6 ]  In this context, ciprofloxacin is especially associated with  myoclonus , which derives the term "ciproclonus." [ 9 ]


Ciprofloxacin is active in six of eight  in vitro  assays used as rapid screens for the detection of genotoxic effects, but is not active in  in vivo  assays of genotoxicity. [ 3 ]  Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects due to ciprofloxacin at daily oral dose levels up to 250 and 750 mg/kg to rats and mice, respectively (about 1.7 and 2.5 times the highest recommended therapeutic dose based upon mg/m 2 ). Results from photo co-carcinogenicity testing indicate ciprofloxacin does not reduce the time to appearance of UV-induced skin tumors as compared to vehicle control. [ 3 ]


The other black box warning is that ciprofloxacin should not be used in people with  myasthenia gravis  due to possible exacerbation of muscle weakness which may lead to breathing problems resulting in death or ventilator support. Fluoroquinolones are known to block neuromuscular transmission. [ 3 ]  There are concerns that fluoroquinolones including ciprofloxacin can affect cartilage in young children. [ 3 ]


Clostridioides difficile -associated diarrhea is a serious adverse effect of ciprofloxacin and other fluoroquinolones; it is unclear whether the risk is higher than with other broad-spectrum antibiotics. [ 63 ]


A wide range of rare but potentially fatal adverse effects reported to the US FDA or the subject of case reports includes  aortic dissection , [ 64 ]   toxic epidermal necrolysis ,  Stevens–Johnson syndrome , low blood pressure, allergic pneumonitis, bone marrow suppression, hepatitis or liver failure, and sensitivity to light. [ 3 ] [ 65 ]  The medication should be discontinued if a rash, jaundice, or other sign of hypersensitivity occurs. [ 3 ]


Children and the elderly are at a much greater risk of experiencing adverse reactions. [ 66 ] [ 67 ]


Overdose of ciprofloxacin may result in reversible renal toxicity. Treatment of overdose includes emptying of the stomach by induced vomiting or  gastric lavage , as well as administration of antacids containing magnesium, aluminium, or calcium to reduce drug absorption. Renal function and urinary pH should be monitored. Important support includes adequate hydration and urine acidification if necessary to prevent crystalluria.  Hemodialysis  or  peritoneal dialysis  can only remove less than 10% of ciprofloxacin. [ 68 ]  Ciprofloxacin may be quantified in plasma or serum to monitor for drug accumulation in patients with hepatic dysfunction or to confirm a diagnosis of poisoning in acute overdose victims. [ 69 ]


Ciprofloxacin interacts with certain foods and several other drugs leading to undesirable increases or decreases in the serum levels or distribution of one or both drugs.


Ciprofloxacin should not be taken with antacids containing magnesium or aluminum, highly buffered drugs ( sevelamer ,  lanthanum carbonate ,  sucralfate ,  didanosine ), or with supplements containing calcium, iron, or zinc. It should be taken two hours before or six hours after these products. Magnesium or aluminum antacids turn ciprofloxacin into insoluble salts that are not readily absorbed by the intestinal tract, reducing peak serum concentrations by 90% or more, leading to therapeutic failure. Additionally, it should not be taken with dairy products or calcium-fortified juices alone, as peak serum concentration and the area under the serum concentration-time curve can be reduced up to 40%. However, ciprofloxacin may be taken with dairy products or calcium-fortified juices as part of a meal. [ 68 ] [ 70 ] [ 71 ]


Ciprofloxacin inhibits the drug-metabolizing enzyme  CYP1A2  and thereby can reduce the clearance of drugs metabolized by that enzyme. CYP1A2 substrates that exhibit increased serum levels in ciprofloxacin-treated patients include  tizanidine ,  theophylline ,  caffeine ,  methylxanthines ,  clozapine ,  olanzapine , and  ropinirole . Co-administration of ciprofloxacin with the CYP1A2 substrate tizanidine (Zanaflex) is contraindicated due to a 583% increase in the peak serum concentrations of tizanidine when administered with ciprofloxacin as compared to administration of tizanidine alone. Use of ciprofloxacin is cautioned in patients on theophylline due to its narrow therapeutic index. The authors of one review recommended that patients being treated with ciprofloxacin reduce their caffeine intake. Evidence for significant interactions with several other CYP1A2 substrates such as  cyclosporine  is equivocal or conflicting. [ 71 ] [ 3 ] [ 72 ]


The  Committee on Safety of Medicines  and the FDA warn that  central nervous system  adverse effects, including seizure risk, may be increased when  NSAIDs  are combined with quinolones. [ 3 ] [ 73 ]  The mechanism for this interaction may involve a  synergistic  increased antagonism of GABA neurotransmission. [ 74 ] [ 75 ]


Altered serum levels of the antiepileptic drugs  phenytoin  and  carbamazepine  (increased and decreased) have been reported in patients receiving concomitant ciprofloxacin. [ 3 ] [ 76 ] [ 77 ]


Ciprofloxacin is a potent inhibitor of  CYP1A2 ,  CYP2D6 , and  CYP3A4 . [ 78 ]


Ciprofloxacin is a  broad-spectrum antibiotic  of the  fluoroquinolone  class. It is active against some  Gram-positive  and many  Gram-negative  bacteria. [ 79 ]  It functions by inhibiting a type II  topoisomerase  ( DNA gyrase ) and topoisomerase IV, [ 80 ] [ 81 ]  necessary to separate bacterial DNA, thereby inhibiting cell division. Bacterial DNA fragmentation will occur as a result of inhibition of the enzymes.


Ciprofloxacin for systemic administration is available as immediate-release tablets, extended-release tablets, an oral suspension, and as a solution for intravenous administration. When administered over one hour as an intravenous infusion, [ 3 ]  ciprofloxacin rapidly distributes into the tissues, with levels in some tissues exceeding those in the serum. Penetration into the central nervous system is relatively modest, with cerebrospinal fluid levels normally less than 10% of peak serum concentrations. The serum half-life of ciprofloxacin is about 4–6 hours, with 50–70% of an administered dose being excreted in the urine as unmetabolized drug. An additional 10% is excreted in urine as metabolites. Urinary excretion is virtually complete 24 hours after administration. Dose adjustment is required in the elderly and in those with renal impairment. [ 3 ]


Ciprofloxacin is weakly bound to serum proteins (20–40%). It is an inhibitor of the drug-metabolizing enzyme  cytochrome P450 1A2 , which leads to the potential for clinically important drug interactions with drugs metabolized by that enzyme. [ 5 ]  Ciprofloxacin is about 70% available when administered orally. [ 3 ]


The extended release tablets [ 82 ]  allow once-daily administration by releasing the drug more slowly in the gastrointestinal tract. These tablets contain 35% of the administered dose in an immediate-release form and 65% in a slow-release matrix. Maximum serum concentrations are achieved between 1 and 4 hours after administration. Compared to the 250- and 500-mg immediate-release tablets, the 500-mg and 1000-mg XR tablets provide higher C max , but the 24‑hour AUCs are equivalent.


Ciprofloxacin immediate-release tablets contain ciprofloxacin as the hydrochloride salt, and the XR tablets contain a mixture of the hydrochloride salt and the free base. [ 3 ]


Ciprofloxacin is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C 17 H 18 FN 3 O 3  and its molecular weight is 331.4 g/mol. It is a faintly yellowish to light yellow crystalline substance. [ 68 ]


Ciprofloxacin hydrochloride ( USP ) is the monohydrochloride monohydrate salt of ciprofloxacin. It is a faintly yellowish to light yellow crystalline substance with a molecular weight of 385.8 g/mol. Its empirical formula is C 17 H 18 FN 3 O 3 HCl•H 2 O. [ 68 ]


Ciprofloxacin is the most widely used of the second-generation quinolones. [ 83 ] [ 84 ]  In 2010, over 20 million prescriptions were written, making it the 35th-most-commonly prescribed generic drug and the 5th-most-commonly prescribed antibacterial in the US. [ 85 ]


The first members of the quinolone antibacterial class were relatively low-potency drugs such as  nalidixic acid , used mainly in the treatment of urinary tract infections owing to their renal excretion and propensity to be concentrated in urine. [ 86 ]  In 1979, the publication of a patent [ 87 ]  filed by the pharmaceutical arm of Kyorin Seiyaku Kabushiki Kaisha disclosed the discovery of  norfloxacin , and the demonstration that certain structural modifications including the attachment of a fluorine atom to the quinolone ring leads to dramatically enhanced antibacterial potency. [ 88 ]  In the aftermath of this disclosure, several other pharmaceutical companies initiated research and development programs with the goal of discovering additional antibacterial agents of the fluoroquinolone class.


The fluoroquinolone program at  Bayer  focused on examining the effects of very minor changes to the norfloxacin structure. [ 89 ] [ 90 ]  In 1983, the company published  in vitro  potency data for ciprofloxacin, a fluoroquinolone antibacterial having a chemical structure differing from that of norfloxacin by the presence of a single carbon atom. [ 91 ]  This small change led to a two- to 10-fold increase in potency against most strains of Gram-negative bacteria. Importantly, this structural change led to a four-fold improvement in activity against the important  Gram-negative  pathogen  Pseudomonas aeruginosa , making ciprofloxacin one of the most potent known drugs for the treatment of this intrinsically antibiotic-resistant pathogen. [ medical citation needed ]


The oral tablet form of ciprofloxacin was approved in October 1987, [ 92 ]  just one year after the approval of norfloxacin. [ 93 ]  In 1991, the intravenous formulation was introduced. Ciprofloxacin sales reached a peak of about 2  billion  euros in 2001, before Bayer's patent expired in 2004, after which annual sales have averaged around €200 million. [ 94 ] [ 95 ]


The name probably originates from the International Scientific Nomenclature: ci- (alteration of cycl-) + propyl + fluor- + ox- + az- + -mycin. [ 96 ]


It is available as a generic medication and not very expensive. [ 5 ] [ 16 ]


In October 2001, the Prescription Access Litigation (PAL) project filed suit to dissolve an agreement between Bayer and three of its competitors which produced  generic versions of drugs  ( Barr Laboratories ,  Rugby Laboratories , and  Hoechst-Marion-Roussel ) that PAL claimed was blocking access to adequate supplies and cheaper, generic versions of ciprofloxacin. The plaintiffs charged that Bayer Corporation, a unit of Bayer AG, had unlawfully paid the three competing companies a total of $200 million to prevent cheaper, generic versions of ciprofloxacin from being brought to the market, as well as manipulating its price and supply. Numerous other consumer advocacy groups joined the lawsuit. On 15 October 2008, five years after Bayer's patent had expired, the United States District Court for the Eastern District of New York granted Bayer's and the other defendants' motion for summary judgment, holding that any anticompetitive effects caused by the settlement agreements between Bayer and its codefendants were within the exclusionary zone of the patent and thus could not be redressed by federal antitrust law, [ 97 ]  in effect upholding Bayer's agreement with its competitors.


Ciprofloxacin for systemic administration is available as immediate-release tablets, as extended-release tablets, as an oral suspension, and as a solution for intravenous infusion. It is available for local administration as eye drops and ear drops. It is available in combination with  dexamethasone , with  celecoxib , with  hydrocortisone , and with  fluocinolone acetonide . [ 98 ]


A class action was filed against Bayer AG on behalf of employees of the Brentwood Post Office in Washington, D.C., and workers at the U.S. Capitol, along with employees of American Media, Inc. in Florida and postal workers in general who alleged they developed serious adverse effects from taking ciprofloxacin in the aftermath of the  anthrax attacks in 2001 . The action alleged Bayer failed to warn class members of the potential side effects of the drug, thereby violating the Pennsylvania Unfair Trade Practices and Consumer Protection Laws. The class action was defeated and the litigation abandoned by the plaintiffs. [ 99 ]  A similar action was filed in 2003 in New Jersey by four New Jersey postal workers but was withdrawn for lack of grounds, as workers had been informed of the risks of ciprofloxacin when they were given the option of taking the drug. [ 100 ] [ 101 ]


As resistance to ciprofloxacin has grown since its introduction, research has been conducted to discover and develop analogs that can be effective against resistant bacteria; some have been looked at in antiviral models as well. [ 102 ]


A  dermatotoxin  or  dermatoxin  (from  derma , the  Greek  word for skin) is a  toxic  chemical that damages  skin ,  mucous membranes , or both, often leading to tissue  necrosis . Dermatoxins can be drugs, natural chemicals, or synthetic chemicals.


The severity of the effects of a dermatoxic agent is strongly dependent on the dose, route of exposure, rate at which it spreads, and the health of the afflicted individual.


It can produce  allergic contact dermatitis , changes that lead to  skin cancer ,  chemical burns ,  irritant dermatitis ,  photodermatitis ,  phototoxicity , changes to pigmentation, and  urticaria . [ 1 ]


This  toxicology -related article is a  stub . You can help Wikipedia by  expanding it .


Diclofenac , sold under the brand name  Voltaren  among others, is a  nonsteroidal anti-inflammatory drug  (NSAID) used to treat  pain  and  inflammatory diseases  such as  gout . [ 6 ] [ 9 ]  It can be taken  orally  (swallowed by mouth), inserted  rectally  as a  suppository , injected  intramuscularly , injected  intravenously ,  applied to the skin topically , or  through eye drops . [ 9 ] [ 12 ] [ 13 ]  Improvements in pain last up to eight hours. [ 9 ]  It is also available as the  fixed-dose combination   diclofenac/misoprostol  (Arthrotec) to help protect the stomach. [ 14 ] [ 15 ]


Common side effects include  abdominal pain ,  gastrointestinal bleeding , nausea, dizziness, headache, and swelling. [ 9 ]  Serious side effects may include  heart disease ,  stroke ,  kidney problems , and  stomach ulceration . [ 15 ] [ 9 ]  Use is not recommended in the  third trimester of pregnancy . [ 9 ]  It is likely safe during  breastfeeding . [ 15 ]  Diclofenac is believed to work by decreasing the production of  prostaglandins , like other drugs in this class. [ 16 ]


In 2022, it was the 51st most commonly prescribed medication in the United States, with more than 12   million prescriptions. [ 17 ] [ 18 ]  It is available as its acid or in two salts, as either diclofenac sodium or potassium. [ 15 ]


Diclofenac is used to  treat   pain  related to  arthritis ,  dysmenorrhea ,  rheumatic diseases  and other  inflammatory disorders , [ 9 ]   kidney stones  and  gallstones . An additional indication is the treatment of acute  migraines . [ 7 ]  Diclofenac is used to treat mild to moderate postoperative or post-traumatic pain, in particular when inflammation is also present.


Diclofenac ophthalmic is indicated for the treatment of postoperative inflammation in people who have undergone cataract extraction and for the temporary relief of pain and photophobia in people undergoing corneal refractive surgery. [ 19 ]


Diclofenac is also available in topical forms and is useful for  osteoarthritis  but not other types of long-term musculoskeletal pain. [ 20 ]  Diclofenac may also help with  actinic keratosis  and with acute pain caused by minor strains, sprains and  contusions . [ 21 ]


In many countries, eye drops are sold to treat acute and chronic nonbacterial inflammation of the anterior part of the eyes (such as postoperative states). [ 22 ]  The eye drops have also been used to manage pain for  traumatic corneal abrasion . [ 23 ]


Diclofenac is often used to treat chronic  pain associated with cancer , especially if inflammation is present. [ 24 ]


Diclofenac is contraindicated for pregnant women; for people with active stomach and/or duodenal  ulceration  or  gastrointestinal bleeding ; and for people undergoing  coronary artery bypass surgery . [ 9 ] [ 25 ] [ 26 ]


Diclofenac consumption has been associated with significantly increased vascular and coronary risk in a study including coxib, diclofenac,  ibuprofen  and  naproxen . [ 27 ]  Upper gastrointestinal complications were also reported. [ 27 ]   Major adverse cardiovascular events  were increased by about a third by diclofenac, chiefly due to an increase in major coronary events. [ 27 ]  Compared with placebo, of 1000 patients allocated to diclofenac for a year, three more had major vascular events, one of which was fatal. [ 27 ]  Vascular death is increased significantly by diclofenac. [ 27 ]


In October 2020, the US  Food and Drug Administration  (FDA) required the  prescription label  to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in fetuses that result in low amniotic fluid. [ 28 ] [ 29 ]


In 2013, a study found major vascular events were increased by about a third by diclofenac, chiefly due to an increase in major coronary events. [ 27 ]  Compared with placebo, of 1000 people allocated to diclofenac for a year, three more had major vascular events, one of which was fatal. [ 27 ]  Vascular death was increased by diclofenac (1·65). [ 27 ]


Following the identification of increased risks of heart attacks with the selective  COX-2 inhibitor   rofecoxib  in 2004, attention has focused on all the other members of the nonsteroidal anti-inflammatory drug group, including diclofenac. Research results are mixed, with a meta-analysis of papers and reports up to April 2006 suggesting a relative increased rate of heart disease of 1.63 compared to nonusers. [ 30 ]  Professor Peter Weissberg, medical director of the British Heart Foundation said, "However, the increased risk is small, and many patients with chronic debilitating pain may well feel that this small risk is worth taking to relieve their symptoms". Only  aspirin  was found not to increase the risk of heart disease; however, this is known to have a higher rate of gastric ulceration than diclofenac. As of January 2015, the MHRA announced that diclofenac would be reclassified as a prescription-only medicine (POM) due to the risk of cardiovascular adverse events. [ 31 ]


A subsequent large study of 74,838 Danish users of nonsteroidal anti-inflammatory drugs or  coxibs  found no additional cardiovascular risk from diclofenac use. [ 32 ]  A very large study of 1,028,437 Danish users of various nonsteroidal anti-inflammatory drugs or coxibs found the "Use of the nonselective NSAID diclofenac and the selective cyclooxygenase-2 inhibitor rofecoxib was associated with an increased risk of cardiovascular death ( odds ratio , 1.91; 95% confidence interval, 1.62 to 2.42; and odds ratio, 1.66; 95% confidence interval, 1.06 to 2.59, respectively), with a dose-dependent increase in risk." [ 33 ]


Diclofenac is similar in COX-2 selectivity to  celecoxib . [ 34 ] [ contradictory ]


As with other nonsteroidal anti-inflammatory drugs, the primary  mechanism  responsible for its  anti-inflammatory ,  antipyretic  and  analgesic  action is thought to be inhibition of prostaglandin synthesis through  COX -inhibition.


The main target in the inhibition of prostaglandin synthesis appears to be the transiently expressed prostaglandin-endoperoxide synthase-2 (PGES-2), also known as  cycloxygenase-2  (COX-2). That is, diclofenac is partially selective for COX-2. The reported selectivity for COX-2 varies from 1.5 to 30 depending on the source. [ 38 ] [ 39 ] [ 40 ] [ 41 ]


The drug may be bacteriostatic via inhibiting bacterial DNA synthesis. [ 42 ]


Diclofenac has a relatively high lipid solubility, making it one of the few nonsteroidal anti-inflammatory drugs that are able to enter the brain by crossing the  blood-brain barrier . [ 43 ]  As in the rest of the body, it is thought to exert its effect in the brain through inhibition of COX-2. [ 43 ]  In addition, it may have effects inside the spinal cord. [ 44 ]


Diclofenac may be a unique member of the nonsteroidal anti-inflammatory drugs in other aspects. Some evidence indicates it inhibits the  lipoxygenase  pathways, [ 45 ] [ 46 ]  thus reducing the formation of  leukotrienes  (also pro-inflammatory  autacoids ). It also may inhibit  phospholipase A2 , which may be relevant to its mechanism of action. These additional actions may explain its high potency – it is the most potent NSAID on a broad basis. [ 47 ]


Marked differences exist among nonsteroidal anti-inflammatory drugs in their selective inhibition of the two subtypes of cyclooxygenase, COX-1, and COX-2. [ 48 ]  Drug developers have focused on selective COX-2 inhibition, particularly as a way to minimize the gastrointestinal side effects of nonsteroidal anti-inflammatory drugs. In practice, the use of some  COX-2 inhibitors  with their  adverse effects  has led to massive numbers of lawsuits alleging wrongful death by  heart attack , yet other significantly COX-selective nonsteroidal anti-inflammatory drugs, such as diclofenac, have been well tolerated by most of the population. [ citation needed ]


Besides the COX-inhibition, several other molecular targets of diclofenac possibly contributing to its pain-relieving actions have recently been identified. These include:


The duration of action (i.e., duration of pain relief) of a single dose is longer (6 to 8  h ) than the drug's 1.2–2 h half-life. This could be partly because it persists for over 11 hours in  synovial fluids . [ 53 ]


Diclofenac was first synthesized by Alfred Sallmann and Rudolf Pfister in 1973. [ 54 ] [ 55 ]  The name "diclofenac" derives from its chemical name: 2-(2,6- dichlo ranilino)  phen yl ac etic acid. It was patented in Germany in 1978 by Ciba-Geigy (now  Novartis ). [ 56 ] [ 57 ]  It came into medical use in the United States in 1988. [ 9 ]   GlaxoSmithKline  purchased the rights in 2015. [ 54 ]  It is available as a  generic medication . [ 9 ]


Diclofenac formulations are available worldwide under many different brand names. [ 1 ]


Voltaren and Voltarol contain the sodium salt of diclofenac. In the United Kingdom, Voltarol can be supplied with either the sodium salt or the potassium salt, while Cataflam, sold in some other countries, is the potassium salt only. However, Voltarol Emulgel contains diclofenac diethylammonium 1.16%, being equivalent to 1% sodium salt. In 2016, Voltarol was one of the biggest selling branded over-the-counter medications sold in Great Britain, with sales of £39.3 million. [ 58 ]


In the United States, 1% diclofenac gel was approved by the FDA in 2007 as a prescription drug for the temporary relief of the pain of osteoarthritis of joints in the hands, knees, and feet. In 2020, the FDA approved the gel formulation for  nonprescription  use. [ 8 ]


In January 2015, diclofenac oral preparations were reclassified as prescription-only medicines in the UK. The topical preparations are available without a prescription. [ 59 ]


Use of diclofenac for animals is controversial due to toxicity when eaten by scavenging birds that eat dead animals; [ 60 ] [ 61 ]  the medication has been banned for veterinary use in several countries. [ 62 ] [ 63 ]


Use of diclofenac in animals has been reported to have led to a sharp decline in the  vulture  population in the Indian subcontinent – a 95% decline by 2003 [ 64 ]  and a 99.9% decline by 2008. The mechanism is presumed to be  kidney failure ; [ 65 ]  however, toxicity may be due to direct inhibition of uric acid secretion in vultures. [ 66 ]  Vultures eat the carcasses of  livestock  that have been administered veterinary diclofenac, and are poisoned by the accumulated chemical, [ 67 ]  as vultures do not have a particular enzyme to break down diclofenac. At a meeting of the National Wildlife Board in March 2005, the Government of India announced it intended to phase out the veterinary use of diclofenac. [ 68 ]   Meloxicam  is a safer alternative to replace use of diclofenac. [ 69 ]  It is more expensive than diclofenac, but the cost is dropping [ when? ]  as more pharmaceutical companies are beginning to manufacture it. [ citation needed ]


Steppe eagles  have the same vulnerability to diclofenac as Old World vultures and are therefore at a similar risk from its effects. [ 70 ]  Diclofenac has been shown also to harm freshwater fish species such as rainbow trout. [ 71 ] [ 72 ] [ 73 ] [ 74 ]  In contrast,  New World vultures , such as the  turkey vulture , can tolerate at least 100 times the level of diclofenac that is lethal to  Gyps  species. [ 75 ]


"The loss of tens of millions of vultures over the last decade has had major ecological consequences across the Indian subcontinent that pose a potential threat to human health. In many places, populations of  feral dogs  have increased sharply from the disappearance of  Gyps  vultures as the main scavenger of wild and domestic  ungulate  carcasses. Associated with the rise in dog numbers is an increased risk of  rabies " [ 69 ]  and casualties of almost 50,000 people. [ 76 ]  The Government of India cites this as one of the major consequences of a vulture species extinction. [ 68 ]  A major shift in the transfer of corpse pathogens from vultures to feral dogs and rats could lead to a disease pandemic, causing millions of deaths in a crowded country like India, whereas vultures' digestive systems safely destroy many species of such pathogens. Vultures are long-lived and slow to breed. They start breeding only at the age of six and only 50% of their young survive. Even if the government ban is fully implemented, it will take many years to revive the vulture population. [ 77 ]


The loss of vultures has had a social impact on the Indian  Zoroastrian   Parsi community , who traditionally use vultures to  dispose of human corpses  in  Towers of Silence , but are now compelled to seek alternative methods of disposal. [ 69 ]


Despite the vulture crisis, diclofenac remains available in other countries including many in Europe. [ 78 ]  It was controversially approved for veterinary use in Spain in 2013 and continues to be available, despite Spain being home to around 90% of the European vulture population and an independent simulation showing that the drug could reduce the population of vultures by 1–8% annually.  Spain's medicine agency  presented simulations suggesting that the number of deaths would be quite small. [ 79 ] [ 80 ]  A paper published in 2021 identified the first authenticated death of a vulture from diclofenac in Spain, a  cinereous vulture . [ 61 ] [ 81 ]


Diclofenac is on the European Union's watch list because it pollutes the  Baltic Sea . When the substance enters  freshwater , it has an environmental impact and is considered more difficult to remove in  wastewater treatment plants  than, for example,  ibuprofen . [ 82 ]  Harmful residues have been found in  blue mussels  and fish, among others, where it has been found to cause damage to internal organs such as the  gills , kidneys and liver. [ 83 ]


Diclofenac is used for livestock; such use was responsible for the  Indian vulture crisis , during which in a few years 95% of the country's vulture population was killed, and in many countries, agricultural use is now forbidden. [ 60 ] [ 61 ] [ 62 ] [ 63 ]


Diclofenac is approved as a veterinary medication in some countries [ 60 ] [ 61 ] [ 62 ] [ 63 ]  for the treatment of pets as well as in livestock. In some species of birds, diclofenac causes accumulation of  uric acid  crystals in internal organs—especially the liver and kidneys—resulting in  visceral gout , as well as cellular damage and  necrosis . [ 84 ]  In South Asia in the 2000s,  vulture populations were decimated  after feeding on carcasses of livestock that had been treated with diclofenac. [ 79 ]


Droxicam  is a  non-steroidal anti-inflammatory drug  of the  oxicam  class. A  prodrug  of  piroxicam , it is used for the relief of  pain  and  inflammation  in  musculoskeletal disorders  such as  rheumatoid arthritis  and  osteoarthritis . [ 1 ]


When heated, phenyl pyridin-2-ylcarbamate (1) decomposes to 2-isocyanatopyridine (2) which reacts with the  heterocyclic compound  (3) to give droxicam. [ 2 ] [ 3 ] [ 4 ]


Ethosuximide , sold under the brand name  Zarontin  among others, is a medication used to treat  absence seizures . [ 4 ]  It may be used by itself or with other  antiseizure medications  such as  valproic acid . [ 4 ]  Ethosuximide is taken by mouth. [ 4 ]


Ethosuximide is usually well tolerated. [ 5 ]  Common side effects include loss of appetite, abdominal pain, diarrhea, and feeling tired. [ 4 ]  Serious side effects include  suicidal thoughts ,  low blood cell levels , and  lupus erythematosus . [ 4 ] [ 5 ]  It is unclear if it has adverse effects on the fetus during  pregnancy . [ 4 ]  Ethosuximide is in the  succinimide  family of medications. Its mechanism of action is thought to be due to antagonism of the postsynaptic T-type voltage-gated calcium channel. [ 6 ]


Ethosuximide was approved for medical use in the United States in 1960. [ 7 ]  It is on the  World Health Organization's List of Essential Medicines . [ 8 ]  Ethosuximide is available as a  generic medication . [ 4 ]  As of 2019 [update] , its availability was limited in many countries, with concerns about  price fixing  in the United States. [ 9 ] [ 10 ] [ 11 ]


Ethosuximide is approved for  absence seizures , [ 12 ]  and is considered the first choice medication for treating them, in part because it lacks the idiosyncratic  hepatotoxicity  of the alternative anti-absence drug,  valproic acid . [ 13 ]


As with other anticonvulsants, ethosuximide carries a warning about use during pregnancy. Although a causal relationship with birth defects has not be established, the potential for harm to the baby is weighed against the known harm caused by a mother having even minor seizures. [ 4 ]


The following can occur with or without bone marrow loss:


Valproates  can either decrease or increase the levels of ethosuximide; however, combinations of  valproates  and ethosuximide had a greater  protective index  than either drug alone. [ 14 ]


It may elevate serum  phenytoin  levels.


The mechanism by which ethosuximide affects neuronal excitability includes block of  T-type calcium channels , and may include effects of the drug on other classes of ion channel. The primary finding that ethosuximide is a T-type calcium channel blocker gained widespread support, but initial attempts to replicate the finding were inconsistent. Subsequent experiments on recombinant T-type channels in cell lines demonstrated conclusively that ethosuximide blocks all T-type calcium channel isoforms. [ citation needed ]  Significant T-type calcium channel density occurs in dendrites of neurons, and recordings from reduced preparations that strip away this dendritic source of T-type calcium channels may have contributed to reports of ethosuximide ineffectiveness.


In March 1989, Coulter, Huguenard and Prince showed that ethosuximide and  dimethadione , both effective anti-absence agents, reduced low-threshold  Ca 2+   currents  in  T-type calcium channels  in freshly removed  thalamic   neurons . [ 15 ]  In June of that same year, they also found the mechanism of this reduction to be  voltage -dependent, using acutely dissociated neurons of rats and guinea pigs; it was also noted that  valproic acid , which is also used in absence seizures, did not do that. [ 16 ]  The next year, they showed that anticonvulsant succinimides did this and that the  pro-convulsant  ones did not. [ 17 ]  The first part was supported by  Kostyuk  et al. in 1992, who reported a substantial reduction in current in  dorsal root   ganglia  at concentrations ranging from 7 μmol/L to 1 mmol/L. [ 18 ]


That same year, however, Herrington and Lingle found no such effect at concentrations of up to 2.5 mmol/L. [ 19 ]  The year after, a study conducted on human  neocortical  cells removed during surgery for intractable epilepsy, the first to use human tissue, found that ethosuximide had no effect on Ca 2+  currents at the concentrations typically needed for a therapeutic effect. [ 20 ]


In 1998, Slobodan M. Todorovic and Christopher J. Lingle of Washington University reported a 100% block of T-type current in dorsal root ganglia at 23.7 ± 0.5 mmol/L, far higher than Kostyuk reported. [ 21 ]  That same year, Leresche et al. reported that ethosuximide had no effect on T-type currents, but did decrease noninactivating  Na +  current by 60% and the Ca 2+ -activated K +  currents by 39.1 ± 6.4% in rat and cat thalamocortical cells. It was concluded that the decrease in Na +  current is responsible for the anti-absence properties. [ 22 ]


In the introduction of a paper published in 2001, Dr. Juan Carlos Gomora and colleagues at the  University of Virginia  in  Charlottesville  pointed out that past studies were often done in isolated neurons that had lost most of their T-type channels. [ 23 ]  Using cloned  α 1 G ,  α 1 H , and  α 1 I  T-type calcium channels, Gomora's team found that ethosuximide blocked the channels with an  IC 50  of 12 ± 2 mmol/L and that of  N -desmethylmethsuximide (the active metabolite of  mesuximide ) is 1.95 ± 0.19 mmol/L for α 1 G, 1.82 ± 0.16 mmol/L for α 1 I, and 3.0 ± 0.3 mmol/L for α 1 H. It was suggested that the blockade of open channels is facilitated by ethosuximide's physically plugging the channels when current flows inward.


Ethosuximide is a chiral drug with a  stereocenter . Therapeutically, the  racemate , the 1: 1 mixture of (  S  ) and (  R  ) - isomers used. [ 24 ]


As of 2019 there were concerns in the United States that the price of ethosuximide was inflated by manufacturers. [ 11 ] [ 25 ]


Availability of ethosuximide is limited in many countries. [ 9 ]  It was marketed under the trade names Emeside and Zarontin. However, both capsule preparations were discontinued from production, leaving only generic preparations available. Emeside capsules were discontinued by their manufacturer,  Laboratories for Applied Biology , in 2005. [ 26 ]  Similarly, Zarontin capsules were discontinued by  Pfizer  in 2007. [ 27 ]  Syrup preparations of both brands remained available.


Etifoxine , sold under the trade name  Stresam  among others, is a  nonbenzodiazepine   anxiolytic  agent, primarily indicated for short-term management of  adjustment disorder , specifically instances of situational depression accompanied by  anxiety , such as stress-induced anxiety. [ 2 ] [ 6 ]  Administration is  by mouth . [ 7 ]
 Side effects  associated with etifoxine use include slight  drowsiness ,  headache ,  skin eruptions , and  allergic reactions . [ 2 ] [ 8 ] [ 9 ]  In rare cases, etifoxine has been linked to severe  skin  and  liver toxicity , as well as  menstrual bleeding between periods . [ 8 ] [ 1 ]  Unlike  benzodiazepines , etifoxine does not cause  sedation  or  lack of coordination . [ 10 ] [ 3 ]  Etifoxine acts as a  GABA A  receptor positive allosteric modulator  and as a  ligand  for  translocator proteins . [ 10 ]  Both mechanisms are conjectured to contribute to its anxiolytic properties. [ 10 ] [ 3 ]


Etifoxine was developed in the 1960s and was introduced for medical use in France in 1979. [ 11 ]  Its marketed in 53 countries worldwide, although it remains unavailable in the United States. [ 7 ] [ 11 ] [ 12 ]  Throughout the 2010s and early 2020s, the safety profile of etifoxine was scrutinized within France and the  European Union , prompted by reports of toxicity. [ 13 ] [ 8 ] [ 7 ]  The investigation revealed that instances of toxicity were infrequent, and etifoxine was allowed to remain on the market. [ 13 ] [ 8 ] [ 7 ]


Etifoxine has historically been used in the treatment of " psychosomatic  manifestations of  anxiety ", for instance " autonomic   dystonia , particularly with  cardiovascular  expression". [ 7 ] [ 13 ] [ 8 ] [ 1 ]  Subsequently, the indication for etifoxine has been more formalized as treatment of  adjustment disorder  (situational depression) with anxiety (ADWA) (e.g.,  stress -related anxiety). [ 7 ] [ 14 ] [ 3 ]  Etifoxine has been found to reduce scores on the  Hamilton Anxiety Rating Scale  (HAM-A) in people with adjustment disorder with anxiety by approximately 50 to 75% after 4   weeks of treatment in  clinical trials  (e.g., AMETIS, ETILOR, ETIZAL, STRETI studies). [ 7 ]  The medication is similarly effective or more effective than  benzodiazepines  like  lorazepam ,  alprazolam , and  clonazepam  and more effective than  buspirone  for adjustment disorder with anxiety on the basis of directly comparative  randomized controlled trials . [ 14 ] [ 3 ] [ 15 ] [ 16 ] [ 17 ] [ 4 ]  However, in the AMETIS study, both etifoxine and lorazepam failed to show greater effectiveness over  placebo . [ 7 ]


The usual dosage of etifoxine (as the  hydrochloride   salt ) is 150 to 200   mg per day in divided doses of 50 to 100   mg two to three times per day (e.g., 50   mg–50   mg–100   mg). [ 2 ] [ 7 ] [ 6 ] [ 18 ] [ 1 ] [ 19 ] [ 20 ]  It is taken for a few days to a few weeks, but no longer than 12   weeks. [ 2 ] [ 13 ] [ 7 ] [ 5 ]


Etifoxine is provided in the form of  oral   capsules  containing 50   mg etifoxine hydrochloride. [ 2 ] [ 1 ] [ 21 ] [ 22 ]


Etifoxine is  contraindicated  in people with  circulatory shock , severe  liver impairment , severe  kidney impairment ,  myasthenia gravis ,  galactosemia  (due to  lactose  in the  drug formulation ), severe  respiratory failure , and  hypersensitivity  (allergy) to etifoxine. [ 2 ] [ 5 ]  The medication is not recommended in children or adolescents under the age of 18 [ 5 ]  and is not recommended during  pregnancy  and  breastfeeding  due to insufficient data. [ 2 ] [ 1 ]  Caution is warranted with regard to combining etifoxine and other  central depressants  such as  benzodiazepines ,  central   analgesics ,  antipsychotics ,  sedative   antihistamines , and  alcohol . [ 2 ] [ 1 ]


Side effects  of etifoxine include slight  drowsiness  and  headache . [ 2 ] [ 9 ]  Rarely, etifoxine can cause benign  skin eruptions  or  rashes  and  allergic reactions  such as  hives  and  angioedema . [ 2 ] [ 8 ] [ 1 ]  Etifoxine shows less adverse effects of  anterograde amnesia ,  sedation , impaired psychomotor performance, and  withdrawal syndromes  than those of  benzodiazepines . [ 5 ]  No cases of  misuse  or  dependence  with etifoxine were identified in a French  pharmacovigilance survey , which is also in contrast to benzodiazepines. [ 8 ]


Etifoxine has been associated rarely with cases of severe  dermal toxicity  and  liver toxicity . [ 8 ] [ 23 ]  Skin and subcutaneous disorders are the most frequently reported, but these generally resolve after drug cessation. [ 3 ]  A 2012 review of etifoxine by the French National Pharmacovigilance Committee determined that etifoxine was safe and continued to provide a favorable alternative to benzodiazepine anxiolytics. The committee found (for a ten-year pharmacovigilance period) that safety concerns were rare or very rare and that the incidence of idiosyncratic hepatic (liver) problems were very rare. [ 13 ]


Unlike benzodiazepines, etifoxine may produce its anxiolytic effects through a dual mechanism, by directly binding to  GABA A  receptors  and (purportedly, exact binding site undetermined) to the mitochondrial  translocator protein  (TSPO). This results in stimulation of the  biosynthesis  of  endogenous   neurosteroids , for instance  allopregnanolone , a highly  potent  GABA A  receptor positive allosteric modulator. [ 24 ]


At GABA A  receptors etifoxine binds at the α+β− interface and preferentially potentiates α 2 β 3 γ 2  and α 3 β 3 γ 2  receptor types. [ 25 ]  This direct allosteric potentiation can only be observed at relatively high concentrations (starting at >1   mM) and is perhaps not physiologically relevant at normal human doses. [ 26 ]  This is different from benzodiazepines and etifoxine can be used alongside benzodiazepines to potentiate their effects without competing for binding sites; [ 27 ]  however, it also means that the direct effects of etifoxine are not reversed by the benzodiazepine antagonist  flumazenil . [ 28 ]


Etifoxine is taken via  oral administration . [ 2 ] [ 5 ]  It is rapidly  absorbed  from the  gastrointestinal tract . [ 5 ]  It is well-absorbed, with a  bioavailability  of 90%. [ 2 ] [ 3 ]  The  time to peak levels  of etifoxine is 2 to 3   hours. [ 5 ]  The  plasma protein binding  of etifoxine is 88 to 95%. [ 4 ]  It does not bind to  blood cells . [ 2 ]  The drug is known to cross the  placental barrier . [ 2 ]  Etifoxine is  metabolized  in the  liver  into several  metabolites . [ 5 ]  One of these metabolites, diethyletifoxine, is  pharmacologically active . [ 5 ]  The  elimination half-life  of etifoxine is 6   hours and of diethyletifoxine is almost 20   hours. [ 5 ]  Etifoxine is  eliminated  in three phases. [ 2 ]  The drug is  excreted  mainly in  urine  in the form of metabolites. [ 5 ]  It is also excreted in  bile . [ 5 ]  Only small amounts are excreted unchanged. [ 5 ]


Etifoxine is a  nonbenzodiazepine —that is, it is similarly a  GABA A  receptor positive allosteric modulator  but its  chemical structure  is distinct from that of  benzodiazepines . [ 3 ] [ 29 ]  Instead, it is a  benzoxazine   derivative . [ 3 ]


Etifoxine is used pharmaceutically as the  hydrochloride   salt . [ 30 ] [ 31 ]


( S )-Etifoxine, the ( S )  enantiomer  of etifoxine, was under development by Anvyl Pharmaceuticals for the treatment of  neuropathic pain , but development was discontinued. [ 32 ]  A  deuterated  form of etifoxine with improved  pharmacokinetics  known as  deuterated etifoxine  (GRX-917) is under development by GABA Therapeutics for the treatment  anxiety  and  mood disorders . [ 33 ] [ 34 ] [ 24 ] [ 35 ]


Etifoxine was developed by  Hoechst  in the 1960s. [ 11 ] [ 36 ]  It was introduced for medical use in  France  in 1979. [ 11 ]  Since at least 2000, etifoxine has been marketed by the French  pharmaceutical company  Biocodex. [ 31 ] [ 29 ] [ 37 ] [ 19 ]  Following reports of  post-marketing   toxicity , the  safety  of etifoxine was reassessed by the French government [ 13 ] [ 8 ]  and the  European Medicines Agency  (EMA). [ 38 ] [ 39 ]  In January 2022, the EMA "finalized its review of Stresam and concluded that the medicine can continue to be used for the treatment of anxiety disorders, but it must not be used in patients who previously had severe skin reactions or severe liver problems after taking etifoxine." [ 38 ] [ 39 ]


Etifoxine  is the  generic name  of the drug and its  INN Tooltip International Nonproprietary Name ,  BAN Tooltip British Approved Name , and  DCF Tooltip Dénomination Commune Française . [ 30 ] [ 31 ]  It is also known by the older and much-lesser-used synonym  etafenoxine [ 40 ]  and by its developmental code name  Hoe 36801 . [ 30 ] [ 31 ]  Etifoxine is marketed under the brand name  Stresam . [ 30 ] [ 31 ] [ 19 ]  It has also been marketed under the brand name  Strezam , specifically in Russia. [ 19 ]


Etifoxine has been marketed in 53   countries as of 2022. [ 7 ] [ 11 ]  Some of the countries in which etifoxine has been marketed include  Argentina ,  Bulgaria ,  Chile ,  France ,  Luxembourg ,  Malta ,  Romania ,  Russia ,  South Africa ,  Thailand , and  Ukraine . [ 19 ] [ 13 ] [ 7 ] [ 31 ]  Etifoxine is not approved for use by the  United States   Food and Drug Administration  (FDA) or the  European Medicines Agency  (EMA) of the  European Union , and hence is not marketed in these regions. [ 11 ] [ 7 ]  However, etifoxine is marketed in five European Union member states (France, Bulgaria, Luxembourg, Malta, Romania). [ 13 ] [ 7 ]


Ibuprofen  is a  nonsteroidal anti-inflammatory drug  (NSAID) that is used to relieve  pain ,  fever , and  inflammation . [ 8 ]  This includes  painful menstrual periods ,  migraines , and  rheumatoid arthritis . [ 8 ]  It may also be used to close a  patent ductus arteriosus  in a  premature baby . [ 9 ] [ 8 ]  It can be taken  orally  (by mouth) or  intravenously . [ 8 ]  It typically begins working within an hour. [ 8 ]


Common  side effects  include  heartburn ,  nausea ,  indigestion , and  abdominal pain . [ 8 ]  As with other NSAIDs, potential side effects include  gastrointestinal bleeding . [ 10 ]  Long-term use has been associated with  kidney failure , and rarely  liver failure , and it can exacerbate the condition of patients with  heart failure . [ 8 ]  At low doses, it does not appear to increase the risk of  heart attack ; however, at higher doses it may. [ 10 ]  Ibuprofen can also worsen  asthma . [ 10 ]  While its safety in early  pregnancy  is unclear, [ 8 ]  it appears to be harmful in later pregnancy, so it is not recommended during that period. [ 11 ]  Like other NSAIDs, it works by inhibiting the production of  prostaglandins  by decreasing the activity of the enzyme  cyclooxygenase  (COX). [ 8 ]  Ibuprofen is a weaker anti-inflammatory agent than other NSAIDs. [ 10 ]


Ibuprofen was discovered in 1961 by  Stewart Adams  and John Nicholson [ 12 ]  while working at  Boots UK Limited  and initially marketed as Brufen. [ 13 ]  It is available under a number of brand names including  Advil ,  Motrin , and  Nurofen . [ 8 ] [ 14 ]  Ibuprofen was first marketed in 1969 in the United Kingdom and in 1974 in the United States. [ 8 ] [ 13 ]  It is on the  World Health Organization's List of Essential Medicines . [ 15 ]  It is available as a  generic medication . [ 8 ]  In 2022, it was the 33rd most commonly prescribed medication in the United States, with more than 17   million prescriptions. [ 16 ] [ 17 ]


Ibuprofen is used primarily to treat  fever  (including postvaccination fever), mild to moderate  pain  (including pain relief after  surgery ),  painful menstruation ,  osteoarthritis , dental pain,  headaches , and  pain from kidney stones . About 60% of people respond to any NSAID; those who do not respond well to a particular one may respond to another. [ 18 ]  A Cochrane medical review of 51 trials of NSAIDs for the treatment of  lower back pain  found that "NSAIDs are effective for short-term symptomatic relief in patients with acute low back pain". [ 19 ]


It is used for inflammatory diseases such as  juvenile idiopathic arthritis  and  rheumatoid arthritis . [ 20 ] [ 21 ]  It is also used for  pericarditis  and  patent ductus arteriosus . [ 9 ] [ 22 ] [ 23 ]


In some countries, ibuprofen  lysine  (the lysine salt of ibuprofen, sometimes called "ibuprofen lysinate") is licensed for treatment of the same conditions as ibuprofen; the lysine salt is used because it is more water-soluble. [ 24 ]


In 2006, ibuprofen lysine was approved in the United States by the  Food and Drug Administration  (FDA) for closure of patent ductus arteriosus in premature infants weighing between 500 and 1,500 g (1 and 3 lb), who are no more than 32 weeks gestational age when usual medical management (such as fluid restriction, diuretics, and respiratory support) is not effective. [ 25 ]


Adverse effects include  nausea ,  heartburn ,  indigestion ,  diarrhea ,  constipation ,  gastrointestinal ulceration ,  headache ,  dizziness , rash, salt and fluid retention, and  high blood pressure . [ 8 ] [ 21 ] [ 26 ]


Infrequent adverse effects include esophageal ulceration,  heart failure ,  high blood levels of potassium ,  kidney impairment , confusion, and  bronchospasm . [ 21 ]  Ibuprofen can exacerbate asthma, sometimes fatally. [ 27 ]


Allergic reactions, including  anaphylaxis , may occur. [ 28 ]  Ibuprofen may be quantified in blood, plasma, or serum to demonstrate the presence of the drug in a person having experienced an anaphylactic reaction, confirm a diagnosis of poisoning in people who are hospitalized, or assist in a medicolegal death investigation. A  monograph  relating ibuprofen plasma concentration, time since ingestion, and risk of developing renal toxicity in people who have overdosed has been published. [ 29 ]


In October 2020, the U.S. FDA required the  drug label  to be updated for all NSAID medications to describe the risk of kidney problems in unborn babies that result in low amniotic fluid. [ 30 ] [ 31 ]


Along with several other NSAIDs, chronic ibuprofen use is correlated with the risk of progression to  hypertension  in women, though less than for  paracetamol  (acetaminophen), [ 32 ]  and  myocardial infarction  (heart attack), [ 33 ]  particularly among those chronically using higher doses. On 9 July 2015, the U.S. FDA toughened warnings of increased  heart attack  and  stroke  risk associated with ibuprofen and related NSAIDs; the NSAID  aspirin  is not included in this warning. [ 34 ]  The  European Medicines Agency  (EMA) issued similar warnings in 2015. [ 35 ] [ 36 ]


Along with other NSAIDs, ibuprofen has been associated with the onset of  bullous pemphigoid  or pemphigoid-like blistering. [ 37 ]  As with other NSAIDs, ibuprofen has been reported to be a  photosensitizing  agent, [ 38 ]  but it is considered a weak photosensitizing agent compared to other members of the  2-arylpropionic acid  class. Like other NSAIDs, ibuprofen is an extremely rare cause of the  autoimmune diseases   Stevens–Johnson syndrome  (SJS) and  toxic epidermal necrolysis . [ 39 ] [ 40 ] [ 41 ]


Drinking  alcohol  when taking ibuprofen may increase the risk of  stomach bleeding . [ 42 ]


According to the FDA, "ibuprofen can interfere with the  antiplatelet  effect of low-dose  aspirin , potentially rendering aspirin less effective when used for  cardioprotection  and  stroke  prevention". Allowing sufficient time between doses of ibuprofen and immediate-release (IR) aspirin can avoid this problem. The recommended elapsed time between a dose of ibuprofen and a dose of aspirin depends on which is taken first. It would be 30 minutes or more for ibuprofen taken after IR aspirin, and 8 hours or more for ibuprofen taken before IR aspirin. However, this timing cannot be recommended for  enteric-coated  aspirin. If ibuprofen is taken only occasionally without the recommended timing, though, the reduction of the cardioprotection and stroke prevention of a daily aspirin regimen is minimal. [ 43 ]


Ibuprofen combined with  paracetamol  is considered generally safe in children for short-term usage. [ 44 ]


Ibuprofen overdose has become common since it was licensed for  over-the-counter  (OTC) use. Many overdose experiences are reported in the  medical literature , although the frequency of life-threatening complications from ibuprofen overdose is low. [ 45 ]  Human responses in cases of overdose range from an absence of symptoms to a fatal outcome despite intensive-care treatment. Most symptoms are an excess of the pharmacological action of ibuprofen and include abdominal pain, nausea,  vomiting , drowsiness, dizziness, headache,  ear ringing , and  nystagmus . Rarely, more severe symptoms such as  gastrointestinal bleeding ,  seizures ,  metabolic acidosis ,  hyperkalemia ,  low blood pressure ,  slow heart rate ,  fast heart rate ,  atrial fibrillation ,  coma , liver dysfunction,  acute kidney failure ,  cyanosis ,  respiratory depression , and  cardiac arrest  have been reported. [ 46 ]  The severity of symptoms varies with the ingested dose and the time elapsed; however, individual sensitivity also plays an important role. Generally, the symptoms observed with an overdose of ibuprofen are similar to the symptoms caused by overdoses of other NSAIDs.


The correlation between the severity of symptoms and measured ibuprofen plasma levels is weak. Toxic effects are unlikely at doses below 100   mg/kg, but can be severe above 400   mg/kg (around 150 tablets of 200   mg units for an average adult male); [ 47 ]  however, large doses do not indicate the clinical course is likely to be lethal. [ 48 ]  A precise  lethal dose  is difficult to determine, as it may vary with age, weight, and concomitant conditions of the person.


Treatment to address an ibuprofen overdose is based on how the symptoms present. In cases presenting early, decontamination of the stomach is recommended. This is achieved using  activated charcoal ; charcoal absorbs the drug before it can enter the  bloodstream .  Gastric lavage  is now rarely used, but can be considered if the amount ingested is potentially life-threatening, and it can be performed within 60 minutes of ingestion. Purposeful vomiting is not recommended. [ 49 ]  Most ibuprofen ingestions produce only mild effects, and the management of overdose is straightforward. Standard measures to maintain normal urine output should be instituted and  kidney function  monitored. [ 47 ]  Since ibuprofen has acidic properties and is also excreted in the urine,  forced alkaline diuresis  is theoretically beneficial. However, because ibuprofen is highly protein-bound in the blood, the kidneys' excretion of the unchanged drug is minimal. Forced alkaline diuresis is, therefore, of limited benefit. [ 50 ]


A Canadian study of pregnant women suggests that those taking any type or amount of NSAIDs (including ibuprofen,  diclofenac , and  naproxen ) were 2.4 times more likely to  miscarry  than those not taking the medications. [ 51 ]  However, an Israeli study found no increased risk of miscarriage in the group of mothers using NSAIDs. [ 52 ]


Ibuprofen works by inhibiting  cyclooxygenase  (COX) enzymes, which convert  arachidonic acid  to  prostaglandin H2  (PGH 2 ). PGH 2 , in turn, is converted by other enzymes into various  prostaglandins  (which mediate pain,  inflammation , and fever) and  thromboxane A2  (which stimulates  platelet  aggregation and promotes  blood clot  formation).


Like aspirin and  indomethacin , ibuprofen is a nonselective COX inhibitor, in that it inhibits two  isoforms  of cyclooxygenase,  COX-1  and  COX-2 . The  analgesic ,  antipyretic , and anti-inflammatory activity of NSAIDs appears to operate mainly through inhibition of COX-2, which decreases the synthesis of prostaglandins involved in mediating inflammation, pain, fever, and swelling. Antipyretic effects may be due to action on the hypothalamus, resulting in an increased peripheral blood flow, vasodilation, and subsequent heat dissipation. Inhibition of COX-1 instead would be responsible for unwanted effects on the gastrointestinal tract. [ 53 ]  However, the role of the individual COX isoforms in the analgesic, anti-inflammatory, and gastric damage effects of NSAIDs is uncertain, and different compounds cause different degrees of analgesia and gastric damage. [ 54 ]


Ibuprofen is administered as a  racemic mixture . The  R -enantiomer undergoes extensive interconversion to the  S -enantiomer  in vivo . The  S -enantiomer is believed to be the more pharmacologically active enantiomer. [ 55 ]  The  R -enantiomer is converted through a series of three main enzymes. These enzymes include acyl-CoA-synthetase, which converts the  R -enantiomer to (−)- R -ibuprofen I-CoA; 2-arylpropionyl-CoA epimerase, which converts (−)- R -ibuprofen I-CoA to (+)- S -ibuprofen I-CoA; and hydrolase, which converts (+)- S -ibuprofen I-CoA to the  S -enantiomer. [ 41 ]  In addition to the conversion of ibuprofen to the  S -enantiomer, the body can metabolize ibuprofen to several other compounds, including numerous hydroxyl, carboxyl and glucuronyl metabolites. Virtually all of these have no pharmacological effects. [ 41 ]


Unlike most other NSAIDs, ibuprofen also acts as an inhibitor of  Rho kinase  and may be useful in recovery from spinal cord injury. [ 56 ] [ 57 ]  Another unusual activity is inhibition of the sweet taste receptor. [ 58 ]


After oral administration, peak serum concentration is reached after 1–2 hours, and up to 99% of the drug is bound to plasma proteins. [ 59 ]  The majority of ibuprofen is metabolized and eliminated within 24 hours in the urine; however, 1% of the unchanged drug is removed through biliary excretion. [ 55 ]


Ibuprofen is practically insoluble in water, but very soluble in most organic solvents like  ethanol  (66.18   g/100   mL at 40   °C for 90% EtOH),  methanol ,  acetone  and  dichloromethane . [ 60 ]


The original synthesis of ibuprofen by the Boots Group started with the compound  isobutylbenzene . The synthesis took six steps. A modern, greener technique with fewer waste byproducts for the synthesis involves only three steps and was developed in the 1980s by the Celanese Chemical Company. [ 61 ] [ 62 ]  The synthesis is initiated with the acylation of isobutylbenzene using the recyclable Lewis acid catalyst hydrogen fluoride. [ 63 ] [ 64 ]  The following catalytic hydrogenation of isobutylacetophenone is performed with either Raney nickel or palladium on carbon to lead into the key-step, the  carbonylation  of 1-(4-isobutylphenyl)ethanol. This is achieved by a PdCl 2 (PPh 3 ) 2  catalyst, at around 50 bar of CO pressure, in the presence of HCl (10%). [ 65 ]  The reaction presumably proceeds through the intermediacy of the  styrene  derivative (acidic elimination of the alcohol) and (1-chloroethyl)benzene derivative (Markovnikow addition of HCl to the double bond). [ 66 ]


Ibuprofen, like other 2-arylpropionate derivatives such as  ketoprofen ,  flurbiprofen  and  naproxen , contains a  stereocenter  in the α-position of the  propionate  moiety.


The product sold in pharmacies is a  racemic mixture  of the  S  and  R -isomers. The  S  (dextrorotatory) isomer is the more biologically active; this isomer has been isolated and used medically (see  dexibuprofen  for details). [ 60 ]


The  isomerase  enzyme,  alpha-methylacyl-CoA racemase , converts ( R )-ibuprofen into the ( S )- enantiomer . [ 67 ] [ 68 ] [ 69 ]


(S)-ibuprofen, the  eutomer , harbors the desired therapeutic activity. The inactive (R)-enantiomer, the  distomer , undergoes a unidirectional  chiral inversion  to offer the active (S)-enantiomer. That is, when the ibuprofen is administered as a racemate the distomer is converted  in vivo  into the eutomer while the latter is unaffected. [ 70 ] [ 71 ] [ 72 ]


Ibuprofen was derived from  propionic acid  by the  research  arm of  Boots Group  during the 1960s. [ 73 ]  The name is derived from the 3 functional groups: isobutyl (ibu) propionic acid (pro) phenyl (fen). [ 74 ]  Its discovery was the result of research during the 1950s and 1960s to find a safer alternative to  aspirin . [ 13 ] [ 75 ]  The molecule was discovered and synthesized by a team led by  Stewart Adams , with a patent application filed in 1961. [ 13 ]  Adams initially tested the drug as treatment for his  hangover . [ 76 ]  In 1985, Boots' worldwide patent for ibuprofen expired and generic products were launched. [ 77 ]


The medication was launched as a treatment for  rheumatoid arthritis  in the United Kingdom in 1969, and in the United States in 1974. Later, in 1983 and 1984, it became the first NSAID (other than aspirin) to be available  over-the-counter  (OTC) in these two countries. [ 13 ] [ 75 ]  Boots was awarded the  Queen's Award for Technical Achievement  in 1985 for the development of the drug. [ 78 ]


In November 2013, work on ibuprofen was recognized by the erection of a  Royal Society of Chemistry blue plaque  at Boots' Beeston Factory site in Nottingham, [ 79 ]  which reads:


In recognition of the work during the 1980s by The Boots Company PLC on the development of ibuprofen which resulted in its move from prescription-only status to over-the-counter sale, therefore expanding its use to millions of people worldwide


and another at  BioCity Nottingham , the site of the original laboratory, [ 79 ]  which reads:


In recognition of the pioneering research work, here on Pennyfoot Street, by Dr Stewart Adams and Dr John Nicholson in the Research Department of Boots which led to the discovery of ibuprofen used by millions worldwide for the relief of pain.


Ibuprofen was made available by prescription in the United Kingdom in 1969 and in the United States in 1974. [ 80 ]


Ibuprofen  is the  International nonproprietary name  (INN),  British Approved Name  (BAN),  Australian Approved Name  (AAN) and  United States Adopted Name  (USAN). In the United States, it has been sold under the brand-names Motrin and Advil since 1974 [ 81 ]  and 1984, [ 82 ]  respectively. Ibuprofen is commonly available in the United States up to the FDA's 1984 dose limit OTC, rarely used higher by prescription. [ 83 ] [ failed verification ]


In 2009, the first injectable formulation of ibuprofen was approved in the United States, under the brand name Caldolor. [ 84 ] [ 85 ]


Ibuprofen can be taken  orally  (by mouth) (as a tablet, a capsule, or a suspension) and  intravenously . [ 8 ]


Ibuprofen is sometimes used for the treatment of acne because of its  anti-inflammatory  properties, and has been sold in Japan in topical form for  adult acne . [ 86 ] [ 87 ]  As with other NSAIDs, ibuprofen may be useful in the treatment of severe  orthostatic hypotension  (low blood pressure when standing up). [ 88 ]  NSAIDs are of unclear utility in the prevention and treatment of  Alzheimer's disease . [ 89 ] [ 90 ]


Ibuprofen has been associated with a lower risk of  Parkinson's disease  and may delay or prevent it.  Aspirin , other NSAIDs, and  paracetamol  (acetaminophen) had no effect on the risk for Parkinson's. [ 91 ]  In March 2011, researchers at  Harvard Medical School  announced in  Neurology  that ibuprofen had a  neuroprotective  effect against the risk of developing  Parkinson's disease . [ 92 ] [ 93 ] [ 94 ]  People regularly consuming ibuprofen were reported to have a 38% lower risk of developing Parkinson's disease, but no such effect was found for other pain relievers, such as aspirin and paracetamol. Use of ibuprofen to lower the risk of Parkinson's disease in the general population would not be problem-free, given the possibility of adverse effects on the urinary and digestive systems. [ 95 ]


Some  dietary supplements  might be dangerous to take along with ibuprofen and other NSAIDs, but as of 2016 [update] , more research needs to be conducted to be certain. These supplements include those that can  prevent platelet aggregation , including  ginkgo ,  garlic ,  ginger ,  bilberry ,  dong quai ,  feverfew ,  ginseng ,  turmeric ,  meadowsweet  ( Filipendula ulmaria ), and  willow  ( Salix  spp.); those that contain  coumarin , including  chamomile ,  horse chestnut ,  fenugreek  and  red clover ; and those that increase the risk of bleeding, like  tamarind . [ 96 ]


Ibuprofen lysine is sold for rapid pain relief; [ 97 ]  given in the form of its lysine salt, absorption is much quicker (35 minutes for the salt compared to 90–120 minutes for ibuprofen). However, a clinical trial with 351 participants in 2020, funded by Sanofi, found no significant difference between ibuprofen and ibuprofen lysine concerning the eventual onset of action or analgesic efficacy. [ 98 ]


Isotretinoin , also known as  13- cis -retinoic acid  and sold under the brand name  Accutane  among others, is a medication used to treat skin diseases like  harlequin-type ichthyosis , and  lamellar ichthyosis , and severe cystic  acne  or moderate acne that is unresponsive to antibiotics. [ 6 ]  Isotretinoin is used off-label to treat  basal cell carcinoma  and  squamous cell carcinoma , although clinical evidence suggests it is not effective in this setting. [ 7 ]  It is a  retinoid , meaning it is related to  vitamin A , and is found in small quantities naturally in the body. Its  isomer ,  tretinoin , is also an acne drug.


The most common adverse effects are dry lips ( cheilitis ), dry and fragile skin ( xeroderma ),  dry eyes [ 8 ]  and an  increased susceptibility to sunburn . Uncommon and rare side effects include muscle aches and pains ( myalgias ), and headaches. Some of those side effects can persist long after the discontinuation of the use of the drug. [ 8 ]  Isotretinoin may cause  liver failure , therefore the patient's  blood levels  should be regularly tested. [ 9 ]  It is known to cause  birth defects  due to in-utero exposure because of the molecule's close resemblance to  retinoic acid , a natural vitamin A derivative that controls normal embryonic development. It is associated with psychiatric side effects, most commonly depression but also, more rarely, psychosis and unusual behaviors. Other rare side effects include  hyperostosis  and premature  epiphyseal closure , which have been reported to be persistent.


Isotretinoin was patented in 1969 and approved for medical use in 1982. [ 10 ]  In 2021, it was the 264th most commonly prescribed medication in the United States, with more than 1   million prescriptions. [ 11 ] [ 12 ]


Isotretinoin is used primarily for persistent cystic acne. [ 13 ] [ 14 ] [ 15 ] [ 16 ]   Many dermatologists also support its use for treatment of lesser degrees of acne that prove resistant to other treatments, or that produce scarring or psychological distress. [ 17 ]  Isotretinoin is not indicated for the treatment of prepubertal acne and is not recommended in children less than 12 years of age. [ 18 ]


It is also somewhat effective for  hidradenitis suppurativa  and some cases of severe  rosacea . [ 19 ]  It can also be used to help treat  harlequin ichthyosis ,  lamellar ichthyosis  and is used in  xeroderma pigmentosum  cases to relieve  keratoses . Isotretinoin has been used to treat the extremely rare condition  fibrodysplasia ossificans progressiva . It is also used for the treatment of  pediatric neuroblastoma  in Japan, but data for its efficacy is not conclusive and it has not been approved in other countries. [ 20 ]


Isotretinoin therapy has furthermore proven effective against  genital warts  in experimental use but is rarely used for this indication as there are more effective treatments. Isotretinoin may represent an efficacious and safe alternative systemic form of therapy for  recalcitrant condylomata acuminata  (RCA) of the cervix. In most countries, this therapy is currently unapproved and only used if other therapies fail. [ 21 ] [ 22 ]


Isotretinoin is a  teratogen ; there is about a 20–35% risk for congenital defects in infants exposed to the drug  in utero , and about 30–60% of children exposed to isotretinoin prenatally have been reported to show neurocognitive impairment. [ 23 ]  Because of this risk, there are strict controls prescribing isotretinoin to women who have potential to become (or be) pregnant while taking isotretinoin and many are strongly advised to terminate their pregnancies because of the 20-60% risk. [ 23 ]


In the United States, since March 2006, the dispensing of isotretinoin is run through the  iPLEDGE program , under the direction of the  Food and Drug Administration . [ 24 ] [ 25 ]  Prescribers, pharmacists, and all people to whom the drug is prescribed need to register on the site and log information into it. Women with child-bearing potential must commit to using two forms of effective contraception simultaneously for the duration of isotretinoin therapy and for a month immediately preceding and a month immediately following therapy. Additionally, they must have two negative  pregnancy tests  30 days apart and have negative pregnancy tests before each prescription is written. [ 26 ] [ 27 ]


In most countries, isotretinoin can only be prescribed by dermatologists or specialist physicians; some countries also allow limited prescriptions by general practitioners and family doctors. In the United Kingdom [ 28 ]  and Australia, [ 29 ] [ 30 ]  isotretinoin may be prescribed only by or under the supervision of a consultant  dermatologist . Because severe cystic acne has the potential to cause permanent scarring over a short period, restrictions on its more immediate availability have proved contentious. [ 31 ]  In New Zealand, isotretinoin can be prescribed by any doctor but subsidized only when prescribed by a vocationally-registered general practitioner, dermatologist or nurse practitioner. [ 32 ]


Increasingly higher dosages will result in higher toxicity, resembling  vitamin A toxicity . Adverse effects include: [ 33 ]


Type of disorders


Very common  (≥ 1/10)


Common (≥ 1/100, < 1/10)


Rare (≥ 1/ 10 000 ,< 1/1000)


Very rare (≤ 1/ 10 000 )


and  mediastinal


subcutaneous tissues


connective tissue


and tendons)


The effects of isotretinoin may be permanent. This has been proposed to be due to induction of apoptosis in  sebaceous glands ,  meibomian glands ,  neuroblastoma  cells,  hypothalamic  cells,  hippocampus  cells,  Dalton's lymphoma  ascites cells,  B16F-10 melanoma cells ,  neuronal crest  cells,  stem cells  and others, [ 35 ]  that it changes  epigenetics [ 36 ]  and shortens  telomeres . [ 37 ]


Isotretinoin may stop  long bone  growth in young people who are still growing. [ 16 ]  Premature  epiphyseal  closure can occur in people receiving recommended doses [ 38 ]  of Accutane. [ 39 ] [ 40 ] [ 41 ] [ 42 ]


Isotretinoin is known to cause  meibomian gland  dysfunction which causes persistent  keratoconjunctivitis sicca  (dry eye). [ 43 ]   Problems with the meibomian and salivary glands are likely due to the  non-selective   apoptosis  of the cells of the  exocrine glands . [ 44 ]  Decreased  night vision  has been reported to persist in some people after discontinuation of isotretinoin therapy, [ 45 ] [ 46 ]  although most cases of decreased night vision appear to resolve after discontinuing the medication. [ 46 ]


Isotretinoin is also associated with permanent sexual side effects, namely  erectile dysfunction  and reduced  libido . [ 47 ]  In October 2017, the UK  MHRA  issued a Drug Safety Update to physicians in response to reports of these problems. [ 48 ]  This was in response to an EU review, published in August 2017, which states that a plausible physiological explanation of these side effects "may be a reduction in plasma testosterone". [ 18 ]  The review also stated that "the product information should be updated to include ‘sexual dysfunction including erectile dysfunction and decreased libido’ as an undesirable effect with an unknown frequency". [ 49 ]  There have also been reports of  spermatogenesis  disorders, such as  oligospermia . 27 cases of sexual dysfunction report either negative  dechallenge  or positive dechallenge. [ clarification needed ] [ 18 ]


The most common side effects are mucocutaneous: dry lips, skin, and nose. Other common mucocutaneous side effects are inflammation and chapping of the lips ( cheilitis ), redness of the skin ( erythema ), rashes, peeling, eczema ( dermatitis ), itching ( pruritus ) and nose bleeds ( epistaxis ). [ 50 ]  Absence of dryness of the lips is considered an indication of non-compliance with treatment (not taking the drug as advised), as it occurs in almost all people who take it. [ 50 ]


Regular use of lip balm and moisturizer is recommended throughout treatment to reduce these problems. The dose may need to be decreased to reduce the severity of these side effects. [ 51 ]   The skin becomes more fragile—especially to frictional forces—and may not heal as quickly as normal. Wound healing is delayed. For this reason, elective surgery, waxing of hair, tattooing, tattoo removal, piercings, dermabrasion, exfoliation, etc., are not recommended. Treatment of acne scars is generally deferred until 12 months after completion of a course of isotretinoin.


Isotretinoin is a  teratogen  highly likely to cause birth defects if taken by women during pregnancy or even a short time before conception. A few of the more common birth defects this drug can cause are hearing and visual impairment, missing or malformed earlobes, facial dysmorphism, and abnormalities in brain function. Isotretinoin is classified as  FDA   Pregnancy Category  X and  ADEC  Category X, and use is contraindicated in pregnancy. [ 19 ]  In the EU, isotretinoin (oral) is contraindicated in pregnancy and must not be taken by women able to have children unless the conditions of a pregnancy prevention program are met. [ 52 ]


The manufacturer recommends pregnancy be ruled out two weeks before commencement of isotretinoin, and women should use two simultaneous forms of effective contraception at least one month before commencement, during, and for at least one month following isotretinoin therapy. [ 53 ]


In the US, around 2000 women became pregnant while taking the drug between 1982 and 2000, with most pregnancies ending in  abortion  or  miscarriage . About 160 babies with birth defects were born. After the FDA put the more strict iPLEDGE program in place for the companies marketing the drug in the US, in 2011, 155 pregnancies occurred (0.12%) among 129,544 women of childbearing potential taking isotretinoin. [ 54 ]


People taking isotretinoin are not permitted to donate blood during and for at least one month after discontinuation of therapy due to its teratogenicity. [ 55 ]


Rare psychological side effects may include depression, worsening of pre-existing depression, aggressive tendencies, irritable mood, and anxiety. Very rare effects include abnormal behaviour,  psychosis , suicidal ideation, suicide attempts, and  suicide . [ 15 ] [ 56 ] [ 57 ] [ 58 ]   In a total of 5577  adverse reactions  reported to the UK's  MHRA  up to 31 March 2017, the plurality (1207, or 22%) concerned psychiatric effects. [ 59 ]  There were 85 reports of suicidal ideation, 56 of suicide and 43 of suicide attempts. [ 59 ]


Isotretinoin decreases the brain metabolism in the orbitofrontal cortex by an average of 21%, a brain area known to mediate symptoms of depression. [ 60 ]


The association between isotretinoin use and psychopathology has been controversial. Beginning in 1983, isolated case reports emerged suggesting mood change, particularly depression, occurring during or soon after isotretinoin use. [ 61 ]  Several studies have been conducted since then of the drug's effect on depression, psychosis, suicidal thoughts and other psychological effects. [ 61 ]


Isotretinoin is the only non-psychiatric drug on the  FDA 's top 10 list of drugs associated with depression [ 57 ] [ 62 ]  and is also within the top 10 for suicide attempts. [ 63 ]  A  black box warning  for suicide, depression, and psychosis has been present on isotretinoin's packaging in the United States since 2005. [ 62 ]  In March 2018,  European Medicines Agency  issued a warning on a possible risk of neuropsychiatric disorders (such as depression, anxiety, and mood changes) following the use of oral retinoids, including isotretinoin, though the limitations of the available data did not allow them to establish whether this risk was due to the use of retinoids. [ 52 ]


A Swedish retrospective cohort study with 5756 patients showed a significantly increased risk of attempted suicides from 6 months after the treatment to around 2 years after the treatment. [ 64 ]


In 2012, a systematic review covering all articles in the literature related to isotretinoin, depression, and suicide, as well as articles related to class effect, dose-response, and biological plausibility found that the literature reviewed was consistent with an association of isotretinoin administration and depression and with suicide in a subgroup of vulnerable individuals. [ 56 ]  Following this systematic review, in a 2014 review a group of Australian dermatologists and psychiatrists collaborated on a set of recommendations for safe prescribing of isotretinoin. [ 65 ]  However, whether isotretinoin use is causally associated with mental illness remains controversial. [ 65 ]


Evidence for depression being causally associated with isotretinoin use includes 41 reports of positive  challenge/dechallenge/rechallenge  with isotretinoin, involving administering isotretinoin, withdrawing the drug, and then re-administering it. [ 56 ]  The majority of these cases had no psychiatric history. [ 56 ]  There is also a temporal relationship between the development of depression and initiation of isotretinoin treatment, with most cases developing after 1–2 months of treatment. [ 56 ]  Further, higher doses of isotretinoin increase the risk of developing depression, with 25% of people showing depression on a dose of 3 mg/kg/day as compared with 3–4% at normal doses. [ 56 ]  Studies have uncovered  several biological processes  which may credibly explain the affective changes induced by isotretinoin. [ citation needed ]


Isotretinoin has also been linked to psychosis. [ 33 ]  Many of the side effects of isotretinoin mimic hypervitaminosis A, which has been associated with psychotic symptoms. [ 56 ]  The dopamine hypothesis of schizophrenia and psychosis suggests that an increase in dopaminergic stimulation or sensitivity in the limbic system causes psychotic symptoms. [ 66 ]


It has been suggested that dysregulation of retinoid receptors by retinoids such as isotretinoin may cause schizophrenia. [ 67 ] [ 68 ]  The evidence for this is threefold: transcriptional activation of the  dopamine D2 receptor  – in addition to serotonin and  glutamate receptors  – is regulated by  retinoic acid ; [ 67 ]  schizophrenia and the retinoid  cascade  have been linked to the same  gene loci ; [ 67 ]  and retinoid dysfunction causes congenital anomalies identical to those observed in people with schizophrenia. [ 67 ]  Further, the expression of dopamine receptors has indeed been shown to be regulated by retinoic acid. [ 69 ] [ 70 ]


Isotretinoin has a number of  muscoloskeletal  effects.  Myalgia  (muscular pain) and  arthralgia  (joint pain) are common side effects. [ 50 ]   Retinoids , such as high dose etretinate, are well known to cause bone changes, the most common type of which is  hyperostotic changes  (excessive bone growth), especially in growing children and adolescents. [ 50 ]  While excessive bone growth has been raised as a possible side effect of isotretinoin, a 2006 review found little evidence for this. [ 71 ]  Other problems include premature  epiphyseal closure  and  calcification  of tendons and ligaments. [ 50 ]  The bones of the spine and feet are most commonly affected. Risk factors for skeletal effects include older age, greater dosage, and longer course of treatment. Most bone changes cause no symptoms and may only be noticed using  X-ray imaging . [ 50 ]


Isotretinoin may cause non-specific gastrointestinal symptoms including nausea, diarrhea, and abdominal pain. [ 50 ]  The drug is associated with  inflammatory bowel disease  (IBD)— ulcerative colitis , but not Crohn's disease. [ 72 ]   There are also reports of people developing  irritable bowel syndrome  (IBS) and worsening of existing IBS. [ 73 ]


Isotretinoin and other retinoids are well known to affect the eyes.  Dry eyes  are very common during treatment and is caused by isotretinoin's apoptotic effect on the  meibomian glands . Some people develop contact lens intolerance as a result. [ 50 ]  In some people, these changes are long-lasting or irreversible and represent  Meibomian Gland Dysfunction  (MGD). [ 43 ]  Other common effects on the eyes include inflammation of the eyelid ( blepharitis ), red eye caused by  conjunctivitis  and irritation of the eye. More rare ocular side effects include blurred vision, decreased night vision (which may be permanent),  colour blindness , development of corneal opacities, inflammation of the cornea ( keratitis ), swelling of the optic disk ( papilloedema , associated with  IIH ),  photophobia  and other visual disturbances. [ 15 ]


Isotretinoin's exact  mechanism of action  is unknown, but several studies have shown that isotretinoin induces  apoptosis  (programmatic cell death) in various cells in the body. Cell death may be instigated in the  meibomian glands , [ 44 ] [ 74 ]   hypothalamic  cells, [ 75 ]   hippocampus  cells [ 76 ] [ 77 ]  and—important for treatment of acne—in  sebaceous gland  cells. [ 78 ] [ 79 ]  Isotretinoin has a low affinity for  retinoic acid receptors  (RAR) and  retinoid X receptors  (RXR), but may be converted intracellularly to metabolites that act as  agonists  of RAR and RXR  nuclear receptors . [ 14 ]


One study suggests the drug amplifies production of  neutrophil gelatinase-associated lipocalin  (NGAL) in the skin, which has been shown to reduce  sebum  production by inducing apoptosis in sebaceous gland cells, while exhibiting an antimicrobial effect on  Cutibacterium acnes . [ 80 ] [ 81 ] [ 82 ]  The drug decreases the size and sebum output of the sebaceous glands. [ 83 ]  Isotretinoin is the only available acne drug that affects all four major pathogenic processes in acne, which distinguishes it from alternative treatments (such as antibiotics) and accounts for its efficacy in severe, nodulocystic cases. [ 84 ]  The effect of isotretinoin on sebum production can be temporary, [ 16 ]  or remission of the disease can be "complete and prolonged." [ 83 ] [ 85 ] [ 86 ]


Isotretinoin has been speculated to down-regulate the enzyme  telomerase  and  hTERT , inhibiting " cellular immortalization  and  tumorigenesis ." [ 87 ]  In a 2007 study, isotretinoin was proven to inhibit the action of the metalloprotease  MMP-9  ( gelatinase ) in  sebum  without any influence in the action of  TIMP1  and  TIMP2  (the tissue inhibitors of metalloproteases). [ 88 ] [ unreliable medical source? ]  It is already known that metalloproteases play an important role in the  pathogenesis  of acne. [ 89 ]


A possible biological basis for the case reports of depression involves decreased metabolism in the  orbitofrontal cortex  (OFC) of the  frontal lobe . [ 56 ]  It has also been found that decreased OFC metabolism was correlated with headaches. [ 56 ]  People reporting headache as a side effect often report comorbid neuropsychiatric symptoms, especially depression; a statistically significant relationship between headache and depression has been established. [ 90 ]  It is suggested that people sensitive to isotretinoin-induced CNS effects may also be susceptible to other psychiatric side effects such as depression. [ 56 ]


Studies in mice and rats have found that retinoids, including isotretinoin, bind to  dopaminergic receptors  in the central nervous system. [ 57 ] [ 91 ] [ 92 ]  Isotretinoin may affect dopaminergic  neurotransmission  by disrupting the structure of dopamine receptors and decreasing dopaminergic activity. [ 58 ]  The dopaminergic system is implicated in numerous psychological disorders, including depression. Isotretinoin is also thought to affect the  serotonergic  system – it increases expression of  5-HT 1A  receptors  in the pre-synaptic neuron, which inhibit serotonin secretion. [ 58 ]  Isotretinoin also, directly and indirectly, increases the translation of the  serotonin transporter protein  (SERT), leading to increased  reuptake  and consequently reduced synaptic availability of serotonin. [ 58 ]


Inhibition of  hippocampal   neurogenesis  may also play a role in the development of isotretinoin-induced depression. [ 56 ]  A further effect of isotretinoin on the brain involves retinoic acid function in the  hypothalamus , the hormone regulatory centre of the brain and part of the  hypothalamus-pituitary-adrenal axis , a key part of the body's stress response. [ 56 ]  Other brain regions regulated by  retinoic acid  and potentially disrupted by isotretinoin include the  frontal cortex  and the  striatum . [ 56 ]


Oral isotretinoin is best absorbed when taken with a high-fat meal because it has a high level of  lipophilicity . [ 93 ]  The efficacy of isotretinoin doubles when taken after a high-fat meal compared to when taken without food. [ 94 ]  Due to isotretinoin's molecular relationship to vitamin A, it should not be taken with vitamin A supplements due to the danger of toxicity through cumulative overdosing. [ 95 ]  Accutane also negatively interacts with tetracycline, another class of acne drug, and with micro-dosed ('mini-pill')  progesterone  preparations,  norethisterone / ethinylestradiol  ('OrthoNovum 7/7/7'),  St. John's Wort ,  phenytoin , and systemic  corticosteroids .


Isotretinoin is primarily (99.9%) bound to plasma proteins, mostly  albumin . Three metabolites of isotretinoin are detectable in human plasma after oral administration: 4- oxo -isotretinoin, retinoid acid (tretinoin), and 4- oxo -retinoic acid (4- oxo -tretinoin). Isotretinoin also oxidizes, irreversibly, to 4- oxo -isotretinoin—which forms its geometric isomer 4- oxo -tretinoin. After an orally administered 80 mg dose of liquid suspension  14 C-isotretinoin,  14 C-activity in blood declines with a half-life of 90 hours. [ 93 ]  The metabolites of isotretinoin and its conjugates are then excreted in the subject's  urine  and  faeces  in relatively equal amounts. [ 93 ]  After a single, 80 mg oral dose of Isotretinoin to 74 healthy adult subjects under fed conditions, the mean ±SD  elimination half-life  (t 1/2 ) of isotretinoin and 4- oxo -isotretinoin were 21.0 ± 8.2 hours and 24.0 ± 5.3 hours, respectively. [ 93 ]  After both single and multiple doses, the observed accumulation ratios of isotretinoin ranged from 0.90 to 5.43 in people with cystic acne. [ 93 ]


The compound 13-cis retinoic acid was first studied in the 1960s at Roche Laboratories in Switzerland by Werner Bollag as a treatment for skin cancer. Experiments completed in 1971 showed that the compound was likely to be ineffective for cancer but, surprisingly, that it could be useful to treat acne. However, they also showed that the compound was likely to cause birth defects, so in light of the events around  thalidomide , Roche abandoned the product. [ 96 ]  In 1979, an article was published reporting the drug's effectiveness as a treatment of cystic and conglobate acne on fourteen patients, thirteen of which experienced complete clearing of their disease. [ 83 ]  In clinical trials, subjects were carefully screened to avoid including women who were or might become pregnant. Roche's  New Drug Application  for isotretinoin for the treatment of acne included data showing that the drug caused birth defects in rabbits. [ medical citation needed ]  The FDA approved the application in 1982. [ 96 ]