Cresemba

Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Isavuconazonium is available in a capsule form, and also in an injectable form.

Read all patient information, medication guides, and instruction sheets provided to you. Ask your doctor or pharmacist if you have any questions.

Isavuconazonium is first given in a "loading dose" every 8 hours for 48 hours. You will then use the medicine once daily as your "maintenance dose." Follow your doctor's dosing instructions very carefully.

You may take the capsule with or without food.

Do not crush, chew, open, or dissolve the capsule. Swallow it whole.

Store the capsules at room temperature, away from moisture and heat. Keep the capsules in their original blister pack, along with the packet or canister of moisture-absorbing preservative. Do not put isavuconazonium capsules into a daily pill box or pill organizer.

The injectable form of isavuconazonium is injected into a vein through an IV. You may be shown how to use an IV at home. Do not self-inject this medicine if you do not understand how to give the injection and properly dispose of used needles, IV tubing, and other items used to inject the medicine.

Isavuconazonium injection is a powder medicine that must be mixed with a liquid (diluent) before using it. You will then need to further dilute this mixture into a solution with another liquid in an IV bag. If you are using the injections at home, be sure you understand how to properly mix and store the medicine.

Each single-use vial (bottle) of the powder is for one use only. Throw away after one use, even if there is still some medicine left in it after injecting your dose.

Store the dry unmixed powder medicine in a refrigerator. After you mix the powder and diluent, keep the mixture in a refrigerator for up to 1 hour before further diluting it. If you store the final diluted solution in a refrigerator, use it within 24 hours after it was mixed. Do not freeze this medicine before or after mixing.

You may also store the final diluted solution at cool room temperature, but you must use it within 6 hours after mixing.

Use a disposable needle and syringe only once. Follow any state or local laws about throwing away used needles and syringes. Use a puncture-proof "sharps" disposal container (ask your pharmacist where to get one and how to throw it away). Keep this container out of the reach of children and pets.

You will need frequent blood tests to check your liver function.

Do not stop using isavuconazonium unless your doctor tells you to.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include dizziness, drowsiness, hot flashes, headache, joint pain, anxiety, feeling restless, numbness or tingling, trouble concentrating, dry mouth, altered sense of taste, numbness in or around your mouth, diarrhea, vomiting, and fast or pounding heartbeats.

Call your doctor for instructions if you miss a dose of isavuconazonium.

Cresemba is a prescription medication used to treat adults with invasive aspergillosis and invasive mucormycosis, which are rare but serious fungal infections. Cresemba belongs to a group of drugs called azole antifungal agents, which stop the synthesis of a key component of the fungal cell wall and, ultimately, kill the fungus.

Cresemba is available in an oral capsule formulations and is usually taken once a day. It can be taken with or without food. Do not crush, chew, dissolve, or open the Cresemba capsules. Swallow the capsules whole.

This medication is also available in an injectable form to be given directly into a vein (IV) by a healthcare professional.

Common side effects include nausea, vomiting, diarrhea, and headache.

Cresemba can also cause dizziness. Do not drive or operate heavy machinery until you know how Cresemba affects you.

• Astellas Pharma US, Inc.

Serious side effects have been reported with Cresemba. See the "Cresemba Precautions" section.

Common side effects of Crsemba include:

• nausea
• vomiting
• diarrhea
• headache
• changes in liver function decreased levels of potassium in the blood
• shortness of breath
• cough
• swelling of the extremities
• back pain

This is not a complete list of Cresemba side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if Cresemba crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. Your doctor and you will decide if the benefits outweigh the risk of using Cresemba.

You should not use this medicine if you have a genetic heart rhythm disorder called "Short QT syndrome."

Many drugs can interact with isavuconazonium, and some drugs should not be used together. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Tell your doctor about all medicines you use, and those you start or stop using during your treatment with isavuconazonium.

You should not use isavuconazonium if you are allergic to it, or if you have:

• a genetic heart rhythm disorder called "Short QT syndrome."

Some medicines can cause unwanted or dangerous effects when used with isavuconazonium. Your doctor may need to change your treatment plan if you use any of the following drugs:

• carbamazepine;

• ketoconazole;

• phenobarbital;

• rifampin;

• ritonavir (at high doses); or

• St. John's wort.

To make sure isavuconazonium is safe for you, tell your doctor if you have:

• liver disease;

• a heart rhythm disorder; or

• history of an allergic reaction to antifungal medicine, such as fluconazole, itraconazole, ketoconazole, posaconazole, or voriconazole.

Using isavuconazonium during pregnancy could harm the unborn baby. Tell your doctor if you are pregnant or if you become pregnant while using this medicine.

It is not known whether isavuconazonium passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Follow your doctor's instructions about any restrictions on food, beverages, or activity.

Contraindications

• Hypersensitivity to isavuconazole (active metabolite of isavuconazonium).1

• Familial short QT syndrome.1 (See Cardiovascular Effects under Cautions.)

• Concomitant use with potent CYP3A4 inhibitors or inducers.1 (See Interactions.)

Warnings/Precautions

Sensitivity Reactions

Serious hypersensitivity (e.g., anaphylaxis) and severe skin reactions (e.g., Stevens-Johnson syndrome) reported in patients receiving other azole antifungals.1

Data regarding cross-sensitivity with other azole antifungals not available.1 Use with caution in patients hypersensitive to other azoles.1

If severe adverse cutaneous reaction occurs, discontinue isavuconazonium.1

Hepatic Effects

Serious hepatic effects, including hepatitis, cholestasis, and hepatic failure (sometimes fatal), reported in patients with serious underlying medical conditions (e.g., hematologic malignancy) receiving an azole antifungal, including isavuconazonium.1

Less severe hepatic effects (e.g., increased ALT, AST, alkaline phosphatase, total bilirubin concentrations) also reported.1 Liver function test elevations generally were reversible and did not require discontinuance of isavuconazonium.1

Perform liver function tests prior to and monitor during isavuconazonium therapy.1 If abnormal liver function tests occur during therapy, monitor for development of more severe hepatic injury.1 If signs and symptoms of liver disease occur, discontinue isavuconazonium.1

Infusion Reactions

Infusion reactions (e.g., hypotension, dyspnea, chills, dizziness, paresthesia, hypoesthesia) reported.1

To reduce risk of infusion reactions, dilute reconstituted solution in 250 mL of compatible diluent and administer by IV infusion over ≥1 hour.1 (See IV Administration under Dosage and Administration.)

If infusion reaction occurs, discontinue the IV infusion.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.1 Has been associated with increased perinatal mortality and skeletal abnormalities in animals;1 skeletal abnormalities also observed in animal studies evaluating other azole antifungals.1

Use during pregnancy only if potential benefits to the woman outweigh potential risks to fetus.1 (See Pregnancy under Cautions.)

Cardiovascular Effects

Shortens corrected QT (QTc) interval in a dose-related manner.1 Contraindicated in patients with familial short QT syndrome (see Contraindications under Cautions).1 Concomitant use with other drugs that shorten QTc interval not evaluated.1 (See Drugs that Shorten the QT Interval under Interactions.)

Atrial fibrillation, atrial flutter, bradycardia, palpitations, supraventricular extrasystoles, supraventricular tachycardia, ventricular extrasystoles, and cardiac arrest also reported.1

Interactions

Concomitant use with drugs that are potent CYP3A4 inhibitors (e.g., ketoconazole, high-dose ritonavir) or inducers (e.g., rifampin, carbamazepine, St. John's wort [Hypericum perforatum], long-acting barbiturates) is contraindicated.1 (See Interactions.)

Administration Precautions

IV solutions of isavuconazonium must be given by IV infusion through an inline filter to remove any insoluble particulates that may be present.1 (See IV Administration under Dosage and Administration.)

Selection and Use of Antifungals

Prior to initiation of isavuconazonium, obtain appropriate specimens for fungal culture and other relevant laboratory studies (including histopathology) to isolate and identify causative organism(s).1 May be started pending availability of results, but adjust antifungal therapy as needed when results become available.1

Specific Populations

Pregnancy

Category C.1

Use during pregnancy only if potential benefits to the woman justify potential risks to fetus.1

No adequate and well-controlled studies in pregnant women.1 Based on data from animal reproduction studies, isavuconazonium is predicted to have the potential for increasing the risk of adverse developmental outcomes above background risk.1

Lactation

Distributed into milk in rats.1 Do not breast-feed while receiving isavuconazonium.1

Pediatric Use

Safety and efficacy not established in patients <18 years of age.1

Geriatric Use

No substantial difference in pharmacokinetics between geriatric and younger adults.1

Hepatic Impairment

Mild or moderate hepatic impairment (Child-Pugh class A or B): AUC increased, systemic clearance decreased, half-life prolonged.1 12 Clinical importance unknown.12

Severe hepatic impairment (Child-Pugh class C): Use isavuconazonium only if benefits outweigh risks.1 If used in such patients, monitor for adverse effects.1 Pharmacokinetics not evaluated.1

Renal Impairment

Mild, moderate, or severe renal impairment: No clinically important effects on pharmacokinetics.1

Common Adverse Effects

GI effects (nausea, vomiting, diarrhea, abdominal pain, constipation, dyspepsia, decreased appetite),1 elevated bilirubin and liver enzymes (e.g., ALT, AST, alkaline phosphatase, γ-glutamyltransferase),1 metabolic effects (hypokalemia, hypomagnesemia),1 respiratory effects (dyspnea, cough, acute respiratory failure),1 headache,1 fatigue,1 insomnia,1 back pain,1 chest pain,1 peripheral edema,1 hypotension,1 renal failure,1 delirium (e.g., agitation, confusional state, disorientation, mental status changes),1 anxiety,1 rash,1 pruritus,1 administration site reactions.1

Absorption

Bioavailability

Following oral or IV administration, isavuconazonium sulfate is rapidly and almost completely (>98%) hydrolyzed by esterases in the blood to yield the active moiety, isavuconazole, and an inactive cleavage product.1 10 11

Well absorbed following oral administration (absolute bioavailability 98%).1

Peak plasma concentrations achieved in approximately 2–4 hours after oral administration1 10 11 or 0.7–1 hour after start of IV infusion.1 10

Food

Administration with high-fat meal has no clinically important effect on oral absorption.1

Plasma Concentrations

Steady-state concentrations probably not achieved until after 2 weeks.11

Special Populations

Reduced bioavailability possible in patients with Roux-en-Y gastric bypass.13

Distribution

Extent

Extensively distributed into tissues.1 10

Distributed into milk in rats.1

Plasma Protein Binding

>99% (mainly albumin).1 10

Elimination

Metabolism

In vivo studies indicate isavuconazole is metabolized by CYP3A4 and 3A5 and, subsequently, by UGT.1

Elimination Route

Following oral administration of radiolabeled isavuconazonium sulfate, 46% of total radioactive dose recovered in feces (approximately 33% as isavuconazole) and 46% recovered in urine (principally as metabolites of isavuconazole and metabolites of the inactive cleavage product).1 4

Only negligible amounts (<1%) of a dose of isavuconazonium sulfate are eliminated in urine as active isavuconazole.1 10

Isavuconazole is not readily dialyzable.1

Half-life

Single-dose study in adults using oral or IV isavuconazonium sulfate indicates mean distribution half-life of isavuconazole is 1.7–2.1 or 0.42–1.6 hours, respectively, and mean terminal elimination half-life of isavuconazole is 56–77 or 76–104 hours, respectively.10

Special Populations

Mild or moderate hepatic impairment (Child-Pugh class A or B): Mean AUC increased by 64 or 84%. respectively.1 After IV administration, half-life increased to 224 or 302 hours, respectively, compared with 123 hours in healthy individuals.12

Mild, moderate, or severe renal impairment: Pharmacokinetics not altered.1

Geriatric patients: Pharmacokinetics not affected by age.1

• Triazole antifungal;1 5 6 7 9 structurally similar to fluconazole and voriconazole.7 22

• Isavuconazonium is a prodrug and is inactive until hydrolyzed in the blood to isavuconazole.1 6 7 9

• Like other triazole antifungals, inhibits 14-α-demethylase, which leads to accumulation of methylated sterols (e.g., 14-α-methylated lanosterol, 4,14-dimethylzymosterol, 24-methylenedihydrolanosterol) and decreased concentrations of ergosterol in fungal cell membranes.1 6 7 Depletion of ergosterol affects cell membrane integrity and function and can lead to fungal cell death.1 6 7

• Aspergillus: Active in vitro and in clinical infections against A. flavus,1 14 19 20 21 A. fumigatus,1 14 19 20 21 and A. niger.1 14 19 20 21 Also has in vitro activity against A. nidulans14 20 21 and A. terreus.14 19 20 21

• Mucorales: Active in vitro and in clinical infections against fungi in the order Mucorales, including Rhizopus (R. oryzae, R. azygospurus, R. microspores),1 19 Mucor (M. amphibiorum,1 M. circinelloides1 14 ), Lichtheimia (L. corymbifera; formerly Absidia corymbifera),1 14 and Rhizomucor (R. pusillus).1 14 19

• Candida: Active in vitro against C. albicans,14 19 20 C. dublinensis,14 19 C. glabrata,14 18 19 20 C. guilliermondii,14 18 19 C. krusei,14 18 19 20 C. lusitaniae,14 19 C. parapsilosis,14 19 20 and C. tropicalis.14 19 20 Has in vitro activity against some Candida that have resistance or reduced susceptibility to fluconazole.6 14 19

• Other fungi: Active in vitro against Blastomyces dermatitidis,14 Coccidioides posadasii,14 Cryptococcus gattii,14 C. neoformans,14 19 Geotrichum capitatum,14 Histoplasma capsulatum,14 Penicillium,19 Pichia,14 Rhodotorula,14 Saccharomyces cerevisiae,14 Scedosporium,14 19 Trichosporon,14 19 and dermatophytes (Trichophyton rubrum, T. mentagrophytes, T. tonsurans, Epidermophyton floccosum, Microsporum canis).14

• Resistance or reduced susceptibility to isavuconazole may occur.1 5 6 14 18 22 Cross-resistance can occur between isavuconazole and other azole antifungals (e.g., itraconazole, voriconazole).1 5 19 22

In the U.S.

• Cresemba

Available Dosage Forms:

• Capsule

Therapeutic Class: Antifungal

Chemical Class: Isavuconazonium

Isavuconazonium is used to treat serious fungal or yeast infections, such as invasive aspergillosis and invasive mucormycosis. This medicine works by killing the fungus or yeast and preventing its growth.

This medicine is available only with your doctor's prescription.

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 (6.1)].

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 (6.1)].

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 (8.1)].

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 (13.1)].

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 (4) and Drug Interactions (7)].

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 (2.4)].

The following are discussed in more detail in other sections of the labeling:

• Hepatic Adverse Drug Reactions [see Warnings and Precautions (5.1)] • Infusion-Related Reactions [see Warnings and Precautions (5.2)] • Hypersensitivity Reactions [see Warnings and Precautions (5.3)] • Embryo-Fetal Toxicity [see Warnings and Precautions (5.4)]

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

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.
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 pain	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 system 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)

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 which 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.

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 (12.3)].

Table 3. Drug(s) Affecting Pharmacokinetics of Cresemba

a 400 mg of lopinavir in combination with 100 mg of ritonavir.
	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 (12.3)].
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 (12.3)].
Rifampin	Contraindicate coadministration of all potent CYP3A4 inducers	There is a 97% decrease in exposure of isavuconazole upon coadministration with rifampin [see Clinical Pharmacology (12.3)].

Table 4. The Effect of Cresemba on the Pharmacokinetics of Other Drugs

a 400 mg of lopinavir in combination with 100 mg of ritonavir.
	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 (12.3)].
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 (12.3)].
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 (12.3)].
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 (12.3)].
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 (12.3)].
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 (12.3)].
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 [see Clinical Pharmacology (12.3)].
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 when dosed concurrently with Cresemba [see Clinical Pharmacology (12.3)].

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 (13.1)]. 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 (12.3)]. 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/1.73 m2. 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 (12.3)].

Hepatic Impairment

No dose adjustment is necessary in patients with mild or moderate hepatic impairment (Child-Pugh Class A and B) [see Clinical Pharmacology (12.3)]. 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 (5.1)].

Cresemba contains isavuconazonium sulfate, which is the prodrug of isavuconazole, an azole antifungal drug. Isavuconazonium sulfate drug substance is an amorphous, white to yellowish-white powder. The chemical name of isavuconazonium sulfate is glycine, N-methyl-, [2-[[[1-[1-[(2R,3R)-3-[4-(4-cyanophenyl)-2-thiazolyl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-4H-1,2,4-triazolium-4-yl]ethoxy]carbonyl]methylamino]-3-pyridinyl]methyl ester, sulfate (1:1). The empirical formula is C35H35F2N8O5S·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, hypromellose, 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 lyophilized 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.

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.

Product of Portugal

Marketed and Distributed by:
Astellas Pharma US, Inc.
Northbrook, IL 60062

Cresemba is a registered trademark of Astellas Pharma Inc.

Licensed from: Basilea Pharmaceutica International Ltd.

Revised: June 2015

15D034-ISA

Cresemba® (Crē sem’ bah)
(isavuconazonium sulfate)
Capsules, for oral administration

Cresemba® (Crē sem’ bah)
(isavuconazonium sulfate)
For injection, for intravenous administration

Read this Patient Information before you start taking Cresemba and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.

What is Cresemba?

Cresemba is a prescription medicine used to treat people 18 years of age and older with certain types of fungal infections in the blood or body called “aspergillosis,” and “mucormycosis” (zygomycosis). Cresemba may be given as capsules or through an IV placed in your arm (intravenously).

It is not known if Cresemba is safe and effective in children under 18 years of age.

Who should not take Cresemba?

Do not take Cresemba if you:

• are allergic to Cresemba or any of the ingredients. See the end of this leaflet for a complete list of ingredients in Cresemba. • have a genetic problem that affects the electrical system of the heart (familial short QT syndrome). • are taking any of the following medicines: • ketoconazole • high-dose ritonavir • rifampin • carbamazepine • St. John’s wort (herbal supplement) • long-acting barbiturates

Talk to your healthcare provider or pharmacist if you are not sure if you are taking any of these medicines or have any of the conditions listed above.

Do not start taking a new medicine without talking to your healthcare provider or pharmacist.

What should I tell my healthcare provider before taking Cresemba?

Before you take Cresemba, tell your healthcare provider if you:

• have or ever had an abnormal heart rate or rhythm. Your healthcare provider may order a test to check your heart (ECG) before starting Cresemba. • have liver problems. Your healthcare provider may do blood tests to make sure you can take Cresemba. • have ever had an allergic reaction to other antifungal medications such as ketoconazole, fluconazole, itraconazole, voriconazole or posaconazole. • have any other medical conditions. • are pregnant or plan to become pregnant. It is not known if Cresemba will harm your unborn baby. • are breastfeeding or plan to breastfeed. Cresemba can pass into your breast milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take Cresemba. You should not breastfeed while taking Cresemba.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Cresemba may affect the way other medicines work, and other medicines may affect how Cresemba works causing side effects.

Ask your healthcare provider or pharmacist for a list of these medicines, if you are not sure.

Know the medicines you take. Keep a list of them with you to show your healthcare provider and pharmacist when you get a new medicine.

How should I take Cresemba capsules?

• Take Cresemba exactly as your healthcare provider tells you to take it. • Do not stop taking Cresemba until your healthcare provider tells you to. • If you take too much Cresemba, call your healthcare provider. • Cresemba capsules can be taken with or without food. • Swallow Cresemba capsules whole. Do not chew, crush, dissolve, or open the capsules.

Instructions on opening Cresemba capsules blister packaging:

• Cresemba capsules are in child resistant blister packaging. Each blister section contains two pockets – One for the Cresemba capsule, and one for the desiccant to protect the capsule from moisture (located to the left of the capsule). • Only open the blister packaging at time of use. Ensure only Cresemba capsule pocket is opened. • Please refer to the picture below. • To open the blister packaging, open from the printed side as shown above.

Bend & tear along the horizontal perforated dotted line.

Peel the paper away from the foil backing.

Then push the capsule through the exposed foil until released.

If difficult to peel, scissors may be used to open package.

What are the possible side effects of Cresemba?

Cresemba may cause serious side effects, including:

• liver problems. Liver problems can happen in some people taking Cresemba. Some people who also have other serious medical problems may get severe liver problems which can lead to hepatitis, gallbladder problems, liver failure or death. Your healthcare provider should do blood tests to check your liver before you start and while you are taking Cresemba. Call your healthcare provider right away if you have any of the following symptoms of liver problems: • itchy skin • nausea or vomiting • yellowing of your eyes • feeling very tired • flu-like symptoms
   • drug interactions with cyclosporine, sirolimus, or tacrolimus. If you take Cresemba with cyclosporine, sirolimus, or tacrolimus, your blood levels of cyclosporine, sirolimus, or tacrolimus may increase. Serious side effects can happen in your kidney or brain if you have high levels of cyclosporine, sirolimus, or tacrolimus in your blood. Your healthcare provider should do blood tests to check your levels of cyclosporine, sirolimus, or tacrolimus if you are taking these medicines while taking Cresemba. Tell your healthcare provider right away if you have swelling in your arm or leg or shortness of breath.
   • infusion reactions. Infusion reactions can happen in people receiving Cresemba intravenously. If an infusion reaction happens, your infusion will be stopped. Symptoms of an infusion reaction may include: • low blood pressure • difficulty breathing • chills • dizziness • numbness and tingling • changes in your sense of touch (hypoesthesia)
    • severe allergic and skin reactions.
    • medicine interactions. Taking Cresemba with some other medicines may affect the way other medicines work causing serious side effects. Other medicines may affect the way Cresemba works, causing serious side effects. Tell your healthcare provider about all the medicines you take.

The most common side effects of Cresemba include:

• nausea • vomiting • diarrhea • headache • changes in the level of a liver enzyme in your blood • low potassium • back pain • shortness of breath • cough • swelling of arms or legs • constipation

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Cresemba. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Cresemba capsules?

• Store Cresemba at room temperature between 68°F to 77°F (20°C to 25°C). • Keep Cresemba in the original package and protect it from moisture. • Do not remove Cresemba from original packaging until your scheduled dose. • Do not put Cresemba in pill boxes or pill organizers. • Safely throw away medicine that is out of date or no longer needed.

Keep Cresemba and all medicines out of the reach of children.

General information about the safe and effective use of Cresemba.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Cresemba for a condition for which it was not prescribed. Do not give Cresemba to other people, even if they have the same symptoms that you have. It may harm them.

This Patient Information leaflet summarizes the most important information about Cresemba. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Cresemba that is written for healthcare professionals.

For more information go to www.Cresemba.com or call 1-800-727-7003.

What are the ingredients of Cresemba capsules?
Active ingredient: isavuconazonium sulfate
Inactive ingredients: magnesium citrate, microcrystalline cellulose, talc, colloidal silicon dioxide, stearic acid, hypromellose, red iron oxide, titanium dioxide, purified water, gellan gum, potassium acetate, disodium edetate, sodium laurylsulfate, shellac, propylene glycol, strong ammonia solution, potassium hydroxide, black iron oxide

This Patient Information has been approved by the U.S. Food and Drug Administration.

Marketed and Distributed by:
Astellas Pharma US, Inc.
Northbrook, IL 60062

Cresemba is a registered trademark of Astellas Pharma Inc.

Licensed from: Basilea Pharmaceutica International Ltd.

15D034-ISA

Revised: June 2015

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include dizziness, drowsiness, hot flashes, headache, joint pain, anxiety, feeling restless, numbness or tingling, trouble concentrating, dry mouth, altered sense of taste, numbness in or around your mouth, diarrhea, vomiting, and fast or pounding heartbeats.