Drug: Cresemba

CRESEMBA contains isavuconazonium sulfate, which is the prodrug of isavuconazole. an azole antifungal drug. Isavuconazonium sulfate ding substance is an amorphous, white to yellowisli-white powder. The chemical name of isavuconazonium sulfate is glycine. N-methyl-, [2-[[[l-[l-[(2i?.3i?)-3-[4-(4-cyanophenyl)-2-thiazolyl]-2-(2.5- difluorophenyl)-2- hydroxybutyl]-4//-l,2,4-triazolium-4-yl]ethoxy]carbonyl]niethylainino]-3-pyridinyl]niethyl ester, sulfate (1:1). The empirical formula is C3SH35F2N8O5S•HSO4, the molecular weight is 814.84 and the structural formula is: CRESEMBA (isavuconazonium sulfate) capsules are available for oral administration. Each CRESEMBA capsule contains 186 mg isavuconazonium sulfate, equivalent to 100 mg isavuconazole. The inactive ingredients include magnesium citrate, microcrystalline cellulose, talc, colloidal silicon dioxide, stearic acid, liypromellose. red iron oxide, titanium dioxide, purified water, gellan gum. potassium acetate, disodium edetate, sodium laurylsulfate, shellac, propylene glycol, strong ammonia solution, potassium hydroxide and black iron oxide. CRESEMBA (isavuconazonium sulfate) for injection is available for intravenous administration. CRESEMBA for injection is a white to yellow sterile lyopliilized powder containing 372 mg isavuconazonium sulfate, equivalent to 200 mg isavuconazole, per vial. Inactive ingredients included in each vial are 96 mg mannitol and sulfuric acid for pH adjustment. Last reviewed on RxList: 3/18/2015
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

The following are discussed in more detail in other sections of the labeling:
  • Hepatic Adverse Drug Reactions [see WARNINGS AND PRECAUTIONS]
  • Infusion-Related Reactions [see WARNINGS AND PRECAUTIONS]
  • Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]
  • Embryo-Fetal Toxicity [see WARNINGS AND PRECAUTIONS]
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of CRESEMBA cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trial Experience A total of 403 patients were exposed to CRESEMBA in two clinical trials. 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%). Serious adverse reactions occurred in 223/403 (55%) of patients and 56/403 (14%) of patients permanently discontinued treatment with CRESEMBA due to an adverse reaction in the two trials. 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%). Patients in the clinical trials were immunocompromised with underlying conditions including hematological malignancy, neutropenia post-chemotherapy, graft-versus-host disease, and hematopoietic stem cell transplant. The patient population was 61% male, had a mean age of 51 years (range 17-92, including 85 patients aged greater than 65 years), and was 79% white and 3% black. One hundred forty-four (144) patients had a duration of CRESEMBA therapy of greater than 12 weeks, with 52 patients receiving CRESEMBA for over six months. In Trial 1, a randomized, double-blind, active-controlled clinical trial for treatment of invasive aspergillosis, treatment-emergent adverse reactions occurred in 247/257 (96%), and 255/259 (99%) patients in the CRESEMBA and voriconazole treatment groups, respectively. Treatment-emergent adverse reactions resulting in permanent discontinuation were reported in 37 (14%) CRESEMBA-treated patients and 59 (23%) voriconazole-treated patients. Table 2 includes selected treatment-emergent adverse reactions which were reported at an incidence of ≥ 5% during CRESEMBA therapy in Trial 1. In Trial 2, an open-label, non-comparative trial of CRESEMBA in patients with invasive aspergillosis and renal impairment or invasive mucormycosis, treatment-emergent adverse reactions occurred in 139/146 (95%) of patients in the CRESEMBA treatment group. Adverse reactions resulting in permanent discontinuation were reported in 19 (13%) CRESEMBA-treated patients. The frequencies and types of adverse reactions observed in CRESEMBA-treated patients were similar between Trial 1 and Trial 2. Table 2: Selected Treatment-Emergent Adverse Reactions with Rates of 5% or Greater in CRESEMBA-treated Patients in Trial 1
System Organ Class Preferred Term Trial 1 CRESEMBA
(N=257) n (%) Voriconazole
(N=259) n (%) Gastrointestinal disorders   Nausea 71 (27.6) 78 (30.1)   Vomiting 64 (24.9) 73 (28.2)   Diarrhea 61 (23.7) 60 (23.2)   Abdominal pain 43 (16.7) 59 (22.8)   Constipation 36(14.0) 54 (20.8)   Dyspepsia 16 (6.2) 14 (5.4) General disorders and administration site conditions   Edema peripheral 39(15.2) 46(17.8)   Fatigue 27(10.5) 18 (6.9)   Chest Pam 23 (8.9) 16 (6.2)   Injection site reaction 16 (6.2) 4(1.5)   Hepatobiliary disorders   Elevated liver laboratory testsa 44(17.1) 63 (24.3) Metabolism and nutrition disorders   Hypokalemia 49(19.1) 58 (22.4)   Decreased appetite 22 (8.6) 28(10.8)   Hypomagnesemia 14 (5.4) 27 (10.4) Musculoskeletal and connective tissue disorders   Back pain 26(10.1) 19 (7.3) Nervous svstern disorders   Headache 43 (16.7) 38 (14.7) Psychiatric disorders   Insomnia 27(10.5) 25 (9.7)   Deliriumb 22 (8.6) 30(11.6)   Anxiety 21 (8.2) 18 (6.9) Renal and urinary disorders   Renal failure 26(10.1) 21 (8.1) Respiratory, thoracic and mediastinal disorders   Dyspnea 44(17.1) 35 (13.5)   Acute respiratory failure 19 (7.4) 22 (8.5) Skin and subcutaneous tissue disorders   Rash 22 (8.6) 36(13.9)   Pruritus 21 (8.2) 15 (5.8) Vascular disorders   Hypotension 21 (8.2) 28(10.8) a Elevated liver laboratory tests include reactions of increased alanine aminotransferase, aspartate aminotransferase, blood alkaline phosphatase, blood bilirubin, and gamma-glutamyltransferase.
b Delirium includes adverse reactions of agitation, confusional state, delirium, disorientation, and mental status changes. The following adverse reactions occurred in less than 5% of all CRESEMBA-treated patients in Trial 1 or 2. The list does not include reactions presented in Table 2. This listing includes adverse reactions where a causal relationship to isavuconazole cannot be ruled out or those wliich may help the physician in managing the risks to the patients. Blood and lymphatic system disorders: agranulocytosis, leukopenia, pancytopenia Cardiac disorders: atrial fibrillation, atrial flutter, bradycardia, reduced QT interval on electrocardiogram, palpitations, supraventricular extrasystoles, supraventricular tachycardia, ventricular extrasystoles, cardiac arrest Ear and labyrinth disorders: tinnitus, vertigo Eye disorders: optic neuropathy Gastrointestinal disorders: abdominal distension, gastritis, gingivitis, stomatitis General disorders and administration site conditions: catheter thrombosis, malaise, chills Hepatobiliary disorders: cholecystitis, cholelithiasis, hepatitis, hepatomegaly, hepatic failure Immune system disorders: hypersensitivity Injury, poisoning and procedural complications: fall Metabolism and nutrition disorders: hypoalbuminemia, hypoglycemia, hyponatremia Musculoskeletal and connective tissue disorders: myositis, bone pain, neck pain Nervous system disorders: convulsion, dysgeusia, encephalopathy, hypoesthesia, migraine, peripheral neuropathy, paraesthesia, somnolence, stupor, syncope, tremor Psychiatric disorders: confusion, hallucination, depression Renal and urinary disorders: hematuria, proteinuria Respiratory, thoracic and mediastinal disorders: bronchospasm, tachypnea Skin and subcutaneous tissue disorders: alopecia, dermatitis, exfoliative dermatitis, erythema, petechiae, urticaria Vascular disorders: thrombophlebitis Laboratory effects In Trial 1, elevated liver transaminases (alanine aminotransferase or aspartate aminotransferase) greater than three times the upper limit of normal were reported at the end of study treatment in 4.4% of patients who received CRESEMBA. Elevations of liver transaminases greater than ten times the upper limit of normal developed in 1.2% of patients who received CRESEMBA. Read the Cresemba (isavuconazonium sulfate injection and capsules) Side Effects Center for a complete guide to possible side effectsLearn More »

Source: http://www.rxlist.com

Important Instructions For Intravenous Administration
  • Intravenous formulation must be administered via an infusion set with an in-line filter (pore size 0.2 to 1.2 micron).
  • Infuse the intravenous formulation over a minimum of 1 hour in 250 mL of a compatible diluent, to reduce the risk for infusion-related reactions. Do not administer as an intravenous bolus injection.
  • Do not infuse CRESEMBA with other intravenous medications.
  • Flush intravenous lines with 0.9% sodium chloride injection, USP or 5% dextrose injection, USP prior to and after infusion of CRESEMBA.
  • After dilution of the intravenous formulation, avoid unnecessary vibration or vigorous shaking of the solution. Do not use a pneumatic transport system.
Dosage Regimen CRESEMBA (isavuconazonium sulfate) is the prodrug of isavuconazole, an azole antifungal drug. Prescribe CRESEMBA as shown in Table 1 below. Table 1: Dosage Regimen for CRESEMBA
  Loading Dose Maintenance Dosec CRESEMBA for Injection 372 mga of isavuconazonium sulfate per vial 1 reconstituted vial (372 mga) intravenously every 8 hours for 6 doses (48 hours) 1 reconstituted vial (372 mga) intravenously once daily CRESEMBA Capsules 186 mgb of isavuconazonium sulfate per capsule 2 capsules (372 mga) orally every 8 hours for 6 doses (48 hours) 2 capsules (372 mga) orally once daily a372 mg of isavuconazonium sulfate is equivalent to 200 mg of isavuconazole
b186 mg of isavuconazonium sulfate is equivalent to 100 mg of isavuconazole
cStart maintenance doses 12 to 24 hours after the last loading dose Switching between the intravenous and oral formulations of CRESEMBA is acceptable as bioequivalence has been demonstrated. Loading dose is not required when switching between formulations. With oral administration, swallow capsules whole. Do not chew, crush, dissolve, or open the capsules. CRESEMBA capsules can be taken with or without food. Reconstitution Instructions For The Injection Formulation Aseptic technique must be strictly observed in all handling since no preservative or bacteriostatic agent is present in CRESEMBA or in the materials specified for reconstitution. CRESEMBA is water soluble, preservative-free, sterile, and nonpyrogenic.
  • Reconstitute one vial of CRESEMBA by adding 5 mL water for injection, USP to the vial.
  • Gently shake to dissolve the powder completely.
  • Visually inspect the reconstituted solution for particulate matter and discoloration. Reconstituted CRESEMBA should be clear and free of visible particulate.
  • The reconstituted solution may be stored below 25°C for maximum 1 hour prior to preparation of the patient infusion solution.
Dilution And Preparation Instructions For The Injection Formulation
  • Remove 5 mL of the reconstituted solution from the vial and add it to an infusion bag containing 250 mL (approximately 1.5 mg isavuconazonium sulfate per mL) of compatible diluent. The diluted solution may show visible translucent to white particulates of isavuconazole (which will be removed by in-line filtration).
  • Use gentle mixing or roll bag to minimize the formation of particulates. Avoid unnecessary vibration or vigorous shaking of the solution.
  • Apply in-line filter with a microporous membrane pore size of 0.2 to 1.2 micron and in-line filter reminder sticker to the infusion bag.
  • Do not use a pneumatic transport system.
  • The intravenous administration should be completed within 6 hours of dilution at room temperature. If this is not possible, immediately refrigerate (2° to 8°C / 36° to 46°F) the infusion solution after dilution and complete the infusion within 24 hours. Do not freeze the infusion solution.
Compatibility For The Injection Formulation CRESEMBA for injection should only be administered with the following diluents:
  • 0.9% sodium chloride injection, USP
  • 5% dextrose injection, USP

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Isavuconazole is a sensitive substrate of CYP3A4. CYP3A4 inhibitors or inducers may alter the plasma concentrations of isavuconazole. Isavuconazole is a moderate inhibitor of CYP3A4, and a mild inhibitor of P-glycoprotein (P-gp), and organic cation transporter 2 (OCT2). Drug interaction studies were conducted to investigate the effect of co-administered drugs on pharmacokinetics of isavuconazole and the effect of isavuconazole on the pharmacokinetics of co-administered drugs [see CLINICAL PHARMACOLOGY]. Table 3: Drug(s) Affecting Pharmacokinetics of CRESEMBA
  Recommendation Comments Ketoconazole Contraindicate coadministration of all potent CYP3A4 inhibitors There is more than a 5-fold increase in exposure of isavuconazole upon coadministration with ketoconazole [see CLINICAL PHARMACOLOGY]. Lopinavir/ ritonavira Caution is advised when CRESEMBA is coadministered with lopinavir/ritonavir There is a 96% increase in exposure of isavuconazole when coadministered with lopinavir/ritonavir [see CLINICAL PHARMACOLOGY]. Rifampin Contraindicate coadministration of all potent CYP3A4 inducers There is a 97% decrease in exposure of isavuconazole upon coadministration with rifampin [see CLINICAL PHARMACOLOGY]. a400 mg of lopinavir in combination with 100 mg of ritonavir. Table 4: The Effect of CRESEMBA on the Pharmacokinetics of Other Drugs
  Recommendation Comments Lopinavir/ ritonavira Use with Caution Concomitant administration of lopinavir/ritonavir and CRESEMBA resulted in decreased exposure of lopinavir and ritonavir that could possibly result in loss of antiviral efficacy [see CLINICAL PHARMACOLOGY]. Atorvastatin Use with Caution Caution should be used when atorvastatin is used with CRESEMBA due to a potential increase in atorvastatin exposure. Monitor patients for adverse reactions that are typical of atorvastatin. Cyclosporine Use with Caution Concomitant administration of CRESEMBA and cyclosporine results in increase in cyclosporine exposure. Monitor drug concentrations of cyclosporine and adjust dose as needed [see CLINICAL PHARMACOLOGY]. Sirolimus Use with Caution Concomitant administration of CRESEMBA and sirolimus results in increase in sirolimus exposure. Monitor drug concentrations of sirolimus and adjust dose as needed [see CLINICAL PHARMACOLOGY]. Tacrolimus Use with Caution Concomitant administration of CRESEMBA and tacrolimus results in increase in tacrolimus exposure. Monitor drug concentrations of tacrolimus and adjust dose as needed [see CLINICAL PHARMACOLOGY]. Midazolam Use with Caution Concomitant administration of CRESEMBA and midazolam results in increase in midazolam exposure. Consider dose reduction of midazolam when isavuconazole is coadministered [see CLINICAL PHARMACOLOGY]. Bupropion Use with Caution Concomitant administration of CRESEMBA and bupropion results in decrease in bupropion exposure. Dose increase of bupropion may be necessary when coadministered with CRESEMBA, but should not exceed the maximum recommended dose [see CLINICAL PHARMACOLOGY]. Mycophenolate Mofetil Use with Caution Concomitant administration of CRESEMBA and MMF results in increase in MMF exposure. Patients receiving CRESEMBA concurrently with MMF should be monitored for MPA-related toxicities [seeCLINICAL PHARMACOLOGY]. Digoxin Use with Caution Concomitant administration of CRESEMBA and digoxin results in increase in digoxin exposure. Serum digoxin concentrations should be monitored and used for titration of when dosed concurrently with CRESEMBA [see CLINICAL PHARMACOLOGY]. a400 mg of lopinavir in combination with 100 mg of ritonavir. Last reviewed on RxList: 3/18/2015
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

Invasive Aspergillosis CRESEMBA is an azole antifungal indicated for patients 18 years of age and older for the treatment of invasive aspergillosis. [see Clinical Studies and CLINICAL PHARMACOLOGY]. Invasive Mucormycosis CRESEMBA is an azole antifungal indicated for patients 18 years of age and older for the treatment of invasive mucormycosis. [see Clinical Studies and CLINICAL PHARMACOLOGY]. Usage 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.

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  • 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 [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].
  • 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 [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].
  • CRESEMBA shortened the QTc interval in a concentration-related manner. CRESEMBA is contraindicated in patients with familial short QT syndrome [see CLINICAL PHARMACOLOGY].
Last reviewed on RxList: 3/18/2015
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

During clinical studies, total daily CRESEMBA doses higher than the recommended dose regimen were associated with an increased rate of adverse reactions. At supratherapeutic doses (three times the recommended maintenance dose) evaluated in a thorough QT study, there were proportionally more treatment-emergent adverse reactions than in the therapeutic dose group (maintenance dose) for the following: headache, dizziness, paresthesia, somnolence, disturbance in attention, dysgeusia. dry mouth, diarrhea, oral hypoesthesia. vomiting, hot flush, anxiety, restlessness, palpitations, tachycardia, photophobia and arthralgia. Treatment-emergent adverse reactions leading to discontinuation of smdy drug occurred in 7 of 39 (17.9%) subjects in the supratherapeutic dose group. Isavuconazole is not removed by hemodialysis. There is no specific antidote for isavuconazole. Treatment should be supportive with appropriate monitoring.

Source: http://www.rxlist.com

Dosage Forms And Strengths Each CRESEMBA capsule contains 186 mg isavuconazonium sulfate (equivalent to 100 mg of isavuconazole). Capsules are opaque and elongated, and have a Swedish orange (reddish-brown) body imprinted with the Astellas logo in black ink and a white cap imprinted with “ISA” in black ink. Each single-dose vial of CRESEMBA for injection contains 372 mg isavuconazonium sulfate (equivalent to 200 mg of isavuconazole). CRESEMBA for injection is supplied in a single-dose vial as a sterile lyophilized white to yellow powder. Capsules CRESEMBA (isavuconazonium sulfate) capsules are available in aluminum blister packs. Each capsule contains 186 mg isavuconazonium sulfate (equivalent to 100 mg of isavuconazole). Capsules are opaque and elongated, and have a Swedish orange (reddish-brown) body imprinted with the Astellas logo in black ink and a white cap imprinted with “ISA” in black ink. Store in original container to protect from moisture. Capsules are packaged in aluminum blister packs, seven (7) capsules per sheet with desiccant. (NDC 0469-0320-14) Injection CRESEMBA (isavuconazonium sulfate) for injection is supplied in a single-dose vial as white to yellow sterile lyophilized powder containing 372 mg isavuconazonium sulfate (equivalent to 200 mg isavuconazole). Individually packaged vials are available for intravenous administration. (NDC 0469-0420-99) Storage And Handling Store CRESEMBA capsules at 20°C to 25°C (68°F to 77°F) in the original packaging to protect from moisture. Excursions are permitted from 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Store CRESEMBA for injection unreconstituted vials at 2° to 8°C (36° to 46°F) in a refrigerator. CRESEMBA is a single-dose vial of unpreserved sterile lyophile. Following reconstitution of the lyophile with water for injection USP, the reconstituted solution should be used immediately, or stored below 25°C for a maximum of 1 hour prior to preparation of the patient infusion solution. The prepared infusion solution should be kept for not more than 6 hours at room temperature [20°C to 25°C (68°F to 77°F)] or 24 hours at 2° to 8°C (36° to 46°F) prior to use. CRESEMBA for injection vials are for single-dose use only. Product of Portugal. Marketed and Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062 Licensed from: Basilea Pharmaceutica International Ltd. Approved: March 2015. Last reviewed on RxList: 3/18/2015
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

Hepatic Adverse Drug Reactions Hepatic adverse drug reactions (e.g., elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin) have been reported in clinical trials. The elevations in liver-related laboratory tests were generally reversible and did not require discontinuation of CRESEMBA. Cases of more 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-related laboratory tests at the start and during the course of CRESEMBA therapy. Monitor patients who develop abnormal liver-related laboratory tests during CRESEMBA therapy for the development of more severe hepatic injury. Discontinue CRESEMBA if clinical signs and symptoms consistent with liver disease develop that may be attributable to CRESEMBA [see ADVERSE REACTIONS]. Infusion-Related Reactions 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 [see ADVERSE REACTIONS]. Hypersensitivity Reactions Serious hypersensitivity and severe skin reactions, such as anaphylaxis or Stevens Johnson syndrome, have been reported during treatment with other azole antifungal agents. Discontinue CRESEMBA if a patient develops a severe cutaneous adverse reaction. There is no information regarding cross-sensitivity between CRESEMBA and other azole antifungal agents. Caution should be used when prescribing CRESEMBA to patients with hypersensitivity to other azoles. Embryo-Fetal Toxicity CRESEMBA may cause fetal harm when administered to a pregnant woman. CRESEMBA should be used during pregnancy only 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 [see Use in Specific Populations]. Perinatal mortality was significantly increased in the offspring of pregnant rats dosed orally with isavuconazonium sulfate at 90 mg/kg/day (less than half the maintenance human dose based on AUC comparisons) during pregnancy through the weaning period. Isavuconazonium chloride administration was associated with dose-related increases in the incidences of rudimentary cervical ribs in rats and rabbits at 30 and 45 mg/kg, respectively, doses equivalent to about one fifth and one tenth of the clinical exposures based on AUC comparisons. In rats, dose-related increases in the incidences of zygomatic arch fusion and supernumerary ribs/rudimentary supernumerary ribs were also noted at 30 mg/kg and above, equivalent to one fifth the clinical dose based on AUC comparisons [see Nonclinical Toxicology]. 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 [see CONTRAINDICATIONS and DRUG INTERACTIONS]. Drug Particulates Following dilution, CRESEMBA intravenous formulation may form precipitate from the insoluble isavuconazole. Administer CRESEMBA through an in-line filter [see DOSAGE AND ADMINISTRATION]. Patient Counseling Information Advise patients to read the FDA-approved patient labeling (PATIENT INFORMATION). Advise patients that CRESEMBA can be taken with or without food. Each capsule should be swallowed whole. Do not chew, crush, dissolve, or open the capsules. Advise patients to inform their physician if they are taking other drugs or before they begin taking other drugs as certain drugs can decrease or increase the plasma concentrations of CRESEMBA. CRESEMBA can decrease or increase the plasma concentrations of other drugs. Advise patients to inform their physician if they are pregnant, plan to become pregnant, or are nursing. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Two-year carcinogenicity studies of isavuconazonium sulfate have not been performed. Hepatocellular adenomas and carcinomas have been reported in mice and rats in carcinogenicity studies for other drugs in the azole class at near human recommended doses. No mutagenic or clastogenic effects were detected in the in vitro bacterial reverse mutation assay and the in vivo bone marrow micronucleus assay in rats. Oral administration of isavuconazonium sulfate did not affect the fertility in male or female rats treated at doses up to 90 mg/kg/day (less than a half the clinical dose based on AUC comparisons). Use In Specific Populations Pregnancy Pregnancy Category C There are no adequate and well-controlled clinical studies of CRESEMBA in pregnant women. CRESEMBA should be used during pregnancy only if the potential benefit to the patient outweighs the risk to the fetus. Women who become pregnant during CRESEMBA treatment are encouraged to contact their physician. Risk Summary Based on animal data, CRESEMBA is predicted to have the potential for increasing the risk of adverse developmental outcomes above background risk. Animal Data Perinatal mortality was significantly increased in the offspring of pregnant rats dosed orally with isavuconazonium sulfate at 90 mg/kg/day (less than half the maintenance human dose based on AUC comparisons) during pregnancy through the weaning period. Isavuconazonium chloride administration was associated with dose-related increases in the incidences of rudimentary cervical ribs in rats and rabbits at 30 and 45 mg/kg, respectively, doses equivalent to about one fifth and one tenth of the clinical exposures based on AUC comparisons. In rats, dose-related increases in the incidences of zygomatic arch fusion and supernumerary ribs/rudimentary supernumerary ribs were also noted at 30 mg/kg and above, equivalent to one fifth the clinical dose based on AUC comparisons [see Nonclinical Toxicology]. Skeletal abnormalities have also been observed in embryo-fetal development studies of other azole antifungal agents. Nursing Mothers Isavuconazole is excreted in the milk of lactating rats following intravenous administration. Mothers should not breast feed while taking CRESEMBA. Pediatric Use The safety and efficacy of CRESEMBA in pediatric patients less than 18 years of age have not been established. Geriatric Use Of the 547 patients who received CRESEMBA in the Phase 2 and 3 trials, 86 (16%) of patients were greater than 65 years of age and 20 (4%) were greater than 75 years of age. The pharmacokinetics of isavuconazole are comparable in young and elderly subjects (65 years of age and older) [see CLINICAL PHARMACOLOGY]. No dose adjustment of CRESEMBA is needed in elderly patients. Renal Impairment Of the 403 patients who received CRESEMBA in the Phase 3 trials, 79 (20%) of patients had an estimated glomerular filtration rate (GFR) less than 60 ml/min/1.73m². No dose adjustment is needed in patients with mild, moderate, or severe renal impairment, including those patients with End Stage Renal Disease (ESRD) [see CLINICAL PHARMACOLOGY]. Hepatic Impairment No dose adjustment is necessary in patients with mild or moderate hepatic impairment (Child-Pugh Class A and B) [see CLINICAL PHARMACOLOGY]. CRESEMBA has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) and should be used in these patients only when the benefits outweigh the risks. Clinical monitoring for CRESEMBA-related adverse reactions is recommended when treating patients with severe hepatic impairment [see WARNINGS AND PRECAUTIONS]. Last reviewed on RxList: 3/18/2015
This monograph has been modified to include the generic and brand name in many instances.

Source: http://www.rxlist.com

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