posaconazole

Indications and Usage ( 1.1 , 1.2 ) 1/2026 Dosage and Administration ( 2 ) 1/2026

1 INDICATIONS AND USAGE Posaconazole is an azole antifungal indicated as follows: Posaconazole delayed-release tablets are indicated for the treatment of invasive aspergillosis in adults and pediatric patients 2 years of age and older who weigh greater than 40 kg. ( 1.1 ) 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 2 years of age and older who weigh greater than 40 kg Posaconazole oral suspension: adults and pediatric patients 13 years of age and older Posaconazole oral suspension is indicated for the treatment of oropharyngeal candidiasis (OPC), including OPC refractory (rOPC) to itraconazole and/or fluconazole in adults and pediatric patients 13 years of age and older. ( 1.3 ) 1.1 Treatment of Invasive Aspergillosis Posaconazole delayed-release tablets are indicated for the treatment of invasive aspergillosis in 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 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 [see Clinical Studies (14.1) ] as follows: Posaconazole delayed-release tablets : adults and pediatric patients 2 years of age and older who weigh greater than 40 kg Posaconazole oral suspension: adults and pediatric patients 13 years of age and older 1.3 Treatment of Oropharyngeal Candidiasis Including Oropharyngeal Candidiasis Refractory to Itraconazole and/or Fluconazole Posaconazole oral suspension is indicated for the treatment of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole in adults and pediatric patients 13 years of age and older.

2 DOSAGE AND ADMINISTRATION Posaconazole formulations are supplied in different dose strengths of posaconazole, are approved for different indications, age groups, and weights, have different dosages and duration of therapy; and have different preparation and administration instructions. ( 2.1 ) Posaconazole 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 ) Administer Posaconazole oral suspension with a full meal. ( 2.1 ) See the full prescribing information for important administration and preparation instructions for Posaconazole (delayed-release tablets and Posaconazole oral suspension ( 2.5 , 2.6 , 2.7 ) For adult and pediatric patients aged 2 years of age and older, see the Full Prescribing Information for dosing recommendations for Posaconazole delayed-release tablets and Posaconazole oral suspension based on the indication, age, and weight associated with the dosage form. ( 1.1 , 1.2 , 1.3 , 2.1 , 2.2 , 2.3 , 2.4 ) 2.1 Important Administration Instructions Posaconazole delayed-release tablets and Posaconazole oral suspension are approved for different indications, age groups and weights; have different dosages and duration of therapy; and have different preparation and administration instructions. Therefore, select the recommended dosage form based on the indication, age group, and weight and carefully follow the recommended dosage, preparation and administration instructions described for each product [see Dosage and Administration (2.2 to 2.8) ] , and the following important administration instructions described below. Non-substitutable Posaconazole 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 (2.2) and Clinical Pharmacology (12.3) ] . For patients who cannot eat a full meal, Posaconazole delayed-release tablets should be used instead of Posaconazole oral suspension for the prophylaxis indication. Posaconazole delayed-release tablets generally provide higher plasma drug exposures than Posaconazole oral suspension under both fed and fasted conditions [see Dosage and Administration (2.6) ] . Posaconazole oral suspension Administer with a full meal or with a liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale) in patients who cannot eat a full meal [see Dosage and Administration (2.8) ]. 2.2 Recommended Dosage of Posaconazole in Adult Patients The recommended dosage of Posaconazole delayed-release tablets and Posaconazole oral suspension in adult patients for the treatment of invasive aspergillosis, prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised, or for the treatment of oropharyngeal candidiasis (OPC) is shown in Table 1 [see Dosage and Administration (2.5 , 2.6 , 2.7) and Clinical Pharmacology (12.3) ]. Table 1: Recommended Dosage of Posaconazole Delayed-Release Tablets and Posaconazole Oral Suspension in Adult Patients Dosage Duration of Therapy Treatment of Invasive Aspergillosis Switching between the Noxafil injection and Posaconazole delayed-release tablets is acceptable. A loading dose is not required when switching between dosage forms. Posaconazole Delayed-Release Tablets: Loading dose: 300 mg (three 100 mg delayed-release tabl …

3 DOSAGE FORMS AND STRENGTHS Posaconazole Delayed-Release Tablets 100 mg of posaconazole: Yellow, coated, oblong tablets, debossed with "100" on one side. Posaconazole Oral Suspension 4,200 mg/105 mL (40 mg/mL) of posaconazole: White, cherry-flavored suspension in amber glass bottles with child-resistant closures. Posaconazole delayed-release tablet: 100 mg ( 3 ) Posaconazole oral suspension: 40 mg per mL ( 3 )

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) ].

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 he …

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 unless otherwise noted. All drug interactions with Noxafil ® oral suspension, except for those that affect the absorption of posaconazole (via gastric pH and motility), are considered relevant to posaconazole delayed-release tablet as well [see Drug Interactions (7.9) and (7.13) ]. Interaction Drug Interaction Rifabutin, phenytoin, efavirenz, cimetidine, esomeprazole* 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, metoclopramide* Monitor for breakthrough fungal infections ( 7.6 , 7.13 ) *The drug interactions with esomeprazole and metoclopramide do not apply to posaconazole tablets. 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) ]. 7.3 HMG-CoA Reductase Inhibitors (Statins) Primarily Metabolized Through CYP3A4 Concomitant administration of posaconazole with simvastatin increases the simvastatin plasma concentrations by approximately 10-fold. Therefore, posaconazole is contraindicated with HMG-CoA reductase inhibitors primarily metabolized through CYP3A4 [ see Contraindications (4.4) and Clinical Pharmacology (12.3) ]. 7.4 Ergot Alkaloids Most of the ergot alkaloids are substrates of CYP3A4. Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead t …

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm. ( 8.1 ) Pediatrics: Safety and effectiveness in patients younger than 2 years of age have not been established. ( 8.4 ) Severe Renal Impairment : Monitor closely for breakthrough fungal infections. ( 8.6 ) 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 Noxafil 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 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 Noxafil in healthy volunteers. In pregnant rabbits dosed orally during organogenesis, doses of ≥3 times the clinical exposure caused an increase in resorptions (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 oral suspension regimen based on steady-state plasma concentrations of drug in healthy volunteers). The no-effect dose for malformations and maternal toxicity in rats was 9 mg/kg, which is 0.7 times the exposure achieved with the 400 mg twice daily oral suspension regimen. No malformations were seen in rabbits dosed during organogenesis (Gestational Days 7 through 19) at doses up to 80 mg/kg (5 times the exposure achieved with the 400 mg twice daily oral suspension regimen). In the rabbit, the no-effect dose was 20 mg/kg, while high doses of 40 mg/kg and 80 mg/kg (3 or 5 times the clinical exposure) caused an increase in resorptions. In rabbits dosed at 80 mg/kg, a reduction in body weight gain of females and a reduction in litter size were seen. 8.2 Lactation Risk Summary There are no data on the presence of posaconazole in human milk, the effects on the breastfed infant, or the effects on milk production. Posaconazole is excreted in the milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for posaconazole and any potential adverse effects on the breastfed child from posaconazole or from the underlying maternal condition. 8.4 Pediatric Use The posaconazole dosage forms (delayed-release tablets and oral suspension) are different products; are approved for different pediatric indications, age groups, and weights; have different dosing regimens; and have different preparation and administration instructions. Therefore, select the recommended dosage form based on the pediatric indication, age group, and weight [see Dosage and Administration (2.1) ]. Treatment of Invasive Aspergillosis The safety and effectiveness of Posaconazole delayed-release tablets have been established for the treatment of invasive aspergillosis in pediatric patients 2 years of age and older. Use of posaconazole for these pediatric indications is supported by evidence from adequate and well-controlled studies of Noxafil in adults and safety and pharmacokinetic (PK) data from pediatric studies [se …

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

11 DESCRIPTION Posaconazole delayed-release tablets and Posaconazole oral suspension contain posaconazole; an azole antifungal agent. Posaconazole is designated chemically as 4-[4-[4-[4-[[ (3 R ,5 R )-5- (2,4-difluorophenyl)tetrahydro-5- (1 H -1,2,4-triazol-1-ylmethyl)-3-furanyl]methoxy]phenyl]-1-piperazinyl]phenyl]-2-[(1 S ,2 S )-1-ethyl-2-hydroxypropyl]-2,4-dihydro-3 H -1,2,4-triazol-3-one with an empirical formula of C 37 H 42 F 2 N 8 O 4 and a molecular weight of 700.8. The chemical structure is: Posaconazole is a white powder with a low aqueous solubility. Posaconazole Delayed-Release Tablets Posaconazole delayed-release tablet, for oral use, is yellow, coated, and oblong and contains 100 mg of posaconazole. Each delayed-release tablet contains the inactive ingredients: croscarmellose sodium, hydroxypropylcellulose, hypromellose acetate succinate, iron oxide yellow, Macrogol/PEG 3350, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol partially hydrolyzed, silicon dioxide, talc, and titanium dioxide. Posaconazole Oral Suspension Posaconazole oral suspension is a white, cherry-flavored immediate-release suspension that contains 40 mg of posaconazole per mL and the following inactive ingredients: artificial cherry flavor, citric acid monohydrate, glycerin, liquid glucose, polysorbate 80, purified water, simethicone, sodium benzoate, sodium citrate dihydrate, titanium dioxide, and xanthan gum. Chemical Structure

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.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Posaconazole Delayed-Release Tablets Posaconazole delayed-release tablets are yellow, coated, oblong, debossed with "100" on one side containing 100 mg of posaconazole. Bottles with child-resistant closures of 60 delayed-release tablets (NDC 0254-2045-02). Posaconazole Oral Suspension Posaconazole oral suspension is a white, cherry-flavored suspension in 4-ounce (123 mL) amber glass bottles with child-resistant closures containing 105 mL of suspension (40 mg of posaconazole per mL). Supplied with each oral suspension bottle is a plastic dosing spoon calibrated for measuring 2.5-mL and 5-mL doses (NDC 0254-1016-36). 16.2 Storage and Handling Posaconazole Delayed-Release Tablets Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Posaconazole Oral Suspension Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature]. DO NOT FREEZE.

16.1 How Supplied Posaconazole Delayed-Release Tablets Posaconazole delayed-release tablets are yellow, coated, oblong, debossed with "100" on one side containing 100 mg of posaconazole. Bottles with child-resistant closures of 60 delayed-release tablets (NDC 0254-2045-02). Posaconazole Oral Suspension Posaconazole oral suspension is a white, cherry-flavored suspension in 4-ounce (123 mL) amber glass bottles with child-resistant closures containing 105 mL of suspension (40 mg of posaconazole per mL). Supplied with each oral suspension bottle is a plastic dosing spoon calibrated for measuring 2.5-mL and 5-mL doses (NDC 0254-1016-36).