VA Class:AM700

AHFS Class:

• Antifungals, Miscellaneous 8:14.92

Generic Name(s):

• Griseofulvin

Griseofulvin is a fungistatic antibiotic.

Dermatophytoses

Griseofulvin is used in the treatment of tineas (ringworm infections) of the skin, hair, and nails, including tinea barbae, tinea capitis, tinea corporis, tinea cruris, tinea pedis, and tinea unguium (onychomycosis) caused by susceptible species of Trichophyton, Microsporum , or Epidermophyton. Because the drug is not effective against other fungal infections, the infecting organism should be identified as a dermatophyte before initiating therapy. Griseofulvin is not effective in the treatment of pityriasis (tinea) versicolor, candidiasis, deep mycotic infections, or bacterial infections, and safety and efficacy of the drug for prophylaxis of fungal infections have not been established. Griseofulvin should not be used indiscriminately, but should be reserved for infections not amenable to topical antifungal agents. Concomitant therapy should include general hygienic measures to control infection and to prevent reinfection. Appropriate agents should also be employed when infections are complicated by the presence of bacteria or yeasts, as may occur in tinea pedis.

Response to therapy depends upon the rate of keratinization and time necessary for desquamation of infected keratinized structures. Soles, palms, and nails respond more slowly than less keratinized skin, and toenails respond at the slowest rate. Although symptomatic improvement of skin infections may be seen after a few days of oral griseofulvin therapy, the drug should be administered until previously infected tissue is devoid of fungi, usually a minimum of 2-4 weeks in the treatment of tinea corporis and a year or longer in the treatment of fungal nail infections. There are no published clinical studies comparing ultramicrosize and microsize griseofulvin for the treatment of tinea infections, and there is no clinical evidence that one formulation has any advantage over the other.

Tinea barbae and tinea capitis generally require treatment with an oral antifungal regimen.124,131,135,137,140 Tinea corporis and tinea cruris generally can be effectively treated using a topical antifungal agent; however, an oral antifungal regimen may be necessary if the disease is extensive, dermatophyte folliculitis is present, the infection does not respond to topical therapy, or the patient is immunocompromised or has coexisting disease (e.g., diabetes mellitus).124,130,131,132,133,134,136,140 While topical antifungals usually are effective for the treatment of acute, uncomplicated tinea manuum and tinea pedis,124,131,132,134,136,140 an oral antifungal regimen usually is necessary for the treatment of severe, chronic, or recalcitrant tinea pedis,124 chronic moccasin-type (dry-type) tinea pedis, and for the treatment of tinea unguium (onychomycosis).131,134,136,140

In a double-blind study in adults with tinea corporis and/or tinea cruris randomized to receive oral griseofulvin (500 mg once daily) or oral fluconazole (150 mg once weekly) for 4-6 weeks, a clinical cure was obtained in 62 or 74% of patients, respectively.142

Oral griseofulvin generally has been considered a drug of choice for treatment of tinea capitis;124,131,132,133,135,140,141 however, prolonged therapy usually is necessary to cure the infection and poor compliance may affect response to the drug.131,135,138,140,141 In a prospective, randomized study in pediatric patients 2-15 years of age with mycologically confirmed tinea capitis who were randomized to receive oral griseofulvin (10 mg/kg daily) or oral terbinafine, the response rate to both drugs was 100%.139 However, in a retrospective review of pediatric patients 3 months to 12 years of age who received oral griseofulvin (mean dosage: 12.5 mg/kg of microsize once daily for 5 weeks) for treatment of mycologically confirmed tinea capitis, the initial response rate to the drug was 60.7%, and almost 40% of patients had signs and symptoms of persistent disease 8 months after the initial diagnosis.138

Other Uses

Because griseofulvin has some vasodilatory activity, its use has resulted in some improvement in a small number of patients with Raynaud's disease† or angina pectoris†. Because it is structurally similar to colchicine and shares its activity as a metaphase inhibitor, griseofulvin has been used in the treatment of gout†.

Administration

Griseofulvin is administered orally as a single daily dose or in 2-4 equally divided doses.

Dosage

Dosage of griseofulvin varies depending on whether the drug is administered as griseofulvin microsize or griseofulvin ultramicrosize.103,104,123,124,125 In addition, dosage recommendations for ultramicrosize griseofulvin vary slightly depending on the manufacturer and the particular formulation of the drug.103,104,123

Dosage and duration of griseofulvin therapy should be individualized according to the requirements and response of the patient. Griseofulvin therapy generally needs to be continued for at least 4-12 weeks for the treatment of tinea capitis;103,104,123,124,125,132,133,135,140,141 at least 2-4 weeks for the treatment of tinea corporis;103,104,123,124,125 at least 4-8 weeks for tinea pedis; and from 4-6 months to a year or longer for tinea unguium.103,104,123,124,125

Adult Dosage

The usual adult dosage of ultramicrosize griseofulvin for the treatment of tinea capitis, tinea corporis, or tinea cruris is 330 or 375 mg daily, depending on the manufacturer and formulation of the drug.103,104,123 The usual adult dosage of ultramicrosize griseofulvin for the treatment of infections that are more difficult to eradicate, such as tinea pedis and tinea unguium, is 660 or 750 mg daily, depending on the manufacturer and formulation of the drug.103,104,123

The usual adult dosage of microsize griseofulvin is 500 mg daily for the treatment of tinea capitis, tinea corporis, or tinea cruris and 1 g daily for the treatment of infections that are more difficult to eradicate, such as tinea pedis and tinea unguium.125

Pediatric Dosage

The usual dosage of ultramicrosize griseofulvin for children older than 2 years of age is approximately 7.3 mg/kg daily,103,104,123 although dosages ranging up to 10-15 mg/kg daily have been used.140 The manufacturers suggest that children weighing approximately 14-23 kg may receive 82.5-165 mg of ultramicrosize griseofulvin daily and those weighing greater than 23 kg may receive 165-330 mg daily.103 Alternatively, the manufacturers suggest that children weighing approximately 16-27 kg may receive 125-187.5 mg of ultramicrosize griseofulvin daily and those weighing greater than 27 kg may receive 187.5-375 mg daily.104,123 For the treatment of tinea capitis or tinea corporis, the American Academy of Pediatrics (AAP) recommends that children receive ultramicrosize griseofulvin in a dosage of 5-10 mg/kg (maximum dose 750 mg) once daily.124 The manufacturers state that dosage of ultramicrosize griseofulvin has not been established in children 2 years of age and younger.103,104,123

The usual pediatric dosage of microsize griseofulvin is 10-11 mg/kg daily, although dosages ranging up to 20-25 mg/kg daily have been used.124,125,140 The AAP recommends that children receive microsize griseofulvin in a dosage of 15-20 mg/kg (maximum dose: 1 g) once daily.124 The manufacturers suggest that children weighing approximately 14-23 kg may receive 125-250 mg of microsize griseofulvin daily and that children weighing greater than 23 kg may receive 250-500 mg daily.125 Alternatively, some clinicians suggest that children be given microsize griseofulvin in a dosage of 300 mg/m² daily.

Nervous System Effects

Headache is a frequent adverse effect of griseofulvin, occurring in the early stages of therapy. Although headache may be severe, it often disappears with continued therapy. Fatigue, dizziness, and insomnia also have been reported. Rarely, paresthesia of hands and feet has followed extended therapy with griseofulvin. Occasionally, large doses have produced mental confusion, impairment of performance of routine activities, or psychotic symptoms.

GI Effects

Adverse GI effects occurring occasionally during griseofulvin therapy include epigastric distress, nausea and vomiting, excessive thirst, flatulence, and diarrhea. Oral thrush due to Candida overgrowth has also occurred. GI bleeding has been reported rarely.

Dermatologic and Sensitivity Reactions

Hypersensitivity reactions have been reported and may necessitate discontinuance of the drug. These reactions include rash, urticaria, and rarely angioedema, erythema multiforme-like reactions, and a reaction resembling serum sickness. Griseofulvin has produced photosensitivity in some individuals. Lupus erythematosus, lupus-like syndrome, or exacerbation of preexisting lupus erythematosus has also been reported in patients receiving the drug. Toxic epidermal necrolysis, which may be fatal,121 has been reported rarely.103,108,121,123

Other Adverse Effects

Proteinuria, nephrosis, hepatotoxicity, and menstrual irregularities have been reported rarely in patients receiving griseofulvin. Griseofulvin has been reported to produce estrogen-like effects in children.

Rarely, transient diminution of hearing has occurred in connection with griseofulvin therapy. Treatment with griseofulvin has also produced reversible leukopenia.

Precautions and Contraindications

During prolonged griseofulvin therapy, periodic assessment of renal, hepatic, and hematopoietic functions should be performed. The drug should be discontinued if granulocytopenia occurs. When rare, serious adverse effects occur with griseofulvin, they are usually associated with high dosages of the drug and/or prolonged therapy.

Since griseofulvin has occasionally been associated with photosensitivity reactions, patients should be cautioned to avoid exposure to intense natural or artificial sunlight. Photosensitivity reactions may aggravate lupus erythematosus.

Griseofulvin interferes with porphyrin metabolism. Chronic administration has resulted in elevated concentrations of porphyrins in feces and erythrocytes and may precipitate an acute attack of intermittent porphyria.

Because griseofulvin is produced by species of Penicillium , the possibility of cross-sensitivity with penicillins should be considered; however, patients hypersensitive to penicillin have been treated with griseofulvin without adverse effects.

Griseofulvin is contraindicated in patients with porphyria, hepatocellular failure, or a history of hypersensitivity to the drug. Because of possible teratogenic and abortifacient effects of the drug, griseofulvin therapy should not be initiated in pregnant women or in women of childbearing potential who may become pregnant.101,103,104,123 (See Cautions: Pregnancy and Fertility.)

Pediatric Precautions

Griseofulvin is used for the treatment of dermatophytoses in pediatric patients.103,104,123,124,138,139,140,141 Microsize griseofulvin has been used in children as young as 3 months of a 138 the manufacturers state that dosage of ultramicrosize griseofulvin has not been established in children 2 years of age and younger.103,104,123

Mutagenicity and Carcinogenicity

Griseofulvin has produced evidence of mutagenic potential in vitro in several test systems.106,107 Griseofulvin interferes with chromosomal distribution during cell division, causing aneuploidy in plant and mammalian cells.103,123,125 These effects have been demonstrated in vitro at concentrations that may be achieved in serum with the recommended therapeutic dosage.103,123,125

Animal studies with griseofulvin have revealed evidence of carcinogenic potential.103,104,106,123 The drug appeared to act either to promote carcinogenicity or as a cocarcinogen.103,104,106,123 In mice, chronic oral administration of griseofulvin resulted in the development of hepatic tumors; in subacute toxicity studies, hepatocellular necrosis occurred. Subcutaneous administration of relatively small doses of the drug once weekly during the first 3 weeks of life has also been reported to induce hepatomata in mice. Thyroid tumors, mostly adenomas but some carcinomas, have been reported in rats who received oral griseofulvin in concentrations of 0.2-2% of their diet. Similar effects have not been observed when the drug was administered to other animal species.

Pregnancy and Fertility

Pregnancy

Griseofulvin may cause fetal toxicity when administered to pregnant women.101,103,104,111,117,118,123 Griseofulvin is embryotoxic and/or teratogenic in animals.101,103,104,106,113,114,115,116,123,125 Fetal abnormalities have included multiple defects in rats; cleft palate in dogs; cleft palate and cardiac, CNS, and ocular defects in cats; and skeletal defects in mice.101,113,116 Although the potential risk to the fetus of maternal use of griseofulvin remains to be clearly established in humans,111,112 at least two women who received griseofulvin therapy during the first trimester of pregnancy delivered conjoined twins, and some women who received the drug during pregnancy reportedly have had spontaneous abortions or delivered infants with other congenital malformations.101,103,104,111,117,118,123 In an analysis of spontaneous or threatened abortion diagnoses in one large group of women, the estimated relative risk of spontaneous abortion in women who received griseofulvin within the 3 months prior to such diagnoses was estimated to be increased 2.5 times.101,118 Some experts state that while limited data indicate that the outcome for most pregnancies is likely to be normal after fetal exposure to the drug, evidence from the US Food and Drug Administration's teratogen information system indicates that an association between conjoined twins and griseofulvin use exists and data are insufficient to exclude a moderate association between use of the drug and other defects.101,117,118 However, other experts have questioned whether an association between use of the drug and conjoined twinning has been established.111,112 The manufacturers state that griseofulvin is contraindicated in women who are or may become pregnant.103,104,123,125 One manufacturer states that additional contraceptive precautions should be taken during and for 1 month after griseofulvin therapy and that griseofulvin should not be used in any woman who intends to become pregnant within 1 month after therapy with the drug would be discontinued.125 If griseofulvin is inadvertently administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.104

Fertility

In rats, griseofulvin has been reported to suppress spermatogenesis, but studies in humans have not confirmed this effect.103,104,123,125 Sperm abnormalities also have been observed in mice.106 Since griseofulvin has demonstrated harmful effects in vitro on the genotype in bacteria, plants, and fungi, males should wait at least 6 months after completing therapy with the drug before fathering a child.103,123,125

Alcohol

Griseofulvin has been reported to cause tachycardia and flushing and to potentiate effects of alcohol when concurrently ingested. Some clinicians have suggested that patients be warned of this possible reaction and to avoid alcohol; others consider this reaction to be of questionable clinical importance.

Phenobarbital

Phenobarbital may decrease blood griseofulvin concentrations, possibly by impairing griseofulvin absorption and/or by inducing hepatic microsomal enzymes, and it is preferable to avoid concomitant administration of these drugs. If concomitant therapy is necessary, it has been suggested that absorption of griseofulvin may be best if the drug is administered in 3 divided doses daily. Blood griseofulvin concentrations should be monitored and dosage of the antifungal increased if necessary.

Coumarin Anticoagulants

In a small number of patients stabilized on warfarin who then received griseofulvin, decreases in the patients' prothrombin times were noted. The decrease in warfarin effectiveness has been attributed to enzyme induction by griseofulvin. Although this interaction has been reported only rarely, the potential seriousness of the interaction warrants caution when griseofulvin and warfarin are administered concurrently; dosage of the anticoagulant may require adjustment during concomitant therapy and after griseofulvin is discontinued.

Oral Contraceptives

Griseofulvin reportedly may cause amenorrhea, increased breakthrough bleeding, and possibly decreased contraceptive efficacy during concomitant use with oral contraceptives.100,103,105,123 These effects may be caused by enhanced metabolism of the estrogenic component of oral contraceptives, presumably by induction of hepatic microsomal enzymes.100,103,105,123 At least one pregnancy has occurred in a patient receiving an oral contraceptive who received concomitant therapy with griseofulvin (330 mg of griseofulvin ultramicrosize twice daily); the patient had been using the contraceptive effectively for several years prior to initiation of griseofulvin and was receiving no other drugs (other than griseofulvin and the oral contraceptive) at the time of pregnancy.129 The possibility of decreased contraceptive efficacy should be considered if the drugs are used concomitantly.100,105,129 (See Cautions: Pregnancy and Fertility.)

Other Drugs

Concomitant administration of griseofulvin and theophylline has resulted in increased clearance of theophylline and a shorter theophylline half-life; however, the extent of this interaction appears to vary and increased clearance of theophylline is not evident in all individuals who receive the drugs concomitantly.126

Initiation of griseofulvin therapy in a patient who was receiving aspirin resulted in decreased plasma salicylate concentrations.127

In at least one patient, concomitant administration of griseofulvin and cyclosporine resulted in decreased blood concentrations of cyclosporine.128

Mechanism of Action

Griseofulvin exerts its fungistatic action primarily by disrupting the cell's mitotic spindle structure, thus arresting the metaphase of cell division. Although the effect on mitosis is similar to that caused by colchicine, a different mechanism is probably involved. Another proposed mechanism of action is that griseofulvin causes production of defective DNA which is unable to replicate. Griseofulvin is deposited in keratin precursor cells, which renders them an unfavorable environment for fungal invasion. Infected skin, hair, or nails are then replaced with tissue not infected with the dermatophyte.

Griseofulvin also has some direct vasodilatory effect.

Spectrum

In vitro, griseofulvin concentrations of 0.15-0.5 mcg/mL inhibit species of Trichophyton, Microsporum , and Epidermophyton when they are exposed to the drug for 72 hours. Specifically, griseofulvin is active against Trichophyton rubrum, T. tonsurans, T. mentagrophytes, T. verrucosum, T. megninii, T. gallinae , and T. schoenleinii. The drug also is active against Microsporum audouinii, M. canis , M. gypseum , and Epidermophyton floccosum. Griseofulvin is not active against bacteria, Candida, Actinomyces, Aspergillus, Blastomyces, Cryptococcus, Coccidioides, Geotrichum, Histoplasma, Nocardia, Saccharomyces, Sporotrichum , or Malassezia furfur (Pityrosporum orbiculare).

Pharmacokinetics

Absorption

Following oral administration, griseofulvin is absorbed principally from the duodenum. Absorption of microsize griseofulvin is variable and unpredictable and ranges from 25-70% of an oral dose. A single 500-mg dose of microsize griseofulvin administered to fasting adults produces mean peak serum concentrations of 0.5-2 mcg/mL 4 hours after oral administration.125 Absorption of microsize griseofulvin apparently can be enhanced by administration with a high-fat meal. Ultramicrosize griseofulvin is almost completely absorbed following oral administration.

Distribution

Following absorption, griseofulvin is concentrated in skin, hair, nails, liver, fat, and skeletal muscles. Griseofulvin is deposited in keratin precursor cells and has a high affinity for diseased tissue; the drug is tightly bound to new keratin. The drug can be detected in the outer layers of the stratum corneum soon after it is ingested. Within 4 hours after administration of a single 500-mg dose of microsize griseofulvin, concentrations of 1 mcg/g of skin have been found; 8 hours after the dose, the concentration has been reported to be 3 mcg/g of skin. When microsize griseofulvin is given in a dosage of 500 mg every 12 hours, concentrations of 6-12 mcg/g of skin may be reached within 30 hours, and if this dosage is continued for several weeks, griseofulvin concentrations of 12-25 mcg/g are maintained. Concurrent serum concentrations remain at 1-2 mcg/mL. When the drug is discontinued, griseofulvin concentrations in the skin decline more rapidly than do those in plasma. Within 2 days after discontinuance, the drug is undetectable in skin, and within 4 days after discontinuance, it is undetectable in plasma. Griseofulvin concentrations in skin are higher in warm climates than in cold, possibly because the drug is dissolved in perspiration and deposited in the horny layer of skin when perspiration evaporates. This explanation has also been used to account for the reversed concentration gradient of the drug in skin; highest concentrations are found in the outermost horny layer, while concentrations are much lower in deeper layers. Griseofulvin does not penetrate keratin tissue following topical administration to the skin.

Elimination

Griseofulvin has an elimination half-life of 9-24 hours.

Griseofulvin is oxidatively demethylated and conjugated with glucuronic acid, principally in the liver. The major metabolite, 6-desmethylgriseofulvin, is microbiologically inactive.

In one study, 30% of a single oral dose of microsize griseofulvin was excreted in urine within 24 hours as 6-desmethylgriseofulvin and its glucuronide conjugate; 50% of the dose was excreted in urine within 5 days. Unchanged griseofulvin in the urine accounts for less than 1% of the administered drug. Approximately one-third of a single dose of microsize griseofulvin is excreted in feces within 5 days. Griseofulvin is also excreted in perspiration.

Chemistry and Stability

Chemistry

Griseofulvin is a fungistatic antibiotic produced by Penicillium griseofulvum or other species of Penicillium , including P. chrysogenum. Griseofulvin occurs as a white to creamy white, bitter tasting, thermostable powder which is very slightly soluble in water and sparingly soluble in alcohol. The drug is commercially available for oral administration as griseofulvin microsize125 and griseofulvin ultramicrosize.103,104,123 Microsize griseofulvin contains predominantly particles of the order of 4 µm in diameter, and ultramicrosize griseofulvin contains predominantly particles of less than 1 µm in diameter.

Stability

Griseofulvin preparations should generally be stored at a temperature less than 40°C, preferably between 15-30°C.103,104,123,125 Microsize griseofulvin oral suspension should be protected from freezing and stored in tight, light-resistant containers. Microsize griseofulvin tablets and ultramicrosize griseofulvin tablets should be stored in well-closed containers. Preparations of griseofulvin have expiration dates of 2-5 years following the date of manufacture, depending on the formulation.

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