CRESEMBA efficacy in the treatment of
invasive aspergillosis in adult patients1
CRESEMBA efficacy in the treatment of invasive aspergillosis in adult patients
CRESEMBA demonstrated noninferiority to voriconazole in the treatment of invasive aspergillosis in adult patients1
All-cause mortality through Day 421
*Intent-to-treat (ITT) population includes all randomized patients who received at least 1 dose of study drug.†372 mg of isavuconazonium sulfate is equivalent to 200 mg of isavuconazole.
CI=confidence interval; IV=intravenous; LD=loading dose; MD=maintenance dose; PO=by mouth.
A Phase 3, randomized, double-blind, noninferiority trial was designed to evaluate the safety and efficacy of CRESEMBA vs voriconazole for primary treatment of invasive fungal disease caused by Aspergillus species or other filamentous fungi. Eligible patients had proven, probable, or possible invasive fungal infections based on European Organisation for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria. Adjusted treatment difference (CRESEMBA–voriconazole) by Cochran-Mantel-Haenszel method stratified by randomization factors.1,2
- CRESEMBA® (isavuconazonium sulfate) demonstrated noninferiority to voriconazole in all-cause mortality through Day 42 in the ITT population (18.6% and 20.2%, respectively, adjusted treatment difference –1.0 [95% CI: –8.0, 5.9])1
- Similar results were seen in patients with proven or probable invasive aspergillosis confirmed by serology, culture, or histology1
- Mean treatment duration was 47 days for both treatment groups, of which 8–9 days were by an IV route of administration1
About Trial 1 (the SECURE study): A noninferiority trial of CRESEMBA vs voriconazole1
- A Phase 3, randomized, double-blind, noninferiority trial to evaluate the safety and efficacy of CRESEMBA vs voriconazole for primary treatment of invasive fungal disease caused by Aspergillus species or other filamentous fungi1,2
- Eligible patients had proven, probable, or possible invasive fungal disease caused by Aspergillus species or other filamentous fungi based on EORTC/MSG criteria1
- Patients were randomized 1:1 to receive antifungal treatment with CRESEMBA or voriconazole and stratified by history of allogeneic bone marrow transplant, uncontrolled malignancy at baseline, and by geographic region1,2
Patient demographics and baseline characteristics in Trial 1
- Mean patient age was 51 years old (range 17–87)1
- The majority of patients were Caucasian (78%) and male (60%)1
- 95% of patients presented with a fungal lung infection1
- Patients with moderate to severe renal impairment (creatinine clearance <50 mL/min, or currently on or likely to require dialysis) were excluded per labeling restrictions associated with the active comparator2,3
| Baseline risk factors in ITT population1 | CRESEMBA N=258 n(%) |
Voriconazole N=258 n(%) |
| Hematologic malignancy | 211 (82) | 222 (86) |
| Allogeneic hematopoietic stem cell transplant (HSCT) | 54 (21) | 51 (20) |
| Neutropenia‡ | 163 (63) | 175 (68) |
| Corticosteroid use | 48 (19) | 39 (15) |
| T-cell immuno- suppressant use |
111 (43) | 109 (42) |
‡Neutropenia defined as <500 cells/mm3.
-
At least 1 Aspergillus species was identified in 30% of the subjects1
- A. fumigatus and A. flavus were the most common pathogens identified
- Other Aspergillus species identified include A. niger, A. sydowii, A. terreus, and A. westerdijkiae
Invasive Mucormycosis Clinical Trial Data in Adult Patients
CRESEMBA is the first and only azole FDA approved to treat invasive mucormycosis in adults.
Recommended Dosing for CRESEMBA
Review recommended dosing regimen for CRESEMBA injection and PO formulations.
IMPORTANT SAFETY INFORMATION AND USE OF CRESEMBA
CONTRAINDICATIONS
- CRESEMBA is contraindicated in persons with known hypersensitivity to isavuconazole
- Coadministration of strong CYP3A4 inhibitors, such as ketoconazole or high-dose ritonavir (400 mg every 12 hours), with CRESEMBA is contraindicated because strong CYP3A4 inhibitors can significantly increase the plasma concentration of isavuconazole
- Coadministration of strong CYP3A4 inducers, such as rifampin, carbamazepine, St. John’s wort, or long acting barbiturates with CRESEMBA is contraindicated because strong CYP3A4 inducers can significantly decrease the plasma concentration of isavuconazole
- CRESEMBA shortened the QTc interval in a concentration-related manner. CRESEMBA is contraindicated in patients with familial short QT syndrome
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.
INDICATIONS AND USAGE
CRESEMBA (isavuconazonium sulfate) is an azole antifungal indicated for the treatment of invasive aspergillosis and invasive mucormycosis as follows:
- CRESEMBA for injection: adults and pediatric patients 1 year of age and older
- CRESEMBA capsules: adults and pediatric patients 6 years of age and older who weigh 16 kg and greater
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.
INDICATIONS AND USAGE
CRESEMBA (isavuconazonium sulfate) is an azole antifungal indicated for the treatment of invasive aspergillosis and invasive mucormycosis as follows:
- CRESEMBA for injection: adults and pediatric patients 1 year of age and older
- CRESEMBA capsules: adults and pediatric patients 6 years of age and older who weigh 16 kg and greater
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).