Vfend Drug Information
Generic name: VORICONAZOLE
Azole Antifungal [EPC]
Uses of Vfend
Invasive Aspergillosis VFEND is indicated in adults and pediatric patients (2 years of age and older) for the treatment of invasive aspergillosis (IA). 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.
Candidemia in Non-neutropenic Patients and Other Deep Tissue Candida Infections VFEND is indicated in adults and pediatric patients (2 years of age and older) for the treatment of candidemia in non-neutropenic patients and the following Candida infections: disseminated infections in skin and infections in abdomen, kidney, bladder wall, and wounds.
Esophageal Candidiasis VFEND is indicated in adults and pediatric patients (2 years of age and older) for the treatment of esophageal candidiasis (EC).
Scedosporiosis and Fusariosis VFEND is indicated for the treatment of serious fungal infections caused by Scedosporium apiospermum (asexual form of Pseudallescheria boydii ) and Fusarium spp. including Fusarium solani, in adults and pediatric patients (2 years of age and older) intolerant of, or refractory to, other therapy.
Usage 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.
Dosage & Administration of Vfend
Important Administration Instructions for Use in All Patients VFEND I.V. for Injection requires reconstitution to 10 mg/mL and subsequent dilution to 5 mg/mL or less prior to administration as an infusion, at a maximum rate of 3 mg/kg per hour over 1 to 3 hours. Administer diluted VFEND I.V. by intravenous infusion over 1 to 3 hours only. Do not administer as an IV bolus injection.
Use of VFEND I.V. with Other Parenteral Drug Products Blood products and concentrated electrolytes VFEND I.V. must not be infused concomitantly with any blood product or 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 and during VFEND therapy. Intravenous solutions containing (non-concentrated) electrolytes VFEND I.V. can be infused at the same time as other intravenous solutions containing (non-concentrated) electrolytes, but must be infused through a separate line.
Total parenteral nutrition (TPN) VFEND I.V. 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 VFEND I.V.
Recommended Dosing Regimen 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 VFEND 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 VFEND may be utilized. 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 (Adults) Infection Loading Dose Maintenance Dose Increase dose when VFEND is coadministered with phenytoin or efavirenz; Decrease dose in patients with hepatic impairment, In healthy volunteer studies, the 200 mg oral every 12 hours dose provided an exposure (AUC τ ) similar to a 3 mg/kg intravenous infusion every 12 hours dose; the 300 mg oral every 12 hours dose provided an exposure (AUC τ ) similar to a 4 mg/kg intravenous infusion every 12 hours dose.
The median duration of oral VFEND therapy was 76 days (range 2 to 232 days). For pediatric patients 12 to 14 years of age with a body weight greater than or equal to 50 kg and those 15 years of age and above regardless of body weight, administer the adult dosing regimen of VFEND. Consider an oral regimen only after there is a significant clinical improvement.
Note that an 8 mg/kg intravenous dose will provide voriconazole exposure approximately 2-fold higher than a 9 mg/kg oral dose. Oral bioavailability may be limited in pediatric patients 2 to 12 years with malabsorption and very low body weight for age. In that case, intravenous VFEND administration is recommended.
Method for Adjusting the Dosing Regimen in Pediatric Patients Pediatric Patients 2 to less than 12 years of age and 12 to 14 years of age with body weight less than 50 kg If patient response is inadequate and the patient is able to tolerate the initial intravenous maintenance dose, the maintenance dose may be increased by 1 mg/kg steps. If patients are unable to tolerate the initial intravenous maintenance dose, reduce the dose by 1 mg/kg steps. Pediatric patients 12 to 14 years of age weighing greater than or equal to 50 kg and 15 years of age and older regardless of body weight: Use the optimal method for titrating dosage recommended for adults.
Dosage Modifications in Patients With Hepatic Impairment Adults The maintenance dose of VFEND should be reduced in adult patients with mild to moderate hepatic impairment, Child-Pugh Class A and B. 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.
Adult patients with baseline liver function tests (ALT, AST) of up to 5 times the upper limit of normal (ULN) were included in the clinical program. Dose adjustments are not necessary for adult patients with this degree of abnormal liver function, but continued monitoring of liver function tests for further elevations is recommended. It is recommended that the recommended VFEND loading dose regimens be used, but that the maintenance dose be halved in adult patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B).
VFEND has not been studied in adult patients with severe hepatic cirrhosis (Child-Pugh Class C) or in patients with chronic hepatitis B or chronic hepatitis C disease. VFEND has been associated with elevations in liver function tests and with clinical signs of liver damage, such as jaundice. VFEND 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. Pediatric Patients Dosage adjustment of VFEND in pediatric patients with hepatic impairment has not been established.
Dosage Modifications in Patients With Renal Impairment Adult Patients The pharmacokinetics of orally administered VFEND are not significantly affected by renal impairment. Therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment. In patients with moderate or severe renal impairment (creatinine clearance <50 mL/min) who are receiving an intravenous infusion of VFEND, 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 VFEND. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral VFEND therapy. Voriconazole and the intravenous vehicle, SBECD, are dialyzable.
A 4-hour hemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment.
Preparation and Intravenous Administration of VFEND for Injection Reconstitution 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. Dilution VFEND must be infused over 1 to 3 hours, at a concentration of 5 mg/mL or less. Therefore, the required volume of the 10 mg/mL VFEND concentrate should be further diluted as follows (appropriate diluents listed below): 1.
Calculate the volume of 10 mg/mL VFEND concentrate required based on the patient's weight (see Table 3). 2. In order to allow the required volume of VFEND concentrate to be added, withdraw and discard at least an equal volume of diluent from the infusion bag or bottle to be used. The volume of diluent remaining in the bag or bottle should be such that when the 10 mg/mL VFEND concentrate is added, the final concentration is not less than 0.5 mg/mL nor greater than 5 mg/mL. 3.
Using a suitable size syringe and aseptic technique, withdraw the required volume of VFEND concentrate from the appropriate number of vials and add to the infusion bag or bottle. Discard Partially Used Vials. The final VFEND solution must be infused over 1 to 3 hours at a maximum rate of 3 mg/kg per hour.
Table 3: Required Volumes of mL - - 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°C to 8°C (36°F to 46°F).
This medicinal product is for single use only and any unused solution should be discarded. Only clear solutions without particles should be used. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Incompatibilities VFEND I.V. must not be diluted with 4.2% Sodium Bicarbonate Infusion. The mildly alkaline nature of this diluent caused slight degradation of VFEND after 24 hours storage at room temperature. Although refrigerated storage is recommended following reconstitution, use of this diluent is not recommended as a precautionary measure.
Compatibility with other concentrations is unknown.
| Infection | Loading Dose | Maintenance Dose | ||
|---|---|---|---|---|
| Intravenous infusion | Intravenous infusion | Oral tablets | Oral suspension | |
| Invasive Aspergillosis | 6 mg/kg every 12 hours for the first 24 hours | 4 mg/kg every 12 hours | 200 mg every 12 hours | 5 mL every 12 hours |
| Candidemia in nonneutropenics and other deep tissue Candida infections | 3–4 mg/kg every 12 hours | 200 mg every 12 hours | 5 mL every 12 hours | |
| Scedosporiosis and Fusariosis | 4 mg/kg every 12 hours | 200 mg every 12 hours | 5 mL every 12 hours | |
| Esophageal Candidiasis | Not Evaluated | Not Evaluated | 200 mg every 12 hours | 5 mL every 12 hours |
| Infection | Loading Dose | Maintenance Dose | ||
|---|---|---|---|---|
| Intravenous infusion | Intravenous infusion | Oral tablets | Oral suspension | |
| Invasive Aspergillosis | 9 mg/kg every 12 hours for the first 24 hours | 8 mg/kg every 12 hours after the first 24 hours | 9 mg/kg every 12 hours (maximum dose of 350 mg every 12 hours) | 0.225 mL/kg every 12 hours [maximum dose of 8.75 mL (350 mg) every 12 hours] |
| Candidemia in nonneutropenics and other deep tissue Candida infections | ||||
| Scedosporiosis and Fusariosis | ||||
| Esophageal Candidiasis | Not Evaluated | 4 mg/kg every 12 hours | 9 mg/kg every 12 hours (maximum dose of 350 mg every 12 hours) | 0.225 mL/kg every 12 hours [maximum dose of 8.75 mL (350 mg) every 12 hours] |
| Infection | Loading Dose | Maintenance Dose Increase dose when VFEND is coadministered with phenytoin or efavirenz (7); Decrease dose in patients with hepatic impairment (2.5), In healthy volunteer studies, the 200 mg oral every 12 hours dose provided an exposure (AUC τ ) similar to a 3 mg/kg intravenous infusion every 12 hours dose; the 300 mg oral every 12 hours dose provided an exposure (AUC τ ) similar to a 4 mg/kg intravenous infusion every 12 hours dose (12). | ||
|---|---|---|---|---|
| Intravenous infusion | Intravenous infusion | Oral tablets Adult patients who weigh less than 40 kg should receive half of the oral maintenance dose. | Oral suspension | |
| Invasive Aspergillosis In a clinical study of IA, the median duration of intravenous VFEND therapy was 10 days (range 2 to 85 days). The median duration of oral VFEND therapy was 76 days (range 2 to 232 days) (14.1). | 6 mg/kg every 12 hours for the first 24 hours | 4 mg/kg every 12 hours | 200 mg every 12 hours | 5 mL every 12 hours |
| Candidemia in nonneutropenic patients and other deep tissue Candida infections | 6 mg/kg every 12 hours for the first 24 hours | 3–4 mg/kg every 12 hours In clinical trials, patients with candidemia received 3 mg/kg intravenous infusion every 12 hours as primary therapy, while patients with other deep tissue Candida infections received 4 mg/kg every 12 hours as salvage therapy. Appropriate dose should be based on the severity and nature of the infection. | 200 mg every 12 hours | 5 mL every 12 hours |
| Esophageal Candidiasis | Not Evaluated Not evaluated in patients with EC. | Not Evaluated | 200 mg every 12 hours | 5 mL every 12 hours |
| Scedosporiosis and Fusariosis | 6 mg/kg every 12 hours for the first 24 hours | 4 mg/kg every 12 hours | 200 mg every 12 hours | 5 mL every 12 hours |
| Loading Dose | Maintenance Dose | |||
|---|---|---|---|---|
| Intravenous infusion | Intravenous infusion | Oral tablets | Oral suspension | |
| Invasive Aspergillosis In the Phase 3 clinical trials, patients with IA received intravenous (IV) treatment for at least 6 weeks and up to a maximum of 12 weeks. Patients received IV treatment for at least the first 7 days of therapy and then could be switched to oral VFEND therapy. | 9 mg/kg every 12 hours for the first 24 hours | 8 mg/kg every 12 hours after the first 24 hours | 9 mg/kg every 12 hours (maximum dose of 350 mg every 12 hours) | 0.225 mL/kg every 12 hours [maximum dose of 8.75 mL (350 mg) every 12 hours] |
| Candidemia in nonneutropenics and other deep tissue Candida infections Study treatment for primary or salvage invasive candidiasis and candidemia (ICC) or EC consisted of intravenous VFEND, with an option to switch to oral therapy after at least 5 days of IV therapy, based on subjects meeting switch criteria. For subjects with primary or salvage ICC, VFEND was administered for at least 14 days after the last positive culture. A maximum of 42 days of treatment was permitted. Patients with primary or salvage EC were treated for at least 7 days after the resolution of clinical signs and symptoms. A maximum of 42 days of treatment was permitted. | ||||
| Scedosporiosis and Fusariosis | ||||
| Esophageal Candidiasis | Not Evaluated | 4 mg/kg every 12 hours | 9 mg/kg every 12 hours (maximum dose of 350 mg every 12 hours) | 0.225 mL/kg every 12 hours [maximum dose of 8.75 mL (350 mg) every 12 hours] |
| Body Weight (kg) | Volume of VFEND Concentrate (10 mg/mL) required for: | ||||
|---|---|---|---|---|---|
| 3 mg/kg dose (number of vials) | 4 mg/kg dose (number of vials) | 6 mg/kg dose (number of vials) | 8 mg/kg dose (number of vials) | 9 mg/kg dose (number of vials) | |
| 10 | - | 4 mL (1) | - | 8 mL (1) | 9 mL (1) |
| 15 | - | 6 mL (1) | - | 12 mL (1) | 13.5 mL (1) |
| 20 | - | 8 mL (1) | - | 16 mL (1) | 18 mL (1) |
| 25 | - | 10 mL (1) | - | 20 mL (1) | 22.5 mL (2) |
| 30 | 9 mL (1) | 12 mL (1) | 18 mL (1) | 24 mL (2) | 27 mL (2) |
| 35 | 10.5 mL (1) | 14 mL (1) | 21 mL (2) | 28 mL (2) | 31.5 mL (2) |
| 40 | 12 mL (1) | 16 mL (1) | 24 mL (2) | 32 mL (2) | 36 mL (2) |
| 45 | 13.5 mL (1) | 18 mL (1) | 27 mL (2) | 36 mL (2) | 40.5 mL (3) |
| 50 | 15 mL (1) | 20 mL (1) | 30 mL (2) | 40 mL (2) | 45 mL (3) |
| 55 | 16.5 mL (1) | 22 mL (2) | 33 mL (2) | 44 mL (3) | 49.5 mL (3) |
| 60 | 18 mL (1) | 24 mL (2) | 36 mL (2) | 48 mL (3) | 54 mL (3) |
| 65 | 19.5 mL (1) | 26 mL (2) | 39 mL (2) | 52 mL (3) | 58.5 mL (3) |
| 70 | 21 mL (2) | 28 mL (2) | 42 mL (3) | - | - |
| 75 | 22.5 mL (2) | 30 mL (2) | 45 mL (3) | - | - |
| 80 | 24 mL (2) | 32 mL (2) | 48 mL (3) | - | - |
| 85 | 25.5 mL (2) | 34 mL (2) | 51 mL (3) | - | - |
| 90 | 27 mL (2) | 36 mL (2) | 54 mL (3) | - | - |
| 95 | 28.5 mL (2) | 38 mL (2) | 57 mL (3) | - | - |
| 100 | 30 mL (2) | 40 mL (2) | 60 mL (3) | - | - |
Side Effects of Vfend
Clinical Trials Experience
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. The adverse reactions which most often led to discontinuation of voriconazole therapy were elevated liver function tests, rash, and visual disturbances. The data described in Table 4 reflect exposure to voriconazole in 1655 patients in nine 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. 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.
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 (OLAT) in the primary treatment of patients with acute IA. The rate of discontinuation from voriconazole study medication due to adverse reactions was 21.4% (42/196 patients). The rate of discontinuation from voriconazole study medication due to adverse reactions 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 EC. The rate of discontinuation from voriconazole study medication in Study 305 due to adverse reactions was 7% (14/200 patients). Laboratory test abnormalities for these studies are discussed under Clinical Laboratory Values below.
Possibly Related to Therapy or Causality Unknown Study 307/602: IA; Study 608: candidemia; Study 305: EC Special Senses See Warnings and Precautions Visual Disturbances VFEND 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.
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, VFEND 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.
These effects were noted early in administration of VFEND and continued through the course of study drug treatment. Fourteen days after the end of dosing, ERG, visual fields and color perception returned to normal. Dermatological Reactions Dermatological reactions were common in patients treated with VFEND.
The mechanism underlying these dermatologic adverse reactions remains unknown. Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported during treatment with VFEND. Erythema multiforme has also been reported during treatment with VFEND.
VFEND has also been associated with additional photosensitivity related skin reactions such as pseudoporphyria, cheilitis, and cutaneous lupus erythematosus. Less Common Adverse Reactions The following adverse reactions 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 4 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, ascites, asthenia, back pain, chest pain, cellulitis, edema, face edema, flank pain, flu syndrome, graft versus host reaction, granuloma, infection, bacterial infection, fungal infection, injection site pain, injection site infection/inflammation, mucous membrane disorder, multi-organ failure, pain, pelvic pain, peritonitis, sepsis, substernal chest pain. Cardiovascular: atrial arrhythmia, atrial fibrillation, AV block complete, bigeminy, bradycardia, bundle branch block, cardiomegaly, cardiomyopathy, cerebral hemorrhage, cerebral ischemia, cerebrovascular accident, congestive heart failure, deep thrombophlebitis, endocarditis, extrasystoles, heart arrest, hypertension, hypotension, myocardial infarction, nodal arrhythmia, palpitation, phlebitis, postural hypotension, pulmonary embolus, QT interval prolonged, supraventricular extrasystoles, supraventricular tachycardia, syncope, thrombophlebitis, vasodilatation, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia (including torsade de pointes ).
Digestive: anorexia, cheilitis, cholecystitis, cholelithiasis, constipation, diarrhea, duodenal ulcer perforation, duodenitis, dyspepsia, dysphagia, dry mouth, esophageal ulcer, esophagitis, flatulence, gastroenteritis, gastrointestinal hemorrhage, GGT/LDH elevated, gingivitis, glossitis, gum hemorrhage, gum hyperplasia, hematemesis, hepatic coma, hepatic failure, hepatitis, intestinal perforation, intestinal ulcer, jaundice, enlarged liver, melena, mouth ulceration, pancreatitis, parotid gland enlargement, periodontitis, proctitis, pseudomembranous colitis, rectal disorder, rectal hemorrhage, stomach ulcer, stomatitis, tongue edema. Endocrine: adrenal cortex insufficiency, diabetes insipidus, hyperthyroidism, hypothyroidism. Hemic and Lymphatic: agranulocytosis, anemia (macrocytic, megaloblastic, microcytic, normocytic), aplastic anemia, hemolytic anemia, bleeding time increased, cyanosis, DIC, ecchymosis, eosinophilia, hypervolemia, leukopenia, lymphadenopathy, lymphangitis, marrow depression, pancytopenia, petechia, purpura, enlarged spleen, thrombocytopenia, thrombotic thrombocytopenic purpura.
Metabolic and Nutritional: albuminuria, BUN increased, creatine phosphokinase increased, edema, glucose tolerance decreased, hypercalcemia, hypercholesteremia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hyperuricemia, hypocalcemia, hypoglycemia, hypomagnesemia, hyponatremia, hypophosphatemia, peripheral edema, uremia. Musculoskeletal: arthralgia, arthritis, bone necrosis, bone pain, leg cramps, myalgia, myasthenia, myopathy, osteomalacia, osteoporosis. Nervous System: abnormal dreams, acute brain syndrome, agitation, akathisia, amnesia, anxiety, ataxia, brain edema, coma, confusion, convulsion, delirium, dementia, depersonalization, depression, diplopia, dizziness, encephalitis, encephalopathy, euphoria, Extrapyramidal Syndrome, grand mal convulsion, Guillain-Barré syndrome, hypertonia, hypesthesia, insomnia, intracranial hypertension, libido decreased, neuralgia, neuropathy, nystagmus, oculogyric crisis, paresthesia, psychosis, somnolence, suicidal ideation, tremor, vertigo.
Respiratory System: cough increased, dyspnea, epistaxis, hemoptysis, hypoxia, lung edema, pharyngitis, pleural effusion, pneumonia, respiratory disorder, respiratory distress syndrome, respiratory tract infection, rhinitis, sinusitis, voice alteration. Skin and Appendages: alopecia, angioedema, contact dermatitis, discoid lupus erythematosis, eczema, erythema multiforme, exfoliative dermatitis, fixed drug eruption, furunculosis, herpes simplex, maculopapular rash, melanoma, melanosis, photosensitivity skin reaction, pruritus, pseudoporphyria, psoriasis, skin discoloration, skin disorder, skin dry, Stevens-Johnson syndrome, squamous cell carcinoma (including cutaneous SCC in situ, or Bowen’s disease), 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 in Adults The overall incidence of transaminase increases >3× upper limit of normal (not necessarily comprising an adverse reaction) was 17.7% (268/1514) in adult subjects treated with VFEND for therapeutic use in pooled clinical trials. 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 resolved following dose adjustment, including discontinuation of therapy. VFEND has been infrequently associated with cases of serious hepatic toxicity including cases of jaundice and rare cases of hepatitis and hepatic failure leading to death. Most of these patients had other serious underlying conditions.
Liver function tests should be evaluated at the start of and during the course of VFEND therapy. Patients who develop abnormal liver function tests during VFEND therapy should be monitored for the development of more severe hepatic injury. Patient management should include laboratory evaluation of hepatic function (particularly liver function tests and bilirubin).
Discontinuation of VFEND must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to VFEND. Acute renal failure has been observed in severely ill patients undergoing treatment with VFEND. Patients being treated with VFEND are likely to be treated concomitantly with nephrotoxic medications and may have concurrent conditions that can result in decreased renal function.
It is recommended that patients are monitored for the development of abnormal renal function. This should include laboratory evaluation of serum creatinine. Tables 5 to 7 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 EC were randomized to either oral VFEND or oral fluconazole. In study 307/602, patients with definite or probable IA were randomized to either VFEND or amphotericin B therapy. In study 608, patients with candidemia were randomized to either VFEND or the regimen of amphotericin B followed by fluconazole.
Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation In clinical studies, serious adverse reactions occurred in 46% (48/105) of VFEND treated pediatric patients. Treatment discontinuations due to adverse reactions occurred in 12 /105 (11%) of all patients. Hepatic adverse reactions i.e.
ALT increased; liver function test abnormal; jaundice 6% (6/105) accounted for the majority of VFEND treatment discontinuations. Most Common Adverse Reactions The most common adverse reactions occurring in ≥5% of pediatric patients receiving VFEND in the pooled pediatric clinical trials are displayed by body system, in Table 8. Table 8: Adverse Reactions Occurring in ≥5% of Pediatric Patients Receiving VFEND in the Pooled Pediatric Clinical Trials 9 The following adverse reactions with incidence less than 5% were reported in 105 pediatric patients treated with VFEND: Blood and Lymphatic System Disorders: anemia, leukopenia, pancytopenia Cardiac Disorders: bradycardia, palpitations, supraventricular tachycardia Eye Disorders: dry eye, keratitis Ear and Labyrinth Disorders: tinnitus, vertigo Gastrointestinal Disorders: abdominal tenderness, dyspepsia General Disorders and Administration Site Conditions: asthenia, catheter site pain, chills, hypothermia, lethargy Hepatobiliary Disorders: cholestasis, hyperbilirubinemia, jaundice Immune System Disorders: hypersensitivity, urticaria Infections and Infestations: conjunctivitis Laboratory Investigations: AST increased, blood creatinine increased, gamma-glutamyl transferase increased Metabolism and Nutrition Disorders: hypercalcemia, hypermagnesemia, hyperphosphatemia, hypoglycemia Musculoskeletal and Connective Tissue Disorders: arthralgia, myalgia Nervous System Disorders: ataxia, convulsion, dizziness, nystagmus, paresthesia, syncope Psychiatric Disorders: affect lability, agitation, anxiety, depression, insomnia Respiratory Disorders: bronchospasm, nasal congestion, respiratory failure, tachypnea Skin and Subcutaneous Tissue Disorders: alopecia, dermatitis (allergic, contact, and exfoliative), pruritus Vascular Disorders: flushing, phlebitis Hepatic-Related Adverse Reactions in Pediatric Patients The frequency of hepatic-related adverse reactions in pediatric patients exposed to VFEND in therapeutic studies was numerically higher than that of adults (28.6% compared to 24.1%, respectively).
The higher frequency of hepatic adverse reactions in the pediatric population was mainly due to an increased frequency of liver enzyme elevations (21.9% in pediatric patients compared to 16.1% in adults), including transaminase elevations (ALT and AST combined) 7.6% in the pediatric patients compared to 5.1% in adults. The majority of abnormal liver function tests either resolved on treatment with or without dose adjustment or after VFEND discontinuation. A higher frequency of clinically significant liver laboratory abnormalities, irrespective of baseline laboratory values (>3× ULN ALT or AST), was consistently observed in the combined therapeutic pediatric population (15.5% AST and 22.5% ALT) when compared to adults (12.9% AST and 11.6% ALT).
The incidence of bilirubin elevation was comparable between adult and pediatric patients. The incidence of hepatic abnormalities in pediatric patients is shown in Table 9. Table 9: Incidence of Hepatic Abnormalities among Pediatric Subjects 8/97
Postmarketing Experience in Adult and Pediatric Patients
The following adverse reactions have been identified during post-approval use of VFEND. 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. Dermatological Reactions Increased risk of skin toxicity with concomitant use of methotrexate, a drug associated with UV reactivation, was observed in postmarketing reports.
Adults Skeletal: fluorosis and periostitis have been reported during long-term voriconazole therapy. Eye disorders: prolonged visual adverse reactions, including optic neuritis and papilledema. Skin and Appendages: drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported.
Endocrine disorders: adrenal insufficiency, Cushing's syndrome (when voriconazole has been used concomitantly with corticosteroids). Pediatric Patients There have been postmarketing reports of pancreatitis in pediatric patients.
| Therapeutic Studies Studies 303, 304, 305, 307, 309, 602, 603, 604, 608 | Studies 307/602 and 608 (IV/ oral therapy) | Study 305 (oral therapy) | ||||
|---|---|---|---|---|---|---|
| Voriconazole N=1655 | Voriconazole N=468 | Ampho B Amphotericin B followed by other licensed antifungal therapy N=185 | Ampho B→ Fluconazole N=131 | Voriconazole N=200 | Fluconazole N=191 | |
| N (%) | N (%) | N (%) | N (%) | N (%) | N (%) | |
| Special Senses See Warnings and Precautions (5.4) | ||||||
| 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 |
| SGOT increased | 31 (1.9) | 9 (1.9) | 0 | 1 (0.8) | 8 (4.0) | 2 (1.0) |
| SGPT 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 |
| 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 | |||
| AST = Aspartate aminotransferase; ALT= alanine aminotransferase | |||
| ULN = upper limit of normal | |||
| Criteria Without regard to baseline value | Voriconazole | Fluconazole | |
| n/N (%) | n /N (%) | ||
| T. Bilirubin | >1.5× ULN | 8/185 (4.3) | 7/186 (3.8) |
| AST | >3.0× ULN | 38/187 (20.3) | 15/186 (8.1) |
| ALT | >3.0× ULN | 20/187 (10.7) | 12/186 (6.5) |
| Alkaline Phosphatase | >3.0× ULN | 19/187 (10.2) | 14/186 (7.5) |
| 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 | |||
| AST = Aspartate aminotransferase; ALT= alanine aminotransferase | |||
| ULN = upper limit of normal | |||
| LLN = lower limit of normal | |||
| Criteria Without regard to baseline value | Voriconazole | Amphotericin B Amphotericin B followed by other licensed antifungal therapy | |
| n/N (%) | n/N (%) | ||
| T. Bilirubin | >1.5× ULN | 35/180 (19.4) | 46/173 (26.6) |
| AST | >3.0× ULN | 21/180 (11.7) | 18/174 (10.3) |
| ALT | >3.0× ULN | 34/180 (18.9) | 40/173 (23.1) |
| Alkaline Phosphatase | >3.0× ULN | 29/181 (16.0) | 38/173 (22.0) |
| Creatinine | >1.3× ULN | 39/182 (21.4) | 102/177 (57.6) |
| Potassium | <0.9× LLN | 30/181 (16.6) | 70/178 (39.3) |
| 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 | |||
| AST = Aspartate aminotransferase; ALT= alanine aminotransferase | |||
| ULN = upper limit of normal | |||
| LLN = lower limit of normal | |||
| Criteria Without regard to baseline value | Voriconazole | Amphotericin B followed by Fluconazole | |
| n/N (%) | 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) |
| Alkaline Phosphatase | >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) |
| Abbreviations: ALT = alanine aminotransferase; LFT = liver function test | ||
| Body System | Adverse Reaction | Pooled Pediatric Data Reflects all adverse reactions and not treatment-related only. N=105 n (%) |
| Blood and Lymphatic Systems Disorders | Thrombocytopenia | 10 (10) |
| Cardiac Disorders | Tachycardia | 7 (7) |
| Eye Disorders | Visual Disturbances Pooled reports include such terms as: amaurosis (partial or total blindness without visible change in the eye); asthenopia (eye strain); chromatopsia (abnormally colored vision); color blindness; diplopia; photopsia; retinal disorder; vision blurred, visual acuity decreased, visual brightness; visual impairment. Several patients had more than one visual disturbance. | 27 (26) |
| Photophobia | 6 (6) | |
| Gastrointestinal Disorders | Vomiting | 21 (20) |
| Nausea | 14 (13) | |
| Abdominal pain Pooled reports include such terms as: abdominal pain and abdominal pain, upper. | 13 (12) | |
| Diarrhea | 12 (11) | |
| Abdominal distention | 5 (5) | |
| Constipation | 5 (5) | |
| General Disorders and Administration Site Conditions | Pyrexia | 25 (25) |
| Peripheral edema | 9 (9) | |
| Mucosal inflammation | 6 (6) | |
| Infections and Infestations | Upper respiratory tract infection | 5 (5) |
| Investigations | ALT abnormal Pooled reports include such terms as: ALT abnormal and ALT increased. | 9 (9) |
| LFT abnormal | 6 (6) | |
| Metabolism and Nutrition Disorders | Hypokalemia | 11 (11) |
| Hyperglycemia | 7 (7) | |
| Hypocalcemia | 6 (6) | |
| Hypophosphotemia | 6 (6) | |
| Hypoalbuminemia | 5 (5) | |
| Hypomagnesemia | 5 (5) | |
| Nervous System Disorders | Headache | 10 (10) |
| Dizziness | 5 (5) | |
| Psychiatric Disorders | Hallucinations Pooled reports include such terms as: hallucination; hallucination, auditory; hallucination, visual. Several patients had both visual and auditory hallucinations. | 5 (5) |
| Renal and Urinary Disorders | Renal impairment Pooled reports include such terms as: renal failure and a single patient with renal impairment. | 5 (5) |
| Respiratory Disorders | Epistaxis | 17 (16) |
| Cough | 10 (10) | |
| Dyspnea | 6 (6) | |
| Hemoptysis | 5 (5) | |
| Skin and Subcutaneous Tissue Disorders | Rash Pooled reports include such terms as: rash; rash generalized; rash macular; rash maculopapular; rash pruritic. | 14 (13) |
| Vascular Disorders | Hypertension | 12 (11) |
| Hypotension | 9 (9) | |
| 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 | ||
| AST = Aspartate aminotransferase; ALT = alanine aminotransferase | ||
| ULN = upper limit of normal | ||
| Criteria | n/N (%) | |
| Total bilirubin | >1.5× ULN | 19/102 (19) |
| AST | >3.0× ULN | 16/103 (16) |
| ALT | >3.0× ULN | 23/102 (23) |
| Alkaline Phosphatase | >3.0× ULN | 8/97 (8) |
Warnings & Cautions for Vfend
Hepatic Toxicity
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. A higher frequency of liver enzyme elevations was observed in the pediatric population. Hepatic function should be monitored in both adult and pediatric patients.
Measure serum transaminase levels and bilirubin at the initiation of VFEND 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, VFEND should be discontinued unless the medical judgment of the benefit/risk of the treatment for the patient justifies continued use.
Arrhythmias and QT Prolongation
Some azoles, including VFEND, have been associated with prolongation of the QT interval on the electrocardiogram. During clinical development and postmarketing 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.
VFEND 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 Rigorous attempts to correct potassium, magnesium and calcium should be made before starting and during voriconazole therapy.
Infusion Related Reactions
During infusion of the intravenous formulation of VFEND 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.
Visual Disturbances
The effect of VFEND on visual function is not known if treatment continues beyond 28 days. There have been postmarketing reports of prolonged visual adverse reactions, including optic neuritis and papilledema. If treatment continues beyond 28 days, visual function including visual acuity, visual field, and color perception should be monitored.
Severe Cutaneous Adverse Reactions
Severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported during treatment with VFEND. If a patient develops a severe cutaneous adverse reaction, VFEND should be discontinued.
Photosensitivity VFEND has been associated with photosensitivity skin reaction. Patients, including pediatric patients, should avoid exposure to direct sunlight during VFEND 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 VFEND discontinuation should be considered.
If VFEND is continued despite the occurrence of phototoxicity-related 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 (including cutaneous SCC in situ, or Bowen’s disease) and melanoma have been reported during long-term VFEND therapy in patients with photosensitivity skin reactions. If a patient develops a skin lesion consistent with premalignant skin lesions, squamous cell carcinoma or melanoma, VFEND should be discontinued.
In addition, VFEND has been associated with photosensitivity related skin reactions such as pseudoporphyria, cheilitis, and cutaneous lupus erythematosus, as well as increased risk of skin toxicity with concomitant use of methotrexate, a drug associated with ultraviolet (UV) reactivation. There is the potential for this risk to be observed with other drugs associated with UV reactivation. Patients should avoid strong, direct sunlight during VFEND therapy.
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.
Renal Toxicity
Acute renal failure has been observed in patients undergoing treatment with VFEND. Patients being treated with voriconazole are likely to be treated concomitantly with nephrotoxic medications and may 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 of serum creatinine.
Adrenal Dysfunction
Reversible cases of azole-induced adrenal insufficiency have been reported in patients receiving azoles, including VFEND. Adrenal insufficiency has been reported in patients receiving azoles with or without concomitant corticosteroids. In patients receiving azoles without corticosteroids adrenal insufficiency is related to direct inhibition of steroidogenesis by azoles.
In patients taking corticosteroids, voriconazole associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression. Cushing's syndrome with and without subsequent adrenal insufficiency has also been reported in patients receiving VFEND concomitantly with corticosteroids. Patients receiving VFEND and corticosteroids (via all routes of administration) should be carefully monitored for adrenal dysfunction both during and after VFEND treatment.
Patients should be instructed to seek immediate medical care if they develop signs and symptoms of Cushing's syndrome or adrenal insufficiency.
Embryo-Fetal Toxicity Voriconazole can cause fetal harm when administered to a pregnant woman. In animals, voriconazole administration was associated with fetal malformations, embryotoxicity, increased gestational length, dystocia and embryomortality. If VFEND is used during pregnancy, or if the patient becomes pregnant while taking VFEND, inform the patient of the potential hazard to the fetus.
Advise females of reproductive potential to use effective contraception during treatment with VFEND.
Laboratory Tests
Electrolyte disturbances such as hypokalemia, hypomagnesemia and hypocalcemia should be corrected prior to initiation of and during VFEND therapy. Patient management should include laboratory evaluation of renal (particularly serum creatinine) and hepatic function (particularly liver function tests and bilirubin).
Pancreatitis Pancreatitis has been observed in patients undergoing treatment with VFEND Patients with risk factors for acute pancreatitis (e.g., recent chemotherapy, hematopoietic stem cell transplantation ) should be monitored for the development of pancreatitis during VFEND treatment.
Skeletal Adverse Reactions Fluorosis and periostitis have been reported during long-term VFEND therapy. If a patient develops skeletal pain and radiologic findings compatible with fluorosis or periostitis, VFEND should be discontinued.
Clinically Significant Drug Interactions See Table 10 for a listing of drugs that may significantly alter voriconazole concentrations. Also, see Table 11 for a listing of drugs that may interact with voriconazole resulting in altered pharmacokinetics or pharmacodynamics of the other drug.
Drug Interactions with Vfend
- Voriconazole is metabolized by cytochrome P450 isoenzymes, CYP2C19, CYP2C9, and CYP3A4. Therefore, inhibitors or inducers of these isoenzymes may increase or decrease voriconazole plasma concentrations, respectively. Voriconazole is a strong inhibitor of CYP3A4, and also inhibits CYP2C19 and CYP2C9. Therefore, voriconazole may increase the plasma concentrations of substances metabolized by these CYP450 isoenzymes. Table 10 and Table 11 provide listings of clinically significant drug interactions, including contraindicated drugs. Drugs listed in Table 10 and Table 11 are a guide and not considered a comprehensive list of all possible drugs and herbal products that are contraindicated or may interact with VFEND. Table 10: Effect of Other Drugs on Voriconazole Pharmacokinetics Table 11: Effect of Voriconazole on Pharmacokinetics of Other Drugs No dosage adjustment for prednisolone when concomitantly administered with VFEND. Monitor for potential adrenal dysfunction when VFEND is administered with other corticosteroids.
- CYP3A4, CYP2C9, and CYP2C19 inhibitors and inducers: Adjust VFEND dosage and monitor for adverse reactions or lack of efficacy
- VFEND may increase the concentrations and activity of drugs that are CYP3A4, CYP2C9 and CYP2C19 substrates. Reduce dosage of these other drugs and monitor for adverse reactions
- Phenytoin or Efavirenz: With coadministration, increase maintenance oral and intravenous dosage of VFEND
| Drug/Drug Class (Mechanism of Interaction by the Drug) | Voriconazole Plasma Exposure (C max and AUC τ after 200 mg every 12 hours) | Prevention or Management Recommendations |
|---|---|---|
| Rifampin Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg every 12 hours voriconazole to healthy subjects and Rifabutin (CYP450 Induction) | Significantly Reduced | Contraindicated |
| Efavirenz (400 mg every 24 hours) Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects (CYP450 Induction) | Significantly Reduced | Contraindicated |
| Efavirenz (300 mg every 24 hours) (CYP450 Induction) | Slight Decrease in AUC τ | When voriconazole is concomitantly administered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg every 12 hours and efavirenz should be decreased to 300 mg every 24 hours. |
| High-dose Ritonavir (400 mg every 12 hours) (CYP450 Induction) | Significantly Reduced | Contraindicated |
| Low-dose Ritonavir (100 mg every 12 hours) (CYP450 Induction) | Reduced | Concomitant administration of voriconazole and low-dose ritonavir (100 mg every 12 hours) 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 (e.g., phenobarbital, mephobarbital) (CYP450 Induction) | Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction | Contraindicated |
| Phenytoin (CYP450 Induction) | Significantly Reduced | Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV every 12 hours or from 200 mg to 400 mg orally every 12 hours (100 mg to 200 mg orally every 12 hours in patients weighing less than 40 kg). |
| Letermovir (CYP2C9/2C19 Induction) | Reduced | If concomitant administration of voriconazole with letermovir cannot be avoided, monitor for reduced effectiveness of voriconazole. |
| 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 reactions and toxicity related to voriconazole is recommended for concomitant administration with oral contraceptives. |
| Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition) | Significantly Increased | Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse reactions and toxicity related to voriconazole is started within 24 hours 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 for concomitant administration with indinavir. Frequent monitoring for adverse reactions and toxicity related to voriconazole for concomitant administration with other HIV protease inhibitors. |
| Other NNRTIs Non-Nucleoside Reverse Transcriptase Inhibitors (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 reactions 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. |
| Drug/Drug Class (Mechanism of Interaction by Voriconazole) | Drug Plasma Exposure (C max and AUC τ ) | Prevention or Management Recommendations |
|---|---|---|
| Sirolimus Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects (CYP3A4 Inhibition) | Significantly Increased | Contraindicated |
| Rifabutin (CYP3A4 Inhibition) | Significantly Increased | Contraindicated |
| Efavirenz (400 mg every 24 hours) Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects (CYP3A4 Inhibition) | Significantly Increased | Contraindicated |
| Efavirenz (300 mg every 24 hours) (CYP3A4 Inhibition) | Slight Increase in AUC τ | When voriconazole is concomitantly administered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg every 12 hours and efavirenz should be decreased to 300 mg every 24 hours. |
| High-dose Ritonavir (400 mg every 12 hours) (CYP3A4 Inhibition) | No Significant Effect of Voriconazole on Ritonavir C max or AUC τ | Contraindicated because of significant reduction of voriconazole C max and AUC τ. |
| Low-dose Ritonavir (100 mg every 12 hours) | Slight Decrease in Ritonavir C max and AUC τ | Concomitant administration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided (due to the reduction in voriconazole C max and AUC τ ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. |
| Pimozide, Quinidine, Ivabradine (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 |
| Naloxegol (CYP3A4 Inhibition) | Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions | Contraindicated |
| Tolvaptan (CYP3A4 Inhibition) | Although Not Studied Clinically, Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Tolvaptan | Contraindicated |
| Lurasidone (CYP3A4 Inhibition) | Not Studied In Vivo or In Vitro, but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Lurasidone | Contraindicated |
| Finerenone (CYP3A4 Inhibition) | Not Studied In Vivo or In Vitro, but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Finerenone | Contraindicated |
| Eplerenone (CYP3A4 Inhibition) | Not Studied In Vivo or In Vitro, but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Eplerenone | Contraindicated |
| Voclosporin (CYP3A4 Inhibition) | Not Studied In Vivo or In Vitro, but Voriconazole is Likely to Significantly Increase the Plasma Concentrations of Voclosporin | Contraindicated |
| Venetoclax (CYP3A4 Inhibition) | Not Studied In Vivo or In Vitro, but Venetoclax Plasma Exposure Likely to be Significantly Increased | Concomitant administration of voriconazole is contraindicated at initiation and during the ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Refer to the venetoclax labeling for safety monitoring and dose reduction in the steady daily dosing phase in CLL/SLL patients. For patients with acute myeloid leukemia (AML), dose reduction and safety monitoring are recommended across all dosing phases when concomitantly administered VFEND with venetoclax. Refer to the venetoclax prescribing information for dosing instructions. |
| Lemborexant (CYP3A4 Inhibition) | Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased | Avoid concomitant use of VFEND with lemborexant. |
| Glasdegib (CYP3A4 Inhibition) | Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased | Consider alternative therapies. If concomitant use cannot be avoided, monitor patients for increased risk of adverse reactions including QTc interval prolongation. |
| Tyrosine kinase inhibitors (including but not limited to axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, ribociclib) (CYP3A4 Inhibition) | Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased | Avoid concomitant use of VFEND. If concomitant use cannot be avoided, dose reduction of the tyrosine kinase inhibitor is recommended. Refer to the prescribing information for the relevant product. |
| Cyclosporine (CYP3A4 Inhibition) | AUC τ Significantly Increased; No Significant Effect on C max | 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. |
| Methadone Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 4 days voriconazole to subjects receiving a methadone maintenance dose (30–100 mg every 24 hours) (CYP3A4 Inhibition) | Increased | Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse reactions and toxicity related to methadone is recommended when concomitantly administered with VFEND. 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 concomitantly administered with VFEND. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary. |
| Alfentanil (CYP3A4 Inhibition) | Significantly Increased | An increase in the incidence of delayed and persistent alfentanil-associated nausea and vomiting were observed when concomitantly administered with VFEND. Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when concomitantly administered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse reactions may be necessary. |
| Oxycodone (CYP3A4 Inhibition) | Significantly Increased | Increased visual effects (heterophoria and miosis) of oxycodone were observed when concomitantly administered with VFEND. Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when concomitantly administered with VFEND. Extended and frequent monitoring for opiate-associated adverse reactions may be necessary. |
| NSAIDs Non-Steroidal Anti-Inflammatory Drug including. ibuprofen and diclofenac (CYP2C9 Inhibition) | Increased | Frequent monitoring for adverse reactions and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed. |
| Tacrolimus (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. |
| 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 reactions related to oral contraceptives is recommended during concomitant administration. |
| Prednisolone and other corticosteroids (CYP3A4 Inhibition) | In Vivo Studies Showed No Significant Effects of VFEND on Prednisolone Exposure Not Studied In Vitro or In vivo for Other Corticosteroids, but Drug Exposure Likely to be Increased | No dosage adjustment for prednisolone when concomitantly administered with VFEND [see Clinical Pharmacology (12.3) ]. Monitor for potential adrenal dysfunction when VFEND is administered with other corticosteroids [see Warnings and Precautions (5.8) ]. |
| Warfarin (CYP2C9 Inhibition) | Prothrombin Time Significantly Increased | If patients receiving coumarin preparations are treated simultaneously with voriconazole, the prothrombin time or other suitable anticoagulation tests should be monitored at close intervals and the dosage of anticoagulants adjusted accordingly. |
| Other Oral Coumarin Anticoagulants (CYP2C9/3A4 Inhibition) | Not Studied In Vivo or In Vitro for other Oral Coumarin Anticoagulants, but Drug Plasma Exposure Likely to be Increased | |
| Ivacaftor (CYP3A4 Inhibition) | Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Adverse Reactions | Dose reduction of ivacaftor is recommended. Refer to the prescribing information for ivacaftor. |
| Eszopiclone (CYP3A4 Inhibition) | Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased which may Increase the Sedative Effect of Eszopiclone | Dose reduction of eszopiclone is recommended. Refer to the prescribing information for eszopiclone. |
| Mavacamten (CYP2C19/3A4/2C9 Inhibition) | Not Studied In Vivo or In Vitro, but Mavacamten Drug Plasma Exposure Likely to be Increased which may Increase the Risk of Heart Failure | Refer to the prescribing information for mavacamten. |
| Omeprazole (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. |
| 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 concomitantly administered with VFEND. Frequent monitoring for adverse reactions and toxicity related to other HIV protease inhibitors. |
| Other NNRTIs Non-Nucleoside Reverse Transcriptase Inhibitors (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 reactions and toxicity related to NNRTI. |
| Tretinoin (CYP3A4 Inhibition) | Although Not Studied, Voriconazole may Increase Tretinoin Concentrations and Increase the Risk of Adverse Reactions | Frequent monitoring for signs and symptoms of pseudotumor cerebri or hypercalcemia. |
| Midazolam (CYP3A4 Inhibition) | Significantly Increased | Increased plasma exposures may increase the risk of adverse reactions and toxicities related to benzodiazepines. Refer to drug-specific labeling for details. |
| Other benzodiazepines including triazolam and alprazolam (CYP3A4 Inhibition) | In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) | |
| HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition) | In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) | Frequent monitoring for adverse reactions 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 reactions 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 reactions 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. |
Pregnancy Safety for Vfend
Pregnancy Risk Summary Voriconazole can cause fetal harm when administered to a pregnant woman. There are no available data on the use of VFEND in pregnant women. In animal reproduction studies, oral voriconazole was associated with fetal malformations in rats and fetal toxicity 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 RMD 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.
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. 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 mg/kg/day. Voriconazole was associated with increased incidences of the malformations hydroureter and hydronephrosis at 10 mg/kg/day or greater, approximately 0.3 times the recommended human dose (RMD) based on body surface area comparisons, and cleft palate at 60 mg/kg, approximately 2 times the RMD based on body surface area comparisons. Reduced ossification of sacral and caudal vertebrae, skull, pubic, and hyoid bone, supernumerary ribs, anomalies of the sternebrae, 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 mg/kg/day. Voriconazole was associated with increased post-implantation loss and 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 body surface area comparisons).
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.
Pediatric Use of Vfend
Pediatric Use The safety and effectiveness of VFEND have been established in pediatric patients 2 years of age and older based on evidence from adequate and well-controlled studies in adult and pediatric patients and additional pediatric pharmacokinetic and safety data. Safety and effectiveness in pediatric patients below the age of 2 years has not been established. Therefore, VFEND is not recommended for pediatric patients less than 2 years of age.
A higher frequency of liver enzyme elevations was observed in the pediatric patients. The frequency of phototoxicity reactions is higher in the pediatric population. Squamous cell carcinoma has been reported in patients who experience photosensitivity reactions.
Stringent measures for photoprotection are warranted. Sun avoidance and dermatologic follow-up are recommended in pediatric patients experiencing photoaging injuries, such as lentigines or ephelides, even after treatment discontinuation. VFEND has not been studied in pediatric patients with hepatic or renal impairment.
Hepatic function and serum creatinine levels should be closely monitored in pediatric patients.
Contraindications for Vfend
- VFEND is contraindicated in patients with known hypersensitivity to voriconazole or its excipients. There is no information regarding cross-sensitivity between VFEND and other azole antifungal agents. Refer to the prescribing information for other azole antifungal agents.
- Concomittant use of VFEND with the interacting drugs described and listed below in this section are a guide and not considered a comprehensive list of all possible drugs that may be contraindicated with VFEND. 1. Concomitant use of VFEND is contraindicated with drugs that are highly dependent on CYP3A4 for metabolism, and for which elevated plasma concentrations are associated with serious and/or life‑threatening reactions:
- Eplerenone
- Ergot alkaloids (e.g., ergotamine, dihydroergotamine)
- Finerenone
- Ivabradine
- Lurasidone
- Naloxegol
- Pimozide
- Quinidine
- Rifabutin
- Sirolimus
- Tolvaptan
- Venetoclax: Coadministration at initiation and during the ramp-up phase is contraindicated in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) due to the potential for increased risk of tumor lysis syndrome.
- Voclosporin 2. Concomitant use of VFEND is contraindicated with drugs and herbal products that induce CYP2C19, CYP2C9, and/or CYP3A4 and for which significantly reduced voriconazole plasma concentrations may be associated with loss of efficacy:
- Carbamazepine
- Efavirenz Concomitant use with efavirenz dosages of 400 mg every 24 hours or higher is contraindicated.
- Long-acting barbiturates
- Rifabutin
- Rifampin
- Ritonavir Concomitant use with high-dose ritonavir (400 mg every 12 hours) is contraindicated. Concomitant use with low-dose ritonavir (100 mg every 12 hours) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of VFEND.
- St. John’s Wort
- Known hypersensitivity to voriconazole or its excipients
- Concomitant use with drugs that are highly dependent on CYP3A4 for metabolism, and for which elevated plasma concentrations are associated with serious and/or life-threatening reactions
Overdosage Information for Vfend
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 reaction 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.
Clinical Studies of Vfend
Invasive Aspergillosis (IA) Voriconazole was studied in patients for primary therapy of IA (randomized, controlled study 307/602), for primary and salvage therapy of aspergillosis (non-comparative study 304) and for treatment of patients with IA 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 IA 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 IA of the lungs. Other aspergillosis infections included disseminated disease, CNS infections and sinus infections.
Diagnosis of definite or probable IA 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). Therapy could then be switched to the oral formulation at a dose of 200 mg every 12 hours. Median duration of IV voriconazole therapy was 10 days (range 2–85 days).
After IV voriconazole therapy, the median duration of PO voriconazole therapy was 76 days (range 2–232 days). Patients in the comparator group received conventional amphotericin B as a slow infusion at a daily dose of 1.0–1.5 mg/kg/day. Median duration of IV amphotericin therapy was 12 days (range 1–85 days).
Treatment was then continued with 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 15). Table 13 also summarizes the response (success) based on mycological confirmation and species. Table 13: Overall Efficacy and Success by Species in the Primary Treatment of Acute Invasive Aspergillosis Study 307/602 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 in patients who received voriconazole as salvage therapy is presented in Table 14. 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 16. In this non-comparative study, overall mycological eradication for culture-documented infections due to fumigatus and non- fumigatus species of Aspergillus was 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 14. Table 14: Combined Response Data in Salvage Patients with Single Aspergillus Species (Studies 304 and 309/604) 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.
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 ), 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 15. 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.
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 EC, as presented in Table 16. Table 16: Success Rates in Patients Treated for Esophageal Candidiasis Microbiologic success rates by Candida species are presented in Table 17.
Table 17: Clinical and Mycological Outcome by Baseline Pathogen in Patients with Esophageal Candidiasis (Study-150-305)
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%). 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. 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. Fifty-three pediatric patients aged 2 to less than 18 years old were treated with voriconazole in two prospective, open-label, non-comparative, multicenter clinical studies.
One study was designed to enroll pediatric patients with IA or infections with rare molds (such as Scedosporium or Fusarium ). After completing 7 days of intravenous therapy patients had an option to switch to oral VFEND. The oral maintenance dose was 9 mg/kg every 12 hours (maximum dose of 350 mg).
All other pediatric patients aged 12 to less than 18 years received the adult VFEND dosage regimen. Patients received VFEND for at least 6 weeks and up to a maximum of 12 weeks. The study enrolled 31 patients with possible, proven, or probable IA.
No patients with rare mold were enrolled. A successful global response was defined as resolution or improvement in clinical signs and symptoms and at least 50% resolution of radiological lesions attributed to IA. The overall rate of successful global response at 6 weeks in the MITT population is presented in Table 18 below.
Table 18: Global Response Global response rate was defined as the number of subjects with a successful response (complete or partial) as a percentage of all subjects (including subjects with an indeterminate or missing response) at 6 weeks in the MITT population. in Patients with Invasive Aspergillosis, Modified Intent-to-Treat (MITT) The Modified Intent-to-Treat (MITT) population was defined as all subjects who received at least 1 dose of study drug and who were diagnosed with proven or probable IA as defined by the modified EORTC/MSG criteria. The second study enrolled 22 patients with invasive candidiasis including candidemia (ICC) and EC requiring either primary or salvage therapy. VFEND was administered for at least 14 days after the last positive culture.
A maximum of 42 days of treatment was permitted. VFEND was administered for at least 7 days after the resolution of clinical signs and symptoms. For EC, study treatment was initiated without a loading dose of intravenous voriconazole.
Seventeen of these patients had confirmed Candida infection and were included in the MITT efficacy analyses. For ICC and EC, a successful global response was defined as clinical cure or improvement with microbiological eradication or presumed eradication. The overall rate of successful global response at EOT in the MITT population is presented in Table 19 below.
Table 19: Global Response Global response was determined based on the investigator's assessment of clinical and microbiological response in the Modified Intent-to-Treat (MITT) analysis population at end of treatment. Subjects with missing data or whose response was deemed indeterminate were considered failures. at the End of Treatment in the Treatment of Invasive Candidiasis with Candidemia and Esophageal Candidiasis Modified Intent-to-Treat (MITT) Population The MITT population was defined as all subjects who received at least 1 dose of study drug and who had microbiologically confirmed invasive candidiasis with candidemia (ICC) and EC, or subjects with EC who had at least confirmation of oropharyngeal candidiasis without confirmation on esophagoscopy.
| Voriconazole | Ampho B Amphotericin B followed by other licensed antifungal therapy | Stratified Difference (95% CI) Difference and corresponding 95% confidence interval are stratified by protocol | |
|---|---|---|---|
| n/N (%) | n/N (%) | ||
| Efficacy as Primary Therapy | |||
| Satisfactory Global Response Assessed by independent Data Review Committee (DRC) | 76/144 (53) | 42/133 (32) | 21.8% (10.5%, 33.0%) p<0.0001 |
| Survival at Day 84 Proportion of subjects alive | 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 Not all mycologically confirmed specimens were speciated | 37/84 (44) | 16/67 (24) | |
| Aspergillus spp. Some patients had more than one species isolated at baseline | |||
| 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 | |
| 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 |
| 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 |
| Population | Voriconazole | Fluconazole | Difference % (95% CI) Confidence Interval for the difference (Voriconazole – Fluconazole) in success rates. |
|---|---|---|---|
| PP 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). | 113/115 (98.2%) | 134/141 (95.0%) | 3.2 (-1.1, 7.5) |
| ITT ITT (Intent to Treat) patients without endoscopy or clinical assessment at EOT were treated as failures. | 175/200 (87.5%) | 171/191 (89.5%) | -2.0 (-8.3, 4.3) |
| Pathogen Some patients had more than one species isolated at baseline | Voriconazole | Fluconazole | ||
|---|---|---|---|---|
| Favorable endoscopic response Patients with endoscopic and/or mycological assessment at end of therapy | 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 |
| Parameter | Global Response at Week 6 | ||
|---|---|---|---|
| Ages 2–<12 years N=5 | Ages 12–<18 years N=9 | Overall N=14 | |
| Number of successes, n (%) | 2 (40%) | 7 (78%) | 9 (64%) |
| Parameter | Global Response at End of Treatment | |||
|---|---|---|---|---|
| EC N=10 | ICC All subjects with ICC were aged 2 to less than 12. N=7 | |||
| Ages 2–<12 N=2 | Ages 12–<18 N=8 | Overall N=10 | Overall N=7 | |
| Number of successes, n (%) | 2 (100%) | 5 (63%) | 7 (70%) | 6 (86%) |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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