Griseofulvin

D01B - Antifungals for systemic use ATC D01BA01 Small molecule approved 1962 Oral Natural product

JFDA label: Grisovin Tablets

Mechanism of Action

Inhibitor of Tubulin — Tubulin inhibitor

Target	Action	Gene / class
Tubulin efficacy	INHIBITOR

Indications

Approved

Dermatophyte infections

Antimicrobial Spectrum

Expected / intrinsic spectrum (EUCAST breakpoints & labels) — not local resistance. Source: openfda-label.

Fungi

Organism	Activity	MIC
Epidermophyton floccosum	Active	—
Microsporum audouinii	Active	—
Microsporum canis	Active	—
Microsporum gypseum	Active	—
Trichophyton crateriform	Active	—
Trichophyton crateriformis	Active	—
Trichophyton gallinae	Active	—
Trichophyton interdigitalis	Active	—
Trichophyton megnini	Active	—
Trichophyton mentagrophytes	Active	—
Trichophyton rubrum	Active	—
Trichophyton schoenleini	Active	—
Trichophyton sulphureum	Active	—
Trichophyton tonsurans	Active	—
Trichophyton verrucosum	Active	—

Class profile

antifungalClass	Antimitotic
targetMolecule	Microtubule assembly (beta-tubulin)
isFungicidal	0
spectrumCandida	Resistant
spectrumAspergillus	Resistant
spectrumCryptococcus	Resistant
spectrumDermatophytes	S (oral only, Trichophyton/Microsporum)
resistanceMechanisms	Beta-tubulin mutations,Slow clinical resistance; replaced by terbinafine
source	Pappas2016/Lass-Florl2011

Contraindications

Source: Lexicomp

Hypersensitivity to griseofulvin or any component of the formulation Absolute
hepatic failure Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Nervous system disorders (5)

Not Known Confusion · dizziness · fatigue · headache · insomnia

Hepatobiliary disorders (1)

Not Known Hepatotoxicity

Renal and urinary disorders (1)

Not Known Nephrosis

Blood and lymphatic system disorders (1)

Not Known Granulocytopenia

Gastrointestinal disorders (6)

Not Known Diarrhea · epigastric distress · gastrointestinal hemorrhage · nausea · oral candidiasis · vomiting

Skin and subcutaneous tissue disorders (4)

Not Known Dermatological reaction (erythema multiforme-like drug reaction) · skin photosensitivity · skin rash (most common) · urticaria (most common)

Dosing

Source: Lexicomp

Dermatophyte infections: Oral: Microsize: 500 mg/day in single or divided doses; for more widespread lesions initial doses of 750 to 1,000 mg/day in single or divided doses may be needed; may decrease gradually to 500 mg/day or less if patient responds to higher dose. Ultramicrosize: 375 mg daily in single or divided doses; doses up to 750 mg/day in divided doses have been used for infections more difficult to eradicate such as tinea unguium and tinea pedis Duration of therapy depends on the site of infection: Tinea corporis: 2 to 4 weeks Tinea cruris: Duration not specified in manufacturer’s labeling; in pediatric patients 6 weeks has been recommended (Red Book, 2015) Tinea capitis: 4 to 6 weeks Tinea pedis: 4 to 8 weeks Tinea unguium: 4 to 6 months or longer

(For additional information see "Griseofulvin: Pediatric drug information") Dermatophyte infections: Children >2 years and Adolescents: Oral: Microsize: Manufacturer's labeling: Dosage should be individualized; 10 mg/kg/day in a single or divided doses (maximum daily dose: 500 mg/day) or: 13.6 to 22.7 kg: 125 to 250 mg/day in divided doses >22.7 kg: 250 to 500 mg/day in divided doses Alternate dosing: 10 to 20 mg/kg/day in single or 2 divided doses (maximum: 1,000 mg/day) (Red Book [AAP 2015]); Note: Tinea capitis: 20 to 25 mg/kg/day has been recommended (Ali 2007; Lipozenic 2002; Sethi 2006). Ultramicrosize: 5 to 15 mg/kg/day in single dose or 2 divided doses (maximum dose/day: 750 mg/day) (Red Book [AAP 2015]) Duration of therapy depends on the site of infection: Tinea corporis: Manufacturer's labeling: 2 to 4 weeks Alternate recommendations: 6 weeks (Red Book [AAP 2015]) Tinea cruris: 6 weeks (Red Book [AAP 2015]) Tinea capitis: Manufacturer's labeling: 4 to 6 weeks Alternate recommendations: Children: 6 to 12 weeks; use up to 16 weeks may be required (AAP Red Book recommends continuing treatment for 6 weeks or more and 2 weeks after clinical resolution of symptoms) (Red Book [AAP 2015]; Ali 2007; Lipozenic 2002; Sethi 2006) Tinea pedis: 4 to 8 weeks Tinea unguium: 4 to 6 months or longer

Refer to adult dosing.

Warnings & Precautions

Source: Lexicomp

Hematologic effects

Leukopenia has been reported (rare); discontinue therapy if granulocytopenia occurs.

Hepatic effects

May cause jaundice and elevated liver function tests or bilirubin (may be serious or even fatal); monitor hepatic function and discontinue therapy if necessary.

Penicillin allergy

Hypersensitivity cross reaction between penicillins and griseofulvin is possible, however, known penicillin-sensitive patients have been treated successfully without complications.

Photosensitivity

Avoid exposure to intense sunlight to prevent photosensitivity reactions.

Skin reactions

Severe skin reactions (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme) have been reported (may be serious or even fatal); discontinue use if severe skin reactions occur. Disease-related concerns:

Lupus erythematosus

Development of lupus erythematosus, lupus-like syndromes or exacerbation of existing lupus erythematosus has been reported. Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Other warnings/precautions:

Appropriate use

Use for the prophylaxis of fungal infections has not been established; not effective for the treatment of tinea versicolor.

Pregnancy & Lactation

Pregnancy

FDA category X Teratogenic Contraindicated

Teratogenic effects have been observed in animal reproduction studies. Griseofulvin crosses the placenta (Pacifici, 2006). Because adverse events have also been observed in humans (two cases of conjoined twins), use during pregnancy is contraindicated. Effective contraception should be used during therapy and for 1 month after therapy is discontinued in women of reproductive potential. Men should avoid fathering a child for at least 6 months after therapy.

Lactation

Avoid

It is not known if griseofulvin is excreted in breast milk. Due to the potential for serious adverse reactions in the nursing infant, breast-feeding is not recommended.

Monitoring

Efficacy	Fungal culture and species identification; minimum inhibitory concentration (MIC) where available; clinical response (temperature, imaging for invasive fungal disease)
Toxicity	LFTs (hepatotoxicity — azoles in particular); renal function; ECG for QT prolongation (azoles); drug levels if available (itraconazole, voriconazole)
Clinical pearl	Voriconazole levels are highly variable due to CYP2C19 polymorphism — TDM recommended (target trough 2–5 mg/L). Check for drug interactions with CYP3A4 substrates.
Counseling	Report visual disturbances (voriconazole), jaundice, or rash. Take azoles with food or as directed to optimise absorption.

Chemistry & Properties

Formula	C17H17ClO6
Molecular weight	352.77 g/mol
IUPAC name	(2S,5'R)-7-chloro-3',4,6-trimethoxy-5'-methylspiro[1-benzofuran-2,4'-cyclohex-2-ene]-1',3-dione
CAS	126-07-8
PubChem CID	441140
InChIKey	`DDUHZTYCFQRHIY-RBHXEPJQSA-N`
logP	2.81 (XLogP 2.2)
Polar surface area	71.06 Å²
H-bond acceptors / donors	6 / 0
Drug-likeness (QED)	0.83
Lipinski violations	0

SMILES

COC1=CC(=O)C[C@@H](C)[C@]12Oc1c(Cl)c(OC)cc(OC)c1C2=O

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	10.0%
Half-life	0.838 h
Volume of distribution	1.709 L/kg
Protein binding	85.2%
BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP2C19	Inhibitor	—
CYP2C19	Substrate	—
CYP2C8	Inhibitor	—
CYP2C9	Inhibitor	—

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Aminolevulinic acid	major
Dienogest	major
Drospirenone	major
Ethinylestradiol	major
Etonogestrel	major
Levacetylmethadol	major
Levonorgestrel	major
Lumateperone	major
Medroxyprogesterone acetate	major
Norethisterone	major
Norgestimate	major
Norgestrel	major
Ranolazine	major
Abemaciclib	moderate
Acalabrutinib	moderate
Alfentanil	moderate
Alpelisib	moderate
Aminolevulinic acid (topical)	moderate
Amobarbital	moderate
Amprenavir	moderate
Anisindione	moderate
Apixaban	moderate
Apremilast	moderate
Aprepitant	moderate
Aripiprazole	moderate
Armodafinil	moderate
Artemether	moderate
Atazanavir	moderate
Atorvastatin	moderate
Avanafil	moderate
Avapritinib	moderate
Axitinib	moderate
Bedaquiline	moderate
Benzhydrocodone	moderate
Bictegravir	moderate
Boceprevir	moderate
Bosutinib	moderate
Brigatinib	moderate
Buprenorphine	moderate
Buspirone	moderate

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Registered Products (1)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Grisovin Tablets	Tablet 500 mg	25 tab	Suleiman Tannous & Sons Co. Ltd	2.300