For US Healthcare Professionals Only
CRESEMBA® (isavuconazonium sulfate) is a sensitive substrate of CYP3A4, a moderate inhibitor of CYP3A4, and a mild inhibitor of P-glycoprotein (P-gp) and organic cation transporter 2 (OCT2).1
| Concomitant drug(s) | Effect on CRESEMBA | Comments on concomitant use |
|---|---|---|
| Ketoconazole | >5-fold increase in exposure | Contraindicated with all potent CYP3A4 inhibitors |
| Rifampin | 97% decrease in exposure | Contraindicated with all potent CYP3A4 inducers |
| Concomitant drug(s) | Drug monitoring/dose adjustment for concomitant drug |
Effect on CRESEMBA PK | Effect on concomitant drug PK |
||
|---|---|---|---|---|---|
| Cmax | AUC | Cmax | AUC | ||
| Cyclosporine (300 mg) |
Monitor drug concentrations and dose adjust as needed |
30% | 3% | 6% | 29% |
| Tacrolimus (5 mg) |
Monitor drug concentrations and dose adjust as needed |
26% | 12% | 42% | 125% |
| Sirolimus (2 mg) |
Monitor drug concentrations and dose adjust as needed |
4% | 11% | 65% | 84% |
| Mycophenolate mofetil (1000 mg) |
Monitor for mycophenolic acid– related toxicities |
4% | NS | 11% | 35% |
| Digoxin (0.5 mg) |
Monitor and titrate digoxin dose to clinical effect |
NS | NS | 33% | 25% |
| Midazolam (3 mg) |
Consider dose reduction | NS | NS | 72% | 103% |
| Bupropion (100 mg) |
Consider dose increase; should not exceed maximum dose |
NS | NS | 31% | 42% |
| Atorvastatin (20 mg) |
Monitor for atorvastatin-related adverse events |
NS | NS | 3% | 37% |
| Lopinavir (400 mg) |
Possible loss of antiviral efficacy | 74% | 96% | 23% | 27% |
| Ritonavir (100 mg) |
33% | 31% | |||
AUC=area under the curve; Cmax=maximum plasma concentration; NS=not significant; PK=pharmacokinetics.
| Esomeprazole | Omeprazole | Cell | Norethindrone |
| Warfarin | Dextromethorphan | Ethinyl estradiol | Prednisone |
| Caffeine | Repaglinide | Methotrexate | Metformin |
Review recommended dosing regimen for CRESEMBA injection and PO formulations.
Watch a presentation of CRESEMBA pharmacokinetic information, including dosing and drug interaction considerations.
Indications and Usage
CRESEMBA (isavuconazonium sulfate) is an azole antifungal indicated for the treatment of invasive aspergillosis and invasive mucormycosis as follows:
Specimens for fungal culture and other relevant laboratory studies (including histopathology) to isolate and identify causative organism(s) should be obtained prior to initiating antifungal therapy. 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.
Please see full Prescribing Information for CRESEMBA (isavuconazonium sulfate).
CONTRAINDICATIONS
WARNINGS AND PRECAUTIONS
Hepatic Adverse Drug Reactions (e.g., elevations in ALT, AST, alkaline phosphatase, total bilirubin) have been reported in clinical trials and were generally reversible and did not require discontinuation of CRESEMBA. Cases of severe hepatic adverse drug reactions including hepatitis, cholestasis or hepatic failure including death have been reported in patients with serious underlying medical conditions (e.g., hematologic malignancy) during treatment with azole antifungal agents, including CRESEMBA. Evaluate liver tests at the start and during therapy. Monitor patients who develop liver abnormalities during CRESEMBA therapy for severe hepatic injury. Discontinue if clinical signs and symptoms consistent with liver disease develop that may be attributable to CRESEMBA.
Infusion-Related Reactions including hypotension, dyspnea, chills, dizziness, paresthesia, and hypoesthesia were reported during intravenous administration of CRESEMBA. Discontinue the infusion if these reactions occur.
Hypersensitivity Reactions: Anaphylactic reactions, with fatal outcome, have been reported during treatment with CRESEMBA. Serious skin reactions, such as Stevens Johnson syndrome, have been reported during treatment with other azole antifungal agents. Discontinue CRESEMBA if anaphylactic or serious skin reactions occur, and initiate supportive treatment as needed.
Embryo-Fetal Toxicity: During pregnancy, CRESEMBA may cause fetal harm when administered, and CRESEMBA should only be used if the potential benefit to the patient outweighs the risk to the fetus. Women who become pregnant while receiving CRESEMBA are encouraged to contact their physician.
Drug Interactions: Coadministration of CRESEMBA with strong CYP3A4 inhibitors such as ketoconazole or high-dose ritonavir and strong CYP3A4 inducers such as rifampin, carbamazepine, St. John’s Wort, or long acting barbiturates is contraindicated.
Drug Particulates: Following dilution, CRESEMBA intravenous formulation may form precipitate from the insoluble isavuconazole. Administer CRESEMBA through an in-line filter.
ADVERSE REACTIONS
In adult patients, the most frequently reported adverse reactions among CRESEMBA-treated patients were nausea (26%), vomiting (25%), diarrhea (22%), headache (17%), elevated liver chemistry tests (16%), hypokalemia (14%), constipation (13%), dyspnea (12%), cough (12%), peripheral edema (11%), and back pain (10%).
In adult patients, the adverse reactions which most often led to permanent discontinuation of CRESEMBA therapy during the clinical trials were confusional state (0.7%), acute renal failure (0.7%), increased blood bilirubin (0.5%), convulsion (0.5%), dyspnea (0.5%), epilepsy (0.5%), respiratory failure (0.5%), and vomiting (0.5%).
In pediatric patients, the most frequently reported adverse reactions were diarrhea (26%), abdominal pain (23%), vomiting (21%), elevated liver chemistry tests (18%), rash (14%), nausea (13%), pruritus (13%), and headache (12%).
In general, adverse reactions in pediatric patients (including serious adverse reactions and adverse reactions leading to permanent discontinuation of CRESEMBA) were similar to those reported in adults.
Reference: 1. CRESEMBA [package insert]. Northbrook, IL: Astellas Pharma US, Inc. 2. Groll AH, Desai A, Han D, et al. Pharmacokinetic assessment of drug-drug interactions of isavuconazole with the immunosuppressants cyclosporine, mycophenolic acid, prednisolone, sirolimus, and tacrolimus in healthy adults. Clin Pharmacol Drug Dev 2017;6(1):76-85. 3. Yamazaki T, Desai A, Goldwater R, et al. Pharmacokinetic interactions between isavuconazole and the drug transporter substrates atorvastatin, digoxin, metformin, and methotrexate in healthy subjects. Clin Pharmacol Drug Dev 2017;6(1):66-75. 4. Townsend R, Dietz A, Hale C, et al. Pharmacokinetic evaluation of CYP3A4-mediated drug-drug interactions of isavuconazole with rifampin, ketoconazole, midazolam, and ethinyl estradiol/norethindrone in healthy adults. Clin Pharmacol Drug Dev 2017;6(1):44-53. 5. Yamazaki T, Desai A, Goldwater R, et al. Pharmacokinetic effects of isavuconazole coadministration with the cytochrome P450 enzyme substrates bupropion, repaglinide, caffeine, dextromethorphan, and methadone in healthy subjects. Clin Pharmacol Drug Dev 2017;6(1):54-65. 6. Yamazaki T, Desai A, Han D, et al. Pharmacokinetic interaction between isavuconazole and a fixed-dose combination of lopinavir 400 mg / ritonavir 100 mg in healthy subjects. Clin Pharmacol Drug Dev 2017;6(1):93-101. 7. Desai A, Yamazaki T, Dietz AJ, et al. Pharmacokinetic and pharmacodynamic evaluation of the drug-drug interaction between isavuconazole and warfarin in healthy subjects. Clin Pharmacol Drug Dev 2017;6(1):86-92. 8. Schmitt-Hoffman A, Desai A, Kowalski D, Pearlman H, Yamazaki T, Townsend R. Isavuconazole absorption following oral administration in healthy subjects is comparable to intravenous dosing, and is not affected by food, or drugs that alter stomach pH. Int J Clin Pharmacol Ther 2016;54(8):572-80.
Indications and Usage
CRESEMBA (isavuconazonium sulfate) is an azole antifungal indicated for the treatment of invasive aspergillosis and invasive mucormycosis as follows:
Specimens for fungal culture and other relevant laboratory studies (including histopathology) to isolate and identify causative organism(s) should be obtained prior to initiating antifungal therapy. 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.
Please see full Prescribing Information for CRESEMBA (isavuconazonium sulfate).
CONTRAINDICATIONS
WARNINGS AND PRECAUTIONS
Hepatic Adverse Drug Reactions (e.g., elevations in ALT, AST, alkaline phosphatase, total bilirubin) have been reported in clinical trials and were generally reversible and did not require discontinuation of CRESEMBA. Cases of severe hepatic adverse drug reactions including hepatitis, cholestasis or hepatic failure including death have been reported in patients with serious underlying medical conditions (e.g., hematologic malignancy) during treatment with azole antifungal agents, including CRESEMBA. Evaluate liver tests at the start and during therapy. Monitor patients who develop liver abnormalities during CRESEMBA therapy for severe hepatic injury. Discontinue if clinical signs and symptoms consistent with liver disease develop that may be attributable to CRESEMBA.
Infusion-Related Reactions including hypotension, dyspnea, chills, dizziness, paresthesia, and hypoesthesia were reported during intravenous administration of CRESEMBA. Discontinue the infusion if these reactions occur.
Hypersensitivity Reactions: Anaphylactic reactions, with fatal outcome, have been reported during treatment with CRESEMBA. Serious skin reactions, such as Stevens Johnson syndrome, have been reported during treatment with other azole antifungal agents. Discontinue CRESEMBA if anaphylactic or serious skin reactions occur, and initiate supportive treatment as needed.
Embryo-Fetal Toxicity: During pregnancy, CRESEMBA may cause fetal harm when administered, and CRESEMBA should only be used if the potential benefit to the patient outweighs the risk to the fetus. Women who become pregnant while receiving CRESEMBA are encouraged to contact their physician.
Drug Interactions: Coadministration of CRESEMBA with strong CYP3A4 inhibitors such as ketoconazole or high-dose ritonavir and strong CYP3A4 inducers such as rifampin, carbamazepine, St. John’s Wort, or long acting barbiturates is contraindicated.
Drug Particulates: Following dilution, CRESEMBA intravenous formulation may form precipitate from the insoluble isavuconazole. Administer CRESEMBA through an in-line filter.
ADVERSE REACTIONS
In adult patients, the most frequently reported adverse reactions among CRESEMBA-treated patients were nausea (26%), vomiting (25%), diarrhea (22%), headache (17%), elevated liver chemistry tests (16%), hypokalemia (14%), constipation (13%), dyspnea (12%), cough (12%), peripheral edema (11%), and back pain (10%).
In adult patients, the adverse reactions which most often led to permanent discontinuation of CRESEMBA therapy during the clinical trials were confusional state (0.7%), acute renal failure (0.7%), increased blood bilirubin (0.5%), convulsion (0.5%), dyspnea (0.5%), epilepsy (0.5%), respiratory failure (0.5%), and vomiting (0.5%).
In pediatric patients, the most frequently reported adverse reactions were diarrhea (26%), abdominal pain (23%), vomiting (21%), elevated liver chemistry tests (18%), rash (14%), nausea (13%), pruritus (13%), and headache (12%).
In general, adverse reactions in pediatric patients (including serious adverse reactions and adverse reactions leading to permanent discontinuation of CRESEMBA) were similar to those reported in adults.
Reference: 1. CRESEMBA [package insert]. Northbrook, IL: Astellas Pharma US, Inc. 2. Groll AH, Desai A, Han D, et al. Pharmacokinetic assessment of drug-drug interactions of isavuconazole with the immunosuppressants cyclosporine, mycophenolic acid, prednisolone, sirolimus, and tacrolimus in healthy adults. Clin Pharmacol Drug Dev 2017;6(1):76-85. 3. Yamazaki T, Desai A, Goldwater R, et al. Pharmacokinetic interactions between isavuconazole and the drug transporter substrates atorvastatin, digoxin, metformin, and methotrexate in healthy subjects. Clin Pharmacol Drug Dev 2017;6(1):66-75. 4. Townsend R, Dietz A, Hale C, et al. Pharmacokinetic evaluation of CYP3A4-mediated drug-drug interactions of isavuconazole with rifampin, ketoconazole, midazolam, and ethinyl estradiol/norethindrone in healthy adults. Clin Pharmacol Drug Dev 2017;6(1):44-53. 5. Yamazaki T, Desai A, Goldwater R, et al. Pharmacokinetic effects of isavuconazole coadministration with the cytochrome P450 enzyme substrates bupropion, repaglinide, caffeine, dextromethorphan, and methadone in healthy subjects. Clin Pharmacol Drug Dev 2017;6(1):54-65. 6. Yamazaki T, Desai A, Han D, et al. Pharmacokinetic interaction between isavuconazole and a fixed-dose combination of lopinavir 400 mg / ritonavir 100 mg in healthy subjects. Clin Pharmacol Drug Dev 2017;6(1):93-101. 7. Desai A, Yamazaki T, Dietz AJ, et al. Pharmacokinetic and pharmacodynamic evaluation of the drug-drug interaction between isavuconazole and warfarin in healthy subjects. Clin Pharmacol Drug Dev 2017;6(1):86-92. 8. Schmitt-Hoffman A, Desai A, Kowalski D, Pearlman H, Yamazaki T, Townsend R. Isavuconazole absorption following oral administration in healthy subjects is comparable to intravenous dosing, and is not affected by food, or drugs that alter stomach pH. Int J Clin Pharmacol Ther 2016;54(8):572-80.