Griseofulvin

Griseofulvin is an antifungal agent belonging to the pharmacological class of Heterocyclic Benzofuran.

Griseofulvin has been approved to relieve symptoms and also for the treatment and maintenance of Onychomycosis, Tinea Infection.

Griseofulvin is poorly absorbed from the gastrointestinal tract, with absorption ranging from 25% to 70% of an oral dose. However, this absorption can be significantly improved when administered with or after a fatty meal. The volume of distribution and protein binding characteristics of griseofulvin are not available. Regarding metabolism, it primarily occurs in the liver, where major metabolites such as 6-methyl-griseofulvin and its glucuronide conjugate are formed.

The common side effects involved in using Griseofulvin are Nausea, Vomiting, Upset stomach, Diarrhea, Headache, Tiredness, Rash Sleep problems (insomnia), and Dizziness.

Griseofulvin is available in the form of Tablets, Oral suspension.

Griseofulvin is approved in Germany, Japan, Malaysia, India, the U.K., the U.S., and China.

Griseofulvin belongs to the pharmacological class Heterocyclic Benzofuran is an antifungal agent.

Griseofulvin is classified as fungistatic, meaning it slows down the growth of dermatophytes, but the precise mechanism underlying its action remains unclear. It is believed to impede fungal cell mitosis and the synthesis of nuclear acids. Additionally, it disrupts the normal function of spindle and cytoplasmic microtubules by binding to alpha and beta tubulin. This medication also forms a bond with keratin present in human cells. Once it reaches the fungal site, it specifically binds to fungal microtubules, leading to alterations in the fungal mitosis process.

Griseofulvin has been approved to relieve symptoms and also for the treatment and maintenance of Onychomycosis, Tinea Infection.

Griseofulvin is found to be available in the form of Tablets, Oral suspension.

Griseofulvin can be used in the following treatment:

• Onychomycosis
• Tinea Infection

Griseofulvin can help to relieve symptoms and also for the treatment and maintenance of Onychomycosis, Tinea Infection.

Griseofulvin is approved for use in the following clinical indications:

• Onychomycosis
• Tinea Infection

Onychomycosis (alternative agent):

• Microsize: Oral: 1 g/day in single or divided doses .
• Ultramicrosize: Oral: 750 mg/day in single or divided doses .
• Duration: More than 4 months (e.g., 6 to 9 months ) for fingernail and more than 6 months (e.g., 12 to 18 months [Ameen 2014]) for toenail infection .

Tinea infections:

Dermatophyte folliculitis (tinea barbae, Majocchi granuloma) (alternative agent):

• Microsize: Oral: 500 mg/day in single or divided doses .
• Ultramicrosize: Oral: 375 mg/day in single or divided doses.
• Duration: 4 to 8 weeks or until clinical resolution.

Tinea capitis:

• Microsize: Oral: 500 mg to 1 g/day in single or divided doses .
• Ultramicrosize: Oral: 375 to 750 mg/day in single or divided doses .
• Duration: 4 to 6 weeks, according to the manufacturer's labeling, but based on experience in pediatrics, up to 12 weeks may be required .

Tinea corporis/tinea cruris (alternative agent):

• Microsize: Oral: 500 mg to 1 g/day in single or divided doses .
• Ultramicrosize: Oral: 375 to 500 mg/day in single or divided doses .
• Duration: 2 to 4 weeks .

Tinea pedis (labeled use)/tinea manuum (off-label use) (alternative agent):

• Microsize: Oral: 1 g/day in single or divided doses .
• Ultramicrosize: Oral: 750 mg/day in divided doses .
• Duration: 4 to 8 weeks.

• Microsize oral suspension: Each 5 mL contains 125mg of griseofulvin.
• Microsize tablet: Each tablet contains 500mg of griseofulvin and is marketed under the brand name "Grifulvin V."
• Ultramicrosize tablet: Each tablet contains 125mg of griseofulvin and is marketed under the brand name "Gris-PEG."
• Ultramicrosize tablet: Each tablet contains 250mg of griseofulvin and is marketed under the brand name "Gris-PEG."

Tablets, Oral suspension.

• Dosage Adjustments in Pediatric Patients:

General dosing for susceptible infection:

Children >2 years and Adolescents:

• Microsize: Oral: 20 to 25 mg/kg/day in single or 2 divided doses; maximum daily dose: 1,000 mg/day
• Ultramicrosize: Oral: 10 to 15 mg/kg/day once daily; maximum daily dose: 750 mg/day

Tinea capitis:

• Note: Preferred therapy for Microsporum canis infection; may be used in combination with adjunctive topical therapy (e.g., selenium or antifungal shampoo). Patients receiving doses on the lower end of the dose range may require longer durations of treatment for fungal eradication .

Infants >1 month to Children ≤2 years:

• Limited data available: Oral: Microsize: 15 to 25 mg/kg/day in single or 2 divided doses (maximum daily dose: 1,000 mg/day) until resolution; usually 6 to 8 weeks duration, although resistant cases may require longer duration; tinea capitis is rare in ages <1 year, infant dosing based on small case-series/reports .

Children >2 years and Adolescents:

• Microsize: Oral: 20 to 25 mg/kg/day in a single daily dose or in 2 divided doses (maximum daily dose: 1,000 mg/day) for 6 to 8 weeks or until fungal cultures clear; in some cases, treatment up to 12 to 18 weeks may be necessary. Although lower doses (10 to 15 mg/kg/day) have been suggested previously by experts and by the manufacturer, they are associated with extended treatment durations and/or potentially lower cure rates and have fallen out of favor .

Ultramicrosize:

• Oral: 10 to 15 mg/kg/day once daily (maximum daily dose: 750 mg/day) for 6 to 8 weeks or until fungal cultures clear; in some cases, treatment up to 12 to 18 weeks may be necessary

There are no specific dietary restrictions associated with the use of Griseofulvin. Griseofulvin can be administered with or without food, and no specific foods or beverages are known to interact with Griseofulvin.

Griseofulvin may be contraindicated under the following conditions:

• Since 1977, two instances of conjoined twins have been reported in patients who took griseofulvin during the first trimester of pregnancy. As a precautionary measure, griseofulvin should not be prescribed to pregnant patients. If a patient becomes pregnant while using this medication, they should be informed about the potential risk to the fetus.
• Griseofulvin is contraindicated in patients with porphyria or hepatocellular failure and individuals who have a history of hypersensitivity to griseofulvin.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows:

• Prophylactic Usage: It is unclear whether griseofulvin is effective in preventing fungal infections. However, it has been reported that the use of griseofulvin can cause severe skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme. These reactions can be serious and may require hospitalization or even result in death. If severe skin reactions occur, griseofulvin should be discontinued
• Additionally, using griseofulvin may result in liver damage, which is indicated by elevations in AST, ALT, bilirubin, and jaundice. This may lead to hospitalization or death. Patients should be monitored for hepatic adverse events, and discontinuation of griseofulvin should be considered if necessary.
• In animal studies, chronic feeding of griseofulvin has been linked to the development of liver tumors in mice, especially in males, when given at levels ranging from 0.5%-2.5% of the diet. Subcutaneous administration of relatively small doses of griseofulvin has also been reported to induce hepatomata in mice. In rats, griseofulvin has been linked to thyroid tumors, mostly adenomas but some carcinomas, at levels of 2.0%, 1.0%, and 0.2% of the diet in males and the two higher dose levels in females. Studies in other animal species have not provided evidence of tumorigenicity, but they were not designed adequately to draw definitive conclusions. Subacute toxicity studies have shown that orally administered griseofulvin induced hepatocellular necrosis in mice, but this effect has not been observed in other species. Disturbances in porphyrin metabolism have also been reported in laboratory animals treated with griseofulvin. Additionally, griseofulvin has been reported to have a colchicine-like effect on mitosis and to have carcinogenicity with methylcholanthrene in cutaneous tumor induction in laboratory animals.

The excretion of griseofulvin in breast milk is currently unknown. Considering the possibility of severe adverse reactions in the nursing infant, it is advisable to avoid breastfeeding while taking griseofulvin.

Pregnancy:

Category D

The use of griseofulvin has been contraindicated in pregnant women.

No specific food restrictions or dietary modifications are required when using Griseofulvin. Griseofulvin can be administered with or without food.

The adverse reactions related to Griseofulvin can be categorized as follows:

Common:

• Red, irritated eyes
• Sore throat
• Chills
• Cough
• Diarrhea
• Fever
• Itching
• Joint or muscle pain
• Sores, ulcers, or white spots in the mouth or on the lips
• Unusual tiredness or weakness

Less common:

• Skin rash, hives, or itching
• Confusion
• Increased sensitivity of the skin to sunlight
• Soreness or irritation of the mouth or tongue

Rare

• Black, tarry stools
• Chest pain
• Cloudy urine
• Large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• Swollen glands
• Numbness, tingling, pain, or weakness in the hands or feet
• Painful or difficult urination
• Shortness of breath
• Unusual bleeding or bruising
• Yellow eyes or skin.

• Patients on warfarin-type anticoagulant therapy may need dosage adjustment of the anticoagulant while undergoing griseofulvin treatment. Also, concomitant use of barbiturates can often reduce griseofulvin activity, leading to a potential need for dosage adjustment.
• The concomitant use of griseofulvin has been reported to decrease the effectiveness of oral contraceptives and increase the occurrence of breakthrough bleeding.

The following are the side effects involving Griseofulvin:

• Nausea,
• Vomiting,
• Upset stomach,
• Diarrhea
• Headache,
• Tiredness
• Rash
• Sleep problems (insomnia)
• Dizziness

Pregnancy:

Category D

The use of griseofulvin has been contraindicated in pregnant women.

Lactation:

The excretion of griseofulvin in breast milk is currently unknown. Considering the possibility of severe adverse reactions in the nursing infant, it is advisable to avoid breastfeeding while taking griseofulvin.

Pediatric:

For most pediatric patients, an effective dose of ultramicro size griseofulvin is approximately 7.3 mg per kg of body weight per day. Based on this, the recommended dosage schedule is as follows:

● For children weighing between 16 to 27 kg: 125 mg to 187.5 mg daily.

● For children weighing over 27 kg: 187.5 mg to 375 mg daily.

It has not been determined what the appropriate dosage is for children and infants under the age of 2. However, clinical trials have demonstrated that a single daily dose of griseofulvin is effective for children with tinea capitis. It is important to continue taking the medication until the infection is completely eliminated to avoid any chance of a relapse.

Geriatric Use:

The clinical studies conducted on Griseofulvin did not include an adequate number of patients aged 65 and above to establish whether they exhibit different responses compared to younger patients. Although the number of elderly patients was insufficient for a statistical analysis, no notable discrepancies in safety or effectiveness were observed between this age group and younger patients. In healthy older men and women (aged 65 years and above), plasma concentrations of Griseofulvin exhibited a slight increase (approximately 28% in AUC) compared to young healthy men. Similar effects of age on pharmacokinetics were observed in patients with candidemia or other Candida infections, such as intra-abdominal abscesses, peritonitis, or pleural space infections. No dose adjustment is recommended for the elderly population; however, it is important to acknowledge that certain older individuals may potentially be more sensitive to the medication, although this cannot be definitively determined.

There is no sufficient scientific evidence traceable regarding overdosage of Griseofulvin.

Pharmacodynamics:

Griseofulvin, derived from Penicillium spp., was the first oral antifungal agent available for treating dermatophytoses, and it has been in use for over four decades. This fungistatic medication demonstrates in vitro activity against various Microsporum, Epidermophyton, and Trichophyton species, specifically targeting these fungi without affecting bacteria or other fungal genera.

Upon oral administration, griseofulvin is selectively accumulated in keratin precursor cells and exhibits a stronger affinity for diseased tissues. The drug forms a tight bond with newly synthesized keratin, rendering it highly resistant to fungal invasions. Once the keratin-griseofulvin complex reaches the site of action on the skin, it binds to fungal microtubules (tubulin), thereby disrupting fungal mitosis.

Pharmacokinetics:

Absorption:

● Griseofulvin is poorly absorbed from the gastrointestinal (GI) tract, with absorption rates ranging from 25% to 70% of an oral dose.

● Administration with or after a fatty meal significantly enhances its absorption.

Volume of Distribution:

● Information about the volume of distribution is not available.

Protein Binding:

● Information about protein binding is not available.

Metabolism:

● Griseofulvin undergoes primarily hepatic metabolism.

● The major metabolites include 6-methyl-griseofulvin and its glucuronide conjugate.

Route of Elimination:

● Detailed information about the route of elimination is not available.

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• https://reference.medscape.com/drug/grifulvin-v-gris-peg-griseofulvin-342590
• https://www.medicines.org.uk/emc/product/10746/smpc#gref
• https://www.everydayhealth.com/drugs/griseofulvin
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/050475s057lbl.pdf
• https://www.goodrx.com/griseofulvin-microsize/what-is
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