Posaconazole

FDA Drug Information • Also known as: Noxafil, Posaconazole

Brand Names: Noxafil, Posaconazole
Dosage Form: POWDER
Product Type: BULK INGREDIENT

Description

11 DESCRIPTION Posaconazole is an azole antifungal agent available as delayed-release tablet for oral administration. Posaconazole is designated chemically as 4-(4-(4-(4-(((3R,5R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl) oxolan-3-yl) methoxy) phenyl) piperazin-1-yl) phenyl)-2- ((2S,3S)-2-hydroxypentan-3-yl)-1,2,4-triazol-3-one with an empirical formula of C 37 H 42 F 2 N 8 O 4 and molecular weight of 700.77. The chemical structure is: Posaconazole is a white-off white crystalline powder with a low aqueous solubility. Posaconazole delayed-release tablet is a yellow, coated, capsule shaped tablet containing 100 mg of posaconazole. Each delayed-release tablet contains the inactive ingredients: hypromellose AS-MG, hypromellose AS-MF, silicified microcrystalline cellulose, hydroxy propyl cellulose HFP, hydroxy propyl cellulose SSL SFP, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, and Opadry ® II Yellow (consists of the following ingredients: polyvinyl alcohol, Macrogol/PEG, titanium dioxide, talc, and iron oxide yellow). Structure

What Is Posaconazole Used For?

1 INDICATIONS AND USAGE Posaconazole is an azole antifungal agent 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 ) Posaconazole delayed-release tablets: adults and pediatric patients 13 years of age and older. 1.2 Prophylaxis of Invasive Aspergillus and Candida Infections Posaconazole delayed-release tablets are indicated for 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 13 years of age and older. Additional Pediatric Use information is approved for Merck Sharp & Dohme Corp.’s NOXAFIL (posaconazole) delayed-release tablets. However, due to Merck Sharp & Dohme Corp.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Dosage and Administration

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. ( 2.1 , 2.2 , 2.3 ) Administer posaconazole delayed-release tablets with or without food. ( 2.1 ) Table 1: Recommended Dosage in Adult Patients and Pediatric Patients aged 13 years and older Indication Dosage Form, Dose, and Duration of Therapy Prophylaxis of invasive Aspergillus and Candida infections Posaconazole 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 ) 2.1 Important Administration Instructions 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 , 2.8 ) ]. 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. Posaconazole delayed-release tablets generally provide higher plasma drug exposures than Noxafil ® oral suspension under both fed and fasted conditions [see Dosage and Administration (2.6) ]. 2.2 Dosing Regimen in Adult Patients Table 1: Posaconazole Delayed-Release Tablets Dosing Regimens in Adult Patients Indication Dose and Frequency Duration of Therapy Prophylaxis of invasive Aspergillus and Candida infections 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. Loading dose: 1 day Maintenance dose: Duration of therapy is based on recovery from neutropenia or immunosuppression. 2.3 Dosing Regimen in Pediatric Patients (ages 13 to less than 18 years of age) The recommended dosing regimen of posaconazole for pediatric patients 13 to less than 18 years of age is shown in Table 2 [see Dosage and Administration (2.5 , 2.6 , 2.8 ) and Clinical Pharmacology (12.3) ]. Table 2: Posaconazole Delayed-Release Tablets Dosing Regimens for Pediatric Patients (ages 13 to less than 18 years of age) Indication Dose and Frequency Duration of Therapy Prophylaxis of invasive Aspergillus and Candida infections Loading dose: 300 mg twice a day on the first day Maintenance dose: 300 mg once daily Duration of therapy is based on recovery from neutropenia or immunosuppression....

Side Effects (Adverse Reactions)

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 Westminster Pharmaceuticals, LLC at 1-844-221-7294 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 19-78 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 Body 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) 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 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%). Additional Pediatric Use information is approved for Merck Sharp & Dohme Corp.’s NOXAFIL (posaconazole) products. However, due to Merck Sharp & Dohme Corp.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 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

Drug Interactions

7 DRUG INTERACTIONS Posaconazole is primarily metabolized via UDP glucuronosyltransferase and is a substrate of p- glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. Coadministration of drugs that can decrease the plasma concentrations of posaconazole should generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections. Posaconazole is also a strong inhibitor of CYP3A4. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole [see Clinical Pharmacology (12.3) ] . The following information was derived from data with Noxafil ® oral suspension or early tablet formulation. Interaction Drug Interaction Rifabutin, phenytoin, efavirenz, cimetidine, Avoid coadministration unless the benefit outweighs the risks ( 7.6 , 7.7 , 7.8 , 7.9 ) Other drugs metabolized by CYP3A4 Consider dosage adjustment and monitor for adverse effects and toxicity ( 7.1 , 7.10 , 7.11 ) Digoxin Monitor digoxin plasma concentrations ( 7.12 ) Fosamprenavir Monitor for breakthrough fungal infections ( 7.6 , 7.13 ) 7.1 Immunosuppressants Metabolized by CYP3A4 Sirolimus: Concomitant administration of posaconazole with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity. Therefore, posaconazole is contraindicated with sirolimus [see Contraindications (4.2) and Clinical Pharmacology (12.3) ] . Tacrolimus: Posaconazole has been shown to significantly increase the C max and AUC of tacrolimus. At initiation of posaconazole treatment, reduce the tacrolimus dose to approximately one-third of the original dose. Frequent monitoring of tacrolimus whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus dose adjusted accordingly [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ] . Cyclosporine: Posaconazole has been shown to increase cyclosporine whole blood concentrations in heart transplant patients upon initiation of posaconazole treatment. It is recommended to reduce cyclosporine dose to approximately three-fourths of the original dose upon initiation of posaconazole treatment. Frequent monitoring of cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the cyclosporine dose adjusted accordingly [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ] . 7.2 CYP3A4 Substrates Concomitant administration of posaconazole with CYP3A4 substrates such as pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and cases of torsades de pointes. Therefore, posaconazole is contraindicated with these drugs [see Contraindications (4.3) and Warnings and Precautions (5.2) ] ....

Contraindications

4 CONTRAINDICATIONS Known hypersensitivity to posaconazole or other azole antifungal agents. ( 4.1 ) Coadministration of posaconazole delayed-release tablets 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: can result in ergotism ( 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 , 5.10 , 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...

Pregnancy and Breastfeeding

8.1 Pregnancy Risk Summary Based on findings from animal data, posaconazole may cause fetal harm when administered to pregnant women. Available data for use of posaconazole in pregnant women are insufficient to establish a drug- associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, skeletal malformations (cranial malformations and missing ribs) and maternal toxicity (reduced food consumption and reduced body weight gain) were observed when posaconazole was dosed orally to pregnant rats during organogenesis at doses ≥1.4 times the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations of posaconazole in healthy volunteers. In pregnant rabbits dosed orally during organogenesis, increased resorptions, reduced litter size, and reduced body weight gain of females were seen at doses 5 times the exposure achieved with the 400 mg twice daily oral suspension regimen. Doses of ≥ 3 times the clinical exposure caused an increase in resorptions in these rabbits (see Data ) . Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Posaconazole resulted in maternal toxicity (reduced food consumption and reduced body weight gain) and skeletal malformations (cranial malformations and missing ribs) when given orally to pregnant rats during organogenesis (Gestational Days 6 through 15) at doses ≥27 mg/kg (≥1.4 times the 400 mg twice daily Noxafil ® oral suspension regimen based on steady-state plasma concentrations of drug in healthy volunteers). The no-effect dose for...

Overdosage

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.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Posaconazole delayed-release tablets are available as yellow, coated, oblong, debossed with "100" on one side containing 100 mg of posaconazole. Bottles with child-resistant closures of 60 (NDC 69367-248-06) 16.2 Storage and Handling Store at 20 to 25°C (68 to 77°F), excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature].

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.