Voriconazole (Page 4 of 12)

5.4 Visual Disturbances

The effect of Voriconazole for injection on visual function is not known if treatment continues beyond 28 days. There have been post-marketing reports of prolonged visual adverse reactions, 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)].

5.5 Severe Cutaneous Adverse Reactions

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

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. 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, 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 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

Hydroxypropyl-β-cyclodextrin (HPβCD), 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 HPβCD 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 for injection [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

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

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

In animals, voriconazole administration was associated with fetal malformations, embryotoxicity, increased gestational length, dystocia and embryomortality [see Use in Specific Populations (8.1)].

If Voriconazole for injection is used during pregnancy, or if the patient becomes pregnant while taking Voriconazole for injection, inform the patient of the potential hazard to the fetus. Advise females of reproductive potential to use effective contraception during treatment with Voriconazole for injection [see Use in Specific Populations (8.3)].

5.10 Laboratory Tests

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

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

5.11 Pancreatitis

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

Patients with risk factors for acute pancreatitis (e.g., recent chemotherapy, hematopoietic stem cell transplantation [HSCT]) should be monitored for the development of pancreatitis during Voriconazole for injection treatment.

5.12 Skeletal Adverse Reactions

Fluorosis and periostitis have been reported during long-term Voriconazole for injection therapy. If a patient develops skeletal pain and radiologic findings compatible with fluorosis or periostitis, Voriconazole for injection should be discontinued [see Adverse Reactions (6.2)].

5.13 Clinically Significant Drug Interactions

See Table 6 for a listing of drugs that may significantly alter voriconazole concentrations. Also, see Table 7 for a listing of drugs that may interact with voriconazole resulting in altered pharmacokinetics or pharmacodynamics of the other drug [see Contraindications (4) and Drug Interactions (7)] .

6 ADVERSE REACTIONS

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)]

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