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Vfend IV for injection requires reconstitution to 10 mg/mL and subsequent dilution to ≤5 mg/mL prior to administration as an infusion, at a maximum rate of 3 mg/kg/hr over 1-2 hrs (see IV administration).
Not for IV bolus injection.
Electrolyte disturbances eg, hypokalemia, hypomagnesemia and hypocalcemia should be corrected prior to initiation of Vfend therapy (see Precautions).
Adults: Therapy must be initiated with the specific loading dose regimen of IV Vfend to achieve plasma concentrations on Day 1 that are close to steady state. On the basis of high oral bioavailability, switching between IV and oral administration is appropriate when clinically indicated (see Actions).
For the treatment of adults with invasive aspergillosis and infections due to Fusarium spp and Scedosporium apiospermum, the recommended dosing regimen is as follows: Loading dose of 6 mg/kg Vfend IV every 12 hrs for 2 doses, followed by a maintenance of 4 mg/kg Vfend IV every 12 hrs.
Once the patient can tolerate medication given by mouth, the oral tablet form of voriconazole may be utilized. Patients who weigh >40 kg should receive an oral maintenance dose of 200 mg Vfend tablet every 12 hrs. Adult patients who weigh <40 kg should receive an oral maintenance dose of 100 mg every 12 hrs.
Detailed information on dosage recommendations is provided in the following table: (See Table 6.)
Click on icon to see table/diagram/imageDosage Adjustment: If patient response is inadequate, the oral maintenance dose may be increased from 200 mg every 12 hrs to 300 mg every 12 hrs. For adult patients weighing <40 kg, the oral maintenance dose may be increased from 100 mg every 12 hrs to 150 mg every 12 hrs.
If patient's response at 3 mg/kg every 12 hrs is inadequate, the IV maintenance dose may be increased to 4 mg/kg every 12 hrs. If patients are unable to tolerate treatment, reduce the IV maintenance dose to 3 mg/kg every 12 hrs and the oral maintenance dose by 50 mg steps to a minimum of 200 mg every 12 hrs (or to 100 mg every 12 hrs for adult patients weighing <40 kg).
Phenytoin may be co-administered with Vfend if the maintenance dose of Vfend is increased to 5 mg/kg IV every 12 hrs, or from 200-400 mg every 12 hrs orally (100-200 mg every 12 hrs orally in adult patients weighing <40 kg) (see Actions and Interactions).
When voriconazole is co-administered with adjusted dose of efavirenz, voriconazole maintenance dose should be increased to 400 mg every 12 hrs (see Contraindications, Warnings, Precautions and Interactions).
Duration of therapy should be based on the severity of the patient's underlying disease, recovery from immunosuppression and clinical response.
Elderly: No dose adjustment is necessary for geriatric patients.
Children: Safety and effectiveness in pediatric <2 years has not been established (see Pharmacology under Actions). Therefore, voriconazole is not recommended for children <2 years.
The recommended maintenance dosing regimen in pediatric patients 2 to <12 years is as follows (see Table 7):
Click on icon to see table/diagram/imageIf pediatric patients are unable to tolerate an IV dose of 7 mg/kg twice daily, a dose reduction from 7 mg/kg to 4 mg/kg twice daily may be considered based on the population pharmacokinetic analysis and previous clinical experiences. This provides equivalent exposure to 3 mg/kg twice daily in adults (see previously mentioned texts).
Use in pediatric patients aged 2 to <12 years with hepatic or renal insufficiency has not been studied (see Pharmacokinetics under Actions and Adverse Reactions).
These pediatric dose recommendations are based on studies in which Vfend was administered as the powder oral suspension formulation. Bioequivalence between the powder for oral suspension and tablets has not been investigated in a pediatric population. Considering the assumed limited gastroenteric transit time in pediatrics, the absorption of tablets may be different in pediatric compared to adult patients.
Adolescents (12-16 years) should be dosed as adults.
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 eg, 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.
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 Pharmacokinetics: Special Populations under Actions).
In patients with moderate to severe renal insufficiency (CrCl <50 mL/min), accumulation of the IV 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 IV 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.
Voriconazole is hemodialyzed with clearance of 121 mL/min. The IV vehicle, SBECD, is hemodialyzed with clearance of 55 mL/min. A 4-hr hemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment.
IV Administration: Vfend for IV 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 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 hrs at a concentration of ≤5 mg/mL. Therefore, the required volume of the 10 mg/mL Vfend concentrate should be further diluted as follows (appropriate diluents listed as follows):
Calculate the volume of 10 mg/mL Vfend concentrate required based on the patient's weight (see Table 7).
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 hrs at a maximum rate of 3 mg/kg/hr. (See Table 8.)
Click on icon to see table/diagram/imageVfend 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 hrs at 2°-8°C. This medicinal product is for single use only and any unused solution should be discarded. Only clear solutions without particles should be used.
The reconstitution solutions can be diluted with: 9 mg/mL (0.9%) Sodium Chloride, Lactated Ringer's, 5% Dextrose and Lactated Ringer's, 5% Dextrose and 0.45% Sodium Chloride, 5% Dextrose, 5% Dextrose and 20 mEq Potassium Chloride, 0.45% Sodium Chloride, 5% Dextrose and 0.9% Sodium Chloride.
The compatibility of Vfend IV with diluents other than those described previously is unknown (see Interactions: Incompatibilities).
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
