Isavuconazonium

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Isavuconazonium
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Martin Nino [2]

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Overview

Isavuconazonium is an azole antifungal that is FDA approved for the treatment of invasive aspergillosis and invasive mucormycosis. Common adverse reactions include nausea, vomiting, diarrhea, headache, elevated liver chemistry tests, hypokalemia, constipation, dyspnea, cough, peripheral edema, and back pain.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Inidcations

Isavuconazonium is an azole antifungal indicated for patients 18 years of age and older for the treatment of invasive aspergillosis.

Isavuconazonium is an azole antifungal indicated for patients 18 years of age and older for the treatment of invasive mucormycosis.


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.

Dosage

Prescribe Isavuconazonium as shown in TABLE 1 below.

TABLE 1

Switching between the intravenous and oral formulations of Isavuconazonium 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. Isavuconazonium capsules can be taken with or without food.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Isavuconazonium in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Isavuconazonium in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Safety and effectiveness have not been established in pediatric patients.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Isavuconazonium in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Isavuconazonium in pediatric patients.

Contraindications

  • Isavuconazonium is contraindicated in persons with known hypersensitivity to Isavuconazonium.
  • Coadministration of strong CYP3A4 inhibitors, such as ketoconazole or high-dose ritonavir (400 mg every 12 hours), with Isavuconazonium is contraindicated because strong CYP3A4 inhibitors can significantly increase the plasma concentration of Isavuconazonium.
  • Coadministration of strong CYP3A4 inducers, such as rifampin, carbamazepine, St. John’s wort, or long acting barbiturates with Isavuconazonium is contraindicated because strong CYP3A4 inducers can significantly decrease the plasma concentration of Isavuconazonium.
  • Isavuconazonium shortened the QTc interval in a concentration-related manner. Isavuconazonium is contraindicated in patients with familial short QT syndrome.

Warnings

  • 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 Isavuconazonium. 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 Isavuconazonium.

Evaluate liver-related laboratory tests at the start and during the course of Isavuconazonium therapy. Monitor patients who develop abnormal liver-related laboratory tests during Isavuconazonium therapy for the development of more severe hepatic injury. Discontinue Isavuconazonium if clinical signs and symptoms consistent with liver disease develop that may be attributable to Isavuconazonium.

  • Infusion-Related Reactions

Infusion-related reactions including hypotension, dyspnea, chills, dizziness, paresthesia, and hypoesthesia were reported during intravenous administration of Isavuconazonium. Discontinue the infusion if these reactions occur.

Serious hypersensitivity and severe skin reactions, such as anaphylaxis or Stevens Johnson syndrome, have been reported during treatment with other azole antifungal agents. Discontinue Isavuconazonium if a patient develops a severe cutaneous adverse reaction. There is no information regarding cross-sensitivity between Isavuconazonium and other azole antifungal agents. Caution should be used when prescribing Isavuconazonium to patients with hypersensitivity to other azoles.

  • Embryo-Fetal Toxicity

Isavuconazonium may cause fetal harm when administered to a pregnant woman. Isavuconazonium 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 Isavuconazonium are encouraged to contact their physician.

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.

  • Drug Interactions

Coadministration of Isavuconazonium 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, Isavuconazonium intravenous formulation may form precipitate from the insoluble Isavuconazonium. Administer Isavuconazonium through an in-line filter.

Adverse Reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of Isavuconazonium cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice.

A total of 403 patients were exposed to Isavuconazonium in two clinical trials. The most frequently reported adverse reactions among Isavuconazonium-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 Isavuconazonium due to an adverse reaction in the two trials. The adverse reactions which most often led to permanent discontinuation of Isavuconazonium 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 Isavuconazonium therapy of greater than 12 weeks, with 52 patients receiving Isavuconazonium 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 Isavuconazonium and voriconazole treatment groups, respectively. Treatment-emergent adverse reactions resulting in permanent discontinuation were reported in 37 (14%) Isavuconazonium-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 Isavuconazonium therapy in Trial 1.

In Trial 2, an open-label, non-comparative trial of Isavuconazonium in patients with invasive aspergillosis and renal impairment or invasive mucormycosis, treatment-emergent adverse reactions occurred in 139/146 (95%) of patients in the Isavuconazonium treatment group. Adverse reactions resulting in permanent discontinuation were reported in 19 (13%) Isavuconazonium-treated patients. The frequencies and types of adverse reactions observed in Isavuconazonium-treated patients were similar between Trial 1 and Trial 2.

TABLE 2

The following adverse reactions occurred in less than 5% of all Isavuconazonium-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 Isavuconazonium cannot be ruled out or those which may help the physician in managing the risks to the patients.

  • Injury, poisoning and procedural complications: fall

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 Isavuconazonium. Elevations of liver transaminases greater than ten times the upper limit of normal developed in 1.2% of patients who received Isavuconazonium.

Postmarketing Experience

There is limited information regarding Isavuconazonium Postmarketing Experience in the drug label.

Drug Interactions

Isavuconazole is a sensitive substrate of CYP3A4. CYP3A4 inhibitors or inducers may alter the plasma concentrations of Isavuconazonium.

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.

TABLE 3 TABLE 4

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): C . There are no adequate and well-controlled clinical studies of Isavuconazonium in pregnant women. Isavuconazonium should be used during pregnancy only if the potential benefit to the patient outweighs the risk to the fetus. Women who become pregnant during Isavuconazonium treatment are encouraged to contact their physician.

  • Risk Summary

Based on animal data, Isavuconazonium 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. Skeletal abnormalities have also been observed in embryo-fetal development studies of other azole antifungal agents.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Isavuconazonium in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Isavuconazonium during labor and delivery.

Nursing Mothers

Isavuconazole is excreted in the milk of lactating rats following intravenous administration. Mothers should not breast feed while taking Isavuconazonium.

Pediatric Use

The safety and efficacy of Isavuconazonium in pediatric patients less than 18 years of age have not been established.

Geriatic Use

Of the 547 patients who received Isavuconazonium 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). No dose adjustment of Isavuconazonium is needed in elderly patients.

Gender

There is no FDA guidance on the use of Isavuconazonium with respect to specific gender populations.

Race

There is no FDA guidance on the use of Isavuconazonium with respect to specific racial populations.

Renal Impairment

Of the 403 patients who received Isavuconazonium 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).

Hepatic Impairment

No dose adjustment is necessary in patients with mild or moderate hepatic impairment (Child-Pugh Class A and B). Isavuconazonium 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 Isavuconazonium-related adverse reactions is recommended when treating patients with severe hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Isavuconazonium in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Isavuconazonium in patients who are immunocompromised.

Administration and Monitoring

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 Isavuconazonium 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 Isavuconazonium.
  • After dilution of the intravenous formulation, avoid unnecessary vibration or vigorous shaking of the solution. Do not use a pneumatic transport system.
  • Reconstitution Instructions for the Injection Formulation

Aseptic technique must be strictly observed in all handling since no preservative or bacteriostatic agent is present in Isavuconazonium or in the materials specified for reconstitution. Isavuconazonium is water soluble, preservative-free, sterile, and nonpyrogenic.

  • Reconstitute one vial of Isavuconazonium 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 Isavuconazonium 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

Isavuconazonium for injection should only be administered with the following diluents:

Monitoring

There is limited information regarding Isavuconazonium Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Isavuconazonium and IV administrations.

Overdosage

During clinical studies, total daily Isavuconazonium 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 study 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.

Pharmacology

There is limited information regarding Isavuconazonium Pharmacology in the drug label.

Mechanism of Action

There is limited information regarding Isavuconazonium Mechanism of Action in the drug label.

Structure

There is limited information regarding Isavuconazonium Structure in the drug label.

Pharmacodynamics

There is limited information regarding Isavuconazonium Pharmacodynamics in the drug label.

Pharmacokinetics

There is limited information regarding Isavuconazonium Pharmacokinetics in the drug label.

Nonclinical Toxicology

There is limited information regarding Isavuconazonium Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Isavuconazonium Clinical Studies in the drug label.

How Supplied

There is limited information regarding Isavuconazonium How Supplied in the drug label.

Storage

There is limited information regarding Isavuconazonium Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Isavuconazonium Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Isavuconazonium interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Isavuconazonium Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Isavuconazonium Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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