Posaconazoleside effects

The following serious and otherwise important adverse reactions are discussed in detail in another section of the labeling:

Arrhythmias and QT Prolongation

Electrolyte Disturbances

Pseudoaldosteronism

Hepatic Toxicity

Adult Patients: Common adverse reactions in studies with posaconazole in adults are diarrhea, nausea, fever, vomiting, headache, coughing, and hypokalemia. To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical

Trials Experience 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 Trials Safety Experience with Posaconazole Oral Suspension: The safety of posaconazole oral suspension has been assessed in 1,844 patients, including:

605 patients in the active-controlled studies for the prophylaxis of invasive Aspergillus and Candida infections

557 patients in the active-controlled OPC studies (not refractory to itraconazole or fluconazole)

239 patients in refractory OPC studies (refractory to itraconazole or fluconazole) (rOPC), and

443 patients in other patient populations These studies included immunocompromised patients (e.g., patients with hematological malignancy, neutropenia post-chemotherapy, GVHD post HSCT, and HIV infection), as well as non-neutropenic patients. This patient population was 71% male, had a mean age of 42 years (range 8 to 84 years, 6% of patients were ≥65 years of age and 1% was <18 years of age), and were 64% White, 14% Black, 16% Hispanic. Posaconazole oral suspension therapy was given to 171 patients for ≥6 months, including 58 patients who received posaconazole oral suspension therapy for ≥12 months. Table 10 presents adverse reactions observed at an incidence of >10% in the studies for prophylaxis of invasive Aspergillus and Candida infections. Table 11 presents adverse reactions observed at an incidence of at least 10% in the OPC/rOPC studies. Prophylaxis of Invasive Aspergillus and Candida Infections (posaconazole oral suspension): In the two randomized, comparative studies for prophylaxis Aspergillus and Candida infections in those at high risk of developing these infections due to being severely immunocompromised (Posaconazole Oral Suspension Study 1 and 2), the safety of posaconazole oral suspension 200 mg three times a day was compared to fluconazole 400 mg once daily or itraconazole 200 mg twice a day in severely immunocompromised patients. The most frequently reported adverse reactions (>30%) in these trials were fever, diarrhea, and nausea. The most common adverse reactions leading to discontinuation of posaconazole oral suspension were GI adverse reactions, specifically, nausea (2%), vomiting (2%), and increased hepatic enzymes (2%). Table 10: Adverse Reactions in at least 10% of Patients Receiving Posaconazole Oral Suspension for the Prophylaxis of Invasive Aspergillus and Candida Infections Adverse Reactions Posaconazole Oral Suspension n=605 (%) Fluconazole n=539 (%) Itraconazole n=58 (%) Percentage of Patients Reporting any Adverse Reaction 98 99 100 Fever 45 47 55 Diarrhea 42 39 60 Nausea 38 37 52 Hypokalemia 30 26 52 Thrombocytopenia 29 27 34 Vomiting 29 32 41 Headache 28 26 40 Abdominal Pain 27 27 36 Anemia 25 23 28 Coughing 24 24 24 Neutropenia 23 23 40 Constipation 21 17 17 Dyspnea 20 22 26 Rigors 20 16 29 Rash 19 18 43 Hypertension 18 16 5 Hypomagnesemia 18 16 19 Fatigue 17 18 9 Insomnia 17 17 19 Musculoskeletal Pain 16 15 16 Anorexia 15 17 28 Edema Legs 15 12 19 Epistaxis 14 14 21 Hypotension 14 15 17 Pharyngitis 12 11 21 Tachycardia 12 14 5 Arthralgia 11 12 9 Dizziness 11 10 9 Hyperglycemia 11 14 3 Petechiae 11 10 16 Pruritus 11 12 19 Back Pain 10 12 7 Bilirubinemia 10 9 19 Dyspepsia 10 9 10 Vaginal Hemorrhage Percentage of sex-specific adverse reactions are based on the number of males/females. 10 9 12 Treatment of Nonrefractory OPC and Refractory OPC (posaconazole oral suspension) In two randomized comparative studies for the treatment of nonrefractory OPC, the safety of posaconazole oral suspension (less than or equal to 400 mg once daily) in 557 HIV-infected patients was compared to the safety of fluconazole (100 mg once daily) in 262 HIV-infected patients. An additional 239 HIV-infected patients with refractory OPC (rOPC) received posaconazole oral suspension in two non-comparative trials for rOPC. Of these patients, 149 received the 800 mg/day dosage and the remainder received the less than or equal to 400 mg once daily dosage. In the nonrefractory OPC and rOPC studies, the most common adverse reactions in patients treated with posaconazole oral suspension were fever, diarrhea, nausea, headache, vomiting, and coughing. Adverse reactions were reported more frequently in the studies of patients with refractory OPC. Among these highly immunocompromised patients with advanced HIV disease, serious adverse reactions were reported in 55% (132/239) of posaconazole oral suspension-treated patients. The most commonly reported serious adverse reactions were fever (13%) and neutropenia (10%). Table 11: Adverse Reactions in at least 10% of Patients Receiving Posaconazole Oral Suspension for the Treatment of Nonrefractory and Refractory OPC Adverse Reactions Controlled OPC Pool Refractory OPC Pool Posaconazole Oral Suspension Fluconazole Posaconazole Oral Suspension n=557 (%) n=262 (%) n=239 (%) Percentage of Patients that Reported any Adverse Reaction Based on patients reporting adverse reactions at least once during the study, without regard to relationship to treatment. Patients may have reported more than 1 adverse reaction. 64 67 92 Diarrhea 10 13 29 Nausea 9 11 29 Headache 8 9 20 Vomiting 7 7 28 Fever 6 8 34 Abdominal Pain 5 6 18 Neutropenia 4 3 16 Coughing 3 4 25 Fatigue 3 5 13 Herpes Simplex 3 3 11 Pneumonia 3 2 10 Rash 3 4 15 Anemia 2 2 14 Anorexia 2 2 19 Asthenia 2 2 13 Sweating Increased 2 2 10 Candidiasis, Oral 1 <1 12 Dehydration 1 3 11 Dyspnea 1 3 12 Insomnia 1 1 16 Pain 1 1 11 Weight Decrease 1 <1 14 Rigors <1 2 12 OPC=oropharyngeal candidiasis Additional Adverse Reactions Reported in Less Than 5% of Posaconazole-Treated Patients in Clinical Trials 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

Cardiac Disorders: torsades de pointes

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 Liver Test Abnormalities in the Clinical Trials of Posaconazole Oral Suspension Liver Test Abnormalities in the Clinical Trials with Posaconazole Oral Suspension for Prophylaxis of Invasive Aspergillus and Candida Infections In the prophylaxis of invasive Aspergillus and Candida infections studies, the number and percentage of patients with changes in liver tests from Common Toxicity Criteria (CTC) Grade 0, 1, or 2 at baseline to Grade 3 or 4 at the end of the studies is presented in Table 12. Table 12: Changes in Liver Test Results from CTC Grade 0, 1, or 2 at Baseline to Grade 3 or 4 in Prophylaxis of Invasive Aspergillus and Candida Infections Studies (Posaconazole Oral Suspension Study 1 and Study 2). Number (%) of Patients with Change Change from Grade 0 to 2 at baseline to Grade 3 or 4 during the study. These data are presented in the form X/Y, where X represents the number of patients who met the criterion as indicated, and Y represents the number of patients who had a baseline observation and at least one post-baseline observation. Posaconazole Oral Suspension Study 1 Laboratory Parameter Posaconazole Oral Suspension n=301 Fluconazole n=299 AST 11/266 13/266 ALT 47/271 39/272 Bilirubin 24/271 20/275 Alkaline Phosphatase 9/271 8/271 Posaconazole Oral Suspension Study 2 Laboratory Parameter Posaconazole Oral Suspension (n=304) Fluconazole/Itraconazole (n=298) AST 9/286 5/280 ALT 18/289 13/284 Bilirubin 20/290 25/285 Alkaline Phosphatase 4/281 1/276 (<1) Liver Test Abnormalities in the Clinical Trials with Posaconazole Oral Suspension for the Treatment of OPC The number and percentage of patients treated for OPC with clinically significant liver test abnormalities at any time during the studies is provided in Table 13 (liver test abnormalities were present in some of these patients prior to initiation of the study drug). Table 13: Clinically Significant Liver Test Abnormalities without Regard to Baseline Value (Posaconazole Oral Suspension Studies for the Treatment of OPC) Laboratory Test Nonrefractory OPC Refractory OPC Posaconazole Oral Suspension Fluconazole Posaconazole Oral Suspension n=557 (%) n=262 (%) n=239 (%) ALT > 3.0 × ULN 16/537 13/254 25/226 AST > 3.0 × ULN 33/537 26/254 39/223 Total Bilirubin > 1.5 × ULN 15/536 5/254 9/197 Alkaline Phosphatase > 3.0 × ULN 17/535 15/253 24/190 ALT= Alanine Aminotransferase; AST= Aspartate Aminotransferase. Liver Test Abnormalities in the Clinical Trials with Posaconazole Oral Suspension for the Treatment of Invasive Aspergillosis The number and percentage of patients treated for invasive aspergillosis with clinically significant liver test abnormalities at any time during the Aspergillosis Treatment Study is provided in Table 14. Liver test abnormalities present prior to the initiation of study drug included: ALT (22% of the patients), AST (13% of the patients), and bilirubin (13% of the patients). Table 14: Changes in Liver Test Results from CTC Grade 0, 1, or 2 at Baseline to Grade 3 or 4 (Aspergillosis Treatment Study) Number (%) of Patients with Change Change from Grade 0 to 2 at baseline to Grade 3 or 4 during the study. These data are presented in the form n/N, where n represents the number of patients who met the criterion as indicated, and N represents the number of patients who had a baseline observation and at least one post-baseline observation. Laboratory Parameter Posaconazole n/N (%) Voriconazole n/N (%) AST 22/281 21/285 ALT 29/281 23/282 Bilirubin 26/280 25/284 Alkaline Phosphatase 12/282 20/284 In healthy volunteers and patients, elevation of liver test values did not appear to be associated with higher plasma posaconazole concentrations.

6.2 Postmarketing

Experience The following adverse reaction has been identified during the post-approval use of posaconazole. 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.

Endocrine Disorders: Pseudoaldosteronism