Itraconazole: Cautions
Itraconazole generally is well tolerated. However, serious potentially life-threatening adverse effects, including congestive heart failure, pulmonary edema, and hepatotoxicity, have occurred rarely in patients receiving IV or oral itraconazole. In clinical studies evaluating itraconazole for the treatment of systemic fungal infections, adverse effects requiring discontinuance of the drug occurred in up to 11% of patients; the median duration of therapy before discontinuance was 81 days (range: 2-776 days).
In patients receiving oral itraconazole capsules for the treatment of onychomycosis of the toenails or fingernails, adverse effects requiring temporary or permanent discontinuance of the drug occurred in 1-4% of patients. The most frequent adverse effects of itraconazole involve the GI tract, and the frequency of adverse effects may be increased during prolonged therapy.
GI Effects
Adverse GI effects have been reported in about 1-11% of patients receiving IV or oral itraconazole for the treatment of systemic fungal infections or oropharyngeal or esophageal candidiasis or for empiric anti-fungal therapy.
These adverse GI effects usually are transient and respond to symptomatic treatment without alteration of itraconazole therapy; however, reduction of dosage or discontinuance of the drug occasionally may be required. Nausea is the most frequently reported adverse effect of itraconazole, occurring in 9-11% of patients receiving the drug for the treatment of systemic fungal infections, oropharyngeal or esophageal candidiasis, or for empiric anti-fungal therapy.
However, this effect occasionally has been reported to occur more frequently. Vomiting has occurred in about 5-7%, diarrhea in about 3-10%, and abdominal pain or anorexia in about 1-3% of patients being treated for systemic fungal infections, oropharyngeal or esophageal candidiasis, or for empiric antifungal prophylaxis.
Constipation, dyspepsia, dysphagia, flatulence, gastritis, taste perversion, and ulcerative stomatitis also have been reported. In patients receiving oral itraconazole capsules for the treatment of onychomycosis of the fingernails (a pulse-dosing regimen consisting of two 1-week treatment periods given 3 weeks apart), abdominal pain, constipation, dyspepsia, nausea, gingivitis, and ulcerative stomatitis were reported in 3-5%. In those receiving itraconazole capsules for the treatment of onychomycosis of the toenails (a continuous dosing regimen for 12 consecutive weeks), abdominal pain, diarrhea, dyspepsia, and flatulence were reported in 7% and constipation, gastritis, gastroenteritis, increased appetite, and nausea were reported in 3-4% of patients.
Adverse GI effects requiring temporary or permanent discontinuance of itraconazole capsules occurred in 4% of those receiving the drug for the treatment of toenail infections.
Dermatologic and Sensitivity Reactions
Rash has occurred in 3-9% of patients receiving IV or oral itraconazole for the treatment of systemic fungal infections, oropharyngeal or esophageal candidiasis, or for empiric anti-fungal therapy. Rash tends to occur more frequently in immunocompromised patients who are receiving immunosuppressive therapy. Pruritus has occurred in up to 3% of patients with systemic fungal infections or oropharyngeal or esophageal candidiasis receiving itraconazole.
Urticaria, angioedema, alopecia, and toxic epidermal necrolysis also have been reported in patients receiving itraconazole. In addition, anaphylaxis and Stevens-Johnson syndrome occurred rarely in patients receiving the drug. In patients receiving oral itraconazole capsules for the treatment of onychomycosis of the fingernails or toenails, pruritus and rash were reported in 5-8% of patients; these adverse effects required temporary or permanent discontinuance of itraconazole capsules in 3%.
Nervous System Effects
Headache and dizziness have been reported in 2-4% of patients receiving IV or oral itraconazole for the treatment of systemic fungal infections, oropharyngeal or esophageal candidiasis, or for empiric anti-fungal prophylaxis. Somnolence, decreased libido, insomnia, depression, and tremor have occurred in up to 1% of patients.
Although a causal relationship to itraconazole has not been established, neuropathy (including peripheral neuropathy) has occurred rarely in patients receiving the drug. In patients receiving oral itraconazole capsules for the treatment of onychomycosis of the fingernails (a pulse-dosing regimen consisting of two 1-week treatment periods given 3 weeks apart), headache was reported in 8% and anxiety, depression, fatigue, and malaise were reported in 3%. In those receiving itraconazole capsules for the treatment of onychomycosis of the toenails (a continuous dosing regimen for 12 consecutive weeks), headache was reported in 10% and asthenia, dizziness, and tremor were reported in 2-4% of patients.
Adverse nervous system effects (headache, malaise, vertigo) requiring temporary or permanent discontinuance of itraconazole capsules occurred in 1% of those receiving the drug for the treatment of toenail infections.
Cardiovascular Effects
Congestive heart failure, peripheral edema, and pulmonary edema have been reported rarely in patients receiving itraconazole for the treatment of systemic fungal infections and/or onychomycosis.
Results from animal studies indicate that IV administration of itraconazole is associated with a dose-related negative inotropic effect. In addition, IV administration of itraconazole in healthy individuals has resulted in transient, asymptomatic decreases in left ventricular ejection fraction (observed using grated SPECT imaging) which resolved before the next infusion, 12 hours later. If congestive heart failure develops in a patient receiving oral itraconazole capsules, the drug should be discontinued; if congestive heart failure develops in patients receiving IV itraconazole or itraconazole oral solution, the benefits and risks of therapy should be reassessed. Hypertension has been reported in up to 3% of patients receiving itraconazole for the treatment of systemic fungal infections and has been reported in less than 1% of patients receiving itraconazole for other uses. Ventricular fibrillation secondary to itraconazole-induced hypokalemia has been reported in a patient with HIV infection and blastomycosis receiving high dosage of the drug (e.g., 400 mg twice daily). (See Cautions: Electrolyte and Metabolic Effects.)
Rare cases of serious adverse cardiovascular effects, including death, cardiac arrest, QT prolongation, ventricular tachycardia, and atypical ventricular tachycardia (torsades de pointes), have occurred in patients receiving itraconazole (or other drugs that inhibit the CYP3A4 isoenzyme) and cisapride, dofetilide, pimozide, or quinidine concomitantly.
Hepatic Effects
Hepatic function abnormalities, manifested principally as mild transient increases in serum liver enzyme concentrations, have occurred in about 3% of patients receiving itraconazole. However, serious hepatotoxicity, including liver failure and death, has occurred rarely and has been reported in patients with or without preexisting liver disease or a serious underlying medical condition. Hepatitis has been reported during postmarketing surveillance. In patients receiving oral itraconazole capsules for the treatment of onychomycosis of the toenails (a continuous dosing regimen for 12 consecutive weeks), increased serum hepatic enzymes (greater than twice the upper limit of normal) that required temporary or permanent discontinuance of the drug have occurred in 4% of patients. Itraconazole should be discontinued immediately and the risks and benefits of continuing therapy with the drug should be reassessed if signs and symptoms consistent with liver disease develop during therapy with the drug.
Electrolyte and Metabolic Effects
Hypokalemia has been reported in 2-9% of patients receiving IV or oral itraconazole for the treatment of systemic fungal infections or oropharyngeal or esophageal candidiasis or for empiric antifungal prophylaxis. Itraconazole-induced hypokalemia may be mild to severe, may require potassium replacement and/or discontinuance of the drug, and has occurred principally at dosages of 400 mg daily or higher.Edema (e.g., pedal) has occurred in up to 4% of patients with systemic fungal infections receiving itraconazole. Adrenal insufficiency, gynecomastia, and male breast pain have occurred patients receiving the drug. Itraconazole generally does not appear to inhibit testicular or adrenal steroidogenesis substantially at usual dosages. However, at relatively high dosages (e.g., 600 mg daily or more) and/or with accumulation of the drug, adrenal suppression, which appears to be distinct from that associated with ketoconazole, may occur. Although a causal relationship to itraconazole has not been established, hypertriglyceridemia or hyperglycemia has been reported in patients receiving itraconazole.
Genitourinary Effects
Albuminuria and impotence have occurred in about 1% of patients with systemic fungal infections receiving itraconazole. Urinary tract infection, cystitis, renal function abnormality, and menstrual disorder also have occurred in patients receiving itraconazole.
Other Adverse Effects
Fatigue, fever, bursitis, myalgia, pain, herpes zoster infection, and injury have occurred in up to 7% of patients receiving itraconazole. Rhinitis, upper respiratory tract infection, sinusitis, and pharyngitis have been reported in up to 9% of itraconazole-treated patients. Neutropenia also has occurred in patients receiving the drug.
Precautions and Contraindications
Precautions Related to Cardiovascular Effects
Congestive heart failure, peripheral edema, and pulmonary edema have been reported in immunocompromised or immunocompetent patients receiving IV or oral itraconazole for the treatment of systemic fungal infections and also have been reported in immunocompetent patients receiving oral itraconazole capsules for the treatment of onychomycosis. Itraconazole capsules should not be used for the treatment of onychomycosis in patients with evidence of ventricular dysfunction, such as congestive heart failure or history of congestive heart failure.
For other indications (e.g., treatment of systemic fungal infections) in patients with evidence of ventricular dysfunction, IV or oral itraconazole should be used only when the benefits clearly outweigh the risks.
Clinicians should carefully review the risks and benefits of itraconazole therapy in patients with risk factors for congestive heart failure (e.g., those with cardiac disease such as ischemic and valvular disease, clinically important pulmonary disease such as chronic obstructive pulmonary disease, or renal failure and other edematous disorders), and IV itraconazole and itraconazole oral solution should be used with caution in these patients.
If itraconazole is considered necessary in patients with risk factors for congestive heart failure, they should be informed of the signs and symptoms of congestive heart failure and carefully monitored during therapy. Itraconazole oral capsules should be discontinued in patients who develop congestive heart failure while receiving the drug. If congestive heart failure occurs during therapy with IV itraconazole or itraconazole oral solution, the patient should be carefully monitored and therapeutic options (including possible discontinuance of the drug) evaluated.
Because itraconazole and its major metabolite, hydroxyitraconazole, are potent inhibitors of the cytochrome P-450 (CYP) 3A4 isoenzyme system, concomitant use of the antifungal agent with drugs metabolized by these enzymes can increase plasma concentrations of these drugs resulting in potential increases in their therapeutic and adverse effects. Serious adverse cardiovascular effects (QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death) have been reported in patients receiving itraconazole concomitantly with certain drugs metabolized by CYP3A4 enzymes (e.g., cisapride, dofetilide, pimozide, quinidine), and concomitant use with these drugs is contraindicated.
Precautions Related to Hepatic Effects
Because rare cases of serious hepatotoxicity have been reported with itraconazole, including some cases within the first week of therapy, itraconazole therapy should not be used in patients with increased serum hepatic enzymes, active liver disease, or a history of liver toxicity with other drugs unless the potential benefits exceed the risks. Serum hepatic enzyme concentrations should be monitored in any patient with preexisting hepatic function abnormalities and in those who have experienced liver toxicity with other drugs.
In addition, serum hepatic enzyme monitoring should be considered for all patients receiving itraconazole, especially those who receive itraconazole therapy continuously for longer than 1 month. Itraconazole should be discontinued immediately and liver function testing performed if signs and symptoms consistent with liver disease develop during therapy. The risks and benefits of itraconazole should be reassessed in these patients. Patients should be instructed to stop itraconazole immediately and contact their clinician if any signs or symptoms of liver dysfunction occur, including unusual fatigue, dark urine, pale stool, anorexia, nausea, vomiting, or jaundice, so that appropriate laboratory testing can be performed.
Other Precautions and Contraindications
If neuropathy occurs that may be attributable to itraconazole, the drug should be discontinued. Because itraconazole may cause hypokalemia, some clinicians recommended that serum potassium concentrations be monitored in patients receiving relatively high dosages and/or prolonged therapy with the drug. Itraconazole is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation.
Although information concerning cross-sensitivity between itraconazole and other triazole or imidazole antifungal agents is not available, the manufacturer states that itraconazole should be used with caution in individuals hypersensitive to other azoles.
Pediatric Precautions
Safety and efficacy of itraconazole in children younger than 18 years of age have not been established. A limited number of patients aged 3-16 years of age with systemic nonmeningeal fungal infections have received itraconazole capsules in a dosage of 100 mg daily without unusual adverse effect. In addition, a limited number of pediatric patients 6 months to 12 years of age have received itraconazole oral solution in a dosage of 5 mg/kg once daily for 2 weeks without any unusual adverse effects.
However, data from animal studies have shown that itraconazole induces bone defects in rats receiving dosages as low as 20 mg/kg daily (2. times the maximum recommended human dosage). The defects included decreased bone plate activity, thinning of the zona compacta of large bones, and increased bone fragility. At a dosage of 80 mg/kg daily (10 times the maximum recommended human dosage) for longer than 1 year or 160 mg/kg daily (20 times the maximum recommended human dosage), the drug induced small tooth pulp with hypocellular appearance in some rats.
While bone toxicity observed in animals has not been reported to date in adult patients receiving the drug, the long-term effect of itraconazole therapy in children is not known.
Geriatric Precautions
Clinical studies of IV itraconazole did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients. While other clinical experience has not revealed differences in response, drug dosage should be selected cautiously in geriatric patients. The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.
Mutagenicity and Carcinogenicity
There was no evidence of mutagenicity when itraconazole was assayed in appropriate bacterial, mammalian, and nonmammalian test systems. There was no evidence of carcinogenicity in mice receiving oral itraconazole for 23 months at dosages up to 80 mg/kg daily (about 10 times the maximum recommended human dosage). There was a slight increase in the incidence of soft tissue sarcoma in male rats receiving 25 mg/kg daily (3.1 times the maximum recommended human dosage). These sarcomas may have been a consequence of hypercholesterolemia, a response to chronic itraconazole administration observed in rats but not in dogs or humans.
An increase in the incidence of squamous cell carcinoma of the lung was observed in female rats receiving 50 mg/kg of itraconazole daily (6.25 times the maximum recommended human dosage). Although the occurrence of squamous cell carcinoma in the lung is extremely uncommon in untreated rats, the increased incidence in this study was not statistically significant. Commercially available itraconazole oral solution and itraconazole injection contain hydroxypropyl-b-cyclodextrin (HP-b-CD) as an excipient. HP-b-CD has produced pancreatic adenocarcinomas in rat carcinogenicity studies but similar effects were not observed in a mouse carcinogenicity study.
The clinical relevance of this finding is not known. It has been estimated that, based on body surface area comparisons, patients receiving the usual dosage of commercially available itraconazole oral solution would be exposed to concentrations of HP-b-CD that are equivalent to 1.7 times that the exposure of the lowest dose used in the rat study.
Whether findings in animal studies using orally administered HP-b-CD apply to parenterally administered itraconazole remains to be determined.
Pregnancy, Fertitlity and Lactation
Although there are no adequate and controlled studies to date in humans, itraconazole has been shown to be teratogenic and embryotoxic in animals. Therefore, itraconazole should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.
For the treatment of onychomycosis, use of itraconazole is contraindicated in pregnant women and also is contraindicated in women contemplating pregnancy.
If itraconazole therapy for the treatment of onychomycosis is initiated in a woman of childbearing potential, the first dose of the drug should be given on the second or third day of the next normal menstrual period and measures should be taken to ensure that effective contraception is continued throughout itraconazole therapy and for 2 additional months following discontinuance of the drug. In reproduction studies, itraconazole caused a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats at dosages of approximately 40-160 mg/kg daily (5-20 times the maximum recommended human dosage) and in mice at dosages of approximately 80 mg/kg daily (10 times the maximum recommended human dosage).
Teratogenicity consisted of major skeletal defects in rats and encephaloceles and/or macroglossia in mice.
Although parental toxicity was observed, reproduction studies in male and female rats receiving oral itraconazole dosages up to 40 mg/kg daily (5 times the maximum recommended human dosage) did not reveal evidence of impaired fertility. More severe parental toxicity, including death, occurred at a dosage of 160 mg/kg daily (20 times the maximum recommended human dosage).
Itraconazole is distributed into human milk and the expected benefits of itraconazole for the nursing woman should be weighed against the potential risk to the infant from exposure to the drug. Because of the potential for transmission of HIV to an uninfected child, the US Centers for Disease Control and Prevention (CDC) currently recommends that HIV-infected women not breastfeed infants.
Drug Interactions
Antiarrhythmic Agents
Concomitant use of quinidine or dofetilide (antiarrhythmics that increase the QT interval) and itraconazole is contraindicated. Administration of itraconazole with quinidine or dofetilide would be expected to increase plasma concentrations of the antiarrhythmic agent which could result in serious adverse cardiovascular effects. Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients receiving quinidine concomitantly with itraconazole and/or other drugs that inhibit the CYP3A4 enzyme.
Antilipemic Agents
Concomitant use of hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors (e.g., atorvastatin, cerivastatin, lovastatin, simvastatin) and itraconazole may increase plasma concentrations of these antilipemic agents resulting in increased effects and increased risk of toxicity (e.g., myopathy including rhabdomyolysis).
Concomitant use of itraconazole and these antilipemic agents is contraindicated.
Astemizole and Terfenadine
Concomitant use of itraconazole and astemizole or terfenadine (drugs no longer commercially available in the US) is contraindicated. Rare cases of serious adverse cardiovascular effects, including death, ventricular tachycardia, and atypical ventricular tachycardia (torsades de pointes), have occurred in patients receiving itraconazole and terfenadine concomitantly. Similar effects have been reported when ketoconazole, a structurally similar antifungal agent, was used concomitantly with terfenadine. The antifungal agents appear to inhibit the metabolism of astemizole or terfenadine, probably via inhibition of the cytochrome P-450 (CYP) microsomal enzyme system, resulting in increased plasma concentrations of unchanged drug (to measurable levels) and reduced clearance of the active desmethyl or carboxylic acid metabolite, respectively. Such alterations in the pharmacokinetics of these antihistamines may have been associated with prolongation of the QT and QTc intervals.
Benzodiazepines
Concomitant use of itraconazole and benzodiazepines (e.g., alprazolam, diazepam, oral midazolam, triazolam) may result in increased plasma concentrations of these benzodiazepines that could potentiate and prolong the sedative and hypnotic effects of the drugs. Concomitant use of itraconazole and oral midazolam or triazolam is contraindicated; if midazolam is administered parenterally in patients receiving itraconazole, special precaution and patient monitoring is required since the sedative effect of the benzodiazepine may be prolonged.
Cisapride
Concomitant use of itraconazole and cisapride (no longer commercially available in the US) is contraindicated since itraconazole inhibits metabolism of cisapride and such use can result in increased plasma cisapride concentrations and increase the potential for serious adverse cardiovascular effects.
Pimozide
Concomitant use of pimozide and itraconazole is contraindicated. Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients receiving pimozide concomitantly with itraconazole and/or other drugs that inhibit the CYP3A4 enzyme. Spectrum Itraconazole and its principal metabolite hydroxyitraconazole are active against many fungi, including yeasts and dermatophytes. The antifungal spectrum of activity of the drug is similar to that of fluconazole and ketoconazole, although differences in specific in vitro and in vivo activity on weight and pharmacodynamic bases exist. In addition, itraconazole more consistently exhibits clinically important activity against Aspergillus.
In Vitro Susceptibility Testing
Optimal methods for antifungal agent in vitro susceptibility testing have been difficult to identify and are still being investigated.
The National Committee for Clinical Laboratory Standards (NCCLS) has recommended standardized procedures for reference broth dilution antifungal susceptibility testing that can be used to test in vitro susceptibility of yeasts (e.g., Candida, Cryptococcus neoformans) to itraconazole and has established interpretive MIC guidelines for Candida based principally on data involving oropharyngeal candidiasis.
The clinical relevance of these interpretive guidelines in terms of invasive candidal infections is unclear. While routine antifungal agent in vitro susceptibility testing is not recommended, such testing may be warranted under certain circumstances. When the NCCLS reference broth dilution procedure is used to evaluate susceptibility to itraconazole, Candida with MICs of 0.125 mcg/mL or less should be considered susceptible to itraconazole and those with MICs of 1 mcg/mL or greater should be considered resistant to the drug. Candida with MICs of 0.25-0. mcg/mL should be considered to have dose-dependent susceptibility, and measures to ensure adequate drug absorption and plasma itraconazole concentrations of greater than 0.5 mcg/mL may be required for optimal response.
Fungi
In vitro, the MIC90 of itraconazole for C. guilliermondii, C. krusei, C. parapsilosis, and C. tropicalis is 0.12-1 mcg/mL and the MIC90 of the drug for C. albicans and C. glabrata (formerly Torulopsis glabrata) is 0.12-4 mcg/mL. When the NCCLS standardized procedure was used to test in vitro susceptibility of clinical isolates of C. dubliniensis obtained from patients with or without human immunodeficiency virus (HIV) infection, these strains were inhibited by itraconazole concentrations of 0.03-0.5 mcg/mL. Some strains of C. lusitaniae are inhibited in vitro by itraconazole concentrations of 0.06-0.5 mcg/mL. The MIC90 of itraconazole reported for C. neoformans is 0.5 mcg/mL.
Blastomyces dermatitidis generally is inhibited in vitro by itraconazole concentrations of 0.07 mcg/mL or less. The MIC of itraconazole reported for clinical isolates of Sporothrix schenckii has ranged from 0.03-8 mcg/mL.
Several clinical isolates of Basidiobolus ranarum had itraconazole MICs of 1-8 mcg/mL when the NCCLS reference broth dilution procedure was used. Scopulariopsis, including S. acremonium and S. brevicaulis, generally are resistant to itraconazole in vitro.
Chemistry and Stability
Chemistry
Itraconazole, a synthetic triazole derivative, is an azole antifungal agent. The drug is structurally related to imidazole-derivative azole antifungal agents (e.g., butoconazole, clotrimazole, econazole, ketoconazole, oxiconazole); however, imidazoles have 2 nitrogens in the azole ring (imidazole ring) while itraconazole and other triazoles (e.g., fluconazole, terconazole) have 3 nitrogens in the ring (triazole ring).
For additional information on the chemistry of triazoles, including structure-activity relationships. Itraconazole is a 1:1:1:1 racemic mixture of 4 diastereomers (2 enantiomeric pairs), each possessing 3 chiral centers. The drug occurs as a white to slightly yellowish powder and is insoluble in water and very slightly soluble in alcohol.
Each mL of itraconazole oral solution contains 10 mg of itraconazole solubilized by 400 mg of hydroxypropyl-b-cyclodextrin as a molecular inclusion complex. The oral solution is clear and yellowish in color with a target pH of 2; the solution also contains hydrochloric acid, propylene glycol, sodium hydroxide, sodium saccharin, and sorbitol. Each mL of itraconazole injection contains 10 mg of itraconazole solubilized by 400 mg hydroxypropyl-b-cyclodextrin as a molecular inclusion complex. The injection also contains hydrochloric acid, propylene glycol, and sodium hydroxide for pH adjustment in sterile water for injection and has a pH of 4.5.
Stability
Itraconazole capsules should be stored at a controlled room temperature of 15-25°C and protected from light and moisture. Itraconazole oral solution should be stored at 25°C or lower and should not be frozen. Commercially available itraconazole injection should be stored at 25°C or lower and protected from light; freezing should be avoided.
Following dilution of itraconazole injection in the 0.9% sodium chloride injection diluent supplied by the manufacturer, itraconazole injections may be stored at 2-8° or 15-25°C for up to 48 hours. The injection should be protected from light during storage, but may be exposed to normal room light during administration.
The manufacturer states that itraconazole injection should not be diluted with 5% dextrose injection or with lactated Ringer’s injection, alone or in combination with any other diluent, since information is not available regarding the physical and/or chemical compatibility of itraconazole with these diluents.
Preparations
Itraconazole Oral Capsules 100 mg Sporanox®, (available in PulsePak® and regular packages) Janssen Solution 10 mg/mL Sporanox®, (with hydroxypropyl-b-cyclodextrin 400 mg/mL and with propylene glycol) OrthoBiotech Parenteral for injection, 10 mg/mL (250 mg for Sporanox®, (with hydroxypropyl-concentrate, for delivery of 200 mg) b-cyclodextrin 400 mg/mL and IV infusion with propylene glycol and with 50 mL 0.9% sodium chloride for injection diluent and one filtered infusion set) Ortho Biotech