Noxafil Adverse Reactions

Posaconazole Oral Suspension: Drug-related adverse reactions observed in 2 400 subjects dosed with posaconazole oral suspension are shown in Table 12. 172 patients received posaconazole oral suspension therapy for ≥6 months; 58 of these received posaconazole oral suspension therapy for ≥12 months.
The safety of posaconazole has been assessed in >2400 patients and healthy volunteers enrolled in clinical trials and from post-marketing experience.
The most frequently reported serious related adverse reactions/events reported across the whole population of healthy volunteers and patients included were nausea (6%), headache (6%), vomiting, diarrhea, pyrexia and increased bilirubin. (See Table 10.)

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Serious adverse events that were considered treatment related were reported in 8% (35/428) of patients in the refractory invasive fungal infection pool. Most individual treatment related serious adverse events were reported by <1% of patients and are largely reflective of the serious underlying conditions that predisposed to the development of the invasive fungal infection. Treatment related serious adverse events reported in 1% of subjects (3 or 4 subjects each) included altered concentration of other medicinal products, increased hepatic enzymes, nausea, rash, and vomiting. Treatment-related serious adverse events reported in 605 patients treated with posaconazole oral suspension for prophylaxis (1% each) included bilirubinaemia, increased hepatic enzymes, hepatocellular damage, nausea, and vomiting.
Uncommon and rare treatment related medically significant adverse events reported during clinical trials with posaconazole oral suspension have included adrenal insufficiency, pancreatitis, allergic and/or hypersensitivity reactions.
Some azoles have been associated with prolongation of the QT interval on the electrocardiogram. A pooled analysis of 173 posaconazole oral suspension-dosed healthy volunteers utilizing time matched ECGs did not show a potential to prolong the QT interval. In addition, rare cases of torsade de pointes have been reported in patients taking posaconazole oral suspension.
In addition, rare cases of haemolytic uremic syndrome and thrombotic thrombocytopenic purpura have been reported primarily among patients who had been receiving concomitant cyclosporine or tacrolimus for management of transplant rejection or graft vs. host disease. (See Tables 11, 12 and 13.)

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Posaconazole Modified Release Tablets: In clinical trials, the type and frequency of adverse effects reported for posaconazole modified release tablets were generally similar to that reported in trials of posaconazole oral suspension.
The safety of posaconazole modified release tablets has been assessed in 230 patients in clinical trials. Patients were enrolled in a non-comparative pharmacokinetic and safety trial of posaconazole modified release tablets when given as antifungal prophylaxis (P05615). Patients were immunocompromised with underlying conditions including haematological malignancy, neutropenia post- chemotherapy, GVHD, and post HSCT. This patient population was 62% male, had a mean age of 51 years (range 19-78 years, 17% of patients were ≥65 years of age), and were 93% white and 16% Hispanic. Posaconazole therapy was given for a median duration of 28 days. Twenty patients received 200 mg daily dose and 210 patients received 300 mg daily dose (following BD dosing on Day 1 in each cohort).
The most frequently reported treatment-related adverse reactions (≥5%) with posaconazole modified release tablets (300 mg once daily) were nausea and diarrhoea. The most frequently reported adverse reaction leading to discontinuation of posaconazole modified release tablets 300 mg once daily was nausea.
Table 14 presents treatment-emergent adverse reactions observed in patients treated with 300 mg daily dose at an incidence of ≥10% in posaconazole modified release tablet study. (See Table 14.)

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Clinical Laboratory Values: In (uncontrolled) trials of patients with invasive fungal infections treated with NOXAFIL oral suspension doses of 800 mg/day, the incidence of clinically significant liver function test abnormalities was: ALT and AST (>3 X Upper Limit Normal {ULN}) 11% and 10%, respectively; total bilirubin (>1.5 X ULN) 22%; and alkaline phosphatase (>3 X ULN) 14%. In healthy volunteers, elevation of hepatic enzymes did not appear to be associated with higher plasma concentrations of posaconazole. In patients, the majority of abnormal liver function tests results showed minor and transient changes and rarely led to discontinuation of therapy.
In the comparative trials of patients infected with HIV treated with NOXAFIL at doses up to 400 mg, the incidence of clinically significant liver function test abnormalities was as follows: ALT and AST (>3 X ULN) 3% and 6%, respectively: total bilirubin (>1.5 X ULN) 3%; and alkaline phosphatase (>3 X ULN) 3%.
The number of patients with changes in liver function tests from Common Toxicity Criteria (CTC) Grade 0, 1, or 2 at Baseline to Grade 3 or 4 during the study are presented in Table 15 for the prophylaxis studies 316 and 1899. (See Table 15.)

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Post-marketing Experience: The following post-marketing adverse experience has been reported: Endocrine Disorders: pseudoaldosteronism.