Usage
Itraconazole + Terbinafine is prescribed for the treatment of various fungal infections, including onychomycosis (nail fungus), tinea corporis (ringworm), tinea pedis (athlete’s foot), tinea cruris (jock itch), and systemic fungal infections such as aspergillosis, blastomycosis, and histoplasmosis. It belongs to the azole antifungals and allylamine antifungals pharmacological classifications. The combination exerts its antifungal effect by inhibiting the synthesis of ergosterol, a crucial component of fungal cell membranes. Itraconazole inhibits the enzyme lanosterol 14α-demethylase, whereas terbinafine inhibits squalene epoxidase, both vital for ergosterol production. This dual inhibition disrupts fungal cell membrane integrity, leading to fungal cell death.
Alternate Names
No widely recognized alternate names exist for this specific drug combination. However, itraconazole and terbinafine are individually available under various brand names. Some popular brand names for itraconazole include Sporanox®, Onmel™, and Itraconazole. Popular brand names for terbinafine include Lamisil® and Terbinex®.
How It Works
Pharmacodynamics: Itraconazole + Terbinafine disrupts fungal cell membrane integrity by inhibiting ergosterol synthesis. This leads to increased fungal cell membrane permeability and ultimately fungal cell death.
Pharmacokinetics:
- Itraconazole: Itraconazole is well-absorbed orally, particularly with food. It is extensively metabolized in the liver by CYP3A4 enzymes. Itraconazole exhibits high plasma protein binding and is eliminated primarily via the biliary route with minimal renal excretion.
- Terbinafine: Terbinafine is also well-absorbed orally and its absorption is not significantly affected by food. It undergoes hepatic metabolism, primarily by CYP2D6, and is eliminated primarily through urine and, to a lesser extent, bile.
Mode of Action:
- Itraconazole: Inhibits the fungal cytochrome P450 enzyme lanosterol 14α-demethylase, leading to the depletion of ergosterol and the accumulation of 14α-methylated sterols, which disrupt fungal cell membrane function.
- Terbinafine: Inhibits squalene epoxidase, another enzyme in the ergosterol biosynthesis pathway, leading to the accumulation of squalene, which is toxic to fungal cells, and the depletion of ergosterol.
Elimination Pathways:
- Itraconazole: Primarily biliary excretion (feces).
- Terbinafine: Primarily renal excretion (urine) and to a lesser extent, biliary excretion (feces).
Dosage
Standard Dosage
Adults: Itraconazole 200 mg twice daily for one week in a pulse dose along with Terbinafine 250 mg twice daily for eight weeks is recommended, and for another four weeks itraconazole 200mg pulse dose is used for preventing relapse.
Children: The safety and efficacy of Itraconazole + Terbinafine have not been established in children under 12 years of age. For adolescents above 12 years, itraconazole + terbinafine can be used under strict medical supervision.
Special Cases:
- Elderly Patients: Monitor for potential drug interactions and adverse effects, and adjust dosage if necessary.
- Patients with Renal Impairment: Caution is advised in patients with renal impairment, particularly for terbinafine, as dose adjustments might be required.
- Patients with Hepatic Dysfunction: Use with caution due to potential hepatotoxicity; monitor liver function tests.
- Patients with Comorbid Conditions: Consider individual patient factors and potential drug interactions.
Clinical Use Cases No information is available about the specified clinical use cases with the combined use of itraconazole and terbinafine. These medications are not routinely used in the described contexts.
Dosage Adjustments
Dose adjustments should be considered for patients with hepatic or renal dysfunction. For patients with liver disease, a lower starting dose of itraconazole may be considered, and liver function tests should be closely monitored. For patients with renal impairment, a dose reduction of terbinafine may be required.
Side Effects
Common Side Effects
Nausea, headache, diarrhea, abdominal pain, rash.
Rare but Serious Side Effects
Hepatotoxicity (liver damage), Stevens-Johnson syndrome, toxic epidermal necrolysis, serious allergic reactions.
Long-Term Effects
Potential for liver damage with prolonged use of itraconazole.
Adverse Drug Reactions (ADR)
Hepatotoxicity, severe skin reactions, cardiac effects (itraconazole).
Contraindications
Hypersensitivity to itraconazole or terbinafine, pre-existing liver disease (especially with itraconazole), concurrent use with certain medications (e.g., cisapride, triazolam, midazolam, pimozide), pregnancy (itraconazole, systemic terbinafine).
Drug Interactions
Itraconazole is a potent inhibitor of CYP3A4, and terbinafine is primarily metabolized by CYP2D6. Concurrent use with substrates of these enzymes can lead to clinically significant drug interactions. Itraconazole can interact with statins, digoxin, and certain antihistamines. Terbinafine can interact with antidepressants (e.g., tricyclic antidepressants, selective serotonin reuptake inhibitors), beta-blockers, and certain antiarrhythmics.
Pregnancy and Breastfeeding
- Itraconazole is contraindicated during pregnancy. Terbinafine should be avoided during pregnancy unless the potential benefit outweighs the risk to the fetus.
- Itraconazole is excreted in breast milk and should be avoided during breastfeeding. While limited information suggests low levels of terbinafine in breast milk, it’s generally recommended to avoid it during breastfeeding or discontinue breastfeeding while taking it.
Drug Profile Summary
- Mechanism of Action: Inhibits ergosterol synthesis, disrupting fungal cell membrane integrity.
- Side Effects: Nausea, headache, diarrhea, rash, hepatotoxicity (itraconazole), taste disturbances (terbinafine).
- Contraindications: Hypersensitivity, liver disease, pregnancy, concurrent use with certain medications.
- Drug Interactions: CYP3A4 interactions (itraconazole), CYP2D6 interactions (terbinafine).
- Pregnancy & Breastfeeding: Contraindicated in pregnancy (itraconazole).
- Dosage: Adults: As mentioned above; Children: Not established.
- Monitoring Parameters: Liver function tests, complete blood count, electrolyte levels.
Popular Combinations
Although itraconazole and terbinafine are frequently prescribed separately, there isn’t extensive evidence supporting the widespread use of this specific combination in routine clinical practice. Further research is required to assess the potential synergistic effects or clinical benefits of combining these drugs compared with their individual use.
Precautions
- Monitor liver function tests and complete blood count periodically.
- Patients with pre-existing liver or cardiac conditions should be closely monitored.
- Avoid alcohol consumption during treatment with itraconazole.
- Caution while driving or operating machinery, especially in patients experiencing dizziness with terbinafine.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Itraconazole + Terbinafine?
A: The standard adult dose is Itraconazole 200 mg pulse dose twice daily for one week along with Terbinafine 250 mg twice daily for eight weeks, followed by itraconazole pulse dose alone for another four weeks to prevent relapses. Pediatric dosing is not established, and the combination is generally avoided in children under 12.
Q2: What are the most common side effects?
A: The most common side effects include nausea, headache, diarrhea, abdominal pain, and rash.
Q3: What are the serious side effects I should watch for?
A: Serious side effects include hepatotoxicity, allergic reactions, Stevens-Johnson syndrome, and toxic epidermal necrolysis.
Q4: Are there any contraindications to using this medication?
A: Contraindications include hypersensitivity, pre-existing liver disease, concurrent use with certain medications (e.g., cisapride), pregnancy (itraconazole, systemic terbinafine).
Q5: What are the potential drug interactions?
A: Itraconazole can interact with medications metabolized by CYP3A4, while terbinafine can interact with those metabolized by CYP2D6. Examples include certain statins, digoxin, certain antihistamines, antidepressants, beta-blockers, and certain antiarrhythmics.
Q6: Can Itraconazole + Terbinafine be used during pregnancy or breastfeeding?
A: Itraconazole and terbinafine are generally avoided or contraindicated during pregnancy, especially the oral formulation. They should also be avoided during breastfeeding or used cautiously after consulting with a physician.
Q7: How does this drug combination work?
A: It inhibits ergosterol synthesis, a crucial component of the fungal cell membrane, leading to fungal cell death. Itraconazole and terbinafine act on different enzymes in the ergosterol synthesis pathway, resulting in dual inhibition.
Q8: What precautions should I take when prescribing Itraconazole + Terbinafine?
A: Monitor liver function and complete blood count. Exercise caution in patients with pre-existing liver or cardiac conditions, and be mindful of potential drug interactions. Avoid alcohol during itraconazole treatment. Advise caution while driving or operating machinery, especially with terbinafine if dizziness occurs.
Q9: How long does treatment usually last?
A: Treatment duration varies depending on the type and severity of the infection. It may range from several weeks to several months, especially for nail infections.
