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 Table 13 reflect exposure to voriconazole in 1655 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 subjects
and patients treated in the compassionate use and non-therapeutic studies. This
patient population was 62% male, had a mean age of 46 years (range 11-90, including
51 patients aged 12-18 years), and was 78% white and 10% black. In the initial regulatory
filing, 561 patients had a duration of voriconazole therapy of greater than 12 weeks,
with 136 patients receiving voriconazole for over six months. Table 13 includes
all adverse events which were reported at an incidence of ≥2% during voriconazole
therapy in the all therapeutic studies population, studies 307/602 and 608 combined,
or study 305, as well as events of concern which occurred at an incidence of <2%.
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.
In study 608, 403 patients with candidemia were treated to compare voriconazole
(272 patients) to the regimen of amphotericin B followed by fluconazole (131 patients).
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 13
Treatment Emergent Adverse Events
Rate ≥ 2% on Voriconazole or Adverse Events of Concern in All Therapeutic
Studies Population, Studies 307/602-608 Combined, or Study 305. Possibly Related to Therapy
or Causality Unknown†
VISUAL DISTURBANCES: Voriconazole treatment-related visual disturbances
are common. In therapeutic trials, approximately 21% of patients experienced abnormal
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.
There have been post-marketing reports of prolonged visual adverse events, including optic
neuritis and papilledema. These events occurred primarily in severely ill patients who had
underlying conditions and/or concomitant medications which may have caused or contributed to these events (see WARNINGS).
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 subjects
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 7% (110/1655) 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 < 2% of all voriconazole-treated patients
in all therapeutic studies (N=1655). 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 13 above and does not include every event reported in the voriconazole
clinical program.
Body as a Whole: abdominal pain, abdomen enlarged, allergic reaction, anaphylactoid
reaction (see PRECAUTIONS), ascites, asthenia, back pain, chest 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, hypertension,
hypotension, myocardial infarction, nodal arrhythmia, palpitation, phlebitis, postural
hypotension, pulmonary embolus, QT interval prolonged, supraventricular extrasystoles,
supraventricular tachycardia, syncope, thrombophlebitis, vasodilatation, ventricular
arrhythmia, ventricular fibrillation, ventricular tachycardia (including torsade
de pointes)
Digestive: anorexia, cheilitis, cholecystitis, cholelithiasis, constipation,
diarrhea, duodenal ulcer perforation, duodenitis, dyspepsia, dysphagia, dry mouth,
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,
jaundice, 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, leukopenia, lymphadenopathy,
lymphangitis, marrow depression, pancytopenia, petechia, purpura, enlarged spleen,
thrombocytopenia, 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, hypomagnesemia, hyponatremia, hypophosphatemia, peripheral edema,
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, dizziness, 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, maculopapular rash, melanosis, photosensitivity skin
reaction, pruritus, 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, eye hemorrhage, dry
eyes, hypoacusis, 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 all
therapeutic studies was 12.4% (206/1655) 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 12 and 13 and 14 show the number of patients with hypokalemia and clinically
significant changes in renal and liver function tests in three randomized, comparative
multicenter studies. In study 305, patients with esophageal candidiasis were randomized
to either oral voriconazole or oral fluconazole. In study 307/602, patients with
definite or probable invasive aspergillosis were randomized to either voriconazole
or amphotericin B therapy. In study 608, patients with candidemia were randomized
to either voriconazole or the regimen of amphotericin B followed by fluconazole.
Table 14
Protocol 305
Clinically Significant Laboratory Test Abnormalities
Table 15
Protocol 307/602
Clinically Significant Laboratory Test Abnormalities
Table 16
Protocol 608
Clinically Significant Laboratory Test Abnormalities
