CRESEMBA was effective against invasive mucormycosis
in an open-label, noncomparative trial in adult patients1
CRESEMBA was effective against invasive mucormycosis
in an open-label, noncomparative trial in adult patients1
CRESEMBA is the first and only FDA-approved azole antifungal for the treatment of invasive mucormycosis1,2
- Results from Trial 2 provide evidence that CRESEMBA® (isavuconazonium sulfate) is effective for the treatment of mucormycosis in light of the natural history of untreated mucormycosis1
- The efficacy of CRESEMBA for the treatment of invasive mucormycosis has not been evaluated in concurrent, controlled clinical trials1
All-cause mortality through Day 421
*372 mg of isavuconazonium sulfate is equivalent to 200 mg of isavuconazole.
IV=intravenous; LD=loading dose; MD=maintenance dose; PO=by mouth.
A Phase 3, open-label, noncomparative trial was designed to evaluate the safety and efficacy of CRESEMBA in the treatment of invasive aspergillosis in patients with renal impairment or in patients with invasive fungal disease caused by rare molds, yeasts, or dimorphic fungi. 37 patients had proven or probable mucormycosis based on European Organisation for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria. The Data Review Committee (DRC) classified patients receiving CRESEMBA (1) as primary therapy, (2) for invasive mold disease refractory to prior antifungal therapy, or (3) due to intolerance of prior antifungal therapy.1‑3
- All-cause mortality through Day 42 was 33% (7/21) for patients with invasive mucormycosis who received CRESEMBA as primary antifungal therapy, 46% (5/11) for CRESEMBA-treated patients with invasive mucormycosis refractory to other antifungal therapy, and 40% (2/5) who were intolerant of other antifungal therapy1
- Median treatment duration was 102 days for patients classified as primary, 33 days for refractory, and 85 days for intolerant1
About Trial 2 (the VITAL study): CRESEMBA in the treatment of invasive mucormycosis1,3
- A Phase 3, open-label, noncomparative trial to evaluate the safety and efficacy of CRESEMBA in the treatment of invasive aspergillosis in patients with renal impairment or in patients with invasive fungal disease caused by rare molds, yeasts, or dimorphic fungi1-3
- A total of 37 patients in Trial 2 were assessed by an independent DRC as having proven or probable invasive mucormycosis based on criteria established by the EORTC/MSG. These patients comprised the modified intent-to-treat (mITT)-Mucorales population1
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The mITT-Mucorales population was further stratified by therapy status as assessed by an independent DRC1,3
- Primary: patients who received CRESEMBA as primary therapy
- Refractory: patients who had an underlying infection not adequately treated by prior therapy
- Intolerant: patients who were unable to tolerate prior therapy
Patient demographics and baseline characteristics in the mITT-Mucorales population
- Mean patient age was 49 years old (range 22–79)1
- The majority of patients were Caucasian (68%) and male (81%)1
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59% of patients had fungal lung infection caused by Mucorales, half of whom also had a fungal infection involving other organs1
- The most common nonpulmonary disease locations were sinus (43%), eye (19%), central nervous system (16%), and bone (14%)
| Baseline risk factors in Mucorales patients1 | Primary N=21 n(%) |
Refractory N=11 n(%) |
Intolerant N=5 n(%) |
Total N=37 n(%) |
| Hematologic malignancy | 11 (52) | 7 (64) | 4 (80) | 22 (60) |
| Allogeneic hematopoietic stem cell transplant (HSCT) | 4 (19) | 4 (36) | 5 (100) | 13 (35) |
| Neutropenia† | 4 (19) | 5 (46) | 1 (20) | 10 (27) |
| Corticosteroid use | 5 (24) | 3 (27) | 2 (40) | 10 (27) |
| T-cell immunosuppressant use | 7 (33) | 6 (55) | 5 (100) | 18 (49) |
| Diabetic | 4 (19) | 0 | 0 | 4 (11) |
| Baseline risk factors in Mucorales patients1 | Primary N=21 n(%) |
Refractory N=11 n(%) |
| Hematologic malignancy | 11 (52) | 7 (64) |
| Allogeneic hematopoietic stem cell transplant (HSCT) | 4 (19) | 4 (36) |
| Neutropenia† | 4 (19) | 5 (46) |
| Corticosteroid use | 5 (24) | 3 (27) |
| T-cell immuno- suppressant use |
7 (33) | 6 (55) |
| Diabetic | 4 (19) | 0 |
| Baseline risk factors in Mucorales patients1 | Intolerant N=5 n(%) |
Total N=37 n(%) |
| Hematologic malignancy | 4 (80) | 22 (60) |
| Allogeneic hematopoietic stem cell transplant (HSCT) | 5 (100) | 13 (35) |
| Neutropenia† | 1 (20) | 10 (27) |
| Corticosteroid use | 2 (40) | 10 (27) |
| T-cell immuno- suppressant use |
5 (100) | 18 (49) |
| Diabetic | 0 | 4 (11) |
†Neutropenia defined as <500 cells/mm3.
Therapy status assessed by DRC: Primary=patients received CRESEMBA as primary treatment; Refractory=patients’ underlying infection not adequately treated by prior therapy; Intolerant=patients unable to tolerate prior therapy.
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Rhizopus oryzae and Mucormycetes were the most common pathogens identified1
- Other Mucorales identified include Lichtheimia corymbifera, Mucor amphibiorum, Mucor circinelloides, Rhizomucor pusillus, Rhizopus azygosporus, and Rhizopus microsporus
Invasive Aspergillosis Clinical Trial Data in Adult Patients
CRESEMBA was effective in the treatment of adult patients with proven or probable invasive aspergillosis.
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).