Fluzak

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FLUZAC (FLUZAC)

Composition:

Active substance: fluconazole;

1 tablet contains 50 mg, 150 mg, or 200 mg of fluconazole;

Excipients: calcium hydrogen phosphate, maize starch, colloidal anhydrous silicon dioxide, magnesium stearate, sodium starch glycolate (type A), sodium lauryl sulfate, methylparahydroxybenzoate (E 218), propylparahydroxybenzoate (E 216), talc, azorubine (Ponceau 4R, E 124).

Pharmaceutical form. Tablets.

Main physicochemical properties: flat, round, pink-colored tablets with specks, beveled edges, a break line on one side, and smooth on the other.

Pharmacotherapeutic group. Antifungal agents for systemic use. Triazole derivatives. ATC code J02A C01.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of Action.

Fluconazole is an antifungal agent of the triazole class. Its primary mechanism of action is the inhibition of fungal 14-alpha-lanosterol-demethylation, mediated by cytochrome P450, which is an essential step in the biosynthesis of fungal ergosterol. Accumulation of 14-alpha-methyl-sterols correlates with subsequent loss of ergosterol from the fungal cell membrane and may account for the antifungal activity of fluconazole. Fluconazole is more selective for fungal cytochrome P450 enzymes than for various cytochrome P450 enzyme systems in mammals.

Administration of fluconazole at a dose of 50 mg once daily for 28 days does not affect plasma testosterone levels in men or endogenous steroid levels in women of reproductive age. Fluconazole at doses of 200–400 mg daily does not produce clinically significant effects on endogenous steroid levels or on the response to adrenocorticotropic hormone (ACTH) stimulation in healthy male volunteers.

A study of interaction with antipyrine demonstrated that single or repeated administration of 50 mg fluconazole does not affect antipyrine metabolism.

In vitro Susceptibility.

Fluconazole demonstrates in vitro antifungal activity against the most common Candida species (including C. albicans, C. parapsilosis, C. tropicalis). C. glabrata shows reduced susceptibility to fluconazole, while C. krusei and C. auris are resistant to fluconazole. Minimal inhibitory concentrations and the epidemiological cut-off value (ECOFF) according to EUCAST for fluconazole against C. guilliermondii are higher than those for C. albicans.

Fluconazole also demonstrates in vitro activity against Cryptococcus neoformans and Cryptococcus gattii, as well as against endemic mould fungi Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum, and Paracoccidioides brasiliensis.

Pharmacokinetic/Pharmacodynamic Relationships.

According to animal studies, there is a correlation between the minimal inhibitory concentration (MIC) and efficacy against experimental models of mycoses caused by Candida species. Clinical studies have shown a linear relationship between AUC and fluconazole dose (approximately 1:1). There is also a direct, but not fully sufficient, correlation between AUC or dose and positive clinical response in the treatment of oral candidiasis and, to a lesser extent, candidemia. Similarly, treatment of infections caused by strains with high minimal inhibitory concentrations to fluconazole is less effective.

Mechanisms of Resistance.

Candida species exhibit multiple mechanisms of resistance to azole antifungal agents. Fluconazole shows high minimal inhibitory concentrations against fungal strains possessing one or more resistance mechanisms, which negatively impacts its in vivo efficacy and clinical effectiveness. In normally susceptible Candida species, the most common resistance mechanism involves the target enzymes of azoles responsible for ergosterol biosynthesis. Resistance may result from mutations, increased enzyme production, drug efflux mechanisms, or development of compensatory pathways.

Superinfections caused by Candida spp. other than C. albicans have been reported, often involving strains with reduced susceptibility (C. glabrata) or resistance (e.g., C. krusei, C. auris) to fluconazole. Alternative antifungal agents should be used for the treatment of such infections. Resistance mechanisms are not yet fully understood in some naturally resistant (C. krusei) or emerging (C. auris) Candida species.

EUCAST (European Committee on Antimicrobial Susceptibility Testing) Breakpoints.

Based on pharmacokinetic/pharmacodynamic data, in vitro susceptibility, and clinical response, breakpoints for fluconazole have been established for Candida species (EUCAST accompanying document for fluconazole (2020) – version 3; European Committee on Antimicrobial Susceptibility Testing, Antifungal agents, Breakpoint tables for interpretation of MICs, version 10.0, effective from 04.02.2020). These have been categorized into non-species-related breakpoints, primarily determined based on pharmacokinetic/pharmacodynamic information and not dependent on species-specific MIC distributions, and species-specific breakpoints, typically associated with human infections. These breakpoints are listed below.

Antifungal agent	Species-specific breakpoints, S ≤ / R > in mg/l						Non-species-specific breakpoints,a S ≤ / R > in mg/l
	Candida albicans	Candida dubliniensis	Candida glabrata	Candida krusei	Candida parapsilosis	Candida tropicalis
Fluconazole	2/4	2/4	0.001*/16	--	2/4	2/4	2/4

S = susceptible;
R = resistant;
a – non-species-related breakpoints, primarily determined based on pharmacokinetic/pharmacodynamic information and not dependent on species-specific minimal inhibitory concentration distributions. These were studied only in microorganisms lacking a specific breakpoint;
-- susceptibility testing not recommended, as this species is not a target for drug therapy;
* All C. glabrata isolates fall into the I category. MICs against C. glabrata should be interpreted as resistant when they exceed 16 mg/L. The susceptible category (≤ 0.001 mg/L) is used solely to prevent misclassification of I strains as S. I – susceptible with increased exposure: a microorganism is categorized as "susceptible with increased exposure" when there is a high probability of therapeutic success due to increased drug exposure achieved by adjusting the dosing regimen or increased drug concentration at the site of infection.

Pharmacokinetics.

The pharmacokinetic properties of fluconazole are similar following intravenous and oral administration.

Absorption.

Fluconazole is well absorbed after oral administration, and plasma drug levels and systemic bioavailability exceed 90% of those achieved after intravenous administration. Concomitant food intake does not affect drug absorption following oral administration. Peak plasma concentrations are reached within 0.5–1.5 hours after dosing on an empty stomach. Plasma drug concentration is proportional to dose. Steady-state 90% concentration is achieved by day 4–5 of daily treatment. A steady-state 90% concentration is reached by day 2 of treatment when a loading dose twice the normal daily dose is administered on the first day.

Distribution.

The volume of distribution is approximately equal to total body water. Plasma protein binding is low (11–12%).

Fluconazole penetrates well into all studied body fluids. Fluconazole levels in saliva and sputum are similar to plasma concentrations. In patients with fungal meningitis, fluconazole concentrations in cerebrospinal fluid reach 80% of plasma levels.

High fluconazole concentrations exceeding serum levels are achieved in the skin, specifically in the stratum corneum, epidermis, dermis, and sweat. Fluconazole accumulates in the stratum corneum. With a 50 mg once-daily dose, fluconazole concentration after 12 days of treatment was 73 µg/g, and 7 days after treatment completion, the concentration remained at 5.8 µg/g. With a 150 mg once-weekly dose, fluconazole concentration on day 7 of treatment was 23.4 µg/g; 7 days after the next dose, the concentration was still 7.1 µg/g.

Fluconazole concentration in nails after 4 months of 150 mg once-weekly administration was 4.05 µg/g in healthy volunteers and 1.8 µg/g in patients with nail disease; fluconazole was detectable in nail samples up to 6 months after therapy completion.

Biotransformation.

Fluconazole is minimally metabolized. After administration of radiolabeled doses, only 11% of fluconazole is excreted in urine as metabolites. Fluconazole is a moderate inhibitor of CYP2C9 and CYP3A4 isoenzymes and a potent inhibitor of the CYP2C19 isoenzyme.

Elimination.

The plasma elimination half-life of fluconazole is approximately 30 hours. The majority of the drug is excreted by the kidneys, with 80% of the administered dose recovered unchanged in urine. Fluconazole clearance is proportional to creatinine clearance. No circulating metabolites have been identified.

The prolonged plasma elimination half-life allows for single-dose administration in vaginal candidiasis and once-weekly dosing for other indications.

Renal impairment.

In patients with severe renal impairment (glomerular filtration rate < 20 mL/min), the elimination half-life increases from 30 to 98 hours. Therefore, this patient group requires a reduced fluconazole dose. Fluconazole is removed by hemodialysis and, to a lesser extent, by intraperitoneal dialysis. A 3-hour hemodialysis session reduces plasma fluconazole levels by approximately 50%.

Lactation.

Fluconazole concentrations in plasma and breast milk were evaluated over 48 hours after a single 150 mg dose in a pharmacokinetic study involving ten lactating women who temporarily or permanently discontinued breastfeeding. Fluconazole was detected in breast milk at an average concentration of approximately 98% of maternal plasma levels. The mean peak concentration in breast milk was 2.61 mg/L, reached 5.2 hours after dosing. The daily fluconazole dose received by the infant via breast milk (assuming an average milk intake of 150 mL/kg/day), calculated based on the mean peak milk concentration, was 0.39 mg/kg/day, representing approximately 40% of the dose recommended for neonates (age < 2 weeks) or 13% of the dose recommended for infants for treatment of mucosal candidiasis.

Children.

Pharmacokinetic data were evaluated in 113 children across five studies: two single-dose studies, two multiple-dose studies, and one study in premature neonates.

After administration of 2–8 mg/kg fluconazole to children aged 9 months to 15 years, AUC was approximately 38 µg*h/mL per 1 mg/kg dose. After multiple dosing, the mean plasma elimination half-life of fluconazole ranged between 15 and 18 hours; the volume of distribution was 880 mL/kg. A longer plasma elimination half-life of approximately 24 hours was observed after single-dose administration. This is comparable to the plasma elimination half-life after a single 3 mg/kg intravenous dose in children aged 11 days to 11 months. The volume of distribution in this age group was approximately 950 mL/kg.

Experience with fluconazole in neonates is limited to pharmacokinetic studies in 12 premature infants with a gestational age of approximately 28 weeks. The mean age at first dose was 24 hours (range 9–36 hours); mean birth weight was 900 g (range 750–1100 g). The study protocol was completed in 7 patients. Up to 5 intravenous doses of fluconazole 6 mg/kg were administered every 72 hours. The mean elimination half-life was 74 hours (44–185) on day 1, decreasing to 53 hours (30–131) on day 7 and 47 hours (27–68) on day 13. The area under the curve (µg*h/mL) was 271 (173–385) on day 1, increased to 490 (292–734) on day 7, then decreased to 360 (167–566) on day 13. The volume of distribution (mL/kg) was 1183 (1070–1470) on day 1, increased to 1184 (510–2130) on day 7, and to 1328 (1040–1680) on day 13.

Elderly patients.

A pharmacokinetic study was conducted in 22 patients (aged ≥65 years) who received 50 mg oral fluconazole. Ten patients were concurrently receiving diuretics. Cmax was 1.54 µg/mL, reached within 1.3 hours after fluconazole administration. Mean AUC was 76.4±20.3 µg*h/mL. Mean elimination half-life was 46.2 hours. These pharmacokinetic parameters are higher than those observed in younger healthy volunteers. Concomitant diuretic use had no significant effect on Cmax or AUC. Additionally, creatinine clearance (74 mL/min), percentage of unchanged fluconazole excreted in urine (0–24 hours, 22%), and renal fluconazole clearance (0.124 mL/min/kg) in this age group were lower than in younger volunteers. Therefore, the observed pharmacokinetic changes in elderly patients are likely dependent on renal function parameters.

Clinical Characteristics.

Indications.

Treatment of fungal infections in adults (see section “Pharmacodynamics”), such as:

• cryptococcal meningitis (see section “Special precautions for use”);
• coccidioidomycosis (see section “Special precautions for use”);
• invasive candidiasis;
• mucosal candidiasis, including oropharyngeal candidiasis and esophageal candidiasis, candiduria, chronic cutaneous and mucosal candidiasis;
• chronic atrophic oral candidiasis (denture-related candidiasis), when oral hygiene or topical therapy is ineffective;
• vaginal candidiasis, acute or recurrent, when topical therapy is not appropriate;
• candidal balanitis, when topical therapy is not appropriate;
• dermatomycoses, including tinea pedis, cutaneous fungal infections, tinea cruris, pityriasis versicolor, and cutaneous candidiasis, when systemic therapy is indicated;
• dermatophyte onychomycosis, when use of other medicinal products is not appropriate.

Prevention of the following conditions in adults:

• recurrence of cryptococcal meningitis in patients at high risk of developing it;
• recurrence of oropharyngeal or esophageal candidiasis in HIV-infected patients at high risk of developing it;
• reduction in the frequency of recurrent vaginal candidiasis (4 or more episodes per year);
• prevention of candidiasis in patients with prolonged neutropenia (e.g., patients with hematological malignancies receiving chemotherapy or patients undergoing hematopoietic stem cell transplantation) (see section “Pharmacological properties. Pharmacodynamics”).

Children.

The use of the tablet formulation in this patient population is appropriate when children are able to swallow tablets safely, which is generally possible from the age of 5 years.

Fluconazole is used in children for the treatment of mucosal candidiasis (oropharyngeal candidiasis, esophageal candidiasis), invasive candidiasis, cryptococcal meningitis, and for prevention of candidiasis in immunocompromised patients. The drug may be used as maintenance therapy to prevent recurrence of cryptococcal meningitis in children at high risk of developing it (see section “Special precautions for use”).

Treatment with Fluconazole may be initiated before the results of culture and other laboratory tests are available; however, antimicrobial therapy should be adjusted accordingly once results are obtained.

Contraindications.

• Hypersensitivity to fluconazole, other azole compounds, or to any of the excipients of the drug.
• Concomitant use of fluconazole and terfenadine in patients receiving fluconazole repeatedly at doses of 400 mg/day or higher (based on results of multiple-dose interaction studies).
• Concomitant use of fluconazole and other medicinal products that prolong the QT interval and are metabolized via the CYP3A4 enzyme (e.g., cisapride, astemizole, pimozide, quinidine, and erythromycin) (see sections “Special precautions for use” and “Interaction with other medicinal products and other forms of interaction”).

Interaction with other medicinal products and other forms of interaction.

Concomitant use of fluconazole and the following medicinal products is contraindicated.

Cisapride. Cases of cardiac adverse reactions, including paroxysmal ventricular tachycardia of the torsade de pointes type, have been reported in patients receiving fluconazole and cisapride concomitantly. A controlled study demonstrated that concomitant administration of 200 mg fluconazole once daily and 20 mg cisapride four times daily significantly increased plasma levels of cisapride and prolonged the QT interval. Concomitant use of fluconazole and cisapride is contraindicated (see section “Contraindications”).

Terfenadine. Due to cases of severe cardiac arrhythmias caused by QTc interval prolongation in patients receiving azole antifungal agents concomitantly with terfenadine, interaction studies between these drugs were conducted. In one study, administration of fluconazole at a dose of 200 mg daily did not result in QTc prolongation. Another study using fluconazole at doses of 400 mg and 800 mg daily demonstrated that fluconazole at doses of 400 mg daily or higher significantly increased plasma levels of terfenadine when administered concomitantly. Concomitant use of fluconazole at doses of 400 mg or higher with terfenadine is contraindicated (see section “Contraindications”). When fluconazole is used at doses below 400 mg daily concomitantly with terfenadine, careful patient monitoring is required.

Astemizole. Concomitant use of fluconazole and astemizole may reduce the clearance of astemizole. This increase in astemizole plasma concentration may lead to QT interval prolongation and, rarely, to paroxysmal ventricular tachycardia of the torsade de pointes type. Concomitant use of fluconazole and astemizole is contraindicated (see section “Contraindications”).

Pimozide and quinidine. Concomitant use of fluconazole and pimozide or quinidine may lead to inhibition of pimozide or quinidine metabolism, although appropriate in vitro and in vivo studies have not been conducted. Increased plasma concentrations of pimozide or quinidine may cause QT interval prolongation and, rarely, lead to the development of paroxysmal ventricular tachycardia of the torsade de pointes type. Concomitant use of fluconazole and pimozide or quinidine is contraindicated (see section “Contraindications”).

Erythromycin. Concomitant use of erythromycin and fluconazole may increase the risk of cardiotoxicity (QT interval prolongation, paroxysmal ventricular tachycardia of the torsade de pointes type) and, as a consequence, sudden cardiac death. Use of this combination is contraindicated (see section “Contraindications”).

Concomitant use of fluconazole and the following medicinal products is not recommended.

Halofantrine. Fluconazole may increase halofantrine plasma concentration by inhibiting CYP3A4. Concomitant use of these medicinal products may increase the risk of cardiotoxicity (QT interval prolongation, paroxysmal ventricular tachycardia of the torsade de pointes type) and, consequently, sudden cardiac death. The use of this combination should be avoided (see section “Special precautions for use”).

Concomitant use of fluconazole and the following medicinal products requires caution.

Amiodarone. Concomitant use of fluconazole with amiodarone may lead to QT interval prolongation. Fluconazole should be used with caution together with amiodarone, especially when high-dose fluconazole (800 mg) is prescribed.

Concomitant use of fluconazole and the following medicinal products requires caution and dose adjustment.

Effect of other medicinal products on fluconazole.

Interaction studies have demonstrated that oral administration of fluconazole simultaneously with food, cimetidine, antacids, or total body irradiation for bone marrow transplantation does not have a clinically significant effect on fluconazole absorption.

Rifampicin. Concomitant use of fluconazole and rifampicin resulted in a 25 % decrease in AUC and a 20 % reduction in the elimination half-life of fluconazole. Therefore, for patients receiving rifampicin, consideration should be given to increasing the dose of fluconazole.

Hydrochlorothiazide. In a pharmacokinetic interaction study, repeated concomitant administration of hydrochlorothiazide in healthy volunteers receiving fluconazole increased plasma concentrations of fluconazole by 40 %. Such interaction parameters do not require changes in the dosing regimen of fluconazole for patients receiving diuretics concomitantly.

Effect of fluconazole on other medicinal products.

Fluconazole is a moderate inhibitor of cytochrome P450 (CYP) isoenzyme 2C9 and a moderate inhibitor of CYP3A4. Fluconazole is a potent inhibitor of the CYP2C19 isoenzyme. In addition to the observed/documented interactions described below, there is a risk of increased plasma concentrations of other compounds metabolized by CYP2C9, CYP2C19, and CYP3A4 when co-administered with fluconazole. Therefore, such combinations should be used with caution; close monitoring of patients is necessary. The inhibitory effect of fluconazole on enzymes persists for 4–5 days after administration due to its long elimination half-life (see section “Contraindications”).

Abrocitinib: fluconazole (inhibitor of CYP2C19, 2C9, 3A4) increased exposure to the active moiety of abrocitinib by 155 %. When used concomitantly with fluconazole, the dose of abrocitinib should be adjusted according to the abrocitinib prescribing information.

Alfentanil. When alfentanil at a dose of 20 µg/kg and fluconazole at a dose of 400 mg were administered concomitantly to healthy volunteers, a twofold increase in AUC was observed, possibly due to inhibition of CYP3A4. Dose adjustment of alfentanil may be necessary.

Amitriptyline, nortriptyline. Fluconazole enhances the effects of amitriptyline and nortriptyline. Measurement of plasma concentrations of 5-nortriptyline and/or S-amitriptyline is recommended at the start of combination therapy and after 1 week. The dose of amitriptyline/nortriptyline should be adjusted if necessary.

Amphotericin B. Concomitant use of fluconazole and amphotericin B in immunocompetent and immunocompromised infected mice yielded the following results: slight additive antifungal effect in systemic C. albicans infection, no interaction in intracranial Cryptococcus neoformans infection, and antagonism between the two drugs in systemic Aspergillus fumigatus infection. The clinical significance of these findings is unknown.

Anticoagulants. As with other azole antifungal agents, cases of bleeding (hematomas, epistaxis, gastrointestinal bleeding, hematuria, and melena) associated with prolonged prothrombin time have been reported with concomitant use of fluconazole and warfarin. A twofold increase in prothrombin time was observed with concomitant use of fluconazole and warfarin, likely due to inhibition of warfarin metabolism via CYP2C9. Prothrombin time should be closely monitored in patients receiving coumarin anticoagulants or indanediones concomitantly. Dose adjustment of the anticoagulant may be necessary.

Short-acting benzodiazepines, e.g., midazolam, triazolam. Administration of fluconazole after oral administration of midazolam resulted in a significant increase in midazolam concentration and enhanced psychomotor effects. Concomitant use of fluconazole 200 mg and 7.5 mg oral midazolam increased AUC and elimination half-life by 3.7 and 2.2 times, respectively. Administration of fluconazole 200 mg/day and 0.25 mg oral triazolam increased AUC and elimination half-life of triazolam by 4.4 and 2.3 times, respectively. Potentiation and prolongation of triazolam effects were observed with concomitant use of fluconazole and triazolam.

If benzodiazepines must be administered to a patient undergoing fluconazole therapy, the dose of benzodiazepines should be reduced and appropriate patient monitoring established.

Carbamazepine. Fluconazole inhibits carbamazepine metabolism and increases serum carbamazepine levels by 30 %. There is a risk of carbamazepine toxicity. Dose adjustment of carbamazepine may be necessary depending on its serum concentration and clinical effects.

Calcium channel blockers. Some calcium antagonists (nifedipine, isradipine, amlodipine, and felodipine) are metabolized by the CYP3A4 enzyme. Fluconazole may potentially increase systemic exposure to calcium channel blockers. Close monitoring for adverse reactions is recommended.

Celecoxib. When fluconazole (200 mg daily) and celecoxib (200 mg) were administered concomitantly, Cmax and AUC of celecoxib increased by 68 % and 134 %, respectively. When celecoxib and fluconazole are used concomitantly, a halving of the celecoxib dose may be necessary.

Cyclophosphamide. Concomitant use of cyclophosphamide and fluconazole leads to increased serum bilirubin and creatinine levels. These drugs may be used concomitantly, considering the risk of increased serum bilirubin and creatinine levels.

Fentanyl. A fatal case of fentanyl intoxication due to a possible interaction between fentanyl and fluconazole has been reported. In addition, a study in healthy volunteers demonstrated that fluconazole significantly slowed fentanyl elimination. Increased fentanyl concentration may lead to respiratory depression; therefore, close monitoring of the patient is required. Dose adjustment of fentanyl may be necessary.

HMG-CoA reductase inhibitors. Concomitant use of fluconazole and HMG-CoA reductase inhibitors metabolized by CYP3A4 (atorvastatin and simvastatin), or HMG-CoA reductase inhibitors metabolized by CYP2C9 (fluvastatin (reduced hepatic metabolism of statin)), increases the risk of myopathy and rhabdomyolysis (dose-dependent). If concomitant use of these drugs is necessary, patients should be closely monitored for symptoms of myopathy and rhabdomyolysis, and creatine kinase levels should be monitored. If significant increases in creatine kinase levels occur, or if myopathy/rhabdomyolysis is diagnosed or suspected, HMG-CoA reductase inhibitors should be discontinued. Dose reduction of HMG-CoA reductase inhibitors may be necessary, as indicated in the statin prescribing information.

Ibrutinib. Moderate CYP3A4 inhibitors, such as fluconazole, increase plasma concentrations of ibrutinib and may increase the risk of toxicity. If combination cannot be avoided, the dose of ibrutinib should be reduced to 280 mg once daily to continue inhibitor therapy, with continuous clinical monitoring.

Ivacaftor (as monotherapy or in combination with drugs of the same therapeutic class). Concomitant use of ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, increased exposure to ivacaftor by 3 times and exposure to hydroxymethylivacaftor (M1) by 1.9 times. Dose reduction of ivacaftor (as monotherapy or in combination) is necessary, as specified in the ivacaftor prescribing information (as monotherapy or in combination).

Olaparib. Moderate CYP3A4 inhibitors, such as fluconazole, increase plasma concentrations of olaparib; their concomitant use is not recommended. If such a combination cannot be avoided, olaparib intake should be limited to 200 mg twice daily.

Immunosuppressants (e.g., cyclosporine, everolimus, sirolimus, and tacrolimus).

Cyclosporine. Fluconazole significantly increases cyclosporine concentration and AUC. When fluconazole 200 mg/day and cyclosporine 2.7 mg/kg/day were administered concomitantly, AUC of cyclosporine increased by 1.8 times. These drugs may be used concomitantly provided cyclosporine dose is reduced based on its concentration.

Everolimus. Although in vitro and in vivo studies have not been conducted, it is known that fluconazole may increase serum concentrations of everolimus by inhibiting CYP3A4.

Sirolimus. Fluconazole increases sirolimus plasma concentration, likely by inhibiting CYP3A4 and P-glycoprotein metabolism of sirolimus. These drugs may be used concomitantly provided sirolimus dose is adjusted based on concentration and clinical effects.

Tacrolimus. Fluconazole may increase serum concentrations of tacrolimus up to 5 times with oral administration due to inhibition of CYP3A4-mediated metabolism in the intestine. No significant changes in pharmacokinetics were observed with intravenous tacrolimus. Elevated tacrolimus levels are associated with nephrotoxicity. The oral dose of tacrolimus should be reduced based on tacrolimus concentration.

Losartan. Fluconazole inhibits the metabolism of losartan to its active metabolite (E-3174), which accounts for most of the angiotensin II receptor antagonism during losartan therapy. Continuous monitoring of blood pressure in patients is recommended.

Lurasidone: moderate CYP3A4 inhibitors, such as fluconazole, may increase plasma concentrations of lurasidone. If concomitant use cannot be avoided, the dose of lurasidone should be reduced as specified in the lurasidone prescribing information.

Methadone. Fluconazole may increase methadone serum concentration. Dose adjustment of methadone may be necessary when methadone and fluconazole are used concomitantly.

Nonsteroidal anti-inflammatory drugs (NSAIDs). When administered concomitantly with fluconazole, Cmax and AUC of flurbiprofen increased by 23 % and 81 %, respectively, compared to flurbiprofen alone. Similarly, when fluconazole was administered concomitantly with racemic ibuprofen (400 mg), Cmax and AUC of the pharmacologically active S-(+)-ibuprofen isomer increased by 15 % and 82 %, respectively, compared to racemic ibuprofen alone.

Fluconazole may potentially increase systemic exposure to other NSAIDs metabolized by CYP2C9 (e.g., naproxen, lornoxicam, meloxicam, diclofenac). Periodic monitoring for adverse and toxic effects associated with NSAIDs is recommended. Dose adjustment of NSAIDs may be required.

Phenytoin. Fluconazole inhibits hepatic metabolism of phenytoin. Repeated concomitant administration of 200 mg fluconazole and 250 mg intravenous phenytoin increased AUC24 of phenytoin by 75 % and Cmin by 128 %. Monitoring of phenytoin serum concentration is necessary when these drugs are used concomitantly to avoid phenytoin toxicity.

Prednisone. A case has been reported in which a liver transplant recipient developed acute adrenal insufficiency after discontinuation of a three-month course of fluconazole therapy while receiving prednisone. Discontinuation of fluconazole likely led to increased CYP3A4 activity, resulting in accelerated prednisone metabolism. Patients receiving long-term concomitant fluconazole and prednisone should be closely monitored to prevent adrenal insufficiency after stopping fluconazole.

Rifabutin. Fluconazole increases serum concentrations of rifabutin, leading to an increase in AUC of rifabutin by up to 80 %. Uveitis has been reported with concomitant use of fluconazole and rifabutin. Symptoms of rifabutin toxicity should be considered when this combination is used.

Saquinavir. Fluconazole increases AUC and Cmax of saquinavir by approximately 50 % and 55 %, respectively, due to inhibition of hepatic metabolism of saquinavir by CYP3A4 and inhibition of P-glycoprotein. Interactions between fluconazole and saquinavir/ritonavir have not been studied and may be more pronounced. Dose adjustment of saquinavir may be necessary.

Sulfonylurea derivatives. When administered concomitantly, fluconazole prolongs the elimination half-life of oral sulfonylurea derivatives (chlorpropamide, glyburide, glipizide, and tolbutamide) in healthy volunteers. Frequent blood glucose monitoring and appropriate dose reduction of sulfonylurea derivatives are recommended when used concomitantly with fluconazole.

Theophylline. Administration of 200 mg fluconazole for 14 days reduced the average plasma clearance of theophylline by 18 %. Patients receiving high-dose theophylline or those at increased risk of theophylline toxicity for other reasons should be monitored for signs of theophylline toxicity. Therapy should be modified if signs of toxicity appear.

Tofacitinib. The effect of tofacitinib increases when used concomitantly with medicinal products that cause moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole). Therefore, it is recommended to reduce the dose of tofacitinib to 5 mg once daily when used in combination with these drugs.

Tolvaptan. Exposure to tolvaptan significantly increased (200 % AUC, 80 % Cmax) when tolvaptan, a CYP3A4 substrate, was administered concomitantly with fluconazole, a moderate CYP3A4 inhibitor, significantly increasing the risk of adverse reactions, including marked diuresis, dehydration, and acute renal failure. When co-administered, the dose of tolvaptan should be reduced according to the prescribing information, and the patient should be regularly checked for any adverse reactions associated with tolvaptan.

Vinca alkaloids. Fluconazole, likely through inhibition of CYP3A4, may increase plasma concentrations of vinca alkaloids (e.g., vincristine and vinblastine), leading to neurotoxic effects.

Vitamin A. A case has been reported in which a patient receiving concomitant all-trans retinoic acid (the acid form of vitamin A) and fluconazole developed central nervous system (CNS) adverse reactions in the form of pseudotumor cerebri; this effect resolved after discontinuation of fluconazole. These medicinal products may be used concomitantly, but the risk of CNS adverse reactions should be considered.

Voriconazole (inhibitor of CYP2C9, CYP2C19, and CYP3A4). Concomitant oral administration of voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 2.5 days) and fluconazole (400 mg on day 1, then 200 mg every 24 hours for 4 days) resulted in an average increase in Cmax and AUC of voriconazole by 57 % (90 % CI: 20 %, 107 %) and 79 % (90 % CI: 40 %, 128 %), respectively. It is unknown whether reducing the dose and/or frequency of voriconazole or fluconazole eliminates this effect. When voriconazole is administered after fluconazole, monitoring for adverse effects associated with voriconazole is recommended.

Zidovudine. Fluconazole increases Cmax and AUC of zidovudine by 84 % and 74 %, respectively, due to a reduction in zidovudine clearance of approximately 45 % after oral administration. The elimination half-life of zidovudine was also prolonged by approximately 128 % after administration of the fluconazole-zidovudine combination. Patients receiving this combination should be monitored for adverse reactions associated with zidovudine. Consideration may be given to reducing the dose of zidovudine.

Azithromycin. In an open-label, randomized, three-way crossover study involving 18 healthy volunteers, the effects of azithromycin and fluconazole on each other's pharmacokinetics were evaluated after single oral doses of 1200 mg and 800 mg, respectively. No significant pharmacokinetic interactions were observed.

Oral contraceptives. Two multiple-dose pharmacokinetic studies were conducted on concomitant use of fluconazole and combined oral contraceptives. No effect on hormone levels was observed with fluconazole 50 mg, whereas administration of fluconazole 200 mg daily resulted in a 40 % increase in AUC of ethinylestradiol and a 24 % increase in AUC of levonorgestrel. This indicates that repeated use of fluconazole at these doses is unlikely to affect the efficacy of combined oral contraceptives.

Special precautions for use.

Dermatophytosis. According to studies on fluconazole for the treatment of dermatophytosis in children, fluconazole is not superior to griseofulvin in efficacy, and the overall efficacy rate is less than 20%. Therefore, Fluconazole should not be used for the treatment of dermatophytosis.

Cryptococcosis. Evidence of fluconazole efficacy for the treatment of cryptococcosis at other sites (e.g., pulmonary cryptococcosis and cutaneous cryptococcosis) is insufficient; therefore, dosage recommendations for the treatment of such infections are not available.

Deep endemic mycoses. Evidence of fluconazole efficacy for the treatment of other forms of endemic mycoses, such as paracoccidioidomycosis, histoplasmosis, and cutaneous-lymphatic sporotrichosis, is insufficient; therefore, dosage recommendations for the treatment of such infections are not available.

Renal system. The drug should be used with caution in patients with impaired renal function (see section "Dosage and administration").

Adrenal insufficiency. Ketoconazole is known to cause adrenal insufficiency, and this may also apply to fluconazole, although it is rarely observed. Adrenal insufficiency associated with concomitant prednisone therapy is described in the section "Effect of fluconazole on other medicinal products".

Hepatobiliary system. The drug should be used with caution in patients with impaired liver function. Rare cases of severe hepatotoxicity, including fatal outcomes, have been associated with the use of fluconazole, primarily in patients with serious underlying diseases. When hepatotoxicity has been linked to fluconazole use, there was no clear dependence on the total daily dose, duration of therapy, sex, or age of the patient. Hepatotoxicity caused by fluconazole is usually reversible, and symptoms resolve after discontinuation of therapy.

Patients who develop abnormal liver function test results during fluconazole treatment should be closely monitored for the development of more severe liver damage.

Patients should be informed about symptoms that may indicate serious liver effects (marked asthenia, anorexia, persistent nausea, vomiting, and jaundice). In such cases, fluconazole therapy should be discontinued immediately and medical advice sought.

Cardiovascular system. Some azoles, including fluconazole, are associated with QT interval prolongation on electrocardiogram. Fluconazole prolongs the QT interval by inhibiting the rectifying potassium channel (Ikr). QT interval prolongation caused by other medicinal products (e.g., amiodarone) may be potentiated due to inhibition of the CYP3A4 enzyme of cytochrome P450. Very rare cases of QT interval prolongation and paroxysmal torsades de pointes ventricular tachycardia have been reported during fluconazole use. These reports involved patients with severe underlying diseases and multiple risk factors, such as structural heart disease, electrolyte disturbances, and concomitant use of other drugs affecting the QT interval. Patients with hypokalemia and progressive heart failure are at increased risk of life-threatening ventricular arrhythmias and torsades de pointes.

Fluconazole should be used with caution in patients at risk of developing arrhythmias. Concomitant use with medicinal products that prolong the QTc interval and are metabolized by the CYP3A4 enzyme of cytochrome P450 is contraindicated (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Halofantrine. Halofantrine is a substrate of the CYP3A4 enzyme and prolongs the QTc interval when used at recommended therapeutic doses. Concomitant use of halofantrine and fluconazole is not recommended.

Cutaneous reactions. Rare cases of exfoliative skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported during fluconazole use. Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) has also been reported. Patients with AIDS are more prone to develop severe skin reactions when using many medicinal products. If a patient with superficial fungal infection develops a rash that may be related to fluconazole use, further administration of the drug should be discontinued. If a patient with invasive/systemic fungal infection develops a skin rash, careful monitoring is required, and fluconazole should be discontinued in case of bullous eruptions or erythema multiforme.

Hypersensitivity. Rare cases of anaphylactic reactions have been reported.

Cytochrome P450. Fluconazole is a potent inhibitor of the CYP2C9 enzyme and a moderate inhibitor of the CYP3A4 enzyme. Fluconazole is also an inhibitor of the CYP2C19 enzyme. Patients receiving concomitant fluconazole and drugs with a narrow therapeutic window metabolized by CYP2C9, CYP2C19, and CYP3A4 should be closely monitored.

Terfenadine. Close monitoring of the patient is required when terfenadine and fluconazole are used concomitantly at doses less than 400 mg per day (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Candidiasis. Studies have demonstrated an increased incidence of infections caused by Candida species other than C. albicans. These are often intrinsically resistant (e.g., C. krusei and C. auris) or show reduced susceptibility to fluconazole (C. glabrata). Such infections may require alternative antifungal therapy after treatment failure. Therefore, physicians prescribing this agent are advised to consider the prevalence of resistance among different Candida species to fluconazole.

Use during pregnancy or breastfeeding.

Women of childbearing potential

Before initiating treatment, the patient should be informed about the potential risk to the fetus.

After a single dose, a washout period of approximately 1 week (corresponding to 5–6 half-lives) should be observed before conception (see section "Pharmacokinetics").

For prolonged treatment courses, women of childbearing potential should consider using contraception throughout the treatment period and for 1 week after the last dose.

Pregnancy

Observational studies indicate an increased risk of spontaneous abortion in women who received fluconazole during the first and/or second trimester, compared to women who did not take fluconazole or received topical azoles during the same period.

Data from several thousand women who received a cumulative dose of ≤150 mg fluconazole during the first trimester of pregnancy do not indicate an increased overall risk of fetal malformations. In one large observational cohort study, oral administration of fluconazole during the first trimester was associated with a small increased risk of musculoskeletal malformations, corresponding to approximately 1 additional case per 1000 women receiving a cumulative therapeutic dose ≤450 mg compared to women receiving topical azoles, and approximately 4 additional cases per 1000 women receiving cumulative doses exceeding 450 mg. The relative risk was 1.29 (95% CI 1.05–1.58) for an oral dose of 150 mg fluconazole and 1.98 (95% CI 1.23–3.17) for doses exceeding 450 mg.

Available epidemiological studies on the risk of cardiac malformations following fluconazole use during pregnancy have yielded conflicting results. However, a meta-analysis of 5 observational studies involving several thousand pregnant women who received fluconazole during the first trimester showed a 1.8- to 2-fold increased risk of congenital heart defects in infants compared to infants of mothers who did not use fluconazole and/or used topical azoles.

Congenital malformations have been reported in infants whose mothers received high doses (400 to 800 mg/day) of fluconazole during pregnancy for more than 3 months for the treatment of coccidioidomycosis. Malformations observed in these infants include brachycephaly, ear dysplasia, enlarged anterior fontanelle, femoral bowing, and radioulnar synostosis. A causal relationship between fluconazole use and congenital malformations has not been established.

Fluconazole at usual doses and short-term treatment courses should not be used during pregnancy except when absolutely necessary.

High-dose fluconazole and/or prolonged treatment courses should not be used during pregnancy except for the treatment of life-threatening infections.

Lactation

Fluconazole passes into breast milk and reaches concentrations similar to those in plasma. Breastfeeding may continue after a single standard dose of fluconazole (150 mg).

The benefit of breastfeeding for the infant's development and health, the mother's clinical need for fluconazole, and any potential adverse effects of fluconazole or the mother's underlying condition on the breastfed infant should be carefully evaluated.

Breastfeeding is not recommended with repeated or high-dose fluconazole use.

Fertility

Fluconazole did not affect fertility in male and female rats.

Ability to influence the ability to drive and use machines.

Studies on the effect of Fluconazole on the ability to drive or operate machinery have not been conducted.

Patients should be informed about the possibility of developing dizziness or seizures during Fluconazole use. If such symptoms occur, driving or operating machinery is not recommended.

Administration and dosage.

The daily dose of fluconazole depends on the type and severity of the fungal infection. For most cases of vaginal candidiasis, a single dose of the drug is sufficient.

If repeated administration is required, treatment of infections should be continued until clinical and laboratory signs of active fungal infection have disappeared. Inadequate duration of treatment may lead to recurrence of the active infectious process.

Fluconazole is administered, depending on the dosage form, orally or intravenously by infusion. The route of administration depends on the patient's clinical condition. There is no need to adjust the daily dose when switching from oral to intravenous administration or vice versa.

Tablets should be swallowed whole. The drug can be taken regardless of food intake.

Adults.

Cryptococcosis.

• Treatment of cryptococcal meningitis: loading dose is 400 mg on the first day. Maintenance dose – 200–400 mg/day. The duration of treatment is usually at least 6–8 weeks. For life-threatening infections, the daily dose may be increased up to 800 mg.
• Maintenance therapy to prevent recurrence of cryptococcal meningitis in patients at high risk: the recommended dose is 200 mg/day for an indefinite period.

Coccidioidomycosis.

-Recommended dose is 200–400 mg/day. The duration of treatment is 11–24 months or longer, depending on the patient's condition. For some forms of infection, especially meningitis, a dose of 800 mg/day may be appropriate.

Invasive candidiasis.

• Loading dose is 800 mg on the first day. Maintenance dose – 400 mg/day. The recommended duration of treatment for candidemia is usually 2 weeks after the first negative blood culture results and resolution of signs and symptoms of candidemia.

Candidiasis of mucous membranes.

• Oropharyngeal candidiasis: loading dose is 200–400 mg on the first day, maintenance dose – 100–200 mg/day. The duration of treatment is 7–21 days (until remission is achieved), but may be extended in patients with severe immunodeficiency.
• Esophageal candidiasis: loading dose is 200–400 mg on the first day, maintenance dose – 100–200 mg/day. The duration of treatment is 14–30 days (until remission is achieved), but may be extended in patients with severe immunodeficiency.
• Candiduria: recommended dose is 200–400 mg/day for 7–21 days. The duration of treatment may be extended in patients with severe immunodeficiency.
• Chronic atrophic candidiasis: recommended dose is 50 mg/day for 14 days.
• Chronic mucocutaneous candidiasis: recommended dose is 50–100 mg/day. The duration of treatment is up to 28 days, but may be extended depending on the severity and type of infection or immunosuppression.

Prevention of recurrent mucosal candidiasis in HIV-infected patients at high risk.

• Oropharyngeal candidiasis, esophageal candidiasis: recommended dose is 100–200 mg/day or 200 mg three times a week. The duration of treatment is indefinite in immunocompromised patients.

Prophylaxis of candidiasis in patients with prolonged neutropenia.

-Recommended dose is 200–400 mg. Treatment should be initiated several days before the expected onset of neutropenia and continued for 7 days after neutrophil count rises above 1000/mm³.

Genital candidiasis.

• Acute vaginal candidiasis, candidal balanitis: recommended dose is a single 150 mg dose.
• Treatment and prevention of recurrent vaginal candidiasis (4 or more episodes per year): recommended dose is 150 mg every 3 days. A total of 3 doses should be administered (on day 1, day 4, and day 7). After that, a maintenance dose of 150 mg once weekly should be given for 6 months.

Dermatomycoses.

• Tinea pedis, tinea corporis, tinea cruris, cutaneous candidiasis: recommended dose is 150 mg once weekly or 50 mg once daily. The duration of treatment is 2–4 weeks. Treatment of tinea pedis may last up to 6 weeks.
• Pityriasis versicolor: recommended dose is 300–400 mg once weekly for 1–3 weeks or 50 mg daily for 2–4 weeks.
• Dermatophyte onychomycosis: recommended dose is 150 mg once weekly. Treatment should be continued until the infected nail is replaced by a healthy one. Healthy nail regrowth usually takes 3–6 months for fingernails and 6–12 months for toenails. However, nail growth rate may vary among patients and depend on age. After successful treatment of long-standing chronic infections, nail appearance may sometimes remain altered.

Elderly patients.

Dosage should be adjusted according to renal function (see below).

Patients with renal impairment.

Fluconazole is primarily excreted unchanged in urine. Dose adjustment is not required after a single dose. In patients (including children) with impaired renal function requiring multiple doses, an initial dose of 50–400 mg should be administered on the first day of treatment, depending on the indication. Subsequently, the daily dose (depending on the indication) should be adjusted according to Table 1:

Table 1

Creatinine clearance (mL/min)	Percentage of recommended dose
> 50	100 %
≤ 50 (without dialysis)	50 %
Regular dialysis	100 % after each dialysis

Patients undergoing regular dialysis should receive 100 % of the recommended dose after each dialysis session. On days when dialysis is not performed, the patient should receive a dose adjusted according to creatinine clearance.

Patients with hepatic impairment.

Fluconazole should be administered with caution to patients with hepatic dysfunction, as there is insufficient information regarding the use of fluconazole in this patient population.

Children.

The maximum daily dose of 400 mg should not be exceeded.

As with similar infections in adults, the duration of treatment depends on clinical and mycological response. FluZAK is administered once daily.

Dosage recommendations for children with renal impairment are provided below. The pharmacokinetics of fluconazole have not been studied in children with renal insufficiency.

Children aged 12 years and older.

Depending on body weight and pubertal development, the physician should assess whether the adult or pediatric dosage is optimal for the patient. Clinical data indicate that fluconazole clearance is higher in children than in adults. Administration of doses of 100, 200, and 400 mg to adults and doses of 3, 6, and 12 mg/kg to children results in comparable systemic exposure.

The efficacy and safety of the drug for the treatment of genital candidiasis in children have not been established, despite extensive data on the use of fluconazole in pediatric patients. If there is a compelling need to administer the drug to adolescents (aged 12 to 17 years), standard adult doses should be used.

Children aged 5 to 11 years.

Mucosal candidiasis: initial dose is 6 mg/kg/day, maintenance dose is 3 mg/kg/day. The initial dose may be administered on the first day to achieve steady-state concentration more rapidly.

Invasive candidiasis, cryptococcal meningitis: dosage is 6–12 mg/kg/day depending on the severity of the disease.

Maintenance therapy for prevention of relapse of cryptococcal meningitis in children at high risk of developing the disease: dosage is 6 mg/kg/day depending on the severity of the disease.

Prophylaxis of candidiasis in immunocompromised patients: dosage is 3–12 mg/kg/day depending on the severity and duration of induced neutropenia (see adult dosing).

Children.

The tablet formulation of the medicinal product may be used in this patient population only when children are able to swallow tablets safely, which is usually possible from the age of 5 years (see section "Dosage and administration").

Overdose.

Cases of fluconazole overdose have been reported; hallucinations and paranoid behavior have been reported concurrently.

In case of overdose, symptomatic and supportive therapy should be administered, and gastric lavage should be performed if necessary.

Fluconazole is predominantly excreted in the urine; forced diuresis may accelerate drug elimination. A 3-hour hemodialysis session reduces plasma fluconazole levels by approximately 50 %.

Adverse Reactions

Summary of safety profile

Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) has been reported in association with fluconazole treatment (see section "Special precautions"). The most frequently reported (>1/10) adverse reactions include: headache, abdominal pain, diarrhea, nausea, vomiting, rash, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased alkaline phosphatase levels.

The following classification is used to assess the frequency of adverse reactions: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000), frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders

Uncommon: anemia
Rare: agranulocytosis, leukopenia, neutropenia, thrombocytopenia

Immune system disorders

Rare: anaphylaxis

Metabolism and nutrition disorders

Uncommon: decreased appetite
Rare: hypertriglyceridemia, hypercholesterolemia, hypokalemia

Psychiatric disorders

Uncommon: insomnia, somnolence

Nervous system disorders

Common: headache
Uncommon: convulsions, dizziness, paresthesia, taste disturbance
Rare: tremor

Ear and labyrinth disorders

Uncommon: vertigo

Cardiac disorders

Rare: paroxysmal torsades de pointes ventricular tachycardia, QT interval prolongation (see section "Special precautions")

Gastrointestinal disorders

Common: abdominal pain, diarrhea, nausea, vomiting
Uncommon: constipation, dyspepsia, flatulence, dry mouth

Hepatobiliary disorders

Common: increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased alkaline phosphatase (see section "Special precautions")
Uncommon: cholestasis, jaundice, increased bilirubin levels (see section "Special precautions")
Rare: hepatic failure, hepatocellular necrosis, hepatitis, hepatocellular injury (see section "Special precautions")

Skin and subcutaneous tissue disorders

Common: rash (see section "Special precautions")
Uncommon: pruritus, drug eruption (including fixed drug eruption), urticaria, increased sweating (see section "Special precautions")
Rare: toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, exfoliative dermatitis, angioneurotic edema, facial swelling, alopecia (see section "Special precautions")
Frequency not known: drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)

Musculoskeletal and connective tissue disorders

Uncommon: myalgia

General disorders and administration site conditions

Uncommon: increased fatigue, malaise, asthenia, fever

The presence of the dye Ponceau 4R (E 124) may cause allergic reactions, and methylparaben (E 218) and propylparaben (E 216) may cause allergic reactions (possibly delayed-type).

Children

The frequency and nature of adverse reactions and laboratory abnormalities observed in clinical trials involving children are comparable to those observed in adults.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions in accordance with local regulatory requirements.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C. Keep out of reach of children.

Packaging.

50 mg tablets: 4 or 10 tablets in a blister; 1 blister per cardboard box.
150 mg tablets: 1 tablet in a blister; 3 blisters per cardboard box.
200 mg tablets: 2 tablets in a blister; 1 or 2 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

FDS Limited.

Manufacturer's address and place of business.

L-56/57, Phase II-D, Verna Industrial Estate, Verna, Salcette, Goa – 403 722, India.