POSACONAZOLE

5 WARNINGS AND PRECAUTIONS Calcineurin-Inhibitor Toxicity: Posaconazole increases concentrations of cyclosporine or tacrolimus; reduce dose of cyclosporine and tacrolimus and monitor concentrations frequently. ( 5.1 ) Arrhythmias and QTc Prolongation: Posaconazole has been shown to prolong the QTc interval and cause cases of TdP. Administer with caution to patients with potentially proarrhythmic conditions. Do not administer with drugs known to prolong QTc interval and metabolized through CYP3A4. ( 5.2 , 7.2 ) Electrolyte Disturbances: Monitor and correct, especially those involving potassium (K + ), magnesium (Mg ++ ), and calcium (Ca ++ ), before and during posaconazole therapy. ( 5.3 ) Pseudoaldosteronism : Manifested by the onset or worsening of hypertension, and abnormal laboratory findings. Monitor blood pressure and potassium levels, and manage as necessary. ( 5.4 ) Hepatic Toxicity: Elevations in liver tests may occur. Discontinuation should be considered in patients who develop abnormal liver tests or monitor liver tests during treatment. ( 5.5 ) Concomitant Use with Midazolam: Posaconazole can prolong hypnotic/sedative effects. Monitor patients and benzodiazepine receptor antagonists should be available. ( 5.7 , 7.2 ) Vincristine Toxicity: Concomitant administration of azole antifungals, including posaconazole, with vincristine has been associated with neurotoxicity and other serious adverse reactions; reserve azole antifungals, including posaconazole, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options. ( 5.8 , 7.2 ) Breakthrough Fungal Infections : Monitor patients with severe diarrhea or vomiting when receiving Posaconazole delayed-release tablets and Posaconazole oral suspension. ( 5.9 ) Venetoclax Toxicity: Concomitant administration of posaconazole with venetoclax may increase venetoclax toxicities, including the risk of tumor lysis syndrome, neutropenia, and serious infections; monitor for toxicity and reduce venetoclax dose. ( 4.6 , 5.10 , 7.2 ) 5.1 Calcineurin-Inhibitor Toxicity Concomitant administration of posaconazole with cyclosporine or tacrolimus increases the whole blood trough concentrations of these calcineurin-inhibitors [see Drug Interactions (7.2) and Clinical Pharmacology (12.3) ] . Nephrotoxicity and leukoencephalopathy (including deaths) have been reported in clinical efficacy studies in patients with elevated cyclosporine or tacrolimus concentrations. Frequent monitoring of tacrolimus or cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus or cyclosporine dose adjusted accordingly. 5.2 Arrhythmias and QT Prolongation Some azoles, including posaconazole, have been associated with prolongation of the QT interval on the electrocardiogram. In addition, cases of torsades de pointes have been reported in patients taking posaconazole. Results from a multiple time-matched ECG analysis in healthy volunteers did not show any increase in the mean of the QTc interval. Multiple, time-matched ECGs collected over a 12-hour period were recorded at baseline and steady-state from 173 healthy male and female volunteers (18-85 years of age) administered Noxafil oral suspension 400 mg twice daily with a high-fat meal. In this pooled analysis, the mean QTc (Fridericia) interval change from baseline was –5 msec following administration of the recommended clinical dose. A decrease in the QTc(F) interval (–3 msec) was also observed in a small number of subjects (n=16) administered placebo. The placebo-adjusted mean maximum QTc(F) interval change from baseline was <0 msec (–8 msec). No healthy subject administered Noxafil had a QTc(F) interval ≥500 msec or an increase ≥60 msec in their QTc(F) interval from baseline. Posaconazole should be administered with caution to patients with potentially proarrhythmic conditions. Do not administer with drugs that are known to prolong the QTc interval and are metabolized through CYP3A4 [see Contraindications (4.3) and Drug Interactions (7.2) ] . 5.3 Electrolyte Disturbances Electrolyte disturbances, especially those involving potassium, magnesium or calcium levels, should be monitored and corrected as necessary before and during posaconazole therapy. 5.4 Pseudoaldosteronism Pseudoaldosteronism, manifested by the onset of hypertension or worsening of hypertension, and abnormal laboratory findings (hypokalemia, low serum renin and aldosterone, and elevated 11-deoxycortisol), has been reported with posaconazole use in the postmarket setting. Monitor blood pressure and potassium levels and manage as necessary. Management of pseudoaldosteronism may include discontinuation of posaconazole, substitution with an appropriate antifungal drug that is not associated with pseudoaldosteronism, or use of aldosterone receptor antagonists. 5.5 Hepatic Toxicity Hepatic reactions (e.g., mild to moderate elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin, and/or clinical hepatitis) have been reported in clinical trials. The elevations in liver tests were generally reversible on discontinuation of therapy, and in some instances these tests normalized without drug interruption. Cases of more severe hepatic reactions including cholestasis or hepatic failure including deaths have been reported in patients with serious underlying medical conditions (e.g., hematologic malignancy) during treatment with posaconazole. These severe hepatic reactions were seen primarily in subjects receiving the Posaconazole oral suspension 800 mg daily (400 mg twice daily or 200 mg four times a day) in clinical trials. Liver tests should be evaluated at the start of and during the course of posaconazole therapy. Patients who develop abnormal liver tests during posaconazole therapy should be monitored for the development of more severe hepatic injury. Patient management should include laboratory evaluation of hepatic function (particularly liver tests and bilirubin). Discontinuation of posaconazole must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to posaconazole. 5.6 Renal Impairment Due to the variability in exposure with Posaconazole delayed-release tablets and Posaconazole oral suspension, patients with severe renal impairment should be monitored closely for breakthrough fungal infections [see Dosage and Administration (2.4) and Use in Specific Populations (8.6) ]. 5.7 Midazolam Toxicity Concomitant administration of posaconazole with midazolam increases the midazolam plasma concentrations by approximately 5-fold. Increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects. Patients must be monitored closely for adverse effects associated with high plasma concentrations of midazolam and benzodiazepine receptor antagonists must be available to reverse these effects [see Drug Interactions (7.2) and Clinical Pharmacology (12.3) ] . 5.8 Vincristine Toxicity Concomitant administration of azole antifungals, including posaconazole, with vincristine has been associated with neurotoxicity and other serious adverse reactions, including seizures, peripheral neuropathy, syndrome of inappropriate antidiuretic hormone secretion, and paralytic ileus. Reserve azole antifungals, including posaconazole, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options [see Drug Interactions (7.2) ] . 5.9 Breakthrough Fungal Infections Patients who have severe diarrhea or vomiting should be monitored closely for breakthrough fungal infections when receiving Posaconazole delayed-release tablets or Posaconazole oral suspension. 5.10 Venetoclax Toxicity Concomitant administration of posaconazole, a strong CYP3A4 inhibitor, with venetoclax may increase venetoclax toxicities, including the risk of tumor lysis syndrome (TLS), neutropenia, and serious infections. In patients with CLL/SLL, administration of posaconazole during initiation and the ramp-up phase of venetoclax is contraindicated [see Contraindications (4.6) ] . Refer to the venetoclax labeling for safety monitoring and dose reduction in the steady daily dosing phase in CLL/SLL patients. For patients with acute myeloid leukemia (AML), dose reduction and safety monitoring are recommended across all dosing phases when coadministering posaconazole with venetoclax [see Drug Interactions (7.2) ]. Refer to the venetoclax prescribing information for dosing instructions.

6 ADVERSE REACTIONS The following serious and otherwise important adverse reactions are discussed in detail in another section of the labeling: Arrhythmias and QT Prolongation [see Warnings and Precautions (5.2) ] Electrolyte Disturbances [see Warnings and Precautions (5.3) ] Pseudoaldosteronism [see Warnings and Precautions (5.4) ] Hepatic Toxicity [see Warnings and Precautions (5.5) ] Common adverse reactions in studies with posaconazole are diarrhea, nausea, fever, vomiting, headache, coughing, and hypokalemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme LLC at 1-877-888-4231 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 Noxafil cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Treatment of Invasive Aspergillosis in Adults and Adolescents (Noxafil Injection and Noxafil Delayed-Release Tablets) The safety of Noxafil injection and Noxafil delayed-release tablets was assessed in a randomized, double-blind, active-controlled clinical study of Noxafil injection and Noxafil delayed-release tablets versus voriconazole for treatment of invasive aspergillosis (Aspergillosis Treatment Study). A total of 575 adult and pediatric patients 14 years of age and older (288 in the Noxafil group, 287 in voriconazole group (voriconazole for injection or voriconazole tablets)) with proven, probable or possible invasive aspergillosis were included. The median duration of treatment was 67 days for Noxafil injection or Noxafil delayed-release tablet and 64 days for voriconazole (voriconazole for injection). In this study, with 55% to 60% of patients started intravenous treatment with Noxafil (Noxafil injection) or voriconazole (voriconazole for injection). The median duration of the first instance of intravenous treatment (before switching to oral treatment or discontinuing or completing study treatment) was 9 days for both groups. Table 5 presents adverse reactions reported at an incidence of ≥10% in either one of the treatment groups in the Aspergillosis Treatment Study. Adverse reactions leading to treatment discontinuation were reported for 34% of patients. The most commonly reported adverse reactions (>2% of patients) leading to treatment discontinuation were septic shock, respiratory failure, and bronchopulmonary aspergillosis in the Noxafil group, and septic shock and acute myeloid leukemia in the voriconazole group. The most frequently reported adverse reactions in the Noxafil-treated group were pyrexia (28%), hypokalemia (28%), and nausea (23%). Table 5: Adverse Reactions in at least 10% of Adults and Adolescents Receiving Noxafil Injection or Noxafil Delayed-Release Tablets for the Treatment of Invasive Aspergillosis Adverse Reactions Noxafil injection or Noxafil delayed-release tablets n=288 (%) Voriconazole for injection or Voriconazole tablets n=287 (%) Percentage of Patients Reporting any Adverse Reaction 97.6 97.6 Hypokalemia 28.5 17.1 Pyrexia 28.1 25.1 Nausea 22.6 17.8 Diarrhea 18.1 18.1 Vomiting 18.1 13.6 Alanine aminotransferase increased 14.6 12.9 Febrile neutropenia 14.6 13.2 Aspartate aminotransferase increased 13.2 12.5 Pneumonia 12.5 9.1 Headache 12.2 8.7 Constipation 11.1 8.0 Edema peripheral 11.1 8.4 Epistaxis 11.1 5.9 Cough 10.4 8.4 Abdominal pain 10.1 8.4 Hypomagnesemia 10.1 6.3 Clinical Trial Experience with Noxafil Delayed-Release Tablets for Prophylaxis of Invasive Aspergillus and Candida Infections The safety of Noxafil delayed-release tablets has been assessed in 230 patients in clinical trials. Patients were enrolled in a non-comparative pharmacokinetic and safety trial of Noxafil delayed-release tablets when given as antifungal prophylaxis (Noxafil Delayed-Release Tablet Study). Patients were immunocompromised with underlying conditions including hematological 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. Noxafil delayed-release tablets were given for a median duration of 28 days. In this study, 20 adult patients received 200 mg daily dose and 210 adult patients received 300 mg daily dosage (following twice daily dosing on Day 1 in each cohort). Table 6 presents adverse reactions (incidence of >10%) observed in patients treated with the Noxafil delayed-release tablets 300 mg daily dosage in the Noxafil Delayed-Release Tablet Study. The most frequently reported adverse reactions (>25%) in patients treated with Noxafil delayed-release tablets 300 mg once daily were diarrhea, pyrexia, and nausea. The most common adverse reaction leading to discontinuation of Noxafil delayed-release tablets 300 mg once daily was nausea (2%). Table 6: Adverse Reactions in at least 10% of Adults Receiving Noxafil Delayed-Release Tablets (300 mg Daily Dosage) for the Prophylaxis of Invasive Aspergillus and Candida infections Adverse Reactions Noxafil delayed-release tablet (300 mg) n=210 (%) Percentage of Patients Reporting any Adverse Reaction 99 Diarrhea 29 Pyrexia 28 Nausea 27 Hypokalemia 22 Cough 17 Edema Peripheral 16 Rash 16 Epistaxis 14 Headache 14 Mucosal Inflammation 14 Thrombocytopenia 14 Vomiting 13 Abdominal Pain 11 Hypertension 11 Anemia 10 Asthenia 10 Chills 10 Constipation 10 Hypomagnesemia 10 Clinical Trials Safety Experience with Noxafil Oral Suspension The safety of Noxafil oral suspension has been assessed in 1,844 patients, including: 605 patients in the active-controlled prophylaxis 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: 8-84 years, 6% of patients were ≥65 years of age and 1% was <18 years of age), and were 64% White, 14% Black, and 16% Hispanic. Noxafil oral suspension therapy was given to 171 patients for ≥6 months, including 58 patients who received Noxafil oral suspension therapy for ≥12 months. Table 7 presents adverse reactions observed at an incidence of >10% in the studies for prophylaxis of invasive Aspergillus and Candida infections. Table 8 presents adverse reactions observed at an incidence of at least 10% in the OPC/rOPC studies. Prophylaxis of Invasive Aspergillus and Candida Infections (Noxafil oral suspension) In the two randomized, comparative studies for prophylaxis of invasive Aspergillus and Candida infections in those at high risk of developing these infections due to being severely immunocompromised (Noxafil Oral Suspension Study 1 and 2), the safety of Noxafil 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 Noxafil oral suspension were GI adverse reactions, specifically, nausea (2%), vomiting (2%), and hepatic enzymes increased (2%). Table 7: Adverse Reactions in at least 10% of Patients Receiving Noxafil Oral Suspension for the Prophylaxis of Invasive Aspergillus and Candida Infections Adverse Reactions Noxafil 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 Percentages of sex-specific adverse reactions are based on the number of males/females. 10 9 12 Treatment of Nonrefractory OPC and Refractory OPC (Noxafil oral suspension) In two randomized comparative studies for the treatment of nonrefractory OPC, the safety of Noxafil 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 Noxafil 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 Noxafil 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 Noxafil oral suspension-treated patients. The most commonly reported serious adverse reactions were fever (13%) and neutropenia (10%). Table 8: Adverse Reactions in at least 10% of Patients Receiving Noxafil Oral Suspension for the Treatment of Nonrefractory and Refractory OPC Adverse Reactions Controlled OPC Pool Refractory OPC Pool Noxafil Oral Suspension Fluconazole Noxafil Oral Suspension n=557 (%) n=262 (%) n=239 (%) OPC=oropharyngeal candidiasis 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 Additional Adverse Reactions Reported in Less Than 5% of Noxafil-Treated Patients in Clinical Trials Other clinically significant adverse reactions reported in less than 5% of patients in clinical trials of Noxafil 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 Liver Test Abnormalities in the Clinical Trials of Noxafil Oral Suspension Liver Test Abnormalities in the Clinical Trials with Noxafil 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 9 . Table 9: 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 (Noxafil 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. CTC = Common Toxicity Criteria; AST= Aspartate Aminotransferase; ALT= Alanine Aminotransferase. Noxafil Oral Suspension Study 1 Laboratory Parameter Noxafil Oral Suspension n=301 Fluconazole n=299 AST 11/266 (4) 13/266 (5) ALT 47/271 (17) 39/272 (14) Bilirubin 24/271 (9) 20/275 (7) Alkaline Phosphatase 9/271 (3) 8/271 (3) Noxafil Oral Suspension Study 2 Laboratory Parameter Noxafil Oral Suspension (n=304) Fluconazole/Itraconazole (n=298) AST 9/286 (3) 5/280 (2) ALT 18/289 (6) 13/284 (5) Bilirubin 20/290 (7) 25/285 (9) Alkaline Phosphatase 4/281 (1) 1/276 (<1) Liver Test Abnormalities in the Clinical Trials with Noxafil 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 10 (liver test abnormalities were present in some of these patients prior to initiation of the study drug). Table 10: Clinically Significant Liver Test Abnormalities without Regard to Baseline Value (Noxafil Oral Suspension Studies for the Treatment of OPC) Laboratory Test Nonrefractory OPC Refractory OPC Noxafil Oral Suspension Fluconazole Noxafil Oral Suspension n=557 (%) n=262 (%) n=239 (%) ALT= Alanine Aminotransferase; AST= Aspartate Aminotransferase. ALT > 3.0 x ULN 16/537 (3) 13/254 (5) 25/226 (11) AST > 3.0 x ULN 33/537 (6) 26/254 (10) 39/223 (17) Total Bilirubin > 1.5 x ULN 15/536 (3) 5/254 (2) 9/197 (5) Alkaline Phosphatase > 3.0 x ULN 17/535 (3) 15/253 (6) 24/190 (13) Liver Test Abnormalities in the Clinical Trials with Noxafil 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 11. 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 11: 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 Noxafil n/N (%) Voriconazole n/N (%) N=Number of patients for a given laboratory test with a baseline value of CTC Grade 0, 1, or 2 and at least one post-baseline value. CTC = Common Toxicity Criteria; AST= Aspartate Aminotransferase; ALT= Alanine Aminotransferase. AST 22/281 (8) 21/285 (7) ALT 29/281(10) 23/282 (8) Bilirubin 26/280 (9) 25/284 (9) Alkaline Phosphatase 12/282 (4) 20/284 (7) In healthy volunteers and patients, elevation of liver test values did not appear to be associated with higher plasma concentrations of posaconazole. Clinical Trials in Pediatric Patients 2 Years of Age and Older The safety of Noxafil injection and Noxafil PowderMix (for delayed-release oral suspension) for prophylaxis of invasive fungal infections was evaluated in an open-label uncontrolled dose-ranging pharmacokinetic and safety study of Noxafil injection and Noxafil PowderMix (Pediatric Study 1, NCT02452034). In this study, 115 immunocompromised pediatric patients 2 to less than 18 years of age with known or expected neutropenia initially received Noxafil injection (up to 6 mg/kg twice daily for the first day and then up to 6 mg/kg for at least 7 days) and then 63 patients were transitioned to Noxafil PowderMix (up to 6 mg/kg once daily). The mean overall treatment duration for all treated subjects was 21 days including a mean duration of 14 days (range: 1 to 28 days) on Noxafil injection and a mean duration of 12 days (range: 2 to 18 days) on Noxafil PowderMix for delayed-release oral suspension . In this study, the reported adverse reaction profile of Noxafil injection and Noxafil PowderMix in pediatric patients was consistent with the safety profile of Noxafil in adults. The safety of Noxafil injection, Noxafil delayed-release tablets, and Noxafil PowderMix for delayed-release oral suspension for the treatment of invasive aspergillosis was evaluated in an open-label, non-comparative clinical study in 31 pediatric patients 2 to less than 18 years of age with a diagnosis of possible, probable, or proven invasive aspergillosis (Pediatric Study 2, NCT04218851). In this study, all 31 pediatric patients initially received Noxafil injection (6 mg/kg twice daily on the first day and then 6 mg/kg once daily) for the treatment of invasive aspergillosis; 12 patients were transitioned to Noxafil delayed-release tablets (300 mg once daily) if they weighed ≥40 kg, and 10 patients were transitioned to Noxafil PowderMix (based on weight) if they weighed 10 to 40 kg [see Dosage and Administration (2.3) ] . The mean overall treatment duration was 50 days including 15 days (range: 2 to 78 days) on Noxafil injection, 54 days (range: 6 to 80 days) on Noxafil delayed-release tablets, and 44 days (range: 7 to 76 days) on Noxafil PowderMix. The reported adverse reaction profile of Noxafil injection, Noxafil delayed-release tablets, and Noxafil PowderMix in pediatric patients was consistent with the known safety profile of Noxafil in adults. The most common adverse reactions that occurred in greater than 20% of pediatric patients who received any of the three formulations of Noxafil were vomiting, pyrexia, abdominal pain, liver test abnormalities, and hypertension. 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 casual relationship to drug exposure. Endocrine Disorders: Pseudoaldosteronism

<table width="75%"><caption>Table 5: Adverse Reactions in at least 10% of Adults and Adolescents Receiving Noxafil Injection or Noxafil Delayed-Release Tablets for the Treatment of Invasive Aspergillosis</caption><col width="40%" align="left" valign="top"/><col width="30%" align="center" valign="top"/><col width="30%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule" align="center" valign="middle">Adverse Reactions</th><th styleCode="Rrule">Noxafil injection or Noxafil delayed-release tablets n=288 (%)</th><th styleCode="Rrule">Voriconazole for injection or Voriconazole tablets n=287 (%) </th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Percentage of Patients Reporting any Adverse Reaction</td><td styleCode="Rrule">97.6</td><td styleCode="Rrule">97.6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypokalemia</td><td styleCode="Rrule">28.5</td><td styleCode="Rrule">17.1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pyrexia</td><td styleCode="Rrule">28.1</td><td styleCode="Rrule">25.1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">22.6</td><td styleCode="Rrule">17.8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">18.1</td><td styleCode="Rrule">18.1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vomiting</td><td styleCode="Rrule">18.1</td><td styleCode="Rrule">13.6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Alanine aminotransferase increased</td><td styleCode="Rrule">14.6</td><td styleCode="Rrule">12.9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Febrile neutropenia</td><td styleCode="Rrule">14.6</td><td styleCode="Rrule">13.2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Aspartate aminotransferase increased</td><td styleCode="Rrule">13.2</td><td styleCode="Rrule">12.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pneumonia</td><td styleCode="Rrule">12.5</td><td styleCode="Rrule">9.1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">12.2</td><td styleCode="Rrule">8.7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Constipation</td><td styleCode="Rrule">11.1</td><td styleCode="Rrule">8.0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Edema peripheral</td><td styleCode="Rrule">11.1</td><td styleCode="Rrule">8.4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Epistaxis</td><td styleCode="Rrule">11.1</td><td styleCode="Rrule">5.9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Cough</td><td styleCode="Rrule">10.4</td><td styleCode="Rrule">8.4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Abdominal pain</td><td styleCode="Rrule">10.1</td><td styleCode="Rrule">8.4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypomagnesemia</td><td styleCode="Rrule">10.1</td><td styleCode="Rrule">6.3</td></tr></tbody></table>

<table width="75%"><caption>Table 6: Adverse Reactions in at least 10% of Adults Receiving Noxafil Delayed-Release Tablets (300 mg Daily Dosage) for the Prophylaxis of Invasive Aspergillus and Candida infections</caption><col width="60%" align="left" valign="top"/><col width="40%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule" align="center" valign="middle">Adverse Reactions</th><th styleCode="Rrule">Noxafil delayed-release tablet (300 mg) n=210 (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Percentage of Patients Reporting any Adverse Reaction</td><td styleCode="Rrule">99</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">29</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pyrexia</td><td styleCode="Rrule">28</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">27</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypokalemia</td><td styleCode="Rrule">22</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Cough</td><td styleCode="Rrule">17</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Edema Peripheral</td><td styleCode="Rrule">16</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Rash</td><td styleCode="Rrule">16</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Epistaxis</td><td styleCode="Rrule">14</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">14</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Mucosal Inflammation</td><td styleCode="Rrule">14</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Thrombocytopenia</td><td styleCode="Rrule">14</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vomiting</td><td styleCode="Rrule">13</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Abdominal Pain</td><td styleCode="Rrule">11</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypertension</td><td styleCode="Rrule">11</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Anemia</td><td styleCode="Rrule">10</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Asthenia</td><td styleCode="Rrule">10</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Chills</td><td styleCode="Rrule">10</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Constipation</td><td styleCode="Rrule">10</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypomagnesemia</td><td styleCode="Rrule">10</td></tr></tbody></table>

<table width="75%"><caption>Table 7: Adverse Reactions in at least 10% of Patients Receiving Noxafil Oral Suspension for the Prophylaxis of Invasive Aspergillus and Candida Infections</caption><col width="40%" align="left" valign="top"/><col width="20%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule" align="center" valign="middle">Adverse Reactions</th><th styleCode="Rrule">Noxafil Oral Suspension n=605 (%)</th><th styleCode="Rrule">Fluconazole n=539 (%) </th><th styleCode="Rrule">Itraconazole n=58 (%) </th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Percentage of Patients Reporting any Adverse Reaction</td><td styleCode="Rrule">98</td><td styleCode="Rrule">99</td><td styleCode="Rrule">100</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Fever</td><td styleCode="Rrule">45</td><td styleCode="Rrule">47</td><td styleCode="Rrule">55</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">42</td><td styleCode="Rrule">39</td><td styleCode="Rrule">60</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">38</td><td styleCode="Rrule">37</td><td styleCode="Rrule">52</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypokalemia</td><td styleCode="Rrule">30</td><td styleCode="Rrule">26</td><td styleCode="Rrule">52</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Thrombocytopenia</td><td styleCode="Rrule">29</td><td styleCode="Rrule">27</td><td styleCode="Rrule">34</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vomiting</td><td styleCode="Rrule">29</td><td styleCode="Rrule">32</td><td styleCode="Rrule">41</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">28</td><td styleCode="Rrule">26</td><td styleCode="Rrule">40</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Abdominal Pain</td><td styleCode="Rrule">27</td><td styleCode="Rrule">27</td><td styleCode="Rrule">36</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Anemia</td><td styleCode="Rrule">25</td><td styleCode="Rrule">23</td><td styleCode="Rrule">28</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Coughing</td><td styleCode="Rrule">24</td><td styleCode="Rrule">24</td><td styleCode="Rrule">24</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Neutropenia</td><td styleCode="Rrule">23</td><td styleCode="Rrule">23</td><td styleCode="Rrule">40</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Constipation</td><td styleCode="Rrule">21</td><td styleCode="Rrule">17</td><td styleCode="Rrule">17</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dyspnea</td><td styleCode="Rrule">20</td><td styleCode="Rrule">22</td><td styleCode="Rrule">26</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Rigors</td><td styleCode="Rrule">20</td><td styleCode="Rrule">16</td><td styleCode="Rrule">29</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Rash</td><td styleCode="Rrule">19</td><td styleCode="Rrule">18</td><td styleCode="Rrule">43</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypertension</td><td styleCode="Rrule">18</td><td styleCode="Rrule">16</td><td styleCode="Rrule">5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypomagnesemia</td><td styleCode="Rrule">18</td><td styleCode="Rrule">16</td><td styleCode="Rrule">19</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Fatigue</td><td styleCode="Rrule">17</td><td styleCode="Rrule">18</td><td styleCode="Rrule">9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Insomnia</td><td styleCode="Rrule">17</td><td styleCode="Rrule">17</td><td styleCode="Rrule">19</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Musculoskeletal Pain</td><td styleCode="Rrule">16</td><td styleCode="Rrule">15</td><td styleCode="Rrule">16</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Anorexia</td><td styleCode="Rrule">15</td><td styleCode="Rrule">17</td><td styleCode="Rrule">28</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Edema Legs</td><td styleCode="Rrule">15</td><td styleCode="Rrule">12</td><td styleCode="Rrule">19</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Epistaxis</td><td styleCode="Rrule">14</td><td styleCode="Rrule">14</td><td styleCode="Rrule">21</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypotension</td><td styleCode="Rrule">14</td><td styleCode="Rrule">15</td><td styleCode="Rrule">17</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pharyngitis</td><td styleCode="Rrule">12</td><td styleCode="Rrule">11</td><td styleCode="Rrule">21</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Tachycardia</td><td styleCode="Rrule">12</td><td styleCode="Rrule">14</td><td styleCode="Rrule">5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Arthralgia</td><td styleCode="Rrule">11</td><td styleCode="Rrule">12</td><td styleCode="Rrule">9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dizziness</td><td styleCode="Rrule">11</td><td styleCode="Rrule">10</td><td styleCode="Rrule">9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hyperglycemia</td><td styleCode="Rrule">11</td><td styleCode="Rrule">14</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Petechiae</td><td styleCode="Rrule">11</td><td styleCode="Rrule">10</td><td styleCode="Rrule">16</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pruritus</td><td styleCode="Rrule">11</td><td styleCode="Rrule">12</td><td styleCode="Rrule">19</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Back Pain</td><td styleCode="Rrule">10</td><td styleCode="Rrule">12</td><td styleCode="Rrule">7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Bilirubinemia</td><td styleCode="Rrule">10</td><td styleCode="Rrule">9</td><td styleCode="Rrule">19</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dyspepsia</td><td styleCode="Rrule">10</td><td styleCode="Rrule">9</td><td styleCode="Rrule">10</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vaginal Hemorrhage<footnote ID="t7f1">Percentages of sex-specific adverse reactions are based on the number of males/females.</footnote></td><td styleCode="Rrule">10</td><td styleCode="Rrule">9</td><td styleCode="Rrule">12</td></tr></tbody></table>