Notice of DSCSA exemption
The Food and Drug Administration (FDA) granted an exemption to Astellas from section 582 of the Federal Food, Drug, and Cosmetic Act (FDCA), as amended by the Drug Supply Chain Security Act (DSCSA), requirements for CRESEMBA 186 mg capsules packaged without product identifiers from November 27, 2018 through May 31, 2019 (See Batch Numbers for impacted product below). These exemptions were to facilitate the movement of the exempted product through the supply chain and ensure that trading partners will not be in violation of the law for transacting such product or failing to utilize their product identifiers to carry out verification activities and thus are appropriate.
Wholesale distributors and trading partners (including those that are not immediate customers of Astellas) are also exempted from the following requirements that go into effect November 27, 2019 for transactions of CRESEMBA products packaged without product identifiers, from November 27, 2018 through May 31, 2019 (See Batch Numbers for impacted product below):
- The section 582(c)(2) requirement to only engage in transactions involving product encoded with a product identifier. This exemption is in effect until expiry of the CRESEMBA products packaged without product identifiers
- The section 582(c)(4)(A)(i)(II)) requirement to verify product using the product identifier. However, wholesale distributors must still validate any applicable transaction history and transaction information in its possession and otherwise investigate the product to determine if it is illegitimate in accordance with section 582(c)(4)(A)(i)(II)); the exemption does not extend to these requirements. This exemption is in effect until expiry of the CRESEMBA products packaged without product identifiers
- The section 582(c)(4)(D) requirement to verify the product identifier of saleable returned product packaged without product identifiers by Astellas before May 31, 2019 that is intended for further distribution. This exemption is in effect until expiry of the CRESEMBA products packaged without product identifiers
Astellas and its trading partners must comply with all other applicable requirements of section 582 of the FDCA for transactions of products packaged without product identifiers by Astellas, from November 27, 2018 through May 31, 2019.
Batch numbers for impacted product
The Batch/Lot numbers included in this exemption period are as follows:
| FG Lot # | Astellas Release |
|---|---|
| W043884A | 14-Jan-19 |
| W043885A | 30-Jan-19 |
| W046384A | 13-Feb-19 |
| W046385A | 20-Feb-19 |
| W046386A | 5-Mar-19 |
| W046450A | 12-Mar-19 |
| W046453A | 11-Mar-19 |
Should you need assistance or have any questions regarding these lots, please contact Astellas for support at 800-727-7003.
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).