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VFEND is a brand name for Voriconazole. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: 1 INDICATIONS AND USAGE VFEND is an azole antifungal indicated for the treatment of adults and pediatric patients 2 years of age and older with: • Invasive aspergillosis ( 1.1 ) • Candidemia in non-neutropenics and other deep tissue Candida infections ( 1.2 ) • Esophageal candidiasis ( 1.3 ) • Serious fungal…
Verbatim from this product's FDA label. Tap a section to expand.
4 ) o For pediatric patients 2 to less than 12 years of age and 12 to 14 years of age weighing less than 50 kg see Table below. 75 mL (350 mg) every 12 hours] o For pediatric patients aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight use adult dosage.
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. V. by intravenous infusion over 1 to 3 hours only.
Do not administer as an IV bolus injection. V. 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).
10) ] . V. can be infused at the same time as other intravenous solutions containing (non-concentrated) electrolytes, but must be infused through a separate line. V. can be infused at the same time as total parenteral nutrition, but must be infused in a separate line.
V. 3 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. 3) ] . 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.
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) .
7) ] • Adult Patients : The most common adverse reactions (incidence ≥2%) were visual disturbances, fever, nausea, rash, vomiting, chills, headache, liver function test abnormal, tachycardia, hallucinations ( 6 ) • Pediatric Patients : The most common adverse reactions (incidence ≥5%) were visual disturbances, pyrexia, vomiting, epistaxis, nausea, rash, abdominal pain, diarrhea, hypertension, hypokalemia, cough, headache, thrombocytopenia, ALT abnormal, hypotension, peripheral edema, hyperglycemia, tachycardia, dyspnea, hypocalcemia, hypophosphatemia, LFT abnormal, mucosal inflammation, photophobia, abdominal distention, constipation, dizziness, hallucinations, hemoptysis, hypoalbuminemia, hypomagnesemia, renal impairment, upper respiratory tract infection ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc.
gov/medwatch . 1 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.
4%). 1) ] . The data described in Table 4 reflect exposure to voriconazole in 1655 patients in nine therapeutic studies. , patients with hematological malignancy or HIV and non-neutropenic patients. This subgroup does not include healthy subjects and patients treated in the compassionate use and non-therapeutic studies.
This patient population was 62% male, had a mean age of 46 years (range 11–90, including 51 patients aged 12–18 years), and was 78% White and 10% Black. Five hundred sixty one patients had a duration of voriconazole therapy of greater than 12 weeks, with 136 patients receiving voriconazole for over six months.
Table 4 includes all adverse reactions which were reported at an incidence of ≥2% during voriconazole therapy in the all therapeutic studies population, studies 307/602 and 608 combined, or study 305, as well as events of concern which occurred at an incidence of <2%.
5 WARNINGS AND PRECAUTIONS • Hepatic Toxicity : Serious hepatic reactions reported. 6 ) • Adrenal Dysfunction : Carefully monitor patients receiving VFEND and corticosteroids (via all routes of administration) for adrenal dysfunction both during and after VFEND treatment.
8 ) • Embryo-Fetal Toxicity : Voriconazole can cause fetal harm when administered to a pregnant woman. Inform pregnant patients of the potential hazard to the fetus. 3 ) • Skeletal Adverse Reactions : Fluorosis and periostitis with long-term voriconazole therapy.
1 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. 1) ] . 1) ] . 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. 1) ] . 2 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. 3) ] .
2) ] . 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. 3) ] • 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 [see Drug Interactions (7) ] .
• Voclosporin 2. 3) ] . • Long-acting barbiturates • Rifabutin • Rifampin • Ritonavir Concomitant use with high-dose ritonavir (400 mg every 12 hours) is contraindicated. 3) ] . • St. 3) ] • Known hypersensitivity to voriconazole or its excipients ( 4 ) • 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 ( 4 , 7 ) • Concomitant use 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 ( 4 , 7 )
Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
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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).
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. 5 mL) every 12 hours. 75 mL) every 12 hours.
5 mL) every 12 hours for adult patients weighing less than 40 kg. • If the patient is unable to tolerate 4 mg/kg intravenously every 12 hours, reduce the intravenous maintenance dose to 3 mg/kg every 12 hours. 4 Recommended Dosing Regimen in Pediatric Patients The recommended dosing regimen for pediatric patients 2 to less than 12 years of age and 12 to 14 years of age with body weight less than 50 kg is shown in Table 2.
3) ] .
Table 2:
Recommended Dosing Regimen for Pediatric Patients 2 to less than 12 years of age and 12 to 14 years of age with body weight less than 50 kg Based on a population pharmacokinetic analysis in 112 immunocompromised pediatric patients aged 2 to less than 12 years of age and 26 immunocompromised pediatric patients aged 12 to less than 17 years of age.
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. 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. 75 mL (350 mg) every 12 hours] Initiate therapy with an intravenous infusion regimen. 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.
75 mL) every 12 hours. If patients are unable to tolerate the initial intravenous maintenance dose, reduce the dose by 1 mg/kg steps. 25 mL) steps. 3) ] . 5 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. 1) ] . 3) ] . 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. 4) ] . 6 Dosage Modifications in Patients With Renal Impairment Adult Patients The pharmacokinetics of orally administered VFEND are not significantly affected by renal impairment.
3) ] . 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.
7) ] . Voriconazole and the intravenous vehicle, SBECD, are dialyzable. 3) ] . 4) ] . 7 Dosage Adjustment When Coadministered With Phenytoin or Efavirenz The maintenance dose of voriconazole should be increased when coadministered with phenytoin or efavirenz.
3) ] . 8 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.
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. 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. 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. V. with diluents other than those described above is unknown (see Incompatibilities below). Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
V. 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.
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.
4% (42/196 patients). In study 608, 403 patients with candidemia were treated to compare voriconazole (272 patients) to the regimen of amphotericin B followed by fluconazole (131 patients). 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.
Table 4:
Adverse Reactions Rate ≥ 2% on Voriconazole or Adverse Reactions of Concern in Therapeutic Studies Population, Studies 307/602–608 Combined, or Study 305. 3) 0 0 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. 4) ] . 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.
2) ] . 2) ] . 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. 3) ] , 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.
2) ] . 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.
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). 1) ] . 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.
Table 5:
Protocol 305 – Patients with Esophageal Candidiasis Clinically Significant Laboratory Test Abnormalities n = number of patients with a clinically significant abnormality while on study therapy N = total number of patients with at least one observation of the given lab test while on study therapy AST = Aspartate aminotransferase; ALT= alanine aminotransferase ULN = upper limit of normal Criteria Without regard to baseline value Voriconazole Fluconazole n/N (%) n /N (%) T.
5) Table 6: Protocol 307/602 – Primary Treatment of Invasive Aspergillosis Clinically Significant Laboratory Test Abnormalities n = number of patients with a clinically significant abnormality while on study therapy N = total number of patients with at least one observation of the given lab test while on study therapy 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.
3) Table 7: Protocol 608 – Treatment of Candidemia Clinically Significant Laboratory Test Abnormalities n = number of patients with a clinically significant abnormality while on study therapy N = total number of patients with at least one observation of the given lab test while on study therapy 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.
7) Clinical Trials Experience in Pediatric Patients The safety of VFEND was investigated in 105 pediatric patients aged 2 to less than 18 years, including 52 pediatric patients less than 18 years of age who were enrolled in the adult therapeutic studies.
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.
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 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.
1%, respectively). 1% in adults. 7% (268/1514) in adult patients treated with VFEND in pooled clinical trials. The majority of abnormal liver function tests either resolved on treatment with or without dose adjustment or after VFEND discontinuation.
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. 2 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. 1) ]. 12) ] . 4) ] . 1) ] . 8) ] .
Pediatric Patients There have been postmarketing reports of pancreatitis in pediatric patients.
3 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. 4 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. 2) ] . 5 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.
2) ] . 6 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.
7 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. 6) ] . 8 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. 3) ] . 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.
9 Embryo-Fetal Toxicity Voriconazole can cause fetal harm when administered to a pregnant woman. 1) ] . 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.
3) ] . 10 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).
, recent chemotherapy, hematopoietic stem cell transplantation [HSCT]) should be monitored for the development of pancreatitis during VFEND treatment. 12 Skeletal Adverse Reactions Fluorosis and periostitis have been reported during long-term VFEND therapy.
2) ] . 13 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 [see Contraindications (4) and Drug Interactions (7) ] .