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Vfend (Voriconazole) - Indications and Dosage

 
 



INDICATIONS AND USAGE

VFEND is indicated for use in the treatment of the following fungal infections:

Invasive aspergillosis. 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, MICROBIOLOGY).

Candidemia in nonneutropenic patients and the following Candida infections: disseminated infections in skin and infections in abdomen, kidney, bladder wall, and wounds (see CLINICAL STUDIES, MICROBIOLOGY).

Esophageal candidiasis (see CLINICAL STUDIES, MICROBIOLOGY).

Serious fungal infections caused by Scedosporium apiospermum (asexual form of Pseudallescheria boydii) and Fusarium spp. including Fusarium solani, in patients intolerant of, or refractory to, other therapy (see CLINICAL STUDIES, MICROBIOLOGY).

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 AND ADMINISTRATION

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
InfectionLoading doseMaintenance Dose
IVIVOral 1
Invasive Aspergillosis 6 mg/kg q12h for the first 24 hours4 mg/kg q12h200 mg q12h
Candidemia in nonneutropenic patients and other deep tissue Candida infections 6 mg/kg q12h for the first 24 hours3–4 mg/kg q12h 2 200 mg q12h
Esophageal Candidiasis 3 200 mg q12h
Scedosporiosis and Fusariosis 6 mg/kg q12h for the first 24 hours4 mg/kg q12h200 mg q12h

1 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.
2 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.
3 Not evaluated in patients with esophageal candidiasis.

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):

  1. Calculate the volume of 10 mg/mL VFEND concentrate required based on the patient's weight (see Table 18).
  2. In order to allow the required volume of VFEND concentrate to be added, withdraw and discard at least an equal volume of diluent from the infusion bag or bottle to be used. The volume of diluent remaining in the bag or bottle should be such that when the 10 mg/mL VFEND concentrate is added, the final concentration is not less than 0.5 mg/mL nor greater than 5 mg/mL.
  3. Using a suitable size syringe and aseptic technique, withdraw the required volume of VFEND concentrate from the appropriate number of vials and add to the infusion bag or bottle. Discard Partially Used Vials.

The final VFEND solution must be infused over 1–2 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)
309.0 mL (1)12 mL (1)18 mL (1)
3510.5 mL (1)14 mL (1)21 mL (2)
4012.0 mL (1)16 mL (1)24 mL (2)
4513.5 mL (1)18 mL (1)27 mL (2)
5015.0 mL (1)20 mL (1)30 mL (2)
5516.5 mL (1)22 mL (2)33 mL (2)
6018.0 mL (1)24 mL (2)36 mL (2)
6519.5 mL (1)26 mL (2)39 mL (2)
7021.0 mL (2)28 mL (2)42 mL (3)
7522.5 mL (2)30 mL (2)45 mL (3)
8024.0 mL (2)32 mL (2)48 mL (3)
8525.5 mL (2)34 mL (2)51 mL (3)
9027.0 mL (2)36 mL (2)54 mL (3)
9528.5 mL (2)38 mL (2)57 mL (3)
10030.0 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.

HOW SUPPLIED

Powder for Solution for Injection

VFEND I.V. for Injection is supplied in a single use vial as a sterile lyophilized powder equivalent to 200 mg VFEND and 3200 mg sulfobutyl ether beta-cyclodextrin sodium (SBECD).

Individually packaged vials of 200 mg VFEND I.V.
      (NDC 0049-3190-28)

Tablets

VFEND 50 mg tablets; white, film-coated, round, debossed with "Pfizer" on one side and "VOR50" on the reverse.
     Bottles of 30 (NDC 0049-3170-30)

VFEND 200 mg tablets; white, film-coated, capsule shaped, debossed with "Pfizer" on one side and "VOR200" on the reverse.
     Bottles of 30 (NDC 0049-3180-30)

Powder for Oral Suspension

VFEND for Oral Suspension is supplied in 100 mL high density polyethylene (HDPE) bottles. Each bottle contains 45 g of powder for oral suspension. Following reconstitution, the volume of the suspension is 75 mL, providing a usable volume of 70 mL (40 mg voriconazole/mL). A 5 mL oral dispenser and a press-in bottle adaptor are also provided.
     (NDC 0049-3160-44)

STORAGE

VFEND I.V. for Injection unreconstituted vials should be stored at 15° – 30°C (59° – 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° to 8°C (36° to 46°F). Chemical and physical in-use stability has been demonstrated for 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 (see DOSAGE AND ADMINISTRATION - Intravenous Administration).

VFEND Tablets should be stored at 15° – 30°C (59° – 86°F) [see USP Controlled Room Temperature].

VFEND Powder for Oral Suspension should be stored at 2° – 8°C (36° – 46° F) (in a refrigerator) before reconstitution. The shelf-life of the powder for oral suspension is 18 months.

The reconstituted suspension should be stored at 15° – 30°C (59° – 86°F) [see USP Controlled Room Temperature]. Do not refrigerate or freeze. Keep the container tightly closed. The shelf-life of the reconstituted suspension is 14 days. Any remaining suspension should be discarded 14 days after reconstitution.

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