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Sporanox Oral Solution

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Sporanox Oral Solution

Side Effects
Interactions

SIDE EFFECTS

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 (Total)

Body System/ Adverse Event Itraconazole Fluconazole
(n = 125†) %
Clotrimazole
(n = 81‡) %
Total
(n = 350*) %
Allcontrolled studies
(n = 272) %
Gastrointestinal disorders
  Nausea 11 10 11 5
  Diarrhea 11 10 10 4
  Vomiting 7 6 8 1
  Abdominal pain 6 4 7 7
  Constipation 2 2 1 0
Body as a whole
  Fever 7 6 8 5
  Chest pain 3 3 2 0
  Pain 2 2 4 0
  Fatigue 2 1 2 0
Respiratory disorders
  Coughing 4 4 10 0
  Dyspnea 2 3 5 1
  Pneumonia 2 2 0 0
  Sinusitis 2 2 4 0
  Sputum increased 2 3 3 1
Skin and appendages disorders
  Rash 4 5 4 6
  Increased sweating 3 4 6 1
  Skin disorder unspecified 2 2 2 1
Central/peripheral nervous system
  Headache 4 4 6 6
  Dizziness 2 2 4 1
Resistance mechanism disorders
  Pneumocystis carinii infection 2 2 2 0
Psychiatric disorders
  Depression 2 1 0 1
* 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;

Hepatobiliary Disorders: hepatic failure, hyperbilirubinemia;

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;

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

In addition, the following adverse drug reaction was reported in children only who participated in SPORANOX® Oral Solution clinical trials: mucosal inflammation.

Post-marketing Experience

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 Reactions

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
Gastrointestinal Disorders: Pancreatitis
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

DRUG INTERACTIONS

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.  
Alpha Blockers   tamsulosin    
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.
Antibacterials   rifabutin    
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’.
Antidiabetics   repaglinide, saxagliptin    
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’.
Beta Blockers     nadolol  
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.
Respiratory Drugs   salmeterol    
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.

Pediatric Population

Interaction studies have only been performed in adults.

Last reviewed on RxList: 6/19/2014
This monograph has been modified to include the generic and brand name in many instances.

Side Effects
Interactions
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