Tab fluconazole
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Here is a comprehensive monograph on Tablet Fluconazole:
Fluconazole (Tab/IV)
Brand name: Diflucan (and generics)
Class: Triazole antifungal (fluorinated bis-triazole)
Mechanism of Action
Fluconazole inhibits fungal cytochrome P450–dependent 14α-demethylase, blocking the conversion of lanosterol to ergosterol — the essential sterol of the fungal cell membrane. Depletion of ergosterol disrupts membrane integrity and function. — Katzung's Basic & Clinical Pharmacology, 16e
Formulations
| Form | Strengths |
|---|---|
| Tablets | 50, 100, 150, 200 mg |
| Injection | 2 mg/mL (50, 100, 200 mL) |
| Oral suspension | 10 mg/mL, 40 mg/mL |
Pharmacokinetics
| Parameter | Details |
|---|---|
| Oral bioavailability | ~95% — nearly complete absorption; unaffected by food or gastric pH |
| Peak plasma conc | 4–8 µg/mL (after 100 mg repetitive dosing) |
| CSF penetration | 50–90% of simultaneous plasma levels — one of the best among azoles |
| Protein binding | ~11–12% |
| Elimination | >90% renal (excreted unchanged) |
| Half-life (t½) | 25–30 hours |
| Distribution | Widely distributed: CSF, breast milk, saliva, sputum, urine |
Unlike ketoconazole and itraconazole, oral and IV plasma concentrations are essentially equivalent. — Goodman & Gilman, 14e
Spectrum of Activity
| Organism | Activity |
|---|---|
| Candida albicans, C. parapsilosis | Active |
| Cryptococcus neoformans | Active |
| Coccidioides immitis | Active (drug of choice for coccidioidal meningitis) |
| Candida krusei | Intrinsically resistant |
| Candida glabrata | ~10–30% primary resistance |
| Aspergillus spp. and filamentous fungi | No activity |
| Mucor (mucormycosis) | No activity |
| Histoplasma, Blastomyces, Sporothrix | Little to no clinically useful activity |
Dosing (Adults)
| Indication | Dose |
|---|---|
| Vaginal candidiasis | 150 mg PO × 1 dose |
| Oropharyngeal candidiasis | LD 200 mg → 100–200 mg Q24h × 7–14 days |
| Esophageal candidiasis | LD 400 mg → 200–400 mg Q24h |
| Systemic candidiasis / candidemia | LD 800 mg → 400–800 mg Q24h |
| Cryptococcal meningitis (consolidation, HIV) | 400 mg Q24h × 8 weeks, then 200 mg Q24h indefinitely |
| Suppressive therapy (HIV, cryptococcal) | 200–400 mg Q24h |
| Bone marrow transplant prophylaxis | 400 mg Q24h |
| Coccidioidal meningitis | High-dose fluconazole (often 400–800 mg/d) |
Renal dose adjustment (Goodman & Gilman)
| CrCl (mL/min) | Dosing interval |
|---|---|
| 21–40 | Q48h |
| 10–20 | Q72h |
| Hemodialysis | 100–200 mg after each dialysis session |
Pediatric Dosing (Harriet Lane, 23e)
| Indication | Child ≥1 month | Max dose |
|---|---|---|
| Oropharyngeal candidiasis | 6–12 mg/kg Q24h | 400 mg |
| Esophageal candidiasis | 6–12 mg/kg Q24h | 600 mg |
| Invasive candidiasis / cryptococcal meningitis | 12 mg/kg Q24h | 800 mg |
| Suppressive (HIV + cryptococcal) | 6 mg/kg Q24h | 200 mg |
Clinical Uses
- Vulvovaginal candidiasis — first-line single-dose oral treatment
- Oropharyngeal & esophageal candidiasis — most commonly used agent
- Cryptococcal meningitis — consolidation and maintenance phase (after amphotericin B + flucytosine induction)
- Coccidioidal meningitis — drug of choice due to excellent CSF penetration
- Candidemia — acceptable alternative to echinocandins in non-neutropenic, non-critically ill patients; used as step-down therapy once isolate proven susceptible
- Prophylaxis — bone marrow transplant recipients; AIDS patients at risk for cryptococcal/candidal disease
- Not effective against aspergillosis, mucormycosis, histoplasmosis, sporotrichosis
Adverse Effects
- Nausea, vomiting, abdominal pain, diarrhea
- Headache, skin rash
- Hepatotoxicity — hepatitis, cholestasis (monitor LFTs)
- QT prolongation (especially with other QT-prolonging drugs)
- Neutropenia, agranulocytosis, thrombocytopenia (rare)
- Exfoliative skin disorders: SJS, TEN, DRESS (rare but serious)
- Adrenal insufficiency (reversible, rare)
Drug Interactions
Fluconazole inhibits CYP2C9 and CYP3A4 (weak inhibitor — less pronounced than other azoles):
| Drug | Interaction |
|---|---|
| Warfarin | ↑ INR — risk of bleeding |
| Phenytoin | ↑ phenytoin levels |
| Cyclosporine, tacrolimus | ↑ immunosuppressant levels |
| Statins (HMG-CoA reductase inhibitors) | ↑ risk myopathy/rhabdomyolysis |
| Oral hypoglycemics | ↑ hypoglycemic effect |
| Theophylline | ↑ theophylline levels |
| Rifampin | ↓ fluconazole levels (rifampin induces metabolism) |
| QT-prolonging drugs (e.g., erythromycin) metabolised via CYP3A4 | Contraindicated |
| Zidovudine (AZT) | ↑ AZT levels |
Contraindications / Precautions
- Hepatic dysfunction — use with caution; monitor LFTs
- Renal dysfunction — dose adjustment required
- QT prolongation, hypokalemia, advanced cardiac failure — use with caution
- Pregnancy:
- Single 150 mg dose for vaginal candidiasis: Category C (some risk of miscarriage weeks 7–22)
- High-dose / prolonged use: Category D (first trimester teratogenicity — associated with tetralogy of Fallot and other skeletal defects)
- Avoid during pregnancy unless benefit clearly outweighs risk
Key Advantages Over Other Azoles
- Highest oral bioavailability (~95%) among azoles
- Excellent CSF penetration
- Minimal effect on hepatic CYP enzymes → widest therapeutic index of the azoles
- Better GI tolerability
- Available orally and IV with equivalent blood levels
Sources: Katzung's Basic & Clinical Pharmacology 16e | Goodman & Gilman 14e | Harriet Lane Handbook 23e | Lippincott Illustrated Reviews: Pharmacology
Tab terbinafine
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Here is a comprehensive monograph on Tablet Terbinafine:
Terbinafine (Tab / Topical)
Brand name: Lamisil, Lamisil AT (and generics)
Class: Allylamine antifungal (synthetic)
Mechanism of Action
Terbinafine inhibits fungal squalene epoxidase, blocking the conversion of squalene → ergosterol. This causes:
- Depletion of ergosterol — disrupts fungal cell membrane integrity
- Accumulation of squalene — directly toxic to the fungal organism
Unlike azoles, terbinafine does not act on the cytochrome P450 14α-demethylase step. This makes it fungicidal (not merely fungistatic) against dermatophytes. — Katzung 16e, Goodman & Gilman 14e
Formulations
| Form | Strength |
|---|---|
| Tablet | 250 mg |
| Oral suspension | 25 mg/mL |
| Topical cream | 1% (12, 15, 30 g) |
| Topical spray | 1% (15 mL) |
Pharmacokinetics
| Parameter | Details |
|---|---|
| Oral bioavailability | ~40% (due to first-pass hepatic metabolism) |
| Food effect | None — absorption unaffected by food |
| Protein binding | Highly protein bound |
| Distribution | Highly lipophilic; accumulates in skin, nails, hair follicles, and adipose tissue |
| Metabolism | Hepatic (primarily CYP2D6) |
| Elimination | Primarily renal (urine) |
| t½ (initial) | ~12–17 hours |
| t½ (terminal/steady state) | 200–400 hours — due to slow release from skin and nail tissues |
| Topical absorption | ~3–5% (clinically insignificant) |
The very long terminal half-life explains sustained therapeutic concentrations in nails even after stopping therapy. — Fitzpatrick's Dermatology; Lippincott Pharmacology
Spectrum of Activity
| Organism | Activity |
|---|---|
| Dermatophytes (Trichophyton, Microsporum, Epidermophyton) | Excellent (fungicidal) — primary indication |
| Malassezia furfur (tinea versicolor) | Active |
| Candida spp. | Variable (some activity but not primary agent) |
| Scopulariopsis | May be effective |
| Aspergillus, systemic fungi | Poor penetration into deeper tissues — not used |
Dosing
Adults
| Indication | Dose | Duration |
|---|---|---|
| Onychomycosis – toenails | 250 mg PO once daily | 12 weeks |
| Onychomycosis – fingernails | 250 mg PO once daily | 6 weeks |
| Tinea capitis | 250 mg PO once daily | 4–6 weeks |
Cure rate up to 90% for onychomycosis — more effective than griseofulvin or itraconazole. — Katzung 16e
Pediatric (Tinea capitis / Onychomycosis) — Harriet Lane 23e
| Weight | Dose (once daily) |
|---|---|
| 10–20 kg | 62.5 mg |
| 20–40 kg | 125 mg |
| >40 kg | 250 mg |
Tinea capitis duration:
- Trichophyton tonsurans: 2–6 weeks
- Microsporum canis: 8–12 weeks
Topical (≥12 years)
| Indication | Application | Duration |
|---|---|---|
| Tinea pedis (interdigital) | Cream/spray BID | 1 week |
| Tinea corporis / tinea cruris | Cream/spray once daily | 1 week |
| Tinea versicolor | Spray once daily | 1 week |
Clinical Uses
- Onychomycosis — drug of choice (especially toenail dermatophyte infections); superior to itraconazole and griseofulvin
- Tinea capitis — oral therapy required (topicals ineffective for scalp/hair infections)
- Tinea pedis, tinea corporis, tinea cruris — topical or oral
- Tinea versicolor — topical
- Not used for systemic mycoses (aspergillosis, candidiasis, cryptococcosis) — poor tissue penetration beyond skin/nails
Adverse Effects
Systemic (Oral)
| Effect | Frequency |
|---|---|
| GI disturbances (diarrhea, dyspepsia, nausea) | Common |
| Headache | Common |
| Rash | Common |
| Elevated LFTs / hepatotoxicity | Uncommon — monitor baseline AST/ALT |
| Liver failure | Rare but potentially fatal — discontinue if signs of liver injury |
| Taste disturbance (dysgeusia) | Notable — can be prolonged |
| Visual disturbances | Reported |
| Neutropenia, thrombotic microangiopathy | Rare |
| SJS / TEN | Rare but serious |
| Hearing loss | Reported |
Monitor: Baseline LFTs + CBC; repeat if therapy >6 weeks. Discontinue immediately with jaundice, RUQ pain, persistent nausea, fatigue, or anorexia. — Harriet Lane 23e
Topical
- Generally well tolerated
- Local irritation, pruritus, contact dermatitis, dryness
Contraindications / Precautions
- Chronic or acute liver disease — contraindicated for systemic use
- Renal impairment (CrCl ≤50 mL/min): clearance reduced ~50% — use with caution, consider dose adjustment
- Pregnancy: Category B — systemic therapy should be postponed until after pregnancy if possible (nail infections are not life-threatening)
- Breastfeeding: Excreted in breast milk — avoid systemic use
Drug Interactions
Terbinafine inhibits CYP2D6:
| Drug | Interaction |
|---|---|
| β-blockers (metoprolol, propranolol) | ↑ levels/effect |
| Tricyclic antidepressants (amitriptyline) | ↑ levels/toxicity |
| SSRIs (fluoxetine) | ↑ levels |
| Amphetamines | ↑ effects/toxicity |
| Risperidone | ↑ levels |
| Rifampin | ↓ terbinafine concentrations (induces metabolism) |
| Cimetidine | ↑ terbinafine concentrations (inhibits metabolism) |
Unlike azoles, terbinafine has minimal effect on CYP3A4 — fewer interactions with cyclosporine, warfarin, etc. — Katzung 16e
Comparison: Terbinafine vs Other Agents for Onychomycosis
| Feature | Terbinafine | Itraconazole | Griseofulvin |
|---|---|---|---|
| Action | Fungicidal | Fungistatic | Fungistatic |
| Mechanism | Squalene epoxidase | 14α-demethylase | Mitotic spindle |
| Cure rate (toenail) | ~90% | Lower | Lower |
| Duration (toenail) | 12 weeks | 12 weeks (or pulse) | 12–18 months |
| CYP interactions | CYP2D6 inhibitor only | CYP3A4 inhibitor | Induces CYP enzymes |
Sources: Katzung Basic & Clinical Pharmacology 16e | Goodman & Gilman 14e | Harriet Lane Handbook 23e | Lippincott Illustrated Reviews: Pharmacology | Fitzpatrick's Dermatology
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