Kaspofungin
When ATH:
J02AX04
Characteristic.
Semi-synthetic lipopeptide compound (exinokandin), synthesized from the product of fermentation Gravel lozoyensis. Kaspofungina acetate is a hygroscopic white or almost white powder; freely soluble in water, methanol, slightly soluble in ethanol; pH of aqueous solutions of caspofungin acetate is about 6,6; molecular weight 1213,41.
Pharmacological action.
Antifungal.
Application.
Empirical therapy in patients with febrile neutropenia in suspected fungal infection, invasive candidiasis (incl. kandidemija) in patients with neutropenia or without, invasive aspergillosis (patients, refractory to other therapy or it neperenosyaschih), oesophageal candidiasis, oropharyngeal candidiasis.
Contraindications.
Hypersensitivity.
Restrictions apply.
The combination with cyclosporine, moderate hepatic insufficiency (from 7 to 9 points on the Child-Pugh), Youngest 18 years (safety and effectiveness in children have not identified).
Pregnancy and breast-feeding.
Animals (rats, Rabbits) caspofungin crosses the placental barrier and is determined by the plasma fetuses of pregnant animals. It is shown to be embryotoxic in rats and rabbits (incl. incomplete ossification of skull and torso, increasing the frequency of occurrence of cervical ribs in rats). In rabbits, there was increase in the frequency of incomplete ossification of talus / calcaneus. Caspofungin also caused an increase of resorption in rats and rabbits, and rats loss periimplantatsionnye. These effects were observed at doses, causing exposure, similar to that of patients, dosed 70 mg.
Clinical experience in the use of the drug in pregnant women is not, adequate and well-controlled studies have been conducted. Caspofungin should not be administered to women during pregnancy, except in cases, when use of the drug is essential.
Category actions result in FDA - C. (The study of reproduction in animals has revealed adverse effects on the fetus, and adequate and well-controlled studies in pregnant women have not held, However, the potential benefits, associated with drugs in pregnant, may justify its use, in spite of the possible risk.)
If necessary, the appointment during lactation should stop breastfeeding (caspofungin penetrates into the milk of lactating rats, no data on the penetration of a woman's breast milk).
Side effects.
Reported histamine-mediated symptoms, such as rashes (≥2%), swelling of the face, itch, feeling the heat, bronchospasm; known cases of anaphylaxis after administration of caspofungin.
In clinical trials during empirical therapy in patients with febrile neutropenia (randomized, double-blind study, n=564), receiving caspofungin acetate 50 mg / day after the loading dose 70 mg (in 73 patients, the dose was increased to 70 mg / day), side effects were observed in 39% patients. In 5% patients discontinued therapy due to adverse effects.
From the digestive tract: ≥2% nausea, vomiting, diarrhea, elevated liver enzymes (IS, GOLD, Alkaline phosphatase), increasing the concentration of direct and total bilirubin; abdominal pain (1,4%).
With the genitourinary system: increase in serum creatinine (1,2%).
Cardio-vascular system and blood (hematopoiesis, hemostasis): redness of the face (1,8%), tachycardia (1,4%), increased blood pressure (1,1%).
Allergic reactions: ≥2% rash.
Other: ≥2% chills, hyperthermia, increased sweating, headache, breathlessness, kaliopenia, gipomagniemiya; backache (0,7%), tachypnea (0,4%).
In a randomized double-blind phase III trial in patients with invasive candidiasis (n=114), receiving caspofungin acetate 50 mg / day after the loading dose 70 mg, side effects were observed in 28,9% cases.
From the digestive tract: ≥2% diarrhea, vomiting, elevated liver enzymes (GOLD, Alkaline phosphatase), increasing the concentration of direct and total bilirubin; nausea (1,8%), jaundice (0,9%), increase in AST (1,9%), increase in blood urea (1,9%).
With the genitourinary system: ≥2% - increased serum creatinine level; renal failure (0,9%).
Cardio-vascular system and blood (hematopoiesis, hemostasis): ≥2% - phlebitis / thrombophlebitis; tachycardia (1,8%), increased blood pressure (1,8%), gipotenziya (0,9%), anemia (decrease in hemoglobin - 0,9% and hematocrit - 0,9%).
Allergic reactions: rash (0,9%).
Other: ≥2% chills, hyperthermia; tremor (1,8%), decrease / increase serum potassium levels (9,9/0,9%), Sweating (0,9%).
The safety and efficacy of caspofungin acetate in patients with esophageal and / or oropharyngeal candidiasis was evaluated in several studies.
In controlled trials in patients with esophageal and / or oropharyngeal candidiasis, receiving caspofungin acetate 50 mg / day (Phase III study, n=83) or 50/70 mg / day (phase II study, n=80/65), The following side effects were noted.
From the digestive tract: ≥2% - abdominal pain, nausea, diarrhea, vomiting, elevated liver enzymes (GOLD, IS, Alkaline phosphatase), hypoalbuminemia.
Cardio-vascular system and blood (hematopoiesis, hemostasis): ≥2% - anemia (decrease in hemoglobin and hematocrit).
Allergic reactions: rash and erythema (1,2–1,5%).
Other: ≥2% chills, hyperthermia, venous complications postinfuzionnye, flebit / tromboflebit, headache, hypoalbuminemia, kaliopenia; It was also noted (at different rates in different studies) changes in laboratory parameters, incl. increasing the concentration of direct bilirubin, hypocalcemia, increase in blood urea, increase in serum creatinine, hypoproteinemia, eozinofilija, leukopenia, neutropenia, thrombocytopenia, increase in partial thromboplastin and PV, leucocyturia, proteinuria.
In the open-label study in patients with invasive aspergillosis (n=69), receiving caspofungin acetate (1 day 70 mg / day, then 50 mg / day), The following side effects observed: 2,9% - hyperthermia, venous complications postinfuzionnye, nausea, vomiting, redness of the face, increase in AP, kaliopenia; eozinofilija (3,2%), increase of urinary protein (4,2%), mikrogematuriâ (2,2%); rarely observed pulmonary edema, acute respiratory distress syndrome, and radiographic infiltrates.
In post-marketing period were marked by the following adverse events:
From the digestive tract: Rare cases of clinically significant hepatic dysfunction.
Cardio-vascular system: peripheral edema.
Other: hypercalcemia.
Cooperation.
Caspofungin acetate is not an inhibitor of an enzyme of the cytochrome P450 (CYP), and is not an inducer of metabolism of other drugs, опосредованного CYP3A4. Caspofungin is not a substrate for P-glycoprotein enzymes and represents a poor substrate for cytochrome P450 enzymes.
Pharmacokinetics caspofungin not affect itraconazole, Amphotericin B, Mycophenolate mofetil, Nelfinavir, tacrolimus. Caspofungin has no effect on the pharmacokinetic parameters of itraconazole, Amphotericin B, rifampin, or active metabolite of mycophenolate mofetil.
Caspofungin reduces the rate of 12-hour concentrations (C12 no) in the blood of tacrolimus on 26%. Patients, receiving both drugs, It recommended monitoring the concentration of tacrolimus in the blood and, if necessary, correction of its batching.
With simultaneous use of caspofungin and cyclosporin possible transient (disappear after drug withdrawal) increasing the concentration of AST and ALT (no more, than 3 fold compared with the upper limit of normal), as well as increase in the AUC of approximately caspofungin 35% without changing the concentration of cyclosporin. The joint appointment of these drugs (for up to 290 d) There were no serious adverse events from the liver. Co-administration of caspofungin and cyclosporin can be justified, if the potential benefits of such a purpose greater than the potential risk.
Rifampicin can either accelerate, and slow down the distribution of caspofungin. The joint appointment of rifampicin and caspofungin for 14 days observed transitory increase in the plasma concentration of caspofungin in the 1st day (increase in AUC of about 60%). In the same time, this inhibiting effect was not observed, when the appointment took place against caspofungin held for 14 days of monotherapy with rifampicin, at the same time against the background of sustainable inductor effect of rifampicin noted a slight decrease in AUC and concentration of caspofungin by the end of the infusion, and the threshold concentration is approximately 30%.
Concomitant use of caspofungin with the inducers of drug clearance (efavirenz, Nevirapine, phenytoin, Dexamethasone, Carbamazepine) may result in a clinically significant decrease in the concentration of caspofungin. Available evidence suggests that, that induced by these drugs decrease the concentration of caspofungin happening soon due to the acceleration of elimination, rather than metabolism. Therefore, concomitant use of caspofungin with efavirenz, nelfinavirom, nevirapine, rifampicin, deksametazonom, with phenytoin or carbamazepine, increasing the daily daily dose of caspofungin to 70 mg.
Overdose.
Data on drug overdose no. The highest dose tested, a single single dose, was well tolerated in clinical trials 210 mg (6 Healthy volunteers). It was also shown good tolerability of the drug in his introduction to the daily dose 100 mg for 21 day (15 Healthy volunteers). In overdose caspofungin dialysis is not carried out.
Dosing and Administration.
B /, by slow I / Infusion (≥1) 1 once a day. If empirical therapy, adult: in 1-St day introduces a single loading dose 70 mg, on the 2nd and subsequent days - until 50 mg per day. The duration depends on the clinical and microbiological efficacy. Empirical therapy should be carried out to the full resolution of neutropenia. Upon confirmation of a fungal infection, patients should receive the drug at least 14 Nights, drug therapy should be continued for at least 7 the day after the disappearance of clinical manifestations as a fungal infection, and neutropenia. It is possible to increase the daily dose up to 70 mg, if the dose 50 mg well tolerated, but it does not give the desired clinical effect.
