Vfend

Vfend Manufacturers

• Cardinal Health
  

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  Vfend | Cardinal Health

  

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  Administration

  VFEND Tablets or Oral Suspension should be taken at least one hour before, or one hour following, a meal.

  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 1–2 hours (see Intravenous Administration).

  NOT FOR 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 VFEND therapy (see PRECAUTIONS).

  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.

  Use in Adults Invasive aspergillosis and serious fungal infections due to Fusarium spp. and Scedosporium apiospermum

  For the treatment of adults with invasive aspergillosis and infections due to Fusarium spp. and Scedosporium apiospermum, therapy must be initiated with the specified loading dose regimen of intravenous VFEND to achieve plasma concentrations on Day 1 that are close to steady state. On the basis of high oral bioavailability, switching between intravenous and oral administration is appropriate when clinically indicated (see CLINICAL PHARMACOLOGY). Once the patient can tolerate medication given by mouth, the oral tablet form or oral suspension form of VFEND may be utilized. (See Table 17.)

  Candidemia in nonneutropenic patients and other deep tissue Candida infections

  See Table 17. 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 17. Patients should be treated for a minimum of 14 days and for at least 7 days following resolution of symptoms.

  Table 17: Recommended Dosing Regimen Infection Loading dose Maintenance Dose IV IV Oral* * Patients who weigh 40 kg or more should receive an oral maintenance dose of 200 mg VFEND every 12 hours. Adult patients who weigh less than 40 kg should receive an oral maintenance dose of 100 mg every 12 hours. † In clinical trials, patients with candidemia received 3 mg/kg q12h as primary therapy, while patients with other deep tissue Candida infections received 4 mg/kg as salvage therapy. Appropriate dose should be based on the severity and nature of the infection. ‡ Not evaluated in patients with esophageal candidiasis. Invasive Aspergillosis 6 mg/kg q12h for the first 24 hours 4 mg/kg q12h 200 mg q12h Candidemia in nonneutropenic patients and other deep tissue Candida infections 6 mg/kg q12h for the first 24 hours 3–4 mg/kg q12h † 200 mg q12h Esophageal Candidiasis ‡ ‡ 200 mg q12h Scedosporiosis and Fusariosis 6 mg/kg q12h for the first 24 hours 4 mg/kg q12h 200 mg q12h Dosage Adjustment

  If patient response is inadequate, the oral maintenance dose may be increased from 200 mg every 12 hours to 300 mg every 12 hours. For adult patients weighing less than 40 kg, the oral maintenance dose may be increased from 100 mg every 12 hours to 150 mg every 12 hours. If patients are unable to tolerate 300 mg orally every 12 hours, reduce the oral maintenance dose by 50 mg steps to a minimum of 200 mg every 12 hours (or to 100 mg every 12 hours for adult patients weighing less than 40 kg).

  If patients are unable to tolerate 4 mg/kg IV, reduce the intravenous maintenance dose to 3 mg/kg every 12 hours.

  Phenytoin may be coadministered with VFEND if the intravenous maintenance dose of VFEND is increased to 5 mg/kg every 12 hours, or the oral maintenance dose is increased from 200 mg to 400 mg every 12 hours (100 mg to 200 mg every 12 hours in adult patients weighing less than 40 kg) (see CLINICAL PHARMACOLOGY, PRECAUTIONS - Drug Interactions).

  When voriconazole is coadministered with efavirenz, the voriconazole maintenance dose should be increased to 400 mg Q12h and the efavirenz dose should be decreased to 300 mg Q24h. When treatment with voriconazole is stopped, the initial dosage of efavirenz should be restored (see CLINICAL PHARMACOLOGY and PRECAUTIONS – Drug Interactions).

  Duration of therapy should be based on the severity of the patient's underlying disease, recovery from immunosuppression, and clinical response.

  Use in Geriatric Patients

  No dose adjustment is necessary for geriatric patients.

  Use in Patients with Hepatic Insufficiency

  In the clinical program, patients were included who had baseline liver function tests (ALT, AST) up to 5 times the upper limit of normal. No dose adjustment is necessary in patients with this degree of abnormal liver function, but continued monitoring of liver function tests for further elevations is recommended (see WARNINGS).

  It is recommended that the standard loading dose regimens be used but that the maintenance dose be halved in patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B).

  VFEND has not been studied in patients with severe hepatic cirrhosis (Child-Pugh Class C) or in patients with chronic hepatitis B or chronic hepatitis C disease. VFEND has been associated with elevations in liver function tests and clinical signs of liver damage, such as jaundice, and should only be used in patients with severe hepatic insufficiency if the benefit outweighs the potential risk. Patients with hepatic insufficiency must be carefully monitored for drug toxicity.

  Use in Patients with Renal Insufficiency

  The pharmacokinetics of orally administered VFEND are not significantly affected by renal insufficiency. Therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment (see CLINICAL PHARMACOLOGY - Special Populations).

  In patients with moderate or severe renal insufficiency (creatinine clearance <50 mL/min), accumulation of the intravenous vehicle, SBECD, occurs. Oral voriconazole should be administered to these patients, unless an assessment of the benefit/risk to the patient justifies the use of intravenous voriconazole. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral voriconazole therapy (see DOSAGE and ADMINISTRATION).

  Voriconazole is hemodialyzed with clearance of 121 mL/min. The intravenous vehicle, SBECD, is hemodialyzed with clearance of 55 mL/min. A 4-hour hemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment.

  Intravenous Administration VFEND I.V. 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 1–2 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):

  Calculate the volume of 10 mg/mL VFEND concentrate required based on the patient's weight (see Table 18). 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. 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 1–2 hours at a maximum rate of 3 mg/kg per hour.

  Table 18: Required Volumes of 10 mg/mL VFEND Concentrate 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) 30 9.0 mL (1) 12 mL (1) 18 mL (1) 35 10.5 mL (1) 14 mL (1) 21 mL (2) 40 12.0 mL (1) 16 mL (1) 24 mL (2) 45 13.5 mL (1) 18 mL (1) 27 mL (2) 50 15.0 mL (1) 20 mL (1) 30 mL (2) 55 16.5 mL (1) 22 mL (2) 33 mL (2) 60 18.0 mL (1) 24 mL (2) 36 mL (2) 65 19.5 mL (1) 26 mL (2) 39 mL (2) 70 21.0 mL (2) 28 mL (2) 42 mL (3) 75 22.5 mL (2) 30 mL (2) 45 mL (3) 80 24.0 mL (2) 32 mL (2) 48 mL (3) 85 25.5 mL (2) 34 mL (2) 51 mL (3) 90 27.0 mL (2) 36 mL (2) 54 mL (3) 95 28.5 mL (2) 38 mL (2) 57 mL (3) 100 30.0 mL (2) 40 mL (2) 60 mL (3)

  VFEND I.V. for Injection is a single dose unpreserved sterile lyophile. Therefore, from a microbiological point of view, once reconstituted, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 2° to 8°C (36° 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.

  The reconstituted solution can be diluted with:

  9 mg/mL (0.9%) Sodium Chloride USP

  Lactated Ringers USP

  5% Dextrose and Lactated Ringers USP

  5% Dextrose and 0.45% Sodium Chloride USP

  5% Dextrose USP

  5% Dextrose and 20 mEq Potassium Chloride USP

  0.45% Sodium Chloride USP

  5% Dextrose and 0.9% Sodium Chloride USP

  The compatibility of VFEND I.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.

  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.

  VFEND for Oral Suspension Reconstitution

  Tap the bottle to release the powder. Add 46 mL of water to the bottle. Shake the closed bottle vigorously for about 1 minute. Remove child-resistant cap and push bottle adaptor into the neck of the bottle. Replace the cap. Write the date of expiration of the reconstituted suspension on the bottle label (the shelf-life of the reconstituted suspension is 14 days at controlled room temperature 15–30°C [59–86°F]).

  Instructions for use

  Shake the closed bottle of reconstituted suspension for approximately 10 seconds before each use. The reconstituted oral suspension should only be administered using the oral dispenser supplied with each pack.

  Incompatibilities

  VFEND for Oral Suspension and the 40 mg/mL reconstituted oral suspension should not be mixed with any other medication or additional flavoring agent. It is not intended that the suspension be further diluted with water or other vehicles.

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  Vfend | Roerig

  

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  2.1 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 2 hours.

  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 (5.7)].

  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 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 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 IV; a 300 mg oral dose achieves an exposure similar to 4 mg/kg IV. Switching between the intravenous and oral formulations is appropriate because of the high bioavailability of the oral formulation in adults [see Clinical Pharmacology (12)].

  Candidemia in non-neutropenic patients and other deep tissue Candida infections

  See Table 1. Patients should be treated for at least 14 days following resolution of symptoms or following last positive culture, whichever is longer.

  Esophageal Candidiasis

  See Table 1. Patients should be treated for a minimum of 14 days and for at least 7 days following resolution of symptoms.

  Table 1: Recommended Dosing Regimen Infection Loading dose Maintenance Dose*,† IV IV Oral‡ * Increase dose when VFEND is co-administered with phenytoin or efavirenz ( 7); Decrease dose in patients with hepatic impairment ( 2.6) † In healthy volunteer studies, the 200 mg oral q12h dose provided an exposure (AUC τ) similar to a 3 mg/kg IV q12h dose; the 300 mg oral q12h dose provided an exposure (AUC τ) similar to a 4 mg/kg IV q12h dose [see Clinical Pharmacology (12)]. ‡ Adult patients who weigh less than 40 kg should receive half of the oral maintenance dose. § In a clinical study of invasive aspergillosis, the median duration of IV VFEND therapy was 10 days (range 2–85 days). The median duration of oral VFEND therapy was 76 days (range 2–232 days) [see Clinical Studies (14.1)]. ¶ In clinical trials, patients with candidemia received 3 mg/kg IV q12h as primary therapy, while patients with other deep tissue Candida infections received 4 mg/kg q12h as salvage therapy. Appropriate dose should be based on the severity and nature of the infection. # Not evaluated in patients with esophageal candidiasis.   Invasive Aspergillosis§ 6 mg/kg q12h for the first 24 hours 4 mg/kg q12h 200 mg q12h   Candidemia in nonneutropenic patients and other deep tissue Candida infections 6 mg/kg q12h for the first 24 hours 3–4 mg/kg q12h¶ 200 mg q12h   Esophageal Candidiasis # # 200 mg q12h   Scedosporiosis and Fusariosis 6 mg/kg q12h for the first 24 hours 4 mg/kg q12h 200 mg q12h 2.4 Dosage Adjustment

  If patient response is inadequate, the oral maintenance dose may be increased from 200 mg every 12 hours (similar to 3 mg/kg IV q12h) to 300 mg every 12 hours (similar to 4 mg/kg IV q12h). For adult patients weighing less than 40 kg, the oral maintenance dose may be increased from 100 mg every 12 hours to 150 mg every 12 hours. If patient is unable to tolerate 300 mg orally every 12 hours, reduce the oral maintenance dose by 50 mg steps to a minimum of 200 mg every 12 hours (or to 100 mg every 12 hours for adult patients weighing less than 40 kg).

  If patient is unable to tolerate 4 mg/kg IV q12h, reduce the intravenous maintenance dose to 3 mg/kg q12h.

  The maintenance dose of voriconazole should be increased when co-administered with phenytoin or efavirenz [see Drug Interactions (7)].

  The maintenance dose of voriconazole should be reduced in patients with mild to moderate hepatic impairment, Child-Pugh Class A and B [see Dosage and Administration (2.7)]. There are no PK data to allow for dosage adjustment recommendations in patients with severe hepatic impairment (Child-Pugh Class C).

  Duration of therapy should be based on the severity of the patient's underlying disease, recovery from immunosuppression, and clinical response.

  2.5 Intravenous Administration

  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 1–2 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):

  Calculate the volume of 10 mg/mL VFEND concentrate required based on the patient's weight (see Table 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. 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 1–2 hours at a maximum rate of 3 mg/kg per hour.

  Table 2: Required Volumes of 10 mg/mL VFEND Concentrate Volume of VFEND Concentrate (10 mg/mL) required for: Body Weight
  (kg) 3 mg/kg dose
  (number of vials) 4 mg/kg dose
  (number of vials) 6 mg/kg dose
  (number of vials) 30 9.0 mL (1) 12 mL (1) 18 mL (1) 35 10.5 mL (1) 14 mL (1) 21 mL (2) 40 12.0 mL (1) 16 mL (1) 24 mL (2) 45 13.5 mL (1) 18 mL (1) 27 mL (2) 50 15.0 mL (1) 20 mL (1) 30 mL (2) 55 16.5 mL (1) 22 mL (2) 33 mL (2) 60 18.0 mL (1) 24 mL (2) 36 mL (2) 65 19.5 mL (1) 26 mL (2) 39 mL (2) 70 21.0 mL (2) 28 mL (2) 42 mL (3) 75 22.5 mL (2) 30 mL (2) 45 mL (3) 80 24.0 mL (2) 32 mL (2) 48 mL (3) 85 25.5 mL (2) 34 mL (2) 51 mL (3) 90 27.0 mL (2) 36 mL (2) 54 mL (3) 95 28.5 mL (2) 38 mL (2) 57 mL (3) 100 30.0 mL (2) 40 mL (2) 60 mL (3)

  VFEND I.V. for Injection is a single dose unpreserved sterile lyophile. Therefore, from a microbiological point of view, once reconstituted, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 2° to 8°C (36° 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.

  The reconstituted solution can be diluted with:

  9 mg/mL (0.9%) Sodium Chloride USP
  Lactated Ringers USP
  5% Dextrose and Lactated Ringers USP
  5% Dextrose and 0.45% Sodium Chloride USP
  5% Dextrose USP
  5% Dextrose and 20 mEq Potassium Chloride USP
  0.45% Sodium Chloride USP
  5% Dextrose and 0.9% Sodium Chloride USP

  The compatibility of VFEND I.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.

  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.

  2.6 Use in Patients With Hepatic Impairment

  In the clinical program, patients were included who had baseline liver function tests (ALT, AST) up to 5 times the upper limit of normal. No dose adjustment is necessary in patients with this degree of abnormal liver function, but continued monitoring of liver function tests for further elevations is recommended [see Warnings and Precautions (5.9)].

  It is recommended that the standard loading dose regimens be used but that the maintenance dose be halved in patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B) [see Clinical Pharmacology (12.3)].

  VFEND has not been studied in patients with severe hepatic cirrhosis (Child-Pugh Class C) or in patients with chronic hepatitis B or chronic hepatitis C disease. VFEND has been associated with elevations in liver function tests and clinical signs of liver damage, such as jaundice, and should only be used in patients with severe hepatic impairment if the benefit outweighs the potential risk. Patients with hepatic insufficiency must be carefully monitored for drug toxicity.

  2.7 Use in Patients With Renal Impairment

  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 [see Clinical Pharmacology (12.3)].

  In patients with moderate or severe renal impairment (creatinine clearance <50 mL/min), accumulation of the intravenous vehicle, SBECD, occurs. Oral voriconazole should be administered to these patients, unless an assessment of the benefit/risk to the patient justifies the use of intravenous voriconazole. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral voriconazole therapy [see Warnings and Precautions (5.10)].

  Voriconazole is hemodialyzed with clearance of 121 mL/min. The intravenous vehicle, SBECD, is hemodialyzed with clearance of 55 mL/min. A 4-hour hemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment.

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  Vfend | Laboratoires Clarins S.a.

  

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  • apply liberally 15 minutes before sun exposure
  • apply to all skin exposed to the sun
  • children under 6 months: Ask a doctor
  • Sun Protection Measures. Spending time in the sun in creases your risk of skin cancer and early skin aging. To decrease this risk, regularly use a sunscreen with broad spectrum SPF of 15 or higher and other sun protection measures including:
  • limit time in the sun, especially from 10 a.m. – 2 p.m.
  • wear long-sleeved shirts, pants, hats and sunglasses
  • reapply at least every 2 hours
  • use a water resistant sun screen if swimming or sweating

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  Vfend | Taro Pharmaceuticals U.s.a., Inc.

  

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  Apply a thin film of betamethasone dipropionate ointment (augmented) to the affected skin areas once or twice daily.

  Therapy should be discontinued when control is achieved. If no improvement is seen within 2 weeks, reassessment of diagnosis may be necessary.

  Betamethasone dipropionate ointment (augmented) is a super-high-potency topical corticosteroid. Treatment with betamethasone dipropionate ointment (augmented) should not exceed 50 g per week because of the potential for the drug to suppress the hypothalamic-pituitary-adrenal (HPA) axis.

  Betamethasone dipropionate ointment (augmented) should not be used with occlusive dressings unless directed by a physician.

  Betamethasone dipropionate ointment (augmented) is for topical use only. It is not for oral, ophthalmic, or intravaginal use.

  Avoid use on the face, groin, or axillae, or if skin atrophy is present at the treatment site.

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  Vfend | Roerig

  

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  2.1 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 2 hours.

  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 (5.7)].

  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 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 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 IV; a 300 mg oral dose achieves an exposure similar to 4 mg/kg IV. Switching between the intravenous and oral formulations is appropriate because of the high bioavailability of the oral formulation in adults [see Clinical Pharmacology (12)].

  Candidemia in non-neutropenic patients and other deep tissue Candida infections

  See Table 1. Patients should be treated for at least 14 days following resolution of symptoms or following last positive culture, whichever is longer.

  Esophageal Candidiasis

  See Table 1. Patients should be treated for a minimum of 14 days and for at least 7 days following resolution of symptoms.

  Table 1: Recommended Dosing Regimen Infection Loading dose Maintenance Dose*,† IV IV Oral‡ * Increase dose when VFEND is co-administered with phenytoin or efavirenz (7); Decrease dose in patients with hepatic impairment ( 2.6) † In healthy volunteer studies, the 200 mg oral q12h dose provided an exposure (AUC τ) similar to a 3 mg/kg IV q12h dose; the 300 mg oral q12h dose provided an exposure (AUC τ) similar to a 4 mg/kg IV q12h dose [see Clinical Pharmacology (12)]. ‡ Adult patients who weigh less than 40 kg should receive half of the oral maintenance dose. § In a clinical study of invasive aspergillosis, the median duration of IV VFEND therapy was 10 days (range 2–85 days). The median duration of oral VFEND therapy was 76 days (range 2–232 days) [see Clinical Studies (14.1)]. ¶ In clinical trials, patients with candidemia received 3 mg/kg IV q12h as primary therapy, while patients with other deep tissue Candida infections received 4 mg/kg q12h as salvage therapy. Appropriate dose should be based on the severity and nature of the infection. # Not evaluated in patients with esophageal candidiasis. Invasive Aspergillosis§ 6 mg/kg q12h for the first 24 hours 4 mg/kg q12h 200 mg q12h Candidemia in nonneutropenic patients and other deep tissue Candida infections 6 mg/kg q12h for the first 24 hours 3–4 mg/kg q12h¶ 200 mg q12h Esophageal Candidiasis # # 200 mg q12h Scedosporiosis and Fusariosis 6 mg/kg q12h for the first 24 hours 4 mg/kg q12h 200 mg q12h 2.4 Dosage Adjustment

  If patient response is inadequate, the oral maintenance dose may be increased from 200 mg every 12 hours (similar to 3 mg/kg IV q12h) to 300 mg every 12 hours (similar to 4 mg/kg IV q12h). For adult patients weighing less than 40 kg, the oral maintenance dose may be increased from 100 mg every 12 hours to 150 mg every 12 hours. If patient is unable to tolerate 300 mg orally every 12 hours, reduce the oral maintenance dose by 50 mg steps to a minimum of 200 mg every 12 hours (or to 100 mg every 12 hours for adult patients weighing less than 40 kg).

  If patient is unable to tolerate 4 mg/kg IV q12h, reduce the intravenous maintenance dose to 3 mg/kg q12h.

  The maintenance dose of voriconazole should be increased when co-administered with phenytoin or efavirenz [see Drug Interactions (7)].

  The maintenance dose of voriconazole should be reduced in patients with mild to moderate hepatic impairment, Child-Pugh Class A and B [see Dosage and Administration (2.7)]. There are no PK data to allow for dosage adjustment recommendations in patients with severe hepatic impairment (Child-Pugh Class C).

  Duration of therapy should be based on the severity of the patient's underlying disease, recovery from immunosuppression, and clinical response.

  2.5 Intravenous Administration

  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 1–2 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):

  Calculate the volume of 10 mg/mL VFEND concentrate required based on the patient's weight (see Table 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. 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 1–2 hours at a maximum rate of 3 mg/kg per hour.

  Table 2: Required Volumes of 10 mg/mL VFEND Concentrate 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) 30 9.0 mL (1) 12 mL (1) 18 mL (1) 35 10.5 mL (1) 14 mL (1) 21 mL (2) 40 12.0 mL (1) 16 mL (1) 24 mL (2) 45 13.5 mL (1) 18 mL (1) 27 mL (2) 50 15.0 mL (1) 20 mL (1) 30 mL (2) 55 16.5 mL (1) 22 mL (2) 33 mL (2) 60 18.0 mL (1) 24 mL (2) 36 mL (2) 65 19.5 mL (1) 26 mL (2) 39 mL (2) 70 21.0 mL (2) 28 mL (2) 42 mL (3) 75 22.5 mL (2) 30 mL (2) 45 mL (3) 80 24.0 mL (2) 32 mL (2) 48 mL (3) 85 25.5 mL (2) 34 mL (2) 51 mL (3) 90 27.0 mL (2) 36 mL (2) 54 mL (3) 95 28.5 mL (2) 38 mL (2) 57 mL (3) 100 30.0 mL (2) 40 mL (2) 60 mL (3)

  VFEND I.V. for Injection is a single dose unpreserved sterile lyophile. Therefore, from a microbiological point of view, once reconstituted, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 2° to 8°C (36° 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.

  The reconstituted solution can be diluted with:

  9 mg/mL (0.9%) Sodium Chloride USP

  Lactated Ringers USP

  5% Dextrose and Lactated Ringers USP

  5% Dextrose and 0.45% Sodium Chloride USP

  5% Dextrose USP

  5% Dextrose and 20 mEq Potassium Chloride USP

  0.45% Sodium Chloride USP

  5% Dextrose and 0.9% Sodium Chloride USP

  The compatibility of VFEND I.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.

  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.

  2.6 Use in Patients With Hepatic Impairment

  In the clinical program, patients were included who had baseline liver function tests (ALT, AST) up to 5 times the upper limit of normal. No dose adjustment is necessary in patients with this degree of abnormal liver function, but continued monitoring of liver function tests for further elevations is recommended [see Warnings and Precautions (5.9)].

  It is recommended that the standard loading dose regimens be used but that the maintenance dose be halved in patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B) [see Clinical Pharmacology (12.3)].

  VFEND has not been studied in patients with severe hepatic cirrhosis (Child-Pugh Class C) or in patients with chronic hepatitis B or chronic hepatitis C disease. VFEND has been associated with elevations in liver function tests and clinical signs of liver damage, such as jaundice, and should only be used in patients with severe hepatic impairment if the benefit outweighs the potential risk. Patients with hepatic insufficiency must be carefully monitored for drug toxicity.

  2.7 Use in Patients With Renal Impairment

  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 [see Clinical Pharmacology (12.3)].

  In patients with moderate or severe renal impairment (creatinine clearance <50 mL/min), accumulation of the intravenous vehicle, SBECD, occurs. Oral voriconazole should be administered to these patients, unless an assessment of the benefit/risk to the patient justifies the use of intravenous voriconazole. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral voriconazole therapy [see Warnings and Precautions (5.10)].

  Voriconazole is hemodialyzed with clearance of 121 mL/min. The intravenous vehicle, SBECD, is hemodialyzed with clearance of 55 mL/min. A 4-hour hemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment.

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