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Conazole

Afrab-Chem Ltd
No. 22, Abimbola Street, Isolo Industrial Estate, Isolo, P.O. Box 1647, Lagos, Nigeria.
Email: info@afrabchem.com
Tel: 234-1-2700057
Fax: 234-1-4520328
Website: http://afrabchem.com/

Brand Name

Conazole

Manufacturer

Joswe Medicals, Na'ur Jordan.

Therapeutic Class

Antifungals, Systemic

Dosage Form, Composition & NAFDAC Registration Number (NRN)

Capsule (NRN: 04-8631): Each capsule contains 100 mg Itraconazole in a pellet formulation supplied in blister packs.

conazole

Pharmacology

Pharmacodynamics:

In vitro studies have demonstrated that Itraconazole impairs the synthesis of ergosterol in fungal cells. Ergosterol is a vital cell membrane component in fungi. Impairment of its synthesis ultimately results in antifungal effect. Itraconazole, a triazole derivative is active against infections with dermatophytes (Trichophyton spp., Microsporum spp., Epidermophyton floccosum), yeasts (Cryptococcus neoformans, Pityrosporum spp., Candida spp., including C. albicans, C. glabrata and C. krusei), Aspergillus spp., Histoplasma spp., Paracoccidiodes brasiliensis, Sporothrix schenckii, Fansecaea spp., Cladosporium spp., Blastomyces dermatitidis, and various other yeasts and fungi.

Pharmacokinetics:

The oral bioavailability of Itraconazole is maximal when the capsules are taken immediately after a full meal. Peak plasma levels are reached 3 to 4 hours following an oral dose. Elimination from plasma is biphasic with a terminal half-life of 1 to 1.5 days. During chronic administration, steady state is reached after 1-2 weeks. Steady state plasma concentrations of Itraconazole 3-4 hours after drug intake are 0.4 mcg/mL (100 mg o.d.), 1.1 mcg/mL (200 mg o.d.) and 2.0 mcg/mL (200 mg b.i.d).

The plasma protein binding of Itraconazole is 99.8%. Concentrations of Itraconazole in whole blood are 60% of those in plasma. Uptake in keratinous tissues, especially the skin, is up to 4 times higher than in plasma, and elimination of Itraconazole is related to epidermal regeneration. In contrast to the plasma levels which become undetectable within 7 days of stopping therapy, therapeutic levels in the skin persist for 2 to 4 weeks after discontinuation of a 4-week treatment. Levels of Itraconazole have been detected in the nail keratin as early as 1 week after start of treatment and persist for at least 6 months after the end of a 3-month course of therapy. Itraconazole is also present in sebum and to a lesser extent in sweat. Itraconazole is also extensively distributed into tissues that are prone to fungal invasion. Concentrations in lung, kidney, liver, bone, stomach, spleen and muscle were found to be two to three times higher than the corresponding plasma concentration.

Therapeutic levels in vaginal tissue are maintained for another 2 days after discontinuation of a 3-day course with 200 mg daily, and for another 3 days after discontinuation of a 1-day course with 200 mg b.i.d.

Itraconazole is extensively metabolised by the liver into a larger number of metabolites. One of the metabolites is hydroxy-itraconazole, which has a comparable antifungal activity in vitro to Itraconazole. Antifungal drug levels measured by bio-assay were about 3 times those of Itraconazole assayed by high-performance liquid chromatography (HPLC).

Faecal excretion of the parent drug varies between 3-18% of the dose. Renal excretion of the parent drug is less than 0.03% of the dose. About 35% of a dose is excreted as metabolites in the urine within 1 week.

Indications

Conazole is indicated for the treatment of the following conditions:

  • Gynaecological Indications: Vulvovaginal candidiasis 
  • Dermatological/ophthalmological indications: Pityriasis versicolor, dermatomycosis, fungal keratitis and oral candidiasis; Onychomycosis caused by dermatophytes and/or yeasts
  • Systemic mycoses: Systemic aspergillosis and candidiasis, cryptococcosis (including cryptococcal meningitis), histoplasmosis, sporotrichosis, paracoccidiodomycosis, blastomycosis and other rarely occurring systemic or tropical mycoses.

Contra-indications

Hypersensitivity to the drug or its excipients.

Itraconazole should only be given to pregnant women in life-threatening cases and when in these cases, the potential benefit outweighs the potential harm to the foetus. Adequate contraceptive precautions should be taken by women of childbearing potential using Itraconazole until the next menstrual period following the end of Itraconazole therapy.

Avoid co-administration of Itraconazole with Terfenadine, Astemizole, Cisapride, Quinidine, Pimozide, CYP3A4-metabolised HMG-CoA reductase inhibitors (such as Atorvastatin, Lovastatin and Simvastatin), Triazolam and oral Midazolam.

Precautions/Warnings

Itraconazole has a potential for clinically important drug interactions:

Decreased gastric acidity: Absorption of Itraconazole from Conazole is impaired when the gastric acidity is decreased. In patients also receiving acid neutralising medicines (e.g. aluminiun hydroxide) these should be administered at least 2 hours after the intake of Itraconazole. In patients with achlorhydria such as certain AIDS patients and patients on acid secretion suppression (e.g. H2- receptor antagonists, proton pump inhibitors) it is advisable to administer Itraconazole with a cola beverage.

Paediatric use: Since clinical data on the use of Itraconazole in paediatric patients is limited, Itraconazole should not be used in these patients unless the potential benefit outweigh the potential risks.

It is advisable to monitor liver function in patients receiving continous treatment of more than one month and promptly in patients developing symptoms suggestive of hepatitis such as anorexia, nausea, vomiting, fatigue, abdominal pain or dark urine. If abnormal, treatment should be stopped.

In patients with raised liver enzymes or an active liver disease, or who have experienced liver toxicity with other drugs, treatment should not be started unless the expected benefit outweigh the risk of hepatic injury. In such cases, liver enzyme monitoring is necessary.

Hepatic impairment: Itraconazole is predominantly metabolized in the liver. The terminal half-life of Itraconazole in cirrhotic patients is somewhat prolonged. The oral bioavailability in cirrhotic is somewhat decreased. A dose adjustment may be considered.

Renal impairment: The oral bioavailability of Itraconazole may be lower in patients with renal insufficiency. A dose adjustment may be considered. If neuropathy occurs that may be attributable to Itraconazole, the treatment should be discontinued.

There is no information regarding cross hypersensitivity between Itraconazole and other azole antifungal agents. Caution should be used in prescribing Itraconazole to patients with hypersensitivity to other azoles.

Pregnancy and Lactation:

When administered at high doses to pregnant rats (40 mg/kg/day or higher) and mice (80 mg/kg/day or higher), Itraconazole was shown to increase the incidence of fetal abnormalities and did produce adverse effects on the embryo. Studies on the use of Itraconazole in pregnant women are not available. Therefore, Itraconazole should only be given in life-threatening cases of systemic mycosis and when in these cases the potential benefit outweighs the potential risk of breastfeeding. In case of doubt, the patient should not breastfeed.

Effect on driving ability and use of machine: No effects have been observed.

Interactions

Drugs affecting the metabolism of Itraconazole: Interaction studies have been performed with rifampicin, rifabutin and phenytoin. Since the bioavailability of Itraconazole and hydroxy-itraconazole was decreased in these studies to such an extent that efficacy may be largely reduced, the combination of Itraconazole with these potent enzymes inducers is not recommended. No formal study data are available for other enzyme inducers, such as carbamazepine, phenobarbital and isoniazid, but similar effects should be anticipated.

As Itraconazole is mainly metabolised through CYP3A4, potent inhibitors of this enzyme may increase the bioavailability of Itraconazole. Example are ritonavir, indinavir and clarithromycin.

Effect of Itraconazole on the metabolism of other drugs: Itraconazole can inhibit the metabolism of drugs metabolised by the cytochrome 3A family. This can result in an increase and/or a prolongation of their effects, including side effects. After stopping treatment, Itraconazole plasma levels decline gradually, depending on the dose and duration of treatment. This should be taken into account when the inhibitory effect of Itraconazole on co-medicated drugs is considered.

Examples are: Drugs which should not be used during treatment with Itraconazole: Terfenadine, astemizole, cisapride, triazolam, oral midazolam, quinine, pimozide, CYP3A4-metabolised HMG-CoA reductase inhibitors (such as atorvastatin, simvastatin and lovastatin).

Drugs whose plasma levels effects or side effects should be monitored. Their dosage, if co-administered with itraconazole should be reduced if necessary: Oral Anticoagulants; Anti HIV Protease inhibitiors such as ritonavir, indinavir, saquinavir; Certain Antineoplastic Agents such as vinca alkaloids, busulphan, docetaxel and trimetrexate; CYP3A4 metabolised Calcium Channel Blockers such as dihydropyridines and verapamil; Certain Immunosuppressive Agents: cyclosporine, tacrolimus, rapamycin. Others: digoxin, carbamazepine, buspirone, alfentanil, alprazolam, midazolam IV, rifabutin, methylprednisolone.

No interaction of itraconazole with AZT (zidovudine) and fluvastatin has been observed.

No inducing effects of itraconazole on the metabolism of ethinyloestradiol and norethisterone were observed

Effect on protein binding: In vitro studies have shown that there are no interactions on the plasma protein binding between itraconazole and imipramine, propranolol, diazepam, cimetidine, indomethacin, tolbutamide and sulfamethazine.

Adverse Effects

The most frequently reported adverse experiences in association with the use of itraconazole were of gastrointestinal origin, such as dyspepsia, nausea, abdominal pain and constipation. Less frequently reported adverse experiences include headache, reversible increases in hepatic enzymes, menstrual disorder, dizziness and allergic reactions (such as pruritis, rash, urticaria and angio-oedema). Isolated cases of peripheral neuropathy and of Stevens-Johnson syndrome have also been reported.

Especially in patients receiving prolonged (approximately 1 month) continous treatment, cases of hypokalaemia, oedema, hepatitis and hair loss have been observed.

Dosage & Administration

For optimal absorption, it is essential to administer Conazole immediately after a full meal. The capsule must be swallowed whole.

Overdosage:

No data available. In the event of accidental overdosage, supportive measures should be employed. Within the first hour after ingestion, gastric lavage may be performed. Activated charcoal may be given if considered appropriate.

Itraconazole cannot be removed by haemodialysis. No specific antidote is available.

Storage/Handling Recommendations

Conazole capsules must be stored below 30ºC.

Review Date

2017-09-19 07:40:01