Drug Interactions
Interactions with herbal products have not been established.
Drug/Drug Class
(Mechanism of Interaction by Voriconazole) | Drug Plasma Exposure
(Cmax and AUCt) | Recommendations for Drug Dosage
Adjustment/Comments |
| Contraindications |
Sirolimusa
(CYP3A4 Inhibition) | Significantly increased | Contraindicated |
Rifabutina
(CYP3A4 Inhibition) | Significantly increased | Contraindicated |
| Efavirenz (CYP3A4 Inhibition) | Significantly increased | Coadministration of standard doses of efavirenz with voriconazole is contraindicated.
When voriconazole is coadministered with efavirenz, voriconazole maintenance dose should be increased to 400 mg every 12 hours and that of efavirenz should be decreased to 300 mg once daily. When treatment with voriconazole is stopped, the initial dosage of efavirenz should be restored. |
Other NNRTIsc
(CYP3A4 Inhibition or CYP450 Induction) | In vitro studies demonstrated potential for inhibition of voriconazole metabolism by delavirdine and other NNRTIs (increased plasma exposure) | Frequent monitoring for adverse events and toxicity related to voriconazole |
| A voriconazole-efavirenz drug interaction study demonstrated the potential for the metabolism of voriconazole to be induced by efavirenz and other NNRTIs (decreased plasma exposure) | Careful assessment of voriconazole effectiveness |
High-dose ritonavir (400 mg Q12h HIV Protease Inhibitor)b
(CYP3A4 Inhibition) | No significant effect of voriconazole on ritonavir Cmax or AUCt | Contraindicated because of significant reduction of voriconazole Cmax and AUCt |
| Low-dose ritonavir (100 mg Q12h HIV Protease Inhibitor) (CYP3A4 Inhibition) | Slight decrease in Ritonavir Cmax or AUCt | Coadministration of voriconazole and low-dose ritonavir (100 mg Q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCt) unless an assessment of the benefit/risk justifies the use of voriconazole. |
Terfenadinee, Astemizolee, Cisapridee, 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 torsades de pointes |
Ergot Alkaloids
(CYP450 Inhibition) | Not studied in vivo or in vitro, but drug plasma exposure likely to be increased | Contraindicated |
| Drug Interactions |
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. |
Cyclosporinea
(CYP3A4 Inhibition) | AUCt significantly increased; no significant effect on Cmax | When initiating therapy with VFEND 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 VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary. |
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. |
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. |
Methadonec
(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 |
Omeprazolea
(CYP2C19/3A4 Inhibition) | Significantly increased | When initiating therapy with VFEND 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. |
| Oral contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) | Increased | Monitoring for adverse events related to oral contraceptives is recommended during coadministration. |
Phenytoina
(CYP2C9 Inhibition) | Significantly increased | Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin. |
| Short acting opiates (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 VFEND. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary. |
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. During post-marketing surveillance, cases of severe hypoglycemia have been reported in patients receiving voriconazole and glipizide. Adjustment of oral hypoglycemic drug dosage may be needed. |
Tacrolimusa
(CYP3A4 Inhibition) | Significantly increased | When initiating therapy with VFEND 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 VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary. |
Vinca Alkaloids
(CYP3A4 Inhibition) | Not studied in vivo or in vitro, but drug plasma exposure likely to be increased | Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed. |
Warfarina
(CYP2C9 Inhibition) | Prothrombin time significantly increased | Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed. |
Other HIV Protease Inhibitors
(CYP3A4 Inhibition) | In vivo studies showed no significant effects on indinavir exposure | No dosage adjustment for indinavir when coadministered with VFEND |
| In vitro studies demonstrated potential for voriconazole to inhibit metabolism (increased plasma exposure) | Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors |
a. Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects.
b. Results based on in vivo clinical study following repeat oral dosing with 400 mg Q12h for 1 day, then 200 mg Q12h for 8 days voriconazole to healthy subjects.
c. Results based on in vivo clinical study following repeat oral dosing with 400 mg Q12h for 1 day, then 200 mg Q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30-100 mg QD).
d. Non-Nucleoside Reverse Transcriptase Inhibitors.
e. Not marketed in Canada.
Interactions with food have not been established.
Drug/Drug Class
(Mechanism of Interaction by the Drug) | Voriconazole Plasma Exposure
(Cmax and AUCt after 200 mg Q12h) | Recommendations for Voriconazole
Dosage Adjustment/Comments |
| Contraindications |
| Rifampina and Rifabutina (CYP450 Induction) | Significantly reduced | Contraindicated |
| Efavirenz (CYP450 Induction) | Significantly reduced | Coadministration of standard doses of efavirenz with voriconazole is contraindicated.
When voriconazole is coadministered with efavirenz, voriconazole maintenance dose should be increased to 400 mg every 12 hours and that of efavirenz should be decreased to 300 mg once daily. When treatment with voriconazole is stopped, the initial dosage of efavirenz should be restored. |
Other NNRTIsc
(CYP3A4 Inhibition or CYP450 Induction) | In vitro studies demonstrated potential for inhibition of voriconazole metabolism by delavirdine and other NNRTIs (increased plasma exposure) | Frequent monitoring for adverse events and toxicity related to voriconazole |
| A voriconazole-efavirenz drug interaction study demonstrated the potential for the metabolism of voriconazole to be induced by efavirenz and other NNRTIs (decreased plasma exposure) | Careful assessment of voriconazole effectiveness |
| High-dose ritonavir (400 mg Q12h HIV Protease Inhibitor)b (CYP450 Induction) | Significantly reduced | Contraindicated |
| Low-dose ritonavir (100 mg Q12h HIV Protease Inhibitor) (CYP450 Induction) | Significantly reduced | Coadministration of voriconazole and low-dose ritonavir (100 mg twice daily Q12h) should be avoided unless an assessment of the benefit/risk justifies the use of voriconazole. |
| St John’s Wort (CYP450 Induction and P-gp induction) | Significantly reduced | Contraindicated |
Carbamazepine and Long Acting Barbiturates
(CYP450 Induction) | Not studied in vivo or in vitro, but likely to result in significant reduction | Contraindicated |
| Drug Interactions |
| 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. |
Phenytoina
(CYP450 Induction) | Significantly reduced | There is insufficient data to make specific dosing recommendations. Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin. |
Other HIV Protease Inhibitors
(CYP3A4 Inhibition) | In vivo studies showed no significant effects of indinavir on voriconazole exposure | No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir |
| In vitro studies demonstrated potential for inhibition of voriconazole metabolism (increased plasma exposure) | Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors |
a. Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg Q12h voriconazole to healthy subjects.
b. Results based on in vivo clinical study following repeat oral dosing with 400 mg Q12h for 1 day, then 200 mg Q12h for 8 days voriconazole to healthy subjects.
c. Non-Nucleoside Reverse Transcriptase Inhibitors.
Interactions with laboratory tests have not been established.
Information for the Patient
Vfend
Dosage and Administration
VFEND I.V. for Injection is a single dose unpreserved sterile lyophile. Therefore, from a microbiological point of view, once reconstituted, the product should be used immediately. If not used immediately, in use storage times and conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 2 to 8°C. This medicinal product is for single use only and any unused solution should be discarded.
The reconstituted solution can be diluted with: 0.9% Sodium Chloride USP; Lactated Ringers USP; 5% Dextrose and Lactated Ringers USP; 5% Dextrose and 0.45% Sodium Chloride USP; 5% Dextrose USP; 5% Dextrose and 20 mEq Potassium Chloride USP; 0.45% Sodium Chloride USP; 5% Dextrose and 0.9% Sodium Chloride USP.
The compatibility of VFEND for Injection with diluents other than those described above is unknown (see Incompatibilities).
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
If patient response is inadequate, the oral maintenance dose may be increased from 200 mg every twelve hours to 300 mg every 12 hours. For patients weighing less than 40 kg, the oral dose may be increased from 100 mg every twelve hours to 150 mg every 12 hours. If patients are 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 patients are unable to tolerate 4 mg/kg IV, reduce the intravenous maintenance dose to 3 mg/kg every 12 hours.
Treatment duration depends upon the patient's clinical and mycological response. Patients with candidemia should be treated for at least 14 days following resolution of symptoms or following last positive culture, whichever is longer.
(See Warnings and Precautions.)
VFEND (voriconazole) Tablets should be taken at least one hour before, or two hours following, a meal.
Hepatic impairment is likely to result in increased voriconazole plasma levels in patients with mild to moderate hepatic cirrhosis (Child-Pugh A and B).
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 A and B).
Safety and efficacy of reduced voriconazole dosing in this setting is not established.
Due to the small number of subjects studied, close clinical monitoring is advised.
VFEND has not been studied in patients with severe hepatic cirrhosis (Child-Pugh C). VFEND should be used only if the benefit outweighs the potential risk. Patients should be carefully monitored for drug toxicity (see Warnings and Precautions).
Dosage adjustment does not appear to be required for elderly patients (see Warnings and Precautions).
The powder is reconstituted with 19 mL of “Water For Injection” to obtain an extractable volume of 20 mL of clear concentrate containing 10 mg/mL of voriconazole. It is recommended that a standard 20 mL (non automated) syringe be used to ensure that the exact amount (19.0 mL) of water for injection is dispensed. Discard the vial if a vacuum does not pull the diluent into the vial. Shake the vial until all the powder is dissolved.
| | Loading Dose Regimen (first 24 hours) | Maintenance Dose (after first 24 hours) |
| IV | Oral | IV | Oral |
| | Patients
≥40 kg | Patients
<40 kg | | Patients
≥40 kg | Patients
<40 kg |
| Invasive Aspergillosis | 6 mg/kg BID | 400 mg BID
(two 200 mg tablets or 10 mL of suspension) | 200 mg BID
(one 200 mg tablets or 5 mL of suspension) | 4 mg/kg BID | 200 mg BID
(one 200 mg tablets or 5 mL of suspension) | 100 mg BID
(two 50 mg tablets or 2.5 mL of suspension) |
| Candidemia and invasive candidiasis | 6 mg/kg BID | 400 mg BID
(two 200 mg tablets or 10 mL of suspension) | 400 mg BID
(two 200 mg tablets or 10 mL of suspension) | 3–4 mg/kg BIDa | 200 mg BID
(one 200 mg tablets or 5 mL of suspension) | 100 mg BID
(two 50 mg tablets or 2.5 mL of suspension) |
a. In clinical trials, patients with candidemia received 3 mg/kg every 12 hours as primary therapy, while patients with invasive candidiasis received 4 mg/kg as salvage therapy. Appropriate dose should be based on the severity and nature of the infection.
Legend: BID=twice daily.
The pharmacokinetics of orally administered VFEND do not appear to be affected by renal insufficiency. Therefore, no dosage adjustment is necessary for oral dosing in patients with mild to severe renal impairment.
Due to the small number of subjects studied, close clinical monitoring is advised.
In patients with moderate or severe renal insufficiency (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. Renal function (including serum creatinine levels and creatinine clearance) should be closely monitored in these patients, and, if significant changes occur, consideration should be given to changing to oral voriconazole therapy (see Warnings and Precautions).
Voriconazole is hemodialyzed with clearance of 121 mL/min. The intravenous vehicle, SBECD, is hemodialyzed with clearance of 55 mL/min. The mean amount of voriconazole removed during 4 hour hemodialysis session (8%, range 1 16%) is not enough to warrant dose adjustment.
Patients who miss taking a dose should take their regular dose next time it is due. Patients should not take a double dose to make up for the forgotten dose.
Therapy should be initiated with the specified loading dose regimen.
Dosage is based on weight.
Dose can be adjusted if patient response is inadequate or patient is unable to tolerate treatment.
In patients with mild to moderate hepatic impairment, the maintenance dose should be halved.
In patients with moderate to severe renal insufficiency (CrCl <50 mL/min), oral voriconazole should be used because accumulation of the intravenous vehicle SBECD occurs.
When VFEND is taken concomitantly with other drugs, the dosage of VFEND or the concomitant drugs may need to be adjusted (see Drug Interactions).
Blood products and concentrated electrolytes: Voriconazole must not be infused concomitantly with any blood product or any short-term infusion of concentrated electrolytes, even if the two infusions are running in separate intravenous lines (or cannulas).
Electrolyte disturbances such as hypokalemia, hypomagnesemia and hypocalcemia should be corrected prior to initiation of voriconazole therapy (see Warnings and Precautions, Monitoring and Laboratory Tests).
-
Intravenous solutions containing (non-concentrated) electrolytes: Voriconazole can be infused at the same time as other intravenous solutions containing (nonconcentrated) electrolytes, but must be infused through a separate line.
-
Total Parenteral Nutrition (TPN): Voriconazole can be infused at the same time as total parenteral nutrition, but must be infused in a separate line. If infused through a multiple-lumen catheter, TPN needs to be administered using a different port from the one used for voriconazole.
-
VFEND for Injection must not be diluted with 4.2% Sodium Bicarbonate Infusion. Compatibility with other concentrations is unknown.
As with all parenteral drug products, intravenous admixtures should be inspected visually for clarity, particulate matter, precipitate, discoloration and leakage prior to administration, whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate, discoloration or leakage should not be used. Discard unused portion.
Shake the closed bottle of reconstituted suspension for approximately 10 seconds before each use. The reconstituted oral suspension should only be administered using the oral dispenser supplied with each pack.
Adverse Reactions
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 VFEND above and does not include every event reported in the voriconazole clinical program.
During post-marketing surveillance, cases of severe hypoglycemia have been reported in patients receiving voriconazole and glipizide (see Drug Interactions).
During post-marketing surveillance, there have been rare cases of arrhythmias (including ventricular arrhythmias such as torsades de pointes), cardiac arrests and sudden deaths in patients taking voriconazole. These cases usually involved patients with risk factors such as history of cardiotoxic chemotherapy, cardiomyopathy, hypokalemia and concomitant medications that may have been contributory (see Warnings and Precautions).
There have been post-marketing reports of pancreatitis in pediatric patients (see Warnings and Precautions).
There has been a small number of post-marketing reports of vision loss (including decreased visual acuity or visual fields) where a relationship to voriconazole could not be excluded. These events mostly occurred in medically complex patients, where underlying disease processes and the primary infections themselves confound interpretation (see Warnings and Precautions).
There have been post-marketing reports of prolonged visual adverse events (see Warnings and Precautions).
anorexia, cheilitis, cholecystitis, cholelithiasis, constipation, diarrhea, dry mouth, duodenal ulcer perforation, duodenitis, dyspepsia, dysphagia, esophageal ulcer, esophagitis, flatulence, gastroenteritis, gastrointestinal hemorrhage, GGT/LDH elevated, gingivitis, glossitis, gum hemorrhage, gum hyperplasia, hematemesis, hepatic coma, hepatic failure, hepatitis, intestinal perforation, intestinal ulcer, jaundice, enlarged liver, melena, mouth ulceration, pancreatitis, parotid gland enlargement, periodontitis, proctitis, pseudomembranous colitis, rectal disorder, rectal hemorrhage, stomach ulcer, stomatitis, tongue edema.
abnormality of accommodation, blepharitis, color blindness, conjunctivitis, corneal opacity, deafness, ear pain, eye pain, eye hemorrhage, hypoacusis, dry eyes, keratitis, keratoconjunctivitis, mydriasis, night blindness, optic atrophy, optic neuritis, otitis externa, papilledema, retinal hemorrhage, retinitis, scleritis, taste loss, taste perversion, tinnitus, uveitis, visual field defect.
alopecia, angioedema, contact dermatitis, discoid lupus erythematosis, eczema, erythema multiforme, exfoliative dermatitis, fixed drug eruption, furunculosis, herpes simplex, maculopapular rash, melanosis, photosensitivity skin reaction, psoriasis, pruritus, skin discoloration, skin disorder, skin dry, sweating, toxic epidermal necrolysis, urticaria.
adrenal cortex insufficiency, diabetes insipidus, hyperthyroidism, hypothyroidism.
abdomen enlarged, abdominal pain, allergic reaction, anaphylactoid reaction (see Contraindications), 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.
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
| | All Therapeutic Studies | Studies 307/602 and 608
(iv/oral therapy) | Study 305
(oral therapy) |
Voriconazole
N=1655 | Voriconazole
N=468 | Ampho Ba
N=185 | Ampho B→
Fluconazole
N= 131 | Voriconazole
N=200 | Fluconazole
N=191 |
| N (%) | N (%) | N (%) | N (%) | N (%) | N (%) |
| Special Senses |
| 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 (1.0) |
| Chromatopsia | 20 (1.2) | 2 (0.4) | 0 | 0 | 2 (1.0) | 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 (3.0) | 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 (1.0) | 3 (1.6) |
| Vomiting | 72 (4.4) | 15 (3.2) | 18 (9.7) | 1 (0.8) | 2 (1.0) | 1 (0.5) |
| Liver function tests abnormal | 45 (2.7) | 15 (3.2) | 4 (2.2) | 1 (0.8) | 6 (3.0) | 2 (1.0) |
| Cholestatic jaundice | 17 (1.0) | 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 (5.0) | 3 (1.6) |
| Hepatic enzymes increased | 30 (1.8) | 11 (2.4) | −5 (2.7) | 1 (0.8) | 3 (1.5) | 0 |
| AST increased | 31 (1.9) | 9 (1.9) | 0 | 1 (0.8) | 8 (4.0) | 2 (1.0) |
| ALT increased | 29 (1.8) | 9 (1.9) | 1 (0.5) | 2 (1.5) | 6 (3.0) | 2 (1.0) |
| 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 |
a. Amphotericin B followed by other licensed antifungal therapy.
arthralgia, arthritis, bone necrosis, bone pain, leg cramps, myalgia, myasthenia, myopathy, osteomalacia, osteoporosis.
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.
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.
| | Criteriaa | VORICONAZOLE
n/N (%) | AMPHOTERICIN B followed by FLUCONAZOLE
n/N (%) |
| T. Bilirubin | >1.5×ULN | 50/261 (19.2) | 31/115 (27.0) |
| AST | >3.0×ULN | 40/261 (15.3) | 16/116 (13.8) |
| ALT | >3.0×ULN | 22/261 (8.4) | 15/116 (12.9) |
| Alk phos | >3.0×ULN | 59/261 (22.6) | 26/115 (22.6) |
| Creatinine | >1.3×ULN | 39/260 (15.0) | 32/118 (27.1) |
| Potassium | <0.9×LLN | 43/258 (16.7) | 35/118 (29.7) |
a. Without regard to baseline value.
Legend: 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.
The most frequently reported adverse events (all causalities) in the therapeutic trials were visual disturbances, fever, rash, vomiting, nausea, diarrhea, headache, sepsis, peripheral edema, abdominal pain, and respiratory disorder. The treatment-related adverse events which most often led to discontinuation of voriconazole therapy were elevated liver function tests, rash, and visual disturbances (see Warnings and Precautions).
cough increased, dyspnea, epistaxis, hemoptysis, hypoxia, lung edema, pharyngitis, pleural effusion, pneumonia, respiratory disorder, respiratory distress syndrome, respiratory tract infection, rhinitis, sinusitis, voice alteration.
In clinical trials, Voriconazole treatment-related visual disturbances were common. In these studies, approximately 21% of patients experienced altered/enhanced visual perception, blurred vision, color vision change and/or photophobia. These visual disturbances were generally mild and rarely resulted in discontinuation. Visual disturbances may be associated with higher plasma concentrations and/or doses.
The mechanism of action of the visual disturbance is unknown, although the site of action is most likely to be within the retina. The majority of visual symptoms appeared to spontaneously resolve within 60 minutes. The serious conditions of the patients treated in Phase 3 studies did not generally allow rigorous testing of visual function. In a study in healthy volunteers investigating the effect of 28 days 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 colour perception. The effects were noted early in administration and continued through the course of study drug dosing. Fourteen days after the end of dosing, ERG, visual fields and colour perception returned to normal (see Warnings and Precautions).
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.
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.
A fatal case of ventricular fibrillation occurred where a relationship to voriconazole could not be ruled out. There have been rare cases of torsades de pointes in which a causal relationship to voriconazole could not be excluded.
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 torsades de pointes).
Dermatological reactions were common in the patients treated with voriconazole. The mechanism underlying these dermatologic adverse events remains unknown. In clinical trials, rashes considered related to therapy were reported by 7% (110/1655) of voriconazole-treated patients. The majority of rashes were of mild to moderate severity. Cases of photosensitivity reactions appear to be more likely to occur with long term treatment. Patients have developed serious cutaneous reactions, including Stevens-Johnson syndrome (uncommon), toxic epidermal necrolysis (rare) and erythema multiforme (rare) during treatment with voriconazole. Stevens-Johnson Syndrome and toxic epidermal necrolysis should be considered as a differential diagnosis if patients develop prodromal flu-like symptoms (fever, malaise, rhinitis, chest pain. vomiting, sore throat, cough, diarrhea, headache, myalgia and arthralgia).
Patients should be closely monitored at the first appearance of a skin rash and voriconazole should be discontinued if lesions progress. It is recommended that patients avoid strong, direct sunlight during voriconazole therapy (see Warnings and Precautions).
Indications and Clinical Use
Evidence from clinical studies and experience suggests that safety and effectiveness of VFEND are similar in geriatric and adult subjects (see Warnings and Precautions, Dosage and Administration).
Safety and effectiveness of VFEND in pediatric subjects below the age of twelve years have not been established (see Warnings and Precautions).
Overdosage
For management of a suspected drug overdose, CPhA recommends that you contact your regional Poison Control Centre. See the eCPS Directories section for a list of Poison Control Centres.
There is no known antidote to voriconazole; it is recommended that treatment of overdose is symptomatic and supportive. Administration of activated charcoal may be used to aid in removal of unabsorbed drug.
EKG monitoring is recommended due to the possible prolongation of the QT interval and ensuing risk of arrhythmia.
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.
In clinical trials, there were three cases of accidental overdose with VFEND (voriconazole). 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.
Dosage Forms, Composition and Packaging
Each white, film-coated, capsule-shaped tablet, debossed with “Pfizer” on one side and “VOR200” on the reverse, contains: voriconazole 200 mg. Nonmedicinal ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, povidone, pregelatinized starch; coating: hypromellose, lactose monohydrate, titanium dioxide and triacetin. HDPE bottles of 30.
Each white, film-coated, round tablet, debossed with “Pfizer” on one side and “VOR50” on the reverse, contains: voriconazole 50 mg. Nonmedicinal ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, povidone, pregelatinized starch; coating: hypromellose, lactose monohydrate, titanium dioxide and triacetin. HDPE bottles of 30.
White to off-white powder providing a white to off-white orange-flavored suspension when reconstituted. Bottles containing 3 g voriconazole in 45 g powder for oral suspension (40 mg/mL when reconstituted). Nonmedicinal ingredients: anhydrous citric acid, colloidal silicon dioxide, natural orange flavor, sodium benzoate, sodium citrate dihydrate, sucrose, titanium dioxide and xanthan gum.
Each single use vial of white, sterile lyophilized powder contains: voriconazole 200 mg and SBECD 3200 mg. Preservative-free. Type I clear glass single dose vials of 30 mL. VFEND for Injection is intended for administration by intravenous infusion. Vials containing 200 mg lyophilized voriconazole are intended for reconstitution with Water for Injection to produce a solution containing 10 mg/mL voriconazole and 160 mg/mL of sulphobutylether-β-cyclodextrin sodium (SBECD) as a molecular inclusion complex. The resultant solution is further diluted prior to administration as an intravenous infusion (see Dosage and Administration).
Warnings and Precautions
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.
Voriconazole demonstrated clastogenic activity in human lymphocyte cultures in vitro. Voriconazole did not display mutagenic activity in bacterial or mammalian cells in vitro, or clastogenic activity in vivo.
Safety and effectiveness in pediatric subjects below the age of twelve years have not been established. A limited number of pediatric subjects have received voriconazole at doses comparable to those used in adults on a per kilogram body weight basis. There were no apparent differences in safety or efficacy of voriconazole compared to adults. A total of 22 patients aged 12-18 years of 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 twice daily.
During infusion of the intravenous formulation of voriconazole in healthy subjects, anaphylactoid type reactions, including flushing, fever, sweating, tachycardia, chest tightness, dyspnea, faintness, nausea, pruritus and rash, have occurred uncommonly. Symptoms appeared immediately upon initiating the infusion. Consideration should be given to stopping the infusion should these reactions occur. Other symptoms, including hypotension, were considered to be infusion related in the clinical trial setting.
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. Renal function (including serum creatinine levels and creatinine clearance) should be closely monitored in these patients, and if significant changes occur, consideration should be given to changing to oral voriconazole therapy (see Dosage and Administration).
Voriconazole can cause fetal harm when administered to a pregnant woman. If this drug is used in pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprized of the potential hazard to the fetus.
In reproduction studies in rats, voriconazole was teratogenic (cleft palate, hydronephrosis/hydroureter) from 10 mg/kg (0.3 times the human exposure based on body surface area comparisons) and above. Plasma estradiol in pregnant rats was reduced at all dose levels. Voriconazole treatment in rats produced increased gestational length and dystocia which was associated with increased perinatal pup mortality at the 10 mg/kg dose. In rabbits, voriconazole increased embryolethality, and reduced fetal weight.
Voriconazole may cause visual symptoms including photophobia altered/enhanced visual perception, blurred vision and/or color vision change. The majority of visual symptoms appeared to spontaneously resolve within 60 minutes. The effect of VFEND (voriconazole) on visual function is not known if treatment continues beyond 28 days. If treatment continues beyond 28 days, visual function including visual acuity, visual field and color perception should be monitored.
There has been a small number of post-marketing reports of vision loss (including decreased visual acuity or visual fields) where a relationship to voriconazole could not be excluded. These events mostly occurred in medically complex patients, where underlying disease processes and the primary infections themselves confound interpretation (see Adverse Reactions).
There have been post-marketing reports of prolonged visual adverse events, including optic neuritis and papilledema. These events occurred primarily in severely ill patients who had underlying conditions and/or concomitant medications which may have caused or contributed to these events (see Adverse Reactions, Post-Market Adverse Drug Reactions).
Women of child-bearing potential should always use effective contraception during treatment with voriconazole.
Adults and children with risk factors for acute pancreatitis (e.g. recent chemotherapy, hematopoietic stem cell transplantation [HSCT]), should be monitored for development of pancreatitis during voriconazole treatment.
Voriconazole may cause visual symptoms including blurring and/or photophobia. The majority of visual symptoms appeared to spontaneously resolve within 60 minutes. Patients on voriconazole must avoid potentially hazardous tasks, such as driving or operating machinery if they perceive any change in vision. Patients should not drive at night while taking voriconazole.
VFEND tablets contain lactose and should not be given to patients with rare hereditary problems of galactose intolerance.
VFEND for Oral Suspension contains sucrose and is not recommended for patients with rare hereditary problems of fructose intolerance, sucrase-isomaltase deficiency or glucose-galactose malabsorption.
Voriconazole does not have activity against Zygomycete spp in vitro. Cases of breakthrough zygomycosis, most fatal, have been reported in patients who had received voriconazole.
The excretion of voriconazole in breast milk has not been investigated. Voriconazole should not be used by nursing mothers unless the potential benefit to the patient clearly outweighs the potential risks to the nursing infant.
Patient management should include periodic laboratory evaluation of renal (particularly serum creatinine) and hepatic function (particularly liver function tests and bilirubin).
Electrolyte disturbances such as hypokalemia, hypomagnesemia and hypocalcemia should be corrected prior to initiation of voriconazole therapy (see Dosage and Administration).
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 A and B) receiving voriconazole (see Hepatic, Adverse Reactions, Dosage and Administration).
Safety and efficacy of reduced voriconazole dosing in this setting is not established.
Due to the small number of subjects studied, close clinical monitoring is advised.
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 insufficiency if the benefit outweighs the potential risk. Patients with hepatic insufficiency must be carefully monitored for drug toxicity.
There have been cases of exfoliative cutaneous reactions, such as Stevens-Johnson Syndrome (uncommon), toxic epidermal necrolysis (rare) and erythema multiforme (rare) during treatment with voriconazole (see Adverse Reactions). Stevens-Johnson Syndrome and toxic epidermal necrolysis should be considered as a differential diagnosis if patients develop prodromal flu-like symptoms (fever, malaise, rhinitis, chest pain. vomiting, sore throat, cough, diarrhea, headache, myalgia and arthralgia). Patients should be closely monitored at the first appearance of a skin rash and voriconazole should be discontinued if lesions progress.
Photosensitivity reactions have been observed. It is recommended that patients avoid strong sunlight.
There was a small number of post-marketing reports of squamous cell carcinoma, all of which were preceded by episodes of photosensitivity and/or phototoxicity.
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 clinical pharmacology study in healthy volunteers, some differences were seen in the pharmacokinetic parameters of elderly males compared to young males, and a relationship between plasma concentrations and age was observed in the patients in therapeutic studies. However, the overall safety profile of the elderly patients appeared similar to that of the young. Therefore dosage adjustment does not appear to be required (see Dosage and Administration).
VFEND (voriconazole) has been associated with prolongation of the QT interval of the electrocardiogram in some patients. Prolongation of QT interval may increase the risk of arrhythmia. During clinical development and post-marketing surveillance, there have been rare cases of arrhythmias (including ventricular arrhythmias such as torsades de pointes), cardiac arrests and sudden deaths in patients taking voriconazole. These cases usually involved patients with risk factors such as history of cardiotoxic chemotherapy, cardiomyopathy, hypokalemia and concomitant medications that may have been contributory.
Due to limited clinical experience, voriconazole should be administered with caution to patients with potentially proarrhythmic conditions such as hypokalemia, clinically significant bradycardia, acute myocardial ischemia, congestive heart failure or congenital prolongation of QT.
Caution should be exercised if voriconazole is used in patients taking other drugs that may prolong the QT interval, such as antipsychotics, tricyclic antidepressants, erythromycin, Class IA (e.g. procainamide, quinidine) Class III (e.g. amiodarone, sotalol) antiarrhythmic agents.
There is a report of a life-threatening syncopal episode in a patient receiving concomitant voriconazole and methadone (see Drug Interactions, Effect of Voriconazole on Pharmacokinetics of Other Drugs).
Drugs metabolized by the hepatic cytochrome P450 isoenzymes CYP2C19, CYP2C9 and CYP3A4 may also affect, or be affected by, voriconazole levels, with possible resulting QT effects. Such drugs include tacrolimus, HIV protease inhibitors, and macrolide antibiotics.
See Drug Interactions.
In clinical trials, there have been uncommon cases of serious hepatic reactions during treatment with VFEND (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.
Patients who develop abnormal liver function tests during voriconazole therapy should be monitored for the development of more severe hepatic injury. Discontinuation of voriconazole must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to voriconazole (see Patients with Hepatic Impairment, Adverse Reactions, Dosage and Administration).
Storage and Stability
Store at 15 to 30°C for up to 14 days. Keep the container tightly closed. Discard remaining suspension 14 days after constitution.
Store at controlled room temperature, 15-30°C.
VFEND for Injection is a single dose unpreserved sterile lyophile. From a microbiological point of view, following reconstitution of the lyophile with Water for Injection, the reconstituted solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2-8°C, unless reconstitution has taken place in controlled and validated aseptic conditions. Single dose vials. Discard unused portion.
VFEND Tablets should be stored at controlled room temperature, 15-30°C.
Action and Clinical Pharmacology
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%.
Voriconazole is rapidly and almost completely absorbed following oral administration, with maximum plasma concentrations (Cmax) achieved 1-2 hours after dosing.
VFEND (voriconazole) is a triazole antifungal agent, which exhibits broad-spectrum in vitro activity and fungicidal activity against Aspergillus spp. as well as a range of other filamentous fungi. The primary mode of action of voriconazole is the inhibition of fungal cytochrome P450-mediated 14α-sterol demethylation, an essential step in ergosterol biosynthesis. The subsequent loss of normal sterols correlates with the accumulation of 14α-methyl sterols in fungi and may be responsible for its fungistatic/fungicidal activity.
The voriconazole clinical program included a total of 38 patients with Scedosporium spp. and 21 patients with Fusarium spp. This limited clinical data suggest that voriconazole may be effective against infections caused by these rare pathogens in patients intolerant of or refractory to other therapies.
The major metabolite of voriconazole is the N-oxide, which accounts for 72% of the circulating radiolabelled metabolites in plasma.
Voriconazole is eliminated primarily by hepatic metabolism with less than 2% of the dose excreted unchanged in the urine. The terminal half-life (T1/2) depends on the dose and is approximately 6 hours at 3 mg/kg (intravenously) or 200 mg (oral). Because of non-linear pharmacokinetics, the terminal half-life is not useful in predicting the accumulation or elimination of voriconazole.
Contraindications
VFEND (voriconazole) is contraindicated in patients with known hypersensitivity to voriconazole or its excipients. For a complete listing see Dosage Forms, Composition and Packaging. There is no information regarding cross-sensitivity between voriconazole and other azole antifungal agents. Caution should be used when prescribing VFEND to patients with hypersensitivity to other azoles.
VFEND is a substrate and inhibitor of cytochrome P450 isozymes CYP2C19, CYP2C9 and CYP3A4. Thus, coadministration of voriconazole is contraindicated with drugs that are highly dependent on these isozymes for clearance and for which elevated plasma concentrations are associated with serious and/or life threatening events. In addition, coadministration of voriconazole is contraindicated with drugs that significantly decrease voriconazole plasma concentrations due to induction of these isozymes (see Drug Interactions).
