remote places [25 C:<18 years of age. 1 Geriatric Use No substantial difference in pharmacokinetics between geriatric and younger adults. 1 Hepatic Impairment Mild or moderate hepatic impairment (Child-Pugh class A or B): AUC increased, systemic clearance decreased, half-life prolonged. 1 12 Clinical importance unknown. 12 Severe hepatic impairment (Child-Pugh class C): Use isavuconazonium only if benefits outweigh risks. 1 If used in such patients, monitor for adverse effects. 1 Pharmacokinetics not evaluated. 1 Renal Impairment Mild, moderate, or severe renal impairment: No clinically important effects on pharmacokinetics. 1 Common Adverse Effects GI effects (nausea, vomiting, diarrhea, abdominal pain, constipation, dyspepsia, decreased appetite), 1 elevated bilirubin and liver enzymes (e.g., ALT, AST, alkaline phosphatase, γ-glutamyltransferase), 1 metabolic effects (hypokalemia, hypomagnesemia), 1 respiratory effects (dyspnea, cough, acute respiratory failure), 1 headache, 1 fatigue, 1 insomnia, 1 back pain, 1 chest pain, 1 peripheral edema, 1 hypotension, 1 renal failure, 1 delirium (e.g., agitation, confusional state, disorientation, mental status changes), 1 anxiety, 1 rash, 1 pruritus, 1 administration site reactions. 1 Interactions for Cresemba Because isavuconazonium rapidly metabolized to isavuconazole in vivo, interactions are reported for isavuconazole. 1 Isavuconazole is metabolized by CYP3A4 and 3A5 and subsequently by UGT. 1 Moderate inhibitor of CYP3A4; 1 inhibits CYP2C8, 2C9, 2C19, and 2D6 in vitro. 1 Induces CYP3A4, 2B6, 2C8, and 2C9 in vitro. 1 Weak inhibitor of P-glycoprotein (P-gp) and organic cation transporter (OCT) 2. 1 Also inhibits breast cancer resistance protein (BCRP). 1 Does not inhibit organic anion transporting polypeptide (OATP) 1B1 or OATP1B3. 15 Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes Concomitant use with potent CYP3A4 inhibitors or inducers may increase or decrease plasma concentrations of isavuconazole, respectively, and is contraindicated. 1 Drugs Affecting or Affected by Membrane Transporters If used concomitantly with drugs that are P-gp substrates and have a narrow therapeutic index, dosage adjustment of the P-gp substrate may be required. 1 Drugs that Shorten the QT Interval Possibility of additive effects if used concomitantly with drugs that shorten the QT interval not evaluated to date. 1 (See Cardiovascular Effects under Cautions.) Specific Drugs Drug Interaction Comments Atorvastatin Potential increased atorvastatin exposure 1 Use concomitantly with caution; 1 monitor for atorvastatin-related adverse effects 1 Barbiturates, long-acting Potential decreased isavuconazole exposure 1 Concomitant use contraindicated 1 Bupropion Decreased bupropion exposure 1 Use concomitantly with caution; 1 increased bupropion dosage may be needed (do not exceed maximum recommended dosage) 1 Caffeine No clinically important effect on caffeine pharmacokinetics 1 15 Carbamazepine Potential decreased isavuconazole exposure 1 Concomitant use contraindicated 1 Cyclophosphamide Use concomitantly with caution 4 Dextromethorphan No clinically important effect on dextromethorphan pharmacokinetics 1 15 Digoxin Increased digoxin exposure 1 Use concomitantly with caution; 1 monitor digoxin serum concentrations and adjust digoxin dosage accordingly 1 Efavirenz Use concomitantly with caution 4 Estrogens/Progestins Oral contraceptives containing ethinyl estradiol and norethindrone: No clinically important effect on ethinyl estradiol or norethindrone pharmacokinetics 1 15 Immunosuppressive agents (cyclosporine, mycophenolate mofetil, sirolimus, tacrolimus) Cyclosporine, sirolimus, tacrolimus: Increased concentrations and AUC of the immunosuppressive agent 1 Mycophenolate mofetil: Increased mycophenolic acid exposure 1 Cyclosporine, sirolimus, tacrolimus: Use concomitantly with caution; 1 monitor concentrations of the immunosuppressive agent and adjust immunosuppressive agent dosage accordingly 1 Mycophenolate mofetil: Use concomitantly with caution; 1 monitor for mycophenolic acid-related toxicities 1 Ketoconazole Increased peak concentrations and AUC of isavuconazole 1 Concomitant use contraindicated 1 Lopinavir Fixed combination of lopinavir and ritonavir (lopinavir/ritonavir): Increased isavuconazole peak concentrations and AUCs; decreased lopinavir and ritonavir AUCs and potential loss of antiretroviral efficacy 1 Lopinavir/ritonavir: Use concomitantly with caution 1 Metformin No clinically important effect on metformin pharmacokinetics 1 15 Methadone No clinically important effect on methadone pharmacokinetics 1 15 Methotrexate No clinically important effect on methotrexate pharmacokinetics 1 15 Midazolam Increased midazolam exposure 1 Use concomitantly with caution; 1 consider reducing midazolam dosage 1 Prednisone No clinically important effect on prednisone pharmacokinetics 1 15 Proton-pump inhibitors (esomeprazole, omeprazole) Esomeprazole: No clinically important effect on isavuconazole pharmacokinetics 1 Omeprazole: No clinically important effect on omeprazole pharmacokinetics 1 15 Repaglinide No clinically important effect on repaglinide pharmacokinetics 1 15 Rifampin Decreased peak concentrations and AUC of isavuconazole 1 Concomitant use contraindicated 1 Ritonavir High-dose ritonavir (400 mg twice daily): Potential increased isavuconazole exposure 1 High-dose ritonavir (400 mg twice daily): Concomitant use contraindicated 1 St. John's wort ( Hypericum perforatum ) Potential decreased isavuconazole exposure 1 Concomitant use contraindicated 1 Warfarin No clinically important effect on warfarin pharmacokinetics 1 15 Cresemba Pharmacokinetics Absorption Bioavailability Following oral or IV administration, isavuconazonium sulfate is rapidly and almost completely (> 98%) hydrolyzed by esterases in the blood to yield the active moiety, isavuconazole, and an inactive cleavage product. 1 10 11 Well absorbed following oral administration (absolute bioavailability 98%). 1 Peak plasma concentrations achieved in approximately 2 4 hours after oral administration 1 10 11 or 0.7 1 hour after start of IV infusion. 1 10 Food Administration with high-fat meal has no clinically important effect on oral absorption. 1 Plasma Concentrations Steady-state concentrations probably not achieved until after 2 weeks. 11 Special Populations Reduced bioavailability possible in patients with Roux-en-Y gastric bypass. 13 Distribution Extent Extensively distributed into tissues. 1 10 Distributed into milk in rats. 1 Plasma Protein Binding >99% (mainly albumin). 1 10 Elimination Metabolism In vivo studies indicate isavuconazole is metabolized by CYP3A4 and 3A5 and, subsequently, by UGT. 1 Elimination Route Following oral administration of radiolabeled isavuconazonium sulfate, 46% of total radioactive dose recovered in feces (approximately 33% as isavuconazole) and 46% recovered in urine (principally as metabolites of isavuconazole and metabolites of the inactive cleavage product). 1 4 Only negligible amounts ( <1%) of a dose of isavuconazonium sulfate are eliminated in urine as active isavuconazole. 1 10 Isavuconazole is not readily dialyzable. 1 Half-life Single-dose study in adults using oral or IV isavuconazonium sulfate indicates mean distribution half-life of isavuconazole is 1.7 2.1 or 0.42 1.6 hours, respectively, and mean terminal elimination half-life of isavuconazole is 56 77 or 76 104 hours, respectively. 10 Special Populations Mild or moderate hepatic impairment (Child-Pugh class A or B): Mean AUC increased by 64 or 84%. respectively. 1 After IV administration, half-life increased to 224 or 302 hours, respectively, compared with 123 hours in healthy individuals. 12 Mild, moderate, or severe renal impairment: Pharmacokinetics not altered. 1 Geriatric patients: Pharmacokinetics not affected by age. 1 Stability Storage Oral Capsules 20 25 C (may be exposed to 15 30 C); 1 store in original package and protect from moisture. 1 Parenteral Powder for IV Infusion 2 8 C. 1 Dilute immediately after reconstitution; 1 alternatively, may be stored at> <25 C for a maximum of 1 hour prior to dilution. 1 Total time from dilution to completion of IV infusion should not exceed 6 hours when stored at room temperature or 24 hours when refrigerated at 2 8 C immediately after dilution. 1 Do not freeze. 1 Compatibility For information on systemic interactions resulting from concomitant use, see Interactions. Parenteral Solution Compatibility 1 Compatible Dextrose 5% in water Sodium chloride 0.9% Actions Triazole antifungal; 1 5 6 7 9 structurally similar to fluconazole and voriconazole. 7 22 Isavuconazonium is a prodrug and is inactive until hydrolyzed in the blood to isavuconazole. 1 6 7 9 Like other triazole antifungals, inhibits 14-α-demethylase, which leads to accumulation of methylated sterols (e.g., 14-α-methylated lanosterol, 4,14-dimethylzymosterol, 24-methylenedihydrolanosterol) and decreased concentrations of ergosterol in fungal cell membranes. 1 6 7 Depletion of ergosterol affects cell membrane integrity and function and can lead to fungal cell death. 1 6 7 Aspergillus : Active in vitro and in clinical infections against A. flavus , 1 14 19 20 21 A. fumigatus , 1 14 19 20 21 and A. niger . 1 14 19 20 21 Also has in vitro activity against A. nidulans 14 20 21 and A. terreus . 14 19 20 21 Mucorales: Active in vitro and in clinical infections against fungi in the order Mucorales, including Rhizopus ( R. oryzae , R. azygospurus , R. microspores ), 1 19 Mucor ( M. amphibiorum , 1 M. circinelloides 1 14 ), Lichtheimia ( L. corymbifera ; formerly Absidia corymbifera ), 1 14 and Rhizomucor ( R. pusillus ). 1 14 19 Candida : Active in vitro against C. albicans , 14 19 20 C. dublinensis , 14 19 C. glabrata , 14 18 19 20 C. guilliermondii , 14 18 19 C. krusei , 14 18 19 20 C. lusitaniae , 14 19 C. parapsilosis , 14 19 20 and C. tropicalis . 14 19 20 Has in vitro activity against some Candida that have resistance or reduced susceptibility to fluconazole. 6 14 19 Other fungi: Active in vitro against Blastomyces dermatitidis , 14 Coccidioides posadasii , 14 Cryptococcus gattii , 14 C. neoformans , 14 19 Geotrichum capitatum , 14 Histoplasma capsulatum , 14 Penicillium , 19 Pichia , 14 Rhodotorula , 14 Saccharomyces cerevisiae , 14 Scedosporium , 14 19 Trichosporon , 14 19 and dermatophytes ( Trichophyton rubrum , T. mentagrophytes , T. tonsurans , Epidermophyton floccosum , Microsporum canis ). 14 Resistance or reduced susceptibility to isavuconazole may occur. 1 5 6 14 18 22 Cross-resistance can occur between isavuconazole and other azole antifungals (e.g., itraconazole, voriconazole). 1 5 19 22 Advice to Patients Isavuconazonium can be taken with or without food. 1 Importance of swallowing capsules whole, without crushing, chewing, dissolving, or opening. 1 Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, and any concomitant illnesses (e.g., liver disease, familial short QT syndrome). 1 Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. 1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.) Importance of advising patients of other important precautionary information. 1 (See Cautions.) Preparations Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details. Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations. Isavuconazonium Sulfate Routes Dosage Forms Strengths Brand Names Manufacturer Oral Capsules 186 mg (equivalent to 100 mg isavuconazole) Cresemba Astellas Parenteral For injection, for IV infusion 372 mg (equivalent to 200 mg isavuconazole) Cresemba Astellas AHFS DI Essentials. Copyright 2017, Selected Revisions September 25, 2015. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814. Use is not currently included in the labeling approved by the US Food and Drug Administration. References 1. Astellas Pharma US, Inc. Cresemba (isavuconazonium sulfate) capsules and for injection prescribing information. Northbrook, IL; 2015 Mar. 2. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Rockville, MD. From FDA website. Accessed 2015 Apr 13. 3. Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 207500Orig1s000/207501Orig1s000: Medical review(s). From FDA website. 4. Food and Drug Administration. Center for Drug Evaluation and Research. Application number: 207500Orig1s000/207501Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website. 5. Fera MT, La Camera E, De Sarro A. New triazoles and echinocandins: mode of action, in vitro activity and mechanisms of resistance. Expert Rev Anti Infect Ther . 2009; 7:981-98. [PubMed 19803707] 6. Falci DR, Pasqualotto AC. Profile of isavuconazole and its potential in the treatment of severe invasive fungal infections. Infect Drug Resist . 2013; 6:163-74. [PubMed 24187505] 7. Girmenia C. New generation azole antifungals in clinical investigation. Expert Opin Investig Drugs . 2009; 18:1279-95. [PubMed 19678798] 9. Livermore J, Hope W. Evaluation of the pharmacokinetics and clinical utility of isavuconazole for treatment of invasive fungal infections. Expert Opin Drug Metab Toxicol . 2012; 8:759-65. [PubMed 22530880] 10. Schmitt-Hoffmann A, Roos B, Heep M et al. Single-ascending-dose pharmacokinetics and safety of the novel broad-spectrum antifungal triazole BAL4815 after intravenous infusions (50, 100, and 200 milligrams) and oral administrations (100, 200, and 400 milligrams) of its prodrug, BAL8557, in healthy volunteers. Antimicrob Agents Chemother . 2006; 50:279-85. [PubMed 16377698] 11. Schmitt-Hoffmann A, Roos B, Maares J et al. Multiple-dose pharmacokinetics and safety of the new antifungal triazole BAL4815 after intravenous infusion and oral administration of its prodrug, BAL8557, in healthy volunteers. Antimicrob Agents Chemother . 2006; 50:286-93. [PubMed 16377699] 12. Schmitt-Hoffmann A, Roos B, Spickermann J et al. Effect of mild and moderate liver disease on the pharmacokinetics of isavuconazole after intravenous and oral administration of a single dose of the prodrug BAL8557. Antimicrob Agents Chemother . 2009; 53:4885-90. [PubMed 19667286] 13. Knoll BM. Pharmacokinetics of oral isavuconazole in a patient after Roux-en-Y gastric bypass surgery. J Antimicrob Chemother . 2014; 69:3441-3. [PubMed 25114167] 14. Thompson GR, Wiederhold NP. Isavuconazole: a comprehensive review of spectrum of activity of a new triazole. Mycopathologia . 2010; 170:291-313. [PubMed 20524153] 15. Astellas, Northbrook, IL: Personal Communication. 16. Viljoen J, Azie N, Schmitt-Hoffmann AH et al. A phase 2, randomized, double-blind, multicenter trial to evaluate the safety and efficacy of three dosing regimens of isavuconazole compared with fluconazole in patients with uncomplicated esophageal candidiasis. Antimicrob Agents Chemother . 2015; 59:1671-9. [PubMed 25561337] 17. Isavuconazole (BAL8557) in the treatment of candidemia and other invasive candida infections. Study NCT00413218. From clinicaltrials.gov registry. Accessed 2015 Jun 10. 18. Castanheira M, Messer SA, Rhomberg PR et al. Isavuconazole and nine comparator antifungal susceptibility profiles for common and uncommon Candida species collected in 2012: application of new CLSI clinical breakpoints and epidemiological cutoff values. Mycopathologia . 2014; 178:1-9. [PubMed 24952015] 19. Pfaller MA, Messer SA, Rhomberg PR et al. In vitro activities of isavuconazole and comparator antifungal agents tested against a global collection of opportunistic yeasts and molds. J Clin Microbiol . 2013; 51:2608-16. [PubMed 23740727] 20. Howard SJ, Lass-Flörl C, Cuenca-Estrella M et al. Determination of isavuconazole susceptibility of Aspergillus and Candida species by the EUCAST method. Antimicrob Agents Chemother . 2013; 57:5426-31. [PubMed 23959309] 21. Arendrup MC, Howard S, Lass-Flörl C et al. EUCAST testing of Isavuconazole susceptibility in Aspergillus: comparison of results for Inoculum standardization using Conidium counting versus optical density. Antimicrob Agents Chemother . 2014; 58:6432-6. [PubMed 25136005] 22. Gregson L, Goodwin J, Johnson A et al. In vitro susceptibility of Aspergillus fumigatus to isavuconazole: correlation with itraconazole, voriconazole, and posaconazole. Antimicrob Agents Chemother . 2013; 57:5778-80. [PubMed 24041890] 423. Walsh TJ, Anaissie EJ, Denning DW et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis . 2008; 46:327-60. [PubMed 18177225] Next Interactions Print this page Add to My Med List More about Cresemba (isavuconazonium) Side Effects During Pregnancy Dosage Information Drug Images Drug Interactions Support Group Pricing & Coupons En Español 0 Reviews Add your own review/rating Drug class: azole antifungals Consumer resources Cresemba ... +4 more Professional resources Cresemba (FDA) Isavuconazonium Sulfate (AHFS Monograph) Related treatment guides Aspergillosis, Invasive Mucormycosis, Invasive> ]} FEATURED: CAR-T Cell Therapy Overview Mechanism of Action KTE-C19 Studies KTE-C19 Cancer Targets Adverse Events Manufacturing Drug Status Rx Availability Prescription only C Pregnancy Category Risk cannot be ruled out N/A CSA Schedule Not a controlled drug Approval History Drug history at FDA Manufacturer Astellas Pharma US, Inc. Drug Class Azole antifungals Related Drugs Aspergillosis, Invasive itraconazole , voriconazole , amphotericin b , Sporanox , posaconazole , caspofungin , Noxafil , AmBisome , Abelcet , Vfend , Cancidas , Onmel , More... Mucormycosis, Invasive isavuconazonium , More... Cresemba Rating No Reviews - Be the first! No Reviews - Be the first! Not Rated - Be the first! Cresemba Images Cresemba isavuconazonium sulfate 186 mg (ISA Logo) View larger images} } can probably
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