Posaconazole

1 INDICATIONS AND USAGE Posaconazole is an azole antifungal indicated as follows: Posaconazole is indicated for the prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy as follows: ( 1.2 ) o Posaconazole delayed-release tablets: adults and pediatric patients 2 years of age and older who weigh greater than 40 kg 1.2 Prophylaxis of Invasive Aspergillus and Candida Infections Posaconazole delayed-release tablets are indicated for the prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy [see Clinical Studies (14.2) ] as follows: Posaconazole delayed-release tablets: adults and pediatric patients 2 years of age and older who weigh greater than 40 kg

12.1 Mechanism of Action Posaconazole is an azole antifungal agent [ see Clinical Pharmacology (12.4) ].

2 DOSAGE AND ADMINISTRATION Noxafil ® oral suspension is not substitutable with posaconazole delayed-release tablets or Noxafil ® PowderMix for delayed-release oral suspension due to the differences in the dosing of each formulation. Therefore, follow the specific dosage recommendations for each of the formulations. ( 2.1 , 2.2 , 2.3 ) Administer posaconazole delayed-release tablets with or without food. ( 2.1 ) Table 1: Recommended Dosage in Adult Patients Indication Dosage Form, Dose, and Duration of Therapy Prophylaxis of invasive Aspergillus and Candida infections Delayed-Release Tablets: Loading dose: 300 mg (three 100 mg delayed-release tablets) twice a day on the first day. Maintenance dose: 300 mg (three 100 mg delayed-release tablets) once a day, starting on the second day. Duration of therapy is based on recovery from neutropenia or immunosuppression. ( 2.2 , 2.3 ) For pediatric patients, see the Full Prescribing Information for dosing recommendations for posaconazole delayed-release tablets ( 1.2 , 2.1 , 2.3 ) 2.1 Important Administration Instructions Non-substitutable Noxafil ® oral suspension is not substitutable with posaconazole delayed-release tablets or Noxafil ® PowderMix for delayed-release oral suspension due to the differences in the dosing of each formulation.Therefore, follow the specific dosage recommendations for each of the formulations [see Dosage and Administration (2.2, 2.3 )]. Posaconazole delayed-release tablets Swallow tablets whole. Do not divide, crush, or chew. Administer with or without food [ see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ]. For patients who cannot eat a full meal, posaconazole delayed-release tablets should be used instead of Noxafil ® oral suspension for the prophylaxis indication. Posaconazole delayed-release tablets generally provide higher plasma drug exposures than Noxafil ® oral suspension under both fed and fasted conditions, and therefore is the preferred oral formulation for the prophylaxis indication. 2.2 Dosing Regimen in Adult Patients Table 1: Dosing Regimens in Adult Patients Indication D ose and Frequency D uration of Therapy Prophylaxis of invasive Aspergillus and Cand ida infections Load ingdose : 300 mg (three 100 mg delayed-release tablets) twice a day on the first day. Maintenance dose : 300 mg (three 100 mg delayed-release tablets) once a day, starting on the second day. Load ingdose : 1 day Maintenance dose : Duration of therapy is based on recovery from neutropenia or immunosuppression. 2.3 Dosing Regimen in Pediatric Patients (ages 2 to less than 18 years of age) The recommended dosing regimen of posaconazole for pediatric patients 2 to less than 18 years of age is shown in Tables 2 [ see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ]. Table 2: Posaconazole Delayed-Release Tablet Dosing Regimens for Pediatric Patients (ages 2 to less than 18 years of age) Rec ommended Pediatric Dosage and Formulation Indication Weight/Age Delayed-Release Tablet D uration of therapy Prophylaxis of invasive A spergillus and Candida infections Less than or equal to 40 kg (2 to less than 18 years of age) Greater than 40 kg (2 to less than 18 years of age) Not Applicable Load ing dose: 300 mg twice daily on the first day Maintenance dose: 300 mg once daily Duration of therapy is based on recovery from neutropenia or immunosuppression. 2.5 Administration Instructions for Posaconazole Delayed-Release Tablets Swallow tablets whole. Do not divide, crush, or chew. Administer posaconazole delayed-release tablets with or without food [see Clinical Pharmacology (12.3) ]. 2.7 Non-substitutability between Noxafil ® Oral Suspension and Other Formulations Noxafil ® oral suspension is not substitutable with posaconazole delayed-release tablets or Noxafil ® PowderMix for delayed-release oral suspension due to the differences in the dosing of each formulation. Therefore, follow the specific dosage recommendations for each of the formulations [s

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 (5.5) ] Adult Patients: Common adverse reactions in studies with posaconazole in adults are diarrhea, nausea, fever, vomiting, headache, coughing, and hypokalemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novadoz Pharmaceuticals LLC at 1-855-668-2369 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 Trial Experience in Adults Clinical Trial Experience with Posaconazole Delayed-Release Tablets for Prophylaxis The safety of posaconazole delayed-release tablets has been assessed in 230 patients in clinical trials. Patients were enrolled in a non-comparative pharmacokinetic and safety trial of posaconazole delayed-release tablets when given as antifungal prophylaxis (Posaconazole 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 to 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 9 presents adverse reactions observed in patients treated with 300 mg daily dose at an incidence of ≥10% in Posaconazole Delayed-Release Tablet Study. Table 9: Posaconazole Delayed-Release Tablet Study: Adverse Reactions in at Least 10% of Subjects Treated with 300 mg Daily Dose B ody System Posaconazole 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) Ga s trointestinal Disorders Abdominal Pain 23 (11) Constipation 20 (10) Diarrhea 61 (29) Nausea 56 (27) Vomiting 28 (13) Genera l 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) Ner v ou s System Disorders Headache 30 (14) Re s p iratory, 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 posaconazole delayed-release tablets 300 mg once daily were diarrhea, pyrexia, and nausea. The most common adverse reaction leading to discontinuation of posaconazole delayed-release tablets 300 mg once daily was nausea (2%). 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

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 ) 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, 7.5 ) 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. ( 5.8, 7.10 ) Breakthrough Fungal Infections : Monitor patients with severe diarrhea or vomiting when receiving posaconazole delayed-release tablets. ( 5.10 ) 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. 11, 7.16 ) 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 to 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 posaconazole 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 interva

4 CONTRAINDICATIONS Known hypersensitivity to posaconazole or other azole antifungal agents. ( 4.1 ) Coadministration of posaconazole with the following drugs is contraindicated; posaconazole increases concentrations and toxicities of: Sirolimus ( 4.2 , 5.1 , 7.1 ) CYP3A4 substrates (pimozide, quinidine): can result in QTc interval prolongation and cases of torsades de pointes (TdP) ( 4.3 , 5.2 , 7.2 ) HMG-CoA Reductase Inhibitors Primarily Metabolized through CYP3A4 ( 4.4 , 7.3 ) Ergot alkaloids ( 4.5 , 7.4 ) Venetoclax: In patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) at initiation and during the ramp-up phase ( 4.6 , 5.11 , 7.16 ) 4.1 Hypersensitivity Posaconazole is contraindicated in persons with known hypersensitivity to posaconazole or other azole antifungal agents. 4.2 Use with Sirolimus Posaconazole is contraindicated with sirolimus. Concomitant administration of posaconazole with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity [ see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ]. 4.3 QT Prolongation with Concomitant Use with CYP3A4 Substrates Posaconazole is contraindicated with CYP3A4 substrates that prolong the QT interval. Concomitant administration of posaconazole with the CYP3A4 substrates, pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and cases of torsades de pointes [ see Warnings and Precautions (5.2) and Drug Interactions (7.2) ]. 4.4 HMG-CoA Reductase Inhibitors Primarily Metabolized Through CYP3A4 Coadministration with the HMG-CoA reductase inhibitors that are primarily metabolized through CYP3A4 (e.g., atorvastatin, lovastatin, and simvastatin) is contraindicated since increased plasma concentration of these drugs can lead to rhabdomyolysis [ see Drug Interactions (7.3) and Clinical Pharmacology (12.3) ]. 4.5 Use with Ergot Alkaloids Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism [ see Drug Interactions (7.4) ]. 4.6 Use with Venetoclax Coadministration of posaconazole with venetoclax at initiation and during the ramp-up phase is contraindicated in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) due to the potential for increased risk of tumor lysis syndrome [ see Warnings and Precautions (5.11) and Drug Interactions (7.16) ].

10 OVERDOSAGE There is no experience with overdosage of posaconazole delayed-release tablets. During the clinical trials, some patients received Noxafil ® oral suspension up to 1600 mg/day with no adverse reactions noted that were different from the lower doses. In addition, accidental overdose was noted in one patient who took 1200 mg twice daily Noxafil ® oral suspension for 3 days. No related adverse reactions were noted by the investigator. Posaconazole is not removed by hemodialysis.