FLUCAND HIKMA PHARMACEUTICALS

Transcription

1 09-15 FLUCAND HIKMA PHARMACEUTICALS (Fluconazole) Description Flucand is a crystalline white - whitish powder, which is slightly soluble in water and in a saline solution. Its molecular weight is Flucand is available in the form of gelatine capsules containing respectively 50 mg and 150 mg of fluconazole, and vials containing 100 ml, 50 ml and 25 ml for intravenous infusion, at the concentration of 2 mg/ml in a saline solution. Action Flucand, an antimycotic compound belonging to a new class of triazole agents, is a powerful specific inhibitor of the synthesis of fungal steroids. Flucand, administered orally or via intravenous infusion. Its activity has been proved against opportunistic mycotic infections such as those caused by Candida spp., (including systemic candidiasis and those in animals with compromised immune functions), by Cryptococcus neoformans (including intracranial infections), by Microsporum spp. and by Tricophyton spp. Flucand showed also activity in animal models of endemic mycoses, including those caused by Blastomyces dermafitidis, by Coccidioides immitis (among which also the intracranial infections) and by Istoplasma capsulatum in normal animals and in animals with compromised immune function. The pharmacokinetic properties of Flucand are similar both on intravenous and on oral administration. When Flucand is administered orally, it is well absorbed, showing a systemic bioavailability higher than 90% with respect to the levels reached after intravenous administration. Oral administration is not modified by the concomitant intake of food. Peaks in the plasma concentration under fasted conditions are reached after a period between 30 and 90 minutes. Plasma concentrations are proportional to the dose. 90% of the steady state level is reached after 4 or 5 days of repeated single administration during the day. The administration of a load dose (on the first day) twice as much as the normal daily dose allows the plasma levels to reach about the value of 90% the steady state levels on the second day. The volume of apparent distribution approaches the value of the amount of total body water. The bond with plasma proteins is low (12%). Flucand shows a good penetration throughout all organic fluids investigated. Flucand levels in saliva and in excreta are similar to the plasma levels- in patients affected by mycotic meningitis the Flucand levels in the cerebrospinal fluid are about 80% of corresponding levels in the plasma. The principal way of excretion is the renal way: about 80% of the dose administered is found unchanged in urine. Flucand clearance is proportional to that of creatinine. There is no evidence of metabolites in circulation. The prolonged half-life time of Flucand in the plasma is the rationale of the therapy with a single dose in the treatment of vaginal candidiasis and with a single daily administration in the treatment of all other fungal infections. Flucand shows endowed with high specificity toward the fungal enzymes which depend on cytochrome P-450, It has been shown that Flucand 50 mg/day administered during 28 days does not alter the plasma concentration of testosterone in man and the concentration of steroid compounds in woman of fecund age mg per day of Flucand have not resulted in any clinically significant effect on the levels of the endogenous steroids or on the response to the stimulation by the action of ACTH in healthy volunteers. Studies on the interaction with antipyrine show that Flucand 50 mg administered as a single dose or as multiple doses not alter its metabolism. Indications Flucand is indicated for the treatment of: Acute or recurrent vaginal candidiasis Treatment of tinea cruris. tinea corporis and tinea versicolor and for the treatment of skin candidiasis. Treatment of oropharyngeal candidiasis (thrush), including those cases in which such disease affects patients having compromised immune function due to malignancies or to acquired immunodeficiency syndrome (AIDS), as well as of atrophic oral candidiasis. HIKMA-FLUCAND - p.1/5

2 HIKMA-FLUCAND - p.2/5 Flucand is indicated for the therapy of invasive mycotic infections caused by Candida albicans and Cryptococcus neoformans, including those occurring in patients affected by compromised immune function due to malignancies or to the acquired immunodeficiency syndrome, or mycoses secondary to antineoplastic chemotherapy. Flucand can be administered for the treatment of cryptococcal meningitis and for the maintenance therapy for prevention of relapse, as well as for the treatment of skin and pulmonary cryotococcosis. The treatment of infections caused by Candida includes the following indications: oesophagitis, peritonitis, pulmonary infections, gastrointestinal and genitourinary infections, as well as disseminated candidemia and candidiasis. Flucand is also indicated for prevention of fungal infections which are sensitive to Flucand in patients affected by malignancies who are undergoing cytotoxic chemotherapies. Treatment of skin and mucous membrane infections, the use of the product is to be limited to those cases only which are particularly severe or widely extended and which had not responded to the traditional topical therapy. Dosage and administration The daily dose of Flucand should be based on the nature and seriousness of the mycotic infection. Most patients or vaginal candidiasis respond to a single dose. Therapy for infections that need multiple doses should be continued until the clinical parameters and laboratory tests do not point out that the active mycotic infection is resolved. An unsuitable treatment period may result in the relapse of the active infection. AIDS affected patients and those suffering from cryptococcal meningitis or recurrent oropharyngeal candidiasis usually require the maintenance therapy to prevent the relapse from occurring. For vaginal candidiasis 150 mg as a single dose and for just one day of therapy. For dermatomycoses the usual dose is of mg per day as a single administration during days of therapy. Tinea pedis may require a treatment up to 42 days. For oropharyngeal candidiasis, including patients having compromised immune function, the usual dose is of 50 mg once a day for 7-14 days. If necessary, the treatment can be prolonged during a longer time, especially in patients affected by serious immunodepression. For oral atrophic candidiasis in patients having dentures the normal dose is of 50 mg once a day for 14 days. In some cases a concomitant antiseptic therapy of the oral cavity and of denture must be provided. For serious diseases which could be life threatening, including cryptococcal meningitis and disseminated candidiasis the usual dose is of 400 mg a single administration on the first day. In the following days the advisable doses are 200 mg/day as a single daily administration. According to the clinical response of the patient, also the successive doses can be kept at 400 mg/ day. Generally the duration of the treatment of cryptococcal meningitis is of 6-8 weeks. The duration of the treatment of disseminated candidiasis depends on the clinical response. For preventing the relapses of cryptococcal meningitis in AIDS affected patients from occurring, Flucand can be administered indefinitely at the dose of 200 mg/day, after the patient has come to the end of the first cycle of the therapy and has become negative to the cultural test. For other localized infections caused by Candida, such as esophagitis, infections of the urinary tract etc., the usual effective dose is of 50 mg/day for days. This dose can be increased up to 100 mg/day in cases particularly difficult to treat. For the prophylaxis of fungal infections in patients affected by malignancies and who are undergoing cytotoxic chemotherapy or radiotherapy, the dose should be of 50 mg once a day. The elderly: Where there is no evidence of renal impairment, the dosage normally recommended is to be followed. For patients with renal impairment (creatinine clearance less than 40 ml/min), the dosage is to be adjusted as the following: Patients with renal impairment: Flucand is mainly excreted unchanged in the urine. No adjustments

3 HIKMA-FLUCAND - p.3/5 are necessary when a single dose therapy is realized (vaginal candidiasis). On the contrary, when a repeated dose therapy is realized in patients affected by renal impairment, the normal dose can be administered on the 1st and 2nd day of therapy and next the interval between a dose and the other one is to be modified, on the basis of creatinine clearance, as follows: Creatinine clearance (ml/min) Interval between doses (Hours) >40 24 (normal posology) or half the daily dose or one third the daily dose Patients receiving regular dialysis 1 administration after each dialysis session Administration Flucand can be administered both via oral and intravenous administration through infusion with a rate not faster than 10 ml/min whereas the choice of the administration route will depend on the clinical conditions of the patient. On switching from the intravenous to the oral route or vice versa there is no need to change the daily dosage, Flucand is formulated as a 0.9% sodium chloride solution, each 200 mg (100 ml vial) contain 15 mmol of Na + and CI -. As Flucand is available as a diluted saline solution, the percentage of the liquid administered is to be well taken into consideration for patients who require restrictions as to sodium or to liquids. Flucand for intravenous infusion is compatible with the administration of the following liquids: a) Dextrose 20% b) Ringer s solution c) Harfmann s solution d) Potassium chloride in dextrose e) Sodium bicarbonate 4.2% f) Aminofusin q) Peritoneal dialysis solution Flucand can be administered employing a pre-existing access intravenous way with one of the solutions listed above. Though no specific incompatibilities have been observed, it is not recommended to mix in other drugs before administration through infusion. Contraindications Flucand is not to be used in patients affected by already known hypersensitivity to the drug or to triazole compounds, by acute or chronic hepatopathies, or by hepatic insufficiency. Warnings Before starting the treatment and during the therapy, hepatic function (transaminases etc) must be carefully and frequently checked. Very rarely, in the case of patients who died because of their severe basic pathologies and who had been treated also with multiple doses of Flucand, the post-mortem reports showed alterations, among which there was hepatic necrosis. Such patients had also been taking numerous other drugs at the same time, some of such drugs being known as hepatotoxic, and/or they were patients shown basic disease could have resulted in hepatic alterations. Though no casual relationship was set forth between such events and Flucand, in the case of patients in which a remarkable increase of hepatic enzymes is observed, the opportunity to continue the therapy with Flucand should be estimated. As studies carried out on animals the Drug gives rise to moderate and short cardiovascular alterations (increase in arterial pressure and decrease in cardiac rate) which are correlated to the dose, particular caution is advisable when administering the drug via intravenous infusion. Precautions Use during pregnancy: Flucand is contraindicated during pregnancy. Accordingly, all women in their fecund age are to be shown negative to the pregnancy test before starting the treatment with the Drug and are to take then suitable contraceptive measures. Use during lactation: Flucand is contraindicated during lactation. Use of children: As with similar infections in adults the duration of treatment is based on the clinical and mycological response. The maximum adult daily dosage should not be exceeded in children, Fluconazole is administered as a single dose each day. The recommended dosage of Fluconazole for mucosal candidiasis is 3 mg/kg daily. A loading dose

4 HIKMA-FLUCAND - p.4/5 of 6 mg/kg may be used on the first day to achieve steady state levels more rapidly. For the treatment of systemic candidiasis and cryptococcal infections, the recommended dosage is 6 to 12 mg/kg daily. Depending on the severity of the disease. For the prevention of fungal infections in immunocompromised patients considered at risk as a consequence of neutropenia following cytotoxic chemotherapy of the induced neutropenia (See dosage and administration). (For children with impaired renal function, see use in renal impairment). Use in children 4 weeks of age and younger: Neonates excrete Fluconazole slowly. In the first two weeks of life, the same mg/kg dosing as in older children should be used but administered every 72 hours. During weeks 3 and 4 of life, the same dose should be given every 48 hours. Use of machines/ driving of cars: Experiments carried out with Flucand showed that it does not alter the ability of the patient to drive cars or to use machines. Drug Interactions Flucand shows interaction with warfarin (as it results in the prolongation of the prothrombin time), with tolbutamide and sulphonylureas (whose serum half-lives are prolonged), with hydrochlorothiazide (with a 40% increase in the plasma concentrations of Flucand), with phenytoine (whose hematic levels are increased), with rifampicin (with a 25% decrease of AUC and 20% decrease of Flucand half-life), with theophylline (whose plasma clearance becomes decreased by 18%. When the concomitant administration of one of the drugs mentioned above and of Flucand is necessary, it is sufficient to monitor the hematic levels of the respective drugs and to adapt the doses to the therapeutic requirements. In particular, in the case of simultaneous administration of Flucand and tolbutamide, the dosage of the hypoglycemic drug and the levels of blood sugar are to be monitored. In patients who have undergone kidney transplantation, in the case of concomitant administration of Flucand and cyclosporin A, monitoring of the plasma concentrations of cyclosporin is advised. No clinically significant interactions have been observed during concomitant administration of Flucand and cimetidine or anti-acid agents. No negative effects were observed in the case of simultaneous in take of Flucand and oral contraceptives. Side effects Flucand is generally well tolerated. The commonest side effects are those correlated to the gastrointestinal tract and they include: nausea, abdominal pain, diarrhoea, flatulence and vomiting. After the gastrointestinal symptoms, the other most frequently side effect observed is the skin rash. Headache, asthenia and dizziness are also possible. Occasional abnormalities of liver enzymes have been observed. In some patients in particular those affected by severe pathologies such as AIDS and cancer, alterations of the hepatic, renal and blood functions have been observed during treatment with Flucand and comparison drugs, but the clinical meaning and the correlation with the treatment are uncertain. Patients affected by AIDS are more prone to the development of serious skin reactions to many drugs. A small number or patients with AIDS showed this type of reactions, when they took Flucand simultaneously with other agents whose association with exfoliative cutaneous reactions is known. In the case of cutaneous rash that can be attributed to Flucand, therapy with such agent must be discontinued. In patients affected by systemic fungal infections which result in rash, a careful monitoring should be earned out and the Flucand therapy should be discontinued if bullous lesions or erythema multiform develop, in rare cases anaphylactic phenomena might occur like in the case of other azoles. Overdosage In the case of accidental overdosage, a symptomatic treatment might be necessary (with a suitable support therapy and Possibly a gastric lavage). Flucand is excreted mostly in the urine; a forced diuresis is likely to increase the excretion percentage. A three-hour haemodialysis session causes the plasma levels to decrease by about 50%. Presentations Capsules Flucand 50: Fluconazole 50 mg/capsule Flucand 150: Fluconazole 150 mg/capsule Excipients: Lactose, Starch, Colloidal Silicon Dioxide, Sodium Lauryl Sulfate, Magnesium stearate.

5 Infusion Flucand 200: Fluconazole 200 mg/100 ml Flucand 100: Fluconazole 100 mg/50 ml Flucand 50: Fluconazole 50 mg/25 ml Excipients: Sodium Chloride, Water for Injection HIKMA-FLUCAND - p.5/5