Voriconazole
Dosage Form: tablet, film coated
Indications and Usage for Voriconazole
Voriconazole
tablets are indicated for use in patients 12 years of age and older in the
treatment of the following fungal infections:
Invasive Aspergillosis
In
clinical trials, the majority of isolates recovered were Aspergillus fumigatus.
There was a small number of cases of culture-proven disease due to species
of Aspergillus other than A. fumigatus [see Clinical Studies (14.1) and Clinical Pharmacology (12.4)].
Candidemia in Non-neutropenic Patients and the
Following Candida Infections: Disseminated Infections in Skin and Infections in
Abdomen, Kidney, Bladder Wall, and Wounds
[see Clinical Studies (14.2) and Clinical Pharmacology (12.4)]
Esophageal Candidiasis
[see Clinical Studies (14.3) and Clinical Pharmacology (12.4)]
Serious Fungal Infections Caused by Scedosporium
apiospermum (Asexual Form of Pseudallescheria boydii) and Fusarium spp.
Including Fusarium solani, in Patients Intolerant of, or Refractory to, Other
Therapy
[see Clinical Studies (14.4) and Clinical Pharmacology (12.4)]
Specimens
for fungal culture and other relevant laboratory studies (including
histopathology) should be obtained prior to therapy to isolate and identify
causative organism(s). Therapy may be instituted before the results of the
cultures and other laboratory studies are known. However, once these results
become available, antifungal therapy should be adjusted accordingly.
Voriconazole Dosage and Administration
Instructions for Use in All Patients
Voriconazole
tablets should be taken at least one hour before or after a meal.
Recommended Dosing in Adults
Invasive aspergillosis and serious fungal infections
due to Fusarium spp. and Scedosporium apiospermum
See Table
1. Therapy must be initiated with the specified loading dose regimen of
intravenous Voriconazole on Day 1 followed by the recommended maintenance dose
(RMD) regimen. Intravenous treatment should be continued for at least 7 days.
Once the patient has clinically improved and can tolerate medication given by
mouth, the oral tablet form or oral suspension form of Voriconazole may be
utilized. The recommended oral maintenance dose of 200 mg achieves a
Voriconazole exposure similar to 3 mg/kg IV; a 300 mg oral dose achieves an
exposure similar to 4 mg/kg IV. Switching between the intravenous and oral
formulations is appropriate because of the high bioavailability of the oral
formulation in adults [see Clinical Pharmacology (12)].
Candidemia in non-neutropenic patients and other deep tissue
Candida infections
See Table
1. Patients should be treated for at least 14 days following resolution of
symptoms or following last positive culture, whichever is longer.
Esophageal Candidiasis
See Table
1. Patients should be treated for a minimum of 14 days and for at least 7 days
following resolution of symptoms.
Table 1:Recommended Dosing Regimen
|
|
*
Increase dose
when Voriconazole is co-administered with phenytoin or efavirenz (7);
Decrease dose in patients with hepatic impairment (2.7)
†
In healthy
volunteer studies, the 200 mg oral q12h dose provided an exposure (AUCτ)
similar to a 3 mg/kg IV q12h dose; the 300 mg oral q12h dose provided an
exposure (AUCτ) similar to a 4 mg/kg IV q12h dose [see Clinical Pharmacology
(12)].
‡
Adult patients
who weigh less than 40 kg should receive half of the oral maintenance dose.
§
In a clinical
study of invasive aspergillosis, the median duration of IV Voriconazole
therapy was 10 days (range 2 to 85 days). The median duration of oral
Voriconazole therapy was 76 days (range 2 to 232 days) [see Clinical Studies
(14.1)].
¶
In clinical
trials, patients with candidemia received 3 mg/kg IV q12h as primary therapy,
while patients with other deep tissue Candida infections received 4 mg/kg
q12h as salvage therapy. Appropriate dose should be based on the severity and
nature of the infection.
#
Not evaluated in patients with esophageal
candidiasis.
|
|
Infection
|
Loading dose
|
Maintenance Dose*,†
|
|
|
|
IV
|
IV
|
Oral‡
|
|
Invasive Aspergillosise§
|
6 mg/kg q12h for the first 24 hours
|
4 mg/kg q12h
|
200 mg q12h
|
|
Candidemia in nonneutropenics and other deep tissue Candida infections
|
6 mg/kg q12h for the first 24 hours
|
3 to 4 mg/kg q12h¶
|
200 mg q12h
|
|
Esophageal Candidiasis
|
#
|
#
|
200 mg q12h
|
|
Scedosporiosis and Fusariosis
|
6 mg/kg q12h for the first 24 hours
|
4 mg/kg q12h
|
200 mg q12h
|
Dosage Adjustment
If
patient response is inadequate, the oral maintenance dose may be increased from
200 mg every 12 hours (similar to 3 mg/kg IV q12h) to 300 mg every 12 hours
(similar to 4 mg/kg IV q12h). For adult patients weighing less than 40 kg, the
oral maintenance dose may be increased from 100 mg every 12 hours to 150 mg
every 12 hours. If patient is unable to tolerate 300 mg orally every 12 hours,
reduce the oral maintenance dose by 50 mg steps to a minimum of 200 mg every 12
hours (or to 100 mg every 12 hours for adult patients weighing less than 40
kg).
If
patient is unable to tolerate 4 mg/kg IV q12h, reduce the intravenous
maintenance dose to 3 mg/kg q12h.
The
maintenance dose of Voriconazole should be increased when co-administered with
phenytoin or efavirenz [see Drug Interactions (7)].
The
maintenance dose of Voriconazole should be reduced in patients with mild to
moderate hepatic impairment, Child-Pugh Class A and B [see Dosage and Administration (2.7)]. There are no PK data to allow for dosage
adjustment recommendations in patients with severe hepatic impairment
(Child-Pugh Class C).
Duration
of therapy should be based on the severity of the patient's underlying disease,
recovery from immunosuppression, and clinical response.
Use in Patients With Hepatic Impairment
In the
clinical program, patients were included who had baseline liver function tests
(ALT, AST) up to 5 times the upper limit of normal. No dose adjustment is
necessary in patients with this degree of abnormal liver function, but
continued monitoring of liver function tests for further elevations is
recommended [see Warnings and Precautions (5.9)].
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) [see Clinical Pharmacology (12.3)].
Voriconazole
has not been studied in patients with severe hepatic cirrhosis (Child-Pugh
Class C) or in patients with chronic hepatitis B or chronic hepatitis C
disease. Voriconazole 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 impairment if the benefit outweighs the
potential risk. Patients with hepatic impairment must be carefully monitored
for drug toxicity.
Use in Patients With Renal Impairment
The
pharmacokinetics of orally administered Voriconazole are not significantly
affected by renal impairment. Therefore, no adjustment is necessary for oral dosing in patients with mild to severe
renal impairment [see Clinical Pharmacology (12.3)].
In
patients with moderate or severe renal impairment (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 Warnings and Precautions (5.10)].
Voriconazole
is hemodialyzed with clearance of 121 mL/min. The intravenous vehicle, SBECD,
is hemodialyzed with clearance of 55 mL/min. A 4-hour hemodialysis session does
not remove a sufficient amount of Voriconazole to warrant dose adjustment.
Dosage Forms and Strengths
Voriconazole
Tablets, 50 mg are white to off-white, round, biconvex, film-coated tablet
debossed with "735" on one side and plain on the other side.
Voriconazole
Tablets, 200 mg are white to off-white, oval, biconvex, film-coated tablet debossed
with "736" on one side and plain on the other side.
Contraindications
· Voriconazole tablets are contraindicated in patients
with known hypersensitivity to Voriconazole or its excipients. There is no
information regarding cross-sensitivity between Voriconazole and other azole
antifungal agents. Caution should be used when prescribing Voriconazole to
patients with hypersensitivity to other azoles.
· Coadministration of terfenadine, astemizole,
cisapride, pimozide or quinidine with Voriconazole is contraindicated because
increased plasma concentrations of these drugs can lead to QT prolongation and
rare occurrences of torsadedepointes [see Drug Interactions (7)andClinical Pharmacology (12.3) ].
· Coadministration of Voriconazole with sirolimus is
contraindicated because Voriconazole significantly increases sirolimus
concentrations [see Drug Interactions (7)andClinical Pharmacology (12.3) ].
· Coadministration of Voriconazole with rifampin,
carbamazepine and long-acting barbiturates is contraindicated because these
drugs are likely to decrease plasma Voriconazole concentrations significantly [see Drug Interactions (7)andClinical Pharmacology (12.3) ].
· Coadministration of standard doses of Voriconazole
with efavirenz doses of 400 mg q24h or higher is contraindicated, because
efavirenz significantly decreases plasma Voriconazole concentrations in healthy
subjects at these doses. Voriconazole also significantly increases efavirenz
plasma concentrations [see Drug Interactions (7)andClinical Pharmacology (12.3) ].
· Coadministration of Voriconazole with high-dose
ritonavir (400 mg q12h) is contraindicated because ritonavir (400 mg q12h)
significantly decreases plasma Voriconazole concentrations. Coadministration of
Voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an
assessment of the benefit/risk to the patient justifies the use of Voriconazole
[see Drug Interactions (7)andClinical Pharmacology (12.3) ].
· Coadministration of Voriconazole with rifabutin is
contraindicated since Voriconazole significantly increases rifabutin plasma
concentrations and rifabutin also significantly decreases Voriconazole plasma
concentrations [see Drug Interactions (7)andClinical Pharmacology (12.3) ].
· Coadministration of Voriconazole with ergot alkaloids
(ergotamine and dihydroergotamine) is contraindicated because Voriconazole may
increase the plasma concentration of ergot alkaloids, which may lead to ergotism
[see Drug Interactions (7) andClinical Pharmacology (12.3) ].
· Coadministration of Voriconazole withSt. John'sWort is
contraindicated because this herbal supplement may decrease Voriconazole plasma
concentration [seeDrug Interactions (7)andClinical Pharmacology (12.3) ].
Warnings and Precautions
Drug Interactions
See Table
7 for a listing of drugs that may significantly alter Voriconazole
concentrations. Also, see Table 8 for a listing of drugs that may interact with
Voriconazole resulting in altered pharmacokinetics or pharmacodynamics of the
other drug [see Contraindications (4), and Drug Interactions (7)].
Hepatic Toxicity
In clinical trials, there have been uncommon cases of serious hepatic reactions during treatment with Voriconazole (including clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities). Instances
of hepatic reactions were noted to occur primarily in patients with serious
underlying medical conditions (predominantly hematological malignancy). Hepatic
reactions, including hepatitis and jaundice, have occurred among patients with
no other identifiable risk factors. Liver dysfunction has usually been
reversible on discontinuation of therapy [see Warnings and Precautions (5.9), and Adverse Reactions (6.3)].
Measure
serum transaminase levels and bilirubin at the initiation of Voriconazole
therapy and monitor at least weekly for the first month of treatment.
Monitoring frequency can be reduced to monthly during continued use if no
clinically significant changes are noted. If liver function tests become
markedly elevated compared to baseline, Voriconazole should be discontinued
unless the medical judgment of the benefit-risk of the treatment for the
patient justifies continued use [see Warnings and Precautions (5.9), Dosage and Administration (2.4, 2.7), and Adverse Reactions (6.3)].
Visual Disturbances
The effect of Voriconazole on visual function is not known if treatment continues beyond 28 days.There
have been post-marketing reports of prolonged visual adverse events, including
optic neuritis and papilledema. If treatment continues beyond 28 days, visual
function including visual acuity, visual field and color perception should be
monitored [see Adverse Reactions (6.2)].
Embryo-Fetal Toxicity
Voriconazole
can cause fetal harm when administered to a pregnant woman.
In
animals, Voriconazole administration was associated with teratogenicity,
embryotoxicity, increased gestational length, dystocia and embryomortality [see
Use in Specific Populations (8.1)].
If this
drug is used during pregnancy, or if the patient becomes pregnant while taking
this drug, inform the patient of the potential hazard to the fetus.
Galactose Intolerance
Voriconazole
tablets contain lactose and should not be given to patients with rare
hereditary problems of galactose intolerance, Lapp lactase deficiency or
glucose-galactose malabsorption.
Arrhythmias and QT Prolongation
Some
azoles, including Voriconazole, have been associated with prolongation of the
QT interval on the electrocardiogram. During clinical development and
post-marketing surveillance, there have been rare cases of arrhythmias,
(including ventricular arrhythmias such as torsade de pointes),
cardiac arrests and sudden deaths in patients taking Voriconazole. These cases
usually involved seriously ill patients with multiple confounding risk factors,
such as history of cardiotoxic chemotherapy, cardiomyopathy, hypokalemia and
concomitant medications that may have been contributory.
Voriconazole
should be administered with caution to patients with potentially proarrhythmic
conditions, such as:
· Congenital or acquired QT-prolongation
· Cardiomyopathy, in particular when heart failure is
present
· Sinus bradycardia
· Existing symptomatic arrhythmias
· Concomitant medicinal product that is known to
prolong QT interval [see Contraindications (4), Drug Interactions (7), and Clinical Pharmacology (12.3) ]
Rigorous
attempts to correct potassium, magnesium and calcium should be made before
starting and during Voriconazole therapy [see Clinical Pharmacology (12.3)].
Laboratory Tests
Electrolyte
disturbances such as hypokalemia, hypomagnesemia and hypocalcemia should be
corrected prior to initiation of and during Voriconazole therapy.
Patient
management should include laboratory evaluation of renal (particularly serum
creatinine) and hepatic function (particularly liver function tests and
bilirubin).
Patients With Hepatic Impairment
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 Voriconazole [see Clinical Pharmacology (12.3) and Dosage and Administration (2.7)].
Voriconazole
has not been studied in patients with severe cirrhosis (Child-Pugh Class C).
Voriconazole 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 impairment if the benefit outweighs the potential
risk. Patients with hepatic impairment must be carefully monitored for drug
toxicity.
Patients With Renal Impairment
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 (12.3) and Dosage and Administration (2.8)].
Monitoring of Renal Function
Acute
renal failure has been observed in patients undergoing treatment with
Voriconazole. 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.
Patients
should be monitored for the development of abnormal renal function. This should
include laboratory evaluation, particularly serum creatinine.
Monitoring of Pancreatic Function
Patients
with risk factors for acute pancreatitis (e.g., recent chemotherapy,
hematopoietic stem cell transplantation [HSCT]) should be monitored for the
development of pancreatitis during Voriconazole treatment.
Dermatological Reactions
Serious
exfoliative cutaneous reactions, such as Stevens-Johnson syndrome, have been
reported during treatment with Voriconazole. If a patient develops an
exfoliative cutaneous reaction, Voriconazole should be discontinued.
Voriconazole
has been associated with photosensitivity skin reaction. Patients, including
children, should avoid exposure to direct sunlight during Voriconazole
treatment and should use measures such as protective clothing and sunscreen
with high sun protection factor (SPF). If phototoxic reactions occur, the
patient should be referred to a dermatologist and Voriconazole discontinuation
should be considered. If Voriconazole is continued despite the occurrence of
phototoxicityrelated lesions, dermatologic evaluation should be performed on a
systematic and regular basis to allow early detection and management of
premalignant lesions. Squamous cell carcinoma of the skin and melanoma have
been reported during long-term Voriconazole therapy in patients with
photosensitivity skin reactions. If a patient develops a skin lesion consistent
with premalignant skin lesions, squamous cell carcinoma or melanoma,
Voriconazole should be discontinued.
The
frequency of phototoxicity reactions is higher in the pediatric population.
Because squamous cell carcinoma has been reported in patients who experience
photosensitivity reactions, stringent measures for photoprotection are
warranted in children. In children experiencing photoaging injuries such as
lentigines or ephelides, sun avoidance and dermatologic follow-up are
recommended even after treatment discontinuation.
Skeletal Adverse Events
Fluorosis
and periostitis have been reported during long-term Voriconazole therapy. If a
patient develops skeletal pain and radiologic findings compatible with
fluorosis or periostitis, Voriconazole should be discontinued [see Adverse Reactions (6.4)].
Adverse Reactions
Because
clinical trials are conducted under widely varying conditions, adverse reaction
rates observed in clinical trials of a drug cannot be directly compared to
rates in the clinical trials of another drug and may not reflect the rates
observed in practice.
Overview
The most
frequently reported adverse events (all causalities) in the therapeutic trials
were visual disturbances (18.7%), fever (5.7%), nausea (5.4%), rash (5.3%),
vomiting (4.4%), chills (3.7%), headache (3.0%), liver function test increased
(2.7%), tachycardia (2.4%), hallucinations (2.4%). The treatment-related
adverse events which most often led to discontinuation of Voriconazole therapy
were elevated liver function tests, rash, and visual disturbances [see Warning and Precautions (5.2, 5.3) and Adverse Reactions (6.2, 6.3)].
Clinical Trial Experience in Adults
The data
described in Table 3 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 to 90,
including 51 patients aged 12 to 18 years), and was 78% White and 10% 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 3 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.
The rate of discontinuation from Voriconazole study medication due to adverse events
was 21.4% (42/196 patients). 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). The rate of discontinuation from
Voriconazole study medication due to adverse events was 19.5% out of 272
patients. Study 305 evaluated the effects of oral Voriconazole (200 patients)
and oral fluconazole (191 patients) in the treatment of esophageal candidiasis.
The rate of discontinuation from Voriconazole study medication in Study 305 due
to adverse events was 7% (14/200 patients). Laboratory test abnormalities for
these studies are discussed under Clinical Laboratory Values below.
Table 3: 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*
|
|
*
Study 307/602:
invasive aspergillosis; Study 608: candidemia; Study 305: esophageal
candidiasis
†
Amphotericin B followed by other licensed antifungal
therapy
|
|
|
All Therapeutic Studies
|
Studies 307/602 and 608
(IV/ oral therapy)
|
|
|
Study 305
(oral therapy)
|
|
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|
Voriconazole N=1655
|
Voriconazole N=468
|
Ampho B† N=185
|
Ampho B→ Fluconazole N=131
|
Voriconazole N=200
|
Fluconazole N=191
|
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|
N (%)
|
N (%)
|
N (%)
|
N (%)
|
N (%)
|
N (%)
|
|
Special Senses††
|
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|
|
|
|
|
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Abnormal vision
|
310 (18.7)
|
63 (13.5)
|
1 (0.5)
|
0
|
31 (15.5)
|
8 (4.2)
|
|
Photophobia
|
37 (2.2)
|
8 (1.7)
|
0
|
0
|
5 (2.5)
|
2 (1)
|
|
Chromatopsia
|
20 (1.2)
|
2 (0.4)
|
0
|
0
|
2 (1)
|
0
|
|
Body as a Whole
|
|
|
|
|
|
|
|
Fever
|
94 (5.7)
|
8 (1.7)
|
25 (13.5)
|
5 (3.8)
|
0
|
0
|
|
Chills
|
61 (3.7)
|
1 (0.2)
|
36 (19.5)
|
8 (6.1)
|
1 (0.5)
|
0
|
|
Headache
|
49 (3)
|
9 (1.9)
|
8 (4.3)
|
1 (0.8)
|
0
|
1 (0.5)
|
|
Cardiovascular System
|
|
|
|
|
|
|
|
Tachycardia
|
39 (2.4)
|
6 (1.3)
|
5 (2.7)
|
0
|
0
|
0
|
|
Digestive System
|
|
|
|
|
|
|
|
Nausea
|
89 (5.4)
|
18 (3.8)
|
29 (15.7)
|
2 (1.5)
|
2 (1)
|
3 (1.6)
|
|
Vomiting
|
72 (4.4)
|
15 (3.2)
|
18 (9.7)
|
1 (0.8)
|
2 (1)
|
1 (0.5)
|
|
Liver function tests abnormal
|
45 (2.7)
|
15 (3.2)
|
4 (2.2)
|
1 (0.8)
|
6 (3)
|
2 (1)
|
|
Cholestatic jaundice
|
17 (1)
|
8 (1.7)
|
0
|
1 (0.8)
|
3 (1.5)
|
0
|
|
Metabolic and Nutritional Systems
|
|
|
|
|
|
|
|
Alkaline phosphatase increased
|
59 (3.6)
|
19 (4.1)
|
4 (2.2)
|
3 (2.3)
|
10 (5)
|
3 (1.6)
|
|
Hepatic enzymes increased
|
30 (1.8)
|
11 (2.4)
|
5 (2.7)
|
1 (0.8)
|
3 (1.5)
|
0
|
|
SGOT increased
|
31 (1.9)
|
9 (1.9)
|
0
|
1 (0.8)
|
8 (4)
|
2 (1)
|
|
SGPT increased
|
29 (1.8)
|
9 (1.9)
|
1 (0.5)
|
2 (1.5)
|
6 (3)
|
2 (1)
|
|
Hypokalemia
|
26 (1.6)
|
3 (0.6)
|
36 (19.5)
|
16 (12.2)
|
0
|
0
|
|
Bilirubinemia
|
15 (0.9)
|
5 (1.1)
|
3 (1.6)
|
2 (1.5)
|
1 (0.5)
|
0
|
|
Creatinine increased
|
4 (0.2)
|
0
|
59 (31.9)
|
10 (7.6)
|
1 (0.5)
|
0
|
|
Nervous System
|
|
|
|
|
|
|
|
Hallucinations
|
39 (2.4)
|
13 (2.8)
|
1 (0.5)
|
0
|
0
|
0
|
|
Skin and Appendages
|
|
|
|
|
|
|
|
Rash
|
88 (5.3)
|
20 (4.3)
|
7 (3.8)
|
1 (0.8)
|
3 (1.5)
|
1 (0.5)
|
|
Urogenital
|
|
|
|
|
|
|
|
Kidney function abnormal
|
10 (0.6)
|
6 (1.3)
|
40 (21.6)
|
9 (6.9)
|
1 (0.5)
|
1 (0.5)
|
|
Acute kidney failure
|
7 (0.4)
|
2 (0.4)
|
11 (5.9)
|
7 (5.3)
|
0
|
0
|
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. 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 [see Warnings and Precautions (5.3)].
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 and Precautions (5)].
Dermatological Reactions
Dermatological
reactions were common in the patients treated with Voriconazole. The mechanism
underlying these dermatologic adverse events remains unknown.
Serious
cutaneous reactions, including Stevens-Johnson syndrome, toxic epidermal
necrolysis and erythema multiforme have been reported during treatment with
Voriconazole. If a patient develops an exfoliative cutaneous reaction,
Voriconazole should be discontinued.
In
addition, Voriconazole has been associated with photosensitivity skin
reactions. Patients should avoid strong, direct sunlight during Voriconazole
therapy. In patients with photosensitivity skin reactions, squamous cell
carcinoma of the skin and melanoma have been reported during long-term therapy.
If a patient develops a skin lesion consistent with squamous cell carcinoma or
melanoma, Voriconazole should be discontinued [see Warnings and Precautions (5.13)].
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 3 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 Warnings and Precautions (5.6)], 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) [see Warnings and Precautions (5.6)].
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, melanoma, melanosis, photosensitivity skin
reaction, pruritus, pseudoporphyria, psoriasis, skin discoloration, skin
disorder, skin dry, Stevens-Johnson syndrome, squamous cell carcinoma,
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
Voriconazole therapy. Patients who develop abnormal liver function tests during
Voriconazole 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 Voriconazole must be considered if clinical signs and
symptoms consistent with liver disease develop that may be attributable to Voriconazole
[see Warnings and Precautions (5.2)].
Acute
renal failure has been observed in severely ill patients undergoing treatment
with Voriconazole. 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 4
to 6 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 4:Protocol 305 – Patients with
Esophageal CandidiasisClinically Significant Laboratory Test Abnormalities
|
|
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
|
|
*
Without regard to baseline value
|
|
|
Criteria*
|
Voriconazole
|
Fluconazole
|
|
|
|
n/N (%)
|
n /N (%)
|
|
|
|
|
|
|
T. Bilirubin
|
>1.5x ULN
|
8/185 (4.3)
|
7/186 (3.8)
|
|
AST
|
>3x ULN
|
38/187 (20.3)
|
15/186 (8.1)
|
|
ALT
|
>3x ULN
|
20/187 (10.7)
|
12/186 (6.5)
|
|
Alk phos
|
>3x ULN
|
19/187 (10.2)
|
14/186 (7.5)
|
Table 5:Protocol 307/602 – Primary
Treatment of Invasive AspergillosisClinically Significant Laboratory Test
Abnormalities
|
|
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
|
|
*
Without regard
to baseline value
†
Amphotericin B followed by other licensed antifungal
therapy
|
|
|
Criteria*
|
Voriconazole
|
Amphotericin B†
|
|
|
|
n/N (%)
|
n /N (%)
|
|
|
|
|
|
|
T. Bilirubin
|
>1.5x ULN
|
35/180 (19.4)
|
46/173 (26.6)
|
|
AST
|
>3x ULN
|
21/180 (11.7)
|
18/174 (10.3)
|
|
ALT
|
>3x ULN
|
34/180 (18.9)
|
40/173 (23.1)
|
|
Alk phos
|
>3x ULN
|
29/181 (16)
|
38/173 (22)
|
|
Creatinine
|
>1.3x ULN
|
39/182 (21.4)
|
102/177 (57.6)
|
|
Potassium
|
<0.9x LLN
|
30/181 (16.6)
|
70/178 (39.3)
|
Table 6:Protocol 608 – Treatment of
CandidemiaClinically Significant Laboratory Test Abnormalities
|
|
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
|
|
*
Without regard to baseline value
|
|
|
Criteria*
|
Voriconazole
|
Amphotericin B followed by Fluconazole
|
|
|
|
n/N (%)
|
n /N (%)
|
|
|
|
|
|
|
T. Bilirubin
|
>1.5x ULN
|
50/261 (19.2)
|
31/115 (27)
|
|
AST
|
>3x ULN
|
40/261 (15.3)
|
16/116 (13.8)
|
|
ALT
|
>3x ULN
|
22/261 (8.4)
|
15/116 (12.9)
|
|
Alk phos
|
>3x ULN
|
59/261 (22.6)
|
26/115 (22.6)
|
|
Creatinine
|
>1.3x ULN
|
39/260 (15)
|
32/118 (27.1)
|
|
Potassium
|
<0.9x LLN
|
43/258 (16.7)
|
35/118 (29.7)
|
Postmarketing Experience
The
following adverse reactions have been identified during post approval use of
Voriconazole. Because these reactions are reported voluntarily from a
population of uncertain size, it is not always possible to reliably estimate
their frequency or establish a causal relationship to drug exposure.
Skeletal:
fluorosis and periostitis have been reported during long-term Voriconazole
therapy [see Warnings and Precautions (5.14)].
Drug Interactions
Table 7: Effect of Other Drugs on
Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
|
|
*
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 at least 2 days Voriconazole to healthy subjects.
‡
Non-Nucleoside Reverse Transcriptase Inhibitors.
|
|
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* and Rifabutin* (CYP450 Induction)
|
Significantly Reduced
|
Contraindicated
|
|
Efavirenz (400 mg q24h)† (CYP450 Induction)
Efavirenz (300 mg q24h)†(CYP450 Induction)
|
Significantly Reduced
Slight Decrease in AUCτ
|
Contraindicated
When Voriconazole is coadministered with efavirenz, Voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
|
|
High-dose Ritonavir
(400 mg q12h)†
(CYP450 Induction)
Low-dose Ritonavir
(100 mg q12h)†
(CYP450 Induction)
|
Significantly Reduced
Reduced
|
Contraindicated
Coadministration of Voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of Voriconazole
|
|
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 q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
|
|
St. John’s Wort
(CYP450 inducer; P-gp inducer)
|
Significantly Reduced
|
Contraindicated
|
|
Oral Contraceptives†
containing ethinyl estradiol and norethindrone
(CYP2C19 Inhibition)
|
Increased
|
Monitoring for adverse events and toxicity related to Voriconazole is recommended when coadministered with oral contraceptives
|
|
Fluconazole†
(CYP2C9, CYP2C19 and CYP3A4 Inhibition)
|
Significantly Increased
|
Avoid concomitant administration of Voriconazole and fluconazole. Monitoring for adverse events and toxicity related to Voriconazole is started within 24 h after the last dose of fluconazole.
|
|
Other HIV Protease Inhibitors (CYP3A4 Inhibition)
|
In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure
In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)
|
No dosage adjustment in the Voriconazole dosage needed when coadministered with indinavir
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 Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)
|
Frequent monitoring for adverse events and toxicity related to Voriconazole
Careful assessment of Voriconazole effectiveness
|
|
|
|
|
Table 8. Effect of Voriconazole on Pharmacokinetics of Other
Drugs [see Clinical Pharmacology (12.3)]
|
*
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 at least 2 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 mg to 100 mg q24h)
§
Non-Steroidal
Anti-Inflammatory Drug
¶
Non-Nucleoside Reverse Transcriptase Inhibitors
|
|
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*
(CYP3A4 Inhibition)
|
Significantly Increased
|
Contraindicated
|
|
Efavirenz (400
mg q24h)†
(CYP3A4 Inhibition)
Efavirenz (300 mg q24h)**(CYP3A4 Inhibition)
|
Significantly Reduced
Slight Decrease in AUCτ
|
Contraindicated
When Voriconazole is coadministered with efavirenz, Voriconazole oral
maintenance dose should be increased to 400 mg q12h and efavirenz should be
decreased to 300 mg q24h
|
|
High-dose
Ritonavir
(400 mg q12h)†
(CYP3A4 Inhibition)
Low-dose Ritonavir
(100 mg q12h)†
|
No Significant Effect of Voriconazole on Ritonavir Cmax or AUCτ
Slight Decrease in Ritonavir Cmax and AUCτ
|
Contraindicated because of significant reduction of
Voriconazole Cmaxand
AUCτ
Coadministration of Voriconazole and low-dose ritonavir (100 mg q12h) should
be avoided (due to the reduction in Voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk
to the patient justifies the use of Voriconazole
|
|
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 Voriconazole in
patients already receiving cyclosporine, reduce the cyclosporine dose to
one-half of the starting dose and follow with frequent monitoring of
cyclosporine blood levels. Increased cyclosporine levels have been associated
with nephrotoxicity. When Voriconazole 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 of methadone may be needed
|
|
Fentanyl
(CYP3A4 Inhibition)
|
Increased
|
Reduction in the dose of fentanyl and other
long-acting opiates metabolized by CYP3A4 should be considered when
coadministered with Voriconazole. Extended and frequent monitoring for
opiate-associated adverse events may be necessary [see Drug Interactions (7) ]
|
|
Alfentanil
(CYP3A4 Inhibition)
|
Significantly Increased
|
Reduction in the dose of alfentanil and other
opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when
coadministered with Voriconazole. A longer period for monitoring respiratory
and other opiate-associated adverse events may be necessary [see Drug Interactions (7) ].
|
|
Oxycodone
(CYP3A4 Inhibition)
|
Significantly Increased
|
Reduction in the dose of oxycodone and other
long-acting opiates metabolized by CYP3A4 should be considered when
coadministered with Voriconazole. Extended and frequent monitoring for
opiate-associated adverse events may be necessary [see Drug Interactions (7) ].
|
|
NSAIDs§including. ibuprofen and diclofenac
(CYP2C9 Inhibition)
|
Increased
|
Frequent monitoring for adverse events and toxicity
related to NSAIDs. Dose reduction of NSAIDs may be needed [see Drug Interactions (7) ].
|
|
Tacrolimus*
(CYP3A4 Inhibition)
|
Significantly Increased
|
When initiating therapy with Voriconazole in
patients already receiving tacrolimus, reduce the tacrolimus dose to
one-third of the starting dose and follow with frequent monitoring of
tacrolimus blood levels. Increased tacrolimus levels have been associated
with nephrotoxicity. When Voriconazole 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 to
phenytoin.
|
|
Oral
Contraceptives containing ethinyl estradiol and norethindrone
(CYP3A4 Inhibition)†
|
Increased
|
Monitoring for adverse events related to oral
contraceptives is recommended during coadministration.
|
|
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 Voriconazole in 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
In Vitro Studies
Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma
Exposure)
|
No dosage adjustment for indinavir when
coadministered with Voriconazole
Frequent monitoring for adverse events and toxicity related to other HIV
protease inhibitors
|
|
Other NNRTIs¶
(CYP3A4 Inhibition)
|
A Voriconazole-Efavirenz Drug Interaction Study
Demonstrated 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
Demonstrated 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
Demonstrated 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
Demonstrated 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. Reserve azole antifungals,
including Voriconazole, for patients receiving a vinca alkaloid who have no
alternative antifungal treatment options.
|
|
Everolimus
(CYP3A4 Inhibition)
|
Not Studied In Vivo or In Vitro ,
but Drug Plasma Exposure Likely to be Increased
|
Concomitant administration of Voriconazole and
everolimus is not recommended.
|
USE IN SPECIFIC POPULATIONS
Pregnancy
Risk Summary
Voriconazole
can cause fetal harm when administered to a pregnant woman. There are no
available data on the use of Voriconazole in pregnant women. In animal
reproduction studies, oral Voriconazole was teratogenic in rats and embryotoxic
in rabbits. Cleft palates and hydronephrosis/hydroureter were observed in rat
pups exposed to Voriconazole during organogenesis at and above 10 mg/kg (0.3
times the recommended maintenance dose of 200 mg every 12 hours based on body
surface area comparisons). In rabbits, embryomortality, reduced fetal weight
and increased incidence of skeletal variations, cervical ribs and extrasternal
ossification sites were observed in pups when pregnant rabbits were orally
dosed at 100 mg/kg (6 times the RMD based on body surface area comparisons)
during organogenesis. Rats exposed to Voriconazole from implantation to weaning
experienced increased gestational length and dystocia, which were associated
with increased perinatal pup mortality at the 10 mg/kg dose. [see Data]. If
this drug is used during pregnancy, or if the patient becomes pregnant while
taking this drug, inform the patient of the potential hazard to the fetus [see
Warnings and Precautions (5.4)].
The
background risk of major birth defects and miscarriage for the indicated populations
is unknown. In the U.S. general population, the estimated background risk of
major birth defects and miscarriage in clinically recognized pregnancies is
2-4% and 15-20% respectively.
Data
Animal
Data
Voriconazole
was administered orally to pregnant rats during organogenesis (gestation days
6-17) at 10, 30, and 60 mg/kg/day. Voriconazole was teratogenic with increased
incidences in hydroureter and hydronephrosis at 10 mg/kg/day or greater,
approximately 0.3 times the recommended human dose (RMD) based on mg/m2,
and cleft palate at 60 mg/kg, approximately 2 times the recommended human dose
(RMD) based on mg/m2. Reduced ossification of sacral and caudal vertebrae,
skull, pubic, and hyoid bone, supernumerary ribs, anomalies of the sternbrae,
and dilatation of the ureter/renal pelvis were also observed at doses of 10
mg/kg or greater. There was no evidence of maternal toxicity at any dose.
Voriconazole
was administered orally to pregnant rabbits during the period of organogenesis
(gestation days 7-19) at 10, 40, and 100 mg/kg/day. Voriconazole produced
embryofetal toxicity (increased post-implantation loss, decreased fetal body
weight) in association with maternal toxicity (decreased body weight gain and
food consumption) at 100 mg/kg/day (6 times the RMD based on mg/m2).
Fetal skeletal variations (increases in the incidence of cervical rib and extra
sternebral ossification sites) were observed at 100 mg/kg/day.
In a
peri-and postnatal toxicity study in rats, Voriconazole was administered orally
to female rats from implantation through the end of lactation at 1, 3, and 10
mg/kg/day. Voriconazole prolonged the duration of gestation and labor and
produced dystocia with related increases in maternal mortality and decreases in
perinatal survival of F1 pups at 10 mg/kg/day, approximately 0.3 times the RMD.
Lactation
Risk Summary
No data
are available regarding the presence of Voriconazole in human milk, the effects
of Voriconazole on the breastfed infant, or the effects on milk production. The
developmental and health benefits of breastfeeding should be considered along
with the mother's clinical need for Voriconazole and any potential adverse
effects on the breastfed child from Voriconazole or from the underlying
maternal condition.
Females and Males of Reproductive Potential
Contraception
Advise
females of reproductive potential to use effective contraception during
treatment with Voriconazole. The coadministration of Voriconazole with the oral
contraceptive, Ortho-Novum® (35 mcg ethinyl estradiol and 1 mg norethindrone),
results in an interaction between these two drugs, but is unlikely to reduce
the contraceptive effect. Monitoring for adverse reactions associated with oral
contraceptives and Voriconazole is recommended [see Drug
Interactions (7) and Clinical Pharmacology (12.3)].
Pediatric Use
Safety
and effectiveness in pediatric patients below the age of 12 years have not been
established.
A total
of 22 patients aged 12 to 18 years with invasive aspergillosis were included in
the therapeutic studies. Twelve out of 22 (55%) patients had successful
response after treatment with a maintenance dose of Voriconazole 4 mg/kg q12h.
Sparse
plasma sampling for pharmacokinetics in adolescents was conducted in the
therapeutic studies [see Clinical Pharmacology (12.3)]. A population pharmacokinetic analysis was
conducted on pooled data from 35 immunocompromised pediatric patients aged 2 to
<12 years old who were included in two pharmacokinetic studies of intravenous
Voriconazole (single dose and multiple dose). Twenty-four of these patients
received multiple intravenous maintenance doses of 3 mg/kg and 4 mg/kg. A
comparison of the pediatric and adult population pharmacokinetic data revealed
that the predicted average
steady state plasma concentrations were similar at the maintenance dose of 4
mg/kg every 12 hours in children and 3 mg/kg every 12 hours in adults (medians
of 1.19 μg/mL and 1.16 μg/mL in children and adults, respectively). There have
been postmarketing reports of pancreatitis in
pediatric patients.
Geriatric Use
In
multiple dose therapeutic trials of Voriconazole, 9.2% of patients were ≥65
years of age and 1.8% of patients were ≥75 years of age. In a study in healthy
subjects, the systemic exposure (AUC) and peak plasma concentrations (Cmax) were increased in elderly males compared to young
males. Pharmacokinetic data obtained from 552 patients from 10 Voriconazole
therapeutic trials showed that Voriconazole plasma concentrations in the elderly
patients were approximately 80% to 90% higher than those in younger patients
after either IV or oral administration. However, the overall safety profile of
the elderly patients was similar to that of the young so no dosage adjustment
is recommended [see Clinical Pharmacology (12.3)].
Overdosage
In
clinical trials, there were three cases of accidental overdose. All occurred in
pediatric patients who received up to five times the recommended intravenous
dose of Voriconazole. A single adverse event of photophobia of 10 minutes
duration was reported.
There is
no known antidote to Voriconazole.
Voriconazole
is hemodialyzed with clearance of 121 mL/min. The intravenous vehicle, SBECD,
is hemodialyzed with clearance of 55 mL/min. In an overdose, hemodialysis may
assist in the removal of Voriconazole and SBECD from the body.
Voriconazole Description
Voriconazole,
an azole antifungal agent is available as film-coated tablets for oral
administration. The structural formula is:
Voriconazole
is designated chemically as
(2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol
with an molecular formula of C16H14F3N5O and a molecular weight of 349.3.
Voriconazole
drug substance is a white to almost white powder.
Each
Voriconazole tablet intended for oral administration contains 50 mg or 200 mg
of Voriconazole. In addition, each tablet contains the following inactive
ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate,
povidone and pregelatinized starch. Additionally, each Voriconazole tablets
contain opadry II white 33F28398 which contains hypromellose, lactose
monohydrate, polyethylene glycol, talc and titanium dioxide.
Voriconazole - Clinical Pharmacology
Mechanism of Action
Voriconazole
is an antifungal drug [see Microbiology (12.4)]
Pharmacodynamics
Exposure-Response Relationship For Efficacy and
Safety
In 10
clinical trials (N=1121), the median
values for the average and maximum Voriconazole plasma concentrations in
individual patients across these studies was 2.51 μg/mL (inter-quartile range
1.21 to 4.44 μg/mL) and 3.79 μg/mL (inter-quartile range 2.06 to 6.31 μg/mL), respectively. A pharmacokinetic-pharmacodynamic
analysis of patient data from 6 of these 10 clinical trials (N=280) could not
detect a positive association between mean, maximum or minimum plasma
Voriconazole concentration and efficacy. However, pharmacokinetic/pharmacodynamic
analyses of the data from all 10 clinical trials identified positive
associations between plasma Voriconazole concentrations and rate of both liver
function test abnormalities and visual disturbances [see Adverse
Reactions (6)].
Cardiac Electrophysiology
A
placebo-controlled, randomized, crossover study to evaluate the effect on the
QT interval of healthy male and female subjects was conducted with three single
oral doses of Voriconazole and ketoconazole. Serial ECGs and plasma samples
were obtained at specified intervals over a 24-hour post dose observation
period. The placebo-adjusted mean maximum increases in QTc from baseline after
800, 1200, and 1600 mg of Voriconazole and after ketoconazole 800 mg were all
<10 msec. Females exhibited a greater increase in QTc than males, although
all mean changes were <10 msec. Age was not found to affect the magnitude of
increase in QTc. No subject in any group had an increase in QTc of ≥60 msec
from baseline. No subject experienced an interval exceeding the potentially
clinically relevant threshold of 500 msec. However, the QT effect of
Voriconazole combined with drugs known to prolong the QT interval is unknown [see
Contraindications (4) and Drug Interactions (7)].
Pharmacokinetics
The
pharmacokinetics of Voriconazole have been characterized in healthy subjects,
special populations and patients.
The
pharmacokinetics of Voriconazole are non-linear due to saturation of its
metabolism. The interindividual variability of Voriconazole pharmacokinetics is
high. Greater than proportional increase in exposure is observed with
increasing dose. It is estimated that, on average, increasing the oral dose
from 200 mg q12h to 300 mg q12h leads to an approximately 2.5-fold increase in
exposure (AUCτ), similarly increasing the intravenous dose from 3
mg/kg q12h to 4 mg/kg q12h produces an approximately 2.5-fold increase in
exposure (Table 9).
Table 9:Geometric Mean (%CV) Plasma
Voriconazole Pharmacokinetic Parameters in Adults Receiving Different Dosing
Regimens
|
|
|
6 mg/kg IV
(loading dose)
|
3 mg/kg IV q12h
|
4 mg/kg IV q12h
|
400 mg Oral (loading dose)
|
200 mg Oral q12h
|
300 mg Oral q12h
|
|
N
|
35
|
23
|
40
|
17
|
48
|
16
|
|
AUC12 (mcg•h/mL)
|
13.9 (32)
|
13.7 (53)
|
33.9 (54)
|
9.31 (38)
|
12.4 (78)
|
34.0 (53)
|
|
Cmax (mcg/mL)
|
3.13 (20)
|
3.03 (25)
|
4.77 (36)
|
2.30 (19)
|
2.31 (48)
|
4.74 (35)
|
|
Cmax (mcg/mL)
|
--
|
0.46 (97)
|
1.73 (74)
|
--
|
0.46 (120)
|
1.63 (79)
|
Note:
Parameters were estimated based on non-compartmental analysis from 5
pharmacokinetic studies. AUC12 =
area under the curve over 12 hour dosing interval, Cmax =
maximum plasma concentration, Cmin =
minimum plasma concentration. CV = coefficient of variation.
When the
recommended intravenous loading dose regimen is administered to healthy
subjects, plasma concentrations close to steady state are achieved within the
first 24 hours of dosing (eg, 6 mg/kg IV q12h on day 1 followed by 3 mg/kg IV
q12h). Without the loading dose, accumulation occurs during twice-daily
multiple dosing with steady-state plasma Voriconazole concentrations being
achieved by day 6 in the majority of subjects.
Absorption
The
pharmacokinetic properties of Voriconazole are similar following administration
by the intravenous and oral routes. Based on a population pharmacokinetic
analysis of pooled data in healthy subjects (N=207), the oral bioavailability
of Voriconazole is estimated to be 96% (CV 13%). Bioequivalence was established
between the 200 mg tablet and the 40 mg/mL oral suspension when administered as
a 400 mg Q12h loading dose followed by a 200 mg Q12h maintenance dose.
Maximum
plasma concentrations (Cmax) are
achieved 1 to 2 hours after dosing. When multiple doses of Voriconazole are
administered with high-fat meals, the mean Cmax and AUCτ are reduced by 34% and 24%, respectively when administered
as a tablet and by 58% and 37% respectively when administered as the oral
suspension [see Dosage and Administration (2)].
In
healthy subjects, the absorption of Voriconazole is not affected by
coadministration of oral ranitidine, cimetidine, or omeprazole, drugs that are
known to increase gastric pH.
Distribution
The
volume of distribution at steady state for Voriconazole is estimated to be 4.6
L/kg, suggesting extensive distribution into tissues. Plasma protein binding is
estimated to be 58% and was shown to be independent of plasma concentrations
achieved following single and multiple oral doses of 200 mg or 300 mg
(approximate range: 0.9 to 15 mcg/mL). Varying degrees of hepatic and renal
impairment do not affect the protein binding of Voriconazole.
Elimination
Metabolism
In vitro studies
showed that Voriconazole is metabolized by the human hepatic cytochrome P450
enzymes, CYP2C19, CYP2C9 and CYP3A4 [see Drug Interactions (7)].
In vivo studies
indicated that CYP2C19 is significantly involved in the metabolism of
Voriconazole. This enzyme exhibits genetic polymorphism [see Clinical
Pharmacology (12.5)].
The major
metabolite of Voriconazole is the N-oxide, which accounts for 72% of the
circulating radiolabelled metabolites in plasma. Since this metabolite has
minimal antifungal activity, it does not contribute to the overall efficacy of
Voriconazole.
Excretion–Voriconazole
is eliminated via hepatic metabolism with less than 2% of the dose excreted
unchanged in the urine. After administration of a single radiolabelled dose of
either oral or IV Voriconazole, preceded by multiple oral or IV dosing,
approximately 80% to 83% of the radioactivity is recovered in the urine. The
majority (>94%) of the total radioactivity is excreted in the first 96 hours
after both oral and intravenous dosing.
As a
result of non-linear pharmacokinetics, the terminal half-life of Voriconazole
is dose dependent and therefore not useful in predicting the accumulation or
elimination of Voriconazole.
Specific Populations
Male and Female Patients
In a
multiple oral dose study, the mean Cmax and
AUCτ for healthy young females were 83% and 113%
higher, respectively, than in healthy young males (18 to 45 years), after
tablet dosing. In the same study, no significant differences in the mean Cmax
and AUCτ were observed between healthy elderly males and
healthy elderly females (>65 years). In a similar study, after dosing with
the oral suspension, the mean AUC for healthy young females was 45% higher than
in healthy young males whereas the mean Cmax was
comparable between genders. The steady state trough Voriconazole concentrations
(Cmin) seen in females were 100% and 91% higher than in
males receiving the tablet and the oral suspension, respectively.
In the
clinical program, no dosage adjustment was made on the basis of gender. The
safety profile and plasma concentrations observed in male and female subjects
were similar. Therefore, no dosage adjustment based on gender is necessary.
Geriatric Patients
In an
oral multiple dose study the mean Cmax and
AUCτ in healthy elderly males (≥65 years) were 61%
and 86% higher, respectively, than in young males (18 to 45 years). No
significant differences in the mean Cmax and
AUCτ were observed between healthy elderly females (≥65
years) and healthy young females (18 to 45 years).
In the
clinical program, no dosage adjustment was made on the basis of age. An
analysis of pharmacokinetic data obtained from 552 patients from 10
Voriconazole clinical trials showed that the median Voriconazole plasma
concentrations in the elderly patients (>65 years) were approximately 80% to
90% higher than those in the younger patients (≤65 years) after either IV or
oral administration. However, the safety profile of Voriconazole in young and
elderly subjects was similar and, therefore, no dosage adjustment is necessary
for the elderly [see Use in Special Populations (8.5)].
Pediatric Patients
Sparse
plasma sampling for pharmacokinetics was conducted in the therapeutic studies
in patients aged 12-18 years. In 11
adolescent patients who received a mean Voriconazole maintenance dose of 4
mg/kg IV, the median of the calculated mean plasma concentrations was 1.60
μg/mL (inter-quartile range 0.28 to 2.73 μg/mL). In 17 adolescent patients for whom
mean plasma concentrations were calculated following a mean oral maintenance
dose of 200 mg every 12h, the median of the calculated mean plasma
concentrations was 1.16 μg/mL (inter-quartile range 0.85 to 2.14 μg/mL).
Patients with Hepatic Impairment
After a
single oral dose (200 mg) of Voriconazole in 8 patients with mild (Child-Pugh
Class A) and 4 patients with moderate (Child-Pugh Class B) hepatic impairment,
the mean systemic exposure (AUC) was 3.2-fold higher than in age and weight
matched controls with normal hepatic function. There was no difference in mean
peak plasma concentrations (Cmax) between
the groups. When only the patients with mild (Child-Pugh Class A) hepatic
impairment were compared to controls, there was still a 2.3-fold increase in
the mean AUC in the group with hepatic impairment compared to controls.
In an
oral multiple dose study, AUCτ was
similar in 6 subjects with moderate hepatic impairment (Child-Pugh Class B)
given a lower maintenance dose of 100 mg twice daily compared to 6 subjects
with normal hepatic function given the standard 200 mg twice daily maintenance
dose. The mean peak plasma concentrations (Cmax)
were 20% lower in the hepatically impaired group. No pharmacokinetic data are
available for patients with severe hepatic cirrhosis (Child-Pugh Class C) [see Dosage and Administration (2.7)].
Patients with Renal Impairment
In a
single oral dose (200 mg) study in 24 subjects with normal renal function and mild
to severe renal impairment, systemic exposure (AUC) and peak plasma
concentration (Cmax) of Voriconazole were not significantly affected by
renal impairment. Therefore, no adjustment is necessary for oral dosing in
patients with mild to severe renal impairment.
In a
multiple dose study of IV Voriconazole (6 mg/kg IV loading dose x 2, then 3
mg/kg IV x 5.5 days) in 7 patients with moderate renal dysfunction (creatinine
clearance 30 to 50 mL/min), the systemic exposure (AUC) and peak plasma
concentrations (Cmax) were not significantly different from those in 6
subjects with normal renal function.
However,
in patients with moderate renal dysfunction (creatinine clearance 30 to 50
mL/min), accumulation of the intravenous vehicle, SBECD, occurs. The mean systemic
exposure (AUC) and peak plasma concentrations (Cmax)
of SBECD were increased 4-fold and almost 50%, respectively, in the moderately
impaired group compared to the normal control group.
A
pharmacokinetic study in subjects with renal failure undergoing hemodialysis
showed that Voriconazole is dialyzed with clearance of 121 mL/min. The
intravenous vehicle, SBECD, is hemodialyzed with clearance of 55 mL/min. A
4-hour hemodialysis session does not remove a sufficient amount of Voriconazole
to warrant dose adjustment [see Dosage and Administration (2.8)].
Patients at Risk of Aspergillosis
The
observed Voriconazole pharmacokinetics in patients at risk of aspergillosis
(mainly patients with malignant neoplasms of lymphatic or hematopoietic tissue)
were similar to healthy subjects.
Drug Interactions Studies
Effects of Other Drugs on Voriconazole
Voriconazole
is metabolized by the human hepatic cytochrome P450 enzymes CYP2C19, CYP2C9,
and CYP3A4. Results of in vitro metabolism
studies indicate that the affinity of Voriconazole is highest for CYP2C19,
followed by CYP2C9, and is appreciably lower for CYP3A4. Inhibitors or inducers
of these three enzymes may increase or decrease Voriconazole systemic exposure
(plasma concentrations), respectively.
The systemic exposure to Voriconazole is significantly reduced or is expected to be reduced by the concomitant administration of the following agents and their use is contraindicated:
Rifampin (potent CYP450 inducer)–Rifampin
(600 mg once daily) decreased the steady state Cmax and
AUCτ of Voriconazole (200 mg q12h x 7 days) by an
average of 93% and 96%, respectively, in healthy subjects. Doubling the dose of
Voriconazole to 400 mg q12h does not restore adequate exposure to Voriconazole
during coadministration with rifampin. Coadministration of Voriconazole and rifampin is contraindicated [see Contraindications (4) and Warnings and Precautions (5.1)].
Ritonavir (potent CYP450 inducer; CYP3A4 inhibitor and substrate)–The
effect of the coadministration of Voriconazole and ritonavir (400 mg and 100
mg) was investigated in two separate studies. High-dose ritonavir (400 mg q12h
for 9 days) decreased the steady state Cmax and
AUCτ of oral Voriconazole (400 mg q12h for 1 day,
then 200 mg q12h for 8 days) by an average of 66% and 82%, respectively, in
healthy subjects. Low-dose ritonavir (100 mg q12h for 9 days) decreased the
steady state Cmax and AUCτ of
oral Voriconazole (400 mg q12h for 1 day, then 200 mg q12h for 8 days) by an
average of 24% and 39%, respectively, in healthy subjects. Although repeat oral
administration of Voriconazole did not have a significant effect on steady
state Cmax and AUCτ of
high-dose ritonavir in healthy subjects, steady state Cmax and
AUCτ of low-dose ritonavir decreased slightly by 24%
and 14% respectively, when administered concomitantly with oral Voriconazole in
healthy subjects. Coadministration of Voriconazole and high-dose ritonavir (400 mg q12h) is contraindicated. Coadministration of Voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of Voriconazole [see Contraindications (4) and Warnings and Precautions (5.1)].
St. John's Wort (CYP450 inducer; P-gp inducer)–In
an independent published study in healthy volunteers who were given multiple
oral doses of St. John's Wort (300 mg LI 160 extract three times daily for 15
days) followed by a single 400 mg oral dose of Voriconazole, a 59% decrease in
mean Voriconazole AUC0-∞ was observed. In contrast, coadministration of
single oral doses of St. John's Wort and Voriconazole had no appreciable effect
on Voriconazole AUC0-∞. Because long-term use of St. John's Wort could lead
to reduced Voriconazole exposure, concomitant use of Voriconazole with St. John's Wort is contraindicated [see Contraindications (4)].
Carbamazepine and long-acting barbiturates (potent CYP450 inducers)–Although
not studied in vitro or in vivo,
carbamazepine and long-acting barbiturates (e.g., phenobarbital, mephobarbital)
are likely to significantly decrease plasma Voriconazole concentrations. Coadministration of Voriconazole with carbamazepine or long-acting barbiturates is contraindicated[see Contraindications (4), and Warnings and Precautions (5.1)].
Significant drug interactions that may require Voriconazole dosage adjustment, or frequent monitoring of Voriconazole-related adverse events/toxicity:
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor): Concurrent
administration of oral Voriconazole (400 mg q12h for 1 day, then 200 mg q12h
for 2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg Q24h for 4
days) to 6 healthy male subjects resulted in an increase in Cmax and AUCτ of
Voriconazole by an average of 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%,
128%), respectively. In a follow-on clinical study involving 8 healthy male
subjects, reduced dosing and/or frequency of Voriconazole and fluconazole did
not eliminate or diminish this effect. Concomitant administration of
Voriconazole and fluconazole at any dose is not recommended. Close monitoring
for adverse events related to Voriconazole is recommended if Voriconazole is
used sequentially after fluconazole, especially within 24 hours of the last
dose of fluconazole [see Warnings and Precautions (5.1)].
Minor or no significant pharmacokinetic interactions that do not require dosage adjustment:
Cimetidine (non-specific CYP450 inhibitor and increases gastric pH)–Cimetidine
(400 mg q12h x 8 days) increased Voriconazole steady state Cmax and AUCτ by
an average of 18% (90% CI: 6%, 32%) and 23% (90% CI: 13%, 33%), respectively,
following oral doses of 200 mg q12h x 7 days to healthy subjects.
Ranitidine (increases gastric pH)–Ranitidine
(150 mg q12h) had no significant effect on Voriconazole Cmax and AUCτ following
oral doses of 200 mg q12h x 7 days to healthy subjects.
Macrolide antibiotics–Coadministration
of erythromycin (CYP3A4 inhibitor; 1g q12h for
7 days) or azithromycin (500 mg
q24h for 3 days) with Voriconazole 200 mg q12h for 14 days had no significant
effect on Voriconazole steady state Cmax and
AUCτ in healthy subjects. The effects of
Voriconazole on the pharmacokinetics of either erythromycin or azithromycin are
not known.
Effects of Voriconazole on Other Drugs
In vitro studies
with human hepatic microsomes show that Voriconazole inhibits the metabolic
activity of the cytochrome P450 enzymes CYP2C19, CYP2C9, and CYP3A4. In these
studies, the inhibition potency of Voriconazole for CYP3A4 metabolic activity
was significantly less than that of two other azoles, ketoconazole and
itraconazole. In vitro studies
also show that the major metabolite of Voriconazole, Voriconazole N-oxide,
inhibits the metabolic activity of CYP2C9 and CYP3A4 to a greater extent than
that of CYP2C19. Therefore, there is potential for Voriconazole and its major
metabolite to increase the systemic exposure (plasma concentrations) of other
drugs metabolized by these CYP450 enzymes.
The systemic exposure of the following drugs is significantly increased or is expected to be significantly increased by coadministration of Voriconazole and their use is contraindicated:
Sirolimus (CYP3A4 substrate)–Repeat
dose administration of oral Voriconazole (400 mg q12h for 1 day, then 200 mg
q12h for 8 days) increased the Cmax and
AUC of sirolimus (2 mg single dose) an average of 7-fold (90% CI: 5.7, 7.5) and
11-fold (90% CI: 9.9, 12.6), respectively, in healthy male subjects. Coadministration of Voriconazole and sirolimus is contraindicated [see Contraindications (4) and Warnings and Precautions (5.1)].
Terfenadine, astemizole, cisapride, pimozide and quinidine (CYP3A4 substrates)–Although
not studied in vitro or in vivo,
concomitant administration of Voriconazole with terfenadine, astemizole,
cisapride, pimozide or quinidine may result in inhibition of the metabolism of
these drugs. Increased plasma concentrations of these drugs can lead to QT
prolongation and rare occurrences of torsade de pointes. Coadministration of Voriconazole and terfenadine, astemizole, cisapride, pimozide and quinidine is contraindicated [see Contraindications (4) and Warnings and Precautions (5.1)].
Ergot alkaloids–Although not studied in vitro or in vivo,
Voriconazole may increase the plasma concentration of ergot alkaloids
(ergotamine and dihydroergotamine) and lead to ergotism. Coadministration of Voriconazole with ergot alkaloids is contraindicated [see Contraindications (4) and Warnings and Precautions (5.1)].
Everolimus (CYP3A4 substrate, P-gp substrate)–Although not studied in vitro or in
vivo, Voriconazole may increase plasma concentrations of
everolimus, which could potentially lead to exacerbation of everolimus
toxicity. Currently there are insufficient data to allow dosing recommendations
in this situation. Therefore, co-administration of Voriconazole with everolimus
is not recommended [see Drug Interactions (7)].
Coadministration of Voriconazole with the following agents results in increased exposure or is expected to result in increased exposure to these drugs. Therefore, careful monitoring and/or dosage adjustment of these drugs is needed:
Alfentanil (CYP3A4 substrate)–Coadministration of multiple doses
of oral Voriconazole (400 mg q12h on day 1, 200 mg q12h on day 2) with a single
20 mcg/kg intravenous dose of alfentanil with concomitant naloxone resulted in
a 6-fold increase in mean alfentanil AUC0-∞ and
a 4-fold prolongation of mean alfentanil elimination half-life, compared to
when alfentanil was given alone. An increase in the incidence of delayed and
persistent alfentanil-associated nausea and vomiting during co-administration
of Voriconazole and alfentanil was also observed. Reduction in the dose of
alfentanil or other opiates that are also metabolized by CYP3A4 (e.g.,
sufentanil), and extended close monitoring of patients for respiratory and
other opiate-associated adverse events, may be necessary when any of these
opiates is coadministered with Voriconazole [see Warnings and Precautions (5.1)].
Fentanyl (CYP3A4 substrate): In
an independent published study, concomitant use of Voriconazole (400 mg q12h on
Day 1, then 200 mg q12h on Day 2) with a single intravenous dose of fentanyl (5
mcg/kg) resulted in an increase in the mean AUC0-∞ of
fentanyl by 1.4-fold (range 0.81- to 2.04-fold). When Voriconazole is
co-administered with fentanyl IV, oral or transdermal dosage forms, extended
and frequent monitoring of patients for respiratory depression and other
fentanyl-associated adverse events is recommended, and fentanyl dosage should
be reduced if warranted [see Warnings and Precautions (5.1)].
Oxycodone (CYP3A4 substrate): In
an independent published study, coadministration of multiple doses of oral
Voriconazole (400 mg q12h, on Day 1 followed by five doses of 200 mg q12h on
Days 2 to 4) with a single 10 mg oral dose of oxycodone on Day 3 resulted in an
increase in the mean Cmax and AUC0–∞ of
oxycodone by 1.7-fold (range 1.4- to 2.2-fold) and 3.6-fold (range 2.7- to
5.6-fold), respectively. The mean elimination half-life of oxycodone was also
increased by 2-fold (range 1.4- to 2.5-fold). Voriconazole also increased the
visual effects (heterophoria and miosis) of oxycodone. A reduction in oxycodone
dosage may be needed during Voriconazole treatment to avoid opioid related
adverse effects. Extended and frequent monitoring for adverse effects
associated with oxycodone and other long-acting opiates metabolized by CYP3A4
is recommended [see Warnings and Precautions (5.1)].
Cyclosporine (CYP3A4 substrate)–In
stable renal transplant recipients receiving chronic cyclosporine therapy,
concomitant administration of oral Voriconazole (200 mg q12h for 8 days)
increased cyclosporine Cmax and
AUCτ an average of 1.1 times (90% CI: 0.9, 1.41) and
1.7 times (90% CI: 1.5, 2), respectively, as compared to when cyclosporine was
administered without Voriconazole. When initiating therapy with Voriconazole in
patients already receiving cyclosporine, it is recommended that the
cyclosporine dose be reduced to one-half of the original dose and followed with
frequent monitoring of the cyclosporine blood levels. Increased cyclosporine
levels have been associated with nephrotoxicity. When
Voriconazole is discontinued, cyclosporine levels should be frequently
monitored and the dose increased as necessary [see Warnings and Precautions (5.1)].
Methadone (CYP3A4, CYP2C19, CYP2C9 substrate)–Repeat dose administration of oral
Voriconazole (400 mg q12h for 1 day, then 200 mg q12h for 4 days) increased the
Cmax and AUCτ of
pharmacologically active R-methadone by 31% (90% CI: 22%, 40%) and 47% (90% CI:
38%, 57%), respectively, in subjects receiving a methadone maintenance dose (30
mg to 100 mg q24h). The Cmaxand AUC
of (S)-methadone increased by 65% (90% CI: 53%, 79%) and 103% (90% CI: 85%,
124%), respectively. 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 of methadone may be needed [see Warnings and Precautions (5.1)].
Tacrolimus (CYP3A4 substrate)–Repeat
oral dose administration of Voriconazole (400 mg q12h x 1 day, then 200 mg q12h
x 6 days) increased tacrolimus (0.1 mg/kg single dose) Cmax and
AUCτ in healthy subjects by an average of 2-fold
(90% CI: 1.9, 2.5) and 3-fold (90% CI: 2.7, 3.8), respectively. When initiating
therapy with Voriconazole in patients already receiving tacrolimus, it is
recommended that the tacrolimus dose be reduced to one-third of the original
dose and followed with frequent monitoring of the tacrolimus blood levels.
Increased tacrolimus levels have been associated with nephrotoxicity. When Voriconazole is discontinued, tacrolimus levels should be
carefully monitored and the dose increased as necessary [see Warnings and Precautions (5.1)].
Warfarin (CYP2C9 substrate)–Coadministration
of Voriconazole (300 mg q12h x 12 days) with warfarin (30 mg single dose)
significantly increased maximum prothrombin time by approximately 2 times that
of placebo in healthy subjects. Close monitoring of prothrombin time or other
suitable anticoagulation tests is recommended if warfarin and Voriconazole are
coadministered and the warfarin dose adjusted accordingly [see Warnings and Precautions (5.1)].
Oral Coumarin Anticoagulants (CYP2C9, CYP3A4 substrates)–Although
not studied in vitro or in vivo,
Voriconazole may increase the plasma concentrations of coumarin anticoagulants
and therefore may cause an increase in prothrombin time. If patients receiving
coumarin preparations are treated simultaneously with Voriconazole, the
prothrombin time or other suitable anti-coagulation tests should be monitored
at close intervals and the dosage of anticoagulants adjusted accordingly [see Warnings and Precautions (5.1)].
Statins (CYP3A4 substrates)–Although
not studied clinically, Voriconazole has been shown to inhibit lovastatin
metabolism in vitro (human
liver microsomes). Therefore, Voriconazole is likely to increase the plasma
concentrations of statins that are metabolized by CYP3A4. It is recommended
that dose adjustment of the statin be considered during coadministration.
Increased statin concentrations in plasma have been associated with
rhabdomyolysis [see Warnings and Precautions (5.1)].
Benzodiazepines (CYP3A4 substrates)–Although
not studied clinically, Voriconazole has been shown to inhibit midazolam
metabolism in vitro (human
liver microsomes). Therefore, Voriconazole is likely to increase the plasma
concentrations of benzodiazepines that are metabolized by CYP3A4 (e.g.,
midazolam, triazolam, and alprazolam) and lead to a prolonged sedative effect.
It is recommended that dose adjustment of the benzodiazepine be considered
during coadministration [see Warnings and Precautions (5.1)].
Calcium Channel Blockers (CYP3A4 substrates)–Although
not studied clinically, Voriconazole has been shown to inhibit felodipine
metabolism in vitro (human
liver microsomes). Therefore, Voriconazole may increase the plasma
concentrations of calcium channel blockers that are metabolized by CYP3A4.
Frequent monitoring for adverse events and toxicity related to calcium channel
blockers is recommended during coadministration. Dose adjustment of the calcium
channel blocker may be needed [see Warnings and Precautions (5.1)].
Sulfonylureas (CYP2C9 substrates)–Although
not studied in vitro or in vivo,
Voriconazole may increase plasma concentrations of sulfonylureas (e.g.,
tolbutamide, glipizide, and glyburide) and therefore cause hypoglycemia.
Frequent monitoring of blood glucose and appropriate adjustment (i.e.,
reduction) of the sulfonylurea dosage is recommended during coadministration [see Warnings and Precautions (5.1)].
Vinca Alkaloids (CYP3A4 substrates)–Although
not studied in vitro or in vivo,
Voriconazole may increase the plasma concentrations of the vinca alkaloids
(e.g., vincristine and vinblastine) and lead to neurotoxicity. Therefore,
reserve azole antifungals, including Voriconazole, for patients receiving a
vinca alkaloid, including vincristine, who have no alternative antifungal
treatment options [see Warnings and Precautions (5.1)].
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs; CYP2C9 substrates): In
two independent published studies, single doses of ibuprofen (400 mg) and
diclofenac (50 mg) were coadministered with the last dose of Voriconazole (400
mg q12h on Day 1, followed by 200 mg q12h on Day 2). Voriconazole increased the
mean Cmax and AUC of the pharmacologically active isomer,
S (+)-ibuprofen by 20% and 100%, respectively. Voriconazole increased the mean
Cmax and AUC of diclofenac by 114% and 78%,
respectively.
A
reduction in ibuprofen and diclofenac dosage may be needed during concomitant
administration with Voriconazole. Patients receiving Voriconazole concomitantly
with other NSAIDs (e.g., celecoxib, naproxen, lornoxicam, meloxicam) that are
also metabolized by CYP2C9 should be carefully monitored for NSAID-related
adverse events and toxicity, and dosage reduction should be made if warranted [see Warnings and Precautions (5.1)].
No significant pharmacokinetic interactions were observed when Voriconazole was coadministered with the following agents. Therefore, no dosage adjustment for these agents is recommended:
Prednisolone (CYP3A4 substrate)–Voriconazole
(200 mg q12h x 30 days) increased Cmax and
AUC of prednisolone (60 mg single dose) by an average of 11% and 34%,
respectively, in healthy subjects.
Digoxin (P-glycoprotein mediated transport)–Voriconazole
(200 mg q12h x 12 days) had no significant effect on steady state Cmax and AUCτ of
digoxin (0.25 mg once daily for 10 days) in healthy subjects.
Mycophenolic acid (UDP-glucuronyl transferase substrate)–Voriconazole
(200 mg q12h x 5 days) had no significant effect on the Cmax and AUCτ of
mycophenolic acid and its major metabolite, mycophenolic acid glucuronide after
administration of a 1 g single oral dose of mycophenolate mofetil.
Two-Way Interactions
Concomitant use of the following agents with Voriconazole is contraindicated:
Rifabutin (potent CYP450 inducer)–Rifabutin
(300 mg once daily) decreased the Cmax and
AUCτ of Voriconazole at 200 mg twice daily by an
average of 67% (90% CI: 58%, 73%) and 79% (90% CI: 71%, 84%), respectively, in
healthy subjects. During coadministration with rifabutin (300 mg once daily),
the steady state Cmax and AUCτ of
Voriconazole following an increased dose of 400 mg twice daily were on average
approximately 2 times higher, compared with Voriconazole alone at 200 mg twice
daily. Coadministration of Voriconazole at 400 mg twice daily with rifabutin
300 mg twice daily increased the Cmax and
AUCτ of rifabutin by an average of 3-times (90% CI:
2.2, 4) and 4 times (90% CI: 3.5, 5.4), respectively, compared to rifabutin
given alone. Coadministration of Voriconazole and rifabutin is contraindicated [see Contraindications (4)].
Significant drug interactions that may require dosage adjustment, frequent monitoring of drug levels and/or frequent monitoring of drug-related adverse events/toxicity:
Efavirenz, a non-nucleoside reverse transcriptase inhibitor (CYP450 inducer; CYP3A4 inhibitor and substrate)–
Standard doses of Voriconazole and efavirenz (400 mg q24h or higher) must not
be coadministered [see Drug Interactions (7)]. Steady state efavirenz (400 mg PO q24h) decreased the steady
state Cmaxand AUCτ of
Voriconazole (400 mg PO q12h for 1 day, then 200 mg PO q12h for 8 days) by an
average of 61% and 77%, respectively, in healthy male subjects. Voriconazole at
steady state (400 mg PO q12h for 1 day, then 200 mg q12h for 8 days) increased
the steady state Cmax and AUCτ of
efavirenz (400 mg PO q24h for 9 days) by an average of 38% and 44%,
respectively, in healthy subjects.
The
pharmacokinetics of adjusted doses of Voriconazole and efavirenz were studied
in healthy male subjects following administration of Voriconazole (400 mg PO
q12h on Days 2 to 7) with efavirenz (300 mg PO q24h on Days 1 to 7), relative
to steady-state administration of Voriconazole (400 mg for 1 day, then 200 mg
PO q12h for 2 days) or efavirenz (600 mg q24h for 9 days). Coadministration of
Voriconazole 400 mg q12h with efavirenz 300 mg q24h, decreased Voriconazole AUCτ by 7% (90% CI: -23%, 13%) and increased Cmax by 23% (90% CI: -1%, 53%); efavirenz AUCτ was increased by 17% (90% CI: 6%, 29%) and Cmax was equivalent.
Coadministration of standard doses of Voriconazole and efavirenz
(400 mg q24h or higher) is contraindicated.
Voriconazole
may be coadministered with efavirenz if the Voriconazole maintenance dose is
increased to 400 mg q12h and the efavirenz dose is decreased to 300 mg q24h.
When treatment with Voriconazole is stopped, the initial dosage of efavirenz
should be restored [see Dosage and Administration (2.4), Contraindications (4), and Drug Interactions (7)].
Phenytoin (CYP2C9 substrate and potent CYP450 inducer)–Repeat
dose administration of phenytoin (300 mg once daily) decreased the steady state
Cmax and AUCτ of
orally administered Voriconazole (200 mg q12h x 14 days) by an average of 50%
and 70%, respectively, in healthy subjects. Administration of a higher
Voriconazole dose (400 mg q12h x 7 days) with phenytoin (300 mg once daily)
resulted in comparable steady state Voriconazole Cmax and
AUCτ estimates as compared to when Voriconazole was
given at 200 mg q12h without phenytoin.
Phenytoin
may be coadministered with Voriconazole if the maintenance dose of Voriconazole
is increased from 4 mg/kg to 5 mg/kg intravenously every 12 hours or from 200
mg to 400 mg orally, every 12 hours (100 mg to 200 mg orally, every 12 hours in
patients less than 40 kg) [see Dosage and Administration (2.4), and Drug Interactions (7)].
Repeat
dose administration of Voriconazole (400 mg q12h x 10 days) increased the
steady state Cmaxand AUCτ of
phenytoin (300 mg once daily) by an average of 70% and 80%, respectively, in
healthy subjects. The increase in phenytoin Cmax and
AUC when coadministered with Voriconazole may be expected to be as high as 2
times the Cmax and AUC estimates when phenytoin is given
without Voriconazole. Therefore, frequent monitoring of plasma phenytoin
concentrations and phenytoin-related adverse effects is recommended when
phenytoin is coadministered with Voriconazole [see Warnings and Precautions (5.1)].
Omeprazole (CYP2C19 inhibitor; CYP2C19 and CYP3A4 substrate)–Coadministration
of omeprazole (40 mg once daily x 10 days) with oral Voriconazole (400 mg q12h
x 1 day, then 200 mg q12h x 9 days) increased the steady state Cmax and AUCτ of
Voriconazole by an average of 15% (90% CI: 5%, 25%) and 40% (90% CI: 29%, 55%),
respectively, in healthy subjects. No dosage adjustment of Voriconazole is
recommended.
Coadministration
of Voriconazole (400 mg q12h x 1 day, then 200 mg x 6 days) with omeprazole (40
mg once daily x 7 days) to healthy subjects significantly increased the steady
state Cmax and AUCτ of
omeprazole an average of 2 times (90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3,
4.4), respectively, as compared to when omeprazole is given without
Voriconazole. When initiating Voriconazole in patients already receiving
omeprazole doses of 40 mg or greater, it is recommended that the omeprazole
dose be reduced by one-half [see Warnings and Precautions (5.1)].
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 these drugs.
Oral Contraceptives (CYP3A4 substrate; CYP2C19 inhibitor)–Coadministration
of oral Voriconazole (400 mg q12h for 1 day, then 200 mg q12h for 3 days) and
oral contraceptive (Ortho-Novum1/35®consisting of 35 mcg ethinyl estradiol and 1 mg
norethindrone, q24h) to healthy female subjects at steady state increased the Cmax and AUCτ of
ethinyl estradiol by an average of 36% (90% CI: 28%, 45%) and 61% (90% CI: 50%,
72%), respectively, and that of norethindrone by 15% (90% CI: 3%, 28%) and 53%
(90% CI: 44%, 63%), respectively in healthy subjects. Voriconazole Cmax and AUCτ increased
by an average of 14% (90% CI: 3%, 27%) and 46% (90% CI: 32%, 61%),
respectively. Monitoring for adverse events related to oral contraceptives, in
addition to those for Voriconazole, is recommended during coadministration [see Warnings and Precautions (5.1)].
No significant pharmacokinetic interaction was seen and no dosage adjustment of these drugs is recommended:
Indinavir (CYP3A4 inhibitor and substrate)–Repeat
dose administration of indinavir (800 mg TID for 10 days) had no significant
effect on Voriconazole Cmax and
AUC following repeat dose administration (200 mg q12h for 17 days) in healthy
subjects.
Repeat
dose administration of Voriconazole (200 mg q12h for 7 days) did not have a
significant effect on steady state Cmax and
AUCτ of indinavir following repeat dose
administration (800 mg TID for 7 days) in healthy subjects.
Other Two-Way Interactions Expected to be Significant Based on In Vitro and In Vivo Findings:
Other HIV Protease Inhibitors (CYP3A4 substrates and inhibitors)–In vitro studies
(human liver microsomes) suggest that Voriconazole may inhibit the metabolism
of HIV protease inhibitors (e.g., saquinavir, amprenavir and nelfinavir). In vitro studies
(human liver microsomes) also show that the metabolism of Voriconazole may be
inhibited by HIV protease inhibitors (e.g., saquinavir and amprenavir).
Patients should be frequently monitored for drug toxicity during the coadministration
of Voriconazole and HIV protease inhibitors [see Warnings and Precautions (5.1)].
Other Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) (CYP3A4 substrates, inhibitors or CYP450 inducers)–In vitro studies
(human liver microsomes) show that the metabolism of Voriconazole may be
inhibited by a NNRTI (e.g., delavirdine). The findings of a clinical
Voriconazole-efavirenz drug interaction study in healthy male subjects suggest
that the metabolism of Voriconazole may be induced by a NNRTI. This in vivo study
also showed that Voriconazole may inhibit the metabolism of a NNRTI [see Drug Interactions (7), and Warnings and Precautions (5.9)]. Patients should be frequently monitored for drug
toxicity during the coadministration of Voriconazole and other NNRTIs (e.g.,
nevirapine and delavirdine) [see Warnings and Precautions (5.1)]. Dose adjustments are required when Voriconazole is
co-administered with efavirenz [see Drug Interactions (7), and Warnings and Precautions (5.1)].
Microbiology
Mechanism of Action
Voriconazole
is an azole antifungal drug. The primary mode of action of Voriconazole is the
inhibition of fungal cytochrome P-450-mediated 14 alpha-lanosterol
demethylation, an essential step in fungal ergosterol biosynthesis. The
accumulation of 14 alpha-methyl sterols correlates with the subsequent loss of
ergosterol in the fungal cell wall and may be responsible for the antifungal
activity of Voriconazole.
Drug Resistance
A
potential for development of resistance to Voriconazole is well known. The
mechanisms of resistance
may include mutations in the gene ERG11 (encodes for the target enzyme,
lanosterol 14-α-demethylase), upregulation of genes encoding the ATP-binding
cassette efflux transporters i.e., Candida drug resistance (CDR) pumps and
reduced access of the drug to the
target, or some combination of those mechanisms. The frequency of drug
resistance development for the various fungi for which this drug is indicated
is not known.
Fungal
isolates exhibiting reduced susceptibility to fluconazole or itraconazole may
also show reduced susceptibility to Voriconazole, suggesting cross-resistance
can occur among these azoles. The relevance of cross-resistance and clinical
outcome has not been fully characterized. Clinical cases where azole
cross-resistance is demonstrated may require alternative antifungal therapy.
Antimicrobial Activity
Voriconazole
has been shown to be active against most isolates of the following
microorganisms, both in vitro and in
clinical infections.
Aspergillus fumigatus
Aspergillus flavus
Aspergillus niger
Aspergillus terreus
Candida albicans
Candida glabrata (In
clinical studies, the Voriconazole MIC90 was 4 mcg/mL)*
Candida krusei
Candida parapsilosis
Candida tropicalis
Fusarium spp.
including Fusarium solani
Scedosporium apiospermum
* In clinical studies, Voriconazole MIC90 for C. glabrata baseline
isolates was 4 mcg/mL; 13/50 (26%) C. glabrata baseline
isolates were resistant (MIC ≥4 mcg/mL) to Voriconazole. However, based on 1054
isolates tested in surveillance studies the MIC90 was
1 mcg/mL.
The
following data are available, but their clinical significance is
unknown. At least 90 percent of the following fungi
exhibit an in vitro minimum
inhibitory concentration (MIC) less than or equal to the susceptible breakpoint
for Voriconazole against isolates of similar genus or organism group. However,
the effectiveness of Voriconazole in treating clinical infections due to these
fungi has not been established in adequate and well-controlled clinical trials:
Candida lusitaniae
Candida guilliermondii
Susceptibility Testing Methods1,2,3
Aspergillus species and other filamentous fungi
No
interpretive criteria have been established for Aspergillus species
and other filamentous fungi.
Candida species
The
interpretive standards for Voriconazole against Candida species
are applicable only to tests performed using Clinical Laboratory and Standards
Institute (CLSI) microbroth dilution reference method M27 for MIC read at 24
hours or disk diffusion reference method M44 for zone diameter read at 24
hours.1,2,3
Dilution Techniques
Quantitative
methods are used to determine antifungal MICs. These MICs provide estimates of
the susceptibility of Candida spp.
to antifungal agents. The MICs should be determined using a standardized test
method at 24 hours1,2 (broth dilution). The MIC values should be interpreted
according to the criteria provided in Table 10.
Diffusion Techniques
Qualitative
methods that require measurement of zone diameters also provide reproducible
estimates of the susceptibility of Candida spp.
to an antifungal agent. One such standardized procedure requires the use of
standardized inoculum concentrations.2This
procedure uses paper disks impregnated with 1 mcg of Voriconazole to test the
susceptibility of yeasts to Voriconazole at 24 hours. Disk diffusion
interpretive criteria are also provided in Table 10.
Table 10: Susceptibility Interpretive
Criteria for Voriconazole1,2,3
|
|
*The current data are insufficient to
demonstrate a correlation between in vitro susceptibility
testing and clinical outcome for glabrata and
Voriconazole.
|
|
|
Broth Microdilution
at 24 hours
(MIC in mcg/mL)
|
Disk Diffusion at 24
hours*
(Zone diameters in mm)
|
|
|
Susceptible (S)
|
Intermediate
(I)
|
Resistant (R)
|
Susceptible (S)
|
Intermediate
(I)
|
Resistant (R)
|
|
C. albicans
|
≤0.12
|
0.25 to 0.5
|
≥1
|
≥17
|
15 to 16
|
≤14
|
|
C. krusei
|
≤0.5
|
1
|
≥2
|
≥15
|
13 to 14
|
≤12
|
|
C. parapsilosis
|
≤0.12
|
0.25 to 0.5
|
≥1
|
≥17
|
15 to 16
|
≤14
|
|
C. tropicalis
|
≤0.12
|
0.25 to 0.5
|
≥1
|
≥17
|
15 to 16
|
≤14
|
A report
of Susceptible (S) indicates that the antimicrobial
drug is likely to inhibit growth of the pathogen if the antimicrobial drug
reaches the concentration usually achievable at the site of infection. A report
of Intermediate (I) indicates that the result
should be considered equivocal, and, if the microorganism is not fully
susceptible to alternative, clinically feasible drugs, the test should be
repeated. This category implies possible clinical applicability in body sites
where the drugs are physiologically concentrated or when a high dosage of drug
is used. This category also provides a buffer zone that prevents small
uncontrolled technical factors from causing major discrepancies in
interpretation. A report of Resistant (R)
indicates that the antimicrobial is not likely to inhibit growth of the
pathogen if the antimicrobial drug reaches the concentrations usually
achievable at the infection site; other therapy should be selected.
Quality Control
Standardized
susceptibility test procedures require the use of laboratory controls to
monitor and ensure the accuracy and precision of supplies and reagents used in
the assay, and the techniques of the individuals performing the test1,2,3. Standard Voriconazole powder should provide the
following range of MIC values noted in Table 11. For the diffusion technique
using the 1 mcg disk, the criteria in Table 11 should be achieved.
NOTE: Quality
control microorganisms are specific strains of organisms with intrinsic
biological properties relating to resistance mechanisms and their genetic
expression within fungi; the specific strains used for microbiological control
are not clinically significant.
Table11:
AcceptableQualityControlRangesforVoriconazoletobeusedinValidationofSusceptibilityTestResults
|
|
* Quality
control ranges have not been established for this strain/antifungal agent
combination due to their extensive interlaboratory variation during initial
quality control studies.
|
|
ATCC is a registered trademark of the
American Type Culture Collection .
|
|
QC Strain
|
Broth Microdilution
(MIC in mcg/mL) at
24-hour
|
Disk Diffusion
(Zone diameter in mm)
at 24-hour
|
|
Candida parapsilosis ATCC 22019
|
0.016 to 0.12
|
28 to 37
|
|
Candida krusei
ATCC 6258
|
0.06 to 0.5
|
16 to 25
|
|
Candida albicans
ATCC 90028
|
*
|
31 to 42
|
Pharmacogenomics
CYP2C19,
significantly involved in the metabolism of Voriconazole, exhibits genetic
polymorphism. Approximately 15-20% of Asian populations may be expected to be
poor metabolizers. For Caucasians and Blacks, the prevalence of poor
metabolizers is 3-5%. Studies conducted in Caucasian and Japanese healthy subjects have shown that poor
metabolizers have, on average, 4-fold higher Voriconazole exposure (AUCτ) than
their homozygous extensive metabolizer counterparts. Subjects who are
heterozygous extensive metabolizers have, on average, 2-fold higher Voriconazole exposure than their homozygous
extensive metabolizer counterparts [see Clinical Pharmacology (12.3)].
Carcinogenesis, Mutagenesis, Impairment of Fertility
Two-year
carcinogenicity studies were conducted in rats and mice. Rats were given oral
doses of 6, 18 or 50 mg/kg Voriconazole, or 0.2, 0.6, or 1.6 times the
recommended maintenance dose on a mg/m2basis.
Hepatocellular adenomas were detected in females at 50 mg/kg and hepatocellular
carcinomas were found in males at 6 and 50 mg/kg. Mice were given oral doses of
10, 30 or 100 mg/kg Voriconazole, or 0.1, 0.4, or 1.4 times the RMD on a mg/m2basis. In mice, hepatocellular adenomas were detected in males
and females and hepatocellular carcinomas were detected in males at 1.4 times
the RMD of Voriconazole.
Voriconazole
demonstrated clastogenic activity (mostly chromosome breaks) in human
lymphocyte cultures in vitro. Voriconazole was
not genotoxic in the Ames assay, CHO HGPRT assay, the mouse micronucleus assay
or the in vitro DNA repair
test (Unscheduled DNA Synthesis assay).
Voriconazole
administration induced no impairment of male or female fertility in rats dosed
at 50 mg/kg, or 1.6 times the RMD (recommended maintenance dose).
Clinical Studies
Voriconazole,
administered orally or parenterally, has been evaluated as primary or salvage
therapy in 520 patients aged 12 years and older with infections caused by Aspergillus spp., Fusarium spp.,
and Scedosporium spp.
Invasive Aspergillosis
Voriconazole
was studied in patients for primary therapy of invasive aspergillosis
(randomized, controlled study 307/602), for primary and salvage therapy of
aspergillosis (non-comparative study 304) and for treatment of patients with
invasive aspergillosis who were refractory to, or intolerant of, other
antifungal therapy (non-comparative study 309/604).
Study 307/602 – Primary Therapy of Invasive Aspergillosis
The
efficacy of Voriconazole compared to amphotericin B in the primary treatment of
acute invasive aspergillosis was demonstrated in 277 patients treated for 12
weeks in a randomized, controlled study (Study 307/602). The majority of study
patients had underlying hematologic malignancies, including bone marrow
transplantation. The study also included patients with solid organ
transplantation, solid tumors, and AIDS. The patients were mainly treated for
definite or probable invasive aspergillosis of the lungs. Other aspergillosis
infections included disseminated disease, CNS infections and sinus infections.
Diagnosis of definite or probable invasive aspergillosis was made according to
criteria modified from those established by the National Institute of Allergy
and Infectious Diseases Mycoses Study Group/European Organisation for Research
and Treatment of Cancer (NIAID MSG/EORTC).
Voriconazole
was administered intravenously with a loading dose of 6 mg/kg every 12 hours
for the first 24 hours followed by a maintenance dose of 4 mg/kg every 12 hours
for a minimum of seven days. Therapy could then be switched to the oral
formulation at a dose of 200 mg q12h. Median duration of IV Voriconazole
therapy was 10 days (range 2 to 85 days). After IV Voriconazole therapy, the
median duration of PO Voriconazole therapy was 76 days (range 2 to 232 days).
Patients
in the comparator group received conventional amphotericin B as a slow infusion
at a daily dose of 1 to 1.5 mg/kg/day. Median duration of IV amphotericin
therapy was 12 days (range 1 to 85 days). Treatment was then continued with
other licensed antifungal therapy (OLAT), including itraconazole and lipid
amphotericin B formulations. Although initial therapy with conventional
amphotericin B was to be continued for at least two weeks, actual duration of
therapy was at the discretion of the investigator. Patients who discontinued
initial randomized therapy due to toxicity or lack of efficacy were eligible to
continue in the study with OLAT treatment.
A
satisfactory global response at 12 weeks (complete or partial resolution of all
attributable symptoms, signs, radiographic/bronchoscopic abnormalities present
at baseline) was seen in 53% of Voriconazole treated patients compared to 32%
of amphotericin B treated patients (Table 14). A benefit of Voriconazole
compared to amphotericin B on patient survival at Day 84 was seen with a 71%
survival rate on Voriconazole compared to 58% on amphotericin B (Table 12).
Table 12
also summarizes the response (success) based on mycological confirmation and
species.
Table 12:Overall Efficacy and Success by
Species in the Primary Treatment of Acute Invasive Aspergillosis Study
307/602
|
|
*
Amphotericin B
followed by other licensed antifungal therapy
†
Difference and
corresponding 95% confidence interval are stratified by protocol
‡
Assessed by
independent Data Review Committee (DRC)
§
Proportion of
subjects alive
¶
Not all
mycologically confirmed specimens were speciated
#
Some patients had more than one species isolated at
baseline
|
|
|
Voriconazole
|
Ampho B*
|
Stratified
Difference
(95% CI)†
|
|
|
n/N (%)
|
n/N (%)
|
|
|
Efficacy as Primary Therapy
|
|
|
|
|
Satisfactory Global Response‡
|
76/144 (53)
|
42/133 (32)
|
21.8%
(10.5%, 33%) p<0.0001
|
|
Survival at Day 84§
|
102/144 (71)
|
77/133 (58)
|
13.1%
(2.1%, 24.2%)
|
|
Success by Species
|
|
|
|
|
|
Success n/N (%)
|
|
|
|
Overall success
|
76/144 (53)
|
42/133 (32)
|
|
|
|
|
|
|
|
Mycologically confirmed¶
|
37/84 (44)
|
16/67 (24)
|
|
|
Aspergillus spp.#
|
|
|
|
|
A. fumigatus
|
28/63 (44)
|
12/47 (26)
|
|
|
A. flavus
|
3/6
|
4/9
|
|
|
A. terreus
|
2/3
|
0/3
|
|
|
A. niger
|
1/4
|
0/9
|
|
|
A. nidulans
|
1/1
|
0/0
|
|
Study 304 – Primary and Salvage Therapy of Aspergillosis
In this
non-comparative study, an overall success rate of 52% (26/50) was seen in
patients treated with Voriconazole for primary therapy. Success was seen in
17/29 (59%) with Aspergillus fumigatus infections
and 3/6 (50%) patients with infections due to non-fumigatus species
[A. flavus (1/1); A. nidulans (0/2); A.niger (2/2); A. terreus (0/1)]. Success
in patients who received Voriconazole as salvage therapy is presented in Table
13.
Study 309/604 – Treatment of Patients with Invasive Aspergillosis who were Refractory to, or Intolerant of, other Antifungal Therapy
Additional
data regarding response rates in patients who were refractory to, or intolerant
of, other antifungal agents are also provided in Table 15. In this
non-comparative study, overall mycological eradication for culture-documented
infections due to fumigatus and non-fumigatus species
of Aspergillus was 36/82 (44%) and 12/30 (40%),
respectively, in Voriconazole treated patients. Patients had various underlying
diseases and species other than A. fumigatus contributed to mixed infections in
some cases.
For
patients who were infected with a single pathogen and were refractory to, or
intolerant of, other antifungal agents, the satisfactory response rates for
Voriconazole in studies 304 and 309/604 are presented in Table 13.
Table 13:Combined Response Data in
SalvagePatients with Single Aspergillus Species(Studies 304 and 309/604)
|
|
|
Success
n/N
|
|
A. fumigatus
|
43/97 (44%)
|
|
A. flavus
|
5/12
|
|
A. nidulans
|
1/3
|
|
A. niger
|
4/5
|
|
A. terreus
|
3/8
|
|
A. versicolor
|
0/1
|
Nineteen
patients had more than one species of Aspergillus isolated.
Success was seen in 4/17 (24%) of these patients.
Candidemia in Non-neutropenic Patients and Other Deep
Tissue Candida Infections
Voriconazole
was compared to the regimen of amphotericin B followed by fluconazole in Study
608, an open label, comparative study in nonneutropenic patients with
candidemia associated with clinical signs of infection. Patients were
randomized in 2:1 ratio to receive either Voriconazole (n=283) or the regimen
of amphotericin B followed by fluconazole (n=139). Patients were treated with
randomized study drug for a median of 15 days. Most of the candidemia in
patients evaluated for efficacy was caused by C. albicans (46%),
followed by C. tropicalis (19%), C. parapsilosis (17%), C. glabrata (15%),
and C. krusei (1%).
An
independent Data Review Committee (DRC), blinded to study treatment, reviewed
the clinical and mycological data from this study, and generated one assessment
of response for each patient. A successful response required all of the
following: resolution or improvement in all clinical signs and symptoms of
infection, blood cultures negative for Candida,
infected deep tissue sites negative for Candida or
resolution of all local signs of infection, and no systemic antifungal therapy
other than study drug. The primary analysis, which counted DRC-assessed
successes at the fixed time point (12 weeks after End of Therapy [EOT]),
demonstrated that Voriconazole was comparable to the regimen of amphotericin B
followed by fluconazole (response rates of 41% and 41%, respectively) in the
treatment of candidemia. Patients who did not have a 12-week assessment for any
reason were considered a treatment failure.
The overall
clinical and mycological success rates by Candida species
in Study 150-608 are presented in Table 14.
Table 14:Overall Success Rates Sustained
From EOT To The Fixed 12-Week Follow-Up Time Point By Baseline Pathogen*,†
|
|
*
A few patients
had more than one pathogen at baseline.
†
Patients who did not have a 12-week assessment for
any reason were considered a treatment failure.
|
|
Baseline Pathogen
|
Clinical and Mycological Success (%)
|
|
|
|
Voriconazole
|
Amphotericin B --> Fluconazole
|
|
C. albicans
|
46/107 (43%)
|
30/63 (48%)
|
|
C. tropicalis
|
17/53 (32%)
|
1/16 (6%)
|
|
C. parapsilosis
|
24/45 (53%)
|
10/19 (53%)
|
|
C. glabrata
|
12/36 (33%)
|
7/21 (33%)
|
|
C. krusei
|
1/4
|
0/1
|
In a
secondary analysis, which counted DRC-assessed successes at any time point
(EOT, or 2, 6, or 12 weeks after EOT), the response rates were 65% for
Voriconazole and 71% for the regimen of amphotericin B followed by fluconazole.
In
Studies 608 and 309/604 (non-comparative study in patients with invasive fungal
infections who were refractory to, or intolerant of, other antifungal agents),
Voriconazole was evaluated in 35 patients with deep tissue Candida infections.
A favorable response was seen in 4 of 7 patients with intra-abdominal
infections, 5 of 6 patients with kidney and bladder wall infections, 3 of 3
patients with deep tissue abscess or wound infection, 1 of 2 patients with
pneumonia/pleural space infections, 2 of 4 patients with skin lesions, 1 of 1
patients with mixed intraabdominal and pulmonary infection, 1 of 2 patients
with suppurative phlebitis, 1 of 3 patients with hepatosplenic infection, 1 of
5 patients with osteomyelitis, 0 of 1 with liver infection, and 0 of 1 with
cervical lymph node infection.
Esophageal Candidiasis
The
efficacy of oral Voriconazole 200 mg twice daily compared to oral fluconazole
200 mg once daily in the primary treatment of esophageal candidiasis was
demonstrated in Study 150-305, a double-blind, double-dummy study in
immunocompromised patients with endoscopically-proven esophageal candidiasis.
Patients were treated for a median of 15 days (range 1 to 49 days). Outcome was
assessed by repeat endoscopy at end of treatment (EOT). A successful response
was defined as a normal endoscopy at EOT or at least a 1 grade improvement over
baseline endoscopic score. For patients in the Intent to Treat (ITT) population
with only a baseline endoscopy, a successful response was defined as
symptomatic cure or improvement at EOT compared to baseline. Voriconazole and
fluconazole (200 mg once daily) showed comparable efficacy rates against
esophageal candidiasis, as presented in Table 15.
Table 15:Success Rates in Patients
Treated for Esophageal Candidiasis
|
|
*
Confidence
Interval for the difference (Voriconazole – Fluconazole) in success rates.
†
PP (Per
Protocol) patients had confirmation of Candida esophagitis by endoscopy,
received at least 12 days of treatment, and had a repeat endoscopy at EOT
(end of treatment).
‡
ITT (Intent to Treat) patients without endoscopy or
clinical assessment at EOT were treated as failures.
|
|
Population
|
Voriconazole
|
Fluconazole
|
Difference % (95% CI)*
|
|
PP†
|
113/115 (98.2%)
|
134/141 (95%)
|
3.2 (-1.1, 7.5)
|
|
ITT‡
|
175/200 (87.5%)
|
171/191 (89.5%)
|
-2 (-8.3, 4.3)
|
Microbiologic
success rates by Candida species are
presented in Table 16.
Table 16:Clinical and mycological outcome
by baseline pathogen in patients with esophageal candidiasis (Study-150-305)
|
|
*
Some patients
had more than one species isolated at baseline
†
Patients with endoscopic and/or mycological
assessment at end of therapy
|
|
Pathogen*
|
Voriconazole
|
|
Fluconazole
|
|
|
|
Favorable endoscopic response†
|
Mycological eradication†
|
Favorable endoscopic response†
|
Mycological eradication†
|
|
|
Success/
Total (%)
|
Eradication/
Total (%)
|
Success/
Total (%)
|
Eradication/
Total (%)
|
|
C. albicans
|
134/140 (96%)
|
90/107 (84%)
|
147/156 (94%)
|
91/115 (79%)
|
|
C. glabrata
|
8/8 (100%)
|
4/7 (57%)
|
4/4 (100%)
|
1/4 (25%)
|
|
C. krusei
|
1/1
|
1/1
|
2/2 (100%)
|
0/0
|
Other Serious Fungal Pathogens
In pooled
analyses of patients, Voriconazole was shown to be effective against the
following additional fungal pathogens:
Scedosporium apiospermum -
Successful response to Voriconazole therapy was seen in 15 of 24 patients
(63%). Three of these patients relapsed within 4 weeks, including 1 patient
with pulmonary, skin and eye infections, 1 patient with cerebral disease, and 1
patient with skin infection. Ten patients had evidence of cerebral disease and
6 of these had a successful outcome (1 relapse). In addition, a successful
response was seen in 1 of 3 patients with mixed organism infections.
Fusarium spp.
- Nine of 21 (43%) patients were successfully treated with Voriconazole. Of
these 9 patients, 3 had eye infections, 1 had an eye and blood infection, 1 had
a skin infection, 1 had a blood infection alone, 2 had sinus infections, and 1
had disseminated infection (pulmonary, skin, hepatosplenic). Three of these
patients (1 with disseminated disease, 1 with an eye infection and 1 with a
blood infection) had Fusarium solani and
were complete successes. Two of these patients relapsed, 1 with a sinus
infection and profound neutropenia and 1 post surgical patient with blood and
eye infections.
REFERENCES
1. Clinical Laboratory Standards Institute (CLSI).
Reference Method for Broth Dilution Antifungal Susceptibility Testing of
Yeasts. Approved Standard M27-A3. Clinical Laboratory Standards Institute, 940
West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898, USA, 2008.
2. Clinical and Laboratory Standards Institute (CLSI).
Reference Method for Broth Dilution Antifungal Susceptibility Testing of
Yeasts; Fourth Informational Supplement. CLSI document M27-S4 (2012). Clinical
and Laboratory Standards Institute, 940 West Valley Road, Suite 2500, Wayne,
Pennsylvania 19087 USA.
3. Clinical Laboratory Standards Institute (CLSI).
Method for Antifungal Disk Diffusion Susceptibility Testing of Yeasts. Approved
Guideline M44-A2. Clinical Laboratory Standards Institute, 940 West Valley
Road, Suite 1400, Wayne, Pennsylvania 19087-1898, USA, 2009
How Supplied/Storage and Handling
How Supplied
Voriconazole
Tablets, 50 mg are white to off-white, round, biconvex, film-coated tablet
debossed with "735" on one side and plain on the other side and are
supplied as follows:
NDC
68382-735-06 in bottles of 30 tablets
NDC
68382-735-16 in bottles of 90 tablets
NDC
68382-735-01 in bottles of 100 tablets
NDC
68382-735-05 in bottles of 500 tablets
NDC
68382-735-10 in bottles of 1000 tablets
NDC
68382-735-77 in unit-dose blister cartons of 100 (10 x 10) unit-dose tablets
Voriconazole
Tablets, 200 mg are white to off-white, oval, biconvex, film-coated tablet
debossed with "736" on one side and plain on the other side and are
supplied as follows:
NDC
68382-736-06 in bottles of 30 tablets
NDC
68382-736-16 in bottles of 90 tablets
NDC
68382-736-01 in bottles of 100 tablets
NDC 68382-736-05
in bottles of 500 tablets
NDC
68382-736-10 in bottles of 1000 tablets
NDC
68382-736-77 in unit-dose blister cartons of 100 (10 x 10) unit-dose tablets
Storage
Store at
20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
Dispense in
a tight container (USP).
Patient Counseling Information
Advise
the Patient to read the FDA-Approved Patient Labeling
Embryo-Fetal Toxicity
· Advise female patients of the potential risks to a
fetus.
· Advise females of reproductive potential to use
effective contraception during treatment with Voriconazole.
Manufactured by:
Cadila
Healthcare Ltd.
Baddi,
India
Distributed by:
Zydus Pharmaceuticals USA Inc.
Pennington,
NJ 08534
Rev.:
11/17
SPL PATIENT PACKAGE INSERT
Voriconazole (vor i KON a zole) Tablets
Read the
Patient Information that comes with Voriconazole Tablets before you start
taking it and each time you get a refill. There may be new information. This
information does not take the place of talking with your healthcare provider
about your condition or treatment.
What are Voriconazole
Tablets?
Voriconazole
Tablets are a prescription medicine used to treat certain serious fungal
infections in your blood and body. These infections are called
"aspergillosis," "esophageal candidiasis," "Scedosporium,"
"Fusarium," and "candidemia".
It is not
known if Voriconazole Tablets are safe and effective in children younger than
12 years old.
Who should not take Voriconazole
Tablets?
Do not take Voriconazole
Tablets if you:
· areallergictoVoriconazoleoranyoftheingredientsinVoriconazole
Tablets .
See the end of this leaflet for a complete list of ingredients in Voriconazole
Tablets.
· aretakinganyofthefollowingmedicines:
· cisapride (Propulsid®)
· pimozide (Orap®)
· quinidine (like Quinaglute®)
· sirolimus (Rapamune®)
· rifampin (Rifadin®)
· carbamazepine (Tegretol®)
· long-acting barbiturates
like phenobarbital (Luminal®)
· efavirenz (Sustiva®)
· ritonavir (Norvir®)
· rifabutin (Mycobutin®)
· ergotamine,
dihydroergotamine (ergot alkaloids)
· St. John's Wort (herbal
supplement)
Ask your healthcare provider or pharmacist if you
are not sure if you are taking any of the medicines listed above.
Do not start taking a new medicine without talking
to your healthcare provider or pharmacist.
What should I tell my healthcare provider before taking Voriconazole
Tablets?
Before you take Voriconazole Tablets, tell your
healthcare provider if you:
· have or ever had heart
disease, or an abnormal heart rate or rhythm. Your healthcare provider may
order a test to check your heart (EKG) before starting Voriconazole Tablets.
· have liver or kidney
problems. Your healthcare provider may do blood tests to make sure you can take
Voriconazole Tablets.
· have trouble digesting
dairy products, lactose (milk sugar), or regular table sugar. Voriconazole
Tablets contain lactose.
· are pregnant or plan to
become pregnant. Voriconazole Tablets can harm your unborn baby. Talk to your
healthcare provider if you are pregnant or plan to become pregnant. Women who
can become pregnant should use effective birth control while taking
Voriconazole Tablets.
· are breast-feeding or plan
to breast-feed. It is not known if Voriconazole Tablets passes into breast
milk. Talk to your healthcare provider about the best way to feed your baby if
you take Voriconazole Tablets.
Tell your healthcare provider about all the medicines you take, including prescription
and non-prescription medicines, vitamins and herbal supplements.
Voriconazole Tablets may affect the way other
medicines work, and other medicines may affect how Voriconazole Tablets works.
Know what medicines you take. Keep a list of them
to show your healthcare provider or pharmacist when you get a new medicine.
How should I take Voriconazole
Tablets?
· Take Voriconazole Tablets
exactly as your healthcare provider tells you to.
· Take Voriconazole Tablets
at least 1 hour before or at least 1 hour after meals.
· If you take too much
Voriconazole Tablets, call your healthcare provider or go to the nearest
hospital emergency room.
What should I avoid while taking Voriconazole
Tablets?
· You should not drive at
night while taking Voriconazole Tablets. Voriconazole Tablets can cause changes
in your vision such as blurring or sensitivity to light.
· Do not drive or operate
machinery, or do other dangerous activities until you know how Voriconazole
Tablets affect you.
· Avoid direct sunlight.
Voriconazole Tablets can make your skin sensitive to the sun and the light from
sunlamps and tanning beds. You could get a severe sunburn. Use sunscreen and
wear a hat and clothes that cover your skin if you have to be in sunlight. Talk
to your healthcare provider if you get sunburn.
What are possible side effects of Voriconazole
Tablets?
Voriconazole Tablets may cause serious side effects
including:
· liverproblems. Symptoms of liver
problems may include:
· itchy skin
· yellowing of your eyes
· feeling very tired
· flu-like symptoms
· nausea or vomiting
· visionchanges. Symptoms of vision
changes may include:
· blurred vision
· changes in the way you see
colors
· sensitivity to light
(photophobia)
· seriousheartproblems. Voriconazole Tablets
may cause changes in your heart rate or rhythm, including your heart stopping
(cardiac arrest).
· allergicreactions. Symptoms of an
allergic reaction may include:
· fever
· sweating
· feels like your heart is
beating fast (tachycardia)
· chest tightness
· trouble breathing
· feel faint
· nausea
· itching
· skin rash
· kidneyproblems . Voriconazole
Tablets may cause new or worse problems with kidney function, including kidney
failure. Your healthcare provider should check your kidney function while you
are taking Voriconazole Tablets. Your healthcare provider will decide if you
can keep taking Voriconazole Tablets.
· seriousskinreactions . Symptoms of
serious skin reactions may include:
· rash or hives
· mouth sores
· blistering or peeling of
your skin
· trouble swallowing or
breathing
Call your
healthcare provider or go to the nearest hospital emergency room right away if
you have any of the symptoms listed above.
The most common side effects of Voriconazole
Tablets include:
· vision changes
· rash
· vomiting
· nausea
· headache
· fast heart beat (tachycardia)
· hallucinations (seeing or hearing things that are not
there)
· abnormal liver function tests
Tell your
healthcare provider if you have any side effect that bothers you or that does
not go away.
These are
not all the possible side effects of Voriconazole Tablets. For more
information, ask your healthcare provider or pharmacist.
Call your
doctor for medical advice about side effects. You may report side effects to
FDA at 1-800-FDA-1088.
How should I store Voriconazole
Tablets?
· Store Voriconazole Tablets at room temperature, 20°
to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
· Keep Voriconazole Tablets in a tightly closed
container.
· Safely throw away medicine that is out of date or no
longer needed.
· KeepVoriconazole Tablets , aswellasallothermedicines , outofthereachofchildren.
General information about the safe and effective use of Voriconazole
Tablets
Medicines
are sometimes prescribed for purposes other than those listed in a Patient
Information leaflet. Do not use Voriconazole Tablets for a condition for which
it was not prescribed. Do not give Voriconazole Tablets to other people, even
if they have the same symptoms that you have. It may harm them.
This
Patient Information leaflet summarizes the most important information about
Voriconazole Tablets. If you would like more information, talk to your
healthcare provider. You can ask your healthcare provider or pharmacist for
information about Voriconazole Tablets that is written for health
professionals.
Please address
medical inquiries to, (MedicalAffairs@zydususa.com) Tel.: 1-877-993-8779.
What are the ingredients of Voriconazole
Tablets?
Active
ingredient: Voriconazole
Inactive
ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate,
povidone and pregelatinized starch. Additionally, each Voriconazole tablets
contain opadry II white 33F28398 which contains hypromellose, lactose
monohydrate, polyethylene glycol, talc and titanium dioxide.
Trademarks
are the property of their respective owners.
This
Patient Information has been approved by the U.S. Food and Drug Administration.
Manufactured by:
Cadila
Healthcare Ltd.
Baddi,
India
Distributed by:
Zydus Pharmaceuticals USA Inc.
Pennington,
NJ 08534
Rev.:
11/17
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
NDC
68382-735-01 in bottles of 100 tablets
Voriconazole
Tablets, 50 mg
100
Tablets
Rx only
Zydus
NDC
68382-736-01 in bottles of 100 tablets
Voriconazole
Tablets, 200 mg
100
Tablets
Rx only
Zydus
|
Voriconazole Voriconazole tablet
|
|
Product
Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:68382-735
|
|
Route of
Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
Voriconazole (Voriconazole)
|
Voriconazole
|
50 mg
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
CROSCARMELLOSE SODIUM
|
|
|
HYPROMELLOSE 2910 (6 MPA.S)
|
|
|
LACTOSE MONOHYDRATE
|
|
|
MAGNESIUM STEARATE
|
|
|
POLYETHYLENE GLYCOL 6000
|
|
|
POVIDONE K30
|
|
|
STARCH, PREGELATINIZED CORN
|
|
|
TALC
|
|
|
TITANIUM DIOXIDE
|
|
|
|
Product
Characteristics
|
|
Color
|
WHITE (white to
off-white)
|
Score
|
no score
|
|
Shape
|
ROUND
|
Size
|
7mm
|
|
Flavor
|
|
Imprint Code
|
735
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:68382-735-06
|
30 TABLET in 1
BOTTLE
|
|
|
2
|
NDC:68382-735-16
|
90 TABLET in 1
BOTTLE
|
|
|
3
|
NDC:68382-735-01
|
100 TABLET in 1
BOTTLE
|
|
|
4
|
NDC:68382-735-05
|
500 TABLET in 1
BOTTLE
|
|
|
5
|
NDC:68382-735-10
|
1000 TABLET in
1 BOTTLE
|
|
|
6
|
NDC:68382-735-77
|
10 BLISTER PACK
in 1 CARTON
|
|
|
6
|
NDC:68382-735-30
|
10 TABLET in 1
BLISTER PACK
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
ANDA
|
ANDA206747
|
05/25/2016
|
|
|
|
Voriconazole Voriconazole tablet
|
|
Product
Information
|
|
Product Type
|
HUMAN
PRESCRIPTION DRUG LABEL
|
Item Code
(Source)
|
NDC:68382-736
|
|
Route of
Administration
|
ORAL
|
DEA Schedule
|
|
|
|
Active
Ingredient/Active Moiety
|
|
Ingredient
Name
|
Basis of
Strength
|
Strength
|
|
Voriconazole (Voriconazole)
|
Voriconazole
|
200 mg
|
|
|
Inactive
Ingredients
|
|
Ingredient
Name
|
Strength
|
|
CROSCARMELLOSE SODIUM
|
|
|
HYPROMELLOSE 2910 (6 MPA.S)
|
|
|
LACTOSE MONOHYDRATE
|
|
|
MAGNESIUM STEARATE
|
|
|
POLYETHYLENE GLYCOL 6000
|
|
|
POVIDONE K30
|
|
|
STARCH, PREGELATINIZED CORN
|
|
|
TALC
|
|
|
TITANIUM DIOXIDE
|
|
|
|
Product
Characteristics
|
|
Color
|
WHITE (white to
off-white)
|
Score
|
no score
|
|
Shape
|
OVAL
|
Size
|
16mm
|
|
Flavor
|
|
Imprint Code
|
736
|
|
Contains
|
|
|
|
|
|
Packaging
|
|
#
|
Item Code
|
Package
Description
|
|
|
1
|
NDC:68382-736-06
|
30 TABLET in 1
BOTTLE
|
|
|
2
|
NDC:68382-736-16
|
90 TABLET in 1
BOTTLE
|
|
|
3
|
NDC:68382-736-01
|
100 TABLET in 1
BOTTLE
|
|
|
4
|
NDC:68382-736-05
|
500 TABLET in 1
BOTTLE
|
|
|
5
|
NDC:68382-736-10
|
1000 TABLET in
1 BOTTLE
|
|
|
6
|
NDC:68382-736-77
|
10 BLISTER PACK
in 1 CARTON
|
|
|
6
|
NDC:68382-736-30
|
10 TABLET in 1
BLISTER PACK
|
|
|
|
|
|
Marketing Information
|
|
Marketing
Category
|
Application
Number or Monograph Citation
|
Marketing
Start Date
|
Marketing
End Date
|
|
ANDA
|
ANDA206747
|
05/25/2016
|
|
|
|
Labeler - Zydus Pharmaceuticals (USA) Inc.
(156861945)
|
|
Registrant - Zydus Pharmaceuticals (USA) Inc.
(156861945)
|
|
Establishment
|
|
Name
|
Address
|
ID/FEI
|
Operations
|
|
Cadila
Healthcare Limited
|
|
677605858
|
ANALYSIS(68382-735,
68382-736), MANUFACTURE(68382-735, 68382-736)
|
Revised: 11/2017
Zydus
Pharmaceuticals (USA) Inc.
