Drug Safety-related Labeling Changes (SrLC)

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VORICONAZOLE (NDA-208562)

(VORICONAZOLE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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04/18/2025 (SUPPL-11)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.8 Risk of Hydroxypropyl Beta- Cyclodextrin Toxicity

Newly added subsection:

Due to the hydroxypropyl-Beta-cyclodextrin (HPBetaCD) content of this product, this voriconazole product for injection is not indicated for use in pediatric patients 2 years to less than 12 years of age and 12 years to 14 years of age weighing less than 50 kg. If treatment with voriconazole is indicated for this pediatric subpopulation, use a different voriconazole product [see Indications and Usage (1) and Use in Specific Populations (8.4)].

Nonclinical studies have reported induced vacuolization of renal tubular cells in adult rats after exposure to HPBetaCD that may be reversible after short term exposure for 15 to 21 days, but the impact of long-term renal exposure to HPBetaCD is currently unknown. Nonclinical studies have also reported irreversible sensorineural hearing loss in adult rats after exposure to HPBetaCD. These risks have not been well-characterized in juvenile animals.

The initial loading dose of this voriconazole product contain 192 mg/kg/day HP?CD and the maintenance dosing contain 128 mg/kg/day HPBetaCD [see Description (11)].

The clearance of the HPBetaCD content in a dose of this voriconazole product may be delayed in those with eGFR less than 60 mL/minute/1.73m2 or in those in the first two 2 years of life in whom renal maturation has not been attained [see Dosage and Administration (2.6), Description (11), and Clinical Pharmacology (12.3)].

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

. . .

Due to the hydroxypropyl-Beta-cyclodextrin (HPBetaCD) content in this product, there are risks for renal vacuolization and sensorineural hearing loss in young pediatric patients. As this risk is not well characterized, this VORICONAZOLE for injection product is not indicated for use in pediatric patients 2 years to less than 12 years of age and 12 years to 14 years of age weighing less than 50 kg due to the HPBetaCD content in this product. If treatment with voriconazole is indicated in a pediatric patient (2 years to less than 12 years of age or 12 years to 14 years of age weighing less than 50 kg), use a different voriconazole product [see Warnings and Precautions (5.7 and 5.8)].

. . .

01/03/2023 (SUPPL-5)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions underlined)

• Coadministration of Voriconazole for injection with rifampin, carbamazepine, long-acting barbiturates and St. John's Wort is contraindicated because these drugs are likely to decrease plasma voriconazole concentrations significantly [see Drug Interactions (7) and Clinical Pharmacology (12.3)].

…

• Coadministration of Voriconazole for injection with lurasidone is contraindicated since it may result in significant increases in lurasidone exposure and the potential for serious adverse reactions [see Drug Interactions (7)].

5 Warnings and Precautions

5.6 Photosensitivity

(Additions and/or revisions underlined)

Voriconazole for injection has been associated with photosensitivity skin reaction. Patients, including pediatric patients, should avoid exposure to direct sunlight during Voriconazole for injection 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 Voriconazole for injection discontinuation should be considered. If Voriconazole for injection 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 (including cutaneous SCC in situ, or Bowen’s disease) and melanoma have been reported during long-term Voriconazole for injection therapy in patients with photosensitivity skin reactions…

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

Clinical Trials Experience in Adults

…

Less Common Adverse Reactions

The following adverse reactions occurred in <2% of all voriconazole-treated patients in all therapeutic studies (N=1655). This listing includes events where a causal relationship to voriconazole 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 voriconazole clinical program.

…

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, (including cutaneous SCC in situ, or Bowen’s disease), sweating, toxic epidermal necrolysis, urticaria.

7 Drug Interactions

(Additions and/or revisions underlined)

Voriconazole is metabolized by cytochrome P450 isoenzymes, CYP2C19, CYP2C9, and CYP3A4. Therefore, inhibitors or inducers of these isoenzymes may increase or decrease voriconazole plasma concentrations, respectively. Voriconazole is a strong inhibitor of CYP3A4, and also inhibits CYP2C19 and CYP2C9. Therefore, voriconazole may increase the plasma concentrations of substances metabolized by these CYP450 isoenzymes.

08/16/2022 (SUPPL-6)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 Photosensitivity

Additions and/or revisions underlined:

… In addition, Voriconazole for injection has been associated with photosensitivity related skin reactions such as pseudoporphyria, cheilitis, and cutaneous lupus erythematosus, as well as increased risk of skin toxicity with concomitant use of methotrexate, a with other drugs that are associated with ultraviolet (UV) reactivation (e.g., methotrexate). There is the potential for this risk to be observed with other drugs associated with UV reactivation. Patients should avoid strong, direct sunlight during Voriconazole for injection therapy …

6 Adverse Reactions

6.1 Clinical Trials Experience

Clinical Trials Experience in Adults

Dermatological Reactions

Additions and/or revisions underlined:

… Voriconazole has also been associated with additional photosensitivity related skin reactions such as pseudoporphyria, cheilitis, and cutaneous lupus erythematosus [see Warnings and Precautions (5.6) and Adverse Reactions (6.2)].

6.2 Postmarketing Experience in Adult and Pediatric Patients

Additions and/or revisions underlined:

Dermatological Reactions

Increased risk of skin toxicity with concomitant use of methotrexate, as with other drugs that are associated with UV reactivation, (e.g., methotrexate) was observed in postmarketing reports [see Warnings and Precautions (5.6) and Adverse Reactions (6.1)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Photosensitivity

• Advise patients of the risk of photosensitivity (with or without concomitant methotrexate), accelerated photoaging, and skin cancer.

• Advise patients that Voriconazole for injection can cause serious photosensitivity and to immediately contact their healthcare provider for new or worsening skin rash.

• Advise patients to avoid exposure to direct sun light and to use measures such as protective clothing and sunscreen with high sun protection factor (SPF).

12/17/2021 (SUPPL-4)

Approved Drug Label (PDF)

4 Contraindications

Additions underlined

• Coadministration of , pimozide, quinidine or ivabradine with Voriconazole for injection is contraindicated because increased plasma concentrations of these drugs can lead to QT prolongation and rare occurrences of torsade de pointes [see Drug Interactions (7)].

    …

• Coadministration of Voriconazole for injection with high-dose ritonavir (400 mg every 12 hours) is contraindicated because ritonavir (400 mg every 12 hours) significantly decreases plasma voriconazole concentrations. Coadministration of voriconazole and 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 voriconazole [see Drug Interactions (7) and Clinical Pharmacology (12.3)].

       

  …

• Coadministration of Voriconazole for injection with naloxegol is contraindicated because Voriconazole for injection may increase plasma concentrations of naloxegol which may precipitate opioid withdrawal symptoms [see Drug Interactions (7)].

• Coadministration of Voriconazole for injection with tolvaptan is contraindicated because Voriconazole for injection may increase tolvaptan plasma concentrations and increase risk of adverse reactions [see Drug Interactions (7)].

• Coadministration of Voriconazole for injection with venetoclax 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 [see Drug Interactions (7)].

5 Warnings and Precautions

5.1 Hepatic Toxicity

Additions underlined

…

A higher frequency of liver enzyme elevations was observed in the pediatric population [see Adverse Reactions (6.1)]. Hepatic function should be monitored in both adult and pediatric patients.

…

5.11 Pancreatitis

Additions underlined

Pancreatitis has been observed in patients undergoing treatment with Voriconazole for injection [see Adverse Reactions (6.1, 6.2)].

…

5.5 Severe Cutaneous Adverse Reactions

Additions underlined

Severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported during treatment with Voriconazole for injection. If a patient develops a severe cutaneous adverse reaction, Voriconazole for injection should be discontinued [see Adverse Reactions (6.1, 6.2)].

5.6 Photosensitivity

New subsection created

Voriconazole for injection has been associated with photosensitivity skin reaction. Patients, including pediatric patients, should avoid exposure to direct sunlight during Voriconazole for injection 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 Voriconazole for injection discontinuation should be considered. If Voriconazole for injection 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 Voriconazole for injection therapy in patients with photosensitivity skin reactions. If a patient develops a skin lesion consistent with premalignant skin lesions, squamous cell carcinoma or melanoma, Voriconazole for injection should be discontinued. In addition, Voriconazole for injection has been associated with photosensitivity related skin reactions such as pseudoporphyria, cheilitis, and cutaneous lupus erythematosus.

Patients should avoid strong, direct sunlight during Voriconazole for injection therapy.

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.

5.7 Renal Toxicity

New subsection created

Hydroxypropyl-?-cyclodextrin (HP?CD), the intravenous vehicle of Voriconazole for injection, is eliminated

through glomerular filtration. Therefore, in patients with moderate to severe renal dysfunction (creatinine clearance

<50 mL/min), accumulation of HP?CD occurs. Serum creatinine (Scr) levels should be closely monitored in patients with renal impairment. If increases in Scr occur, consideration should be given to changing to alternate antifungal therapy with similar coverage, unless an assessment of the benefit/risk to the patient justifies the continued use of intravenous voriconazole [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3)].

Acute renal failure has been observed in patients undergoing treatment with Voriconazole for injection. Patients being treated with voriconazole are likely to be treated concomitantly with nephrotoxic medications and may 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 of serum creatinine [see Clinical Pharmacology (12.3) and Dosage and Administration (2.6)].

5.8 Adrenal Dysfunction

New subsection created

Reversible cases of azole-induced adrenal insufficiency have been reported in patients receiving azoles, including Voriconazole for injection. Adrenal insufficiency has been reported in patients receiving azoles with or without concomitant corticosteroids. In patients receiving azoles without corticosteroids adrenal insufficiency is related to direct inhibition of steroidogenesis by azoles. In patients taking corticosteroids, voriconazole associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression [see Drug Interactions (7) and Clinical Pharmacology (12.3)]. Cushing’s syndrome with and without subsequent adrenal insufficiency has also been reported in patients receiving Voriconazole for injection concomitantly with corticosteroids.

Patients receiving Voriconazole for injection and corticosteroids (via all routes of administration) should be carefully monitored for adrenal dysfunction both during and after Voriconazole for injection treatment. Patients should be instructed to seek immediate medical care if they develop signs and symptoms of Cushing’s syndrome or adrenal insufficiency.

5.9 Embryo-Fetal Toxicity

Additions underlined

… Advise females of reproductive potential to use effective contraception during treatment with Voriconazole for injection [see Use in Specific Populations (8.3)].

6 Adverse Reactions

Subsection revised; additions underlined

The following serious adverse reactions are described elsewhere in the labeling:

Hepatic Toxicity [see Warnings and Precautions (5.1)]

Arrhythmias and QT Prolongation [see Warnings and Precautions (5.2)]

Infusion Related Reactions [see Warnings and Precautions (5.3)]

Visual Disturbances [see Warnings and Precautions (5.4)]

Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.5)]

Photosensitivity [see Warnings and Precautions (5.6)]

Renal Toxicity [see Warnings and Precautions (5.7)]

6.1 Clinical Trials Experience

Additions and/or revisions; please refer to label for complete information

6.2 Postmarketing Experience

Additions underlined

…

Adults

Skeletal: fluorosis and periostitis have been reported during long-term voriconazole therapy [see Warnings and Precautions (5.11)].

Eye disorders: prolonged visual adverse reactions, including optic neuritis and papilledema [see Warnings and Precautions (5.4)].

Skin and Appendages: drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)].

Endocrine disorders: adrenal insufficiency, Cushing’s syndrome (when voriconazole has been used concomitantly with corticosteroids) [see Warnings and Precautions (5.8)].

Pediatric Patients

There have been postmarketing reports of pancreatitis in pediatric patients.

7 Drug Interactions

Additions underlined

 

Voriconazole is metabolized by, and inhibits the activity of, cytochrome P450 isoenzymes, CYP2C19, CYP2C9, and CYP3A4. Inhibitors or inducers of these isoenzymes may increase or decrease voriconazole plasma concentrations, respectively, and there is potential for voriconazole to increase the plasma concentrations of substances metabolized by these CYP450 isoenzymes.

Tables 6 and 7 provide the clinically significant interactions between voriconazole and other medical products.

Additions and revisions to tables 6 and Table 7 ; please refer to label for complete information

…

8 Use in Specific Populations

8.1 Pregnancy

Additions underlined

…

Data

 

Animal Data

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 malformations resulting in increased incidences in 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 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.

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.

8.4 Pediatric Use

Subsection revised; additions and/or revisions underlined

The safety and effectiveness of voriconazole have been established in pediatric patients aged 12 to 14 years weighing greater than or equal to 50 kg and those aged 15 years and older regardless of body weight based on evidence from adequate and well-controlled studies in adult and pediatric patients and additional pediatric pharmacokinetic and safety data. A total of 51 pediatric patients aged 12 to less than 18 [N=51] from eight adult therapeutic trials provided safety information for voriconazole use in the pediatric population [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)].

Safety and effectiveness in pediatric patients below the age of 2 years has not been established. Therefore, Voriconazole for injection 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 [see Dosage and Administration (2.5), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].

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 [see Warnings and Precautions (5.6)].

Voriconazole for injection has not been studied in pediatric patients with hepatic or renal impairment [see Dosage and Administration (2.5, 2.6)]. Hepatic function and serum creatinine levels should be closely monitored in pediatric patients [see Dosage and Administration (2.6) and Warnings and Precautions (5.1, 5.9)].

Additional pediatric use information is approved for PF PRISM C.V.’s VFEND (voriconazole) for injection. However, due to PF PRISM C.V.’s marketing exclusivity rights, this drug product is not labeled with that information.

03/26/2018 (SUPPL-2)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions are underlined)

Risk Summary

Voriconazole can cause fetal harm when administered to a pregnant woman. There are no available data on the use of Voriconazole for injection in pregnant women. In animal reproduction studies, oral voriconazole was teratogenic in rats and embryotoxic 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 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 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 population 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.

8.3 Females and Males of Reproductive Potential

(Additions and/or revisions are underlined)

Contraception

Advise females of reproductive potential to use effective contraception during treatment with Voriconazole for injection.

8.4 Pediatric Use

(Additions and/or revisions are underlined)

Sparse plasma sampling for pharmacokinetics in adolescents was conducted in the therapeutic studies. 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 voriconazole (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).

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Embryo-Fetal Toxicity

• Advise female patients of the potential risks to a fetus.

• Advise females of reproductive potential to use effective contraception during treatment with Voriconazole for injection.