Malasiya Product

Eszol Tablets

Eszol Tablets

Why you have been prescribed this medicine?

You have been prescribed this medicine if you have any of the following:

When you should consult your doctor?

You should consult your doctor if you experience any of the following:
Usually the preparation is well tolerated. During a long-term usage of high doses there can be possible follow side effects:

GIT:
nausea, vomiting, heartburn, diarrhea.

CNS:
hyperexcitability of CNS, headache.

Urinary system:
formation of urinary, cystine and oxalate concernments.
Skin and subcutaneous tissue: allergic reactions.

Blood system:
It can cause erythrocyte hemolysis in patients with insufficiency of glucose-6-phosphatdehydrogenase of hematocytes.

What to do if you miss a dose?

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to. Otherwise take it as soon as you remember and then go back to taking it as you would normally.

Things you MUST NOT DO while on this medicine?

Ascozin® increases salicylates (increases a risk of crystalluria), ethynilestradiol, benzylpenicillin and tetracyclines concentrations in blood, and decreases per oral contraceptives concentration in blood. It reduces anticoagulation effect of coumarin derivatives. It improves iron drugs absorption in intestine. It increases general clearance of ethyl alcohol. Quinolone drugs, calcium chloride, salicylate, corticosteroid decrease vitamin C reserve when used for a long term. Corticosteroids (cortisone and prednisolone), which are administered in concrete diseases (arthritis, bronchial astma etc), also reduce vitamin C and zinc levels.
Concurrent usage of ascorbic acid and deferoxamine enhances tissue toxicity of iron, especially in cardiac muscle that can cause decompensation of blood circulatory system. It can be used only in 2 hours after deferoxamine injection. A long-term administration of high doses in patients, who are treated by disulfiram, inhibits disulfamide-alcohol reaction.
High doses of the preparation decrease efficacy of tricyclic depressants.

What to do if you accidentally take too much (overdose) of the medicine?

Symptoms:
nausea, vomiting, intestine spasm, diarrhea; it is possible allergic reaction, kidney dysfunction, blood pressure increase, hyperexcitability of CNS, sleep disturbance.

Treatment:
It is symptomatic.

Is it safe in pregnancy and breast-feeding?

Tell your doctor immediately if you become pregnant while taking this medication. For safety of any drug during pregnancy or breastfeeding – please consult your doctor.

Storage Conditions:

Store in a dry, protected from light place at a temperature not more than 25° C.
Keep it out of reach of children.

Drug Description

Each film coated tablet contains: Itraconazole BP ............ 100 mg Excipients: Sugar spheres, microcrystalline cellulose, hydroxypropyl methyl cellulose, lactose monohydrate, sodium starch glycolate, crascarmellose sodium, low substituted hydroxypropyl cellulose, povidone K-30, magnesium stearate, colloidal anhydrous silica, opadry II pink 85G54039, purified water, dichloromethane & isopropyl alcohol. Pharmaceutical Form: Tablets Pharmacotherapeutic Group: Antifungal
ATC code: J02A C02

Indications and dosage.

INDICATIONS:
 Vulvovaginal candidosis  Pityriasis versicolor  Dermatophytoses caused by organisms susceptible to itraconazole (Trichophyton spp., Microsporum spp., Epidermophyton floccosum) e.g. tinea pedis, tinea cruris, tinea corporis, tinea manuum  Oropharyngeal candidosis  Onychomycosis caused by dermatophytes and/or yeasts  The treatment of histoplasmosis  Eszol is indicated in the following systemic fungal conditions when first-line systemic anti-fungal therapy is inappropriate or has proved ineffective. This may be due to underlying pathology, insensitivity of the pathogen or drug toxicity:  Treatment of aspergillosis and candidosis  Treatment of cryptococcosis (including cryptococcal meningitis): in immunocompromised patients with cryptococcosis and in all patients with cryptococcosis of the central nervous system.  Maintenance therapy in AIDS patients to prevent relapse of underlying fungal infection. Eszol is also indicated in the prevention of fungal infection during prolonged neutropenia when standard therapy is considered inappropriate.  It is also indicated in the prevention of fungal infection during prolonged neutropenia when standard therapy is considered inappropriate.
DOSAGE:
Use in children
Not recommended. See Special Warnings and Precautions for use. In Elderly
Not recommended. See Special Warnings and Precautions for use. Use in patients with renal impairment The oral bioavailability of itraconazole may be lower in patients with renal insufficiency, a dose adjustment may be considered. See Special Warnings and Precautions for use.
Use in patients with hepatic impairment Itraconazole is predominantly metabolised by the liver. The terminal half-life of itraconazole in cirrhotic patients is somewhat prolonged. The oral bioavailability in cirrhotic patients is somewhat decreased. A dose adjustment may be considered. See Special Warnings and Precautions for use.


Indication

Dose1

Remarks

 

 

 

Vulvovaginal candidosis

200 mg twice daily for 1 day

 

 

 

 

Pityriasis versicolor

200 mg once daily for 7 days

 

 

 

 

Tinea corporis, tinea cruris

100 mg once daily for 15 days or 200 mg

 

 

once daily for 7 days

 

 

 

 

Tinea pedis, tinea manuum

100 mg once daily for 30 days

 

 

 

 

Oropharyngeal candidosis

100 mg once daily for 15 days

Increase dose to 200 mg once daily for 15 days

 

 

in AIDS or neutropenic patients because of im-

 

 

paired absorption in these groups.

 

 

 

Onychomycosis (toenails with or without

200 mg once daily for 3 months

 

fingernail involvement)

 

 

 

 

 



Or continuous treatment:
2 tablets per day (200 mg per day) for 3 months. Eszol® excretion out of skin tissues or nails is slower than those one out of plasma. Thus, optimal clinical and mycological effects are reached within 2 – 4 weeks after the treatment of skin infections and 6 – 9 months after the end of the treatment of nail plates infection.


Systemic mycosis:

Septicemia/bacteriemia

500-1000 mg

1-2 times

10-14 days

Intraabdominal infections*

500 mg

1 time

7-14 days


* In combination with antibiotics with an action on anaerobic causative agent. Dosage for patients with kidney function disorders and creatinine clearance less than 50 ml/min:




Indications

Dosage

Average treatment duration

Notes

Aspergillosis

200 mg 1 time per day

2 – 5 months

The dose is increased up to 200 mg 2 times a day in case of invasive or disseminated disease

Candidiasis

100 – 200 mg 1 time per day

3 weeks tо 7 months

Cryptococcosis
(without meningitis signs)

200 mg 1 time per day

2 months tо 1 year

 

Cryptococcal meningitis

200 mg 2 times per day

от 2 months tо 1 year

Supporting treatment (see “Peculiarities in use”)

Histoplasmosis

200 mg 1 time per day tо 200 mg 2 times per day

8 months

 

Sporotrichosis blastomycosis

100 mg 1 time per day

3 months

 

Paracoccidioidosis

100 mg 1 time per day

6 months

There is no sufficient data concerning effectiveness of specified dosage regimen in AIDS patients

Chrome mycosis

100 – 200 mg 1 time per day

6 months

 

Blastomycosis

100 mg 1 time per day tо 200 mg 2 times per day

6 months

 

Side effects and drug interactions.

Drugs affecting the absorption of itraconazole
Drugs that reduce the gastric acidity impair the absorption of itraconazole from Eszol tablets. Drugs affecting the metabolism of itraconazole
Itraconazole is mainly metabolised through the cytochrome CYP3A4. Interaction studies have been performed with rifampicin, rifabutin and phenytoin, which are potent inducers of CYP3A4. 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 enzyme inducers is not recommended. No formal study data are available for other enzyme inducers, such as carbamazepine, Hypericum perforatum |(St John's Wort), phenobarbital and isoniazid, but similar effects should be anticipated. Potent inhibitors of this enzyme such as ritonavir, indinavir, clarithromycin and erythromycin may increase the bioavailability of itraconazole. Effects 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. When using concomitant medication, the corresponding label should be consulted for information on the route of administration. After stopping treatment, itraconazole plasma concentrations decline gradually, depending on the dose and duration of treatment. This should be taken into account when the inhibitory effect of itraconazole on co-administered drugs is considered. Examples are:
The following drugs are contraindicated with itraconazole:
Astemizole, bepridil, cisapride, dofetilide, levacetylmethadol (levomethadyl), mizolastine, pimozide, quinidine, sertindole or terfenadine are contraindicated with Eszol since co-administration may result in increased plasma concentrations of these substrates, which can lead to QT prolongation and rare occurrences of torsades de pointes.  CYP3A4 metabolised HMG-CoA reductase inhibitors such as atorvastatin, lovastatin and simvastatin
 Triazolam and oral midazolam
 Ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine)
 Eletriptan
 Nisoldipine
Caution should be exercised when co-administering itraconazole with calcium channel blockers due to an increased risk of congestive heart failure. In addition to possible pharmacokinetic interactions involving the drug metabolising enzyme CYP3A4, calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole. The following drugs should be used with caution, and their plasma concentrations, effects or side effects should be monitored. Their dosage, if coadministered with itraconazole, should be reduced if necessary:
 Oral anticoagulants
 HIV protease inhibitors such as ritonavir, indinavir, saquinavir
 Certain antineoplastic agents such as vinca alkaloids, busulfan, docetaxel and trimetrexate
 CYP3A4 metabolised calcium channel blockers such as dihydropyridines and verapamil
 Certain immunosuppressive agents: ciclosporin, tacrolimus and rapamycin (also known as sirolimus)
 Certain glucocorticoids such as budesonide, dexamethasone, fluticasone and methyl prednisolone
 Digoxin (via inhibition of P-glycoprotein)
 Others: carbamazepine, cilostazol, buspirone, disopyramide, alfentanil, alprazolam, brotizolam, midazolam IV, rifabutin, ebastine, fentanyl,
halofantrine, repaglinide and reboxetine. The importance of the concentration increase and the clinical relevance of these changes during coadministration with itraconazole remain to be established. No interaction of itraconazole with zidovudine (AZT) 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, indometacin, tolbutamide or sulfamethazine

Warnings and precautions

Pregnancy and lactation:
Eszol tablets must not be used during pregnancy except for life-threatening cases where the potential benefit to the mother outweighs the potential harm to the foetus. In animal studies itraconazole has shown reproduction toxicity. There is limited information on the use of Eszol during pregnancy. During post-marketing experience, cases of congenital abnormalities have been reported. These cases included skeletal, genitourinary tract, cardiovascular and ophthalmic malformations as well as chromosomal and multiple malformations. A causal relationship with Eszol has not been established. Epidemiological data on exposure to Eszol during the first trimester of pregnancy-mostly in patients receiving short-term treatment f or vulvovaginal candidosis-did not show an increased risk for malformations as compared to control subjects not exposed to any known teratogens. Women of child bearing potential
Women of childbearing potential taking Eszol tablets should use contraceptive precautions. Effective contraception should be continued until the next menstrual period following the end of Eszol therapy. Lactation
A very small amount of itraconazole is excreted in human milk. The expected benefits of Eszol therapy should be weighed against the risks of breast feeding. In case of doubt, the patient should not breast feed.
Children:
As there is no enough clinical data concerning Eszol® tablets administration to children, it is not recommended to administer the preparation to patients of this age group.

PRECAUTIONS
The product contains sugar, that should be considered when it is administered to insular patients.
Use with other medicines:
Drugs affecting the absorption of itraconazole
Drugs that reduce the gastric acidity impair the absorption of itraconazole from Eszol tablets. Drugs affecting the metabolism of itraconazole
Itraconazole is mainly metabolised through the cytochrome CYP3A4. Interaction studies have been performed with rifampicin, rifabutin and phenytoin, which are potent inducers of CYP3A4. 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 enzyme inducers is not recommended. No formal study data are available for other enzyme inducers, such as carbamazepine, Hypericum perforatum |(St John's Wort), phenobarbital and isoniazid, but similar effects should be anticipated. Potent inhibitors of this enzyme such as ritonavir, indinavir, clarithromycin and erythromycin may increase the bioavailability of itraconazole. Effects 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. When using concomitant medication, the corresponding label should be consulted for information on the route of administration. After stopping treatment, itraconazole plasma concentrations decline gradually, depending on the dose and duration of treatment. This should be taken into account when the inhibitory effect of itraconazole on co-administered drugs is considered. Examples are:
The following drugs are contraindicated with itraconazole: Astemizole, bepridil, cisapride, dofetilide, levacetylmethadol (levomethadyl), mizolastine, pimozide, quinidine, sertindole or terfenadine are contraindicated with Eszol since co-administration may result in increased plasma concentrations of these substrates, which can lead to QT prolongation and rare occurrences of torsades de pointes.  CYP3A4 metabolised HMG-CoA reductase inhibitors such as atorvastatin, lovastatin and simvastatin
 Triazolam and oral midazolam
 Ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine)
 Eletriptan
 Nisoldipine
Caution should be exercised when co-administering itraconazole with calcium channel blockers due to an increased risk of congestive heart failure. In addition to possible pharmacokinetic interactions involving the drug metabolising enzyme CYP3A4, calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole. The following drugs should be used with caution, and their plasma concentrations, effects or side effects should be monitored. Their dosage, if coadministered with itraconazole, should be reduced if necessary:  Oral anticoagulants
 HIV protease inhibitors such as ritonavir, indinavir, saquinavir
 Certain antineoplastic agents such as vinca alkaloids, busulfan, docetaxel and trimetrexate
 CYP3A4 metabolised calcium channel blockers such as dihydropyridines and verapamil
 Certain immunosuppressive agents: ciclosporin, tacrolimus and rapamycin (also known as sirolimus)
 Certain glucocorticoids such as budesonide, dexamethasone, fluticasone and methyl prednisolone
 Digoxin (via inhibition of P-glycoprotein)
 Others: carbamazepine, cilostazol, buspirone, disopyramide, alfentanil, alprazolam, brotizolam, midazolam IV, rifabutin, ebastine, fentanyl, halofantrine, repaglinide and reboxetine. The importance of the concentration increase and the clinical relevance of these changes during coadministration with itraconazole remain to be established. No interaction of itraconazole with zidovudine (AZT) 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, indometacin, tolbutamide or sulfamethazine.

Overdosage and Contraindications

Overdose:
No data are available. In the event of 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.

CONTRAINDICATIONS:
Eszol tablets are contra-indicated in patients with known hypersensitivity to itraconazole or to any of the excipients. Coadministration of the following drugs is contraindicated with Eszol tablets  CYP3A4 metabolised substrates that can prolong the QT-interval e.g., astemizole, bepridil, cisapride, dofetilide, levacetylmethadol
(levomethadyl), mizolastine, pimozide, quinidine, sertindole and terfenadine are contraindicated with Eszol tablets. Coadministration may result in increased plasma concentrations of these substrates which can lead to QTc prolongation and rare occurrences of torsades de pointes.  CYP3A4 metabolised HMG-CoA reductase inhibitors such as atorvastatin, lovastatin and simvastatin
 Triazolam and oral midazolam
 Ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine)
 Eletriptan
 Nisoldipine
Eszol tablets should not be administered for non-life threatening indications to patients receiving disopyramide or halofantrine. Eszol tablets should not be administered to patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF except for the treatment of life-threatening or other serious infections. Eszol tablets must not be used during pregnancy for non life-threatening indications. Women of childbearing potential taking Eszol tablets should use contraceptive precautions. Effective contraception should be continued until the menstrual period following the end of Eszol tablets therapy.

Clinical pharmacology.

PHARMACOLOGICAL PROPERTIES:

Pharmacodynamics:
Itraconazole, a triazole derivative, has a broad spectrum of activity. 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 an antifungal effect. For itraconazole, breakpoints have only been established for Candida spp. from superficial mycotic infections (CLSI M27-A2, breakpoints have not been established for EUCAST methodology). The CLSI breakpoints are as follows: susceptible < 0.125; susceptible, dose-dependent 0.25-0.5 and resistant > 1μg/mL. Interpretive breakpoints have not been established for the filamentous fungi. In vitro studies demonstrate that itraconazole inhibits the growth of a broad range of fungi pathogenic for humans at concentrations usually < 1 μg/ml. These include: dermatophytes (Trichophyton spp., Microsporum spp., Epidermophyton floccosum); yeasts (Candida spp., including C. albicans, C. glabrata and C. krusei, Cryptococcus neoformans, Pityrosporum spp., Trichosporon spp., Geotrichum spp.); Aspergillus spp.; Histoplasma spp.; Paracoccidioides brasiliensis; Sporothrix schenckii; Fonsecaea spp.; Cladosporium spp.; Blastomyces dermatitidis; Coccidiodes immitis; Pseudallescheria boydii; Penicillium marneffei; and various other yeasts and fungi. Candida krusei, Candida glabrata and Candida tropicalis are generally the least susceptible Candida species, with some isolates showing unequivocal resistance to itraconazole in vitro. The principal fungus types that are not inhibited by itraconazole are Zygomycetes (e.g. Rhizopus spp., Rhizomucor spp., Mucor spp. and Absidia spp.), Fusarium spp., Scedosporium proliferans and Scopulariopsis spp. Azole resistance appears to develop slowly and is often the result of several genetic mutations. Mechanisms that have been described are overexpression of ERG11, which encodes the target enzyme 14α-demethylase, point mutations in ERG11 that lead to decreased target affinity and/or transporter overexpression resulting in increased efflux. Cross resistance between members of the azole class has been observed within Candida spp., although resistance to one member of the class does not necessarily confer resistance to other azoles. Itraconazole-resistant strains of Aspergillus fumigatus have been reported.

Pharmacokinetics:
The pharmacokinetics of itraconazole has been investigated in healthy subjects, special populations and patients after single and multiple dosing. Absorption
Itraconazole is rapidly absorbed after oral administration. Peak plasma concentrations of the unchanged drug are reached within 2 to 5 hours following an oral dose. The observed absolute bioavailability of itraconazole is about 55%. Oral bioavailability is maximal when the tablets are taken immediately after a full meal. Distribution
Most of the itraconazole in plasma is bound to protein (99.8%) with albumin being the main binding component (99.6% for the hydroxy- metabolite). It has also a marked affinity for lipids. Only 0.2% of the itraconazole in plasma is present as free drug. Itraconazole is distributed in a large apparent volume in the body (> 700 L), suggesting its extensive distribution into tissues: Concentrations in lung, kidney, liver, bone, stomach, spleen and muscle were found to be two to three times higher than corresponding concentrations in plasma. Brain to plasma ratios were about 1 as measured in beagle dogs. The uptake into keratinous tissues, skin in particular, is up to four times higher than in plasma. Metabolism
Itraconazole is extensively metabolised by the liver into a large number of metabolites. One of the main metabolites is hydroxy-itraconazole, which has in vitro antifungal activity comparable to itraconazole. Plasma concentrations of the hydroxy-itraconazole are about twice those of itraconazole. As shown in in vitro studies, CYP 3A4 is the major enzyme that is involved in the metabolism of itraconazole. Elimination
Itraconazole is excreted as inactive metabolites to about 35% in urine within one week and to about 54% with faeces. Renal excretion of the parent drug accounts for less than 0.03% of the dose, whereas fecal excretion of unchanged drug varies between 3 – 18% of the dose. Itraconazole clearance decreases at higher doses due to saturable hepatic metabolism. Linearity/non-linearity
As a consequence of non-linear pharmacokinetics, itraconazole accumulates in plasma during multiple dosing. Steady-state concentrations are generally reached within about 15 days, with Cmax and AUC values 4 to 7-fold higher than those seen after a single dose. The mean elimination half-life of itraconazole is about 40 hours after repeated dosing. Special Populations
Hepatic Insufficiency: A pharmacokinetic study using a single 100 mg dose of itraconazole (one 100 mg tablet) was conducted in 6 healthy and 12 cirrhotic subjects. No statistically significant differences in AUC were seen between these two groups. A statistically significant reduction in average C (47%) 00 max and a two fold increase in the elimination half-life (37 ± 17 versus 16 ±5 hours) of itraconazole were noted in cirrhotic subjects compared with healthy subjects. Data are not available in cirrhotic patients during long-term use of itraconazole. Renal Insufficiency: Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when the drug is administered in this patient population

Shelf-life:
2 years.

Storage:
Store below 30°C.
Keep all medicines out of reach of children

Package:
Alu-Alu blister of 10 tablets, 1 or 3 blisters are in a carton.

Conditions of supply:
By prescription<

CERTIFICATES

KEEP IN TOUCH

Kusum Healthcare Pvt Ltd

Regd. Office: D-158A, Okhla Industrial Area

Phase-1, New Delhi-110020, India

Tel: 011-41005147, 40514919

Fax: +91-11-40527575

Email: kusumhealth@kusumhealthcare.com

CIN: U65929DL1997PTC085780