VORICONAZOLE - SAIDAL

Voriconazole (Vfend, Pfizer) is a triazole antifungal medication used to treat serious fungal infections.

It is used to treat invasive fungal infections that are generally seen in patients who are immunocompromised.

These include invasive candidiasis, invasive aspergillosis, and emerging fungal infections.

The increased affinity of voriconazole for 14-alpha sterol demethylase makes it useful against some fluconazole -resistant organisms.

Voriconazole was approved by the FDA under the trade name Vfend on May 24, 2002.

For the treatment of esophageal candidiasis, cadidemia, invasive pulmonary aspergillosis, and serious fungal infections caused by Scedosporium apiospermum and Fusarium spp. 13,

Voriconazole is a fungistatic triazole antifungal used to treat infections by inhibiting fungal growth.

It is known to cause hepatotoxic and photosensitivity reactions in some patients.

The oral bioavailability is estimated to be 96% in healthy adults 13.

Population pharmacokinetic studies report a reduced bioavailability pediatric patients with a mean of 61.8% (range 44.6–64.5%) thought to be due to differences in first-pass metabolism or due to differences in diet 6.

Of note, transplant patients also have reduced bioavailability but this is known to increase with time after transplantation and may be due in part to gastrointestinal upset from surgery and some transplant medications.

Tmax is 1-2 hours with oral administration.

When administered with a high-fat meal

Cmax decreases by 34% and AUC by 24%. pH does not have an effect on absorption of voriconazole.

Differences in Cmax and

AUC have been observed between healthy adult males and females with Cmax increasing by 83% and AUC by 113% although this has not been observed to significantly impact medication safety profiles.

The estimated volume of distribution of voriconazole is 4.6 L/kg 13.

Population pharmacokinetic studies estimate the median volume of distribution to be 77.6 L with the central compartment estimated at 1.07 L/kg 6 Voriconazole is known to achieve therapeutic concentrations in many tissues including the brain, lungs, liver, spleen, kidneys, and heart.

Voriconazole undergoes extensive hepatic metabolism through cytochrome enzymes CYP2C9, CYP2C19, and CYP3A4.

CYP2C19 mediates N-oxidation with an apparent Km of 14 μM and an apparent Vmax of 0.22 nmol/min/nmol CYP2C19.

N-oxide is the major circulating metabolite, accounting for 72% of radiolabeled metabolites found.

CYP3A4 contributes to N-oxidation with a Km of 16 μM and Vmax of 0.05 nmol/min/nmol CYP3A4 as well as 4-hydroxylation with a Km of 11 μM and a Vmax of 0.10 nmol/min/nmol CYP3A4.

CYP3A5 and CYP3A7 provide minor contributions to N-oxidation and 4-hydroxylation.

N-oxide and 4-hydroxylated metabolites undergo glucuronidation and are excreted through the urine with other minor glucuronidated metabolites.

Hover over products below to view reaction partners Voriconazole Voriconazole N-Oxide UK-51,060 UK-215,364 Voriconazole O-glucuronide derivative 4-Hydroxyvoriconazole 4-Hydroxyvoriconazole 4-O-glucuronide.

Voriconazole is eliminated via hepatic metabolism with less than 2% of the dose excreted unchanged in the urine.

Voriconazole follows non-linear kinetics and has a terminal half-life of elimination which is dose-dependent.

The clearance of voriconazole is estimated to be a mean of 5.25-7 L/h in healthy adults for the linear portion of the drug's kinetics. 6, 7.

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Symptoms of overdose include photophobia and possible QTc prolongation. 13, 14 In case of overdose, supportive care and ECG monitoring are recommended.

Activated charcoal may aid in the removal of unabsorbed drug.

Voriconazole is cleared by hemodialysis at a rate of 121 mL/min which may be helpful in removing absorbed drug.

Carcinogenicity studies found hepatocellular adenomas in female rats at doses of 50 mg/kg and hepatocellular carcinomas found in male rats at doses of and 50 mg/kg. These doses are equivalent to 0.2 and 1.6 times the recommended maintenance dose (RMD).

Studies in mice detected hepatocellular carcinomas in males at doses of 100 mg/kg or 1.4 times the RMD.

Hepatocellular adenomas were detected in both male and female mice.

• VFEND is contraindicated in patients with known hypersensitivity to voriconazole or its excipients.

There is no information regarding cross-sensitivity between VFEND and other azole antifungal agents.

Refer to the prescribing information for other azole antifungal agents.

• Concomittant use of VFEND with the interacting drugs described and listed below in this section are a guide and not considered a comprehensive list of all possible drugs that may be contraindicated with VFEND. 1.

• Ergot alkaloids (e.g., ergotamine, dihydroergotamine).

• Venetoclax: Coadministration at initiation and during the ramp-up phase is contraindicated in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) due to the potential for increased risk of tumor lysis syndrome.

• Voclosporin 2.

• Efavirenz Concomitant use with efavirenz dosages of 400 mg every 24 hours or higher is contraindicated.

• Long-acting barbiturates.

• Ritonavir Concomitant use with high-dose ritonavir (400 mg every 12 hours) is contraindicated.

Concomitant use with low-dose ritonavir (100 mg every 12 hours) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of VFEND.

• Known hypersensitivity to voriconazole or its excipients.

• Concomitant use with drugs that are highly dependent on CYP3A4 for metabolism, and for which elevated plasma concentrations are associated with serious and/or life-threatening reactions.

• Concomitant use with drugs and herbal products that induce CYP2C19, CYP2C9, and/or CYP3A4 and for which significantly reduced voriconazole plasma concentrations may be associated with loss of efficacy.

• Dosage in Adults Infection Loading Dose Maintenance Dose Intravenous infusion Intravenous infusion Oral tablets Oral suspension Invasive Aspergillosis 6 mg/kg every 12 hours for the first 24 hours 4 mg/kg every 12 hours 200 mg every 12 hours 5 mL every 12 hours Candidemia in nonneutropenics and other deep tissue Candida infections 3–4 mg/kg every 12 hours 200 mg every 12 hours 5 mL every 12 hours Scedosporiosis and Fusariosis 4 mg/kg every 12 hours 200 mg every 12 hours 5 mL every 12 hours Esophageal Candidiasis Not Evaluated Not Evaluated 200 mg every 12 hours 5 mL every 12 hours o Adult patients weighing less than 40 kg: oral maintenance dose 100 mg or 150 mg every 12 hours o Hepatic Impairment: Use half the maintenance dose in adult patients with mild to moderate hepatic impairment (Child-Pugh Class A and B) o Renal Impairment: Avoid intravenous administration in adult patients with moderate to severe renal impairment (creatinine clearance <50 mL/min).

• Dosage in Pediatric Patients 2 years of age and older o For pediatric patients to less than 12 years of age and to 14 years of age weighing less than 50 kg see Table below.

Infection Loading Dose Maintenance Dose Intravenous infusion Intravenous infusion Oral tablets Oral suspension Invasive Aspergillosis 9 mg/kg every 12 hours for the first 24 hours 8 mg/kg every 12 hours after the first 24 hours 9 mg/kg every 12 hours (maximum dose of 350 mg every 12 hours) 0.225 mL/kg every 12 hours [maximum dose of 8.75 mL (350 mg) every 12 hours] Candidemia in nonneutropenics and other deep tissue Candida infections Scedosporiosis and Fusariosis Esophageal Candidiasis Not Evaluated 4 mg/kg every 12 hours 9 mg/kg every 12 hours (maximum dose of 350 mg every 12 hours) 0.225 mL/kg every 12 hours [maximum dose of 8.75 mL (350 mg) every 12 hours] o For pediatric patients aged to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight use adult dosage. o Dosage adjustment of VFEND in pediatric patients with renal or hepatic impairment has not been established.

• See full prescribing information for instructions on reconstitution of VFEND lyophilized powder for intravenous use and important administration instructions 2.1 Important Administration Instructions for Use in All Patients VFEND I.V. for Injection requires reconstitution to 10 mg/mL and subsequent dilution to 5 mg/mL or less prior to administration as an infusion, at a maximum rate of 3 mg/kg per hour over to 3 hours.

Administer diluted VFEND

I.V. by intravenous infusion over to 3 hours only.

Do not administer as an

IV bolus injection. 2.2 Use of VFEND I.V. with Other Parenteral Drug Products Blood products and concentrated electrolytes VFEND I.V. must not be infused concomitantly with any blood product or short-term infusion of concentrated electrolytes, even if the two infusions are running in separate intravenous lines (or cannulas).

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

Intravenous solutions containing (non-concentrated) electrolytes VFEND I.V. can be infused at the same time as other intravenous solutions containing (non-concentrated) electrolytes, but must be infused through a separate line.

Total parenteral nutrition (TPN) VFEND I.V. can be infused at the same time as total parenteral nutrition, but must be infused in a separate line.

If infused through a multiple-lumen catheter, TPN needs to be administered using a different port from the one used for VFEND I.V. 2.3 Recommended Dosing Regimen in Adults Invasive aspergillosis and serious fungal infections due to Fusarium spp. and Scedosporium apiospermum See Table 1.

Therapy must be initiated with the specified loading dose regimen of intravenous VFEND on Day 1 followed by the recommended maintenance dose (RMD) regimen.

Intravenous treatment should be continued for at least 7 days.

Once the patient has clinically improved and can tolerate medication given by mouth, the oral tablet form or oral suspension form of VFEND may be utilized.

The recommended oral maintenance dose of 200 mg achieves a voriconazole exposure similar to 3 mg/kg intravenously; a 300 mg oral dose achieves an exposure similar to 4 mg/kg intravenously.

Candidemia in non-neutropenic patients and other deep tissue Candida infections See Table 1.

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

Table 1.

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

Table 1: Recommended Dosing Regimen (Adults) Infection Loading Dose Maintenance Dose Increase dose when VFEND is coadministered with phenytoin or efavirenz; Decrease dose in patients with hepatic impairment, In healthy volunteer studies, the 200 mg oral every 12 hours dose provided an exposure (AUC τ ) similar to a 3 mg/kg intravenous infusion every 12 hours dose; the 300 mg oral every 12 hours dose provided an exposure (AUC τ ) similar to a 4 mg/kg intravenous infusion every 12 hours dose.

Intravenous infusion Intravenous infusion Oral tablets

Adult patients who weigh less than 40 kg should receive half of the oral maintenance dose.

Oral suspension Invasive Aspergillosis In a clinical study of IA, the median duration of intravenous VFEND therapy was 10 days (range to 85 days).

The median duration of oral

VFEND therapy was 76 days (range to 232 days) . 6 mg/kg every 12 hours for the first 24 hours 4 mg/kg every 12 hours 200 mg every 12 hours 5 mL every 12 hours Candidemia in nonneutropenic patients and other deep tissue Candida infections 6 mg/kg every 12 hours for the first 24 hours 3–4 mg/kg every 12 hours In clinical trials, patients with candidemia received 3 mg/kg intravenous infusion every 12 hours as primary therapy, while patients with other deep tissue Candida infections received 4 mg/kg every 12 hours as salvage therapy.

Appropriate dose should be based on the severity and nature of the infection. 200 mg every 12 hours 5 mL every 12 hours Esophageal Candidiasis Not Evaluated Not evaluated in patients with EC.

Evaluated 200 mg every 12 hours 5 mL every 12 hours Scedosporiosis and Fusariosis 6 mg/kg every 12 hours for the first 24 hours 4 mg/kg every 12 hours 200 mg every 12 hours 5 mL every 12 hours Method for Adjusting the Dosing Regimen in Adults.

• If the patient's response is inadequate, the oral maintenance dose for VFEND tablets or oral suspension may be increased from 200 mg (or 5 mL) every 12 hours to 300 mg (or 7.5 mL) every 12 hours.

• For adult patients weighing less than 40 kg, the oral maintenance dose for VFEND tablets or oral suspension may be increased from 100 mg (or 2.5 mL) every 12 hours to 150 mg (or 3.75 mL) every 12 hours.

• If the patient is unable to tolerate 300 mg (or 7.5 mL) orally every 12 hours, reduce the oral maintenance dose of VFEND tablets or oral suspension by 50 mg (or 1.25 mL) steps to a minimum of 200 mg (or 5 mL) every 12 hours for adult patients weighing more than 40 kg or to 100 mg (or 2.5 mL) every 12 hours for adult patients weighing less than 40 kg.

• If the patient is unable to tolerate 4 mg/kg intravenously every 12 hours, reduce the intravenous maintenance dose to 3 mg/kg every 12 hours. 2.4 Recommended Dosing Regimen in Pediatric Patients The recommended dosing regimen for pediatric patients to less than 12 years of age and to 14 years of age with body weight less than 50 kg is shown in Table 2.

For pediatric patients to 14 years of age with a body weight greater than or equal to 50 kg and those 15 years of age and above regardless of body weight, administer the adult dosing regimen of VFEND.

Table 2: Recommended Dosing Regimen for Pediatric Patients to less than 12 years of age and to 14 years of age with body weight less than 50 kg Based on a population pharmacokinetic analysis in 112 immunocompromised pediatric patients aged to less than 12 years of age and 26 immunocompromised pediatric patients aged to less than 17 years of age.

Loading Dose Maintenance Dose Intravenous infusion Intravenous infusion Oral tablets Oral suspension Invasive Aspergillosis In the Phase 3 clinical trials, patients with IA received intravenous (IV) treatment for at least 6 weeks and up to a maximum of 12 weeks.

Patients received

IV treatment for at least the first 7 days of therapy and then could be switched to oral VFEND therapy. 9 mg/kg every 12 hours for the first 24 hours 8 mg/kg every 12 hours after the first 24 hours 9 mg/kg every 12 hours (maximum dose of 350 mg every 12 hours) 0.225 mL/kg every 12 hours [maximum dose of 8.75 mL (350 mg) every 12 hours] Candidemia in nonneutropenics and other deep tissue Candida infections Study treatment for primary or salvage invasive candidiasis and candidemia (ICC) or EC consisted of intravenous VFEND, with an option to switch to oral therapy after at least 5 days of IV therapy, based on subjects meeting switch criteria.

For subjects with primary or salvage

ICC, VFEND was administered for at least 14 days after the last positive culture.

A maximum of 42 days of treatment was permitted.

Patients with primary or salvage

EC were treated for at least 7 days after the resolution of clinical signs and symptoms.

Scedosporiosis and Fusariosis Esophageal Candidiasis Not

Evaluated 4 mg/kg every 12 hours 9 mg/kg every 12 hours (maximum dose of 350 mg every 12 hours) 0.225 mL/kg every 12 hours [maximum dose of 8.75 mL (350 mg) every 12 hours] Initiate therapy with an intravenous infusion regimen.

Consider an oral regimen only after there is a significant clinical improvement.

Note that an 8 mg/kg intravenous dose will provide voriconazole exposure approximately 2-fold higher than a 9 mg/kg oral dose.

Oral bioavailability may be limited in pediatric patients to 12 years with malabsorption and very low body weight for age.

In that case, intravenous VFEND administration is recommended.

Method for Adjusting the Dosing Regimen in Pediatric Patients Pediatric Patients to less than 12 years of age and to 14 years of age with body weight less than 50 kg If patient response is inadequate and the patient is able to tolerate the initial intravenous maintenance dose, the maintenance dose may be increased by 1 mg/kg steps.

If patient response is inadequate and the patient is able to tolerate the oral maintenance dose, the dose may be increased by 1 mg/kg (0.025 mL/kg) steps or 50 mg (1.25 mL) steps to a maximum of 350 mg (8.75 mL) every 12 hours.

If patients are unable to tolerate the initial intravenous maintenance dose, reduce the dose by 1 mg/kg steps.

If patients are unable to tolerate the oral maintenance dose, reduce the dose by 1 mg/kg (0.025 mL/kg) or 50 mg (1.25 mL) steps.

Pediatric patients to 14 years of age weighing greater than or equal to 50 kg and 15 years of age and older regardless of body weight: Use the optimal method for titrating dosage recommended for adults. 2.5 Dosage Modifications in Patients With Hepatic Impairment Adults The maintenance dose of VFEND should be reduced in adult patients with mild to moderate hepatic impairment, Child-Pugh Class A and B. There are no PK data to allow for dosage adjustment recommendations in patients with severe hepatic impairment (Child-Pugh Class C).

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

Adult patients with baseline liver function tests (ALT, AST) of up to 5 times the upper limit o.

I.V. for Injection is supplied in a single-dose vial as a sterile lyophilized powder equivalent to 200 mg voriconazole and 3,200 mg sulfobutyl ether beta-cyclodextrin sodium (SBECD).

It does not contain preservatives and is not made with natural rubber latex.

Individually packaged vials of 200 mg VFEND I.V. (NDC 0049-4190-01) 16.2 Storage VFEND I.V. for Injection unreconstituted vials should be stored at 15°C to 30°C (59°F to 86°F) .

VFEND is a single dose unpreserved sterile lyophile.

From a microbiological point of view, following reconstitution of the lyophile with Water for Injection, the reconstituted solution should be used immediately.

If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 2°C to 8°C (36°F to 46°F).

Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C to 8°C (36°F to 46°F).

This medicinal product is for single use only and any unused solution should be discarded.

Only clear solutions without particles should be used.

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

VFEND is a single dose unpreserved sterile lyophile.

From a microbiological point of view, following reconstitution of the lyophile with Water for Injection, the reconstituted solution should be used immediately.

If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 2°C to 8°C (36°F to 46°F).

Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C to 8°C (36°F to 46°F).

This medicinal product is for single use only and any unused solution should be discarded.

Only clear solutions without particles should be used.

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

There are no available data on the use of VFEND in pregnant women.

In animal reproduction studies, oral voriconazole was associated with fetal malformations in rats and fetal toxicity in rabbits.

Cleft palates and hydronephrosis/hydroureter were observed in rat pups exposed to voriconazole during organogenesis at and above 10 mg/kg (0.3 times the RMD 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 voriconazole from implantation to weaning experienced increased gestational length and dystocia, which were associated with increased perinatal pup mortality at the 10 mg/kg dose.

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.

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.

Voriconazole was administered orally to pregnant rats during organogenesis (gestation days 6–17) at 10, 30, and 60 mg/kg/day. Voriconazole was associated with increased incidences of the malformations hydroureter and hydronephrosis at 10 mg/kg/day or greater, approximately 0.3 times the recommended human dose (RMD) based on body surface area comparisons, and cleft palate at 60 mg/kg, approximately 2 times the RMD based on body surface area comparisons.

Reduced ossification of sacral and caudal vertebrae, skull, pubic, and hyoid bone, supernumerary ribs, anomalies of the sternebrae, 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.

Voriconazole was administered orally to pregnant rabbits during the period of organogenesis (gestation days 7–19) at 10, 40, and 100 mg/kg/day. Voriconazole was associated with increased post-implantation loss and 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 body surface area comparisons).

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, voriconazole was administered orally to female rats from implantation through the end of lactation at 1, 3, and 10 mg/kg/day. Voriconazole 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.

The safety and effectiveness of

VFEND have been established in pediatric patients 2 years of age and older based on evidence from adequate and well-controlled studies in adult and pediatric patients and additional pediatric pharmacokinetic and safety data.

A total of 105 pediatric patients aged to less than 12 [N=26] and aged to less than 18 [N=79] from two, non-comparative Phase 3 pediatric studies and eight adult therapeutic trials provided safety information for VFEND use in the pediatric population.

Safety and effectiveness in pediatric patients below the age of 2 years has not been established.

Therefore, VFEND is not recommended for pediatric patients less than 2 years of age.

A higher frequency of liver enzyme elevations was observed in the pediatric patients.

The frequency of phototoxicity reactions is higher in the pediatric population.

Squamous cell carcinoma has been reported in patients who experience photosensitivity reactions.

Stringent measures for photoprotection are warranted.

Sun avoidance and dermatologic follow-up are recommended in pediatric patients experiencing photoaging injuries, such as lentigines or ephelides, even after treatment discontinuation.

VFEND has not been studied in pediatric patients with hepatic or renal impairment.

Hepatic function and serum creatinine levels should be closely monitored in pediatric patients.

In multiple dose therapeutic trials of voriconazole, 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 (C max ) were increased in elderly males compared to young males.

Pharmacokinetic data obtained from 552 patients from 10 voriconazole therapeutic trials showed that voriconazole 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.