Drug Safety-related Labeling Changes (SrLC)

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VFEND (NDA-021630)

(VORICONAZOLE)

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

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10/18/2022 (SUPPL-42)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 Photosensitivity

Additions and/or revisions underlined:

VFEND has been associated with photosensitivity skin reaction. Patients, including pediatric patients, should avoid exposure to direct sunlight during VFEND 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 VFEND discontinuation should be considered. If VFEND 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 VFEND therapy in patients with photosensitivity skin reactions. If a patient develops a skin lesion consistent with premalignant skin lesions, squamous cell carcinoma or melanoma, VFEND should be discontinued. In addition, VFEND 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 drug associated with ultraviolet (UV) reactivation. There is the potential for this risk to be observed with other drugs associated with UV reactivation. Patients should avoid strong, direct sunlight during VFEND 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.

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

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

Updates regarding tyrosine kinase inhibitors have been made to Table 11; please refer to label

08/16/2022 (SUPPL-43)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 Photosensitivity

Additions and/or revisions underlined:

… VFEND should be discontinued. In addition, VFEND 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 drug associated with ultraviolet (UV) reactivation. There is the potential for this risk to be observed with other drugs associated with UV reactivation. Patients should avoid strong, direct sunlight during VFEND therapy …

6 Adverse Reactions

6.1 Clinical Trials Experience

Clinical Trials Experience in Adults

Additions and/or revisions underlined:

VFEND 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

Newly added information:

Dermatological Reactions

Increased risk of skin toxicity with concomitant use of methotrexate, a drug associated with UV reactivation, 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:

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Visual Disturbances

Patients should be instructed that visual disturbances such as blurring and sensitivity to light may occur with the use of VFEND.

Photosensitivity

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

• Advise patients that VFEND 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).

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 VFEND.

PATIENT INFORMATION

Additions and/or revisions underlined:

What are possible side effects of VFEND? VFEND may cause serious side effects including:

• vision changes. Symptoms of vision changes may include:

• blurred vision

• changes in the way you see colors

• sensitivity to light or sun (photosensitivity). VFEND can cause serious photosensitivity. There is an increased chance of skin toxicity while taking VFEND. This can happen with or without taking other medicines like methotrexate.

Photosensitivity reactions may also increase your risk of:

• faster skin aging from the sun

• skin cancer

Call your healthcare provider right away if you get a new skin rash or your skin rash gets worse.

01/28/2022 (SUPPL-41)

Approved Drug Label (PDF)

7 Drug Interactions

Refer to newly added information in Table 11 titled:  Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined: 

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 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.

10/13/2021 (SUPPL-40)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions underlined)

• Coadministration of VFEND 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)].

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.

Other

(The term “events” revised to read “reactions”)

04/15/2021 (SUPPL-39)

Approved Drug Label (PDF)

4 Contraindications

Additions underlined

…

• Coadministration of cisapride, pimozide, quinidine or ivabradine with VFEND 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 VFEND 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)].

7 Drug Interactions

Extensive additions and/or revisions to Tables 10 and 11, please refer to label for complete information.

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

PATIENT INFORMATION

Additions underlined

…

Do not take VFEND if you:

…

• are taking any of the following medicines:

  …

  • ivabradine

  • venetoclax

    …

01/25/2021 (SUPPL-38)

Approved Drug Label (PDF)

4 Contraindications

(Newly added information)

• Coadministration of VFEND with naloxegol is contraindicated because VFEND may increase plasma concentrations of naloxegol which may precipitate opioid withdrawal symptoms [see Drug Interactions (7) and Clinical Pharmacology (12.3)].

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

5 Warnings and Precautions

5.8 Adrenal Dysfunction

(Newly added section)

Reversible cases of azole-induced adrenal insufficiency have been reported in patients receiving azoles, including VFEND. 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 VFEND concomitantly with corticosteroids.

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

6 Adverse Reactions

6.2 Postmarketing Experience in Adult and Pediatric Patients

(Newly added information)

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

7 Drug Interactions

(Extensive changes, including the interaction with letermovir; please refer to label)

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

Patient Information

(Extensive changes; please refer to label)

01/14/2021 (SUPPL-36)

Approved Drug Label (PDF)

4 Contraindications

Newly added information:

Coadministration of VFEND with naloxegol is contraindicated because VFEND may increase plasma concentrations of naloxegol which may precipitate opioid withdrawal symptoms [see Drug Interactions (7) and Clinical Pharmacology (12.3)].

5 Warnings and Precautions

Newly added subsection:

5.8 Adrenal Dysfunction

Reversible cases of azole-induced adrenal insufficiency have been reported in patients receiving azoles, including VFEND. 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 VFEND concomitantly with corticosteroids.

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

6 Adverse Reactions

6.2 Postmarketing Experience in Adult and Pediatric Patients

Adults

Newly added information:

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

7 Drug Interactions

Table 11 Effect of Voriconazole on Pharmacokinetics of Other Drugs (see Clinical Pharmacology (12.3):

Addition of information regarding the interaction between voriconazole and naloxegol, prednisolone and other corticosteroids, and ivacaftor – Please refer to label for complete information

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

PATIENT INFORMATION

Newly added information:

Do not take VFEND if you:

·         are taking any of the following medicines:

o   naloxegol

Before you take VFEND, tell your healthcare provider about all of your medical conditions, including if you:

Newly added information:

·         have low potassium levels, low magnesium levels, and low calcium levels. Your healthcare provider may do blood tests before starting and during treatment with VFEND.

What are possible side effects of VFEND?

VFEND may cause serious side effects including:

Newly added information:

·         adrenal gland problems:

·         Vfend may cause reduced adrenal function (adrenal insufficiency).

·         Vfend may cause overactive adrenal function (Cushing’s syndrome) when voriconazole is used at the same time with corticosteroids.

Symptoms of adrenal insufficiency include:

o   feeling tired

o   lack of energy

o   weakness

o   nausea and vomiting

o   abdominal pain

o   feeling dizzy or lightheaded

o   weight loss

Symptoms of Cushing’s syndrome include:

o   weight gain

o   fatty hump between the shoulders (buffalo hump) and a rounded

o   face (moon face)

o   darkening of the skin on the stomach, thighs, breasts, and arms

o   thinning skin

o   bruising easily

o   high blood sugar

o   excessive hair growth

o   excessive sweating

• bone problems. VFEND may cause weakening of bones and bone pain. Tell your healthcare provider if you have bone pain.

The most common side effects of VFEND in children include:

Newly added information:

• swelling in the arms and legs

• hallucinations (seeing or hearing things that are not there)

• coughing up blood

• upper respiratory infection

09/04/2020 (SUPPL-37)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Severe Cutaneous Adverse Reactions

(Subsection title revised; Additions and/or revisions 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 VFEND. If a patient develops a severe cutaneous adverse reaction, VFEND should be discontinued [see Adverse Reactions (6.1, 6.2)].

6 Adverse Reactions

(Additions and/or revisions 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 underlined)

…

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported during treatment with VFEND. Erythema multiforme has also been reported during treatment with VFEND [see Warnings and Precautions (5.5) and Adverse Reactions (6.2)].

…

6.2 Postmarketing Experience in Adult and Pediatric Patients

(Additions and/or revisions underlined)

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

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)].

Pediatric Patients

There have been postmarketing reports of pancreatitis in pediatric patients.

01/29/2019 (SUPPL-29)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Hepatic Toxicity

Addition of the following 2nd paragraph:

A higher frequency of liver enzyme elevations was observed in the pediatric population. Hepatic function should be monitored in both adult and pediatric patients.

5.4 Visual Disturbances

Addition of the following to end of subsection:

and color perception should be monitored.

Additions and/or revisions underlined:

5.5 Serious Exfoliative Cutaneous Reactions

5.6 Photosensitivity

… Patients, including pediatric patients, should avoid exposure to direct sunlight …

... If a patient develops a skin lesion consistent with premalignant skin lesions, squamous cell carcinoma or melanoma, VFEND should be discontinued. In addition, VFEND has been associated with photosensitivity related skin reactions such as pseudoporphyria, cheilitis, and cutaneous lupus erythematosus. Patients should avoid strong, direct sunlight during VFEND therapy.

5.7 Renal Toxicity

… 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.

5.8 Embryo-Fetal Toxicity

… In animals, voriconazole administration was associated with fetal malformations, embryotoxicity, increased gestational length, dystocia and embryomortality.

If VFEND is used during pregnancy, or if the patient becomes pregnant while taking VFEND, inform the patient of the potential hazard to the fetus. Advise females of reproductive potential to use effective contraception during treatment with VFEND.

5.10 Pancreatitis

Pancreatitis has been observed in patients undergoing treatment with VFEND. Patients with risk factors for acute pancreatitis …

5.11 Skeletal Adverse Reactions

5.12 Clinically Significant Drug Interactions

See Table 10 for a listing of drugs that may significantly alter voriconazole concentrations. Also, see Table 11 for a listing of drugs that may interact with voriconazole resulting in altered pharmacokinetics or pharmacodynamics of the other drug.

6 Adverse Reactions

Addition of the following bulleted line listing:

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

• Hepatic Toxicity

• Arrhythmias and QT Prolongation

• Infusion Related Reactions

• Visual Disturbances

• Serious Exfoliative Cutaneous Reactions

• Photosensitivity

• Renal Toxicity

6.1 Clinical Trials Experience in Adults

Additions and/or revisions underlined:

The most frequently reported adverse reactions (see Table 4) in the adult therapeutic trials …

The data described in Table 4 reflect exposure to voriconazole in 1655 patients in nine therapeutic studies …

In study 307/602, 381 patients (196 on voriconazole, 185 on amphotericin B) were treated to compare voriconazole to amphotericin B followed by other licensed antifungal therapy (OLAT) in the primary treatment of patients with acute IA …

Dermatological Reactions

VFEND has also been associated with additional photosensitivity related skin reactions such as pseudoporphyria, cheilitis, and cutaneous lupus erythematosus.

Clinical Laboratory Values in Adults

The overall incidence of transaminase increases >3x upper limit of normal (not necessarily comprising an adverse reaction) was 17.7% (268/1514) in adult subjects treated with VFEND for therapeutic use in pooled clinical trials. 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 resolved following dose adjustment, including discontinuation of therapy.

Addition of the following:

Clinical Trials Experience in Pediatric Patients

The safety of VFEND was investigated in 105 pediatric patients aged 2 to less than 18 years, including 52 pediatric patients less than 18 years of age who were enrolled in the adult therapeutic studies.

Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation

In clinical studies, serious adverse reactions occurred in 46% (48/105) of VFEND treated pediatric patients. Treatment discontinuations due to adverse reactions occurred in 12 /105 (11%) of all patients. Hepatic adverse reactions (i.e. ALT increased; liver function test abnormal; jaundice) 6% (6/105) accounted for the majority of VFEND treatment discontinuations.

Most Common Adverse Reactions

The most common adverse reactions occurring in ?5% of pediatric patients receiving VFEND in the pooled pediatric clinical trials are displayed by body system, in Table 8.

Table 8: Treatment-Emergent Adverse Reactions Occurring in ?5% of Pediatric Patients Receiving VFEND in the Pooled Pediatric Clinical Trials Please refer to table for complete information.

The following adverse reactions with incidence less than 5% were reported in 105 pediatric patients treated with VFEND:

Blood and Lymphatic System Disorders: anemia, leukopenia, pancytopenia Cardiac Disorders: bradycardia, palpitations, supraventricular tachycardia Eye Disorders: dry eye, keratitis

Ear and Labyrinth Disorders: tinnitus, vertigo

Gastrointestinal Disorders: abdominal tenderness, dyspepsia

General Disorders and Administration Site Conditions: asthenia, catheter site pain, chills, hypothermia, lethargy

Hepatobiliary Disorders: cholestasis, hyperbilirubinemia, jaundice

Immune System Disorders: hypersensitivity, urticaria

Infections and Infestations: conjunctivitis

Laboratory Investigations: AST increased, blood creatinine increased, gamma-glutamyl transferase increased Metabolism and Nutrition Disorders: hypercalcemia, hypermagnesemia, hyperphosphatemia, hypoglycemia Musculoskeletal and Connective Tissue Disorders: arthralgia, myalgia

Nervous System Disorders: ataxia, convulsion, dizziness, nystagmus, paresthesia, syncope

Psychiatric Disorders: affect lability, agitation, anxiety, depression, insomnia

Respiratory Disorders: bronchospasm, nasal congestion, respiratory failure, tachypnea

Skin and Subcutaneous Tissue Disorders: alopecia, dermatitis (allergic, contact, and exfoliative), pruritus

Vascular Disorders: flushing, phlebitis

Hepatic-Related Adverse Reactions in Pediatric Patients

The frequency of hepatic-related adverse reactions in pediatric patients exposed to VFEND in therapeutic studies was numerically higher than that of adults (28.6% compared to 24.1%, respectively). The higher frequency of hepatic adverse reactions in the pediatric population was mainly due to an increased frequency of liver enzyme elevations (21.9% in pediatric patients compared to 16.1% in adults), including transaminase elevations (ALT and AST combined) 7.6% in the pediatric patients compared to 5.1% in adults. Clinical Laboratory Values in Pediatric Patients

The overall incidence of transaminase increases >3x upper limit of normal was 27.2% (28/103) in pediatric and 17.7% (268/1514) in adult patients treated with VFEND in pooled clinical trials. The majority of abnormal liver function tests either resolved on treatment with or without dose adjustment or after VFEND discontinuation.

A higher frequency of clinically significant liver laboratory abnormalities, irrespective of baseline laboratory values (>3x ULN ALT

or AST), was consistently observed in the combined therapeutic pediatric population (15.5% AST and 22.5% ALT) when compared to adults (12.9% AST and 11.6% ALT). The incidence of bilirubin elevation was comparable between adult and pediatric patients. The incidence of hepatic abnormalities in pediatric patients is shown in Table 9.

Table 9: Incidence of Hepatic Abnormalities among Pediatric Subjects Please refer to label for complete information.

Additions and/or revisions underlined:

6.2 Postmarketing Experience in Adults and Pediatric Patients

Adults

Eye disorders: prolonged visual adverse reactions, including optic neuritis and papilledema

Pediatric Patients

There have been postmarketing reports of pancreatitis in pediatric patients.

7 Drug Interactions

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 10 and 11 provide the clinically significant interactions between voriconazole and other medical products.

Table 10: Effect of Other Drugs on Voriconazole Pharmacokinetics Used to be labeled Table 7

Table 11 Effect of Voriconazole on Pharmacokinetics of Other Drugs Used to be labeled Table 8

8 Use in Specific Populations

Additions and/or revisions underlined:

8.1 Pregnancy

Risk Summary

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 …

8.4 Pediatric Use

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 2 to less than 12 [N=26] and aged 12 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.

06/15/2017 (SUPPL-31)

Approved Drug Label (PDF)

7 Drug Interactions

Table 8: Effect of Voriconazole on Pharmacokinetics of Other Drugs (Table’s drug-drug interaction information between voriconazole and vinca alkaloids has been revised; please refer to label)

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; 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 VFEND 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 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

Voriconazole was administered orally to pregnant rats during organogenesis (gestation days 6-17) at 10, 30, and 60 mg/kg/day..Voriconazole 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.

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 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, 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.

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; additions and/or revisions are underlined)

Risk Summary

No data are available regarding the presence of voriconazole in human milk, the effects of voriconazole 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 VFEND and any potential adverse effects on the breastfed child from VFEND or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion)

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

PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Advise the Patient to read the FDA-Approved Patient Labeling

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 VFEND.