FDA label 0a0917f3-71b0-4746-baee-1c2d81655a9f

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 ) Electrolyte Disturbances: Monitor and correct, especially those involving potassium (K + ), magnesium (Mg ++ ), and calcium (Ca ++ ), before and during posaconazole therapy. ( 5.3 ) 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. ( 5.4 ) Concomitant Use with Midazolam: Posaconazole can prolong hypnotic/sedative effects. Monitor patients and benzodiazepine receptor antagonists should be available. ( 5.6 , 7.5 ) 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. ( 5.7 , 7.10 ) Breakthrough Fungal Infections : Monitor patients with severe diarrhea or vomiting when receiving Posaconazole delayed-release tablets and Posaconazole oral suspension. ( 5.8 ) 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 , 5.9 , 7.15 ) 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 (7.1) 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 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. 5.5 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) ]. 5.6 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 (7.5) and Clinical Pharmacology (12.3) ] . 5.7 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 (7.10) ] . 5.8 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. 5.9 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 (7.15) ]. 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: Hypersensitivity [see Contraindications (4.1) ] Arrhythmias and QT Prolongation [see Warnings and Precautions (5.2) ] Hepatic Toxicity [see Warnings and Precautions (5.4) ] 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. Clinical Trial Experience in Adults Clinical Trial Experience with Noxafil Injection and Noxafil Delayed-Release Tablets for the Treatment of Invasive Aspergillosis The safety of Noxafil injection and Noxafil delayed-release tablet 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 (288 in Noxafil arm, 287 in voriconazole arm) adult and pediatric patients 13 years of age and older 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, with 55% to 60% of subjects starting treatment with the IV formulation of either drug. The median duration of the first instance of IV treatment (before switching to oral treatment or discontinuing or completing study treatment) was 9 days for both groups. Table 4 presents adverse reactions reported at an incidence of ≥10% in either one of the groups in Aspergillosis Treatment Study. Adverse reactions leading to treatment discontinuation were reported for 33.9% of subjects. The most commonly reported adverse reactions (>2% of subjects) leading to treatment discontinuation were septic shock, respiratory failure, and bronchopulmonary aspergillosis in the Noxafil arm, and septic shock and acute myeloid leukemia in the voriconazole arm. Table 4: Noxafil Invasive Aspergillosis Treatment Study: Adverse Reactions in at Least 10% of Subjects Treated with Noxafil Injection or Noxafil Delayed-Release Tablets System Organ Class Noxafil injection or tablet (N = 288), n (%) Voriconazole injection or oral (N = 287), n (%) Blood and lymphatic system disorders Anemia 25 (8.7) 29 (10.1) Febrile neutropenia 42 (14.6) 38 (13.2) Gastrointestinal disorders Abdominal pain 29 (10.1) 24 (8.4) Constipation 32 (11.1) 23 (8.0) Diarrhea 52 (18.1) 52 (18.1) Nausea 65 (22.6) 51 (17.8) Vomiting 52 (18.1) 39 (13.6) General disorders and administration site conditions Edema peripheral 32 (11.1) 24 (8.4) Pyrexia 81 (28.1) 72 (25.1) Infections and infestations Pneumonia 36 (12.5) 26 (9.1) Investigations Alanine aminotransferase increased 42 (14.6) 37 (12.9) Aspartate aminotransferase increased 38 (13.2) 36 (12.5) Blood alkaline phosphatase increased 21 (7.3) 29 (10.1) Metabolism and nutrition disorders Hypokalemia 82 (28.5) 49 (17.1) Hypomagnesemia 29 (10.1) 18 (6.3) Nervous system disorders Headache 35 (12.2) 25 (8.7) Respiratory, thoracic and mediastinal disorders Cough 30 (10.4) 24 (8.4) Epistaxis 32 (11.1) 17 (5.9) The most frequently reported adverse reactions in the Noxafil-treated group were pyrexia (28%), hypokalemia (28%), and nausea (23%). Clinical Trial Experience with Noxafil Delayed-Release Tablets for Prophylaxis 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. 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 twice daily dosing on Day 1 in each cohort). Table 5 presents adverse reactions observed in patients treated with 300 mg daily dose at an incidence of ≥10% in Noxafil Delayed-Release Tablet Study. Table 5: Noxafil Delayed-Release Tablet Study: Adverse Reactions in at Least 10% of Subjects Treated with 300 mg Daily Dose Body System Noxafil delayed-release tablet (300 mg) n=210 (%) Subjects Reporting any Adverse Reaction 207 (99) Blood and Lymphatic System Disorder Anemia 22 (10) Thrombocytopenia 29 (14) Gastrointestinal Disorders Abdominal Pain 23 (11) Constipation 20 (10) Diarrhea 61 (29) Nausea 56 (27) Vomiting 28 (13) General Disorders and Administration Site Conditions Asthenia 20 (10) Chills 22 (10) Mucosal Inflammation 29 (14) Edema Peripheral 33 (16) Pyrexia 59 (28) Metabolism and Nutrition Disorders Hypokalemia 46 (22) Hypomagnesemia 20 (10) Nervous System Disorders Headache 30 (14) Respiratory, Thoracic and Mediastinal Disorders Cough 35 (17) Epistaxis 30 (14) Skin and Subcutaneous Tissue Disorders Rash 34 (16) Vascular Disorders Hypertension 23 (11) The most frequently reported adverse reactions (>25%) 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%). Clinical Trial Safety Experience with Noxafil Oral Suspension The safety of Noxafil oral suspension has been assessed in 1844 patients. This includes 605 patients in the active-controlled prophylaxis studies, 557 patients in the active-controlled OPC studies, 239 patients in refractory OPC studies, and 443 patients from other indications. This represents a heterogeneous population, including 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, 16% Hispanic, and 36% non-white (including 14% black). Noxafil therapy was given to 171 patients for ≥6 months, with 58 patients receiving Noxafil therapy for ≥12 months. Table 6 presents adverse reactions observed at an incidence of >10% in Noxafil prophylaxis studies. Table 7 presents adverse reactions observed at an incidence of at least 10% in the OPC/rOPC studies. Prophylaxis of Aspergillus and Candida: In the 2 randomized, comparative prophylaxis studies (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 the prophylaxis clinical trials were fever, diarrhea, and nausea. The most common adverse reactions leading to discontinuation of Noxafil in the prophylaxis studies were associated with GI disorders, specifically, nausea (2%), vomiting (2%), and hepatic enzymes increased (2%). Table 6: Noxafil Oral Suspension Study 1 and Study 2. Adverse Reactions in at Least 10% of the Noxafil Oral Suspension or Fluconazole Treatment Groups (Pooled Prophylaxis Safety Analysis) Body System Noxafil Oral Suspension n=605 (%) Fluconazole n=539 (%) Itraconazole n=58 (%) Subjects Reporting any Adverse Reaction 595 (98) 531 (99) 58 (100) Body as a Whole - General Disorders Fever 274 (45) 254 (47) 32 (55) Headache 171 (28) 141 (26) 23 (40) Rigors 122 (20) 87 (16) 17 (29) Fatigue 101 (17) 98 (18) 5 (9) Edema Legs 93 (15) 67 (12) 11 (19) Anorexia 92 (15) 94 (17) 16 (28) Dizziness 64 (11) 56 (10) 5 (9) Edema 54 (9) 68 (13) 8 (14) Weakness 51 (8) 52 (10) 2 (3) Cardiovascular Disorders, General Hypertension 106 (18) 88 (16) 3 (5) Hypotension 83 (14) 79 (15) 10 (17) Disorders of Blood and Lymphatic System Anemia 149 (25) 124 (23) 16 (28) Neutropenia 141 (23) 122 (23) 23 (40) Disorders of the Reproductive System and Breast Vaginal Hemorrhage Percentages of sex-specific adverse reactions are based on the number of males/females. 24 (10) 20 (9) 3 (12) Gastrointestinal System Disorders Diarrhea 256 (42) 212 (39) 35 (60) Nausea 232 (38) 198 (37) 30 (52) Vomiting 174 (29) 173 (32) 24 (41) Abdominal Pain 161 (27) 147 (27) 21 (36) Constipation 126 (21) 94 (17) 10 (17) Dyspepsia 61 (10) 50 (9) 6 (10) Heart Rate and Rhythm Disorders Tachycardia 72 (12) 75 (14) 3 (5) Infection and Infestations Pharyngitis 71 (12) 60 (11) 12 (21) Liver and Biliary System Disorders Bilirubinemia 59 (10) 51 (9) 11 (19) Metabolic and Nutritional Disorders Hypokalemia 181 (30) 142 (26) 30 (52) Hypomagnesemia 110 (18) 84 (16) 11 (19) Hyperglycemia 68 (11) 76 (14) 2 (3) Hypocalcemia 56 (9) 55 (10) 5 (9) Musculoskeletal System Disorders Musculoskeletal Pain 95 (16) 82 (15) 9 (16) Arthralgia 69 (11) 67 (12) 5 (9) Back Pain 63 (10) 66 (12) 4 (7) Platelet, Bleeding and Clotting Disorders Thrombocytopenia 175 (29) 146 (27) 20 (34) Petechiae 64 (11) 54 (10) 9 (16) Psychiatric Disorders Insomnia 103 (17) 92 (17) 11 (19) Respiratory System Disorders Coughing 146 (24) 130 (24) 14 (24) Dyspnea 121 (20) 116 (22) 15 (26) Epistaxis 82 (14) 73 (14) 12 (21) Skin and Subcutaneous Tissue Disorders Rash 113 (19) 96 (18) 25 (43) Pruritus 69 (11) 62 (12) 11 (19) HIV Infected Subjects with OPC: In 2 randomized comparative studies in OPC, the safety of Noxafil oral suspension at a dose of less than or equal to 400 mg once daily in 557 HIV-infected patients was compared to the safety of fluconazole in 262 HIV-infected patients at a dose of 100 mg once daily. An additional 239 HIV-infected patients with refractory OPC received Noxafil oral suspension in 2 non-comparative trials for refractory OPC (rOPC). Of these subjects, 149 received the 800-mg/day dose and the remainder received the less than or equal to 400 mg once daily dose. In the OPC/rOPC studies, the most common adverse reactions were fever, diarrhea, nausea, headache, vomiting, and coughing. The most common adverse reactions that led to treatment discontinuation of Noxafil in the Controlled OPC Pool included respiratory impairment (1%) and pneumonia (1%). In the refractory OPC pool, the most common adverse reactions that led to treatment discontinuation of Noxafil were AIDS (7%) and respiratory impairment (3%). Table 7: Adverse Reactions in at Least 10% of the Treated Population in OPC Studies with Noxafil Oral Suspension Body System Number (%) of Subjects Controlled OPC Pool Refractory OPC Pool Noxafil Oral Suspension Fluconazole Noxafil Oral Suspension n=557 n=262 n=239 OPC=oropharyngeal candidiasis Subjects Reporting any Adverse Reaction Number of subjects reporting adverse reactions at least once during the study, without regard to relationship to treatment. Subjects may have reported more than 1 event. 356 (64) 175 (67) 221 (92) Body as a Whole – General Disorders Fever 34 (6) 22 (8) 82 (34) Headache 44 (8) 23 (9) 47 (20) Anorexia 10 (2) 4 (2) 46 (19) Fatigue 18 (3) 12 (5) 31 (13) Asthenia 9 (2) 5 (2) 31 (13) Rigors 2 (<1) 4 (2) 29 (12) Pain 4 (1) 2 (1) 27 (11) Disorders of Blood and Lymphatic System Neutropenia 21 (4) 8 (3) 39 (16) Anemia 11 (2) 5 (2) 34 (14) Gastrointestinal System Disorders Diarrhea 58 (10) 34 (13) 70 (29) Nausea 48 (9) 30 (11) 70 (29) Vomiting 37 (7) 18 (7) 67 (28) Abdominal Pain 27 (5) 17 (6) 43 (18) Infection and Infestations Candidiasis, Oral 3 (1) 1 (<1) 28 (12) Herpes Simplex 16 (3) 8 (3) 26 (11) Pneumonia 17 (3) 6 (2) 25 (10) Metabolic and Nutritional Disorders Weight Decrease 4 (1) 2 (1) 33 (14) Dehydration 4 (1) 7 (3) 27 (11) Psychiatric Disorders Insomnia 8 (1) 3 (1) 39 (16) Respiratory System Disorders Coughing 18 (3) 11 (4) 60 (25) Dyspnea 8 (1) 8 (3) 28 (12) Skin and Subcutaneous Tissue Disorders Rash 15 (3) 10 (4) 36 (15) Sweating Increased 13 (2) 5 (2) 23 (10) Adverse reactions were reported more frequently in the pool of patients with refractory OPC. Among these highly immunocompromised patients with advanced HIV disease, serious adverse reactions (SARs) were reported in 55% (132/239). The most commonly reported SARs were fever (13%) and neutropenia (10%). 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 Clinical Laboratory Values: In healthy volunteers and patients, elevation of liver test values did not appear to be associated with higher plasma concentrations of posaconazole. For the prophylaxis studies, the number of patients with changes in liver tests from Common Toxicity Criteria (CTC) Grade 0, 1, or 2 at baseline to Grade 3 or 4 during the study is presented in Table 8. Table 8: Noxafil Oral Suspension Study 1 and Study 2. Changes in Liver Test Results from CTC Grade 0, 1, or 2 at Baseline to Grade 3 or 4 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) The number of patients treated for OPC with clinically significant liver test abnormalities at any time during the studies is provided in Table 9 (liver test abnormalities were present in some of these patients prior to initiation of the study drug). Table 9: Noxafil Oral Suspension Studies: Clinically Significant Laboratory Test Abnormalities without Regard to Baseline Value Laboratory Test Controlled Refractory Noxafil Oral Suspension Fluconazole Noxafil Oral Suspension n=557 (%) n=262 (%) n=239 (%) ALT= Alanine Aminotransferase; AST= Aspartate Aminotransferase. ALT > 3.0 × ULN 16/537 (3) 13/254 (5) 25/226 (11) AST > 3.0 × ULN 33/537 (6) 26/254 (10) 39/223 (17) Total Bilirubin > 1.5 × ULN 15/536 (3) 5/254 (2) 9/197 (5) Alkaline Phosphatase > 3.0 × ULN 17/535 (3) 15/253 (6) 24/190 (13) The number of patients treated for invasive aspergillosis with clinically significant liver test abnormalities at any time during the Aspergillosis Treatment Study is provided in Table 10 . Liver test abnormalities present prior to the initiation of study drug included ALT (22%), AST (13%), and bilirubin (13%). Table 10: Aspergillosis Treatment Study: Changes in Liver Test Results from CTC Grade 0, 1, or 2 at Baseline to Grade 3 or 4 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 subjects 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) Clinical Trial Experience in Pediatrics Clinical Trial Experience in Pediatric Patients (2 to less than 18 Years of Age) The safety of Noxafil 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 (Noxafil injection/ Noxafil PowderMix for delayed-release oral suspension Pediatric Study 1, NCT02452034); hereinafter referred to as Noxafil Pediatric Study) in 115 immunocompromised pediatric patients 2 to less than 18 years of age with known or expected neutropenia. Noxafil 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 Noxafil 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 Noxafil injection and 11.6 days (range: 2 to 18 days) on Noxafil PowderMix for delayed-release oral suspension . Reported adverse reaction profile of Noxafil in pediatric patients was consistent with the safety profile of Noxafil in adults. 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. Endocrine Disorders: Pseudoaldosteronism

<table width="75%"><caption>Table 4: Noxafil Invasive Aspergillosis Treatment Study: Adverse Reactions in at Least 10% of Subjects Treated with Noxafil Injection or Noxafil Delayed-Release Tablets</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">System Organ Class</th><th styleCode="Rrule">Noxafil injection or tablet (N = 288), n (%)</th><th styleCode="Rrule">Voriconazole injection or oral (N = 287), n (%) </th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Blood and lymphatic system disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Anemia</td><td styleCode="Rrule">25 (8.7)</td><td styleCode="Rrule">29 (10.1)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Febrile neutropenia</td><td styleCode="Rrule">42 (14.6)</td><td styleCode="Rrule">38 (13.2)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Gastrointestinal disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Abdominal pain</td><td styleCode="Rrule">29 (10.1)</td><td styleCode="Rrule">24 (8.4) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Constipation </td><td styleCode="Rrule">32 (11.1) </td><td styleCode="Rrule">23 (8.0) </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Diarrhea</td><td styleCode="Rrule">52 (18.1) </td><td styleCode="Rrule">52 (18.1)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Nausea </td><td styleCode="Rrule">65 (22.6) </td><td styleCode="Rrule">51 (17.8)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Vomiting </td><td styleCode="Rrule">52 (18.1) </td><td styleCode="Rrule">39 (13.6)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">General disorders and administration site conditions</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Edema peripheral </td><td styleCode="Rrule">32 (11.1) </td><td styleCode="Rrule">24 (8.4)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pyrexia </td><td styleCode="Rrule">81 (28.1) </td><td styleCode="Rrule">72 (25.1)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Infections and infestations</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pneumonia </td><td styleCode="Rrule">36 (12.5) </td><td styleCode="Rrule">26 (9.1)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Investigations</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Alanine aminotransferase increased </td><td styleCode="Rrule">42 (14.6) </td><td styleCode="Rrule">37 (12.9)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Aspartate aminotransferase increased </td><td styleCode="Rrule">38 (13.2) </td><td styleCode="Rrule">36 (12.5)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Blood alkaline phosphatase increased </td><td styleCode="Rrule">21 (7.3) </td><td styleCode="Rrule">29 (10.1)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Metabolism and nutrition disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hypokalemia </td><td styleCode="Rrule">82 (28.5) </td><td styleCode="Rrule">49 (17.1)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hypomagnesemia </td><td styleCode="Rrule">29 (10.1) </td><td styleCode="Rrule">18 (6.3)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Nervous system disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Headache </td><td styleCode="Rrule">35 (12.2) </td><td styleCode="Rrule">25 (8.7)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Respiratory, thoracic and mediastinal disorders</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Cough </td><td styleCode="Rrule">30 (10.4) </td><td styleCode="Rrule">24 (8.4)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Epistaxis </td><td styleCode="Rrule">32 (11.1) </td><td styleCode="Rrule">17 (5.9)</td></tr></tbody></table>

<table width="75%"><caption>Table 5: Noxafil Delayed-Release Tablet Study: Adverse Reactions in at Least 10% of Subjects Treated with 300 mg Daily Dose</caption><col width="70%" align="left" valign="top"/><col width="15%" align="center" valign="top"/><col width="15%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule"><content styleCode="italics">Body System</content></th><th styleCode="Rrule" colspan="2">Noxafil delayed-release tablet (300 mg) n=210 (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Subjects Reporting any Adverse Reaction</td><td styleCode="Rrule">207</td><td styleCode="Rrule">(99)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="italics">Blood and Lymphatic System Disorder</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Anemia</td><td styleCode="Rrule">22</td><td styleCode="Rrule">(10)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Thrombocytopenia</td><td styleCode="Rrule">29</td><td styleCode="Rrule">(14)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="italics">Gastrointestinal Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Abdominal Pain</td><td styleCode="Rrule">23</td><td styleCode="Rrule">(11)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Constipation</td><td styleCode="Rrule">20</td><td styleCode="Rrule">(10)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">61</td><td styleCode="Rrule">(29)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">56</td><td styleCode="Rrule">(27)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vomiting</td><td styleCode="Rrule">28</td><td styleCode="Rrule">(13)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="italics">General Disorders and Administration Site Conditions</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Asthenia</td><td styleCode="Rrule">20</td><td styleCode="Rrule">(10)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Chills</td><td styleCode="Rrule">22</td><td styleCode="Rrule">(10)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Mucosal Inflammation</td><td styleCode="Rrule">29</td><td styleCode="Rrule">(14)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Edema Peripheral</td><td styleCode="Rrule">33</td><td styleCode="Rrule">(16)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pyrexia</td><td styleCode="Rrule">59</td><td styleCode="Rrule">(28)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="italics">Metabolism and Nutrition Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypokalemia</td><td styleCode="Rrule">46</td><td styleCode="Rrule">(22)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypomagnesemia</td><td styleCode="Rrule">20</td><td styleCode="Rrule">(10)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="italics">Nervous System Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">30</td><td styleCode="Rrule">(14)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="italics">Respiratory, Thoracic and Mediastinal Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Cough</td><td styleCode="Rrule">35</td><td styleCode="Rrule">(17)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Epistaxis</td><td styleCode="Rrule">30</td><td styleCode="Rrule">(14)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="italics">Skin and Subcutaneous Tissue Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Rash</td><td styleCode="Rrule">34</td><td styleCode="Rrule">(16)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="italics">Vascular Disorders</content></td></tr><tr><td styleCode="Lrule Rrule">Hypertension</td><td styleCode="Rrule">23</td><td styleCode="Rrule">(11)</td></tr></tbody></table>

<table width="75%"><caption>Table 6: Noxafil Oral Suspension Study 1 and Study 2. Adverse Reactions in at Least 10% of the Noxafil Oral Suspension or Fluconazole Treatment Groups (Pooled Prophylaxis Safety Analysis)</caption><col width="40%" align="left" valign="top"/><col width="10%" align="center" valign="top"/><col width="10%" align="center" valign="top"/><col width="10%" align="center" valign="top"/><col width="10%" align="center" valign="top"/><col width="10%" align="center" valign="top"/><col width="10%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule"><content styleCode="italics">Body System</content></th><th styleCode="Rrule" colspan="2">Noxafil Oral Suspension n=605 (%)</th><th styleCode="Rrule" colspan="2">Fluconazole n=539 (%)</th><th styleCode="Rrule" colspan="2">Itraconazole n=58 (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Subjects Reporting any Adverse Reaction</td><td styleCode="Rrule">595</td><td styleCode="Rrule">(98)</td><td styleCode="Rrule">531</td><td styleCode="Rrule">(99)</td><td styleCode="Rrule">58</td><td styleCode="Rrule">(100)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="7"><content styleCode="italics">Body as a Whole - General Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Fever</td><td styleCode="Rrule">274</td><td styleCode="Rrule">(45)</td><td styleCode="Rrule">254</td><td styleCode="Rrule">(47)</td><td styleCode="Rrule">32</td><td styleCode="Rrule">(55)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">171</td><td styleCode="Rrule">(28)</td><td styleCode="Rrule">141</td><td styleCode="Rrule">(26)</td><td styleCode="Rrule">23</td><td styleCode="Rrule">(40)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Rigors</td><td styleCode="Rrule">122</td><td styleCode="Rrule">(20)</td><td styleCode="Rrule">87</td><td styleCode="Rrule">(16)</td><td styleCode="Rrule">17</td><td styleCode="Rrule">(29)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Fatigue</td><td styleCode="Rrule">101</td><td styleCode="Rrule">(17)</td><td styleCode="Rrule">98</td><td styleCode="Rrule">(18)</td><td styleCode="Rrule">5</td><td styleCode="Rrule">(9)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Edema Legs</td><td styleCode="Rrule">93</td><td styleCode="Rrule">(15)</td><td styleCode="Rrule">67</td><td styleCode="Rrule">(12)</td><td styleCode="Rrule">11</td><td styleCode="Rrule">(19)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Anorexia</td><td styleCode="Rrule">92</td><td styleCode="Rrule">(15)</td><td styleCode="Rrule">94</td><td styleCode="Rrule">(17)</td><td styleCode="Rrule">16</td><td styleCode="Rrule">(28)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dizziness</td><td styleCode="Rrule">64</td><td styleCode="Rrule">(11)</td><td styleCode="Rrule">56</td><td styleCode="Rrule">(10)</td><td styleCode="Rrule">5</td><td styleCode="Rrule">(9)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Edema</td><td styleCode="Rrule">54</td><td styleCode="Rrule">(9)</td><td styleCode="Rrule">68</td><td styleCode="Rrule">(13)</td><td styleCode="Rrule">8</td><td styleCode="Rrule">(14)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Weakness</td><td styleCode="Rrule">51</td><td styleCode="Rrule">(8)</td><td styleCode="Rrule">52</td><td styleCode="Rrule">(10)</td><td styleCode="Rrule">2</td><td styleCode="Rrule">(3)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="7"><content styleCode="italics">Cardiovascular Disorders, General</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypertension</td><td styleCode="Rrule">106</td><td styleCode="Rrule">(18)</td><td styleCode="Rrule">88</td><td styleCode="Rrule">(16)</td><td styleCode="Rrule">3</td><td styleCode="Rrule">(5)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypotension</td><td styleCode="Rrule">83</td><td styleCode="Rrule">(14)</td><td styleCode="Rrule">79</td><td styleCode="Rrule">(15)</td><td styleCode="Rrule">10</td><td styleCode="Rrule">(17)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="7"><content styleCode="italics">Disorders of Blood and Lymphatic System</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Anemia</td><td styleCode="Rrule">149</td><td styleCode="Rrule">(25)</td><td styleCode="Rrule">124</td><td styleCode="Rrule">(23)</td><td styleCode="Rrule">16</td><td styleCode="Rrule">(28)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Neutropenia</td><td styleCode="Rrule">141</td><td styleCode="Rrule">(23)</td><td styleCode="Rrule">122</td><td styleCode="Rrule">(23)</td><td styleCode="Rrule">23</td><td styleCode="Rrule">(40)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="7"><content styleCode="italics">Disorders of the Reproductive System and Breast</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vaginal Hemorrhage<footnote>Percentages of sex-specific adverse reactions are based on the number of males/females.</footnote></td><td styleCode="Rrule">24</td><td styleCode="Rrule">(10)</td><td styleCode="Rrule">20</td><td styleCode="Rrule">(9)</td><td styleCode="Rrule">3</td><td styleCode="Rrule">(12)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="7"><content styleCode="italics">Gastrointestinal System Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">256</td><td styleCode="Rrule">(42)</td><td styleCode="Rrule">212</td><td styleCode="Rrule">(39)</td><td styleCode="Rrule">35</td><td styleCode="Rrule">(60)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">232</td><td styleCode="Rrule">(38)</td><td styleCode="Rrule">198</td><td styleCode="Rrule">(37)</td><td styleCode="Rrule">30</td><td styleCode="Rrule">(52)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vomiting</td><td styleCode="Rrule">174</td><td styleCode="Rrule">(29)</td><td styleCode="Rrule">173</td><td styleCode="Rrule">(32)</td><td styleCode="Rrule">24</td><td styleCode="Rrule">(41)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Abdominal Pain</td><td styleCode="Rrule">161</td><td styleCode="Rrule">(27)</td><td styleCode="Rrule">147</td><td styleCode="Rrule">(27)</td><td styleCode="Rrule">21</td><td styleCode="Rrule">(36)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Constipation</td><td styleCode="Rrule">126</td><td styleCode="Rrule">(21)</td><td styleCode="Rrule">94</td><td styleCode="Rrule">(17)</td><td styleCode="Rrule">10</td><td styleCode="Rrule">(17)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dyspepsia</td><td styleCode="Rrule">61</td><td styleCode="Rrule">(10)</td><td styleCode="Rrule">50</td><td styleCode="Rrule">(9)</td><td styleCode="Rrule">6</td><td styleCode="Rrule">(10)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="7"><content styleCode="italics">Heart Rate and Rhythm Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Tachycardia</td><td styleCode="Rrule">72</td><td styleCode="Rrule">(12)</td><td styleCode="Rrule">75</td><td styleCode="Rrule">(14)</td><td styleCode="Rrule">3</td><td styleCode="Rrule">(5)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="7"><content styleCode="italics">Infection and Infestations</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pharyngitis</td><td styleCode="Rrule">71</td><td styleCode="Rrule">(12)</td><td styleCode="Rrule">60</td><td styleCode="Rrule">(11)</td><td styleCode="Rrule">12</td><td styleCode="Rrule">(21)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="7"><content styleCode="italics">Liver and Biliary System Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Bilirubinemia</td><td styleCode="Rrule">59</td><td styleCode="Rrule">(10)</td><td styleCode="Rrule">51</td><td styleCode="Rrule">(9)</td><td styleCode="Rrule">11</td><td styleCode="Rrule">(19)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="7"><content styleCode="italics">Metabolic and Nutritional Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypokalemia</td><td styleCode="Rrule">181</td><td styleCode="Rrule">(30)</td><td styleCode="Rrule">142</td><td styleCode="Rrule">(26)</td><td styleCode="Rrule">30</td><td styleCode="Rrule">(52)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypomagnesemia</td><td styleCode="Rrule">110</td><td styleCode="Rrule">(18)</td><td styleCode="Rrule">84</td><td styleCode="Rrule">(16)</td><td styleCode="Rrule">11</td><td styleCode="Rrule">(19)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hyperglycemia</td><td styleCode="Rrule">68</td><td styleCode="Rrule">(11)</td><td styleCode="Rrule">76</td><td styleCode="Rrule">(14)</td><td styleCode="Rrule">2</td><td styleCode="Rrule">(3)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypocalcemia</td><td styleCode="Rrule">56</td><td styleCode="Rrule">(9)</td><td styleCode="Rrule">55</td><td styleCode="Rrule">(10)</td><td styleCode="Rrule">5</td><td styleCode="Rrule">(9)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="7"><content styleCode="italics">Musculoskeletal System Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Musculoskeletal Pain</td><td styleCode="Rrule">95</td><td styleCode="Rrule">(16)</td><td styleCode="Rrule">82</td><td styleCode="Rrule">(15)</td><td styleCode="Rrule">9</td><td styleCode="Rrule">(16)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Arthralgia</td><td styleCode="Rrule">69</td><td styleCode="Rrule">(11)</td><td styleCode="Rrule">67</td><td styleCode="Rrule">(12)</td><td styleCode="Rrule">5</td><td styleCode="Rrule">(9)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Back Pain</td><td styleCode="Rrule">63</td><td styleCode="Rrule">(10)</td><td styleCode="Rrule">66</td><td styleCode="Rrule">(12)</td><td styleCode="Rrule">4</td><td styleCode="Rrule">(7)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="7"><content styleCode="italics">Platelet, Bleeding and Clotting Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Thrombocytopenia</td><td styleCode="Rrule">175</td><td styleCode="Rrule">(29)</td><td styleCode="Rrule">146</td><td styleCode="Rrule">(27)</td><td styleCode="Rrule">20</td><td styleCode="Rrule">(34)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Petechiae</td><td styleCode="Rrule">64</td><td styleCode="Rrule">(11)</td><td styleCode="Rrule">54</td><td styleCode="Rrule">(10)</td><td styleCode="Rrule">9</td><td styleCode="Rrule">(16)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="7"><content styleCode="italics">Psychiatric Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Insomnia</td><td styleCode="Rrule">103</td><td styleCode="Rrule">(17)</td><td styleCode="Rrule">92</td><td styleCode="Rrule">(17)</td><td styleCode="Rrule">11</td><td styleCode="Rrule">(19)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="7"><content styleCode="italics">Respiratory System Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Coughing</td><td styleCode="Rrule">146</td><td styleCode="Rrule">(24)</td><td styleCode="Rrule">130</td><td styleCode="Rrule">(24)</td><td styleCode="Rrule">14</td><td styleCode="Rrule">(24)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dyspnea</td><td styleCode="Rrule">121</td><td styleCode="Rrule">(20)</td><td styleCode="Rrule">116</td><td styleCode="Rrule">(22)</td><td styleCode="Rrule">15</td><td styleCode="Rrule">(26)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Epistaxis</td><td styleCode="Rrule">82</td><td styleCode="Rrule">(14)</td><td styleCode="Rrule">73</td><td styleCode="Rrule">(14)</td><td styleCode="Rrule">12</td><td styleCode="Rrule">(21)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="7"><content styleCode="italics">Skin and Subcutaneous Tissue Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Rash </td><td styleCode="Rrule">113</td><td styleCode="Rrule">(19)</td><td styleCode="Rrule">96</td><td styleCode="Rrule">(18)</td><td styleCode="Rrule">25</td><td styleCode="Rrule">(43)</td></tr><tr><td styleCode="Lrule Rrule">Pruritus</td><td styleCode="Rrule">69</td><td styleCode="Rrule">(11)</td><td styleCode="Rrule">62</td><td styleCode="Rrule">(12)</td><td styleCode="Rrule">11</td><td styleCode="Rrule">(19)</td></tr></tbody></table>