Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/2754
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Eraxis (Kit)
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Candidemia and other Candida infections (intra-abdominal abscess, and peritonitis): The recommended dose is a single 200 mg loading dose of ERAXIS on Day 1, followed by 100 mg daily dose thereafter. Duration of treatment should be based on the patient's clinical response. In general, antifungal therapy should continue for at least 14 days after the last positive culture.<br/>Esophageal candidiasis: The recommended dose is a single 100 mg loading dose of ERAXIS on Day 1, followed by 50 mg daily dose thereafter. Patients should be treated for a minimum of 14 days and for at least 7 days following resolution of symptoms. Duration of treatment should be based on the patient's clinical response. Because of the risk of relapse of esophageal candidiasis in patients with HIV infections, suppressive antifungal therapy may be considered after a course of treatment. No dosing adjustments are required for patients with any degree of renal or hepatic insufficiency, patients using concomitant medications or those in other special populations .<br/>Preparation of ERAXIS for Administration: ERAXIS for Injection must be reconstituted with the companion diluent (20% (w/w) Dehydrated Alcohol in Water for Injection) and subsequently diluted with only 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP (normal saline). The compatibility of reconstituted ERAXIS with intravenous substances, additives, or medications other than 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP (normal saline) has not been established.<br/>Reconstitution 50mg/vial: Aseptically reconstitute each 50 mg vial with 15 mL of the companion diluent (20% (w/w) Dehydrated Alcohol in Water for Injection) to provide a concentration of 3.33 mg/mL. The reconstituted solution should be stored at 25��C (77��F); excursions permitted to 15���30��C (59���86��F) (see USP Controlled Room Temperature). Do not refrigerate or freeze. The reconstituted solution must be further diluted and administered within 24 hours.<br/>Reconstitution 100mg/vial: Aseptically reconstitute each 100 mg vial with 30 mL of the companion diluent (20% (w/w) Dehydrated Alcohol in Water for Injection) to provide a concentration of 3.33 mg/mL. The reconstituted solution should be stored at 25��C (77��F); excursions permitted to 15���30��C (59���86��F) (see USP Controlled Room Temperature). Do not refrigerate or freeze. The reconstituted solution must be further diluted and administered within 24 hours.<br/>Dilution and Infusion: Aseptically transfer the contents of the reconstituted vial(s) into the appropriately sized IV bag (or bottle) containing either 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP (normal saline). Table 10 provides the number of Unit Packs , volumes and infusion solution concentration for each dose. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulate matter or discoloration are identified, discard the solution. The rate of infusion should not exceed 1.1 mg/minute. The infusion solution should be stored at 25��C (77��F); excursions permitted to 15���30��C (59���86��F) (see USP Controlled Room Temperature). Do not refrigerate or freeze.
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ERAXIS for Injection is a sterile, lyophilized product for intravenous (IV) infusion that contains anidulafungin. ERAXIS (anidulafungin) is a semi-synthetic lipopeptide synthesized from a fermentation product of Aspergillus nidulans. Anidulafungin is an echinocandin, a class of antifungal drugs that inhibits the synthesis of 1,3-��-D-glucan, an essential component of fungal cell walls. ERAXIS (anidulafungin) is 1-[(4R,5R)-4,5-Dihydroxy-N-[[4"-(pentyloxy)[1,1':4',1"-terphenyl]-4-yl]carbonyl]-L-ornithine]echinocandin B. Anidulafungin is a white to off-white powder that is practically insoluble in water and slightly soluble in ethanol. In addition to the active ingredient, anidulafungin, ERAXIS for Injection contains the following inactive ingredients: 50mg/vial - fructose (50 mg), mannitol (250 mg), polysorbate 80 (125 mg), tartaric acid (5.6 mg), and sodium hydroxide and/or hydrochloric acid for pH adjustment. 100mg/vial - fructose (100 mg), mannitol(500 mg), polysorbate 80 (250 mg), tartaric acid (11.2 mg), and sodium hydroxide and/or hydrochloric acid for pH adjustment. The empirical formula of anidulafungin is CHNOand the formula weight is 1140.3. The structural formula is: Prior to administration, ERAXIS for Injection requires reconstitution with the companion diluent (20% (w/w) Dehydrated Alcohol in Water for Injection) and subsequent dilution with either 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP (normal saline). DO NOT dilute with other solutions or co-infuse with other medications or electrolytes .
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Pharmacokinetics: The pharmacokinetics of anidulafungin following IV administration have been characterized in healthy subjects, special populations and patients. Systemic exposures of anidulafungin are dose-proportional and have low intersubject variability (coefficient of variation<25%) as shown in Table 1. The steady state was achieved on the first day after a loading dose (twice the daily maintenance dose) and the estimated plasma accumulation factor at steady state is approximately 2. The clearance of anidulafungin is about 1 L/h and anidulafungin has a terminal elimination half-life of 40���50 hours.<br/>Distribution: The pharmacokinetics of anidulafungin following IV administration are characterized by a short distribution half-life (0.5���1 hour) and a volume of distribution of 30���50 L that is similar to total body fluid volume. Anidulafungin is extensively bound (>99%) to human plasma proteins.<br/>Metabolism: Hepatic metabolism of anidulafungin has not been observed. Anidulafungin is not a clinically relevant substrate, inducer, or inhibitor of cytochrome P450 (CYP450) isoenzymes. It is unlikely that anidulafungin will have clinically relevant effects on the metabolism of drugs metabolized by CYP450 isoenzymes. Anidulafungin undergoes slow chemical degradation at physiologic temperature and pH to a ring-opened peptide that lacks antifungal activity. The in vitro degradation half-life of anidulafungin under physiologic conditions is about 24 hours. In vivo, the ring-opened product is subsequently converted to peptidic degradants and eliminated.<br/>Excretion: In a single-dose clinical study, radiolabeled (C) anidulafungin was administered to healthy subjects. Approximately 30% of the administered radioactive dose was eliminated in the feces over 9 days, of which less than 10% was intact drug. Less than 1% of the administered radioactive dose was excreted in the urine. Anidulafungin concentrations fell below the lower limits of quantitation 6 days post-dose. Negligible amounts of drug-derived radioactivity were recovered in blood, urine, and feces 8 weeks post-dose.<br/>Special Populations:<br/>Drug Interaction Studies: In vitro studies showed that anidulafungin is not metabolized by human cytochrome P450 or by isolated human hepatocytes, and does not significantly inhibit the activities of human CYP isoforms (1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A) at clinically relevant concentrations. No clinically relevant drug-drug interactions were observed with drugs likely to be co-administered with anidulafungin.<br/>Cyclosporine (CYP3A4 substrate): In a study in which 12 healthy adult subjects received 100 mg/day maintenance dose of anidulafungin following a 200 mg loading dose (on Days 1 to 8) and in combination with 1.25 mg/kg oral cyclosporine twice daily (on Days 5 to 8), the steady state Cof anidulafungin was not significantly altered by cyclosporine; the steady state AUC of anidulafungin was increased by 22%. A separate in vitro study showed that anidulafungin has no effect on the metabolism of cyclosporine. No dosage adjustment of either drug is warranted when co-administered.<br/>Voriconazole (CYP2C19, CYP2C9, CYP3A4 inhibitor and substrate): In a study in which 17 healthy subjects received 100 mg/day maintenance dose of anidulafungin following a 200 mg loading dose, 200 mg twice daily oral voriconazole (following two 400 mg loading doses) and both in combination, the steady state Cand AUC of anidulafungin and voriconazole were not significantly altered by co-administration. No dosage adjustment of either drug is warranted when co-administered.<br/>Tacrolimus (CYP3A4 substrate): In a study in which 35 healthy subjects received a single oral dose of 5 mg tacrolimus (on Day 1), 100 mg/day maintenance dose of anidulafungin following a 200 mg loading dose (on Days 4 to 12) and both in combination (on Day 13), the steady state Cand AUC of anidulafungin and tacrolimus were not significantly altered by co-administration. No dosage adjustment of either drug is warranted when co-administered.<br/>AmBisome (liposomal amphotericin B): The pharmacokinetics of anidulafungin were examined in 27 patients that were co-administered liposomal amphotericin B. The population pharmacokinetic analysis showed that when compared to data from patients that did not receive amphotericin B, the pharmacokinetics of anidulafungin were not significantly altered by co-administration with amphotericin B. No dosage adjustment of anidulafungin is warranted.<br/>Rifampin (potent CYP450 inducer): The pharmacokinetics of anidulafungin were examined in 27 patients that were co-administered anidulafungin and rifampin. The population pharmacokinetic analysis showed that when compared to data from patients that did not receive rifampin, the pharmacokinetics of anidulafungin were not significantly altered by co-administration with rifampin. No dosage adjustment of anidulafungin is warranted.
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ERAXIS is contraindicated in persons with known hypersensitivity to anidulafungin, any component of ERAXIS, or other echinocandins.
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ERAXIS (anidulafungin) for Injection, is supplied in a single-use vial of sterile, lyophilized, preservative-free, powder. The companion single-use diluent vial contains 20% (w/w) Dehydrated Alcohol in Water for Injection. ERAXIS (anidulafungin) is available in the following packaging configuration: Single Use Unit Pack (containing ERAXIS 50 mg vial and 15 mL Diluent vial)NDC 0049-1010-28 One - 50 mg vial and 15mL diluent vial Single Use Unit Pack (containing ERAXIS 100 mg vial and 30 mL Diluent vial)NDC 0049-0115-28 One - 100 mg vial and 30mL diluent vial
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Hepatic Effects: Laboratory abnormalities in liver function tests have been seen in healthy volunteers and patients treated with ERAXIS. In some patients with serious underlying medical conditions who were receiving multiple concomitant medications along with ERAXIS, clinically significant hepatic abnormalities have occurred. Isolated cases of significant hepatic dysfunction, hepatitis, or worsening hepatic failure have been reported in patients; a causal relationship to ERAXIS has not been established. Patients who develop abnormal liver function tests during ERAXIS therapy should be monitored for evidence of worsening hepatic function and evaluated for risk/benefit of continuing ERAXIS therapy.<br/>Drug Interactions: Pre-clinical in vitro and in vivo and clinical studies demonstrated that anidulafungin is not a clinically relevant substrate, inducer, or inhibitor of cytochrome P450 isoenzymes. Anidulafungin has negligible renal clearance. Minimal interactions are expected from the concomitant medications . Drug interaction studies were performed with anidulafungin and other drugs likely to be co-administered. When used in therapeutic doses, no dosage adjustment of either drug is recommended when anidulafungin is co-administered with voriconazole or tacrolimus, and no dosage adjustment for anidulafungin is recommended when co-administered with amphotericin B or rifampin . Co-administration with cyclosporine slightly increased the steady state AUC of anidulafungin by 22%. A separate in vitro study showed that anidulafungin has no effect on the metabolism of cyclosporine. Adverse events observed in the study were consistent with adverse events observed from other studies with the administration of anidulafungin alone. No dosage adjustment of either drug is warrantedfor patients on concomitant cyclosporine .<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term animal carcinogenicity studies of anidulafungin have not been conducted. Anidulafungin was not genotoxic in the following in vitro studies: bacterial reverse mutation assays, a chromosome aberration assay with Chinese hamster ovary cells, and a forward gene mutation assay with mouse lymphoma cells. Anidulafungin was not genotoxic in mice using the in vivo micronucleus assay. Anidulafungin produced no adverse effects on fertility in male or female rats at intravenous doses of 20 mg/kg/day (equivalent to 2 times the proposed therapeutic maintenance dose of 100 mg/day on the basis of relative body surface area).<br/>Pregnancy:<br/>Pregnancy Category C: Embryo-fetal development studies were conducted with doses up to 20 mg/kg/day in rats and rabbits (equivalent to 2 and 4 times, respectively, the proposed therapeutic maintenance dose of 100 mg/day on the basis of relative body surface area). Anidulafungin administration resulted in skeletal changes in rat fetuses including incomplete ossification of various bones and wavy, misaligned or misshapen ribs. These changes were not dose-related and were within the range of the laboratory's historical control database. Developmental effects observed in rabbits (slightly reduced fetal weights) occurred in the high dose group, a dose that also produced maternal toxicity. Anidulafungin crossed the placental barrier in rats and was detected in fetal plasma. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, ERAXIS should be used during pregnancy only if the potential benefit justifies the risk to the fetus.<br/>Nursing Mothers: ERAXIS should be administered to nursing mothers only if the potential benefit justifies the risk. Anidulafungin was found in the milk of lactating rats. It is not known whether anidulafungin is excreted in human milk.<br/>Pediatric Use: Safety and effectiveness of anidulafungin in pediatric patients has not been established .
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anidulafungin
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Eraxis (Kit)
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General: Possible histamine-mediated symptoms have been reported with ERAXIS, including rash, urticaria, flushing, pruritus, dyspnea, and hypotension. These events are infrequent when the rate of ERAXIS infusion does not exceed 1.1 mg/minute.<br/>Overall ERAXIS Safety Experience: The safety of ERAXIS for Injection was assessed in 929 individuals, including 672 patients in clinical studies and 257 individuals in Phase 1 studies. A total of 633 patients received ERAXIS at daily doses of either 50 or 100 mg. A total of 481 patients received ERAXIS for���14 days.<br/>Candidemia/other Candida Infections: Three studies (one comparative vs. fluconazole, two non-comparative) assessed the efficacy and safety of ERAXIS (100 mg) in patients with candidemia and other Candida infections. Table 8 presents treatment-related adverse events that were reported in���2.0% of subjects receiving ERAXIS or fluconazole therapy in the comparative candidemia study.<br/>Esophageal Candidiasis: A single phase 3, randomized, double-blind study compared the efficacy and safety of ERAXIS to that of fluconazole in patients with esophageal candidiasis. Table 9 presents treatment-related adverse events that were reported in���1.0% of subjects receiving ERAXIS therapy. (No adverse events were reported at a frequency of 2% or greater in patients with esophageal candidiasis). The following events occurred in either<2% of patients treated for candidemia/other Candida infections, or in<1% of patients treated for esophageal candidiasis and were judged by investigators to be at least possibly related to ERAXIS: Blood and Lymphatic: coagulopathy, thrombocytopenia Cardiac: atrial fibrillation, bundle branch block (right), sinus arrhythmia, ventricular extrasystoles Eye: eye pain, vision blurred, visual disturbance Gastrointestinal: abdominal pain upper, constipation, diarrhea NOS, dyspepsia, fecal incontinence, nausea, vomiting General and Administration Site: infusion related reaction, peripheral edema, rigors Hepatobiliary: abnormal liver function tests NOS, cholestasis, hepatic necrosis Infections: candidiasis, clostridial infection, fungemia, oral candidiasis Investigations: amylase���, bilirubin���, CPK���, creatinine���, electrocardiogram QT prolonged, electrocardiogram early transition, gamma-glutamyl transferase���, lipase���, magnesium���, platelet count���, platelet count���, potassium���, prothrombin time prolonged, urea��� Metabolism and Nutrition: hypercalcemia, hyperglycemia, hyperkalemia, hypernatremia, hypomagnesemia Musculoskeletal and Connective Tissue: back pain Nervous System: convulsion, dizziness, headache Respiratory, Thoracic and Mediastinal: cough Skin and Subcutaneous Tissue: angioneurotic edema, erythema, pruritus, pruritus generalized, sweating increased, urticaria, urticaria NOS Vascular: flushing, hot flushes, hypertension, hypotension, thrombophlebitis superficial
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ERAXIS is indicated for use in the treatment of the following fungal infections: Candidemia and other forms of Candida infections (intra-abdominal abscess, and peritonitis) . ERAXIS has not been studied in endocarditis, osteomyelitis, and meningitis due to Candida, and has not been studied in sufficient numbers of neutropenic patients to determine efficacy in this group. Esophageal candidiasis . Specimens for fungal culture and other relevant laboratory studies (including histopathology) should be obtained prior to therapy to isolate and identify causative organism(s). Therapy may be instituted before the results of the cultures and other laboratory studies are known. However, once these results become available, antifungal therapy should be adjusted accordingly.
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Eraxis
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