GIFULDIN®500

Composition: Each tablet contains:
Griseofulvin . . . . . . . . . . . . . . . . . . . . . . 500 mg
Presentation:
Cardboard box containing 2 blisters of 10 tablets.
Indications:
Griseofulvin is indicated for the treatment of dermatophyte infections of the skin, hair, or nails which do not respond to topical treatment including tinea corporis, tinea pedis, tinea cruris, tinea barbae, tinea capitis, tinea unguium caused by susceptible strains of Trichophyton sp., Microsporum sp., or Epidermophyton sp..

Additional information

Dosage and administration

Dosage:
Adults: The usual dose of griseofulvin has been 0.5 g (1 tablet) to 1 g (2 tablets) daily in single dose or divided doses.
Children (over 2 years of age and over 25kg in weight): Usual dose is 1 tablet per day.
Administration:
Griseofulvin should be given with or after meals.
The duration of treatment depends on the thickness of keratin layer at the site of infection and the response of each patient. Therapy should be continued until the infecting organism is completely eradicated as indicated by appropriate clinical or laboratory examination. Treatment periods are at least 2 to 8 weeks for infections of the hair and skin, up to 6 months for infections of the fingernails, and 12 months or more for infections of the toenails.

Contraindications

Hypersensitivity to griseofulvin or any of excipients of the drug.
Patients with porphyria, severe liver disease, systemic lupus erythematosus (SLE) or hepatocellular insufficiency.
Pregnant women and breastfeeding mothers.
Griseofulvin tablets should not be used prophylactically.

Warnings and precautions for use

Griseofulvin may cause severe toxicity. When the treatment with griseofulvin is prolonged hepatic, renal and hematopoietic function should be periodically monitored.
If agranulocytosis is observed, discontinue griseofulvin therapy. In rare cases, serious side effects may occur, usually due to high doses and/ or prolonged treatment.
Since a photosensitivity reaction is occasionally associated with griseofulvin therapy, patients should be warned to avoid exposure to sunlight. Photosensitivity reaction may aggravate lupus erythematosus.
Since Griseofulvin is derived from species of penicillin, the possibility of cross sensitivity with penicillin exists.
This medicine contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Recommendation for pregnancy and breastfeeding

Pregnancy:
Griseofulvin is contraindicated in pregnancy. Women should not become pregnant within 1 month after stopping the treatment. Griseofulvin has been shown to be teratogenic in pregnant animals and there are case reports of human fetal abnormalities associated with griseofulvin. Since in vitro and in vivo studies have demonstrated that griseofulvin can induce aneuploidy (abnormal chromosome segregation at meiosis) in mammal animals exposed to griseofulvin. Griseofulvin should not be used during pregnancy. In addition, women should avoid getting pregnant for at least a month after the treatment has finished.
Breastfeeding:
It is not known whether griseofulvin is excreted into human milk. Therefore, the safety of breastfed infants has not been established. Griseofulvin should not be used during breastfeeding.

Effects on ability to drive and use machines

Griseofulvin can cause headaches, fatigue, drowsiness, dizziness, and impaired co-ordination, which influence the ability to drive and use machines. If affected, patients should not perform activities that require alertness.

Interactions, incompatibilities of medicine

Alcohol: Concomitant use of griseofulvin with alcohol may cause fast heartbeat, flushing, increased sweating.
Phenobarbital: Phenobarbital may decrease blood concentrations of griseofulvin by reducing the absorption of griseofulvin and inducing hepatic microsomal cytochrome P450, so it is best not to take these two drugs simultaneously. If concomitant use is required, the total daily dose may be divided in three doses. Monitor serum levels of griseofulvin and the dose is increased if it is required.
Drugs that induce metabolizing enzymes: Blood concentration of griseofulvin is decreased.
Coumarin anticoagulants: The efficacy of warfarin is reduced; patients receiving these drugs concomitantly may require dosage adjustment of the anticoagulant during and after Griseofulvin therapy.
Oral contraceptives: Griseofulvin may enhance the metabolism of estrogen component of oral contraceptives, resulting in amenorrhea, increase in intermenstrual bleeding and reducing the effectiveness of contraception.
Interactions of other drugs with griseofulvin: Concurrent use of griseofulvin and theophylline increases theophylline clearance and shortens half life of theophylline. However, this increase in clearance is not apparent in all patients who take these drugs concurrently.
Initiating the treatment with griseofulvin in patients receiving aspirin may result in decreased salicylate serum concentrations.
Concomitant use of griseofulvin and cyclosporine may reduce serum cyclosporine levels.
Griseofulvin can block the response to bromocriptine.

Undesirable effects (ADRs)

Undesirable effects are usually mild and transient.
Among mild side effects, which may be up to 15%, headache sometimes becoming severe, is the most common effect and usually disappear during continued treatment.
Nervous system: Peripheral neuritis, peripheral nerve disorders, visual disturbance, lethargy, mental disorders, impairment of performance of routine activities, fatigue, dizziness and drowsiness. In rare cases individual patient experiences drowsiness while taking griseofulvin, they should not drive or operate machinery. Griseofulvin may increase the effects of alcohol, patients should be alerted to this interaction.
Gastrointestinal: Anorexia, nausea, vomiting, diarrhea, heartburn, flatulence, thirst, oral thrush, gastrointestinal bleeding.
Hematological effects include leucopenia and neutropenia; usually disappearing during continued treatment. Blood tests should be performed at least once a week during the first month of therapy or longer. Administration of the drug should be stopped if granulocytopenia occurs.
Adverse effects on the kidneys include albuminuria without evidence of renal failure.
Skin reactions include hives, cold and warm urticaria, photosensitivity, measles-like erythema and blisters.
In patients receiving griseofulvin, proteinuria, renal impairment, hepatotoxicity and menstrual irregularities have been reported rarely.
There have been reports of toxic epidermal necrolysis and erythema multiforme.
Estrogen-like effects in children have been observed.
Frequency of serious reactions caused by griseofulvin is very low.
Serum sickness-like reactions and angioedema rarely occur during treatment with griseofulvin.
Exacerbated systemic lupus erythematosus, lupus-like syndromes or exacerbation of existing lupus erythematosus have been reported in patients receiving griseofulvin.
Moderate though inconsistent increases of fecal protoporphyrin were observed in patients receiving griseofulvin for a long term.
Although griseofulvin is derived from species of Penicillium, cross-sensitivity is possible; however, patients with known sensitivity to penicillin have been treated without adverse effects.
Diaper rash caused by Candida may complicate griseofulvin therapy.
Guidelines for ADR management: General and toxic reactions:
Headache, central nervous system disorders and gastrointestinal disorders may become severe, then griseofulvin must be discontinued.
Exposure to sunlight, even for brief periods of time, may cause a skin rash, itching, redness or other discoloration of the skin, or severe sunburn. Patients should avoid direct sunlight, wear protective clothing, including hats and sunglasses, and apply a sun block product.
Hypersensitivity reactions:
These reactions are mostly in the form of skin rashes but are seldom severe and rarely seen. Attention should be paid to any life-threatening hypersensitivity reactions (angioedema, serum sickness, anaphylaxis) or severe hepatotoxicity. Patients with severe hypersensitivity reactions or hepatic, renal, hematopoietic injury must be hospitalized and, if required, must be monitored in an intensive care unit accompanied by careful monitoring of the patient's respiratory and cardiovascular status.
Stop using the drug and inform the doctor about adverse effects encountered during the treatment with griseofulvin.

Overdose and management

There is no specific antidote.
Gastric lavage associated with respiratory protection may be helpful. There is no evidence to support the use of activated charcoal, laxatives or drug removal by extracorporeal method.
Treatment should be symptomatic and supportive.

Pharmacodynamic properties

Griseofulvin is a fungistatic antibiotic obtained from culture of Penicillium griseofulvum or by other methods. The fungistatic action of griseofulvin is primarily due to disruption of mitotic spindle structure of the fungal cell, which causes an arrest of metaphase of cell division, inhibiting the division of fungal cells. It has also been proposed that griseofulvin causes the production of defective DNA, which is then unable to replicate. Griseofulvin is deposited in the keratin precursor cells and has a greater affinity for diseased tissue. The drug is tightly bound to the new keratin which becomes highly resistant to fungal invasions. Infected skin, hair and nails will be replaced by noninfected tissues. Griseofulvin is effective against skin infections that are widespread and difficult to treat. Griseofulvin inhibits the development of dermatophytes caused by Trichophyton species (especially T. rubrum, T. tonsurans, T. mentagrophytes, T. verrucosum, T. megninii, T. gallinae and T. schoenleinii), Microsporum (M. audouinii, M. canis, M. gypseum) and Epidermophyton floccosum.
Griseofulvin has no activity against bacteria, Candida, Actinomyces, Aspergillus, Blastomyces, Cryptococcus, Coccidioides, Geotrichum, Histoplasma, Nocardia, Saccharomyces, Sporotrichum or Malassezia furfur.

Pharmacokinetic properties

After oral administration, absorption of griseofulvin varies from 25% to 70%. The absorption increases significantly if griseofulvin is taken with or after high-fat meals. Peak plasma levels are achieved within 4 hours and are maintained for some 10 to 20 hours.
After administering a single 500 mg dose of griseofulvin microsize to fasting adults, average peak plasma concentration ranges between 0.5 to 2 mcg/mL at about 4 hours.
Following oral absorption, griseofulvin is concentrated in the skin, hair, nails, liver, adipose tissue and skeletal muscle. Griseofulvin is deposited into keratin precursor cells and has a high affinity for diseased tissue. Griseofulvin is tightly bound to newly formed keratin, which becomes highly resistant to fungal invasion. The drug can be detected in the outer layers of the stratum corneum soon after ingestion. Following oral administration of a single dose of 500 mg griseofulvin microsize, griseofulvin levels found in the skin within 4 hours and 8 hours were 1 mcg/g and 3 mcg/g, respectively. If a 500 mg griseofulvin dose was taken at 12-hourly intervals, a range of 6 – 12 mcg/g was found in the skin within 30 hours. If this dose was repeated and continued for several weeks, the steady level ranged between 12 – 25 mcg/g and concurrent level in the serum was 1 – 2 mcg/ml. When the drug is discontinued, griseofulvin concentrations in the skin decline more rapidly than those in plasma. 2 days and 4 days after griseofulvin discontinuation, griseofulvin will no longer be found in the skin and in plasma, respectively.
About 84% of griseofulvin is bound to plasma proteins.
Griseofulvin has an elimination half life of 9 to 24 hours. Griseofulvin undergoes hepatic metabolism, mainly through oxidative demethylation by P450 enzyme and conjugation with glucuronic acid. Major metabolite 6 – demethyl griseofulvin has no effect on microorganisms.

Storage conditions, shelf-life, quality specification of the medicine

Storage conditions: Protect from humidity and light, below 30 degrees C.
Shelf – life: 36 months from the manufacture date.
Quality specification: In house specification.