Antifungal Medication
Sporanox (itraconazole) Oral Solution
Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER)
BOXED WARNING Congestive Heart Failure, Cardiac Effects and Drug Interactions
- If signs or symptoms of congestive heart failure occur during administration of Sporanox (itraconazole) Oral Solution, continued Sporanox use should be reassessed.
- Coadministration of the following drugs are contraindicated with Sporanox Oral Solution: methadone, disopyramide, dofetilide, dronedarone, quinidine, ergot alkaloids (such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)), irinotecan, lurasidone, oral midazolam, pimozide, triazolam, felodipine, nisoldipine, ranolazine, eplerenone, cisapride, lovastatin, simvastatin and, in subjects with renal or hepatic impairment, colchicine. Coadministration with itraconazole can cause elevated plasma concentrations of these drugs and may increase or prolong both the pharmacologic effects and/or adverse reactions to these drugs. For example, increased plasma concentrations of some of these drugs can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsades de pointes, a potentially fatal arrhythmia.
- Coadministration of a number of CYP3A4 substrates are contraindicated with Sporanox. Plasma concentrations increase for the following drugs: methadone, disopyramide, dofetilide, dronedarone, quinidine, ergot alkaloids (such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)), irinotecan, lurasidone, oral midazolam, pimozide, triazolam, felodipine, nisoldipine, ranolazine, eplerenone, cisapride, lovastatin, simvastatin and, in subjects with renal or hepatic impairment, colchicine. This increase in drug concentrations caused by coadministration with itraconazole may increase or prolong both the pharmacologic effects and/or adverse reactions to these drugs. For example, increased plasma concentrations of some of these drugs can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsade de pointes, a potentially fatal arrhythmia. Specific examples are listed in PRECAUTIONS: Drug Interactions.
- Sporanox has a potential for clinically important drug interactions. Coadministration of specific drugs with itraconazole may result in changes in efficacy of itraconazole and/or the coadministered drug, life-threatening effects and/or sudden death. Drugs that are contraindicated, not recommended or recommended for use with caution in combination with itraconazole are listed in PRECAUTIONS: Drug Interactions.
- Sporanox (itraconazole) Oral Solution and Sporanox Capsules should not be used interchangeably. This is because drug exposure is greater with the Oral Solution than with the Capsules when the same dose of drug is given. Only Sporanox Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis.
- Sporanox Oral Solution contains the excipient hydroxypropyl-β-cyclodextrin which produced adenocarcinomas in the large intestine and exocrine pancreatic adenocarcinomas in a rat carcinogenicity study. These findings were not observed in a similar mouse carcinogenicity study. The clinical relevance of these adenocarcinomas is unknown.
- Sporanox Oral Solution contains …adenocarcinomas in the large intestine and exocrine …The clinical relevance of these adenocarcinomas is unknown.
- Instruct patients that dizziness or blurred/double vision can sometimes occur with itraconazole. Advise patients that if they experience these events, they should not drive or use machines.
Pregnancy: Teratogenic effects. Pregnancy Category C
- Sporanox Oral Solution contains the excipient hydroxypropyl-β-cyclodextrin (HP-β-CD). HP-β-CD has no direct embryotoxic and no teratogenic effect…
- Clinical studies of Sporanox Oral Solution did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. It is advised to use Sporanox Oral Solution in these patients only if it is determined that the potential benefit outweighs the potential risks. In general, it is recommended that the dose selection for an elderly patient should be taken into consideration, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
- … The exposure of itraconazole may be lower in some patients with renal impairment. Caution should be exercised…and dose adjustment may be needed.
- … It is recommended that patients with impaired hepatic function be carefully monitored when taking Sporanox. It is recommended that the prolonged elimination half-life of itraconazole observed in the single oral dose clinical trial with itraconazole capsules in cirrhotic patients be considered when deciding to initiate therapy with other medications metabolized by CYP3A4.
- In patients with elevated or abnormal liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment with Sporanox is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk. It is recommended that liver function monitoring be done in patients with preexisting hepatic function abnormalities or those who have experienced liver toxicity with other medications.
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice…
- Cardiac Disorders: cardiac failure;
- General Disorders and Administration Site Conditions: edema;
- Hepatobiliary Disorders: hepatic failure, hyperbilirubinemia;
- Metabolism and Nutrition Disorders: hypokalemia;
- Reproductive System and Breast Disorders: menstrual disorder
- Cardiac Disorders: left ventricular failure;
- Gastrointestinal Disorders: gastrointestinal disorder;
- General Disorders and Administration Site Conditions: face edema;
- Hepatobiliary Disorders: jaundice, hepatic function abnormal;
- Investigations: alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood lactate dehydrogenase increased, gammaglutamyltransferase increased, urine analysis abnormal;
- Metabolism and Nutrition Disorders: hyperglycemia, hyperkalemia;
- Nervous System Disorders: somnolence;
- Psychiatric Disorders: confusional state;
- Renal and Urinary Disorders: renal impairment;
- Respiratory, Thoracic and Mediastinal Disorders: dysphonia;
- Skin and Subcutaneous Tissue Disorders: rash erythematous;
- Vascular Disorders: hypertension
Source : FDA (July 2014)
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Sporanox (Itraconazole) Capsules - Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER)
Sporanox (itraconazole) is an antifungal medication. Sporanox is used to treat infections caused by fungus, which can invade any part of the body including the lungs, mouth or throat, toenails, or fingernails.
BOXED WARNING
- Coadministration of the following drugs are contraindicated with Sporanox Capsules: methadone, disopyramide, dofetilide, dronedarone, quinidine, ergot alkaloids (such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)), irinotecan, lurasidone, oral midazolam, pimozide, triazolam, felodipine, nisoldipine, ranolazine, eplerenone, cisapride, lovastatin, simvastatin and, in subjects with renal or hepatic impairment, colchicine. Coadministration with itraconazole can cause elevated plasma concentrations of these drugs and may increase or prolong both the pharmacologic effects and/or adverse reactions to these drugs. For example, increased plasma concentrations of some of these drugs can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsades de pointes, a potentially fatal arrhythmia.
- Coadministration of a number of CYP3A4 substrates are contraindicated with Sporanox. Plasma concentrations increase for the following drugs: methadone, disopyramide, dofetilide, dronedarone, quinidine, ergot alkaloids (such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)), irinotecan, lurasidone, oral midazolam, pimozide, triazolam, felodipine, nisoldipine, ranolazine, eplerenone, cisapride, lovastatin, simvastatin and, in subjects with renal or hepatic impairment, colchicine. This increase in drug concentrations caused by coadministration with itraconazole may increase or prolong both the pharmacologic effect and/or adverse reactions to these drugs. For example, increased plasma concentrations of some of these drugs can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsade de pointes, a potentially fatal arrhythmia.
- Calcium channel blockers can have negative… Concomitant administration of Sporanox and felodipine…
- Sporanox has a potential for clinically important drug interactions. Coadministration of specific drugs with itraconazole may result in changes in efficacy of itraconazole and/or the coadministered drug, life-threatening effects and/or sudden death.
- Sporanox (itraconazole) Capsules and Sporanox Oral Solution should not be used interchangeably. This is because drug exposure is greater with the Oral Solution than with the Capsules when the same dose of drug is given. In addition, the topical effects of mucosal exposure may be different between the two formulations. Only the Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis.
- …Sporanox Capsules must be swallowed whole.
- Instruct patients that dizziness, blurred/double vision or hearing loss can sometimes occur with itraconazole. Advise patients that if they experience these events, they should not drive or use machines.
Geriatric Use
- Clinical studies of Sporanox Capsules did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. It is advised to use Sporanox Capsules in these patients only if it is determined that the potential benefit outweighs the potential risks. In general, it is recommended that the dose selection for an elderly patient should be taken into consideration, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
- …The exposure of itraconazole may be lower in some patients with renal insufficiency. Caution should be exercised … and adjusting the dose may be considered..
- …It is recommended that patients with impaired hepatic function be carefully monitored when taking Sporanox. It is recommended that the prolonged elimination half-life of itraconazole observed in the single oral dose clinical trial with itraconazole capsules in cirrhotic patients be considered when deciding to initiate therapy with other medications metabolized by CYP3A4.
- In patients with elevated or abnormal liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment with Sporanox is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk. It is recommended that liver function monitoring be done in patients with preexisting hepatic function abnormalities or those who have experienced liver toxicity with other medications
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
- In addition, the following adverse drug reaction was reported in patients who participated in Sporanox Capsules clinical trials: Hepatobiliary Disorders: hyperbilirubinemia.
- Cardiac Disorders: cardiac failure, left ventricular failure, tachycardia;
- General Disorders and Administration Site Conditions: face edema, chest pain, chills;
- Hepatobiliary Disorders: hepatic failure, jaundice;
- Investigations: alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood lactate dehydrogenase increased, blood urea increased, gamma-glutamyltransferase increased, urine analysis abnormal;
- Metabolism and Nutrition Disorders: hyperglycemia, hyperkalemia, hypomagnesemia;
- Psychiatric Disorders: confusional state;
- Renal and Urinary Disorders: renal impairment;
- Respiratory, Thoracic and Mediastinal Disorders: dysphonia, cough;
- Skin and Subcutaneous Tissue Disorders: rash erythematous, hyperhidrosis;
- Vascular Disorders: hypotension
- Table 5: Postmarketing Reports of Adverse Drug Reactions (Minor editorial edits and addition of)
- Investigations: Blood creatine phosphokinase increased
- disopyramide (such as Norpace)
- dronedarone (such as Multaq)
- ranolazine (such as Ranexa)
- lurasidone (such as Latuda)
- eplerenone (such as Inspra)
- irinotecan (such as Camptosar)
- colchicine (such as Colcrys) [if you also have pre-existing kidney or liver impairment]
- Sporanox can sometimes cause dizziness, blurred/double vision or hearing loss. If you have these symptoms, do not drive or use machines.
- The most common side effects include: headache, and digestive system problems (such as nausea, and abdominal pain).
Source : FDA July 2014
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FDA Drug Safety Communication: FDA limits usage of Nizoral (ketoconazole) oral tablets due to potentially fatal liver injury and risk of drug interactions and adrenal gland problems
The U.S. Food and Drug Administration (FDA) is taking several actions related to Nizoral (ketoconazole) oral tablets, including limiting the drug’s use, warning that it can cause severe liver injuries and adrenal gland problems and advising that it can lead to harmful drug interactions with other medications. FDA has approved label changes and added a new Medication Guide to address these safety issues. As a result, Nizoral oral tablets should not be a first-line treatment for any fungal infection. Nizoral should be used for the treatment of certain fungal infections, known as endemic mycoses, only when alternative antifungal therapies are not available or tolerated. The topical formulations of Nizoral have not been associated with liver damage, adrenal problems, or drug interactions. These formulations include creams, shampoos, foams, and gels applied to the skin, unlike the Nizoral tablets, which are taken by mouth.
Liver Injury (Hepatotoxicity)
Nizoral tablets can cause liver injury, which may potentially result in liver transplantation or death. FDA has revised the Boxed Warning, added a strong recommendation against its use (contraindication) in patients with liver disease, and included new recommendations for assessing and monitoring patients for liver toxicity (see Additional Information sections).
Serious liver damage has occurred in patients receiving high doses of Nizoral for short periods of time as well as those receiving low doses for long periods. Some of these patients had no obvious risk factors for liver disease. The liver injury is sometimes reversible upon stopping the drug, but that is not always possible.
Adrenal Gland Problems (Adrenal Insufficiency)
Nizoral tablets may cause adrenal insufficiency by decreasing the body’s production of hormones called corticosteroids. Corticosteroids are produced by the adrenal glands, which are small glands located on top of each kidney. Corticosteroids affect the body’s balance of water and salts and minerals (electrolytes). Health care professionals should monitor adrenal function in patients taking Nizoral tablets who have existing adrenal problems or in patients who are under prolonged periods of stress such as those who have had a recent major surgery or who are under intensive care in the hospital.
Drug Interactions
Nizoral tablets may interact with other drugs a patient is taking and can result in serious and potentially life-threatening outcomes, such as heart rhythm problems. All medications that a patient is currently taking should be assessed for possible interactions with Nizoral tablets.
In summary, the drug label for Nizoral tablets has been updated to include the following information:
- Limitation of the usage of Nizoral tablets by removing indications in which the risk outweighs the benefits. The use of ketoconazole tablets in Candida and dermatophyte infections is no longer indicated. Nizoral tablets should be used only when other antifungal drugs are not available or tolerated by the patient. (Boxed Warning, Warnings, Precautions, and Indications and Usage sections)
- Nizoral tablets are indicated only for the treatment of the following fungal infections: blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis in patients in whom other treatments have failed or who are intolerant to other therapies (Indications and Usage section).
- Nizoral tablets are not indicated for the treatment of fungal infections of the skin or nails.
- A new contraindication that Nizoral tablets should not be used in patients with acute or chronic liver disease (Contraindications section).
- Updated information on the risk of liver injury, or hepatotoxicity, with new assessment and monitoring recommendations (Boxed Warning, Warnings, and Precautions sections).
- Updated information on drug interactions (Precautions section).
- A warning regarding adrenal insufficiency with recommendations for monitoring populations at risk (Warnings section).
On July 26, 2013, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) announced their negative risk-benefit assessment for oral ketoconazole-containing medicines used to treat infections caused by dermatophytes and yeasts and recommended suspensions of these medicines throughout the European Union (EU). The EMA public announcement of the recommendation to suspend the marketing authorizations of ketoconazole for oral use as antifungal treatment is available at http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2013/07/WC500146613.pdf.
In addition to the indications for treatment of infections caused by dermatophytes and Candida, the previous US drug label also included indications for the following serious fungal infections: blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis. In the revised US drug label, indications for dermatophyte and Candida infections have been removed and the indications for treatment of blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis have been retained only for patients in whom other antifungal treatments have failed or are not tolerated.
FDA will continue to evaluate the safety of Nizoral tablets and will communicate with the public again if additional information becomes available.
Source : FDA (July 2013)
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FDA Drug Safety Communication:Use of long-term, high-dose Diflucan (fluconazole) during pregnancy may be associated with birth defects in infants
Antifungal drug Diflucan (fluconazole)
Used to treat yeast infections of the vagina, mouth, throat, esophagus, and other organs.
Used to treat meningitis caused by a certain type of fungus.
Used to prevent yeast infections in patients who are likely to become infected because they are being treated with chemotherapy or radiation therapy before a bone marrow transplant.
The dose of fluconazole for vaginal candidiasis is a single dose of 150 mg and is lower than for other indications.
The U.S. Food and Drug Administration (FDA) is informing the public that chronic, high doses (400-800 mg/day) of the antifungal drug Diflucan (fluconazole) may be associated with a rare and distinct set of birth defects in infants whose mothers were treated with the drug during the first trimester of pregnancy. This risk does not appear to be associated with a single, low dose of fluconazole 150 mg to treat vaginal yeast infection (candidiasis).
There are several published case reports of birth defects in infants whose mothers were treated with high-dose fluconazole (400-800 mg/day) for serious and life-threatening fungal infections during most or all of the first trimester (see Data Summary below).1-4 The features seen in these infants are listed in Table 1.
Based on this information, the pregnancy category for fluconazole indications (other than vaginal candidiasis) has been changed from category C to category D. The pregnancy category for a single dose of fluconazole 150 mg to treat vaginal candidiasis has not changed and remains category C.
Pregnancy category D means there is positive evidence of human fetal risk based on human data but the potential benefits from use of the drug in pregnant women with serious or life-threatening conditions may be acceptable despite its risks.
Healthcare professionals should be aware of the potential risks with long-term, high-dose use of fluconazole and counsel patients if the drug is used during pregnancy or if a patient becomes pregnant while taking the drug.
Additional Information for Patients
- Use of long-term, high-dose (400-800 mg/day) fluconazole during the first three months of pregnancy (first trimester) may be associated with a rare and distinct set of birth defects in infants.
- A single dose of fluconazole 150 mg to treat vaginal yeast infection during pregnancy does not appear to be associated with the birth defects.
- Patients should notify their healthcare professional if they are pregnant or become pregnant while taking fluconazole.
- Side effects from the use of fluconazole should be reported to the FDA MedWatch program, using the information in the "Contact Us" box at the bottom of the page.
- The pregnancy category for a single 150 mg dose of fluconazole for vaginal candidiasis is category C based on data from animal studies that showed an adverse effect on the fetus. There are no adequate and well-controlled studies of fluconazole in pregnant women. Available human data do not suggest an increased risk of congenital anomalies following a single maternal dose of 150 mg.
- The pregnancy category for fluconazole use for indications other than vaginal candidiasis is now category D. A few published case reports describe a rare pattern of distinct congenital anomalies in infants exposed in utero to high-dose maternal fluconazole (400-800 mg/day) during most or all of the first trimester.
- The features seen in these infants include brachycephaly, abnormal facies, abnormal calvarial development, cleft palate, femoral bowing, thin ribs and long bones, arthrogryposis, and congenital heart disease. These effects are similar to those seen in animal studies.
- If fluconazole is used during pregnancy, or if a patient becomes pregnant while taking fluconazole, the patient should be informed of the potential risk to the fetus.
- Adverse events involving fluconazole should be reported to the FDA MedWatch program using the information in the "Contact Us" box at the bottom of this page.
There are several case reports published in the medical literature that describe rare and distinct congenital anomalies in infants whose mothers were treated with chronic high-dose (400-800 mg/day) fluconazole for fungal infections in the first trimester of pregnancy.1-4 Four reports involved maternal use of chronic high-dose intravenous fluconazole for coccidioidal meningitis and one report involved a human immunodeficiency virus (HIV)-positive mother who received chronic high-dose oral fluconazole for vaginal candidiasis. Cases associated with high-dose fluconazole use all shared some characteristics with the autosomal recessive genetic disorder known as Antley-Bixler syndrome. This combination of congenital anomalies occurs rarely in the general population, and is similar to anomalies seen in animals following in utero fluconazole exposure.
Chronic high-dose fluconazole may be teratogenic in humans when used in the first trimester of pregnancy; however, the magnitude of this potential human teratogenic risk is unknown. The five reports of distinct and rare congenital anomalies following chronic, high-dose in utero exposure to fluconazole suggest a possible drug threshold effect for a fluconazole embryopathy.
The available data in the medical literature do not suggest an association between low-dose oral fluconazole use in the first trimester of pregnancy and congenital anomalies.5-11 The few published epidemiological studies of in utero exposure to low doses of fluconazole (most patients received a single oral dose of 150 mg) showed no consistent pattern of anomalies among affected infants; however, most of these studies were too small to accurately detect an increased risk for major birth defects overall.7, 9-11 In addition, none of these studies were large enough to accurately detect an increased risk for a rare or unique birth defect or syndrome.
Table 1.
Features Seen in Infants Exposed to long-term, high-dose Diflucan (fluconazole) in uteroshort,
broad head
abnormal looking face
abnormal development of the skullcaporal cleft (opening in the lip or palate)
bowing of the thigh bones
thin ribs and long bones
muscle weakness and joint deformities
Congenital (present at birth) heart disease
References
- Lopez-Rangel E, Van Allen MI. Prenatal exposure to fluconazole: an identifiable dysmorphic phenotype. Birth Defects Res A Clin Mol Teratol. 2005;73:919-23.
- Pursley TJ, Blomquist IK, Abraham J, Andersen HF, Bartley JA. Fluconazole-induced congenital anomalies in three infants. Clin Infect Dis. 1996;22:336-40.
- Lee BE, Feinberg M, Abraham JJ, Murthy AR. Congenital malformations in an infant born to a woman treated with fluconazole. Pediatr Infect Dis J. 1992;11:1062-4.
- Aleck KA, Bartley DL. Multiple malformation syndrome following fluconazole use in pregnancy: report of an additional patient. Am J Med Genet. 1997;72:253-6.
- Rubin P, Wilton L, Inman W. Fluconazole and pregnancy: results of a prescription event monitoring study. Int J Gynecol Obstet. 1992;37(Suppl):25-7.
- Inman W, Pearce G, Wilton L. Safety of fluconazole in the treatment of vaginal candidiasis. A prescription-event monitoring study, with special reference to the outcome of pregnancy. Eur J Clin Pharmacol. 1994;46:115-8.
- Mastroiacovo P, Mazzone T, Botto LD, Serafini MA, Finardi A, Caramelli L, et al. Prospective assessment of pregnancy outcomes after first-trimester exposure to fluconazole. Am J Obstet Gynecol. 1996;175:1645-50.
- Sanchez JM, Moya G. Fluconazole teratogenicity. Prenat Diagn. 1998;18:862-3.
- Jick SS. Pregnancy outcomes after maternal exposure to fluconazole. Pharmacotherapy. 1999;19:221-2.
- Sorensen HT, Nielsen GL, Olesen C, Larsen H, Steffensen FH, Schønheyder HC, et al. Risk of malformations and other outcomes in children exposed to fluconazole in utero. Br J Clin Pharmacol. 1999;48:234-8.
- Nørgaard M, Pedersen L, Gislum M, Erichsen R, Søgaard KK, Schønheyder HC, et al. Maternal use of fluconazole and risk of congenital malformations: a Danish population-based cohort study. J Antimicrob Chemother. 2008;62:172-6.
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