Terbinafine

Terbinafine
Clinical data
Trade names	Lamisil, Terbin, others
AHFS/Drugs.com	Monograph
MedlinePlus	a699061
License data	US DailyMed: terbinafine;
Routes of; administration	By mouth, topical
ATC code	D01AE15 (WHO) D01BA02 (WHO);
Legal status
Legal status	AU: S4 (Prescription only); CA: ℞-only; UK: POM (Prescription only) / GSL; US: ℞-only / OTC;
Pharmacokinetic data
Bioavailability	Readily absorbed: 70–90%
Protein binding	>99%
Metabolism	Liver
Elimination half-life	Highly variable
Identifiers
	IUPAC name [(2E)-6,6-dimethylhept-2-en-4-yn-1-yl](methyl)(naphthalen-1-ylmethyl)amine;
CAS Number	91161-71-6 78628-80-5;
PubChem CID	1549008;
DrugBank	DB00857 ;
ChemSpider	1266005 ;
UNII	G7RIW8S0XP;
KEGG	D02375 ;
ChEBI	CHEBI:9448 ;
ChEMBL	ChEMBL822 ;
CompTox Dashboard (EPA)	DTXSID2023640 ;
ECHA InfoCard	100.119.605
Chemical and physical data
Formula	C21H25N
Molar mass	291.438 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES C(#C\C=C\CN(C)Cc2cccc1ccccc12)C(C)(C)C;
	InChI InChI=1S/C21H25N/c1-21(2,3)15-8-5-9-16-22(4)17-19-13-10-12-18-11-6-7-14-20(18)19/h5-7,9-14H,16-17H2,1-4H3/b9-5+ ; Key:DOMXUEMWDBAQBQ-WEVVVXLNSA-N ;
	(what is this?) (verify)

Terbinafine is an antifungal medication used to treat pityriasis versicolor, fungal nail infections, and ringworm including jock itch and athlete's foot.^[1]^[2]^[3] It is either taken by mouth or applied to the skin as a cream or ointment.^[1]^[4] The cream and ointment should not be used for fungal nail infections.^[5]

Common side effects when taken by mouth include nausea, diarrhea, headache, cough, rash, and elevated liver enzymes.^[1] Severe side effects include liver problems and allergic reactions.^[1] Liver injury is, however, unusual.^[6] Oral use during pregnancy is not typically recommended.^[1] The cream and ointment may result in itchiness but are generally well tolerated.^[2] Terbinafine is in the allylamines family of medications.^[1] It works by decreasing the ability of fungi to synthesize ergosterol.^[1] It appears to result in fungal cell death.^[7]

Terbinafine was discovered in 1991.^[8] It is on the World Health Organization's List of Essential Medicines.^[4] In 2022, it was the 255th most commonly prescribed medication in the United States, with more than 1 million prescriptions.^[9]^[10]

Medical uses

Terbinafine is mainly effective on molds of the order Onygenales and some yeasts in the genus Candida.^{[citation needed]}

As a cream or powder, it is used topically for superficial skin infections such as jock itch (tinea cruris), athlete's foot (tinea pedis), and other types of ringworm (tinea corporis).^[11]

Tablets by mouth are often prescribed for the treatment of onychomycosis, a fungal nail infection, typically by a dermatophyte or Candida species. Fungal nail infections are located deep under the nail in the cuticle to which topically applied treatments are unable to penetrate in sufficient amounts. The tablets may, rarely, cause hepatotoxicity, so patients are warned of this and may be monitored with liver function tests. Alternatives to oral administration have been studied.^{[citation needed]}

Terbinafine may induce or exacerbate subacute cutaneous lupus erythematosus. Persons with lupus erythematosus should first discuss possible risks with their doctor before initiation of therapy.^[12]

Side effects

Many side effects and adverse drug reactions have been reported with oral terbinafine hydrochloride,^[13]^[14] possibly due to its extensive biodistribution and the often extended durations involved in antifungal treatment (longer than two months). A comprehensive list of adverse events associated with terbinafine use includes:

Gastrointestinal problems: Diarrhea, constipation, nausea, fullness, abdominal pain, indigestion, dyspepsia, gastritis, cholestasis, flatulence, altered stool colour, abdominal muscular pain
Central nervous system or neurological problems: Headaches, dizziness, vertigo, light-headedness, decreased concentration levels, paraesthesia (pins and needles)
Hepatic problems: Raised liver enzyme levels, liver inflammation (hepatitis), liver damage, liver failure
Immune system problems: Decreased white blood cell counts including pancytopenia, leukopenia, lymphopenia, thrombocytopenia, agranulocytosis, and neutropenia, autoimmune reactions such as lupus erythematosus
Psychological problems: Depression, anxiety, insomnia, increased or unusual dream activity, malaise
Sensory problems: Complete loss of taste (ageusia), decreased taste (hypogeusia) and distorted taste (dysgeusia), often involving a metallic taste sensation and dry mouth, visual disturbances including blurred vision, green vision and double vision. In extremely rare cases, the loss or impairment of taste is permanent ^[15]
Skin problems: Rashes, hives (urticaria), skin irritation, itching, jaundice, Stevens–Johnson syndrome
Other side effects: Fatigue, increased heart rate (tachycardia), hair loss (alopecia), decreased red blood cell count (anemia), muscle pain (myalgia), joint pain (arthralgia)

In 2015, physicians reported^[16] that a patient with an MTHFR enzyme mutation (specifically the C677T variant) had developed an adverse reaction to terbinafine (Lamisil) (headache, fatigue, and dizziness). Genetic testing revealed the MTHFR C677T mutation. It was noted that Lamisil interferes with the methylation cycle and that this can cause side effects in individuals with the MTHFR C677T mutation.

Pharmacology

Like other allylamines, terbinafine inhibits ergosterol synthesis by inhibiting squalene epoxidase, an enzyme that catalyzes the conversion of squalene to lanosterol. In fungi, lanosterol is then converted to ergosterol; in humans, lanosterol becomes cholesterol. However, as fungi and animals diverged around 1.1 billion years ago - there is enough difference in this enzyme that terbinafine preferentially binds fungal squalene epoxidase, making it selective for inhibiting ergosterol production in fungi without significantly affecting cholesterol production in mammals. This is thought to fatally disrupt the fungal cell membrane.^{[citation needed]}

Terbinafine is highly lipophilic and tends to accumulate in hair, skin, nails, and fat cells.

This accumulation results in therapeutic levels of terbinafine even after 80 days following one week treatment of 250 mg/day. Different dosing schedules have been proposed such as 500 mg/day for one week or 250 mg/day for two weeks each followed by a drug-free period of two or three weeks, totaling 3 months of treatment including the drug-free periods. Such intermittent dosing schedules appear to be as effective as continuous regimens.^[17]

Chemistry

Terbinafine hydrochloride is a white crystalline powder that is freely soluble in methanol and dichloromethane, soluble in ethanol, and slightly soluble in water. ^{[citation needed]}

Terbinafine is produced from olefin metathesis of 1,3-dichloropropene and neohexene followed by reaction with N-methyl-1-naphthalenemethanamine.^{[citation needed]}

Despite its name it does not contain terbium.

History

Terbinafine first became available in Europe in 1991 and in the United States in 1996. The U.S. Food and Drug Administration has approved the first generic versions of prescription Lamisil (terbinafine hydrochloride) tablets. The remaining patent or exclusivity for Lamisil expired on June 30, 2007.

On September 28, 2007, the FDA stated that terbinafine is now approved for use by children age four and up. The antifungal granules can be sprinkled on a child's food to treat scalp fungus.^[18]

In the United States the price in 1999 was $547 for a 12-week course; this fell to $10 by 2015, after the patent had expired.^[19]

Society and culture

Brand names

Terbinafine is sold in India as Terboderm by Omega Pharma and Tyza (Abbott Healthcare).^[20]
Lamisil in Argentina, Australia, Bangladesh,^[21] Belgium, Brazil, Canada, Chile, Colombia, Croatia, Egypt, the Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Israel, Mexico, the Netherlands, New Zealand, Norway, Pakistan, Peru, the Philippines,^[22] Romania, Russia, Slovakia, Slovenia, South Africa, Sweden, Thailand, the United Kingdom, the United States, and Venezuela
Corbinal and Terbisil in Turkey, Pakistan, Undofen in Poland. Another alternate is Terbistad (Stada Arzneimittel).
As a generic oral medication, it is sold as Sebifin, Tinasil, Terbisil, Terbicor, and Tamsil in Australia, whilst the generic topical medication is sold there as SolvEasyTinea and Tamsil.^[23]^[24]
It is also available as a generic medication in the United States, the United Kingdom, Belgium, Switzerland, Brazil, Mexico, Canada and France.
In India, terbinafine hydrochloride is available in topical form under the brand names Triabin by Medley Pharmaceuticals, Sebifin (Sun Pharma), Zimig (GSK Pharma) and mycoCeaze (Progreś Laboratories). MycoVa, developed by Apricus Biosciences, is a topical nail solution of terbinafine and DDAIP, which has completed three phase-III studies for the treatment of onychomycosis.
Other names include Terbinaforce (Mankind Pharma) and Tafine (Deurali Janta Pharmaceuticals Pvt Ltd.) Turbo (Apex Pharmaceuticals Pvt Ltd) in Nepal.
The topical form is sold as Lamisil AT in the United States.

References

^ ^a ^b ^c ^d ^e ^f ^g "Terbinafine Hydrochloride". The American Society of Health-System Pharmacists. Archived from the original on 21 December 2016. Retrieved 8 December 2016.
^ ^a ^b "Lamisil 1% w/w Cream – Summary of Product Characteristics (SPC) – (eMC)". electronic Medicines Compendium (eMC). 17 March 2016. Archived from the original on 20 December 2016. Retrieved 17 December 2016.
^ Crawford F (July 2009). "Athlete's foot". BMJ Clinical Evidence. 2009. PMC 2907807. PMID 21696646.
^ ^a ^b World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
^ Rang & Dale's Pharmacology (9th ed.). Elsevier. 2018. p. 694. ISBN 9780702074479.{{cite book}}: CS1 maint: overridden setting (link)
^ Yan J, Wang X, Chen S (August 2014). "Systematic review of severe acute liver injury caused by terbinafine". International Journal of Clinical Pharmacy. 36 (4): 679–683. doi:10.1007/s11096-014-9969-y. PMID 24986266. S2CID 12867807.
^ "Terbinafine". www.drugbank.ca. Retrieved 14 November 2017.
^ Ravina E (2011). The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs. John Wiley & Sons. p. 90. ISBN 978-3-527-32669-3. Archived from the original on 20 December 2016.
^ "The Top 300 of 2022". ClinCalc. Archived from the original on 30 August 2024. Retrieved 30 August 2024.
^ "Terbinafine Drug Usage Statistics, United States, 2013 - 2022". ClinCalc. Retrieved 30 August 2024.
^ Markova T (January 2002). "Clinical inquiries. What is the most effective treatment for tinea pedis (athlete's foot)?". The Journal of Family Practice. 51 (1). Frontline Medical Communications: 21. PMID 11927056. Archived from the original on 6 April 2012.
^ Callen JP, Hughes AP, Kulp-Shorten C (September 2001). "Subacute cutaneous lupus erythematosus induced or exacerbated by terbinafine: a report of 5 cases". Archives of Dermatology. 137 (9): 1196–1198. doi:10.1001/archderm.137.9.1196. PMID 11559217.
^ "Lamisil (terbinafine): Side Effects". Doublecheckmd.com. 16 June 2010. Archived from the original on 21 September 2013. Retrieved 9 November 2013.{{cite web}}: CS1 maint: bot: original URL status unknown (link)
^ McGuire S (5 February 2008). "Australian regulators issue warning on Novartis' Lamisil". Medical Marketing and Media. Mmm-online.com. Archived from the original on 9 November 2013. Retrieved 9 November 2013.
^ Duxbury AJ, Oliver RJ, Pemberton MN (March 2000). "Persistent impairment of taste associated with terbinafine". British Dental Journal. 188 (6): 295–296. doi:10.1038/sj.bdj.4800461. PMID 10800234. Persistent loss of taste associated with terbinafine would however appear to be extremely rare.
^ Trachtman JN, Pagano V (December 2015). "Antifolates and MTHFR". Therapeutic Drug Monitoring. 37 (6): 697–698. doi:10.1097/FTD.0000000000000215. PMID 25929315. S2CID 205604356.
^ Gupta AK, Stec N, Bamimore MA, Foley KA, Shear NH, Piguet V (March 2020). "The efficacy and safety of pulse vs. continuous therapy for dermatophyte toenail onychomycosis" (PDF). Journal of the European Academy of Dermatology and Venereology. 34 (3): 580–588. doi:10.1111/jdv.16101. PMID 31746067. S2CID 208185915.
^ "US FDA approves oral granules for scalp ringworm". Reuters. 28 September 2007. Archived from the original on 23 March 2009.
^ Mikailov A, Cohen J, Joyce C, Mostaghimi A (March 2016). "Cost-effectiveness of Confirmatory Testing Before Treatment of Onychomycosis". JAMA Dermatology. 152 (3): 276–281. doi:10.1001/jamadermatol.2015.4190. PMID 26716567.
^ "Terbinafine brands in India". Brand index. DrugsUpdate India. Archived from the original on 23 September 2015.
^ "Lamisil". Medex.com.bd. Archived from the original on 19 January 2019. Retrieved 17 January 2019.
^ "Mercury Drug – The Leading Drugstore in the Philippines". www.mercurydrug.com. Archived from the original on 18 November 2016. Retrieved 18 November 2016.
^ "Terbinafine". Pharmaceutical Benefits Scheme: A-Z list. Australian Government. Archived from the original on 12 February 2014.
^ "PI and CMI Trade Names and Active Ingredients containing Terbinafine". Therapeutic Goods Administration. Australian Government. Archived from the original on 10 September 2017.

[AHFS2016-1] ^ ^a ^b ^c ^d ^e ^f ^g "Terbinafine Hydrochloride". The American Society of Health-System Pharmacists. Archived from the original on 21 December 2016. Retrieved 8 December 2016.

[UK2016-2] "Lamisil 1% w/w Cream – Summary of Product Characteristics (SPC) – (eMC)". electronic Medicines Compendium (eMC). 17 March 2016. Archived from the original on 20 December 2016. Retrieved 17 December 2016.

[3] Crawford F (July 2009). "Athlete's foot". BMJ Clinical Evidence. 2009. PMC 2907807. PMID 21696646.

[WHO21st-4] World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.

[Ric2015-5] Rang & Dale's Pharmacology (9th ed.). Elsevier. 2018. p. 694. ISBN 9780702074479.{{cite book}}: CS1 maint: overridden setting (link)

[6] Yan J, Wang X, Chen S (August 2014). "Systematic review of severe acute liver injury caused by terbinafine". International Journal of Clinical Pharmacy. 36 (4): 679–683. doi:10.1007/s11096-014-9969-y. PMID 24986266. S2CID 12867807.

[7] "Terbinafine". www.drugbank.ca. Retrieved 14 November 2017.

[8] Ravina E (2011). The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs. John Wiley & Sons. p. 90. ISBN 978-3-527-32669-3. Archived from the original on 20 December 2016.

[9] "The Top 300 of 2022". ClinCalc. Archived from the original on 30 August 2024. Retrieved 30 August 2024.

[10] "Terbinafine Drug Usage Statistics, United States, 2013 - 2022". ClinCalc. Retrieved 30 August 2024.

[11] Markova T (January 2002). "Clinical inquiries. What is the most effective treatment for tinea pedis (athlete's foot)?". The Journal of Family Practice. 51 (1). Frontline Medical Communications: 21. PMID 11927056. Archived from the original on 6 April 2012.

[12] Callen JP, Hughes AP, Kulp-Shorten C (September 2001). "Subacute cutaneous lupus erythematosus induced or exacerbated by terbinafine: a report of 5 cases". Archives of Dermatology. 137 (9): 1196–1198. doi:10.1001/archderm.137.9.1196. PMID 11559217.

[13] "Lamisil (terbinafine): Side Effects". Doublecheckmd.com. 16 June 2010. Archived from the original on 21 September 2013. Retrieved 9 November 2013.{{cite web}}: CS1 maint: bot: original URL status unknown (link)

[14] McGuire S (5 February 2008). "Australian regulators issue warning on Novartis' Lamisil". Medical Marketing and Media. Mmm-online.com. Archived from the original on 9 November 2013. Retrieved 9 November 2013.

[BDJPersistentTasteLoss-15] Duxbury AJ, Oliver RJ, Pemberton MN (March 2000). "Persistent impairment of taste associated with terbinafine". British Dental Journal. 188 (6): 295–296. doi:10.1038/sj.bdj.4800461. PMID 10800234. Persistent loss of taste associated with terbinafine would however appear to be extremely rare.

[16] Trachtman JN, Pagano V (December 2015). "Antifolates and MTHFR". Therapeutic Drug Monitoring. 37 (6): 697–698. doi:10.1097/FTD.0000000000000215. PMID 25929315. S2CID 205604356.

[17] Gupta AK, Stec N, Bamimore MA, Foley KA, Shear NH, Piguet V (March 2020). "The efficacy and safety of pulse vs. continuous therapy for dermatophyte toenail onychomycosis" (PDF). Journal of the European Academy of Dermatology and Venereology. 34 (3): 580–588. doi:10.1111/jdv.16101. PMID 31746067. S2CID 208185915.

[18] "US FDA approves oral granules for scalp ringworm". Reuters. 28 September 2007. Archived from the original on 23 March 2009.

[Mikailov2015-19] Mikailov A, Cohen J, Joyce C, Mostaghimi A (March 2016). "Cost-effectiveness of Confirmatory Testing Before Treatment of Onychomycosis". JAMA Dermatology. 152 (3): 276–281. doi:10.1001/jamadermatol.2015.4190. PMID 26716567.

[20] "Terbinafine brands in India". Brand index. DrugsUpdate India. Archived from the original on 23 September 2015.

[21] "Lamisil". Medex.com.bd. Archived from the original on 19 January 2019. Retrieved 17 January 2019.

[22] "Mercury Drug – The Leading Drugstore in the Philippines". www.mercurydrug.com. Archived from the original on 18 November 2016. Retrieved 18 November 2016.

[23] "Terbinafine". Pharmaceutical Benefits Scheme: A-Z list. Australian Government. Archived from the original on 12 February 2014.

[24] "PI and CMI Trade Names and Active Ingredients containing Terbinafine". Therapeutic Goods Administration. Australian Government. Archived from the original on 10 September 2017.

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Terbinafine

Medical uses

Side effects

Pharmacology

Chemistry

History

Society and culture

Brand names

References

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