Kenyan Health Patient Information Leaflet
Azole Antifungal [EPC]
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 infections caused by Scedosporium apiospermum and Fusarium species including Fusarium solani , in patients intolerant of, or refractory to, other therapy ( 1.4 ) 1.1 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 [see Clinical Studies (14.1 , 14.5) and Microbiology (12.4) ] . 1.2 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 [see Clinical Studies (14.2 , 14.5) and Microbiology (12.4) ] . 1.3 Esophageal Candidiasis VFEND is indicated in adults and pediatric patients (2 years of age and older) for the treatment of esophageal candidiasis (EC) [see Clinical Studies (14.3 , 14.5) and Microbiology (12.4) ] . 1.4 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 [see Clinical Studies (14.4) and Microbiology (12.4) ] . 1.5 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 in Adults ( 2.3 ) 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 o Adult patients weighing less than 40 kg: oral maintenance dose 100 mg or 150 mg every 12 hours o Hepatic Impairment : Use half the maintenance dose in adult patients with mild to moderate hepatic impairment (Child-Pugh Class A and B) ( 2.5 ) o Renal Impairment : Avoid intravenous administration in adult patients with moderate to severe renal impairment (creatinine clearance <50 mL/min) ( 2.6 ) • Dosage in Pediatric Patients 2 years of age and older ( 2.4 ) 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. 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] 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. ( 2.4 ) o Dosage adjustment of VFEND in pediatric patients with renal or hepatic impairment has not been established ( 2.5 , 2.6 ) • See full prescribing information for instructions on reconstitution of VFEND lyophilized powder for intravenous use and important administration instructions ( 2.1 , 2.6 , 2.7 ) 2.1 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. 2.2 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 [see Warnings and Precautions (5.10) ] . 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. 2.3 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. The recommended oral maintenance dose of 200 mg achieves a voriconazole exposure similar to 3 mg/kg intravenously; a 300 mg oral dose achieves an exposure similar to 4 mg/kg intravenously [see Clinical Pharmacology (12.3) ] . 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. Table 1: Recommended Dosing Regimen (Adults) 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 Method for Adjusting the Dosing Regimen in Adults • If the patient's response is inadequate, the oral maintenance dose for VFEND tablets or oral suspension may be increased from 200 mg (or 5 mL) every 12 hours to 300 mg (or 7.5 mL) every 12 hours. • For adult patients weighing less than 40 kg, the oral maintenance dose for VFEND tablets or oral suspension may be increased from 100 mg (or 2.5 mL) every 12 hours to 150 mg (or 3.75 mL) every 12 hours. • If the patient is unable to tolerate 300 mg (or 7.5 mL) orally every 12 hours, reduce the oral maintenance dose of VFEND tablets or oral suspension by 50 mg (or 1.25 mL) steps to a minimum of 200 mg (or 5 mL) every 12 hours for adult patients weighing more than 40 kg or to 100 mg (or 2.5 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. 2.4 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. 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 [see Dosage and Administration (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. 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] 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. If patient response is inadequate and the patient is able to tolerate the oral maintenance dose, the dose may be increased by 1 mg/kg (0.025 mL/kg) steps or 50 mg (1.25 mL) steps to a maximum of 350 mg (8.75 mL) every 12 hours. If patients are unable to tolerate the initial intravenous maintenance dose, reduce the dose by 1 mg/kg steps. If patients are unable to tolerate the oral maintenance dose, reduce the dose by 1 mg/kg (0.025 mL/kg) or 50 mg (1.25 mL) 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 [see Dosage and Administration (2.3) ] . 2.5 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…
labeling: Hepatic Toxicity [see Warnings and Precautions (5.1) ] Arrhythmias and QT Prolongation [see Warnings and Precautions (5.2) ] Infusion Related Reactions [see Warnings and Precautions (5.3) ] Visual Disturbances [see Warnings and Precautions (5.4) ] Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.5) ] Photosensitivity [see Warnings and Precautions (5.6) ] Renal Toxicity [see Warnings and Precautions (5.7) ] • 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. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 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. Clinical Trials Experience in Adults Overview The most frequently reported adverse reactions (see Table 4 ) in the adult therapeutic trials were visual disturbances (18.7%), fever (5.7%), nausea (5.4%), rash (5.3%), vomiting (4.4%), chills (3.7%), headache (3.0%), liver function test increased (2.7%), tachycardia (2.4%), hallucinations (2.4%). The adverse reactions which most often led to discontinuation of voriconazole therapy were elevated liver function tests, rash, and visual disturbances [see Warning and Precautions (5.1 , 5.4) and Adverse Reactions (6.1) ] . 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. 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%. 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). In study 608, 403 patients with candidemia were treated to compare voriconazole (272 patients) to the regimen of amphotericin B followed by fluconazole (131 patients). The rate of discontinuation from voriconazole study medication due to adverse 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. 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. Possibly Related to Therapy or Causality Unknown Study 307/602: IA; Study 608: candidemia; Study 305: EC 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 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 [see Warnings and Precautions (5.4) ] . 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. Erythema multiforme has also been reported during treatment with VFEND [see Warnings and Precautions (5.5) and Adverse Reactions (6.2) ] . VFEND has also been associated with additional photosensitivity related skin reactions such as pseudoporphyria, cheilitis, and cutaneous lupus erythematosus [see Warnings and Precautions (5.6) and Adverse Reactions (6.2) ] . 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. Body as a Whole: abdominal pain, abdomen enlarged, allergic reaction, anaphylactoid reaction [see Warnings and Precautions (5.3) ] , 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. Cardiovascular: atrial arrhythmia, atrial fibrillation, AV block complete, bigeminy, bradycardia, bundle branch block, cardiomegaly, cardiomyopathy, cerebral hemorrhage, cerebral ischemia, cerebrovascular accident, congestive heart failure, deep thrombophlebitis, endocarditis, extrasystoles, heart arrest, hypertension, hypotension, myocardial infarction, nodal arrhythmia, palpitation, phlebitis, postural hypotension, pulmonary embolus, QT interval prolonged, supraventricular extrasystoles, supraventricular tachycardia, syncope, thrombophlebitis, vasodilatation, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia (including torsade de pointes ) [see Warnings and Precautions (5.2) ] . 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…
16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Powder for Solution for Injection VFEND I.V. for Injection is supplied in a single-dose vial as a sterile lyophilized powder equivalent to 200 mg voriconazole and 3,200 mg sulfobutyl ether beta-cyclodextrin sodium (SBECD). It does not contain preservatives and is not made with natural rubber latex. Individually packaged vials of 200 mg VFEND I.V. (NDC 0049-4190-01) 16.2 Storage VFEND I.V. for Injection unreconstituted vials should be stored at 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. VFEND is a single dose unpreserved sterile lyophile. From a microbiological point of view, following reconstitution of the lyophile with Water for Injection, the reconstituted solution should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 2°C to 8°C (36°F to 46°F). Chemical and physical in-use stability has been demonstrated for 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 [see Dosage and Administration (2.1) ] .