Sporanox Oral Solution
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Sporanox Oral Solution
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.
SPORANOX® has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition. If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed. The risks and benefits of SPORANOX® use should be reassessed. (See WARNINGS: Hepatic Effects and PRECAUTIONS: Hepatotoxicity and PATIENT INFORMATION .)
Adverse Events Reported In Oropharyngeal Or Esophageal Candidiasis Trials
U.S. adverse experience data are derived from 350 immunocompromised patients (332 HIV seropositive/AIDS) treated for oropharyngeal or esophageal candidiasis. Table 2 below lists adverse events reported by at least 2% of patients treated with SPORANOX® Oral Solution in U.S. clinical trials. Data on patients receiving comparator agents in these trials are included for comparison.
Table 2: Summary of Adverse Events Reported by
≥ 2% of SPORANOX® Treated Patients in U.S. Clinical Trials
|Body System/ Adverse Event||Itraconazole||Fluconazole
(n = 125†) %
(n = 81‡) %
(n = 350*) %
(n = 272) %
|Body as a whole|
|Skin and appendages disorders|
|Skin disorder unspecified||2||2||2||1|
|Central/peripheral nervous system|
|Resistance mechanism disorders|
|Pneumocystis carinii infection||2||2||2||0|
|* Of the 350 patients, 209 were
treated for oropharyngeal candidiasis in controlled studies, 63 were treated
for esophageal candidiasis in controlled studies and 78 were treated for
oropharyngeal candidiasis in an open study.
† Of the 125 patients, 62 were treated for oropharyngeal candidiasis and 63 were treated for esophageal candidiasis.
‡ All 81 patients were treated for oropharyngeal candidiasis.
Adverse events reported by less than 2% of patients in U.S. clinical trials with SPORANOX® included: adrenal insufficiency, asthenia, back pain, dehydration, dyspepsia, dysphagia, flatulence, gynecomastia, hematuria, hemorrhoids, hot flushes, implantation complication, infection unspecified, injury, insomnia, male breast pain, myalgia, pharyngitis, pruritus, rhinitis, rigors, stomatitis ulcerative, taste perversion, tinnitus, upper respiratory tract infection, vision abnormal, and weight decrease. Edema, hypokalemia and menstrual disorders have been reported in clinical trials with itraconazole capsules.
Adverse Events Reported From Other Clinical Trials
A comparative clinical trial in patients who received intravenous itraconazole followed by SPORANOX® Oral Solution or received Amphotericin B reported the following adverse events in the itraconazole intravenous/SPORANOX® Oral Solution treatment arm which are not listed above in the subsection “Adverse Events Reported in Oropharnyngeal or Esophageal Candidiasis Trials” or listed below as postmarketing reports of adverse drug reactions: serum creatinine increased, blood urea nitrogen increased, renal function abnormal, hypocalcemia, hypomagnesemia, hypophosphatemia, hypotension, tachycardia, tremor, and pulmonary infiltration.
In addition, the following adverse drug reactions were reported in patients who participated in SPORANOX® Oral Solution clinical trials:
Cardiac Disorders: cardiac failure;
General Disorders and Administration Site Conditions: edema;
Metabolism and Nutrition Disorders: hypokalemia;
Reproductive System and Breast Disorders: menstrual disorder
The following is a list of additional adverse drug reactions associated with itraconazole that have been reported in clinical trials of SPORANOX® Capsules and itraconazole IV excluding the adverse reaction term “Injection site inflammation” which is specific to the injection route of administration:
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;
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
In addition, the following adverse drug reaction was reported in children only who participated in SPORANOX® Oral Solution clinical trials: mucosal inflammation.
Adverse drug reactions that have been first identified during post-marketing experience with SPORANOX® (all formulations) are listed in the table below. Because these reactions are reported voluntarily from a population of uncertain size, reliably estimating their frequency or establishing a causal relationship to drug exposure is not always possible.
Table 3: Postmarketing Reports of Adverse Drug
|Blood and Lymphatic System Disorders:||Leukopenia, neutropenia, thrombocytopenia|
|Immune System Disorders:||Anaphylaxis; anaphylactic, anaphylactoid and allergic reactions; serum sickness; angioneurotic edema|
|Metabolism and Nutrition Disorders:||Hypertriglyceridemia|
|Nervous System Disorders:||Peripheral neuropathy, paresthesia, hypoesthesia|
|Eye Disorders:||Visual disturbances, including vision blurred and diplopia|
|Ear and Labyrinth Disorders:||Transient or permanent hearing loss|
|Cardiac Disorders:||Congestive heart failure|
|Respiratory, Thoracic and Mediastinal Disorders:||Pulmonary edema|
|Hepatobiliary Disorders:||Serious hepatotoxicity (including some cases of fatal acute liver failure), hepatitis, reversible increases in hepatic enzymes|
|Skin and Subcutaneous Tissue Disorders:||Toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, erythema multiforme, exfoliative dermatitis, leukocytoclastic vasculitis, alopecia, photosensitivity, urticaria|
|Musculoskeletal and Connective Tissue Disorders:||Arthralgia|
|Renal and Urinary Disorders:||Urinary incontinence, pollakiuria|
|Reproductive System and Breast Disorders:||Erectile dysfunction|
|General Disorders and Administration Site Conditions:||Peripheral edema|
|Investigations:||Blood creatine phosphokinase increased|
There is limited information on the use of SPORANOX® during pregnancy. Cases of congenital abnormalities including skeletal, genitourinary tract, cardiovascular and ophthalmic malformations as well as chromosomal and multiple malformations have been reported during post-marketing experience. A causal relationship with SPORANOX® has not been established. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: DRUG INTERACTIONS for more information.)
Read the Sporanox Oral Solution (itraconazole oral solution) Side Effects Center for a complete guide to possible side effects
Itraconazole is mainly metabolized through CYP3A4. Other drugs that either share this metabolic pathway or modify CYP3A4 activity may influence the pharmacokinetics of itraconazole. Similarly, itraconazole may modify the pharmacokinetics of other drugs that share this metabolic pathway. Itraconazole is a potent CYP3A4 inhibitor and a P-glycoprotein inhibitor. When using concomitant medication, it is recommended that the corresponding label be consulted for information on the route of metabolism and the possible need to adjust dosages.
Drugs that may decrease itraconazole plasma concentrations
Coadministration of itraconazole with potent enzyme inducers of CYP3A4 may decrease the bioavailability of itraconazole and hydroxy-itraconazole to such an extent that efficacy may be reduced. Examples include:
- Antibacterials: isoniazid, rifabutin (see also under 'Drugs that may have their plasma concentrations increased by itraconazole'), rifampicin
- Anticonvulsants: carbamazepine (see also under 'Drugs that may have their plasma concentrations increased by itraconazole'), phenobarbital, phenytoin
- Antivirals: efavirenz, nevirapine
Therefore, administration of potent enzyme inducers of CYP3A4 with itraconazole is not recommended. It is recommended that the use of these drugs be avoided from 2 weeks before and during treatment with itraconazole, unless the benefits outweigh the risk of potentially reduced itraconazole efficacy. Upon coadministration, it is recommended that the antifungal activity be monitored and the itraconazole dose increased as deemed necessary.
Drugs that may increase itraconazole plasma concentrations
Potent inhibitors of CYP3A4 may increase the bioavailability of itraconazole. Examples include:
- Antibacterials: ciprofloxacin, clarithromycin, erythromycin
- Antivirals: ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, indinavir (see also under 'Drugs that may have their plasma concentrations increased by itraconazole'), ritonavir (see also under 'Drugs that may have their plasma concentrations increased by itraconazole')
It is recommended that these drugs be used with caution when coadministered with itraconazole oral solution. It is recommended that patients who must take itraconazole concomitantly with potent inhibitors of CYP3A4 be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of itraconazole, and the itraconazole dose be decreased as deemed necessary.
Drugs that may have their plasma concentrations increased by itraconazole
Itraconazole and its major metabolite, hydroxy-itraconazole, can inhibit the metabolism of drugs metabolized by CYP3A4 and can inhibit the drug transport by P-glycoprotein, which may result in increased plasma concentrations of these drugs and/or their active metabolite(s) when they are administered with itraconazole. These elevated plasma concentrations may increase or prolong both therapeutic and adverse effects of these drugs. CYP3A4-metabolized drugs known to prolong the QT interval may be contraindicated with itraconazole, since the combination may lead to ventricular tachyarrhythmias including occurrences of torsade de pointes, a potentially fatal arrhythmia. Once treatment is stopped, itraconazole plasma concentrations decrease to an almost undetectable concentration within 7 to 14 days, depending on the dose and duration of treatment. In patients with hepatic cirrhosis or in subjects receiving CYP3A4 inhibitors, the decline in plasma concentrations may be even more gradual. This is particularly important when initiating therapy with drugs whose metabolism is affected by itraconazole.
Examples of drugs that may have their plasma concentrations increased by itraconazole presented by drug class with advice regarding coadministration with itraconazole:
Table 1: Drugs that may have
their plasma concentrations increased by itraconazole
|Drug Class||Contraindicated||Not Recommended||Use with Caution||Comments|
|Under no circumstances is the drug to be coadministered with itraconazole, and up to two weeks after discontinuation of treatment with itraconazole.||It is recommended that the use of the drug be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If coadministration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of the interacting drug is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured. The label of the coadministered drug should be consulted for information on dose adjustment and adverse effects.||Careful monitoring is recommended when the drug is coadministered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of the interacting drug, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured The label of the coadministered drug should be consulted for information on dose adjustment and adverse effects.|
|Analgesics||methadone||alfentanil, buprenorphine IV and sublingual, fentanyl, oxycodone, sufentanil||Methadone: The potential increase in plasma concentrations of methadone when coadministered with SPORANOX® may increase the risk of serious cardiovascular events including QTc prolongation and torsade de pointes.
Fentanyl: The potential increase in plasma concentrations of fentanyl when coadministered with SPORANOX® may increase the risk of potentially fatal respiratory depression.
Sufentanil: No human pharmacokinetic data of an interaction with itraconazole are available. In vitro data suggest that sufentanil is metabolized by CYP3A4 and so potentially increased sufentanil plasma concentrations would be expected when coadministered with SPORANOX® .
|Antiarrhythmics||disopyramide, dofetilide, dronedarone, quinidine||digoxin||Disopyramide, dofetilide, dronedarone, quinidine: The potential increase in plasma concentrations of these drugs when coadministered with SPORANOX® may increase the risk of serious cardiovascular events including QTc prolongation.|
|Anticoagulants and Antiplatelet Drugs||rivaroxaban||coumarins, cilostazol, dabigatran||Coumarins: SPORANOX® may enhance the anticoagulant effect of coumarin-like drugs, such as warfarin.|
|Anticonvulsants||carbamazepine||Carbamazepine: In vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. Although there are no data regarding the effect of itraconazole on carbamazepine metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of SPORANOX® and carbamazepine may inhibit the metabolism of carbamazepine. See also under ‘Drugs that may decrease itraconazole plasma concentrations’.|
|Antihelmintics and Antiprotozoals|
|Antimigraine Drugs||ergot alkaloids, such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)||eletriptan||Ergot Alkaloids: The potential increase in plasma concentrations of ergot alkaloids when coadministered with SPORANOX® may increase the risk of ergotism, ie. a risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities.|
|Antineoplastics||irinotecan||dasatinib, nilotinib||bortezomib, busulphan, docetaxel, erlotinib, ixabepilone, lapatinib, trimetrexate, vinca alkaloids||Irinotecan: The potential increase in plasma concentrations of irinotecan when coadministered with SPORANOX® may increase the risk of potentially fatal adverse events.|
|Antipsychotics, Anxiolytics and Hypnotics||lurasidone, oral midazolam, pimozide, triazolam||alprazolam, aripiprazole, buspirone, diazepam, haloperidol, midazolam IV, perospirone, quetiapine, ramelteon, risperidone||Midazolam, triazolam: Coadministration of SPORANOX® and oral midazolam, or triazolam may cause several-fold increases in plasma concentrations of these drugs. This may potentiate and prolong hypnotic and sedative effects, especially with repeated dosing or chronic administration of these agents.
Pimozide: The potential increase in plasma concentrations of pimozide when coadministered with SPORANOX® may increase the risk of serious cardiovascular events including QTc prolongation and torsade de pointes.
|Antivirals||maraviroc, indinavir, ritonavir saquinavir||Indinavir, ritonavir: See also under ‘Drugs that may increase itraconazole plasma concentrations’.|
|Calcium Channel Blockers||felodipine, nisoldipine||other dihydropyridines, verapamil||Calcium channel blockers can have a negative inotropic effect which may be additive to those of itraconazole. The potential increase in plasma concentrations of calcium channel blockers when co-administered with SPORANOX® may increase the risk of congestive heart failure.
Dihydropyridines: Concomitant administration of SPORANOX® may cause several-fold increases in plasma concentrations of dihydropyridines. Edema has been reported in patients concomitantly receiving SPORANOX® and dihydropyridine calcium channel blockers.
|Cardiovascular Drugs, Miscellaneous||ranolazine||aliskiren||Ranolazine: The potential increase in plasma concentrations of ranolazine when coadministered with SPORANOX® may increase the risk of serious cardiovascular events including QTc prolongation.|
|Diuretics||eplerenone||Eplerenone: The potential increase in plasma concentrations of eplerenone when coadministered with SPORANOX® may increase the risk of hyperkalemia and hypotension.|
|Gastrointestinal Drugs||cisapride||aprepitant||Cisapride: The potential increase in plasma concentrations of cisapride when coadministered with SPORANOX® may increase the risk of serious cardiovascular events including QTc prolongation.|
|Immunosuppressants||everolimus, temsirolimus||budesonide, ciclesonide, cyclosporine, dexamethasone, fluticasone, methylprednisolone, rapamycin (also known as sirolimus), tacrolimus|
|Lipid Regulating Drugs||lovastatin, simvastatin||atorvastatin||The potential increase in plasma concentrations of atorvastatin, lovastatin, and simvastatin when coadministered with SPORANOX® may increase the risk of skeletal muscle toxicity, including rhabdomyolysis.|
|Urological Drugs||vardenafil||fesoterodine. sildenafil, solifenacin, tadalafil, tolterodine|
|Other||colchicine, in subjects with renal or hepatic impairment||colchicine||cinacalcet, tolvaptan||Colchicine: The potential increase in plasma concentrations of colchicine when coadministered with SPORANOX® may increase the risk of potentially fatal adverse events.|
Drugs that may have their plasma concentrations decreased by itraconazole
Coadministration of itraconazole with the NSAID meloxicam may decrease the plasma concentration of meloxicam. It is recommended that meloxicam be used with caution when coadministered with itraconazole, and its effects or side effects be monitored. It is recommended that the dosage of meloxicam, if coadministered with itraconazole, be adjusted if necessary.
Interaction studies have only been performed in adults.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 6/19/2014
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