Voritrol

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Voritrol uses


1 INDICATIONS AND USAGE

Voritrol is indicated for use in patients 12 years of age and older in the treatment of the following fungal infections:

Voritrol is an azole antifungal indicated for use in the treatment of:

1.1 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 (14.1) and Clinical Pharmacology (12.4) ].

1.2 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 and Clinical Pharmacology (12.4) ]

1.3 Esophageal Candidiasis

[see Clinical Studies (14.3) and Clinical Pharmacology (12.4) ]

1.4 Serious Fungal Infections Caused by Scedosporium apiospermum and Fusarium spp. Including Fusarium solani, in Patients Intolerant of, or Refractory to, Other Therapy

[see Clinical Studies (14.4) and Clinical Pharmacology (12.4) ]

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.

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2 DOSAGE AND ADMINISTRATION

Infection Loading dose Maintenance Dose
IV IV Oral
Invasive Aspergillosis 6 mg/kg q12h for the first 24 hours 4 mg/kg q12h 200 mg q12h
Candidemia in nonneutropenics and other deep tissue Candida infections 3–4 mg/kg q12h 200 mg q12h
Scedosporiosis and Fusariosis 4 mg/kg q12h 200 mg q12h
Esophageal Candidiasis Not Evaluated not evaluated 200 mg q12h

2.1 Instructions for Use in All Patients

Voritrol Tablets or Oral Suspension should be taken at least one hour before or after a meal.

Voritrol 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 Voritrol I.V. With Other Parenteral Drug Products

Blood products and concentrated electrolytes

Voritrol 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. Electrolyte disturbances such as hypokalemia, hypomagnesemia and hypocalcemia should be corrected prior to initiation of and during Voritrol therapy [see Warnings and Precautions (5.8) ].

Intravenous solutions containing (non-concentrated) electrolytes

Voritrol 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)

Voritrol 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 Voritrol 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 Voritrol 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 Voritrol may be utilized. The recommended oral maintenance dose of 200 mg achieves a Voritrol 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

Esophageal Candidiasis

Infection Loading dose Maintenance DoseIncrease dose when Voritrol is co-administered with phenytoin or efavirenz (7); Decrease dose in patients with hepatic impairment (2.7) , In healthy volunteer studies, the 200 mg oral q12h dose provided an exposure (AUCτ) similar to a 3 mg/kg IV q12h dose; the 300 mg oral q12h dose provided an exposure (AUCτ) similar to a 4 mg/kg IV q12h dose [see Clinical Pharmacology (12) ].
IV IV OralAdult patients who weigh less than 40 kg should receive half of the oral maintenance dose.
Invasive AspergillosisIn a clinical study of invasive aspergillosis, the median duration of IV Voritrol therapy was 10 days (range 2–85 days). The median duration of oral Voritrol therapy was 76 days (range 2–232 days) [see Clinical Studies (14.1) ]. 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 q12hIn 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. 200 mg q12h
Esophageal Candidiasis Not evaluated in patients with 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 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 Voritrol should be increased when co-administered with phenytoin or efavirenz [see Drug Interactions (7) ].

The maintenance dose of Voritrol 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 Voritrol. 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

Voritrol 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 Voritrol concentrate should be further diluted as follows (appropriate diluents listed below):


The final Voritrol solution must be infused over 1–2 hours at a maximum rate of 3 mg/kg per hour.

Volume of Voritrol 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)

Voritrol 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 Voritrol I.V. with diluents other than those described above is unknown.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Incompatibilities

Voritrol I.V. must not be diluted with 4.2% Sodium Bicarbonate Infusion. The mildly alkaline nature of this diluent caused slight degradation of Voritrol 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 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.

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

Voritrol 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.

2.7 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) ].

Voritrol 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. Voritrol 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 impairment must be carefully monitored for drug toxicity.

2.8 Use in Patients With Renal Impairment

The pharmacokinetics of orally administered Voritrol 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 Voritrol should be administered to these patients, unless an assessment of the benefit/risk to the patient justifies the use of intravenous Voritrol. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral Voritrol therapy [see Warnings and Precautions (5.10) ].

Voritrol 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 Voritrol to warrant dose adjustment.

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3 DOSAGE FORMS AND STRENGTHS


Powder for Solution for Injection

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

Tablets

Voritrol 50 mg tablets; white, film-coated, round, debossed with "Pfizer" on one side and "VOR50" on the reverse.

Voritrol 200 mg tablets; white, film-coated, capsule shaped, debossed with "Pfizer" on one side and "VOR200" on the reverse.

Powder for Oral Suspension

Voritrol 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.

4 CONTRAINDICATIONS

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5 WARNINGS AND PRECAUTIONS

5.1 Drug Interactions

See Table 7 for a listing of drugs that may significantly alter Voritrol concentrations. Also, see Table 8 for a listing of drugs that may interact with Voritrol resulting in altered pharmacokinetics or pharmacodynamics of the other drug [see Contraindications (4) and Drug Interactions (7) ].

5.2 Hepatic Toxicity

In clinical trials, there have been uncommon cases of serious hepatic reactions during treatment with Voritrol. 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. Liver dysfunction has usually been reversible on discontinuation of therapy [see Warnings and Precautions (5.9) and Adverse Reactions (6.3) ].

Measure serum transaminase levels and bilirubin at the initiation of Voritrol 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. If liver function tests become markedly elevated compared to baseline, Voritrol should be discontinued unless the medical judgment of the benefit-risk of the treatment for the patient justifies continued use [see Warnings and Precautions (5.9), Dosage and Administration (2.4, 2.7), and Adverse Reactions (6.3) ].

5.3 Visual Disturbances

The effect of Voritrol on visual function is not known if treatment continues beyond 28 days. There have been post-marketing reports of prolonged visual adverse events, including optic neuritis and papilledema. If treatment continues beyond 28 days, visual function including visual acuity, visual field and color perception should be monitored [see Adverse Reactions (6.2) ].

5.4 Embryo-Fetal Toxicity

Voritrol can cause fetal harm when administered to a pregnant woman.

In animals, Voritrol administration was associated with teratogenicity, embryotoxicity, increased gestational length, dystocia and embryomortality [see Use in Specific Populations ].

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, inform the patient of the potential hazard to the fetus.

5.5 Galactose Intolerance

Voritrol tablets contain lactose and should not be given to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

5.6 Arrhythmias and QT Prolongation

Some azoles, including Voritrol, have been associated with prolongation of the QT interval on the electrocardiogram. During clinical development and post-marketing surveillance, there have been rare cases of arrhythmias,, cardiac arrests and sudden deaths in patients taking Voritrol. 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.

Voritrol should be administered with caution to patients with potentially proarrhythmic conditions, such as:


Rigorous attempts to correct potassium, magnesium and calcium should be made before starting and during Voritrol therapy [see Clinical Pharmacology (12.3) ].

5.7 Infusion Related Reactions

During infusion of the intravenous formulation of Voritrol 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.

5.8 Laboratory Tests

Electrolyte disturbances such as hypokalemia, hypomagnesemia and hypocalcemia should be corrected prior to initiation of and during Voritrol therapy.

Patient management should include laboratory evaluation of renal and hepatic function (particularly liver function tests and bilirubin).

5.9 Patients With Hepatic Impairment

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) receiving Voritrol [see Clinical Pharmacology (12.3) and Dosage and Administration (2.7) ].

Voritrol has not been studied in patients with severe cirrhosis (Child-Pugh Class C). Voritrol 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 impairment must be carefully monitored for drug toxicity.

5.10 Patients With Renal Impairment

In patients with moderate to severe renal dysfunction, accumulation of the intravenous vehicle, SBECD, occurs. Oral Voritrol should be administered to these patients, unless an assessment of the benefit/risk to the patient justifies the use of intravenous Voritrol. Serum creatinine levels should be closely monitored in these patients, and if increases occur, consideration should be given to changing to oral Voritrol therapy [see Clinical Pharmacology (12.3) and Dosage and Administration (2.8) ].

5.11 Monitoring of Renal Function

Acute renal failure has been observed in patients undergoing treatment with Voritrol. Patients being treated with Voritrol are likely to be treated concomitantly with nephrotoxic medications and have concurrent conditions that may result in decreased renal function.

Patients should be monitored for the development of abnormal renal function. This should include laboratory evaluation, particularly serum creatinine.

5.12 Monitoring of Pancreatic Function

Patients with risk factors for acute pancreatitis should be monitored for the development of pancreatitis during Voritrol treatment.

5.13 Dermatological Reactions

Serious exfoliative cutaneous reactions, such as Stevens-Johnson syndrome, have been reported during treatment with Voritrol. If a patient develops an exfoliative cutaneous reaction, Voritrol should be discontinued.

Voritrol has been associated with photosensitivity skin reaction. Patients, including children, should avoid exposure to direct sunlight during Voritrol 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 Voritrol discontinuation should be considered. If Voritrol 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 and melanoma have been reported during long-term Voritrol therapy in patients with photosensitivity skin reactions. If a patient develops a skin lesion consistent with premalignant skin lesions, squamous cell carcinoma or melanoma, Voritrol should be discontinued.

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.

5.14 Skeletal Adverse Events

Fluorosis and periostitis have been reported during long-term Voritrol therapy. If a patient develops skeletal pain and radiologic findings compatible with fluorosis or periostitis, Voritrol should be discontinued [see Adverse Reactions (6.4) ].

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6 ADVERSE REACTIONS

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.

Most common adverse reactions : visual disturbances, fever, nausea, rash, vomiting, chills, headache, liver function test abnormal, tachycardia, hallucinations (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 Overview

The most frequently reported adverse events (all causalities) in the 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 treatment-related adverse events which most often led to discontinuation of Voritrol therapy were elevated liver function tests, rash, and visual disturbances [see Warning and Precautions (5.2, 5.3) and Adverse Reactions (6.2, 6.3) ].

6.2 Clinical Trial Experience in Adults

The data described in Table 3 reflect exposure to Voritrol in 1655 patients in the 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, and was 78% White and 10% Black. Five hundred sixty one patients had a duration of Voritrol therapy of greater than 12 weeks, with 136 patients receiving Voritrol for over six months. Table 3 includes all adverse events which were reported at an incidence of ≥2% during Voritrol 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 Voritrol, 185 on amphotericin B) were treated to compare Voritrol to amphotericin B followed by other licensed antifungal therapy in the primary treatment of patients with acute invasive aspergillosis. The rate of discontinuation from Voritrol study medication due to adverse events was 21.4% (42/196 patients). In study 608, 403 patients with candidemia were treated to compare Voritrol (272 patients) to the regimen of amphotericin B followed by fluconazole (131 patients). The rate of discontinuation from Voritrol study medication due to adverse events was 19.5% out of 272 patients. Study 305 evaluated the effects of oral Voritrol (200 patients) and oral fluconazole (191 patients) in the treatment of esophageal candidiasis. The rate of discontinuation from Voritrol study medication in Study 305 due to adverse events was 7% (14/200 patients). Laboratory test abnormalities for these studies are discussed under Clinical Laboratory Values below.

All Therapeutic Studies Studies 307/602 and 608

(IV/ oral therapy)

Study 305

(oral therapy)

Voritrol

N=1655

Voritrol

N=468

Ampho BAmphotericin B followed by other licensed antifungal therapy

N=185

Ampho B→ Fluconazole

N=131

Voritrol

N=200

Fluconazole

N=191

N (%) N (%) N (%) N (%) N (%) N (%)
Special SensesSee Warnings and Precautions (5.3)
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

Voritrol 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.

There have been post-marketing reports of prolonged visual adverse events, including optic neuritis and papilledema [see Warnings and Precautions (5.3) ].

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 Voritrol on retinal function, Voritrol 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. The effects were noted early in administration of Voritrol and continued through the course of study drug dosing. Fourteen days after end of dosing, ERG, visual fields and color perception returned to normal [see Warnings and Precautions (5.7) ].

Dermatological Reactions

Dermatological reactions were common in the patients treated with Voritrol. The mechanism underlying these dermatologic adverse events remains unknown.

Serious cutaneous reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme have been reported during treatment with Voritrol. If a patient develops an exfoliative cutaneous reaction, Voritrol should be discontinued.

In addition, Voritrol has been associated with photosensitivity skin reactions. Patients should avoid strong, direct sunlight during Voritrol therapy. In patients with photosensitivity skin reactions, squamous cell carcinoma of the skin and melanoma have been reported during long-term therapy. If a patient develops a skin lesion consistent with squamous cell carcinoma or melanoma, Voritrol should be discontinued [see Warnings and Precautions (5.13) ].

Less Common Adverse Events

The following adverse events occurred in <2% of all voriconazole-treated patients in all therapeutic studies (N=1655). This listing includes events where a causal relationship to Voritrol 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 3 above and does not include every event reported in the Voritrol clinical program.

Body as a Whole: abdominal pain, abdomen enlarged, allergic reaction, anaphylactoid reaction [see Warnings and Precautions (5.6) ], 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 (5.6) ].

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, 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.

6.3 Clinical Laboratory Values

The overall incidence of clinically significant transaminase abnormalities in all therapeutic studies was 12.4% (206/1655) of patients treated with Voritrol. 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 following dose adjustment, including discontinuation of therapy.

Voritrol 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 Voritrol therapy. Patients who develop abnormal liver function tests during Voritrol 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). Discontinuation of Voritrol must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to Voritrol [see Warnings and Precautions (5.2) ].

Acute renal failure has been observed in severely ill patients undergoing treatment with Voritrol. Patients being treated with Voritrol are likely to be treated concomitantly with nephrotoxic medications and have concurrent conditions that may result in decreased renal function. It is recommended that patients are monitored for the development of abnormal renal function. This should include laboratory evaluation, particularly serum creatinine.

Tables 4 to 6 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 esophageal candidiasis were randomized to either oral Voritrol or oral fluconazole. In study 307/602, patients with definite or probable invasive aspergillosis were randomized to either Voritrol or amphotericin B therapy. In study 608, patients with candidemia were randomized to either Voritrol or the regimen of amphotericin B followed by fluconazole.

CriteriaWithout regard to baseline value Voritrol Fluconazole
n/N (%) n /N (%)
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
ULN = upper limit of normal
T. Bilirubin >1.5× ULN 8/185 (4.3) 7/186 (3.8)
AST >3.0× ULN 38/187 (20.3) 15/186 (8.1)
ALT >3.0× ULN 20/187 (10.7) 12/186 (6.5)
Alk phos >3.0× ULN 19/187 (10.2) 14/186 (7.5)
CriteriaWithout regard to baseline value Voritrol Amphotericin BAmphotericin B followed by other licensed antifungal therapy
n/N (%) n/N (%)
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
ULN = upper limit of normal
LLN = lower limit of normal
T. Bilirubin >1.5× ULN 35/180 (19.4) 46/173 (26.6)
AST >3.0× ULN 21/180 (11.7) 18/174 (10.3)
ALT >3.0× ULN 34/180 (18.9) 40/173 (23.1)
Alk phos >3.0× ULN 29/181 (16.0) 38/173 (22.0)
Creatinine >1.3× ULN 39/182 (21.4) 102/177 (57.6)
Potassium <0.9× LLN 30/181 (16.6) 70/178 (39.3)
CriteriaWithout regard to baseline value Voritrol Amphotericin B followed by Fluconazole
n/N (%) n/N (%)
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
ULN = upper limit of normal
LLN = lower limit of normal
T. Bilirubin >1.5× ULN 50/261 (19.2) 31/115 (27.0)
AST >3.0× ULN 40/261 (15.3) 16/116 (13.8)
ALT >3.0× ULN 22/261 (8.4) 15/116 (12.9)
Alk phos >3.0× ULN 59/261 (22.6) 26/115 (22.6)
Creatinine >1.3× ULN 39/260 (15.0) 32/118 (27.1)
Potassium <0.9× LLN 43/258 (16.7) 35/118 (29.7)

6.4 Postmarketing Experience

The following adverse reactions have been identified during post approval use of Voritrol. 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.

Skeletal: fluorosis and periostitis have been reported during long-term Voritrol therapy [see Warnings and Precautions (5.14) ].

7 DRUG INTERACTIONS

Drug/Drug Class

(Mechanism of Interaction by the Drug)

Voritrol Plasma Exposure

(Cmax and AUCτ after 200 mg q12h)

Recommendations for Voritrol Dosage Adjustment/Comments
RifampinResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h Voritrol to healthy subjects and Rifabutin

(CYP450 Induction)

Significantly Reduced Contraindicated
Efavirenz (400 mg q24h)Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days Voritrol to healthy subjects

(CYP450 Induction)

Significantly Reduced Contraindicated
Efavirenz (300 mg q24h)

(CYP450 Induction)

Slight Decrease in AUC τ When Voritrol is coadministered with efavirenz, Voritrol oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)

(CYP450 Induction)

Significantly Reduced Contraindicated
Low-dose Ritonavir (100 mg q12h)

(CYP450 Induction)

Reduced Coadministration of Voritrol and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of Voritrol
Carbamazepine

(CYP450 Induction)

Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Long Acting Barbiturates

(CYP450 Induction)

Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction Contraindicated
Phenytoin

(CYP450 Induction)

Significantly Reduced Increase Voritrol maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John's Wort

(CYP450 inducer; P-gp inducer)

Significantly Reduced Contraindicated
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) Increased Monitoring for adverse events and toxicity related to Voritrol is recommended when coadministered with oral contraceptives
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition) Significantly Increased Avoid concomitant administration of Voritrol and fluconazole. Monitoring for adverse events and toxicity related to Voritrol is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors

(CYP3A4 Inhibition)

In Vivo Studies Showed No Significant Effects of Indinavir on Voritrol Exposure No dosage adjustment in the Voritrol dosage needed when coadministered with indinavir
In Vitro Studies Demonstrated Potential for Inhibition of Voritrol Metabolism

(Increased Plasma Exposure)

Frequent monitoring for adverse events and toxicity related to Voritrol when coadministered with other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors

(CYP3A4 Inhibition or CYP450 Induction)

In Vitro Studies Demonstrated Potential for Inhibition of Voritrol Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure) Frequent monitoring for adverse events and toxicity related to Voritrol
A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voritrol to be Induced by Efavirenz and Other NNRTIs

(Decreased Plasma Exposure)

Careful assessment of Voritrol effectiveness
Drug/Drug Class

(Mechanism of Interaction by Voritrol)

Drug Plasma Exposure

(Cmax and AUCτ)

Recommendations for Drug Dosage Adjustment/Comments
SirolimusResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID Voritrol to healthy subjects

(CYP3A4 Inhibition)

Significantly Increased Contraindicated
Rifabutin

(CYP3A4 Inhibition)

Significantly Increased Contraindicated
Efavirenz (400 mg q24h)

(CYP3A4 Inhibition)

Significantly Increased Contraindicated
Efavirenz (300 mg q24h)Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days Voritrol to healthy subjects

(CYP3A4 Inhibition)

Slight Increase in AUCτ When Voritrol is coadministered with efavirenz, Voritrol oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)(CYP3A4 Inhibition) No Significant Effect of Voritrol on Ritonavir Cmax or AUCτ Contraindicated because of significant reduction of Voritrol Cmax and AUCτ
Low-dose Ritonavir (100 mg q12h) Slight Decrease in Ritonavir Cmax and AUCτ Coadministration of Voritrol and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in Voritrol Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of Voritrol
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine

(CYP3A4 Inhibition)

Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids

(CYP450 Inhibition)

Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Contraindicated
Cyclosporine

(CYP3A4 Inhibition)

AUCτ Significantly Increased; No Significant Effect on Cmax When initiating therapy with Voritrol in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When Voritrol is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
MethadoneResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days Voritrol to subjects receiving a methadone maintenance dose (30–100 mg q24h) (CYP3A4 Inhibition) Increased Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition) Increased Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with Voritrol. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7) ]
Alfentanil (CYP3A4 Inhibition) Significantly Increased Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with Voritrol. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see Drug Interactions (7) ].
Oxycodone (CYP3A4 Inhibition) Significantly Increased Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with Voritrol. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7) ].
NSAIDsNon-Steroidal Anti-Inflammatory Drug including. ibuprofen and diclofenac Increased Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [see Drug Interactions (7) ].
(CYP2C9 Inhibition)
Tacrolimus

(CYP3A4 Inhibition)

Significantly Increased When initiating therapy with Voritrol in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When Voritrol is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin

(CYP2C9 Inhibition)

Significantly Increased Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition) Increased Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin

(CYP2C9 Inhibition)

Prothrombin Time Significantly Increased Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole

(CYP2C19/3A4 Inhibition)

Significantly Increased When initiating therapy with Voritrol in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by Voritrol and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors

(CYP3A4 Inhibition)

In Vivo Studies Showed No Significant Effects on Indinavir Exposure No dosage adjustment for indinavir when coadministered with Voritrol
In Vitro Studies Demonstrated Potential for Voritrol to Inhibit Metabolism

(Increased Plasma Exposure)

Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors

(CYP3A4 Inhibition)

A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voritrol to Inhibit Metabolism of Other NNRTIs

(Increased Plasma Exposure)

Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines

(CYP3A4 Inhibition)

In Vitro Studies Demonstrated Potential for Voritrol to Inhibit Metabolism

(Increased Plasma Exposure)

Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins)

(CYP3A4 Inhibition)

In Vitro Studies Demonstrated Potential for Voritrol to Inhibit Metabolism

(Increased Plasma Exposure)

Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers

(CYP3A4 Inhibition)

In Vitro Studies Demonstrated Potential for Voritrol to Inhibit Metabolism

(Increased Plasma Exposure)

Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics

(CYP2C9 Inhibition)

Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids

(CYP3A4 Inhibition)

Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Reserve azole antifungals, including Voritrol, for patients receiving a vinca alkaloid who have no alternative antifungal treatment options.
Everolimus

(CYP3A4 Inhibition)

Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased Concomitant administration of Voritrol and everolimus is not recommended.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Voritrol can cause fetal harm when administered to a pregnant woman. There are no available data on the use of Voritrol in pregnant women. In animal reproduction studies, oral Voritrol was teratogenic in rats and embryotoxic in rabbits. Cleft palates and hydronephrosis/hydroureter were observed in rat pups exposed to Voritrol during organogenesis at and above 10 mg/kg (0.3 times the recommended maintenance dose of 200 mg every 12 hours based on body surface area comparisons). In rabbits, embryomortality, reduced fetal weight and increased incidence of skeletal variations, cervical ribs and extrasternal ossification sites were observed in pups when pregnant rabbits were orally dosed at 100 mg/kg (6 times the RMD based on body surface area comparisons) during organogenesis. Rats exposed to Voritrol from implantation to weaning experienced increased gestational length and dystocia, which were associated with increased perinatal pup mortality at the 10 mg/kg dose. [see Data]. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, inform the patient of the potential hazard to the fetus [see Warnings and Precautions (5.4) ].

The background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20% respectively.

Data

Animal Data

Voritrol was administered orally to pregnant rats during organogenesis (gestation days 6–17) at 10, 30, and 60 mg/kg/day..Voritrol was teratogenic with increased incidences in hydroureter and hydronephrosis at 10 mg/kg/day or greater, approximately 0.3 times the recommended human dose (RMD) based on mg/m2, and cleft palate at 60 mg/kg, approximately 2 times the recommended human dose (RMD) based on mg/m2. Reduced ossification of sacral and caudal vertebrae, skull, pubic, and hyoid bone, supernumerary ribs, anomalies of the sternbrae, and dilatation of the ureter/renal pelvis were also observed at doses of 10 mg/kg or greater. There was no evidence of maternal toxicity at any dose.

Voritrol was administered orally to pregnant rabbits during the period of organogenesis (gestation days 7–19) at 10, 40, and 100 mg/kg/day. Voritrol produced embryofetal toxicity (increased post-implantation loss, decreased fetal body weight) in association with maternal toxicity (decreased body weight gain and food consumption) at 100 mg/kg/day (6 times the RMD based on mg/m2). Fetal skeletal variations (increases in the incidence of cervical rib and extra sternebral ossification sites) were observed at 100 mg/kg/day.

In a peri- and postnatal toxicity study in rats, Voritrol was administered orally to female rats from implantation through the end of lactation at 1, 3, and 10 mg/kg/day. Voritrol prolonged the duration of gestation and labor and produced dystocia with related increases in maternal mortality and decreases in perinatal survival of F1 pups at 10 mg/kg/day, approximately 0.3 times the RMD.

8.2 Lactation

Risk Summary

No data are available regarding the presence of Voritrol in human milk, the effects of Voritrol on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Voritrol and any potential adverse effects on the breastfed child from Voritrol or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

Contraception

Advise females of reproductive potential to use effective contraception during treatment with Voritrol. The coadministration of Voritrol with the oral contraceptive, Ortho-Novum® , results in an interaction between these two drugs, but is unlikely to reduce the contraceptive effect. Monitoring for adverse reactions associated with oral contraceptives and Voritrol is recommended [see Drug Interactions (7) and Clinical Pharmacology (12.3) ].

8.4 Pediatric Use

Safety and effectiveness in pediatric patients below the age of 12 years have not been established.

A total of 22 patients aged 12 to 18 years with invasive aspergillosis were included in the therapeutic studies. Twelve out of 22 (55%) patients had successful response after treatment with a maintenance dose of Voritrol 4 mg/kg q12h.

Sparse plasma sampling for pharmacokinetics in adolescents was conducted in the therapeutic studies [see Clinical Pharmacology (12.3) ]. A population pharmacokinetic analysis was conducted on pooled data from 35 immunocompromised pediatric patients aged 2 to <12 years old who were included in two pharmacokinetic studies of intravenous Voritrol (single dose and multiple dose). Twenty-four of these patients received multiple intravenous maintenance doses of 3 mg/kg and 4 mg/kg. A comparison of the pediatric and adult population pharmacokinetic data revealed that the predicted average steady state plasma concentrations were similar at the maintenance dose of 4 mg/kg every 12 hours in children and 3 mg/kg every 12 hours in adults (medians of 1.19 µg/mL and 1.16 µg/mL in children and adults, respectively).

There have been postmarketing reports of pancreatitis in pediatric patients.

8.5 Geriatric Use

In multiple dose therapeutic trials of Voritrol, 9.2% of patients were ≥65 years of age and 1.8% of patients were ≥75 years of age. In a study in healthy subjects, the systemic exposure (AUC) and peak plasma concentrations (Cmax) were increased in elderly males compared to young males. Pharmacokinetic data obtained from 552 patients from 10 Voritrol therapeutic trials showed that Voritrol plasma concentrations in the elderly patients were approximately 80% to 90% higher than those in younger patients after either IV or oral administration. However, the overall safety profile of the elderly patients was similar to that of the young so no dosage adjustment is recommended [see Clinical Pharmacology (12.3) ].

10 OVERDOSAGE

In clinical trials, there were three cases of accidental overdose. All occurred in pediatric patients who received up to five times the recommended intravenous dose of Voritrol. A single adverse event of photophobia of 10 minutes duration was reported.

There is no known antidote to Voritrol.

Voritrol is hemodialyzed with clearance of 121 mL/min. The intravenous vehicle, SBECD, is hemodialyzed with clearance of 55 mL/min. In an overdose, hemodialysis may assist in the removal of Voritrol and SBECD from the body.

11 DESCRIPTION

Voritrol® (voriconazole), an azole antifungal agent is available as a lyophilized powder for solution for intravenous infusion, film-coated tablets for oral administration, and as a powder for oral suspension. The structural formula is:

Voritrol is designated chemically as (2R,3S)-2-(2, 4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol with an empirical formula of C16H14F3N5O and a molecular weight of 349.3.

Voritrol drug substance is a white to light-colored powder.

Voritrol I.V. is a white lyophilized powder containing nominally 200 mg Voritrol and 3200 mg sulfobutyl ether beta-cyclodextrin sodium in a 30 mL Type I clear glass vial.

Voritrol I.V. is intended for administration by intravenous infusion. It is a single-dose, unpreserved product. Vials containing 200 mg lyophilized Voritrol are intended for reconstitution with Water for Injection to produce a solution containing 10 mg/mL Voritrol and 160 mg/mL of sulfobutyl ether beta-cyclodextrin sodium. The resultant solution is further diluted prior to administration as an intravenous infusion [see Dosage and Administration (2) ].

Voritrol Tablets contain 50 mg or 200 mg of Voritrol. The inactive ingredients include lactose monohydrate, pregelatinized starch, croscarmellose sodium, povidone, magnesium stearate and a coating containing hypromellose, titanium dioxide, lactose monohydrate and triacetin.

Voritrol for Oral Suspension is a white to off-white powder providing a white to off-white orange-flavored suspension when reconstituted. Bottles containing 45 g powder for oral suspension are intended for reconstitution with water to produce a suspension containing 40 mg/mL Voritrol. The inactive ingredients include colloidal silicon dioxide, titanium dioxide, xanthan gum, sodium citrate dihydrate, sodium benzoate, anhydrous citric acid, natural orange flavor, and sucrose.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Voritrol is an antifungal drug [see Microbiology ]

12.2 Pharmacodynamics

Exposure-Response Relationship For Efficacy and Safety

In 10 clinical trials (N=1121), the median values for the average and maximum Voritrol plasma concentrations in individual patients across these studies was 2.51 µg/mL (inter-quartile range 1.21 to 4.44 µg/mL) and 3.79 µg/mL (inter-quartile range 2.06 to 6.31 µg/mL), respectively. A pharmacokinetic-pharmacodynamic analysis of patient data from 6 of these 10 clinical trials (N=280) could not detect a positive association between mean, maximum or minimum plasma Voritrol concentration and efficacy. However, pharmacokinetic/pharmacodynamic analyses of the data from all 10 clinical trials identified positive associations between plasma Voritrol concentrations and rate of both liver function test abnormalities and visual disturbances [see Adverse Reactions (6) ].

Cardiac Electrophysiology

A placebo-controlled, randomized, crossover study to evaluate the effect on the QT interval of healthy male and female subjects was conducted with three single oral doses of Voritrol and ketoconazole. Serial ECGs and plasma samples were obtained at specified intervals over a 24-hour post dose observation period. The placebo-adjusted mean maximum increases in QTc from baseline after 800, 1200, and 1600 mg of Voritrol and after ketoconazole 800 mg were all <10 msec. Females exhibited a greater increase in QTc than males, although all mean changes were <10 msec. Age was not found to affect the magnitude of increase in QTc. No subject in any group had an increase in QTc of ≥60 msec from baseline. No subject experienced an interval exceeding the potentially clinically relevant threshold of 500 msec. However, the QT effect of Voritrol combined with drugs known to prolong the QT interval is unknown [see Contraindications (4) and Drug Interactions (7) ].

12.3 Pharmacokinetics

The pharmacokinetics of Voritrol have been characterized in healthy subjects, special populations and patients.

The pharmacokinetics of Voritrol are non-linear due to saturation of its metabolism. The interindividual variability of Voritrol pharmacokinetics is high. Greater than proportional increase in exposure is observed with increasing dose. It is estimated that, on average, increasing the oral dose from 200 mg q12h to 300 mg q12h leads to an approximately 2.5-fold increase in exposure ; similarly, increasing the intravenous dose from 3 mg/kg q12h to 4 mg/kg q12h produces an approximately 2.5-fold increase in exposure (Table 9).

6 mg/kg IV

(loading dose)

3 mg/kg

IV q12h

4 mg/kg

IV q12h

400 mg Oral

(loading dose)

200 mg

Oral q12h

300 mg

Oral q12h

Note: Parameters were estimated based on non-compartmental analysis from 5 pharmacokinetic studies.
AUC12 = area under the curve over 12 hour dosing interval, Cmax = maximum plasma concentration, Cmin = minimum plasma concentration. CV = coefficient of variation.
N 35 23 40 17 48 16
AUC12 (μg∙h/mL) 13.9 (32) 13.7 (53) 33.9 (54) 9.31 (38) 12.4 (78) 34.0 (53)
Cmax (μg/mL) 3.13 (20) 3.03 (25) 4.77 (36) 2.30 (19) 2.31 (48) 4.74 (35)
Cmin (μg/mL) -- 0.46 (97) 1.73 (74) -- 0.46 (120) 1.63 (79)

When the recommended intravenous loading dose regimen is administered to healthy subjects, plasma concentrations close to steady state are achieved within the first 24 hours of dosing (eg, 6 mg/kg IV q12h on day 1 followed by 3 mg/kg IV q12h). Without the loading dose, accumulation occurs during twice-daily multiple dosing with steady-state plasma Voritrol concentrations being achieved by day 6 in the majority of subjects.

Absorption

The pharmacokinetic properties of Voritrol are similar following administration by the intravenous and oral routes. Based on a population pharmacokinetic analysis of pooled data in healthy subjects (N=207), the oral bioavailability of Voritrol is estimated to be 96% (CV 13%). Bioequivalence was established between the 200 mg tablet and the 40 mg/mL oral suspension when administered as a 400 mg q12h loading dose followed by a 200 mg q12h maintenance dose.

Maximum plasma concentrations (Cmax) are achieved 1–2 hours after dosing. When multiple doses of Voritrol are administered with high-fat meals, the mean Cmax and AUCτ are reduced by 34% and 24%, respectively when administered as a tablet and by 58% and 37% respectively when administered as the oral suspension [see Dosage and Administration (2) ].

In healthy subjects, the absorption of Voritrol is not affected by coadministration of oral ranitidine, cimetidine, or omeprazole, drugs that are known to increase gastric pH.

Distribution

The volume of distribution at steady state for Voritrol is estimated to be 4.6 L/kg, suggesting extensive distribution into tissues. Plasma protein binding is estimated to be 58% and was shown to be independent of plasma concentrations achieved following single and multiple oral doses of 200 mg or 300 mg (approximate range: 0.9–15 µg/mL). Varying degrees of hepatic and renal impairment do not affect the protein binding of Voritrol.

Elimination

Metabolism

In vitro studies showed that Voritrol is metabolized by the human hepatic cytochrome P450 enzymes, CYP2C19, CYP2C9 and CYP3A4 [see Drug Interactions (7) ].

In vivo studies indicated that CYP2C19 is significantly involved in the metabolism of Voritrol. This enzyme exhibits genetic polymorphism [see Clinical Pharmacology (12.5) ].

The major metabolite of Voritrol is the N-oxide, which accounts for 72% of the circulating radiolabelled metabolites in plasma. Since this metabolite has minimal antifungal activity, it does not contribute to the overall efficacy of Voritrol.

Excretion

Voritrol is eliminated via hepatic metabolism with less than 2% of the dose excreted unchanged in the urine. After administration of a single radiolabelled dose of either oral or IV Voritrol, preceded by multiple oral or IV dosing, approximately 80% to 83% of the radioactivity is recovered in the urine. The majority (>94%) of the total radioactivity is excreted in the first 96 hours after both oral and intravenous dosing.

As a result of non-linear pharmacokinetics, the terminal half-life of Voritrol is dose dependent and therefore not useful in predicting the accumulation or elimination of Voritrol.

Specific Populations

Male and Female Patients

In a multiple oral dose study, the mean Cmax and AUCτ for healthy young females were 83% and 113% higher, respectively, than in healthy young males (18–45 years), after tablet dosing. In the same study, no significant differences in the mean Cmax and AUCτ were observed between healthy elderly males and healthy elderly females (>65 years). In a similar study, after dosing with the oral suspension, the mean AUC for healthy young females was 45% higher than in healthy young males whereas the mean Cmax was comparable between genders. The steady state trough Voritrol concentrations (Cmin) seen in females were 100% and 91% higher than in males receiving the tablet and the oral suspension, respectively.

In the clinical program, no dosage adjustment was made on the basis of gender. The safety profile and plasma concentrations observed in male and female subjects were similar. Therefore, no dosage adjustment based on gender is necessary.

Geriatric Patients

In an oral multiple dose study the mean Cmax and AUCτ in healthy elderly males (≥65 years) were 61% and 86% higher, respectively, than in young males (18–45 years). No significant differences in the mean Cmax and AUCτ were observed between healthy elderly females (≥65 years) and healthy young females (18–45 years).

In the clinical program, no dosage adjustment was made on the basis of age. An analysis of pharmacokinetic data obtained from 552 patients from 10 Voritrol clinical trials showed that the median Voritrol plasma concentrations in the elderly patients (>65 years) were approximately 80% to 90% higher than those in the younger patients (≤65 years) after either IV or oral administration. However, the safety profile of Voritrol in young and elderly subjects was similar and, therefore, no dosage adjustment is necessary for the elderly [see Use in Special Populations (8.5) ].

Pediatric Patients

Sparse plasma sampling for pharmacokinetics was conducted in the therapeutic studies in patients aged 12–18 years. In 11 adolescent patients who received a mean Voritrol maintenance dose of 4 mg/kg IV, the median of the calculated mean plasma concentrations was 1.60 µg/mL (inter-quartile range 0.28 to 2.73 µg/mL). In 17 adolescent patients for whom mean plasma concentrations were calculated following a mean oral maintenance dose of 200 mg every 12h, the median of the calculated mean plasma concentrations was 1.16 µg/mL (inter-quartile range 0.85 to 2.14 µg/mL).

Patients with Hepatic Impairment

After a single oral dose (200 mg) of Voritrol in 8 patients with mild (Child-Pugh Class A) and 4 patients with moderate (Child-Pugh Class B) hepatic impairment, the mean systemic exposure (AUC) was 3.2-fold higher than in age and weight matched controls with normal hepatic function. There was no difference in mean peak plasma concentrations (Cmax) between the groups. When only the patients with mild (Child-Pugh Class A) hepatic impairment were compared to controls, there was still a 2.3-fold increase in the mean AUC in the group with hepatic impairment compared to controls.

In an oral multiple dose study, AUCτ was similar in 6 subjects with moderate hepatic impairment (Child-Pugh Class B) given a lower maintenance dose of 100 mg twice daily compared to 6 subjects with normal hepatic function given the standard 200 mg twice daily maintenance dose. The mean peak plasma concentrations (Cmax) were 20% lower in the hepatically impaired group. No pharmacokinetic data are available for patients with severe hepatic cirrhosis (Child-Pugh Class C) [see Dosage and Administration (2.7) ].

Patients with Renal Impairment

In a single oral dose (200 mg) study in 24 subjects with normal renal function and mild to severe renal impairment, systemic exposure (AUC) and peak plasma concentration (Cmax) of Voritrol were not significantly affected by renal impairment. Therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment.

In a multiple dose study of IV Voritrol (6 mg/kg IV loading dose × 2, then 3 mg/kg IV × 5.5 days) in 7 patients with moderate renal dysfunction (creatinine clearance 30–50 mL/min), the systemic exposure (AUC) and peak plasma concentrations (Cmax) were not significantly different from those in 6 subjects with normal renal function.

However, in patients with moderate renal dysfunction (creatinine clearance 30–50 mL/min), accumulation of the intravenous vehicle, SBECD, occurs. The mean systemic exposure (AUC) and peak plasma concentrations (Cmax) of SBECD were increased 4-fold and almost 50%, respectively, in the moderately impaired group compared to the normal control group.

A pharmacokinetic study in subjects with renal failure undergoing hemodialysis showed that Voritrol is dialyzed 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 Voritrol to warrant dose adjustment [see Dosage and Administration (2.8) ].

Patients at Risk of Aspergillosis

The observed Voritrol pharmacokinetics in patients at risk of aspergillosis (mainly patients with malignant neoplasms of lymphatic or hematopoietic tissue) were similar to healthy subjects.

Drug Interaction Studies

Effects of Other Drugs on Voritrol

Voritrol is metabolized by the human hepatic cytochrome P450 enzymes CYP2C19, CYP2C9, and CYP3A4. Results of in vitro metabolism studies indicate that the affinity of Voritrol is highest for CYP2C19, followed by CYP2C9, and is appreciably lower for CYP3A4. Inhibitors or inducers of these three enzymes may increase or decrease Voritrol systemic exposure (plasma concentrations), respectively.

The systemic exposure to Voritrol is significantly reduced or is expected to be reduced by the concomitant administration of the following agents and their use is contraindicated:

Rifampin (potent CYP450 inducer)–Rifampin (600 mg once daily) decreased the steady state Cmax and AUCτ of Voritrol (200 mg q12h × 7 days) by an average of 93% and 96%, respectively, in healthy subjects. Doubling the dose of Voritrol to 400 mg q12h does not restore adequate exposure to Voritrol during coadministration with rifampin. Coadministration of Voritrol and rifampin is contraindicated [see Contraindications (4) and Warnings and Precautions (5.1) ].

Ritonavir (potent CYP450 inducer; CYP3A4 inhibitor and substrate)–The effect of the coadministration of Voritrol and ritonavir (400 mg and 100 mg) was investigated in two separate studies. High-dose ritonavir (400 mg q12h for 9 days) decreased the steady state Cmax and AUCτ of oral Voritrol (400 mg q12h for 1 day, then 200 mg q12h for 8 days) by an average of 66% and 82%, respectively, in healthy subjects. Low-dose ritonavir (100 mg q12h for 9 days) decreased the steady state Cmax and AUCτ of oral Voritrol (400 mg q12h for 1 day, then 200 mg q12h for 8 days) by an average of 24% and 39%, respectively, in healthy subjects. Although repeat oral administration of Voritrol did not have a significant effect on steady state Cmax and AUCτ of high-dose ritonavir in healthy subjects, steady state Cmax and AUCτ of low-dose ritonavir decreased slightly by 24% and 14% respectively, when administered concomitantly with oral Voritrol in healthy subjects. Coadministration of Voritrol and high-dose ritonavir (400 mg q12h) is contraindicated. Coadministration of Voritrol and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of Voritrol [see Contraindications (4) and Warnings and Precautions (5.1) ].

St. John's Wort (CYP450 inducer; P-gp inducer)–In an independent published study in healthy volunteers who were given multiple oral doses of St. John's Wort (300 mg LI 160 extract three times daily for 15 days) followed by a single 400 mg oral dose of Voritrol, a 59% decrease in mean Voritrol AUC0–∞ was observed. In contrast, coadministration of single oral doses of St. John's Wort and Voritrol had no appreciable effect on Voritrol AUC0–∞. Because long-term use of St. John's Wort could lead to reduced Voritrol exposure, concomitant use of Voritrol with St. John's Wort is contraindicated [see Contraindications (4) ].

Carbamazepine and long-acting barbiturates (potent CYP450 inducers)–Although not studied in vitro or in vivo, carbamazepine and long-acting barbiturates (e.g., phenobarbital, mephobarbital) are likely to significantly decrease plasma Voritrol concentrations. Coadministration of Voritrol with carbamazepine or long-acting barbiturates is contraindicated [see Contraindications (4) and Warnings and Precautions (5.1) ].

Significant drug interactions that may require Voritrol dosage adjustment, or frequent monitoring of voriconazole-related adverse events/toxicity:

Fluconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor): Concurrent administration of oral Voritrol (400 mg q12h for 1 day, then 200 mg q12h for 2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg q24h for 4 days) to 6 healthy male subjects resulted in an increase in Cmax and AUCτ of Voritrol by an average of 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. In a follow-on clinical study involving 8 healthy male subjects, reduced dosing and/or frequency of Voritrol and fluconazole did not eliminate or diminish this effect. Concomitant administration of Voritrol and fluconazole at any dose is not recommended. Close monitoring for adverse events related to Voritrol is recommended if Voritrol is used sequentially after fluconazole, especially within 24 hours of the last dose of fluconazole [see Warnings and Precautions (5.1) ].

Minor or no significant pharmacokinetic interactions that do not require dosage adjustment:

Cimetidine (non-specific CYP450 inhibitor and increases gastric pH)–Cimetidine (400 mg q12h × 8 days) increased Voritrol steady state Cmax and AUCτ by an average of 18% (90% CI: 6%, 32%) and 23% (90% CI: 13%, 33%), respectively, following oral doses of 200 mg q12h × 7 days to healthy subjects.

Ranitidine (increases gastric pH)–Ranitidine (150 mg q12h) had no significant effect on Voritrol Cmax and AUCτ following oral doses of 200 mg q12h × 7 days to healthy subjects.

Macrolide antibiotics–Coadministration of erythromycin (CYP3A4 inhibitor; 1g q12h for 7 days) or azithromycin (500 mg q24h for 3 days) with Voritrol 200 mg q12h for 14 days had no significant effect on Voritrol steady state Cmax and AUCτ in healthy subjects. The effects of Voritrol on the pharmacokinetics of either erythromycin or azithromycin are not known.

Effects of Voritrol on Other Drugs

In vitro studies with human hepatic microsomes show that Voritrol inhibits the metabolic activity of the cytochrome P450 enzymes CYP2C19, CYP2C9, and CYP3A4. In these studies, the inhibition potency of Voritrol for CYP3A4 metabolic activity was significantly less than that of two other azoles, ketoconazole and itraconazole. In vitro studies also show that the major metabolite of Voritrol, Voritrol N-oxide, inhibits the metabolic activity of CYP2C9 and CYP3A4 to a greater extent than that of CYP2C19. Therefore, there is potential for Voritrol and its major metabolite to increase the systemic exposure (plasma concentrations) of other drugs metabolized by these CYP450 enzymes.

The systemic exposure of the following drugs is significantly increased or is expected to be significantly increased by coadministration of Voritrol and their use is contraindicated:

Sirolimus (CYP3A4 substrate)–Repeat dose administration of oral Voritrol (400 mg q12h for 1 day, then 200 mg q12h for 8 days) increased the Cmax and AUC of sirolimus (2 mg single dose) an average of 7-fold (90% CI: 5.7, 7.5) and 11-fold (90% CI: 9.9, 12.6), respectively, in healthy male subjects. Coadministration of Voritrol and sirolimus is contraindicated [see Contraindications (4) and Warnings and Precautions (5.1) ].

Terfenadine, astemizole, cisapride, pimozide and quinidine (CYP3A4 substrates)–Although not studied in vitro or in vivo, concomitant administration of Voritrol with terfenadine, astemizole, cisapride, pimozide or quinidine may result in inhibition of the metabolism of these drugs. Increased plasma concentrations of these drugs can lead to QT prolongation and rare occurrences of torsade de pointes. Coadministration of Voritrol and terfenadine, astemizole, cisapride, pimozide and quinidine is contraindicated [see Contraindications (4) and Warnings and Precautions (5.1) ].

Ergot alkaloids–Although not studied in vitro or in vivo, Voritrol may increase the plasma concentration of ergot alkaloids (ergotamine and dihydroergotamine) and lead to ergotism. Coadministration of Voritrol with ergot alkaloids is contraindicated [see Contraindications (4) and Warnings and Precautions (5.1) ].

Everolimus (CYP3A4 substrate, P-gp substrate)–Although not studied in vitro or in vivo, Voritrol may increase plasma concentrations of everolimus, which could potentially lead to exacerbation of everolimus toxicity. Currently there are insufficient data to allow dosing recommendations in this situation. Therefore, co-administration of Voritrol with everolimus is not recommended [see Drug Interactions (7) ].

Coadministration of Voritrol with the following agents results in increased exposure or is expected to result in increased exposure to these drugs. Therefore, careful monitoring and/or dosage adjustment of these drugs is needed:

Alfentanil (CYP3A4 substrate)–Coadministration of multiple doses of oral Voritrol (400 mg q12h on day 1, 200 mg q12h on day 2) with a single 20 mcg/kg intravenous dose of alfentanil with concomitant naloxone resulted in a 6-fold increase in mean alfentanil AUC0–∞ and a 4-fold prolongation of mean alfentanil elimination half-life, compared to when alfentanil was given alone. An increase in the incidence of delayed and persistent alfentanil-associated nausea and vomiting during co-administration of Voritrol and alfentanil was also observed. Reduction in the dose of alfentanil or other opiates that are also metabolized by CYP3A4 (e.g., sufentanil), and extended close monitoring of patients for respiratory and other opiate-associated adverse events, may be necessary when any of these opiates is coadministered with Voritrol [see Warnings and Precautions (5.1) ].

Fentanyl (CYP3A4 substrate): In an independent published study, concomitant use of Voritrol (400 mg q12h on Day 1, then 200 mg q12h on Day 2) with a single intravenous dose of fentanyl (5 µg/kg) resulted in an increase in the mean AUC0–∞ of fentanyl by 1.4-fold (range 0.81- to 2.04-fold). When Voritrol is co-administered with fentanyl IV, oral or transdermal dosage forms, extended and frequent monitoring of patients for respiratory depression and other fentanyl-associated adverse events is recommended, and fentanyl dosage should be reduced if warranted [see Warnings and Precautions (5.1) ].

Oxycodone (CYP3A4 substrate): In an independent published study, coadministration of multiple doses of oral Voritrol (400 mg q12h, on Day 1 followed by five doses of 200 mg q12h on Days 2 to 4) with a single 10 mg oral dose of oxycodone on Day 3 resulted in an increase in the mean Cmax and AUC0–∞ of oxycodone by 1.7-fold (range 1.4- to 2.2-fold) and 3.6-fold (range 2.7- to 5.6-fold), respectively. The mean elimination half-life of oxycodone was also increased by 2.0-fold (range 1.4- to 2.5-fold). Voritrol also increased the visual effects (heterophoria and miosis) of oxycodone. A reduction in oxycodone dosage may be needed during Voritrol treatment to avoid opioid related adverse effects. Extended and frequent monitoring for adverse effects associated with oxycodone and other long-acting opiates metabolized by CYP3A4 is recommended [see Warnings and Precautions (5.1) ].

Cyclosporine (CYP3A4 substrate)–In stable renal transplant recipients receiving chronic cyclosporine therapy, concomitant administration of oral Voritrol (200 mg q12h for 8 days) increased cyclosporine Cmax and AUCτ an average of 1.1 times (90% CI: 0.9, 1.41) and 1.7 times (90% CI: 1.5, 2.0), respectively, as compared to when cyclosporine was administered without Voritrol. When initiating therapy with Voritrol in patients already receiving cyclosporine, it is recommended that the cyclosporine dose be reduced to one-half of the original dose and followed with frequent monitoring of the cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When Voritrol is discontinued, cyclosporine levels should be frequently monitored and the dose increased as necessary [see Warnings and Precautions (5.1) ].

Methadone (CYP3A4, CYP2C19, CYP2C9 substrate) –Repeat dose administration of oral Voritrol (400 mg q12h for 1 day, then 200 mg q12h for 4 days) increased the Cmax and AUCτ of pharmacologically active Rmethadone by 31% (90% CI: 22%, 40%) and 47% (90% CI: 38%, 57%), respectively, in subjects receiving a methadone maintenance dose (30–100 mg q24h). The Cmax and AUC of (S)-methadone increased by 65% (90% CI: 53%, 79%) and 103% (90% CI: 85%, 124%), respectively. Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed [see Warnings and Precautions (5.1) ].

Tacrolimus (CYP3A4 substrate)–Repeat oral dose administration of Voritrol (400 mg q12h × 1 day, then 200 mg q12h × 6 days) increased tacrolimus (0.1 mg/kg single dose) Cmax and AUCτ in healthy subjects by an average of 2-fold (90% CI: 1.9, 2.5) and 3-fold (90% CI: 2.7, 3.8), respectively. When initiating therapy with Voritrol in patients already receiving tacrolimus, it is recommended that the tacrolimus dose be reduced to one-third of the original dose and followed with frequent monitoring of the tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When Voritrol is discontinued, tacrolimus levels should be carefully monitored and the dose increased as necessary [see Warnings and Precautions (5.1) ].

Warfarin (CYP2C9 substrate)–Coadministration of Voritrol (300 mg q12h × 12 days) with warfarin (30 mg single dose) significantly increased maximum prothrombin time by approximately 2 times that of placebo in healthy subjects. Close monitoring of prothrombin time or other suitable anticoagulation tests is recommended if warfarin and Voritrol are coadministered and the warfarin dose adjusted accordingly [see Warnings and Precautions (5.1) ].

Oral Coumarin Anticoagulants (CYP2C9, CYP3A4 substrates)–Although not studied in vitro or in vivo, Voritrol may increase the plasma concentrations of coumarin anticoagulants and therefore may cause an increase in prothrombin time. If patients receiving coumarin preparations are treated simultaneously with Voritrol, the prothrombin time or other suitable anti-coagulation tests should be monitored at close intervals and the dosage of anticoagulants adjusted accordingly [see Warnings and Precautions (5.1) ].

Statins (CYP3A4 substrates)–Although not studied clinically, Voritrol has been shown to inhibit lovastatin metabolism in vitro (human liver microsomes). Therefore, Voritrol is likely to increase the plasma concentrations of statins that are metabolized by CYP3A4. It is recommended that dose adjustment of the statin be considered during coadministration. Increased statin concentrations in plasma have been associated with rhabdomyolysis [see Warnings and Precautions (5.1) ].

Benzodiazepines (CYP3A4 substrates)–Although not studied clinically, Voritrol has been shown to inhibit midazolam metabolism in vitro (human liver microsomes). Therefore, Voritrol is likely to increase the plasma concentrations of benzodiazepines that are metabolized by CYP3A4 (e.g., midazolam, triazolam, and alprazolam) and lead to a prolonged sedative effect. It is recommended that dose adjustment of the benzodiazepine be considered during coadministration [see Warnings and Precautions (5.1) ].

Calcium Channel Blockers (CYP3A4 substrates)–Although not studied clinically, Voritrol has been shown to inhibit felodipine metabolism in vitro (human liver microsomes). Therefore, Voritrol may increase the plasma concentrations of calcium channel blockers that are metabolized by CYP3A4. Frequent monitoring for adverse events and toxicity related to calcium channel blockers is recommended during coadministration. Dose adjustment of the calcium channel blocker may be needed [see Warnings and Precautions (5.1) ].

Sulfonylureas (CYP2C9 substrates)–Although not studied in vitro or in vivo, Voritrol may increase plasma concentrations of sulfonylureas (e.g., tolbutamide, glipizide, and glyburide) and therefore cause hypoglycemia. Frequent monitoring of blood glucose and appropriate adjustment (i.e., reduction) of the sulfonylurea dosage is recommended during coadministration [see Warnings and Precautions (5.1) ].

Vinca Alkaloids (CYP3A4 substrates)–Although not studied in vitro or in vivo, Voritrol may increase the plasma concentrations of the vinca alkaloids (e.g., vincristine and vinblastine) and lead to neurotoxicity. Therefore, reserve azole antifungals, including Voritrol, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options [see Warnings and Precautions (5.1) ].

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs; CYP2C9 substrates): In two independent published studies, single doses of ibuprofen (400 mg) and diclofenac (50 mg) were coadministered with the last dose of Voritrol (400 mg q12h on Day 1, followed by 200 mg q12h on Day 2). Voritrol increased the mean Cmax and AUC of the pharmacologically active isomer, S (+)-ibuprofen by 20% and 100%, respectively. Voritrol increased the mean Cmax and AUC of diclofenac by 114% and 78%, respectively.

A reduction in ibuprofen and diclofenac dosage may be needed during concomitant administration with Voritrol. Patients receiving Voritrol concomitantly with other NSAIDs (e.g., celecoxib, naproxen, lornoxicam, meloxicam) that are also metabolized by CYP2C9 should be carefully monitored for NSAID-related adverse events and toxicity, and dosage reduction should be made if warranted [see Warnings and Precautions (5.1) ].

No significant pharmacokinetic interactions were observed when Voritrol was coadministered with the following agents. Therefore, no dosage adjustment for these agents is recommended:

Prednisolone (CYP3A4 substrate)–Voriconazole (200 mg q12h × 30 days) increased Cmax and AUC of prednisolone (60 mg single dose) by an average of 11% and 34%, respectively, in healthy subjects.

Digoxin (P-glycoprotein mediated transport)–Voriconazole (200 mg q12h × 12 days) had no significant effect on steady state Cmax and AUCτ of digoxin (0.25 mg once daily for 10 days) in healthy subjects.

Mycophenolic acid (UDP-glucuronyl transferase substrate)–Voriconazole (200 mg q12h × 5 days) had no significant effect on the Cmax and AUCτ of mycophenolic acid and its major metabolite, mycophenolic acid glucuronide after administration of a 1 g single oral dose of mycophenolate mofetil.

Two-Way Interactions

Concomitant use of the following agents with Voritrol is contraindicated:

Rifabutin (potent CYP450 inducer)–Rifabutin (300 mg once daily) decreased the Cmax and AUCτ of Voritrol at 200 mg twice daily by an average of 67% (90% CI: 58%, 73%) and 79% (90% CI: 71%, 84%), respectively, in healthy subjects. During coadministration with rifabutin (300 mg once daily), the steady state Cmax and AUCτ of Voritrol following an increased dose of 400 mg twice daily were on average approximately 2 times higher, compared with Voritrol alone at 200 mg twice daily. Coadministration of Voritrol at 400 mg twice daily with rifabutin 300 mg twice daily increased the Cmax and AUCτ of rifabutin by an average of 3-times (90% CI: 2.2, 4.0) and 4 times (90% CI: 3.5, 5.4), respectively, compared to rifabutin given alone. Coadministration of Voritrol and rifabutin is contraindicated [see Contraindications (4) ].

Significant drug interactions that may require dosage adjustment, frequent monitoring of drug levels and/or frequent monitoring of drug-related adverse events/toxicity:

Efavirenz, a non-nucleoside reverse transcriptase inhibitor (CYP450 inducer; CYP3A4 inhibitor and substrate)–Standard doses of Voritrol and efavirenz (400 mg q24h or higher) must not be coadministered [see Drug Interactions (7) ]. Steady state efavirenz (400 mg PO q24h) decreased the steady state Cmax and AUCτ of Voritrol (400 mg PO q12h for 1 day, then 200 mg PO q12h for 8 days) by an average of 61% and 77%, respectively, in healthy male subjects. Voritrol at steady state (400 mg PO q12h for 1 day, then 200 mg q12h for 8 days) increased the steady state Cmax and AUCτ of efavirenz (400 mg PO q24h for 9 days) by an average of 38% and 44%, respectively, in healthy subjects.

The pharmacokinetics of adjusted doses of Voritrol and efavirenz were studied in healthy male subjects following administration of Voritrol (400 mg PO q12h on Days 2 to 7) with efavirenz (300 mg PO q24h on Days 1–7), relative to steady-state administration of Voritrol (400 mg for 1 day, then 200 mg PO q12h for 2 days) or efavirenz (600 mg q24h for 9 days). Coadministration of Voritrol 400 mg q12h with efavirenz 300 mg q24h, decreased Voritrol AUCτ by 7% (90% CI: -23%, 13%) and increased Cmax by 23% (90% CI: -1%, 53%); efavirenz AUCτ was increased by 17% (90% CI: 6%, 29%) and Cmax was equivalent.

Coadministration of standard doses of Voritrol and efavirenz (400 mg q24h or higher) is contraindicated. Voritrol may be coadministered with efavirenz if the Voritrol maintenance dose is increased to 400 mg q12h and the efavirenz dose is decreased to 300 mg q24h. When treatment with Voritrol is stopped, the initial dosage of efavirenz should be restored [see Dosage and Administration (2.4), Contraindications (4), and Drug Interactions (7) ].

Phenytoin (CYP2C9 substrate and potent CYP450 inducer)–Repeat dose administration of phenytoin (300 mg once daily) decreased the steady state Cmax and AUCτ of orally administered Voritrol (200 mg q12h × 14 days) by an average of 50% and 70%, respectively, in healthy subjects. Administration of a higher Voritrol dose (400 mg q12h × 7 days) with phenytoin (300 mg once daily) resulted in comparable steady state Voritrol Cmax and AUCτ estimates as compared to when Voritrol was given at 200 mg q12h without phenytoin.

Phenytoin may be coadministered with Voritrol if the maintenance dose of Voritrol is increased from 4 mg/kg to 5 mg/kg intravenously every 12 hours or from 200 mg to 400 mg orally, every 12 hours (100 mg to 200 mg orally, every 12 hours in patients less than 40 kg) [see Dosage and Administration (2.4) and Drug Interactions (7) ].

Repeat dose administration of Voritrol (400 mg q12h × 10 days) increased the steady state Cmax and AUCτ of phenytoin (300 mg once daily) by an average of 70% and 80%, respectively, in healthy subjects. The increase in phenytoin Cmax and AUC when coadministered with Voritrol may be expected to be as high as 2 times the Cmax and AUC estimates when phenytoin is given without Voritrol. Therefore, frequent monitoring of plasma phenytoin concentrations and phenytoin-related adverse effects is recommended when phenytoin is coadministered with Voritrol [see Warnings and Precautions (5.1) ].

Omeprazole (CYP2C19 inhibitor; CYP2C19 and CYP3A4 substrate)–Coadministration of omeprazole (40 mg once daily × 10 days) with oral Voritrol (400 mg q12h × 1 day, then 200 mg q12h × 9 days) increased the steady state Cmax and AUCτ of Voritrol by an average of 15% (90% CI: 5%, 25%) and 40% (90% CI: 29%, 55%), respectively, in healthy subjects. No dosage adjustment of Voritrol is recommended.

Coadministration of Voritrol (400 mg q12h × 1 day, then 200 mg × 6 days) with omeprazole (40 mg once daily × 7 days) to healthy subjects significantly increased the steady state Cmax and AUCτ of omeprazole an average of 2 times (90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3, 4.4), respectively, as compared to when omeprazole is given without Voritrol. When initiating Voritrol in patients already receiving omeprazole doses of 40 mg or greater, it is recommended that the omeprazole dose be reduced by one-half [see Warnings and Precautions (5.1) ].

The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by Voritrol and may result in increased plasma concentrations of these drugs.

Oral Contraceptives (CYP3A4 substrate; CYP2C19 inhibitor)–Coadministration of oral Voritrol (400 mg q12h for 1 day, then 200 mg q12h for 3 days) and oral contraceptive (Ortho-Novum1/35® consisting of 35 mcg ethinyl estradiol and 1 mg norethindrone, q24h) to healthy female subjects at steady state increased the Cmax and AUCτ of ethinyl estradiol by an average of 36% (90% CI: 28%, 45%) and 61% (90% CI: 50%, 72%), respectively, and that of norethindrone by 15% (90% CI: 3%, 28%) and 53% (90% CI: 44%, 63%), respectively in healthy subjects. Voritrol Cmax and AUCτ increased by an average of 14% (90% CI: 3%, 27%) and 46% (90% CI: 32%, 61%), respectively. Monitoring for adverse events related to oral contraceptives, in addition to those for Voritrol, is recommended during coadministration [see Warnings and Precautions (5.1) ].

No significant pharmacokinetic interaction was seen and no dosage adjustment of these drugs is recommended:

Indinavir (CYP3A4 inhibitor and substrate)–Repeat dose administration of indinavir (800 mg TID for 10 days) had no significant effect on Voritrol Cmax and AUC following repeat dose administration (200 mg q12h for 17 days) in healthy subjects.

Repeat dose administration of Voritrol (200 mg q12h for 7 days) did not have a significant effect on steady state Cmax and AUCτ of indinavir following repeat dose administration (800 mg TID for 7 days) in healthy subjects.

Other Two-Way Interactions Expected to be Significant Based on In Vitro and In Vivo Findings:

Other HIV Protease Inhibitors (CYP3A4 substrates and inhibitors)In vitro studies (human liver microsomes) suggest that Voritrol may inhibit the metabolism of HIV protease inhibitors (e.g., saquinavir, amprenavir and nelfinavir). In vitro studies (human liver microsomes) also show that the metabolism of Voritrol may be inhibited by HIV protease inhibitors (e.g., saquinavir and amprenavir). Patients should be frequently monitored for drug toxicity during the coadministration of Voritrol and HIV protease inhibitors [see Warnings and Precautions (5.1) ].

Other Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) (CYP3A4 substrates, inhibitors or CYP450 inducers)In vitro studies (human liver microsomes) show that the metabolism of Voritrol may be inhibited by a NNRTI (e.g., delavirdine). The findings of a clinical voriconazole-efavirenz drug interaction study in healthy male subjects suggest that the metabolism of Voritrol may be induced by a NNRTI. This in vivo study also showed that Voritrol may inhibit the metabolism of a NNRTI [see Drug Interactions (7) and Warnings and Precautions (5.9) ]. Patients should be frequently monitored for drug toxicity during the coadministration of Voritrol and other NNRTIs (e.g., nevirapine and delavirdine) [see Warnings and Precautions (5.1) ]. Dose adjustments are required when Voritrol is co-administered with efavirenz [see Drug Interactions (7) and Warnings and Precautions (5.1) ].

12.4 Microbiology

Mechanism of Action

Voritrol is an azole antifungal drug. The primary mode of action of Voritrol is the inhibition of fungal cytochrome P-450-mediated 14 alpha-lanosterol demethylation, an essential step in fungal ergosterol biosynthesis. The accumulation of 14 alpha-methyl sterols correlates with the subsequent loss of ergosterol in the fungal cell wall and may be responsible for the antifungal activity of Voritrol.

Drug Resistance

A potential for development of resistance to Voritrol is well known. The mechanisms of resistance may include mutations in the gene ERG11 (encodes for the target enzyme, lanosterol 14-α-demethylase), upregulation of genes encoding the ATP-binding cassette efflux transporters i.e., Candida drug resistance (CDR) pumps and reduced access of the drug to the target, or some combination of those mechanisms. The frequency of drug resistance development for the various fungi for which this drug is indicated is not known.

Fungal isolates exhibiting reduced susceptibility to fluconazole or itraconazole may also show reduced susceptibility to Voritrol, suggesting cross-resistance can occur among these azoles. The relevance of cross-resistance and clinical outcome has not been fully characterized. Clinical cases where azole cross-resistance is demonstrated may require alternative antifungal therapy.

Antimicrobial Activity

Voritrol has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections.

Aspergillus fumigatus

Aspergillus flavus

Aspergillus niger

Aspergillus terreus

Candida albicans

Candida glabrata (In clinical studies, the Voritrol MIC90 was 4 µg/mL)In clinical studies, Voritrol MIC90 for C. glabrata baseline isolates was 4 µg/mL; 13/50 (26%) C. glabrata baseline isolates were resistant (MIC ≥4 µg/mL) to Voritrol. However, based on 1054 isolates tested in surveillance studies the MIC90 was 1 µg/mL.

Candida krusei

Candida parapsilosis

Candida tropicalis

Fusarium spp. including Fusarium solani

Scedosporium apiospermum

The following data are available, but their clinical significance is unknown. At least 90 percent of the following fungi exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for Voritrol against isolates of similar genus or organism group. However, the effectiveness of Voritrol in treating clinical infections due to these fungi has not been established in adequate and well-controlled clinical trials:

Candida lusitaniae

Candida guilliermondii

Susceptibility Testing Methods1,2,3

Aspergillus species and other filamentous fungi

No interpretive criteria have been established for Aspergillus species and other filamentous fungi.

Candida species

The interpretive standards for Voritrol against Candida species are applicable only to tests performed using Clinical Laboratory and Standards Institute (CLSI) microbroth dilution reference method M27 for MIC read at 24 hours or disk diffusion reference method M44 for zone diameter read at 24 hours.1,2,3

Dilution Techniques

Quantitative methods are used to determine antifungal MICs. These MICs provide estimates of the susceptibility of Candida spp. to antifungal agents. The MICs should be determined using a standardized test method at 24 hours1,2 (broth dilution). The MIC values should be interpreted according to the criteria provided in Table 10.

Diffusion Techniques

Qualitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of Candida spp. to an antifungal agent. One such standardized procedure requires the use of standardized inoculum concentrations.2 This procedure uses paper disks impregnated with 1 µg of Voritrol to test the susceptibility of yeasts to Voritrol at 24 hours. Disk diffusion interpretive criteria are also provided in Table 10.

Broth Microdilution at 24 hours

(MIC in µg/mL)

Disk Diffusion at 24 hoursThe current data are insufficient to demonstrate a correlation between in vitro susceptibility testing and clinical outcome for C. glabrata and Voritrol.

(Zone diameters in mm)

Susceptible (S) Intermediate (I) Resistant (R) Susceptible (S) Intermediate (I) Resistant (R)
C. albicans ≤0.12 0.25–0.5 ≥1.0 ≥17 15–16 ≤14
C. krusei ≤0.5 1 ≥2 ≥15 13–14 ≤12
C. parapsilosis ≤0.12 0.25–0.5 ≥1 ≥17 15–16 ≤14
C. tropicalis ≤0.12 0.25–0.5 ≥1 ≥17 15–16 ≤14

A report of Susceptible (S) indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the site of infection. A report of Intermediate (I) indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drugs are physiologically concentrated or when a high dosage of drug is used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant (R) indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentrations usually achievable at the infection site; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test1,2,3. Standard Voritrol powder should provide the following range of MIC values noted in Table 11. For the diffusion technique using the 1 mcg disk, the criteria in Table 11 should be achieved.

NOTE: Quality control microorganisms are specific strains of organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within fungi; the specific strains used for microbiological control are not clinically significant.

QC Strain Broth Microdilution (MIC in µg/mL) at 24-hour Disk Diffusion (Zone diameter in mm) at 24-hour
ATCC is a registered trademark of the American Type Culture Collection.
Candida parapsilosis

ATCC 22019

0.016–0.12 28–37
Candida krusei

ATCC 6258

0.06–0.5 16–25
Candida albicans

ATCC 90028

Quality control ranges have not been established for this strain/antifungal agent combination due to their extensive interlaboratory variation during initial quality control studies. 31–42

12.5 Pharmacogenomics

CYP2C19, significantly involved in the metabolism of Voritrol, exhibits genetic polymorphism. Approximately 15–20% of Asian populations may be expected to be poor metabolizers. For Caucasians and Blacks, the prevalence of poor metabolizers is 3–5%. Studies conducted in Caucasian and Japanese healthy subjects have shown that poor metabolizers have, on average, 4-fold higher Voritrol exposure (AUCτ) than their homozygous extensive metabolizer counterparts. Subjects who are heterozygous extensive metabolizers have, on average, 2-fold higher Voritrol exposure than their homozygous extensive metabolizer counterparts [see Clinical Pharmacology (12.3) ].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Two-year carcinogenicity studies were conducted in rats and mice. Rats were given oral doses of 6, 18 or 50 mg/kg Voritrol, or 0.2, 0.6, or 1.6 times the recommended maintenance dose on a mg/m2 basis. Hepatocellular adenomas were detected in females at 50 mg/kg and hepatocellular carcinomas were found in males at 6 and 50 mg/kg. Mice were given oral doses of 10, 30 or 100 mg/kg Voritrol, or 0.1, 0.4, or 1.4 times the RMD on a mg/m2 basis. In mice, hepatocellular adenomas were detected in males and females and hepatocellular carcinomas were detected in males at 1.4 times the RMD of Voritrol.

Voritrol demonstrated clastogenic activity (mostly chromosome breaks) in human lymphocyte cultures in vitro. Voritrol was not genotoxic in the Ames assay, CHO HGPRT assay, the mouse micronucleus assay or the in vivo DNA repair test (Unscheduled DNA Synthesis assay).

Voritrol administration induced no impairment of male or female fertility in rats dosed at 50 mg/kg, or 1.6 times the RMD (recommended maintenance dose).

14 CLINICAL STUDIES

Voritrol, administered orally or parenterally, has been evaluated as primary or salvage therapy in 520 patients aged 12 years and older with infections caused by Aspergillus spp., Fusarium spp., and Scedosporium spp.

14.1 Invasive Aspergillosis

Voritrol was studied in patients for primary therapy of invasive aspergillosis, for primary and salvage therapy of aspergillosis (non-comparative study 304) and for treatment of patients with invasive aspergillosis who were refractory to, or intolerant of, other antifungal therapy (non-comparative study 309/604).

Study 307/602 – Primary Therapy of Invasive Aspergillosis

The efficacy of Voritrol compared to amphotericin B in the primary treatment of acute invasive aspergillosis was demonstrated in 277 patients treated for 12 weeks in a randomized, controlled study (Study 307/602). The majority of study patients had underlying hematologic malignancies, including bone marrow transplantation. The study also included patients with solid organ transplantation, solid tumors, and AIDS. The patients were mainly treated for definite or probable invasive aspergillosis of the lungs. Other aspergillosis infections included disseminated disease, CNS infections and sinus infections. Diagnosis of definite or probable invasive aspergillosis was made according to criteria modified from those established by the National Institute of Allergy and Infectious Diseases Mycoses Study Group/European Organisation for Research and Treatment of Cancer (NIAID MSG/EORTC).

Voritrol was administered intravenously with a loading dose of 6 mg/kg every 12 hours for the first 24 hours followed by a maintenance dose of 4 mg/kg every 12 hours for a minimum of seven days. Therapy could then be switched to the oral formulation at a dose of 200 mg q12h. Median duration of IV Voritrol therapy was 10 days (range 2–85 days). After IV Voritrol therapy, the median duration of PO Voritrol therapy was 76 days (range 2–232 days).

Patients in the comparator group received conventional amphotericin B as a slow infusion at a daily dose of 1.0–1.5 mg/kg/day. Median duration of IV amphotericin therapy was 12 days (range 1–85 days). Treatment was then continued with other licensed antifungal therapy (OLAT), including itraconazole and lipid amphotericin B formulations. Although initial therapy with conventional amphotericin B was to be continued for at least two weeks, actual duration of therapy was at the discretion of the investigator. Patients who discontinued initial randomized therapy due to toxicity or lack of efficacy were eligible to continue in the study with OLAT treatment.

A satisfactory global response at 12 weeks (complete or partial resolution of all attributable symptoms, signs, radiographic/bronchoscopic abnormalities present at baseline) was seen in 53% of Voritrol treated patients compared to 32% of amphotericin B treated patients (Table 14). A benefit of Voritrol compared to amphotericin B on patient survival at Day 84 was seen with a 71% survival rate on Voritrol compared to 58% on amphotericin B (Table 12).

Table 12 also summarizes the response (success) based on mycological confirmation and species.

Voritrol Ampho B Amphotericin B followed by other licensed antifungal therapy Stratified Difference

(95% CI) Difference and corresponding 95% confidence interval are stratified by protocol

n/N (%) n/N (%)
Efficacy as Primary Therapy
Satisfactory Global Response Assessed by independent Data Review Committee (DRC) 76/144 (53) 42/133 (32) 21.8%

(10.5%, 33.0%)

p<0.0001

Survival at Day 84 Proportion of subjects alive 102/144 (71) 77/133 (58) 13.1%

(2.1%, 24.2%)

Success by Species
Success n/N (%)
Overall success 76/144 (53) 42/133 (32)
Mycologically confirmed Not all mycologically confirmed specimens were speciated 37/84 (44) 16/67 (24)
Aspergillus spp.Some patients had more than one species isolated at baseline
A. fumigatus 28/63 (44) 12/47 (26)
A. flavus 3/6 4/9
A. terreus 2/3 0/3
A. niger 1/4 0/9
A. nidulans 1/1 0/0

Study 304 – Primary and Salvage Therapy of Aspergillosis

In this non-comparative study, an overall success rate of 52% (26/50) was seen in patients treated with Voritrol for primary therapy. Success was seen in 17/29 (59%) with Aspergillus fumigatus infections and 3/6 (50%) patients with infections due to non-fumigatus species [A. flavus (1/1); A. nidulans (0/2); A. niger (2/2); A. terreus (0/1)]. Success in patients who received Voritrol as salvage therapy is presented in Table 13.

Study 309/604 – Treatment of Patients with Invasive Aspergillosis who were Refractory to, or Intolerant of, other Antifungal Therapy

Additional data regarding response rates in patients who were refractory to, or intolerant of, other antifungal agents are also provided in Table 15. In this non-comparative study, overall mycological eradication for culture-documented infections due to fumigatus and non-fumigatus species of Aspergillus was 36/82 (44%) and 12/30 (40%), respectively, in Voritrol treated patients. Patients had various underlying diseases and species other than A. fumigatus contributed to mixed infections in some cases.

For patients who were infected with a single pathogen and were refractory to, or intolerant of, other antifungal agents, the satisfactory response rates for Voritrol in studies 304 and 309/604 are presented in Table 13.

Success

n/N

A. fumigatus 43/97 (44%)
A. flavus 5/12
A. nidulans 1/3
A. niger 4/5
A. terreus 3/8
A. versicolor 0/1

Nineteen patients had more than one species of Aspergillus isolated. Success was seen in 4/17 (24%) of these patients.

14.2 Candidemia in Non-neutropenic Patients and Other Deep Tissue Candida Infections

Voritrol was compared to the regimen of amphotericin B followed by fluconazole in Study 608, an open label, comparative study in nonneutropenic patients with candidemia associated with clinical signs of infection. Patients were randomized in 2:1 ratio to receive either Voritrol (n=283) or the regimen of amphotericin B followed by fluconazole (n=139). Patients were treated with randomized study drug for a median of 15 days. Most of the candidemia in patients evaluated for efficacy was caused by C. albicans (46%), followed by C. tropicalis (19%), C. parapsilosis (17%), C. glabrata (15%), and C. krusei (1%).

An independent Data Review Committee (DRC), blinded to study treatment, reviewed the clinical and mycological data from this study, and generated one assessment of response for each patient. A successful response required all of the following: resolution or improvement in all clinical signs and symptoms of infection, blood cultures negative for Candida, infected deep tissue sites negative for Candida or resolution of all local signs of infection, and no systemic antifungal therapy other than study drug. The primary analysis, which counted DRC-assessed successes at the fixed time point (12 weeks after End of Therapy [EOT]), demonstrated that Voritrol was comparable to the regimen of amphotericin B followed by fluconazole (response rates of 41% and 41%, respectively) in the treatment of candidemia. Patients who did not have a 12-week assessment for any reason were considered a treatment failure.

The overall clinical and mycological success rates by Candida species in Study 150-608 are presented in Table 14.

Baseline Pathogen Clinical and Mycological Success (%)
Voritrol Amphotericin B --> Fluconazole
C. albicans 46/107 (43%) 30/63 (48%)
C. tropicalis 17/53 (32%) 1/16 (6%)
C. parapsilosis 24/45 (53%) 10/19 (53%)
C. glabrata 12/36 (33%) 7/21 (33%)
C. krusei 1/4 0/1

In a secondary analysis, which counted DRC-assessed successes at any time point (EOT, or 2, 6, or 12 weeks after EOT), the response rates were 65% for Voritrol and 71% for the regimen of amphotericin B followed by fluconazole.

In Studies 608 and 309/604 (non-comparative study in patients with invasive fungal infections who were refractory to, or intolerant of, other antifungal agents), Voritrol was evaluated in 35 patients with deep tissue Candida infections. A favorable response was seen in 4 of 7 patients with intra-abdominal infections, 5 of 6 patients with kidney and bladder wall infections, 3 of 3 patients with deep tissue abscess or wound infection, 1 of 2 patients with pneumonia/pleural space infections, 2 of 4 patients with skin lesions, 1 of 1 patients with mixed intraabdominal and pulmonary infection, 1 of 2 patients with suppurative phlebitis, 1 of 3 patients with hepatosplenic infection, 1 of 5 patients with osteomyelitis, 0 of 1 with liver infection, and 0 of 1 with cervical lymph node infection.

14.3 Esophageal Candidiasis

The efficacy of oral Voritrol 200 mg twice daily compared to oral fluconazole 200 mg once daily in the primary treatment of esophageal candidiasis was demonstrated in Study 150-305, a double-blind, double-dummy study in immunocompromised patients with endoscopically-proven esophageal candidiasis. Patients were treated for a median of 15 days. Outcome was assessed by repeat endoscopy at end of treatment (EOT). A successful response was defined as a normal endoscopy at EOT or at least a 1 grade improvement over baseline endoscopic score. For patients in the Intent to Treat (ITT) population with only a baseline endoscopy, a successful response was defined as symptomatic cure or improvement at EOT compared to baseline. Voritrol and fluconazole (200 mg once daily) showed comparable efficacy rates against esophageal candidiasis, as presented in Table 15.

Population Voritrol Fluconazole Difference %

(95% CI)Confidence Interval for the difference (Voriconazole – Fluconazole) in success rates.

PPPP (Per Protocol) patients had confirmation of Candida esophagitis by endoscopy, received at least 12 days of treatment, and had a repeat endoscopy at EOT (end of treatment). 113/115 (98.2%) 134/141 (95.0%) 3.2 (-1.1, 7.5)
ITTITT (Intent to Treat) patients without endoscopy or clinical assessment at EOT were treated as failures. 175/200 (87.5%) 171/191 (89.5%) -2.0 (-8.3, 4.3)

Microbiologic success rates by Candida species are presented in Table 16.

PathogenSome patients had more than one species isolated at baseline Voritrol Fluconazole
Favorable endoscopic responsePatients with endoscopic and/or mycological assessment at end of therapy Mycological eradication Favorable endoscopic response Mycological eradication
Success/Total (%) Eradication/Total (%) Success/Total (%) Eradication/Total (%)
C. albicans 134/140 (96%) 90/107 (84%) 147/156 (94%) 91/115 (79%)
C. glabrata 8/8 (100%) 4/7 (57%) 4/4 (100%) 1/4 (25%)
C. krusei 1/1 1/1 2/2 (100%) 0/0

14.4 Other Serious Fungal Pathogens

In pooled analyses of patients, Voritrol was shown to be effective against the following additional fungal pathogens:

Scedosporium apiospermum - Successful response to Voritrol therapy was seen in 15 of 24 patients (63%). Three of these patients relapsed within 4 weeks, including 1 patient with pulmonary, skin and eye infections, 1 patient with cerebral disease, and 1 patient with skin infection. Ten patients had evidence of cerebral disease and 6 of these had a successful outcome (1 relapse). In addition, a successful response was seen in 1 of 3 patients with mixed organism infections.

Fusarium spp. - Nine of 21 (43%) patients were successfully treated with Voritrol. Of these 9 patients, 3 had eye infections, 1 had an eye and blood infection, 1 had a skin infection, 1 had a blood infection alone, 2 had sinus infections, and 1 had disseminated infection (pulmonary, skin, hepatosplenic). Three of these patients (1 with disseminated disease, 1 with an eye infection and 1 with a blood infection) had Fusarium solani and were complete successes. Two of these patients relapsed, 1 with a sinus infection and profound neutropenia and 1 post surgical patient with blood and eye infections.

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Powder for Solution for Injection

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

Individually packaged vials of 200 mg Voritrol I.V.

(NDC 0049-3190-28)

Tablets

Voritrol 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)

Voritrol 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

Voritrol 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)

16.2 Storage

Voritrol I.V. for Injection unreconstituted vials should be stored at 15° – 30°C (59° – 86°F). Voritrol 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 (2.1) ].

Voritrol Tablets should be stored at 15° – 30°C (59° – 86°F).

Voritrol 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 24 months.

The reconstituted suspension should be stored at 15° – 30°C (59° – 86°F). 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.

17 PATIENT COUNSELING INFORMATION

Advise the Patient to read the FDA-Approved Patient Labeling

Embryo-Fetal Toxicity


This product's label may have been updated. For current full prescribing information, please visit www.pfizer.com.

LAB-0271-35.0

Logo

FDA-Approved Patient Labeling

Voritrol® /VEE-fend/

(voriconazole) IV injection, tablets, liquid

Read the Patient Information that comes with Voritrol before you start taking it and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your condition or treatment.

What is Voritrol?

Voritrol is a prescription medicine used to treat certain serious fungal infections in your blood and body. These infections are called "aspergillosis," "esophageal candidiasis," "Scedosporium," "Fusarium," and "candidemia".

It is not known if Voritrol is safe and effective in children younger than 12 years old.

Who should not take Voritrol?

Do not take Voritrol if you:


Ask your healthcare provider or pharmacist if you are not sure if you are taking any of the medicines listed above.

Do not start taking a new medicine without talking to your healthcare provider or pharmacist.

What should I tell my healthcare provider before taking Voritrol?

Before you take Voritrol, tell your healthcare provider if you:


Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements.

Voritrol may affect the way other medicines work, and other medicines may affect how Voritrol works.

Know what medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine.

How should I take Voritrol?


Voritrol oral suspension will be mixed for you by your pharmacist. Do not mix Voritrol oral suspension with any other medicine, flavored liquid, or syrup.


What should I avoid while taking Voritrol?


What are possible side effects of Voritrol?

Voritrol may cause serious side effects including:


Call your healthcare provider or go to the nearest hospital emergency room right away if you have any of the symptoms listed above.

The most common side effects of Voritrol include:


Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Voritrol. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Voritrol?


General information about the safe and effective use of Voritrol

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Voritrol for a condition for which it was not prescribed. Do not give Voritrol to other people, even if they have the same symptoms that you have. It may harm them.

This Patient Information leaflet summarizes the most important information about Voritrol. If you would like more information, talk to your healthcare provider. You can ask your healthcare provider or pharmacist for information about Voritrol that is written for health professionals.

This product's label may have been updated. For current full prescribing information, please visit www.pfizer.com.

What are the ingredients of Voritrol?

Active ingredient: Voritrol

Inactive ingredients:

Voritrol IV: sulfobutyl ether beta-cyclodextrin sodium

Voritrol tablets: lactose monohydrate, pregelatinized starch, croscarmellose sodium, povidone, magnesium stearate, and a coating containing hypromellose, titanium dioxide, lactose monohydrate, and triacetin

Voritrol oral suspension: colloidal silicon dioxide, titanium dioxide, xanthan gum, sodium citrate dihydrate, sodium benzoate, anhydrous citric acid, natural orange flavor, and sucrose

This Patient Information has been approved by the U.S. Food and Drug Administration.

This product's label may have been updated. For current full prescribing information, please visit www.pfizer.com.

LAB-0311-12.0

February 2015

Logo

Pfizer

NDC 0049-3170-30

Voritrol ®

(voriconazole)

50 mg

Tablets

30 Tablets

Rx only

Pfizer

NDC 0049-3180-30

Voritrol ®

(voriconazole)

200 mg

Tablets

30 Tablets

Rx only

NDC 0049-3190-28

Voritrol® I.V.

(voriconazole) for injection

200 mg*

200 mg* of Voritrol

No Latex

No Preservatives

Sterile Single Use Vial

For I.V. Infusion Only

Pfizer Injectables

Rx only

Voritrol pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Voritrol available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Voritrol destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Voritrol Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Voritrol pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."VFEND (VORICONAZOLE) TABLET, FILM COATED VFEND (VORICONAZOLE) INJECTION, POWDER, LYOPHILIZED, FOR SOLUTION VFEND (VORICONAZOLE) POWDER, FOR SUSPENSION ". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."VORICONAZOLE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. "Voriconazole". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Voritrol?

Depending on the reaction of the Voritrol after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Voritrol not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Voritrol addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Voritrol, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Voritrol consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

Visitor reports

Visitor reported useful

No survey data has been collected yet

Visitor reported side effects

No survey data has been collected yet

Visitor reported price estimates

No survey data has been collected yet

Visitor reported frequency of use

No survey data has been collected yet

One visitor reported doses

What is the dose of Voritrol drug you are taking?
According to the survey conducted among sdrugs.com website users, the maximum number of people are using the following dose 101-200mg. Few medications come in only one or two doses. Few are specific for adult dose and child dose. The dose of the medicine given to the patient depends on the severity of the symptom/disease. There can be dose adjustments made by the doctor, based on the progression of the disease. Follow-up is important.
Visitors%
101-200mg1
100.0%

Visitor reported time for results

No survey data has been collected yet

One visitor reported administration

The drugs are administered in various routes, like oral or injection form. They are administered before food or after food. How are you taking Voritrol drug, before food or after food?
Click here to find out how other users of our website are taking it. For any doubts or queries on how and when the medicine is administered, contact your health care provider immediately.
Visitors%
Empty stomach1
100.0%

Visitor reported age

No survey data has been collected yet

Visitor reviews


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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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