Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of posaconazole cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Clinical Trial Experience in Adults
Clinical Trial Experience with Posaconazole Injection for Prophylaxis
Multiple doses of posaconazole injection administered via a peripheral venous catheter were associated with thrombophlebitis (60% incidence). Therefore, in subsequent studies, posaconazole injection was administered via central venous catheter.
The safety of posaconazole injection has been assessed in 268 patients in a clinical trial. Patients were enrolled in a non-comparative pharmacokinetic and safety trial of posaconazole injection when given as antifungal prophylaxis (Posaconazole Injection Study). Patients were immunocompromised with underlying conditions including hematological malignancy, neutropenia post-chemotherapy, GVHD, and post HSCT. This patient population was 55% male, had a mean age of 51 years (range 18 to 82 years, 19% of patients were ≥65 years of age), and were 95% white and 8% Hispanic. Ten patients received a single dose of 200 mg posaconazole injection, 21 patients received 200 mg daily dose for a median of 14 days, and 237 patients received 300 mg daily dose for a median of 9 days.
Table 8presents adverse reactions observed in patients treated with posaconazole injection 300 mg daily dose in the posaconazole Injection Study. Each patient received a loading dose, 300 mg twice on Day 1. Following posaconazole intravenous therapy, patients received Noxafil oral suspension to complete 28 days of total posaconazole therapy.
Table 8: Posaconazole Injection Study: Adverse Reactions in at Least 10% of Subjects Treated with Posaconazole Injection 300 mg Daily Dose
The most frequently reported adverse reactions with an onset during the posaconazole intravenous phase of dosing with 300 mg once daily were diarrhea (32%), hypokalemia (22%), pyrexia (21%), and nausea (19%). These adverse reactions were consistent with those seen in studies with Noxafil oral suspension.
Other clinically significant adverse reactions reported in less than 5% of patients in clinical trials of posaconazole are listed below:
* Blood and lymphatic system disorders:hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, neutropenia aggravated
* Endocrine disorders:adrenal insufficiency
* Nervous system disorders:paresthesia
* Immune system disorders:allergic reaction [see Contraindications (4.1)]
* Cardiac disorders:torsades de pointes [see Warnings and Precautions (5.2)]
* Vascular disorders:pulmonary embolism
* Gastrointestinal disorders:pancreatitis
* Liver and Biliary System Disorders:hepatic enzymes increased, hepatic function abnormal, hepatitis, hepatomegaly, jaundice
* Renal & Urinary System Disorders:renal failure acute
Clinical Trial Experience in Pediatrics
Clinical Trial Experience in Pediatric Patients (2 to less than 18 Years of Age)
The safety of posaconazole injection and Noxafil PowderMix for delayed-release oral suspension for prophylaxis of invasive fungal infections has been assessed in an open label uncontrolled dose-ranging PK and safety study (Posaconazole injection/ Noxafil PowderMix for delayed-release oral suspension Pediatric Study 1, NCT02452034); hereinafter referred to as Posaconazole Pediatric Study) in 115 immunocompromised pediatric patients 2 to less than 18 years of age with known or expected neutropenia. Posaconazole injection and Noxafil PowderMix for delayed-release oral suspension was administered at daily doses of up to 6 mg/kg (twice daily on day 1) in three dose cohorts. All 115 subjects initially received posaconazole injection for at least 7 days, and 63 subjects were transitioned to Noxafil PowderMix for delayed-release oral suspension. The mean overall treatment duration for all treated subjects was 20.6 days with 14.3 days (range: 1 to 28 days) on posaconazole injection and 11.6 days (range: 2 to 18 days) on Noxafil PowderMix for delayed-release oral suspension [see Clinical Pharmacology (12.3)].
Table 15presents adverse reactions observed in greater than or equal to 10% of pediatric patients treated with posaconazole in the Posaconazole Pediatric Study.
Reported adverse reaction profile of posaconazole in pediatric patients was consistent with the safety profile of posaconazole in adults. The most common adverse reactions (occurring in greater than 20% of pediatric patients receiving 6 mg/kg posaconazole injection and Noxafil PowderMix for delayed-release oral suspension daily dose) were pyrexia, febrile neutropenia, vomiting, mucosal inflammation, pruritus, hypertension, hypokalemia, and stomatitis.
Table 15: Adverse Reactions in at Least 10% of Pediatric Patients Treated with Posaconazole Injection and Noxafil PowderMix for Delayed-Release Oral Suspension
The number of patients receiving posaconazole in the Posaconazole Pediatric Study who had changes in liver tests from Grade 0, 1, or 2 at baseline to Grade 3 or 4 is presented in Table 16.