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Sporanox Injection

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Sporanox Injection

SIDE EFFECTS

SPORANOX® (itraconazole injection) 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 INFORMATION FOR PATIENTS.)

Adverse Events Reported in Trials in Patients with SPORANOX® (itraconazole injection) Injection

Adverse events considered at least possibly drug related are shown in Table 2 and are based on the experience of 360 patients treated with SPORANOX® (itraconazole injection) Injection in four pharmacokinetic, one uncontrolled and four active controlled studies where the control was amphotericin B or fluconazole. Nearly all patients were neutropenic or were otherwise immunocompromised and were treated empirically for febrile episodes, for documented systemic fungal infections, or in trials to determine pharmacokinetics. The dose of SPORANOX® (itraconazole injection) Injection was 200 mg twice daily for the first two days followed by a single daily dose of 200 mg for the remainder of the intravenous treatment period. The majority of patients received between 7 and 14 days of SPORANOX® (itraconazole injection) Injection.

Table 2 Summary of Possibly or Definitely Drug-Related Adverse Events Reported by ≥ 2% of Subjects

Adverse Event Total SPORANOX® Injection (N=360) % Comparative Studies
SPORANOX Injection (N=234) % Intravenous Fluconazole (N=32) % Intravenous Amphotericin B (N=202) %
Gastrointestinal system disorders
  Nausea 8 9 0 15
  Diarrhea 6 6 3 9
  Vomiting 4 6 0 10
  Abdominal pain 2 2 0 3
  Constipation 0 1 3 0
Metabolic and nutritional disorders
  Hypokalemia 5 8 0 29
  Alkaline phosphatase increased 1 2 3 2
  Serum creatinine increased 2 2 3 26
  Hypomagnesemia 1 1 0 5
  Blood urea nitrogen increased 0 1 0 7
  Fluid overload 0 0 0 3
  Hypocalcemia 0 0 0 3
Liver and biliary system disorders
  Bilirubinemia 4 6 9 3
  SGPT/ALT Increased 2 3 3 1
  Hepatic function abnormal 1 2 0 2
  Jaundice  1 2 0 0
  SGOT/AST increased 1 2 0 0
Body as a whole – General disorders
  Pain 1 2 0 0
  Rigors 0 0 0 34
  Fever 0 0 0 6
Skin and appendages disorders
  Rash 3 3 3 3
  Sweating increased 1 2 0 0
Respiratory system disorder
  Dyspnea 0 0 0 3
Central and peripheral nervous system disorders
  Dizziness 1 2 0 1
  Headache 2 2 0 3
Urinary system disorders
  Renal function abnormal 1 1 0 11
Application site disorder
  Application site reaction 4 0 0 0
Cardiovascular disorders, general
  Hypotension 0 0 0 3
  Hypertension 0 0 0 2
Heart rate and rhythm disorders
  Tachycardia 0 1 0 3
Vascular (extracardiac) disorders
  Vein disorder 3 0 0 0

The following adverse events occurred in less than 2% of patients in clinical trials of SPORANOX® (itraconazole injection) Injection: LDH increased, edema, albuminuria, hyperglycemia, and hepatitis.

Post-marketing Experience

Adverse drug reactions that have been identified during post-approval use of SPORANOX® (itraconazole injection) (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.

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, hypokalemia
Nervous system disorders: Peripheral neuropathy, paresthesia, hypoesthesia, headache, dizziness
Eye disorders: Visual disturbances, including vision blurred and diplopia
Ear and labyrinth disorders: Transient or permanent hearing loss, tinnitus
Cardiac disorders: Congestive heart failure
Respiratory, thoracic and mediastinal Pulmonary edema disorders:
Gastrointestinal disorders: Abdominal pain, vomiting, dyspepsia, nausea, diarrhea, constipation, dysgeusia
Hepato-biliary 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, exfoliative dermatitis, leukocytoclastic vasculitis, erythemamultiforme, alopecia, photosensitivity, rash, urticaria, pruritus
Musculoskeletal and connective tissue disorders: Myalgia, arthralgia
Renal and urinary disorders: Urinary incontinence, pollakiuria
Reproductive system and breast disorders: Menstrual disorders, erectile dysfunction
General disorders and administration site conditions: Peripheral edema

There is limited information on the use of SPORANOX® (itraconazole injection) 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 Injection (itraconazole injection) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Itraconazole and its major metabolite, hydroxyitraconazole, are inhibitors of CYP3A4. Therefore, the following drug interactions may occur (See Table 1 below and the following drug class subheadings that follow):

  1. SPORANOX® (itraconazole injection) may decrease the elimination of drugs metabolized by CYP3A4, resulting in increased plasma concentrations of these drugs when they are administered with SPORANOX® (itraconazole injection) . These elevated plasma concentrations may increase or prolong both therapeutic and adverse effects of these drugs. Whenever possible, plasma concentrations of these drugs should be monitored, and dosage adjustments made after concomitant SPORANOX® (itraconazole injection) therapy is initiated. When appropriate, clinical monitoring for signs or symptoms of increased or prolonged pharmacologic effects is advised. Upon discontinuation, depending on the dose and duration of treatment, itraconazole plasma concentrations decline gradually (especially in patients with hepatic cirrhosis or in those receiving CYP3A4 inhibitors). This is particularly important when initiating therapy with drugs whose metabolism is affected by itraconazole.
  2. Inducers of CYP3A4 may decrease the plasma concentrations of itraconazole. SPORANOX® (itraconazole injection) may not be effective in patients concomitantly taking SPORANOX® (itraconazole injection) and one of these drugs. Therefore, administration of these drugs with SPORANOX® (itraconazole injection) is not recommended.
  3. Other inhibitors of CYP3A4 may increase the plasma concentrations of itraconazole. Patients who must take SPORANOX® (itraconazole injection) concomitantly with one of these drugs should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of SPORANOX® (itraconazole injection) .

Table 1: Selected Drugs that are Predicted to Alter the Plasma Concentration of Itraconazole or Have Their Plasma Concentration Altered by SPORANOX® (itraconazole injection) 1

Drug plasma concentration increased by itraconazole
Antiarrhythmics digoxin, dofetilide,2 quinidine,2 disopyramide
Anticonvulsants carbamazepine
Antimycobacterials rifabutin
Antineoplastics busulfan, docetaxel, vinca alkaloids
Antipsychotics pimozide2
Benzodiazepines alprazolam, diazepam, midazolam,2,3 triazolam2
Calcium Channel Blockers dihydropyridines (including nisoldipine2), verapamil
Gastrointestinal Motility Agents cisapride2
HMG CoA-Reductase Inhibitors atorvastatin, cerivastatin, lovastatin,2 simvastatin2
Immunosuppressants cyclosporine, tacrolimus, sirolimus
Oral Hypoglycemics oral hypoglycemics
Protease Inhibitors indinavir, ritonavir, saquinavir
Other levacetylmethadol (levomethadyl),2 ergot alkaloids,2 halofantrine, alfentanil, buspirone, methylprednisolone, budesonide, dexamethasone, fluticasone, trimetrexate, warfarin, cilostazol, eletriptan, fentanyl
Decrease plasma concentration of itraconazole
Anticonvulsants carbamazepine, phenobarbital, phenytoin
Antimycobacterials isoniazid, rifabutin, rifampin
Reverse Transcriptase Inhibitors nevirapine
Increase plasma concentration of itraconazole
Macrolide Antibiotics clarithromycin, erythromycin
Protease Inhibitors indinavir, ritonavir
1 This list is not all-inclusive.
2 Contraindicated with SPORANOX® (itraconazole injection) based on clinical and/or pharmacokinetics studies. (See WARNINGS and below.)
3 For information on parenterally administered midazolam, see the Benzodiazepine paragraph below.

Antiarrhythmics

The class IA antiarrhythmic quinidine and class III antiarrhythmic dofetilide are known to prolong the QT interval. Coadministration of quinidine or dofetilide with SPORANOX® (itraconazole injection) may increase plasma concentrations of quinidine or dofetilide which could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX® (itraconazole injection) and quinidine or dofetilide is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.)

The class IA antiarrhythmic disopyramide has the potential to increase the QT interval at high plasma concentrations. Caution is advised when SPORANOX® (itraconazole injection) and disopyramide are administered concomitantly.

Concomitant administration of digoxin and SPORANOX® (itraconazole injection) has led to increased plasma concentrations of digoxin via inhibition of P-glycoprotein.

Anticonvulsants

Reduced plasma concentrations of itraconazole were reported when SPORANOX® (itraconazole injection) was administered concomitantly with phenytoin. Carbamazepine, phenobarbital, and phenytoin are all inducers of CYP3A4. Although interactions with carbamazepine and phenobarbital have not been studied, concomitant administration of SPORANOX® (itraconazole injection) and these drugs would be expected to result in decreased plasma concentrations of itraconazole. In addition, 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® (itraconazole injection) and carbamazepine may inhibit the metabolism of carbamazepine.

Antimycobacterials

Drug interaction studies have demonstrated that plasma concentrations of azole antifungal agents and their metabolites, including itraconazole and hydroxyitraconazole, were significantly decreased when these agents were given concomitantly with rifabutin or rifampin. In vivo data suggest that rifabutin is metabolized in part by CYP3A4. SPORANOX® (itraconazole injection) may inhibit the metabolism of rifabutin. Although no formal study data are available for isoniazid, similar effects should be anticipated. Therefore, the efficacy of SPORANOX® (itraconazole injection) could be substantially reduced if given concomitantly with one of these agents. Coadministration is not recommended.

Antineoplastics

SPORANOX® (itraconazole injection) may inhibit the metabolism of busulfan, docetaxel, and vinca alkaloids.

Antipsychotics

Pimozide is known to prolong the QT interval and is partially metabolized by CYP3A4. Coadministration of pimozide with SPORANOX® (itraconazole injection) could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX® (itraconazole injection) and pimozide is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.)

Benzodiazepines

Concomitant administration of SPORANOX® (itraconazole injection) and alprazolam, diazepam, oral midazolam, or triazolam could lead to increased plasma concentrations of these benzodiazepines. Increased plasma concentrations could potentiate and prolong hypnotic and sedative effects. Concomitant administration of SPORANOX® (itraconazole injection) and oral midazolam or triazolam is contraindicated. (See CONTRAINDICATIONS and WARNINGS.) If midazolam is administered parenterally, special precaution and patient monitoring is required since the sedative effect may be prolonged.

Calcium Channel Blockers

Edema has been reported in patients concomitantly receiving SPORANOX® (itraconazole injection) and dihydropyridine calcium channel blockers. Appropriate dosage adjustment may be necessary.

Calcium channel blockers can have a negative inotropic effect which may be additive to those of itraconazole; itraconazole can inhibit the metabolism of calcium channel blockers such as dihydropyridines (e.g., nifedipine and felodipine) and verapamil. Therefore, caution should be used when co-administering itraconazole and calcium channel blockers due to an increased risk of CHF. Concomitant administration of SPORANOX® (itraconazole injection) and nisoldipine results in clinically significant increases in nisoldipine plasma concentrations which cannot be managed by dosage reduction, therefore the concomitant administration of SPORANOX® (itraconazole injection) and nisoldipine is contraindicated. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, and ADVERSE REACTIONS: Post-marketing Experience for more information.)

Gastrointestinal Motility Agents

Coadministration of SPORANOX® (itraconazole injection) with cisapride can elevate plasma cisapride concentrations which could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX® (itraconazole injection) with cisapride is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.)

HMG CoA-Reductase Inhibitors

Human pharmacokinetic data suggest that SPORANOX® (itraconazole injection) inhibits the metabolism of atorvastatin, cerivastatin, lovastatin, and simvastatin, which may increase the risk of skeletal muscle toxicity, including rhabdomyolysis. Concomitant administration of SPORANOX® (itraconazole injection) with HMG CoA-reductase inhibitors, such as lovastatin and simvastatin, is contraindicated. (See CONTRAINDICATIONS, and WARNINGS.)

Immunosuppressants

Concomitant administration of SPORANOX® (itraconazole injection) and cyclosporine or tacrolimus has led to increased plasma concentrations of these immunosuppressants. Concomitant administration of SPORANOX® (itraconazole injection) and sirolimus could increase plasma concentrations of sirolimus.

Macrolide Antibiotics

Erythromycin and clarithromycin are known inhibitors of CYP3A4 (See Table 1) and may increase plasma concentrations of itraconazole. In a small pharmacokinetic study involving HIV infected patients, clarithromycin was shown to increase plasma concentrations of itraconazole. Similarly, following administration of 1 gram of erythromycin ethyl succinate and 200 mg itraconazole as single doses, the mean Cmax and AUC 0-∞ of itraconazole increased by 44% (90% CI: 119-175%) and 36% (90% CI: 108-171%), respectively.

Oral Hypoglycemic Agents

Severe hypoglycemia has been reported in patients concomitantly receiving azole antifungal agents and oral hypoglycemic agents. Blood glucose concentrations should be carefully monitored when SPORANOX® (itraconazole injection) and oral hypoglycemic agents are coadministered.

Polyenes

Prior treatment with itraconazole, like other azoles, may reduce or inhibit the activity of polyenes such as amphotericin B. However, the clinical significance of this drug effect has not been clearly defined.

Protease Inhibitors

Concomitant administration of SPORANOX® (itraconazole injection) and protease inhibitors metabolized by CYP3A4, such as indinavir, ritonavir, and saquinavir, may increase plasma concentrations of these protease inhibitors. In addition, concomitant administration of SPORANOX® (itraconazole injection) and indinavir and ritonavir (but not saquinavir) may increase plasma concentrations of itraconazole. Caution is advised when SPORANOX® (itraconazole injection) and protease inhibitors must be given concomitantly.

Reverse Transcriptase Inhibitors

Nevirapine is an inducer of CYP3A4. In vivo studies have shown that nevirapine induces the metabolism of ketoconazole, significantly reducing the bioavailability of ketoconazole. Studies involving nevirapine and itraconazole have not been conducted. However, because of the similarities between ketoconazole and itraconazole, concomitant administration of SPORANOX® (itraconazole injection) and nevirapine is not recommended. In a clinical study, when 8 HIV-infected subjects were treated concomitantly with SPORANOX® (itraconazole injection) Capsules 100 mg twice daily and the nucleoside reverse transcriptase inhibitor zidovudine 8 ± 0.4 mg/kg/day, the pharmacokinetics of zidovudine were not affected. Other nucleoside reverse transcriptase inhibitors have not been studied.

Other
  • Levacetylmethadol (levomethadyl) is known to prolong the QT interval and is metabolized by CYP3A4. Co-administration of levacetylmethadol with SPORANOX® (itraconazole injection) could result in serious cardiovascular events. Therefore, concomitant administration of SPORANOX® (itraconazole injection) and levacetylmethadol is contraindicated.
  • Elevated concentrations of ergot alkaloids can cause ergotism, ie. a risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities. Concomitant administration of ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine) with SPORANOX® (itraconazole injection) is contraindicated.
  • Halofantrine has the potential to prolong the QT interval at high plasma concentrations. Caution is advised when SPORANOX® (itraconazole injection) and halofantrine are administered concomitantly.
  • In vitro data suggest that alfentanil is metabolized by CYP3A4. Administration with SPORANOX® (itraconazole injection) may increase plasma concentrations of alfentanil.
  • Human pharmacokinetic data suggest that concomitant administration of SPORANOX® (itraconazole injection) and buspirone results in significant increases in plasma concentrations of buspirone.
  • SPORANOX® (itraconazole injection) may inhibit the metabolism of certain glucocorticosteroids such as budesonide, dexamethasone, fluticasone and methylprednisolone.
  • In vitro data suggest that trimetrexate is extensively metabolized by CYP3A4. In vitro animal models have demonstrated that ketoconazole potently inhibits the metabolism of trimetrexate. Although there are no data regarding the effect of itraconazole on trimetrexate metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of SPORANOX® (itraconazole injection) and trimetrexate may inhibit the metabolism of trimetrexate.
  • Cilostazol and eletriptan are CYP3A4 metabolized drugs that should be used with caution when co-administered with SPORANOX® (itraconazole injection) .
  • SPORANOX® (itraconazole injection) enhances the anticoagulant effect of coumarin-like drugs, such as warfarin.
  • Fentanyl plasma concentrations could be increased or prolonged by concomitant use of SPORANOX® (itraconazole injection) and may cause potentially fatal respiratory depression.

Last reviewed on RxList: 5/18/2009
This monograph has been modified to include the generic and brand name in many instances.

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