A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Vfend Side Effects, and Drug Interactions - Voriconazole
Vfend Side Effects, and Drug Interactions - Voriconazole
SIDE EFFECTS
Overview
The most frequently reported adverse events (all causalities) in the therapeutic trials were visual disturbances, fever, rash, vomiting, nausea, diarrhea, headache, sepsis, peripheral edema, abdominal pain, and respiratory disorder. The treatment-related adverse events which most often led to discontinuation of voriconazole therapy were elevated liver function tests, rash, and visual disturbances (see hepatic toxicity under WARNINGS and discussion of Clinical Laboratory Values and dermatological and visual adverse events below).
Discussion of Adverse Reactions
The data described in the table below reflect exposure to voriconazole in 1493 patients in the therapeutic studies. This represents a heterogeneous population, including immunocompromised patients, e.g., patients with hematological malignancy or HIV and non-neutropenic patients. This subgroup does not include healthy volunteers and patients treated in the compassionate use and non-therapeutic studies. This patient population was 62% male, had a mean age of 45.1 years (range 12-90, including 49 patients aged 12-18 years), and was 81% white and 9% black. Five hundred sixty-one patients had a duration of voriconazole therapy of greater than 12 weeks, with 136 patients receiving voriconazole for over six months. Table 10 includes all adverse events which were reported in therapeutic studies at an incidence of >1% as well as events of concern which occurred at an incidence of <1% during voriconazole therapy.
In study 307/602, 381 patients (196 on voriconazole, 185 on amphotericin B) were treated to compare voriconazole to amphotericin B followed by other licensed antifungal therapy in the primary treatment of patients with acute invasive aspergillosis. Study 305 evaluated the effects of oral voriconazole (200 patients) and oral fluconazole (191 patients) in the treatment of esophageal candidiasis. Laboratory test abnormalities for these studies are discussed under Clinical Laboratory Values below.
Table 10 Treatment Emergent Adverse Events Rate > 1% or Adverse Events of Concern in All Therapeutic Studies Possibly Related to Therapy or Causality Unknown
|
|
All Therapeutic Studies
|
Protocol 305 (oral therapy)
|
Protocol 307/602 (IV/ oral therapy)
|
Voriconazole N=1493 |
Voriconazole N = 200 |
Fluconazole N =191 |
Voriconazole N =196 |
Ampho B** N = 185 |
| |
N (%)
|
N (%)
|
N (%)
|
N (%)
|
N (%)
|
|
Special Senses*
|
Abnormal vision
|
307 (20.6)
|
31 (15.5)
|
8 (4.2)
|
55 (28.1)
|
1 (0.5)
|
Photophobia
|
36 (2.4)
|
5 (2.5)
|
2 (1.0)
|
7 (3.6)
|
0
|
Chromatopsia
|
20 (1.3)
|
2 (1.0)
|
0
|
2 (1.0)
|
0
|
Eye hemorrhage
|
3 (0.2)
|
0
|
0
|
0
|
0
|
|
Body as a Whole
|
Fever
|
93 (6.2)
|
0
|
0
|
7 (3.6)
|
25 (13.5)
|
Chills
|
61 (4.1)
|
1 (0.5)
|
0
|
0
|
36 (19.5)
|
Headache
|
48 (3.2)
|
0
|
1 (0.5)
|
7 (3.6)
|
8 (4.3)
|
Abdominal pain
|
25 (1.7)
|
0
|
0
|
5 (2.6)
|
6 (3.2)
|
Chest pain
|
13 (0.9)
|
0
|
0
|
4 (2.0)
|
2 (1.1)
|
|
Cardiovascular System
|
Tachycardia
|
37 (2.5)
|
0
|
0
|
5 (2.6)
|
5 (2.7)
|
Hypertension
|
29 (1.9)
|
0
|
0
|
1 (0.5)
|
2 (1.1)
|
Hypotension
|
26 (1.7)
|
1 (0.5)
|
0
|
1 (0.5)
|
3 (1.6)
|
Vasodilatation
|
23 (1.5)
|
0
|
0
|
2 (1.0)
|
2 (1.1)
|
|
Digestive System
|
Nausea
|
88 (5.9)
|
2 (1.0)
|
3 (1.6)
|
14 (7.1)
|
29 (15.7)
|
Vomiting
|
71 (4.8)
|
2 (1.0)
|
1 (0.5)
|
11 (5.6)
|
18 (9.7)
|
Liver function tests abnormal
|
41 (2.7)
|
6 (3.0)
|
2 (1.0)
|
9 (4.6)
|
4 (2.2)
|
Diarrhea
|
16 (1.1)
|
0
|
0
|
3 (1.5)
|
6 (3.2)
|
Cholestatic jaundice
|
16 (1.1)
|
3 (1.5)
|
0
|
4 (2.0)
|
0
|
Dry mouth
|
15 (1.0)
|
0
|
1 (0.5)
|
3 (1.5)
|
0
|
Jaundice
|
3 (0.2)
|
1 (0.5)
|
0
|
0
|
0
|
|
Hemic and Lymphatic System
|
Thrombocytopenia
|
7 (0.5)
|
0
|
1 (0.5)
|
2 (1.0)
|
2 (1.1)
|
Anemia
|
2 (0.1)
|
0
|
0
|
0
|
5 (2.7)
|
Leukopenia
|
4 (0.3)
|
0
|
0
|
1 (0.5)
|
0
|
Pancytopenia
|
1 (0.1)
|
0
|
0
|
0
|
0
|
Metabolic and Nutritional Systems
|
Alkaline phosphatase increased
|
54 (3.6)
|
10 (5.0)
|
3 (1.6)
|
6 (3.1)
|
4 (2.2)
|
Hepatic enzymes increased
|
28 (1.9)
|
3 (1.5)
|
0
|
7 (3.6)
|
5 (2.7)
|
SGOT increased
|
28 (1.9)
|
8 (4.0)
|
2 (1.0)
|
1 (0.5)
|
0
|
SGPT increased
|
27 (1.8)
|
6 (3.0)
|
2 (1.0)
|
3 (1.5)
|
1 (0.5)
|
Hypokalemia
|
24 (1.6)
|
0
|
0
|
1 (0.5)
|
36 (19.5)
|
Peripheral edema
|
16 (1.1)
|
1 (0.5)
|
0
|
7 (3.6)
|
9 (4.9)
|
Hypomagnesemia
|
16 (1.1)
|
0
|
0
|
2 (1.0)
|
10 (5.4)
|
Bilirubinemia
|
12 (0.8)
|
1 (0.5)
|
0
|
1 (0.5)
|
3 (1.6)
|
Creatinine increased
|
4 (0.3)
|
1 (0.5)
|
0
|
0
|
59 (31.9)
|
|
Nervous System
|
Hallucinations
|
37 (2.5)
|
0
|
0
|
10 (5.1)
|
1 (0.5)
|
Dizziness
|
20 (1.3)
|
0
|
2 (1.0)
|
5 (2.6)
|
0
|
|
Skin and Appendages
|
Rash
|
86 (5.8)
|
3 (1.5)
|
1 (0.5)
|
13 (6.6)
|
7 (3.8)
|
Pruritus
|
16 (1.1)
|
0
|
0
|
2 (1.0)
|
2 (1.1)
|
Maculopapular rash
|
17 (1.1)
|
3 (1.5)
|
0
|
1 (0.5)
|
0
|
|
Urogenital
|
Kidney function abnormal
|
8 (0.5)
|
1 (0.5)
|
1 (0.5)
|
4 (2.0)
|
40 (21.6)
|
Acute kidney failure
|
7 (0.5)
|
0
|
0
|
0
|
11 (5.9)
|
* See WARNINGS – Visual Disturbances, PRECAUTIONS – Information For Patients |
**Amphotericin B followed by other licensed antifungal therapy
|
VISUAL DISTURBANCES
Voriconazole treatment-related visual disturbances are common. In clinical trials, approximately 30% of patients experienced altered/enhanced visual perception, blurred vision, color vision change and/or photophobia. The visual disturbances were generally mild and rarely resulted in discontinuation. Visual disturbances may be associated with higher plasma concentrations and/or doses.
The mechanism of action of the visual disturbance is unknown, although the site of action is most likely to be within the retina. In a study in healthy volunteers investigating the effect of 28-day treatment with voriconazole on retinal function, voriconazole caused a decrease in the electroretinogram (ERG) waveform amplitude, a decrease in the visual field, and an alteration in color perception. The ERG measures electrical currents in the retina. The effects were noted early in administration of voriconazole and continued through the course of study drug dosing. Fourteen days after end of dosing, ERG, visual fields and color perception returned to normal (see WARNINGS, PRECAUTIONS – Information For Patients).
Dermatological Reactions
Dermatological reactions were common in the patients treated with voriconazole. The mechanism underlying these dermatologic adverse events remains unknown. In clinical trials, rashes considered related to therapy were reported by 6% (86/1493) of voriconazole-treated patients. The majority of rashes were of mild to moderate severity. Cases of photosensitivity reactions appear to be more likely to occur with long-term treatment. Patients have rarely developed serious cutaneous reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme during treatment with VFEND. If patients develop a rash, they should be monitored closely and consideration given to discontinuation of VFEND. It is recommended that patients avoid strong, direct sunlight during VFEND therapy.
Less Common Adverse Events
The following adverse events occurred in <1% of all voriconazole-treated patients, including healthy volunteers and patients treated under compassionate use protocols (total N = 2090). This listing includes events where a causal relationship to voriconazole cannot be ruled out or those which may help the physician in managing the risks to the patients. The list does not include events included in Table 10 above and does not include every event reported in the voriconazole clinical program.
Body as a Whole abdomen enlarged, allergic reaction, anaphylactoid reaction (see PRECAUTIONS), ascites, asthenia, back pain, cellulitis, edema, face edema, flank pain, flu syndrome, graft versus host reaction, granuloma, infection, bacterial infection, fungal infection, injection site pain, injection site infection/inflammation, mucous membrane disorder, multi-organ failure, pain, pelvic pain, peritonitis, sepsis, substernal chest pain
Cardiovascular atrial arrhythmia, atrial fibrillation, AV block complete, bigeminy, bradycardia, bundle branch block, cardiomegaly, cardiomyopathy, cerebral hemorrhage, cerebral ischemia, cerebrovascular accident, congestive heart failure, deep thrombophlebitis, endocarditis, extrasystoles, heart arrest, myocardial infarction, nodal arrhythmia, palpitation, phlebitis, postural hypotension, pulmonary embolus, QT interval prolonged, supraventricular tachycardia, syncope, thrombophlebitis, vasodilatation, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia (including torsade de pointes)
Digestive anorexia, cheilitis, cholecystitis, cholelithiasis, constipation, duodenal ulcer perforation, duodenitis, dyspepsia, dysphagia, esophageal ulcer, esophagitis, flatulence, gastroenteritis, gastrointestinal hemorrhage, GGT/LDH elevated, gingivitis, glossitis, gum hemorrhage, gum hyperplasia, hematemesis, hepatic coma, hepatic failure, hepatitis, intestinal perforation, intestinal ulcer, enlarged liver, melena, mouth ulceration, pancreatitis, parotid gland enlargement, periodontitis, proctitis, pseudomembranous colitis, rectal disorder, rectal hemorrhage, stomach ulcer, stomatitis, tongue edema
Endocrine adrenal cortex insufficiency, diabetes insipidus, hyperthyroidism, hypothyroidism
Hemic and Lymphatic agranulocytosis, anemia (macrocytic, megaloblastic, microcytic, normocytic), aplastic anemia, hemolytic anemia, bleeding time increased, cyanosis, DIC, ecchymosis, eosinophilia, hypervolemia, lymphadenopathy, lymphangitis, marrow depression, petechia, purpura, enlarged spleen, thrombotic thrombocytopenic purpura
Metabolic and Nutritional albuminuria, BUN increased, creatine phosphokinase increased, edema, glucose tolerance decreased, hypercalcemia, hypercholesteremia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hyperuricemia, hypocalcemia, hypoglycemia, hyponatremia, hypophosphatemia, uremia
Musculoskeletal arthralgia, arthritis, bone necrosis, bone pain, leg cramps, myalgia, myasthenia, myopathy, osteomalacia, osteoporosis
Nervous System abnormal dreams, acute brain syndrome, agitation, akathisia, amnesia, anxiety, ataxia, brain edema, coma, confusion, convulsion, delirium, dementia, depersonalization, depression, diplopia, encephalitis, encephalopathy, euphoria, Extrapyramidal Syndrome, grand mal convulsion, Guillain-Barré syndrome, hypertonia, hypesthesia, insomnia, intracranial hypertension, libido decreased, neuralgia, neuropathy, nystagmus, oculogyric crisis, paresthesia, psychosis, somnolence, suicidal ideation, tremor, vertigo
Respiratory System cough increased, dyspnea, epistaxis, hemoptysis, hypoxia, lung edema, pharyngitis, pleural effusion, pneumonia, respiratory disorder, respiratory distress syndrome, respiratory tract infection, rhinitis, sinusitis, voice alteration
Skin and Appendages alopecia, angioedema, contact dermatitis, discoid lupus erythematosis, eczema, erythema multiforme, exfoliative dermatitis, fixed drug eruption, furunculosis, herpes simplex, melanosis, photosensitivity skin reaction, psoriasis, skin discoloration, skin disorder, skin dry, Stevens-Johnson syndrome, sweating, toxic epidermal necrolysis, urticaria
Special Senses abnormality of accommodation, blepharitis, color blindness, conjunctivitis, corneal opacity, deafness, ear pain, eye pain, dry eyes, keratitis, keratoconjunctivitis, mydriasis, night blindness, optic atrophy, optic neuritis, otitis externa, papilledema, retinal hemorrhage, retinitis, scleritis, taste loss, taste perversion, tinnitus, uveitis, visual field defect
Urogenital anuria, blighted ovum, creatinine clearance decreased, dysmenorrhea, dysuria, epididymitis, glycosuria, hemorrhagic cystitis, hematuria, hydronephrosis, impotence, kidney pain, kidney tubular necrosis, metrorrhagia, nephritis, nephrosis, oliguria, scrotal edema, urinary incontinence, urinary retention, urinary tract infection, uterine hemorrhage, vaginal hemorrhage
Clinical Laboratory Values
The overall incidence of clinically significant transaminase abnormalities in the voriconazole clinical program was 13.4% (200/1493) of patients treated with voriconazole. Increased incidence of liver function test abnormalities may be associated with higher plasma concentrations and/or doses. The majority of abnormal liver function tests either resolved during treatment without dose adjustment or following dose adjustment, including discontinuation of therapy.
Voriconazole has been infrequently associated with cases of serious hepatic toxicity including cases of jaundice and rare cases of hepatitis and hepatic failure leading to death. Most of these patients had other serious underlying conditions.
Liver function tests should be evaluated at the start of and during the course of VFEND therapy. Patients who develop abnormal liver function tests during VFEND therapy should be monitored for the development of more severe hepatic injury. Patient management should include laboratory evaluation of hepatic function (particularly liver function tests and bilirubin). Discontinuation of VFEND must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to VFEND (see WARNINGS and PRECAUTIONS - Laboratory Tests).
Acute renal failure has been observed in severely ill patients undergoing treatment with VFEND. Patients being treated with voriconazole are likely to be treated concomitantly with nephrotoxic medications and have concurrent conditions that may result in decreased renal function. It is recommended that patients are monitored for the development of abnormal renal function. This should include laboratory evaluation, particularly serum creatinine.
Tables 11 and 12 show the number of patients with hypokalemia and clinically significant changes in renal and liver function tests in two randomized, comparative multicenter studies. In study 305, patients were randomized to either oral voriconazole or oral fluconazole to evaluate an indication other than invasive aspergillosis in immunocompromised patients. In study 307/602, patients with definite or probable invasive aspergillosis were randomized to either voriconazole or amphotericin B therapy.
|
Table 11 PROTOCOL 305 Clinically Significant Laboratory Test Abnormalities
|
| |
Criteria* |
VORICONAZOLE |
FLUCONAZOLE |
| |
|
n/N (%) |
n /N (%) |
T. Bilirubin |
>1.5x ULN |
8/185 (4.3) |
7/186 (3.8) |
AST |
>3.0x ULN |
38/187 (20.3) |
15/186 (8.1) |
ALT |
>3.0x ULN |
20/187 (10.7) |
12/186 (6.5) |
Alk phos |
>3.0x ULN |
19/187 (10.2) |
14/186 (7.5) |
* Without regard to baseline value |
N number of patients with a clinically significant abnormality while on study therapy |
N total number of patients with at least one observation of the given lab test while on study therapy |
ULN upper limit of normal |
|
Table 12 PROTOCOL 307/602 Clinically Significant Laboratory Test Abnormalities
|
| |
Criteria* |
VORICONAZOLE |
AMPHOTERICIN B** |
| |
|
n/N (%) |
n/N (%) |
T. Bilirubin |
>1.5x ULN |
35/180 (19.4) |
46/173 (26.6) |
AST |
>3.0x ULN |
21/180 (11.7) |
18/174 (10.3) |
ALT |
>3.0x ULN |
34/180 (18.9) |
40/173 (23.1) |
Alk phos |
>3.0x ULN |
29/181 (16.0) |
38/173 (22.0) |
Creatinine |
>1.3x ULN |
39/182 (21.4) |
102/177 (57.6) |
Potassium |
<0.9x LLN |
30/181 (16.6) |
70/178 (39.3) |
* Without regard to baseline value |
** Amphotericin B followed by other licensed antifungal therapy |
N number of patients with a clinically significant abnormality while on study therapy |
N total number of patients with at least one observation of the given lab test while on study therapy |
ULN upper limit of normal |
LLN lower limit of normal |
DRUG INTERACTIONS
Tables 8 and 9 provide a summary of significant drug interactions with voriconazole that either have been studied in vivo (clinically) or that may be expected to occur based on results of in vitro metabolism studies with human liver microsomes. For more details, see CLINICAL PHARMACOLOGY - Drug Interactions.
|
Table 8 Effect of Other Drugs on Voriconazole Pharmacokinetics
|
|
Drug/Drug Class (Mechanism of Interaction by the Drug)
|
Voriconazole Plasma Exposure (Cmax and AUCτ after 200 mg Q12h) |
Recommendations for Voriconazole Dosage Adjustment/Comments
|
Rifampin*, Efavirenz** and Rifabutin*(CYP450 Induction) |
Significantly Reduced |
Contraindicated
|
Ritonavir (400mg Q12h HIV Protease Inhibitor)** (CYP450 Induction) |
Significantly Reduced |
Contraindicated
The effect of ritonavir (100 mg Q12h as used to inhibit CYP3A and increase concentrations of other antiretroviral drugs) on voriconazole concentrations has not been studied. |
Carbamazepine (CYP450 Induction) |
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction |
Contraindicated
|
Long Acting Barbiturates (CYP450 Induction) |
Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction |
Contraindicated
|
Phenytoin* (CYP450 Induction) |
Significantly Reduced |
Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV every 12
hrs or from 200 mg to 400 mg orally every 12 hrs (100 mg to 200 mg orally every 12 hrs in patients weighing less than 40 kg) |
Other HIV Protease Inhibitors
(CYP3A4 Inhibition) |
In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure |
No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir |
In Vitro Studies Demonstrate Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors |
Other NNRTIs*** (CYP3A4 Inhibition or CYP450 Induction) |
In Vitro Studies Demonstrate Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to voriconazole |
A Voriconazole-Efavirenz Drug Interaction Study Demonstrates the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure) |
Careful assessment of voriconazole effectiveness |
*Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg Q12h voriconazole to healthy subjects |
**Results based on in vivo clinical study following repeat oral dosing with 400 mg Q12h for 1 day, then 200 mg Q12h for 8 days voriconazole to healthy subjects |
*** Non-Nucleoside Reverse Transcriptase Inhibitors |
|
Table 9 Effect of Voriconazole on Pharmacokinetics of Other Drugs
|
|
Drug/Drug Class (Mechanism of Interaction by Voriconazole)
|
Drug Plasma Exposure (Cmax and AUCτ) |
Recommendations for Drug Dosage Adjustment/Comments
|
Sirolimus* (CYP3A4 Inhibition) |
Significantly Increased |
Contraindicated
|
Rifabutin* and Efavirenz** (CYP3A4 Inhibition) |
Significantly Increased |
Contraindicated
|
Ritonavir (400 mg Q12h HIV Protease Inhibitor)**(CYP3A4 Inhibition) |
No significant effect of voriconazole on ritonavir Cmax or AUCτ |
Contraindicated because of significant reduction of voriconazole Cmax and AUCτ |
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine
(CYP3A4 Inhibition) |
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased |
Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes |
Ergot Alkaloids (CYP450 Inhibition) |
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased |
Contraindicated
|
Cyclosporine* (CYP3A4 Inhibition) |
AUCτ Significantly Increased; No Significant Effect on Cmax |
When initiating therapy with VFEND patients already receiving cyclosporine, reduce the cyclosporine dose to one-of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary. |
Methadone*** (CYP3A4 Inhibition) |
Increased |
Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction methadone may be needed |
Tacrolimus* (CYP3A4 Inhibition) |
Significantly Increased |
When initiating therapy with VFEND patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus levels. Increased tacrolimus levels been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary. |
Phenytoin* (CYP2C9 Inhibition) |
Significantly Increased |
Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related phenytoin. |
Warfarin* (CYP2C9 Inhibition) |
Prothrombin Time Significantly Increased |
Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed. |
Omeprazole* (CYP2C19/3A4 Inhibition) |
Significantly Increased |
When initiating therapy with VFEND patients already receiving omeprazole doses of 40 mg or greater, reduce the
omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors. |
Other HIV Protease Inhibitors (CYP3A4 Inhibition) |
In Vivo Studies showed No Significant Effects on Indinavir Exposure |
No dosage adjustment for indinavir when coadministered with VFEND |
In Vitro Studies Demonstrate Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors |
Other NNRTIs**** (CYP3A4 Inhibition) |
A Voriconazole-Efavirenz Drug Interaction Study Demonstrates the Potential for
Voriconazole to Inhibit Metabolism of Other NNRTIs
(Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to NNRTI |
Benzodiazepines (CYP3A4 Inhibition) |
In Vitro Studies Demonstrate Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed. |
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition) |
In Vitro Studies Demonstrate Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed. |
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition) |
In Vitro Studies Demonstrate Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) |
Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed. |
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition) |
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased |
Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed. |
Vinca Alkaloids (CYP3A4 Inhibition) |
Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased |
Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed. |
*Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects |
**Results based on in vivo clinical study following repeat oral dosing with 400 mg Q12h for 1 day, then 200 mg Q12h for 8 days voriconazole to healthy subjects |
*** Results based on in vivo clinical study following repeat oral dosing with 400 mg Q12h for 1 day, then 200 mg Q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30-100 mg QD) |
**** Non-Nucleoside Reverse Transcriptase Inhibitors |
Patients with Hepatic Insufficiency
It is recommended that the standard loading dose regimens be used but that the maintenance dose be halved in patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B) receiving VFEND (see CLINICAL PHARMACOLOGY - Hepatic Insufficiency, DOSAGE and ADMINISTRATION - Hepatic Insufficiency).
VFEND has not been studied in patients with severe cirrhosis (Child-Pugh Class C). VFEND has been associated with elevations in liver function tests and clinical signs of liver damage, such as jaundice, and should only be used in patients with severe hepatic insufficiency if the benefit outweighs the potential risk. Patients with hepatic insufficiency must be carefully monitored for drug toxicity.
Patients with Renal Insufficiency
In patients with moderate to severe renal dysfunction (creatinine clearance <50 mL/min), accumulation of the intravenous vehicle, SBECD, occurs. Oral voriconazole should be administered to these patients, unless an assessment of the benefit/risk to the patient justifies the use of intravenous voriconazole. Serum creatinine levels should be closely monitored in these patients, and if increases occur, consideration should be given to changing to oral voriconazole therapy (see CLINICAL PHARMACOLOGY - Renal Insufficiency, DOSAGE AND ADMINISTRATION - Renal Insufficiency).
Renal Adverse Events
Acute renal failure has been observed in severely ill patients undergoing treatment with VFEND. Patients being treated with voriconazole are likely to be treated concomitantly with nephrotoxic medications and have concurrent conditions that may result in decreased renal function.
Monitoring of Renal Function
Patients should be monitored for the development of abnormal renal function. This should include laboratory evaluation, particularly serum creatinine.
Dermatological Reactions
Patients have rarely developed serious cutaneous reactions, such as Stevens-Johnson syndrome, during treatment with VFEND. If patients develop a rash, they should be monitored closely and consideration given to discontinuation of VFEND. VFEND has been infrequently associated with photosensitivity skin reaction, especially during long-term therapy. It is recommended that patients avoid strong, direct sunlight during VFEND therapy.
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