Clinical safety and tolerability issues in use of triazole derivatives in management of fungal infections

Figures & data

Table 1 Summary of major pharmacokinetic characteristics of oral triazole formulations

Agent	Bioavailability	Dosing	Dose adjustment for organ dysfunction	Protein-binding	Metabolism	Elimination half-life	CYP	Excretion	Active metabolite	CSF	Vitreous body
FLU	>90%	Load: 800 mg once IV/PO Maintenance: 100–800 mg/d IV/PO	Renal	12%	Minimal	20–50 hours	2C9, 3A4, 2C19	80% urine	–	>80%	20%–70%
ITR^1	55%^2	Load: 200 mg q8 h × 3 d Maintenance: 200 mg q12 h	None	99%	Liver	21–60 hours	3A4	<1% urine	Hydroxyl-ITR	<1%	∼10%
VOR^1	>95%	Load: 6 mg/kg q12 h IV/PO × 1 day Maintenance: 4 mg/kg IV/PO or 200–300 mg PO q12 h	Liver	58%	Liver	6 hours	2C19, 2C9, 3A4	<2% urine	–	∼50%	38%
POS	NR	Load: 200 mg q6 h × 7 d Maintenance: 400 mg q8 h–12 h	None	98%	Liver^3	35 hours	3A4	71% feces, 13% urine	–	variable	ND

Note:

1 Doses can be further adjusted based on drug levels or drug interactions;

2 oral solution;

3 uridine diphosphate glucuronidation.

Abbreviations: FLU, fluconazole; ITR, itraconazole; VOR, voriconazole; POS, posaconazole; CYP, cytochrome P450; CSF, cerebrospinal fluid; IV, intravenous; PO, oral; ND, no data; NR, not reported; d, day; h, hour.

Table 2 Summary of major documented and potential drug–drug interactions of triazoles*

Type of interaction and agent involved	Triazole	Recommendation
Decrease triazole plasma concentrations
Rifampin	VOR, ITR, FLU, POS	Contraindicated with VOR, monitor ITR levels, consider increasing FLU dose
High dose ritonavir (400 mg BID), St John’s wort	VOR	Contraindicated
Carbamazepine, long-acting barbiturates (eg, phenobarbital)	VOR, ITR	Contraindicated with VOR, monitor ADE and levels with ITR
Low-dose ritonavir (100 mg BID)	VOR	Avoid combination
Cimetidine, efavirenz	POS	Avoid combination
Esomeprazole, metoclopramide	POS	Monitor POS levels and breakthrough infections
Phenytoin, nevirapine	ITR	Monitor ITR levels and breakthrough infections
Plasma concentrations increased by triazole
Levacetylmethadol	ITR	Contraindicated
Astemizole, terfenadine	VOR, FLU	Contraindicated with VOR, FLU ≥ 400 mg is contraindicated with terfenadine, monitor ADE
Cisapride	VOR, POS, ITR FLU	Contraindicated
Pimozide, ergot alkaloids (eg, ergotamine)	VOR, POS, ITR	Contraindicated
Quinidine, dofetilide	VOR, POS, ITR	Quinidine contraindicated, dofetilide contraindicated only with ITR
Sirolimus	VOR, POS, ITR	Contraindicated with VOR, POS; monitor levels and ADE with ITR
Tacrolimus, cyclosporine	VOR, POS, ITR, FLU	Reduce dose, monitor levels
Methadone, short-acting opioids (eg, sufentanil),	VOR	Monitor ADE, dose reduction may be needed
Warfarin	VOR, ITR, FLU	Monitor PT, INR levels
Digoxin	ITR	Monitor ADE
Theophylline	FLU	Monitor theophylline levels
Plasma concentrations potentially increased by triazole
Benzodiazepines	VOR, ITR, FLU	Triazolam, oral midazolam are contraindicated with ITR; monitor ADE, consider dose reduction
Statins	VOR, ITR	Lovastatin, simvastatin are contraindicated with ITR; monitor ADE, consider dose reduction
Calcium channel blockers	VOR, POS, ITR	Nisoldipine is contraindicated with ITR, monitor ADE with other agents
Oral hypoglycemic, vinca alkaloids	VOR, POS, ITR, FLU	Monitor ADE
Other NNRTIs, other protease inhibitors	VOR, POS, ITR	Monitor ADE
Disopyramide	ITR	Monitor QTc interval, other ADE
Two-way interactions
Rifabutin	VOR, POS, ITR	Contraindicated with VOR, avoid combination with POS, ITR
Efavirenz	VOR	Increase VOR dose, reduce efavirenz dose
Phenytoin	VOR, POS	Increase VOR dose, monitor phenytoin levels and ADE
Omeprazole	VOR	Reduce omeprazole dose to ½ if >40 mg/day
Oral contraceptives	VOR	Monitor for ADE of both agents and voriconazole levels

Notes:

* Table adjusted based on.^13,15,19,21

Abbreviations: BID, twice daily; FLU, fluconazole; ITR, itraconazole; VOR, voriconazole; POS, posaconazole; ADE, adverse events; PT, prothrombin time; INR, International Normalized Ratio.

Table 3 Review of major studies reporting on adverse events associated with voriconazole

Study	n	Patient population	Indication	Nausea	Chills	Fever	Visual hallucinations	Visual changes	Liver enzymes	Rash
65	200	Immunocompromised hosts	Esophageal candidiasis	6%	NR	12%	NR	23%	6.5%^1	5.5%
68	415	Heme malignancy, solid tumor, HSCT	Neutropenic fever	9.4%	13.7%	NR	4.3%	21.9%	2.9%–8.9%^2	3.4%^3
70	194	Heme malignancy, HSCT/SOT	IA	NR	3.1%^4	3.1%^4	6.7%	44.8%	3.6%	8.2%
71	137	Heme malignancy, HSCT/SOT, DM, HIV	IA	2.2%	NR	NR	NR	10.9%	14.6%^5	8.8%
96	45	Heme malignancy, HSCT/SOT	IMI	2.2%	NR	NR	NR	NR	8.9%	2.2%
66	52	Heme malignancy, SOT, HIV, other^6	IC	25%	NR	NR	NR	21.2%	23%^7	15.4%
69	272	NR	IC	NR	3%	15%	NR	4%	23%	6%
67	39	Heme malignancy, HSCT/SOT, other	IA, CPA	NR	NR	NR	NR	30.8%^8	33.3%	35.9%^9

Notes:

1 Elevation of alkaline phosphatase only reported;

2 Including together elevation of transaminases and alkaline phosphatase >5 × the baseline value;

3 flushing;

4 rates for chills and fevers reported together;

5 3–5 × upper normal limit;

6 other, chronic obstructive pulmonary disease, tuberculosis, bronchiectasis, diabetes mellitus, alcoholism;

7 predominantly elevated transaminases;

8 visual changes defined as: enhanced light perception, photophobia, color vision changes, blurred vision, and wavy lines on television or on going to sleep;

9 rash in 6 patients, photosensitivity in 3 patients, and cheilitis in 5 patients.

Abbreviations: n, number of patients; NR, not reported; heme, hematologic; HIV, human immunodeficiency virus; HSCT, hematopoietic stem cell transplant; SOT, solid organ transplant; IA, invasive aspergillosis; DM, diabetes mellitus; IMI, invasive mold infection; IC, invasive candidiasis; CPA, chronic pulmonary aspergillosis.

Table 4 Review of major studies reporting on adverse events associated with posaconazole

Study	n	Patient population	Dose	Nausea	Vomiting	Headache	Dizziness	QT prolongation	Rash	Liver enzymes	AST	ALT	ALP
97	448	Healthy volunteers	50–1200 mg/d	NR	NR	17%	6%	None	NR	NR	6%	11%	NR
87	330	Cancer, HSCT	800 mg/d	14%	6%	5%	5%	5%	NR	NR	5%	NR	5%
86	23	SOT	800 mg/d	17.4%	8.7%	NR	NR	NR	NR	NR	8.7%	4.3%	NR
98	53	Heme, HSCT	800 mg/d	NR	NR	NR	NR	NR	NR	NR	0	NR	0
88	107	Cancer, HSCT/SOT, other^1	800 mg/d	12%	5%	<3%	<3%	0	4%	3%	NR	2%	NR
99	304	AML/MDS	600 mg/d	NR	NR	NR	NR	<1%	NR	<1%	NR	<1%	NR
45	301	HSCT	600 mg/d	7%	4%	1%	NR	NR	NR	3%	3%	3%	NR
100	428	Cancer, HSCT/SOT, other^2	800–1200 mg/d	8%	7%	9%	2%	2%	3%	2%	3%	5%	NR
101	21	Cancer, HSCT/SOT, DM	800 mg/d	5%	5%	NR	NR	0	5%	NR	5%	NR	NR

Notes:

1 Other, diabetes mellitus, HIV/AIDS;

2 Other, acquired immunocompromising conditions, no known underlying immunocompromising conditions.

Abbreviations: n, number of patients; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase; d, day; NR, not reported; heme, hematologic malignancy; HSCT, hematopoietic stem cell transplant; SOT, solid organ transplant; AML, acute myelogenous leukemia; MDS, myelodysplastic syndrome; DM, diabetes mellitus.

Diflucan [Package insert]New York, NYRoerig2008

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