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Itraconazole
Allopathy
Prescription Required
DCGI (Drugs Controller General of India)
Schedule H
Germany, Japan, Malaysia, India, China, U.S., U.K.
Itraconazole is an antifungal agent belonging to the pharmacological class of Imidazoles.
Itraconazole has been approved to relieve symptoms and also for the treatment and maintenance of Aspergillosis, Blastomycosis, Candidiasis, Coccidioidomycosis, Histoplasmosis, Onychomycosis, Paracoccidioidomycosis, Prophylaxis against invasive fungal infections, Sporotrichosis, Talaromycosis, Tinea infections.
Itraconazole is well-absorbed orally, with an absolute bioavailability of 55%, reaching maximum levels when taken with a full meal. It has a large volume of distribution of approximately 796 ± 185 L and exhibits high protein binding of 99.8%. The drug undergoes extensive metabolism in the liver, primarily mediated by the cytochrome P450 3A4 isoenzyme system (CYP3A4), resulting in the formation of various metabolites, with hydroxyitraconazole being the major one. The main metabolic pathways involve oxidative scission of the dioxolane ring, aliphatic oxidation at the 1-methylpropyl substituent, N-dealkylation of this substituent, oxidative degradation of the piperazine ring, and triazolone scission. Elimination of the parent drug occurs mainly through fecal excretion (3-18% of the dose) and to a lesser extent through the urine (less than 0.03% of the dose). Approximately 40% of the dose is excreted as inactive metabolites in the urine, with no single metabolite representing more than 5% of the dose.
The common side effects involved in using Itraconazole are Loss of bladder control, Little or no urinating, Pain or burning when you urinate, Leg cramps, Constipation, Irregular heartbeats, Fluttering in your chest, Loss of appetite, Dark urine, Clay-colored stools, Yellowing of the skin or eyes (jaundice), Increased thirst or urination, Feeling tired, Shortness of breath, Cough with mucus, Fast heartbeats, Swelling.
Itraconazole is available in the form of Capsules, Oral Solutions , Tablets.
Itraconazole is approved in Germany, Japan, Malaysia, India, the U.K., the U.S., and China.
Itraconazole belonging to the pharmacological class of Imidazoles, acts as an antifungal agent.
Itraconazole exerts its antifungal activity by interacting with 14-α demethylase, a cytochrome P-450 enzyme crucial for converting lanosterol to ergosterol in fungal cells. As ergosterol is vital for the integrity of the fungal cell membrane, the inhibition of its synthesis by itraconazole leads to increased cellular permeability, resulting in leakage of cellular contents and ultimately the death of the fungus. Additionally, itraconazole may hinder endogenous respiration, interact with membrane phospholipids, prevent the transformation of yeasts into mycelial forms, inhibit purine uptake, and interfere with the biosynthesis of triglycerides and/or phospholipids, further contributing to its broad antifungal effects.
Itraconazole has been approved to relieve symptoms and also for the treatment and maintenance of Aspergillosis, Blastomycosis, Candidiasis, Coccidioidomycosis, Histoplasmosis, Onychomycosis, Paracoccidioidomycosis, Prophylaxis against invasive fungal infections, Sporotrichosis, Talaromycosis, Tinea infections.
After oral administration of Itraconazole, peak plasma concentrations are attained within 2 to 5 hours. Due to non-linear pharmacokinetics, the drug accumulates in plasma with multiple dosing. It takes approximately 15 days to reach steady-state concentrations. The Cmax values at steady-state are 0.5 µg/mL, 1.1 µg/mL, and 2.0 µg/mL when administered orally at 100 mg once daily, 200 mg once daily, and 200 mg twice daily, respectively. The terminal half-life of Itraconazole ranges from 16 to 28 hours following a single dose and increases to 34 to 42 hours with repeated dosing. Itraconazole belonging to the pharmacological class of Imidazoles, acts as an antifungal agent.
Itraconazole exerts its antifungal activity by interacting with 14-α demethylase, a cytochrome P-450 enzyme crucial for converting lanosterol to ergosterol in fungal cells. As ergosterol is vital for the integrity of the fungal cell membrane, the inhibition of its synthesis by itraconazole leads to increased cellular permeability, resulting in leakage of cellular contents and ultimately the death of the fungus. Additionally, itraconazole may hinder endogenous respiration, interact with membrane phospholipids, prevent the transformation of yeasts into mycelial forms, inhibit purine uptake, and interfere with the biosynthesis of triglycerides and/or phospholipids, further contributing to its broad antifungal effects.
Itraconazole has been approved to relieve symptoms and also for the treatment and maintenance of Aspergillosis, Blastomycosis, Candidiasis, Coccidioidomycosis, Histoplasmosis, Onychomycosis, Paracoccidioidomycosis, Prophylaxis against invasive fungal infections, Sporotrichosis, Talaromycosis, Tinea infections.
After oral administration of Itraconazole, peak plasma concentrations are attained within 2 to 5 hours. Due to non-linear pharmacokinetics, the drug accumulates in plasma with multiple dosing. It takes approximately 15 days to reach steady-state concentrations. The Cmax values at steady-state are 0.5 µg/mL, 1.1 µg/mL, and 2.0 µg/mL when administered orally at 100 mg once daily, 200 mg once daily, and 200 mg twice daily, respectively. The terminal half-life of Itraconazole ranges from 16 to 28 hours following a single dose and increases to 34 to 42 hours with repeated dosing.
Itraconazole can be used in the following treatment:
- Aspergillosis
- Blastomycosis
- Candidiasis
- Coccidioidomycosis
- Histoplasmosis
- Onychomycosis
- Paracoccidioidomycosis
- Prophylaxis against invasive fungal infections
- Sporotrichosis
- Talaromycosis
- Tinea infections
Itraconazole is approved for use in the following clinical indications:
- Aspergillosis
- Blastomycosis
- Candidiasis
- Coccidioidomycosis
- Histoplasmosis
- Onychomycosis
- Paracoccidioidomycosis
- Prophylaxis against invasive fungal infections
- Sporotrichosis
- Talaromycosis
- Tinea infections
Aspergillosis:
Oral: 200-400 mg once daily (dose may vary depending on the severity of the infection and response to treatment).
Blastomycosis:
Oral: 200-400 mg once daily (dose may vary depending on the severity of the infection and response to treatment).
Candidiasis:
Oropharyngeal treatment (Fluconazole-refractory):
- Oral solution: 200-400 mg once daily for 7 to 14 days.
- Oral solution: 200 mg once daily for 14 to 21 days.
- Oral solution: 200 mg once daily for 3 to 7 days.
- Oral solution: 200 mg once daily.
Coccidioidomycosis:
- Treatment (Bone and/or joint infection):
- Oral: 200 mg twice daily for ≥12 months (HIV-exposed/-infected).
- Oral: 400 mg twice daily for ≥12 months (Non-HIV-exposed/-infected).
- Meningitis (HIV-exposed/-infected):
- Initial: Oral: 200 mg three times daily for 3 days.
- Maintenance: Oral: 200 mg twice daily.
- Pneumonia, focal (mild disease, HIV-exposed/-infected):
- Oral: 200 mg twice daily.
Histoplasmosis:
- Pulmonary, acute primary disease (HIV-exposed/-infected):
- Initial: Oral: 200 mg three times daily for 3 days.
- Maintenance: Oral: 200 mg twice daily for 12 months (up to 12 weeks of treatment may be required in children with functional cellular immunity).
- Disseminated disease, mild to moderate (HIV-exposed/-infected):
- Oral: 200 mg twice daily for 12 months.
- Onychomycosis:
- Oral: 200 mg once daily for 12 consecutive weeks.
- Paracoccidioidomycosis:
- Oral: 100-200 mg once or twice daily (dose may vary depending on the severity of the infection and response to treatment).
- Prophylaxis against invasive fungal infections:
- Oral: 200 mg once daily.
Sporotrichosis:
- Lymphocutaneous or localized cutaneous:
- Oral: 200 mg twice daily for 3 to 6 months.
- Visceral or disseminated (after initial treatment with amphotericin B):
- Oral: 200 mg twice daily for at least 12 months.
- Talaromycosis:
- Oral: 200 mg twice daily for 2 to 4 weeks (may vary depending on the severity of the infection and response to treatment).
Tinea infections:
- Oral: 100-200 mg once daily (dose may vary depending on the specific type and severity of the tinea infection).
Itraconazole is available in the following dosage forms and strengths:
- Capsules:100 mg
- Oral Solution:10 mg/mL
- Tablets (Pulse Therapy):100 mg
Capsules, Oral Solutions , Tablets
- Dosage Adjustments in Kidney Patients:
Altered kidney function:
- Oral: Initially, no dosage adjustment is necessary for any degree of kidney dysfunction. Dosing should be based on trough serum concentrations .
Augmented renal clearance (measured urinary CrCl ≥130 mL/minute/1.73 m2):
Note: Augmented renal clearance (ARC) is a condition that occurs in certain critically ill patients without organ dysfunction and with normal serum creatinine concentrations. Younger patients (<55 years of age) admitted post-trauma or major surgery are at the highest risk for ARC, as well as those with sepsis, burns, or hematologic malignancies. An 8- to 24-hour measured urinary CrCl is necessary to identify these patients .
- Oral: Initially, no dosage adjustment is necessary for patients with augmented renal clearance. Dosing should be based on trough serum concentrations .
Hemodialysis, intermittent (thrice weekly): Not dialyzable :
- Oral: Initially, no supplemental dose or dosage adjustment is necessary for patients undergoing intermittent hemodialysis. Dosing should be based on trough serum concentrations .
Peritoneal dialysis: Not dialyzable.:
- Oral: Initially, no dosage adjustment is necessary for patients undergoing peritoneal dialysis. Dosing should be based on trough serum concentrations.
- Dosage Adjustments in Hepatic Impairment Patients:
No dosage adjustments are found to be necessary.
- Dosage Adjustments in Pediatric Patients:
Oral formulations of itraconazole are not interchangeable.
General Dosing for Susceptible Infections:
- Infants, Children, and Adolescents: Oral: 5 mg/kg/dose every 12 hours for treatment; usual maximum daily dose: 200 mg/day; some infections may require up to 400 mg/day.
Blastomycosis, Non-CNS Infections:
- Infants, Children, and Adolescents: Oral solution: 5 mg/kg/dose twice daily; maximum dose: 200 mg/dose; duration determined by severity and response; usual duration for mild to moderate disease is 6 to 12 months; for moderately severe to severe disease a total duration of 12 months including 1 to 2 weeks of amphotericin B.
Candidiasis, HIV-Exposed/-Infected:
- Oropharyngeal Treatment:
- Infants and Children (Fluconazole-refractory): Oral solution: 2.5 mg/kg/dose twice daily for 7 to 14 days; maximum daily dose range: 200 to 400 mg/day.
- Adolescents: Oral solution: 200 mg once daily for 7 to 14 days.
- Esophageal Treatment:
- Infants and Children (Fluconazole-refractory): Oral solution: 2.5 mg/kg/dose twice daily for at least 21 days and at least 2 weeks following resolution of symptoms.
- Adolescents: Oral solution: 200 mg once daily for 14 to 21 days.
- Vulvovaginal Uncomplicated:
- Adolescents: Oral solution: 200 mg once daily for 3 to 7 days.
- Secondary Prophylaxis:
- Infants and Children: Oral solution: 2.5 mg/kg/dose twice daily.
- Adolescents: Oral solution: 200 mg twice daily.
Coccidioidomycosis:
- Treatment:
- Bone and/or Joint Infection:
- Infants and Children (Independent of HIV status): Oral solution: 5 mg/kg/dose twice daily for ≥12 months.
- Adolescents (HIV-exposed/-infected): Oral: 200 mg twice daily.
- Meningitis (HIV-exposed/-infected):
- Adolescents:
- Initial: Oral: 200 mg 3 times daily for 3 days.
- Maintenance: 200 mg twice daily.
- Pneumonia, Focal (Mild Disease) HIV-exposed/-infected:
- Infants and Children: Oral:
- Initial: 2 to 5 mg/kg/dose 3 times daily for 3 days; maximum dose: 200 mg/dose.
- Maintenance: 2 to 5 mg/kg/dose twice daily; maximum dose: 200 mg/dose; duration of treatment determined by rate of clinical response.
- Adolescents: Oral: 200 mg twice daily.
- Secondary Prophylaxis/Chronic Suppressive Therapy (HIV-exposed/-infected):
- Infants and Children: Oral: 2 to 5 mg/kg/dose twice daily; maximum dose: 200 mg/dose.
- Adolescents: Oral: 200 mg twice daily.
Cryptococcal Meningitis, HIV-Exposed/-Infected:
- Consolidation Treatment:
- Infants and Children: Oral solution (preferred):
- Initial Load: 2.5 to 5 mg/kg/dose 3 times daily for 3 days; maximum dose: 200 mg/dose.
- Maintenance Dose: 5 to 10 mg/kg/day divided once or twice daily for a minimum of 8 weeks; maximum daily dose: 400 mg/day.
- Adolescents: Oral: 200 mg twice daily for a minimum of 8 weeks.
- Secondary Prophylaxis/Relapse Prevention:
- Infants and Children: Oral solution: 5 mg/kg/dose once daily; maximum daily dose: 200 mg/day.
Histoplasmosis:
- Treatment:
- Pulmonary, Acute Primary Disease (HIV-exposed/-infected):
- Infants and Children: Oral solution (preferred):
- Initial Load: 2 to 5 mg/kg/dose 3 times daily for 3 days; maximum dose: 200 mg/dose.
- Maintenance Dose: 2 to 5 mg/kg/dose twice daily for 12 months; maximum dose: 200 mg/dose.
- Non-HIV-exposed/-infected: Infants, Children, and Adolescents: Oral solution (preferred): 2.5 to 5 mg/kg/dose twice daily for 6 to 12 weeks; maximum dose: 200 mg/dose.
- Disseminated Disease, Mild to Moderate (HIV-exposed/-infected):
- Infants and Children: Oral solution (preferred):
- Initial Load: 2 to 5 mg/kg/dose 3 times daily for 3 days; maximum dose: 200 mg/dose.
- Maintenance Dose: 2 to 5 mg/kg/dose twice daily for 12 months; maximum dose: 200 mg/dose.
- Adolescents: Oral solution (preferred):
- Initial Load: 200 mg 3 times daily for 3 days.
- Maintenance Dose: 200 mg twice daily for at least 12 months.
- Non-HIV-exposed/-infected: Infants, Children, and Adolescents: Oral solution (preferred): 2.5 to 5 mg/kg/dose twice daily for 3 to 12 months.
- Disseminated Disease, Moderately Severe to Severe, Consolidation Treatment Following Appropriate Induction Treatment (HIV-exposed/-infected):
- Infants and Children: Oral solution:
- Initial Load: 2 to 5 mg/kg/dose 3 times daily for 3 days; maximum dose: 200 mg/dose.
- Maintenance Dose: 2 to 5 mg/kg/dose twice daily for 12 months; maximum dose: 200 mg/dose.
- Adolescents: Oral solution (preferred):
- Initial Load: 200 mg 3 times daily for 3 days.
- Maintenance Dose: 200 mg twice daily for ≥12 months.
- Non HIV-exposed/-infected, Step-Down: Infants, Children, and Adolescents: Oral solution (preferred): 2.5 to 5 mg/kg/dose twice daily for 3 to 12 months based on the severity of the disease; maximum dose: 200 mg/dose.
- Prophylaxis:
- Primary (HIV-exposed/-infected): Adolescents: Oral: 200 mg once daily.
- Secondary Prophylaxis/Chronic Suppressive Therapy (HIV-exposed/-infected):
- Infants and Children: Oral solution: 5 to 10 mg/kg/dose once daily; maximum dose: 200 mg/dose.
- Adolescents: Oral: 200 mg once daily.
Microsporidiosis, Disseminated Disease Caused by Trachipleistophora or Anncaliia, Treatment, HIV-Exposed/-Infected:
- Limited data available: Adolescents: Oral: 400 mg once daily in conjunction with albendazole.
Penicilliosis, HIV-Exposed/-Infected:
- Limited data available: Adolescents:
- Primary Prophylaxis: Oral: 200 mg once daily for patients with a CD4 count <100 cells/mm3 who spend extensive time in northern Thailand, Vietnam, and Southern China, especially rural areas.
- Acute Infection (Severely Ill), Treatment: Oral: 200 mg twice daily for 10 weeks; initiate after completion of 2 weeks' induction therapy with amphotericin B.
- Mild Disease, Treatment: Oral: 200 mg twice daily for 8 weeks.
- Secondary Prophylaxis/Chronic Maintenance Therapy: Oral: 200 mg once daily.
Sporotrichosis:
- Limited data available: Infants, Children, and Adolescents:
- Lymphocutaneous or Localized Cutaneous: Oral solution (preferred): 3 to 5 mg/kg/dose twice daily; continue 2 to 4 weeks after all lesions have resolved; usual total duration: 3 to 6 months; maximum dose: 200 mg/dose.
- Step-Down Therapy, Visceral, or Disseminated (After Initial Treatment and Clinical Response with Amphotericin B): Oral: 3 to 5 mg/kg/dose twice daily; continue for at least 12 months; maximum dose: 200 mg/dose.
Tinea Capitis, Microsporum Canis and Trichophyton sp:
- Limited data available: Infants, Children, and Adolescents: Oral: 5 mg/kg/dose once daily; maximum dose: 100 mg/dose; duration of therapy dependent on the organism: Microsporum sp: 4 to 8 weeks; Trichophyton sp: 2 to 3 weeks; up to 12 weeks of treatment may be required. Alternatively, a pulse regimen may be used: 1-week treatment pulses with at least 2 weeks off between pulses.
When taking itraconazole, there are certain dietary restrictions that should be followed to ensure the medication's effectiveness and safety:
- Grapefruit and Grapefruit Juice: Avoid consuming grapefruit and grapefruit juice while taking itraconazole. Grapefruit can interfere with the metabolism of the medication in the liver, leading to increased drug levels in the bloodstream, which may result in adverse effects or reduced efficacy.
- Antacids: Do not take antacids (medications used to neutralize stomach acid) within two hours of itraconazole administration. Antacids can reduce the absorption of itraconazole and may hinder its effectiveness.
- Calcium or Magnesium Supplements: Avoid taking calcium or magnesium supplements within two hours of itraconazole intake. These supplements can also interfere with the absorption of itraconazole.
- Pepcid: Refrain from taking Pepcid (famotidine), a medication used to reduce stomach acid, within two hours of itraconazole ingestion. Pepcid can impact the absorption of itraconazole and should be spaced apart from the medication.
The dietary restriction should be individualized as per patient requirements.
Itraconazole may be contraindicated under the following conditions:
- Itraconazole (itraconazole) Capsules should not be used for the treatment of onychomycosis (nail fungal infection) in patients with evidence of ventricular dysfunction, including congestive heart failure (CHF), or a history of CHF. The use of Itraconazole in such patients may lead to serious cardiac complications and is contraindicated. Patients with underlying cardiac issues should not be treated with Itraconazole for onychomycosis unless the condition is life-threatening or involves other serious infections. If signs or symptoms of congestive heart failure occur during the use of Itraconazole, administration should be discontinued immediately.
- Note: Onychomycosis is a condition where the nails are infected by fungi, resulting in discoloration, thickening, and crumbling of the nails. Itraconazole is an antifungal medication used to treat various fungal infections, but its use in patients with certain cardiac conditions should be avoided in the case of onychomycosis treatment. Always consult a healthcare professional for appropriate treatment options based on individual medical conditions.
The treating physician must closely monitor the patient and keep pharmacovigilance as follows:
Serious Warnings and Precautions
- Congestive Heart Failure: Itraconazole (itraconazole) capsules should not be used in patients with evidence of ventricular dysfunction, such as congestive heart failure (CHF), unless it is for the treatment of life-threatening or serious infections. If signs or symptoms of congestive heart failure occur during Itraconazole administration, discontinue the medication. In animal and human studies, itraconazole has shown negative effects on heart function, and caution should be exercised in patients with underlying cardiac issues.
- Drug Interactions: Coadministration of Itraconazole capsules with certain drugs metabolized by CYP3A4 is contraindicated. The combination can lead to increased plasma concentrations of these drugs, potentially causing serious side effects, including QT prolongation and ventricular tachyarrhythmias, which may be life-threatening.
- Liver Toxicity: Rare cases of serious liver toxicity, including liver failure and death, have been associated with itraconazole treatment. Patients should be monitored for signs of liver dysfunction, and treatment should be discontinued if symptoms like anorexia, nausea, jaundice, or abdominal pain occur. The use of Itraconazole capsules should be strongly discouraged in patients with pre-existing liver disease or liver toxicity history, unless the benefits outweigh the risks.
General Precautions
- Different Formulations: Itraconazole capsules and itraconazole oral solution should not be used interchangeably due to differences in drug exposure and mucosal effects.
- Avoid in Life-Threatening Infections: Itraconazole capsules are not recommended for immediate treatment of life-threatening systemic fungal infections.
- Testing for Fluconazole-Resistant Strains: In cases of systemic candidosis with suspected fluconazole-resistant strains of Candida, sensitivity testing should be done before starting itraconazole therapy.
Cardiovascular Precautions
- Cardiac Dysrhythmias: Concurrent use of itraconazole with certain drugs can cause life-threatening cardiac dysrhythmias or sudden death. Avoid coadministration with cisapride, methadone, pimozide, levacetylmethadol, or quinidine.
- Use in Patients with Underlying Cardiac Disease: Itraconazole may increase the risk of heart failure, especially with higher total daily doses. Caution is advised in patients with cardiac disease, pulmonary disease, renal failure, and other edematous disorders. Monitor patients for signs of congestive heart failure during treatment.
Ear/Nose/Throat Precautions
- Hearing Loss: Transient or permanent hearing loss has been reported with itraconazole treatment, especially when coadministered with quinidine. Hearing should be monitored, and treatment discontinued if hearing loss occurs.
Gastrointestinal Precautions
- Use in Patients with Decreased Gastric Acidity: Absorption of itraconazole may be impaired when gastric acidity is decreased. Administer Itraconazole capsules with an acidic beverage or coadminister antiemetics to improve absorption.
Hepatic Precautions
- Hepatic Effects: Rare cases of serious hepatotoxicity, including liver failure and death, have been reported with itraconazole. Monitor liver function and discontinue treatment if signs of liver dysfunction occur.
Immune Precautions
- Use in AIDS and Neutropenic Patients: Itraconazole plasma concentrations may be lower in neutropenic and AIDS patients. Monitoring and dose adjustment may be necessary. Coadministration with didanosine should be done with a time interval.
Neurologic Precautions
- Neuropathy: Discontinue treatment if neuropathy occurs.
Renal Precautions
- Use in Patients with Renal Insufficiency: Itraconazole exposure may be lower in patients with renal impairment. Caution and possible dose adjustment should be considered.
Effects on Driving and Machinery
- Adverse reactions such as dizziness, visual disturbances, and hearing loss have been reported with itraconazole, which may impair the ability to drive or operate machinery.
Breast Feeding Warning
As itraconazole is excreted in human milk, patients should be advised to discontinue nursing while taking Itraconazole capsules. This precaution is essential to prevent the transfer of the medication to the nursing infant through breast milk, as the safety and potential risks to the infant are not well-established. To ensure the well-being of both the patient and the nursing child, nursing should be temporarily suspended during the course of treatment with Itraconazole capsules.
Pregnancy Warning
Pregnancy:
Pregnancy Category B
Itraconazole capsules should not be used for the treatment of onychomycosis or dermatomycoses in pregnant patients or in women planning to become pregnant. The use of Itraconazole capsules during pregnancy is not recommended except in life-threatening cases where the potential benefits to the mother outweigh the potential harm to the fetus.
Studies on pregnant rats and mice have shown teratogenic effects, such as major skeletal and secondary soft tissue defects, when itraconazole was administered at high doses (40 mg/kg/day or higher in rats and 80 mg/kg/day or higher in mice). These effects included encephaloceles and/or macroglossia in mice. Therefore, caution should be exercised when considering itraconazole use during pregnancy.
Itraconazole should not be given to women of child-bearing potential for the treatment of onychomycosis or dermatomycoses unless they are using effective measures to prevent pregnancy and start therapy on the second or third day after the onset of menstruation. Effective contraception must be used throughout the course of Itraconazole therapy and for 2 months after completing treatment.
There is limited information available on the use of itraconazole during pregnancy, and post-marketing reports have mentioned cases of congenital abnormalities, encompassing skeletal, genitourinary tract, cardiovascular, ophthalmic malformations, and chromosomal and multiple malformations. However, a definitive causal relationship with itraconazole capsules has not been established. To avoid potential risks, it is prudent to exercise caution and carefully consider alternative treatment options for pregnant patients or women planning pregnancy.
Food Warning
For better absorption, it is advised to consume liquid formulations on an empty stomach. One must ensure a two-hour interval between taking this medication and antacids, calcium or magnesium supplements, and Pepcid. Also, consuming grapefruit or grapefruit juice should be refrained while on this medication.
The adverse reactions related to Itraconazole can be categorized as follows:
Common:
● Loss of bladder control
● Little or no urinating
● Pain or burning when you urinate
● Leg cramps
● Constipation
● Irregular heartbeats
● Fluttering in your chest
● Loss of appetite
● Dark urine
● Clay-colored stools
● Yellowing of the skin or eyes (jaundice)
● Increased thirst or urination
● Feeling tired
● Shortness of breath
● Cough with mucus
● Fast heartbeats
● Swelling
● Rapid weight gain
● Sleep problems
● Confusion
● Lightheadedness
● Blurred vision
● Double vision
● Ringing in your ears
● Problems with hearing
● Numbness or tingling feeling
● Muscle weakness
● Limp feeling
● Severe pain in your upper stomach spreading to your back
● Nausea
● Vomiting
● Tiredness
Less common
● Dizziness
● Feeling of faintness or lightheadedness upon sudden changes in position (from lying or sitting)
● Drowsiness
● Feeling unusually cold
● Blurred vision
● Chest pain
● Chills
● Clay-colored stools
● Cloudy urine
● Cold sweats
● Confusion
● Cough
● Dark urine
● Decrease in urine-concentrating ability
● Diarrhea
● Headache
● Itching and skin rash
● Light-colored stools
● Mental changes
● Muscle cramps in the hands, arms, feet, legs, or face
Rare
● Decreased appetite
● Difficulty with swallowing
● Dilated neck veins
● Disturbed color perception
● Double vision
● Extreme tiredness or weakness
● Black, tarry stools
● Bleeding gums
● Blistering, peeling, or loosening of the skin
● Bloating or swelling of the face, arms, hands, lower legs, or feet
● Blood in the urine or stools
● Bluish lips and fingernails
● Burning, crawling, itching, numbness, painful, prickling, "pins and needles," or tingling sensations
● Persistent ringing or buzzing or other unexplained noise in the ears
● Coughing that sometimes produces a pink frothy sputum
● Cracks in the skin
● Fast or irregular breathing
● Feeling of discomfort
● General feeling of tiredness or weakness
● Halos around lights
● Hearing loss
● Hives or welts
● Inflammation of the joints
● Joint pain
The clinically relevant drug interactions of Itraconazole is briefly summarized here:
Itraconazole and its main metabolite, hydroxyitraconazole, act as inhibitors of CYP3A4, leading to potential drug interactions. The following drug interactions may occur:
- Increased Plasma Concentrations: Itraconazole may decrease the elimination of drugs metabolized by CYP3A4, resulting in elevated plasma concentrations of these drugs when co-administered. This can lead to both therapeutic and adverse effects. Monitoring of drug plasma concentrations and dosage adjustments may be necessary after initiating Itraconazole therapy. Clinical monitoring for signs of increased or prolonged pharmacologic effects is advised. After discontinuation, itraconazole plasma concentrations gradually decline, especially in patients with hepatic cirrhosis or those receiving CYP3A4 inhibitors. Caution is crucial when initiating therapy with drugs metabolized by itraconazole.
- Decreased Plasma Concentrations: Inducers of CYP3A4 can reduce itraconazole's plasma concentrations, potentially affecting its effectiveness. Therefore, the concomitant use of these drugs and Itraconazole is not recommended.
- Increased Plasma Concentrations: Other inhibitors of CYP3A4 may elevate itraconazole's plasma concentrations. Patients taking Itraconazole together with one of these drugs should be closely monitored for signs of increased or prolonged pharmacologic effects of Itraconazole.
- Drugs that increase itraconazole plasma concentration: Antiarrhythmics, Anticoagulants, Anticonvulsants, Antimycobacterials, Antineoplastics, Antipsychotics, Benzodiazepines, Calcium Channel Blockers, Gastrointestinal Motility Agents, HMG CoA-Reductase Inhibitors, Immunosuppressants, Oral Hypoglycemics, and Protease Inhibitors.
- Drugs that decrease itraconazole plasma concentration: Anticonvulsants, Antimycobacterials, Gastric Acid Suppressors/Neutralizers, and Reverse Transcriptase Inhibitors.
- Drugs that increase itraconazole plasma concentration: Macrolide Antibiotics and Protease Inhibitors.
Specific Drug Interactions:
- Antiarrhythmics: Concomitant use of quinidine or dofetilide with Itraconazole is contraindicated due to the potential for serious cardiovascular events. Caution is also advised with disopyramide.
- Anticoagulants: Itraconazole enhances the anticoagulant effect of coumarin-like drugs, such as warfarin.
- Anticonvulsants: The plasma concentrations of itraconazole may be reduced when administered with phenytoin or other inducers of CYP3A4.
- Digoxin: Co-administration of Itraconazole may lead to increased plasma concentrations of digoxin through inhibition of P-glycoprotein.
Antimycobacterials:
Studies on drug interactions have shown that when azole antifungal agents like itraconazole and hydroxyitraconazole are given together with rifabutin or rifampin, their plasma concentrations were significantly reduced. It is suggested that rifabutin is partly metabolized by CYP3A4, and Itraconazole might inhibit the metabolism of rifabutin. Although no formal study data exist for isoniazid, similar effects can be expected. Consequently, if Itraconazole is administered concomitantly with any of these agents, the efficacy of Itraconazole could be greatly reduced, and coadministration is not recommended.
Antineoplastics:
Itraconazole may inhibit the metabolism of busulfan, docetaxel, and vinca alkaloids.
Antipsychotics:
Pimozide, a drug known to prolong the QT interval and partially metabolized by CYP3A4, should not be co-administered with Itraconazole to avoid serious cardiovascular events. Therefore, concurrent use of Itraconazole and pimozide is contraindicated.
Benzodiazepines:
When Itraconazole is given together with alprazolam, diazepam, oral midazolam, or triazolam, increased plasma concentrations of these benzodiazepines can occur. This may potentiate and prolong hypnotic and sedative effects. Concomitant administration of Itraconazole with oral midazolam or triazolam is contraindicated. Special precaution and patient monitoring are required if parenteral midazolam is administered.
Calcium Channel Blockers:
Concomitant use of Itraconazole and dihydropyridine calcium channel blockers has been reported to cause edema. The negative inotropic effect of calcium channel blockers may be additive to those of itraconazole, which can inhibit their metabolism. Caution is advised when co-administering itraconazole and calcium channel blockers to avoid an increased risk of congestive heart failure (CHF). Coadministration of Itraconazole and nisoldipine is contraindicated due to significant increases in nisoldipine plasma concentrations.
Gastric Acid Suppressors/Neutralizers:
The absorption of itraconazole may be impaired when gastric acid production is decreased. Itraconazole should be taken with a cola beverage if the patient has achlorhydria or is taking H2-receptor antagonists or other gastric acid suppressors. Antacids should be administered at least 1 hour before or 2 hours after taking Itraconazole Capsules. Concomitant administration of Itraconazole and omeprazole (a proton pump inhibitor) significantly reduces itraconazole bioavailability. Caution is advised when coadministering Itraconazole and H2-antagonists.
Gastrointestinal Motility Agents:
Itraconazole can elevate plasma cisapride concentrations when co-administered, potentially leading to serious cardiovascular events. Concomitant use of Itraconazole with cisapride is contraindicated.
HMG CoA-Reductase Inhibitors:
Itraconazole inhibits the metabolism of atorvastatin, cerivastatin, lovastatin, and simvastatin, increasing the risk of skeletal muscle toxicity, including rhabdomyolysis. Co-administration of Itraconazole with lovastatin or simvastatin is contraindicated.
Immunosuppressants:
Concomitant administration of Itraconazole with cyclosporine or tacrolimus can increase plasma concentrations of these immunosuppressants. The same may happen with sirolimus when administered with Itraconazole.
Macrolide Antibiotics:
Erythromycin and clarithromycin, known inhibitors of CYP3A4, can increase plasma concentrations of itraconazole when co-administered. Caution should be exercised when Itraconazole and these macrolide antibiotics are given together.
Oral Hypoglycemic Agents:
Severe hypoglycemia has been reported in patients receiving azole antifungal agents and oral hypoglycemic agents concomitantly. Close monitoring of blood glucose concentrations is necessary when Itraconazole and oral hypoglycemic agents are co-administered.
Polyenes:
Prior treatment with itraconazole may reduce or inhibit the activity of polyenes like amphotericin B, but the clinical significance of this effect is not clearly defined.
Protease Inhibitors:
Co-administration of Itraconazole with protease inhibitors metabolized by CYP3A4, such as indinavir, ritonavir, and saquinavir, may increase plasma concentrations of these protease inhibitors. Itraconazole and indinavir/ritonavir can also increase plasma concentrations of itraconazole. Caution is advised when using Itraconazole and protease inhibitors together.
Reverse Transcriptase Inhibitors:
Nevirapine is an inducer of CYP3A4 and may reduce the bioavailability of ketoconazole. Although no studies have been conducted with itraconazole, co-administration of Itraconazole and nevirapine is not recommended.
Other:
- Levacetylmethadol (levomethadyl) is known to prolong the QT interval and is metabolized by CYP3A4. Concomitant use of levacetylmethadol and Itraconazole is contraindicated.
- Coadministration of Itraconazole with ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine, or methylergometrine (methylergonovine) is contraindicated due to the risk of elevated concentrations causing vasospasm.
- Halofantrine can prolong the QT interval at high plasma concentrations, and caution should be exercised when co-administering Itraconazole and halofantrine.
- Itraconazole may increase plasma concentrations of alfentanil, buspirone, certain glucocorticosteroids (budesonide, dexamethasone, fluticasone, and methylprednisolone), and trimetrexate.
- Caution should be used when Itraconazole is co-administered with cilostazol and eletriptan.
- Concomitant use of Itraconazole and fentanyl may lead to increased or prolonged fentanyl plasma concentrations, potentially causing respiratory depression.
The following are the side effects involving Itraconazole:
● Loss of bladder control
● Little or no urinating
● Pain or burning when you urinate
● Leg cramps
● Constipation
● Irregular heartbeats
● Fluttering in your chest
● Loss of appetite
● Dark urine
● Clay-colored stools
● Yellowing of the skin or eyes (jaundice)
● Increased thirst or urination
● Feeling tired
● Shortness of breath
● Cough with mucus
● Fast heartbeats
● Swelling
● Rapid weight gain
● Sleep problems
● Confusion
● Lightheadedness
● Blurred vision
● Double vision
● Ringing in your ears
● Problems with hearing
● Numbness or tingling feeling
● Muscle weakness
● Limp feeling
● Severe pain in your upper stomach spreading to your back
● Nausea
● Vomiting
● Tiredness
The use of molecule Itraconazole should be prudent in the following group of special populations:
Pregnancy:
Pregnancy Category B
Itraconazole capsules should not be used for the treatment of onychomycosis or dermatomycoses in pregnant patients or in women planning to become pregnant. The use of Itraconazole capsules during pregnancy is not recommended except in life-threatening cases where the potential benefits to the mother outweigh the potential harm to the fetus.
Studies on pregnant rats and mice have shown teratogenic effects, such as major skeletal and secondary soft tissue defects, when itraconazole was administered at high doses (40 mg/kg/day or higher in rats and 80 mg/kg/day or higher in mice). These effects included encephaloceles and/or macroglossia in mice. Therefore, caution should be exercised when considering itraconazole use during pregnancy.
Itraconazole should not be given to women of child-bearing potential for the treatment of onychomycosis or dermatomycoses unless they are using effective measures to prevent pregnancy and start therapy on the second or third day after the onset of menstruation. Effective contraception must be used throughout the course of Itraconazole therapy and for 2 months after completing treatment.
There is limited information available on the use of itraconazole during pregnancy, and post-marketing reports have mentioned cases of congenital abnormalities, encompassing skeletal, genitourinary tract, cardiovascular, ophthalmic malformations, and chromosomal and multiple malformations. However, a definitive causal relationship with itraconazole capsules has not been established. To avoid potential risks, it is prudent to exercise caution and carefully consider alternative treatment options for pregnant patients or women planning pregnancy.
Lactation:
As itraconazole is excreted in human milk, patients should be advised to discontinue nursing while taking Itraconazole capsules. This precaution is essential to prevent the transfer of the medication to the nursing infant through breast milk, as the safety and potential risks to the infant are not well-established. To ensure the well-being of both the patient and the nursing child, nursing should be temporarily suspended during the course of treatment with Itraconazole capsules.
Pediatric:
For pediatric patients (< 18 years of age), it is essential to note that the efficacy and safety of Itraconazole capsules have not been established. Therefore, the use of these capsules in pediatric patients should be avoided unless there is a clear determination that the potential benefits outweigh the potential risks.
As of now, there are no available pharmacokinetic data in pediatric patients. However, there have been a limited number of cases where patients aged 3 to 16 years were treated with 100 mg/day of itraconazole for systemic fungal infections, and no serious adverse events were reported.
It is worth mentioning that toxicological studies in rats have shown that itraconazole administration can lead to bone toxicity. Although such toxicity has not been reported in adult patients, the long-term effects of itraconazole in children remain unknown. Hence, extra caution should be exercised when considering itraconazole treatment in pediatric patients.
Geriatric Use:
Clinical data regarding the use of itraconazole capsules in elderly patients (> 65 years of age) are limited. Therefore, caution is advised when considering the use of Itraconazole capsules in this age group, and it should only be prescribed if the potential benefits are deemed to outweigh the potential risks.
When prescribing itraconazole to elderly patients, it is essential to carefully consider the dose selection, taking into account the higher likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of concomitant diseases or other drug therapies that may interact with itraconazole. This cautious approach is recommended due to the age-related changes in drug metabolism and potential drug interactions that can affect elderly patients more significantly.
The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Itraconazole.
Dialysis does not effectively remove itraconazole from the body. In case of accidental overdose, appropriate supportive measures should be taken.
Pharmacodynamics:
Itraconazole is classified as an antifungal agent of the imidazole/triazole type. Its mode of action involves highly selective inhibition of the enzyme cytochrome P450 14α-demethylase, responsible for converting lanosterol to ergosterol in fungal cell wall synthesis. This inhibition leads to the accumulation of 14 α-methyl sterols in fungi, resulting in the loss of normal sterols and contributing to the fungistatic activity of fluconazole. Notably, mammalian cell demethylation is less sensitive to fluconazole inhibition.
In vitro studies have demonstrated that itraconazole exhibits activity against Cryptococcus neoformans and Candida spp. Moreover, in animal models, both normal and immunocompromised, itraconazole has shown fungistatic activity against systemic and intracranial fungal infections caused by Cryptococcus neoformans and systemic infections due to Candida albicans.
Pharmacokinetics:
Absorption :
Rapid Absorption: Itraconazole is quickly absorbed after oral intake, with peak plasma concentrations reached within 2 to 5 hours following the administration of an oral capsule dose.
Effect of Food: The oral bioavailability of itraconazole is highest when Itraconazole Capsules are taken immediately after a full meal.
Impact of Gastric Acidity: Absorption of itraconazole capsules is reduced in individuals with reduced gastric acidity, such as those taking gastric acid secretion suppressors (e.g., H2-receptor antagonists, proton pump inhibitors) or individuals with achlorhydria due to certain diseases.
Enhanced Absorption: In subjects with reduced gastric acidity, absorption of itraconazole under fasting conditions can be increased when Itraconazole Capsules are taken with an acidic beverage, such as a non-diet cola, as shown in studies involving ranitidine pretreatment.
Comparison with Oral Solution: When comparing the Capsule formulation to the Oral Solution, itraconazole exposure is lower with the Capsule formulation for the same dose of the drug.
Distribution :
Protein Binding: Most of the itraconazole in the plasma (99.8%) is bound to protein, primarily albumin (99.6% for the hydroxy-metabolite).
Affinity for Lipids: Itraconazole also exhibits a marked affinity for lipids.
Tissue Distribution: Itraconazole demonstrates extensive distribution into tissues, with a large apparent volume in the body (>700 L). Concentrations in various tissues like lung, kidney, liver, bone, stomach, spleen, and muscle are higher than those in plasma, and uptake into keratinous tissues, particularly skin, is notably elevated.
Cerebrospinal Fluid Concentration: Concentrations of itraconazole in cerebrospinal fluid are significantly lower than in plasma.
Metabolism :
Liver Metabolism: Itraconazole undergoes extensive metabolism in the liver, resulting in the formation of numerous metabolites.
Role of Enzyme CYP3A4: In vitro studies indicate that the major enzyme involved in itraconazole metabolism is CYP3A4.
Hydroxy-Itraconazole: The primary metabolite is hydroxy-itraconazole, which exhibits antifungal activity similar to itraconazole. Trough plasma concentrations of this metabolite are about twice as high as itraconazole.
Excretion:
Urine and Feces: Itraconazole is primarily excreted as inactive metabolites, with 35% excreted in urine and 54% in feces within one week of an oral solution dose.
Renal Excretion: Renal excretion of itraconazole and its active metabolite hydroxy-itraconazole accounts for less than 1% of an intravenous dose.
Fecal Excretion: Based on oral radiolabeled doses, fecal excretion of unchanged drug ranges from 3% to 18% of the administered dose.
Persistence in Keratinous Tissues
Slow Elimination: Itraconazole remains in keratinous tissues, such as skin and nail keratin, for an extended period.
Skin Concentrations: Concentrations in the skin persist for 2 to 4 weeks after a 4-week treatment period, and in nail keratin, it can be detected for at least six months after a 3-month treatment period.
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