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GRISEOFULVIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Griseofulvin is a fungistatic antibiotic derived from Penicillium griseofulvum and Penicillium janczewskii with in vitro activity against various species of Microsporum, Epidermophyton, and Trichophyton.

Specific Substances

    1) Curling factor
    2) Griseofulvinum
    3) CAS 126-07-8
    1.2.1) MOLECULAR FORMULA
    1) C17H17ClO6

Available Forms Sources

    A) FORMS
    1) MICROCRYSTALLINE
    a) 250 mg oral capsule, 125 mg/5 mL oral suspension, 250 mg and 500 mg oral tablets.
    2) ULTRAMICROCRYSTALLINE
    a) 125 mg, 250 mg, and 330 mg oral tablets
    B) USES
    1) Griseofulvin is an antifungal agent particularly active against epidermophytin, microsporum, and trichophyton (tinea) organisms. It is used for systemic treatment of various tinea (ringworm); and of infections including tinea capitis, tinea corporis, tinea cruris, tinea pedis, and tinea unguium. Systemic griseofulvin is usually effective in tinea of the body, fingernails, groin, hands, head, soles of the feet, and toenails (Prod Info griseofulvin oral suspension, 2014).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Griseofulvin, a fungistatic antibiotic, is indicated for the treatment of dermatophyte infections of the skin not adequately treated by topical therapy.
    B) PHARMACOLOGY: Griseofulvin may be active against many strains of dermatophytes. Griseofulvin is a fungistatic antibiotic derived from Penicillium griseofulvum and Penicillium janczewskii with in vitro activity against various species of Microsporum, Epidermophyton, and Trichophyton.
    C) EPIDEMIOLOGY: Exposure can occur.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EVENTS: COMMON: If adverse events develop, hypersensitivity such as skin rashes, urticaria, and rarely angioneurotic edema, and erythema multiforme can occur.
    2) POSTMARKETING EXPERIENCE: SERIOUS: Severe skin and hepatic adverse events have been reported following griseofulvin therapy. Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme have occurred with therapy. Elevations in AST, ALT, bilirubin and jaundice have also been reported with therapeutic use. Both of these events may result in hospitalization or death in some cases.
    3) INFREQUENT: Other clinical events, may include oral thrush, nausea, vomiting, epigastric distress, diarrhea, headache, fatigue, dizziness, insomnia, and mental confusion.
    4) RARE: The following events have occurred rarely with therapy: proteinuria, nephrosis (sometimes associated with existing systemic lupus erythematosus), leukopenia, coagulopathy, hepatitis, elevated liver enzymes, hyperbilirubinemia, and gastrointestinal bleeding.
    5) CHRONIC: Peripheral neuropathy and paresthesia of the hands and feet have been reported and appear to be associated with treatment duration. Patients treated for less than 6 months usually have a resolution of neuropathy upon drug withdrawal.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Limited data. There are insufficient data in the literature to accurately determine the events following overdose. However, overdose events are anticipated to be similar to adverse events reported with therapy. Hyperamylasemia and elevated liver enzymes have been reported following griseofulvin overdose in 2 young children.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Headache, dizziness, insomnia, and mental confusion may occasionally occur.
    2) Peripheral neuropathy and paresthesia have occurred and may be related to the duration of therapy.
    0.2.8) GASTROINTESTINAL
    A) WITH THERAPEUTIC USE
    1) Nausea, vomiting, diarrhea, epigastric pain and oral thrush have been occasionally reported with therapeutic use.
    B) WITH POISONING/EXPOSURE
    1) Hyperamylasemia has been reported with griseofulvin overdose.
    0.2.9) HEPATIC
    A) WITH THERAPEUTIC USE
    1) Hepatotoxicity has been reported rarely with therapy. Elevated liver enzymes have also been reported.
    B) WITH POISONING/EXPOSURE
    1) Two children developed elevated liver enzyme levels after inadvertent exposure.
    0.2.14) DERMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Photosensitivity, skin rashes, Kawasaki-like syndrome, and vesicular and morbilliform eruptions have been reported following therapeutic doses.
    2) Urticaria may occur as a result of a hypersensitivity reaction.
    0.2.20) REPRODUCTIVE
    A) Griseofulvin is rated FDA Pregnancy Category X and use is contraindicated during pregnancy. There have been reports of conjoined twins, abortion, and congenital anomalies with the use of griseofulvin during pregnancy. In animal studies, there were also evidence of embryotoxicity, teratogenicity, and abnormalities. There are no data regarding griseofulvin use during breastfeeding.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturer does not report any carcinogenic potential for griseofulvin.

Laboratory Monitoring

    A) Monitor neurologic function following prolonged therapy or as indicated.
    B) Monitor fluids and electrolytes in patients with persistent or prolonged vomiting and/or diarrhea following an acute exposure.
    C) Obtain a baseline CBC and monitor hepatic and renal and function closely in symptomatic patients.
    D) Plasma griseofulvin levels are not clinically useful.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Limited overdose data. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting. Monitor for hypersensitivity reactions (ie, rash, urticaria); treatment may include antihistamines with or without beta agonists, corticosteroids or epinephrine. Monitor liver enzymes (ie, AST, ALT, bilirubin) following a significant exposure or as indicated. Obtain a baseline CBC in patients with an acute on chronic exposure or in symptomatic patients.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. HYPERSENSITIVITY REACTION should be managed by discontinuation of the drug and observation for severe reaction, including anaphylactic shock. Anaphylaxis should be managed with intravenous fluids, airway management, and administration of epinephrine, diphenhydramine, and corticosteroids. Monitor for possible hepatotoxicity and severe skin reactions and erythema multiforme.
    C) DECONTAMINATION
    1) PREHOSPITAL: Toxicity after an acute minor ingestion is unlikely, and is generally only expected with a significant exposure. Gastrointestinal decontamination is generally unnecessary.
    2) HOSPITAL: Toxicity after acute minor ingestion is unlikely, and is generally only expected with a significant exposure. Gastrointestinal decontamination is generally unnecessary. Consider activated charcoal only if coingestants with significant toxicity are involved.
    D) AIRWAY MANAGEMENT
    1) Airway management is unlikely to be necessary following a minor ingestion. Airway support may be necessary in patients that develop significant hypersensitivity or allergic reactions. Ensure adequate ventilation and perform endotracheal intubation early in patients with an acute allergic reaction or as indicated.
    E) ANTIDOTE
    1) There is no known antidote for griseofulvin.
    F) HYPERSENSITIVITY REACTION
    1) MILD/MODERATE: Antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE: Administer oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.
    G) ENHANCED ELIMINATION
    1) It is unknown if enhanced elimination would be beneficial following exposure.
    H) PHARMACOKINETICS
    1) Absorption is variable; range, 27% to 72%. It is metabolized by the liver to 6-desmethylgriseofulvin and its glucuronide conjugate. The peak serum level is about 4 hours in fasting adults given 0.5 g of griseofulvin. Serum levels are likely to be increased when given with a meal with a high fat content. Elimination half-life in plasma is variable (range, 9 to 24 hours). About 30% of an oral dose is excreted within 24 hours and about 50% is excreted within 5 days mostly as metabolites. About 33% of an oral dose is excreted in feces within 5 days. Excretion may also occur through perspiration.
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent minor exposure (1 to 2 tablets), that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.
    3) ADMISSION CRITERIA: Patients with severe symptoms including hypersensitivity and/or allergic reactions, skin reactions (ie, Stevens-Johnson syndrome, toxic epidermal necrolysis), or hepatotoxicity despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.

Range Of Toxicity

    A) TOXICITY: A minimum lethal or toxic dose has not been well established.
    B) THERAPEUTIC DOSE: ADULT: ORAL: 500 mg to 1 g daily; the dosage should be individualized. PEDIATRIC (older than 2 years): ORAL: 10 mg/kg is usually adequate; individualize the dose as needed.

Clinical Effects

Summary Of Exposure

    A) USES: Griseofulvin, a fungistatic antibiotic, is indicated for the treatment of dermatophyte infections of the skin not adequately treated by topical therapy.
    B) PHARMACOLOGY: Griseofulvin may be active against many strains of dermatophytes. Griseofulvin is a fungistatic antibiotic derived from Penicillium griseofulvum and Penicillium janczewskii with in vitro activity against various species of Microsporum, Epidermophyton, and Trichophyton.
    C) EPIDEMIOLOGY: Exposure can occur.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EVENTS: COMMON: If adverse events develop, hypersensitivity such as skin rashes, urticaria, and rarely angioneurotic edema, and erythema multiforme can occur.
    2) POSTMARKETING EXPERIENCE: SERIOUS: Severe skin and hepatic adverse events have been reported following griseofulvin therapy. Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme have occurred with therapy. Elevations in AST, ALT, bilirubin and jaundice have also been reported with therapeutic use. Both of these events may result in hospitalization or death in some cases.
    3) INFREQUENT: Other clinical events, may include oral thrush, nausea, vomiting, epigastric distress, diarrhea, headache, fatigue, dizziness, insomnia, and mental confusion.
    4) RARE: The following events have occurred rarely with therapy: proteinuria, nephrosis (sometimes associated with existing systemic lupus erythematosus), leukopenia, coagulopathy, hepatitis, elevated liver enzymes, hyperbilirubinemia, and gastrointestinal bleeding.
    5) CHRONIC: Peripheral neuropathy and paresthesia of the hands and feet have been reported and appear to be associated with treatment duration. Patients treated for less than 6 months usually have a resolution of neuropathy upon drug withdrawal.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Limited data. There are insufficient data in the literature to accurately determine the events following overdose. However, overdose events are anticipated to be similar to adverse events reported with therapy. Hyperamylasemia and elevated liver enzymes have been reported following griseofulvin overdose in 2 young children.

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Headache, dizziness, insomnia, and mental confusion may occasionally occur.
    2) Peripheral neuropathy and paresthesia have occurred and may be related to the duration of therapy.
    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH THERAPEUTIC USE
    a) Dizziness, insomnia, mental confusion and impairment of performance with routine activities have been occasionally reported with therapeutic use (Prod Info griseofulvin oral tablets, 2013).
    B) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache may occasionally occur with therapy (Prod Info griseofulvin oral tablets, 2013).
    C) DISORDER OF THE PERIPHERAL NERVOUS SYSTEM
    1) WITH THERAPEUTIC USE
    a) Peripheral neuropathy and paresthesia of the hands and feet have developed in individuals and may be related to the duration of therapy. Many patients that had been taking griseofulvin for less than 6 months had a gradual improvement in symptoms once therapy was discontinued (Prod Info griseofulvin oral tablets, 2013).
    b) CASE REPORT: A 76-year-old woman developed paresthesia in all fingers and numbness of feet 10 months after beginning griseofulvin therapy, 500 mg daily, to treat a nail infection. Four months after the onset of these symptoms, nerve conduction studies revealed peripheral neuropathy. All neurological signs and symptoms resolved 4 months later (Lecky, 1990).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Nausea, vomiting, diarrhea, epigastric pain and oral thrush have been occasionally reported with therapeutic use.
    B) WITH POISONING/EXPOSURE
    1) Hyperamylasemia has been reported with griseofulvin overdose.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting have occasionally been reported with therapy (Prod Info griseofulvin oral tablets, 2013).
    B) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea has occasionally been reported with therapy (Prod Info griseofulvin oral tablets, 2013).
    C) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE
    1) WITH THERAPEUTIC USE
    a) Oral thrush and epigastric pain have occasionally been reported with therapy (Prod Info griseofulvin oral tablets, 2013).
    D) GASTROINTESTINAL HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) Gastrointestinal bleeding has rarely been reported with griseofulvin therapy (Prod Info griseofulvin oral tablets, 2013).
    E) SERUM AMYLASE RAISED
    1) WITH POISONING/EXPOSURE
    a) CASE REPORTS: Asymptomatic increases in amylase and AST were reported in 2 children after inadvertent ingestion of approximately 2.5 g of griseofulvin (ie, a 5 g dose was shared between them) (Dyer et al, 1999).

Hepatic

    3.9.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Hepatotoxicity has been reported rarely with therapy. Elevated liver enzymes have also been reported.
    B) WITH POISONING/EXPOSURE
    1) Two children developed elevated liver enzyme levels after inadvertent exposure.
    3.9.2) CLINICAL EFFECTS
    A) LIVER DAMAGE
    1) WITH THERAPEUTIC USE
    a) Hepatitis and hyperbilirubinemia have been rarely reported with griseofulvin therapy (Prod Info griseofulvin oral tablets, 2013; Chiprut et al, 1976).
    B) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Elevated AST, ALT and bilirubin have occurred with therapy. These events may be severe and result in hospitalization or death in some cases (Prod Info griseofulvin oral tablets, 2013).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORTS: Asymptomatic rises in LDH and AST were reported in 2 children after inadvertent ingestion of approximately 2.5 g of griseofulvin (ie, a 5 g dose was shared between them) (Dyer et al, 1999).
    C) JAUNDICE
    1) WITH THERAPEUTIC USE
    a) Jaundice along with elevated liver enzymes have occurred with therapy. These events may be severe and result in hospitalization or death in some cases (Prod Info griseofulvin oral tablets, 2013).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) KIDNEY DISEASE
    1) WITH THERAPEUTIC USE
    a) Proteinuria and nephrosis, occasionally associated with existing systemic lupus erythematosus, have been rarely reported with griseofulvin therapy (Prod Info griseofulvin oral tablets, 2013).
    b) Albuminuria and cylindruria without signs of renal insufficiency have been noted following therapeutic doses (Abramowicz & Edelmann, 1968).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Leukopenia has been rarely reported with griseofulvin therapy (Prod Info griseofulvin oral tablets, 2013).
    B) BLOOD COAGULATION DISORDER
    1) WITH THERAPEUTIC USE
    a) Coagulopathy has been rarely reported with griseofulvin therapy (Prod Info griseofulvin oral tablets, 2013).

Dermatologic

    3.14.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Photosensitivity, skin rashes, Kawasaki-like syndrome, and vesicular and morbilliform eruptions have been reported following therapeutic doses.
    2) Urticaria may occur as a result of a hypersensitivity reaction.
    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Skin rashes have been reported during therapeutic use and are associated with a hypersensitivity type reaction (Prod Info griseofulvin oral tablets, 2013; Guillaume et al, 1987; Taylor & Duffill, 1988).
    B) URTICARIA
    1) WITH THERAPEUTIC USE
    a) Urticaria usually develops as a result of a hypersensitivity reaction to griseofulvin (Prod Info griseofulvin oral tablets, 2013). It occurs much more frequently than fixed drug eruption (Feinstein et al, 1984).
    C) PHOTOSENSITIVITY
    1) WITH THERAPEUTIC USE
    a) Photosensitivity has been occasionally reported with therapy (Prod Info griseofulvin oral tablets, 2013).
    D) MACULOPAPULAR ERUPTION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A case of Kawasaki-like syndrome is reported in a 2-year-old boy after being treated therapeutically for 14 days. The patient presented with fever and maculopapular eruptions (Amita et al, 1993).
    E) LUPUS ERYTHEMATOSUS
    1) WITH THERAPEUTIC USE
    a) Lupus erythematosus, exacerbation of existing lupus erythematosus and lupus-like syndrome have been reported with griseofulvin therapy (Prod Info griseofulvin oral tablets, 2013).
    F) STEVENS-JOHNSON SYNDROME
    1) WITH THERAPEUTIC USE
    a) Severe skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis have occurred with therapy. These events may be severe and result in hospitalization or death in some cases (Prod Info griseofulvin oral tablets, 2013).
    G) ERYTHEMA MULTIFORME
    1) WITH THERAPEUTIC USE
    a) Severe skin reactions including erythema multiforme have occurred with therapy. These events may be severe and result in hospitalization or death in some cases (Prod Info griseofulvin oral tablets, 2013).
    H) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE
    1) WITH THERAPEUTIC USE
    a) CASE REPORTS: Two cases of toxic epidermal necrolysis, one fatal, have been associated with griseofulvin therapy (Taylor & Duffill, 1988; Mion et al, 1989).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) SUMMARY
    1) Hypersensitivity reactions may occur and most commonly result in skin rashes, urticaria, and rarely angioneurotic edema and erythema multiforme (Prod Info griseofulvin oral tablets, 2013).
    2) CIRCULATING AUTOANTIBODIES: In a retrospective review of 45 patients with anti-SSA/Ro and SSB/La autoantibodies, a hypersensitivity reaction was associated with griseofulvin therapy in 4 patients (Miyagawa & Sakamoto, 1989; Miyagawa & Sakamoto, 1989).
    b) CROSS-SENSITIVITY
    1) Griseofulvin is produced by species of PENICILLIUM; therefore, the possibility of CROSS-SENSITIZATION with PENICILLINS should be considered (Prod Info griseofulvin oral tablets, 2013).
    a) However, patients hypersensitive to penicillin have been treated with griseofulvin successfully without adverse effects (Prod Info griseofulvin oral tablets, 2013).

Reproductive

    3.20.1) SUMMARY
    A) Griseofulvin is rated FDA Pregnancy Category X and use is contraindicated during pregnancy. There have been reports of conjoined twins, abortion, and congenital anomalies with the use of griseofulvin during pregnancy. In animal studies, there were also evidence of embryotoxicity, teratogenicity, and abnormalities. There are no data regarding griseofulvin use during breastfeeding.
    3.20.2) TERATOGENICITY
    A) CONJOINED TWINS
    1) The US Food and Drug Administration Teratogen information system reports griseofulvin use during pregnancy has been associated with conjoined twins (Rosa et al, 1987). There have been 2 reported cases of conjoined twins following griseofulvin use during the first trimester of pregnancy since 1977 (Prod Info griseofulvin oral suspension, 2014; Prod Info griseofulvin oral tablets, 2013; Prod Info ultramicrosize griseofulvin oral tablets, 2014).
    2) In 10,962 matched controls in which 3 griseofulvin exposures occurred, no association between griseofulvin and conjoined twinning could be demonstrated in a case-control surveillance in Hungary (Metneki & Czeizel, 1987). Another report from a birth defect registry found no association between griseofulvin and the occurrence of conjoined twins (Knudsen, 1987).
    B) CONGENITAL ANOMALY
    1) The US Food and Drug Administration Teratogen information system reports griseofulvin use during pregnancy has been associated with cleft palate and hypoplastic left heart failure (Rosa et al, 1987).
    2) A case-control surveillance in Hungary reported two congenital anomaly cases associated with griseofulvin use out of 6786 total anomalies reported. One was a case of pyloric stenosis that occurred after exposure in the first month of pregnancy, and the other was a heart defect that occurred after exposure in months two and three (Metneki & Czeizel, 1987).
    C) DOWN'S SYNDROME
    1) In a study of uncontrolled case reports, 2 infants with birth defects, including 1 case of Down's syndrome, were reported (Gotz & Reichenberger, 1972).
    D) ANIMAL STUDIES
    1) MICE: Teratogenic effects were observed in mice administered 5 g/kg/day (40 times the maximum recommended human dose, based on body surface area) for 2 consecutive days at various stages of the pregnancy (Prod Info griseofulvin oral suspension, 2014; Prod Info griseofulvin oral tablets, 2013).
    2) RATS: There was evidence of teratogenicity in pregnant rats administered daily oral 250 mg/kg/day doses (approximately 4 times the maximum recommended human dose, based on body surface area) (Prod Info griseofulvin oral suspension, 2014; Prod Info griseofulvin oral tablets, 2013; Prod Info ultramicrosize griseofulvin oral tablets, 2014).
    3) CATS: Teratogenic effects were observed in cats administered 500 to 1,000 mg/week doses (Prod Info griseofulvin oral suspension, 2014; Prod Info griseofulvin oral tablets, 2013).
    4) DOGS: Teratogenic effects were observed in Golden Retrievers administered 750 mg/day (1.2 times the maximum recommended human dose (MRHD), based on body surface area (BSA)) for 4 weeks prior to and through pregnancy, and in beagles administered 35 mg/kg/day (1.9 times the MRHD, based on BSA) for intervals from 1 weeks up to the entire gestation period (Prod Info griseofulvin oral suspension, 2014; Prod Info griseofulvin oral tablets, 2013).
    3.20.3) EFFECTS IN PREGNANCY
    A) ABORTION
    1) The US Food and Drug Administration Teratogen information system reports griseofulvin use during pregnancy has been associated with spontaneous abortion (Prod Info griseofulvin oral suspension, 2014; Prod Info griseofulvin oral tablets, 2013; Rosa et al, 1987).
    B) PREGNANCY CATEGORY
    1) Griseofulvin is rated FDA Pregnancy Category X and use is contraindicated during pregnancy (Prod Info griseofulvin oral suspension, 2014; Prod Info griseofulvin oral tablets, 2013; Prod Info ultramicrosize griseofulvin oral tablets, 2014).
    2) Male patients should wait at least 6 months after completing treatment before trying to father a child (Prod Info griseofulvin oral suspension, 2014; Prod Info griseofulvin oral tablets, 2013; Prod Info ultramicrosize griseofulvin oral tablets, 2014).
    3) Griseofulvin should not be administered to a pregnant woman (Prod Info ultramicrosize griseofulvin oral tablets, 2014). If a woman becomes pregnant or is pregnant during treatment, the patient should be made aware of the potential fetal hazard (Prod Info griseofulvin oral suspension, 2014; Prod Info griseofulvin oral tablets, 2013; Prod Info ultramicrosize griseofulvin oral tablets, 2014).
    C) ANIMAL STUDIES
    1) CATS: Teratogenic effects were observed in cats administered 500 to 1,000 mg/week doses (Prod Info griseofulvin oral suspension, 2014; Prod Info griseofulvin oral tablets, 2013).
    2) RATS: There was evidence of embryotoxicity in pregnant rats administered daily oral 250 mg/kg/day doses (approximately 4 times the maximum recommended human dose, based on body surface area) (Prod Info griseofulvin oral suspension, 2014; Prod Info griseofulvin oral tablets, 2013; Prod Info ultramicrosize griseofulvin oral tablets, 2014; Prod Info Gris-PEG(R) oral tablets, 2007).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Because of the potential for tumorigenicity, this drug or nursing should be discontinued if this drug is administered during pregnancy, while taking into account the importance of the drug to the mother (Prod Info griseofulvin oral suspension, 2014; Prod Info griseofulvin oral tablets, 2013).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) RATS: Spermatogenesis has been reported to be suppressed in rats, but suppressed spermatogenesis has not been reported in humans (Prod Info griseofulvin oral suspension, 2014; Prod Info griseofulvin oral tablets, 2013).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturer does not report any carcinogenic potential for griseofulvin.
    3.21.4) ANIMAL STUDIES
    A) CUTANEOUS NEOPLASM
    1) In laboratory animals treated with griseofulvin, there have been reports of porphyrin metabolism disturbances. Griseofulvin has affected mitosis and cocarcinogenicity with methylcholanthrene in a colchicine-like fashion resulting in cutaneous tumor induction (Prod Info griseofulvin oral suspension, 2007; Prod Info Gris-PEG(R) oral tablets, 2007; Prod Info GRIFULVIN V(R) oral tablets, oral suspension, 1997).
    B) HEPATIC CARCINOMA
    1) MICE: Hepatic tumors developed in several strains of mice, particularly males, following chronic administration of oral griseofulvin at levels ranging from 0.5% to 2.5% of the diet. There was an enhanced effect when the particle sizes were smaller. No testing has been performed at lower doses. Hepatomata was developed in mice following subQ administration of fairly small griseofulvin doses given once a week during the first 3 weeks of life. The design of these studies was not adequate to determine causality of griseofulvin. Additionally, there is no evidence of tumorigenicity in other animal studies. There was also evidence of hepatocellular necrosis when mice were administered oral griseofulvin doses in subacute toxicity studies; this has not been demonstrated in other animal species (Prod Info griseofulvin oral suspension, 2007; Prod Info Gris-PEG(R) oral tablets, 2007; Prod Info GRIFULVIN V(R) oral tablets, oral suspension, 1997).
    C) THYROID TUMORS
    1) Male rats administered griseofulvin at 2%, 1%, and 0.2% of the diet and female rats administered at 2% and 1% of the diet developed thyroid tumors. The majority of the tumors were adenomas but some were carcinomas (Prod Info Gris-PEG(R) oral tablets, 2007).

Genotoxicity

    A) Griseofulvin was positive for the following tests: sister chromatid exchange in mice, sex chromosome loss/nondisjunction in A. nidulans, DNA inhibition in human fibroblast and lymphocytes, and mutation in A. nidulans (RTECS , 2000).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor neurologic function following prolonged therapy or as indicated.
    B) Monitor fluids and electrolytes in patients with persistent or prolonged vomiting and/or diarrhea following an acute exposure.
    C) Obtain a baseline CBC and monitor hepatic and renal and function closely in symptomatic patients.
    D) Plasma griseofulvin levels are not clinically useful.
    4.1.2) SERUM/BLOOD
    A) HEMATOLOGIC
    1) Blood counts should be monitored not less than weekly during the first 4 to 6 weeks of treatment.
    B) BLOOD/SERUM CHEMISTRY
    1) Electrolytes should be monitored with prolonged use of griseofulvin.
    4.1.3) URINE
    A) URINALYSIS
    1) Renal function should be monitored with prolonged use of griseofulvin therapy (Prod Info griseofulvin oral tablets, 2013).
    2) Both the unchanged drug and its metabolites are excreted primarily in the urine, though albuminuria and cylindruria are generally uncommon following therapeutic doses (Yang & Rankin, 1985).
    B) OTHER
    1) Griseofulvin therapeutic use has been associated with false elevation of urinary concentrations vanillylmandelic acid when analyzed by the method described by Pisano et al (1962) (Pisano et al, 1962; Rampini et al, 1989).
    2) Vanillylmandelic acid concentrations were within normal limits when analyzed by gas chromatography (Wadman et al, 1976).

Methods

    A) CHROMATOGRAPHY
    1) Griseofulvin concentrations can by measured in serum using liquid chromatographic techniques (Ginsburg et al, 1983).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with severe symptoms including hypersensitivity and/or allergic reactions, skin reactions (ie, Stevens-Johnson syndrome, toxic epidermal necrolysis), or hepatotoxicity despite treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent minor exposure (1 to 2 tablets), that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.

Monitoring

    A) Monitor neurologic function following prolonged therapy or as indicated.
    B) Monitor fluids and electrolytes in patients with persistent or prolonged vomiting and/or diarrhea following an acute exposure.
    C) Obtain a baseline CBC and monitor hepatic and renal and function closely in symptomatic patients.
    D) Plasma griseofulvin levels are not clinically useful.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Decontamination may not be necessary following a minor exposure.
    B) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) Toxicity after an acute minor ingestion is unlikely, and is generally only expected with a significant exposure. Gastrointestinal decontamination is generally unnecessary.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. Limited overdose data. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting. Monitor for hypersensitivity reactions (ie, rash, urticaria); treatment may include antihistamines with or without beta agonists, corticosteroids or epinephrine. Monitor liver enzymes (ie, AST, ALT, bilirubin) following a significant exposure or as indicated. Obtain a baseline CBC in patients with an acute on chronic exposure or in symptomatic patients.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. HYPERSENSITIVITY REACTION should be managed by discontinuation of the drug and observation for severe reaction, including anaphylactic shock. Anaphylaxis should be managed with intravenous fluids, airway management, and administration of epinephrine, diphenhydramine, and corticosteroids. Monitor for possible hepatotoxicity and severe skin reactions and erythema multiforme.
    B) MONITORING OF PATIENT
    1) Monitor neurologic function following prolonged therapy or as indicated.
    2) Monitor fluids and electrolytes in patients with persistent or prolonged vomiting and/or diarrhea following an acute exposure.
    3) Obtain a baseline CBC and monitor hepatic and renal and function tests closely in symptomatic patients.
    4) Plasma griseofulvin levels are not clinically useful.
    C) ACUTE ALLERGIC REACTION
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).

Enhanced Elimination

    A) SUMMARY
    1) It is unknown if enhanced elimination would be beneficial following exposure.

Range Of Toxicity

Summary

    A) TOXICITY: A minimum lethal or toxic dose has not been well established.
    B) THERAPEUTIC DOSE: ADULT: ORAL: 500 mg to 1 g daily; the dosage should be individualized. PEDIATRIC (older than 2 years): ORAL: 10 mg/kg is usually adequate; individualize the dose as needed.

Therapeutic Dose

    7.2.1) ADULT
    A) NOTE: The ultramicrocrystalline form is more bioavailable than the microcrystalline form. The ultramicrocrystalline equivalent dose is two-thirds of the microcrystalline dose (Straughn et al, 1980; AMA, 1986).
    B) SPECIFIC SUBSTANCE
    1) MICROCRYSTALLINE (MICROSIZE)
    a) SUSPENSION/TABLETS: The recommended dose is 500 mg/day (0.5 g of oral suspension) orally. Dose may be increased up to 1 g/day (Prod Info griseofulvin oral suspension, 2014; Prod Info griseofulvin oral tablets, 2012).
    2) ULTRAMICROCRYSTALLINE (ULTRAMICROSIZE)
    a) TABLETS: The recommended dose is 375 mg/day orally in single or divided doses until infection has cleared. The dose may be increased to 750 mg as a divided dose for more difficult to treat fungal infections (eg, tinea pedis and tinea unguium) (Prod Info Gris-PEG(R) oral tablets, 2016).
    7.2.2) PEDIATRIC
    A) NOTE: The ultramicrocrystalline form is more bioavailable than the microcrystalline form. The ultramicrocrystalline equivalent dose is two-thirds of the microcrystalline dose (Straughn et al, 1980; AMA, 1986).
    B) SPECIFIC SUBSTANCE
    1) MICROCRYSTALLINE (MICROSIZE)
    a) SUSPENSION/TABLETS: The recommended dose is 10 mg/kg of body weight per day (Prod Info griseofulvin oral suspension, 2014; Prod Info griseofulvin oral tablets, 2012).
    1) CHILDREN WEIGHING 13.6 TO 22.7 KG: 125 to 250 mg/day orally (Prod Info griseofulvin oral suspension, 2014; Prod Info griseofulvin oral tablets, 2012).
    2) CHILDREN WEIGHING OVER 22.7 KG: 250 to 500 mg/day orally (Prod Info griseofulvin oral suspension, 2014; Prod Info griseofulvin oral tablets, 2012).
    3) CHILDREN AND INFANTS 2 YEARS OF AGE OR YOUNGER: Safety and efficacy have not been established (Prod Info griseofulvin oral suspension, 2014; Prod Info griseofulvin oral tablets, 2012).
    2) ULTRAMICROCRYSTALLINE (ULTRAMICROSIZE)
    a) TABLETS: The recommended dose is 7.3 mg/kg of body weight per day (Prod Info Gris-PEG(R) oral tablets, 2016).
    1) CHILDREN WEIGHING 16 TO 27 KG: 125 mg to 187.5 mg orally once daily until infection has cleared (Prod Info Gris-PEG(R) oral tablets, 2016).
    2) CHILDREN WEIGHING OVER 27 KG: 187.5 mg to 375 mg orally once daily until infection has cleared (Prod Info Gris-PEG(R) oral tablets, 2016).
    3) CHILDREN AND INFANTS 2 YEARS AND YOUNGER: Safety and efficacy have not been established (Prod Info Gris-PEG(R) oral tablets, 2016).

Minimum Lethal Exposure

    A) SUMMARY
    1) TOXICITY: A minimum lethal or toxic dose has not been well established.

Maximum Tolerated Exposure

    A) SUMMARY
    1) PEDIATRIC: Asymptomatic increases in amylase and AST were reported in 2 children after inadvertent ingestion of approximately 2.5 g of griseofulvin (ie, a 5 g dose was shared between them) (Dyer et al, 1999).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) GENERAL
    a) No toxic dose has been established.

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (INTRAPERITONEAL)MOUSE:
    1) 200 mg/kg ((RTECS, 2000))
    B) LD50- (SUBCUTANEOUS)MOUSE:
    1) Greater than 12 g/kg ((RTECS, 2000))
    C) LD50- (INTRAPERITONEAL)RAT:
    1) Greater than 5 g/kg ((RTECS, 2000))

Pharmacology Toxicology

Pharmacologic Mechanism

    A) ANTIFUNGAL: Griseofulvin is effective in the treatment of dermatophyte (Epidermophyton, Microsporum, Trichophyton) and tinea infections (Prod Info GRIS-PEG(R) oral tablets, 2005).
    1) Griseofulvin disrupts the mitotic spindle by interacting with polymerized microtubules (Gilman et al, 1990).
    B) PERIPHERAL VASCULAR DISEASE: There is anecdotal evidence that griseofulvin has vasodilator activity and may be of benefit in patients with Raynaud's disease who fail to respond to other vasodilators (Coffman, 1979; Cook, 1979; Creery et al, 1968; DePasquale et al, 1963; Rubin, 1963; Sabri et al, 1973).

Physicochemical

Physical Characteristics

    A) Griseofulvin is a white to pale cream-color, nearly odorless, crystalline powder (NOAA's National Ocean Service, 2010) that is freely soluble in dimethylformamide and tetrachloroethane, soluble in chloroform, slightly soluble in alcohol and methanol, and practically insoluble in water (JEF Reynolds , 2000). Water solubility is less than 1 mg/mL at 70 degrees F and the melting point is 428 degrees F (NOAA's National Ocean Service, 2010).

Molecular Weight

    A) 352.77 (NOAA's National Ocean Service, 2010)

Animal Toxicology

Clinical Effects

    11.1.6) FELINE/CAT
    A) SUMMARY: Hematologic and neurologic abnormalities and fever developed in a 12-week-old male domestic short hair kitten that was associated with 100 mg/kg of griseofulvin administered orally every 8 hours for dermatophytosis caused by Microsporum canis (Levy, 1991).
    1) The hematologic abnormalities and fever resolved following discontinuation of griseofulvin. The neurologic condition persisted at follow-up 4 months after the adverse reaction to griseofulvin.
    2) Three litter mates receiving the same treatment developed no abnormalities.
    B) HEMATOLOGIC: BASOPHILIC STIPPLING, PANLEUKOPENIA, and THROMBOCYTOPENIA were associated with treatment of 100 mg/kg griseofulvin given orally every 8 hours for dermatophytosis (Levy, 1991). Hematologic effects resolved following discontinuation of griseofulvin.
    C) NEUROLOGIC: ATAXIA, DISEQUILIBRIUM, and the inability to avoid obstacles was reported in a 12-week-old male domestic short hair kitten that was associated with adverse drug reaction to treatment of 100 mg/kg griseofulvin given orally every 8 hours for dermatophytosis (Levy, 1991).
    D) TEMPERATURE REGULATION: FEVER was associated with an adverse drug reaction to griseofulvin in a 12-week-old male domestic short hair kitten (Levy, 1991).

Range Of Toxicity

    11.3.1) THERAPEUTIC DOSE
    A) CAT
    1) Oral daily doses of 25 to 132 mg/kg of griseofulvin administered in divided doses and given with a high-fat meal (Muller et al, 1989; Scott, 1980; Sousa & Ihrke, 1983)
    11.3.2) MINIMAL TOXIC DOSE
    A) CAT
    1) MAXIMUM TOLERATED DOSE: Cats have tolerated daily doses up to 145 mg/kg for 11 weeks (Scott et al, 1974).

References

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