DOSAGE FORMS & STRENGTHS SECTION.

3DOSAGE FORMS AND STRENGTHS. Posaconazole delayed-release tablets are available as yellow, modified, oval, convex tablets debossed with logo M inside square on one side and 100 on the opposite side containing 100 mg of posaconazole.. Posaconazole delayed-release tablet: 100 mg (3). Posaconazole delayed-release tablet: 100 mg (3).

DRUG INTERACTIONS SECTION.

7DRUG INTERACTIONS. Posaconazole is primarily metabolized via UDP glucuronosyltransferase and is 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 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(R) Oral Suspension or early tablet formulation unless otherwise noted. All drug interactions with Noxafil(R) Oral Suspension, except for those that affect the absorption of posaconazole (via gastric pH and motility), are considered relevant to posaconazole delayed-release tablets as well [see Drug Interactions (7.9) and (7.13)].. Interaction DrugInteraction 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 Cmax 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 to ergotism. Therefore, posaconazole is contraindicated with ergot alkaloids [see Contraindications (4.5)].. 7.5 Benzodiazepines Metabolized by CYP3A4. 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. Concomitant use of posaconazole and other benzodiazepines metabolized by CYP3A4 (e.g., alprazolam, triazolam) could result in increased plasma concentrations of these benzodiazepines. Patients must be monitored closely for adverse effects associated with high plasma concentrations of benzodiazepines metabolized by CYP3A4 and benzodiazepine receptor antagonists must be available to reverse these effects [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)].. 7.6 Anti-HIV Drugs. Efavirenz: Efavirenz induces UDP-glucuronidase and significantly decreases posaconazole plasma concentrations [see Clinical Pharmacology (12.3)]. It is recommended to avoid concomitant use of efavirenz with posaconazole unless the benefit outweighs the risks.. Ritonavir and Atazanavir: Ritonavir and atazanavir are metabolized by CYP3A4 and posaconazole increases plasma concentrations of these drugs [see Clinical Pharmacology (12.3)]. Frequent monitoring of adverse effects and toxicity of ritonavir and atazanavir should be performed during coadministration with posaconazole.. Fosamprenavir: Combining fosamprenavir with posaconazole may lead to decreased posaconazole plasma concentrations. If concomitant administration is required, close monitoring for breakthrough fungal infections is recommended [see Clinical Pharmacology (12.3)].. 7.7 Rifabutin. Rifabutin induces UDP-glucuronidase and decreases posaconazole plasma concentrations. Rifabutin is also metabolized by CYP3A4. Therefore, coadministration of rifabutin with posaconazole increases rifabutin plasma concentrations [see Clinical Pharmacology (12.3)]. Concomitant use of posaconazole and rifabutin should be avoided unless the benefit to the patient outweighs the risk. However, if concomitant administration is required, close monitoring for breakthrough fungal infections as well as frequent monitoring of full blood counts and adverse reactions due to increased rifabutin plasma concentrations (e.g., uveitis, leukopenia) are recommended.. 7.8 Phenytoin. Phenytoin induces UDP-glucuronidase and decreases posaconazole plasma concentrations. Phenytoin is also metabolized by CYP3A4. Therefore, coadministration of phenytoin with posaconazole increases phenytoin plasma concentrations [see Clinical Pharmacology (12.3)]. Concomitant use of posaconazole and phenytoin should be avoided unless the benefit to the patient outweighs the risk. However, if concomitant administration is required, close monitoring for breakthrough fungal infections is recommended and frequent monitoring of phenytoin concentrations should be performed while coadministered with posaconazole and dose reduction of phenytoin should be considered.. 7.9 Gastric Acid Suppressors/Neutralizers. No clinically relevant effects on the pharmacokinetics of posaconazole were observed when posaconazole delayed-release tablets are concomitantly used with antacids, H2-receptor antagonists and proton pump inhibitors [see Clinical Pharmacology (12.3)]. No dosage adjustment of posaconazole delayed-release tablets is required when posaconazole delayed-release tablets are concomitantly used with antacids, H2-receptor antagonists and proton pump inhibitors. 7.10 Vinca Alkaloids. Most of the vinca alkaloids (e.g., vincristine and vinblastine) are substrates of CYP3A4. Concomitant administration of azole antifungals, including posaconazole, with vincristine has been associated with serious adverse reactions [see Warnings and Precautions (5.7) ]. Posaconazole may increase the plasma concentrations of vinca alkaloids which may lead to neurotoxicity and other serious adverse reactions. Therefore, reserve azole antifungals, including posaconazole, for patients receiving vinca alkaloid, including vincristine, who have no alternative antifungal treatment options.. 7.11 Calcium Channel Blockers Metabolized by CYP3A4. Posaconazole may increase the plasma concentrations of calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, diltiazem, nifedipine, nicardipine, felodipine). Frequent monitoring for adverse reactions and toxicity related to calcium channel blockers is recommended during coadministration. Dose reduction of calcium channel blockers may be needed.. 7.12 Digoxin. Increased plasma concentrations of digoxin have been reported in patients receiving digoxin and posaconazole. Therefore, monitoring of digoxin plasma concentrations is recommended during coadministration.. 7.13 Gastrointestinal Motility Agents. Concomitant administration of metoclopramide with posaconazole delayed-release tablets did not affect the pharmacokinetics of posaconazole [see Clinical Pharmacology (12.3)]. No dosage adjustment of posaconazole delayed-release tablets is required when given concomitantly with metoclopramide. 7.14 Glipizide. Although no dosage adjustment of glipizide is required, it is recommended to monitor glucose concentrations when posaconazole and glipizide are concomitantly used.. 7.16 Venetoclax. Concomitant use of venetoclax (a CYP3A4 substrate) with posaconazole increases venetoclax Cmax and AUC0-INF, which may increase venetoclax toxicities [see Contraindications (4.6), Warnings and Precautions (5.10)]. Refer to the venetoclax prescribing information for more information on the dosing instructions and the extent of increase in venetoclax exposure.

OVERDOSAGE SECTION.

10OVERDOSAGE. There is no experience with overdosage of posaconazole delayed-release tablets.During the clinical trials, some patients received Noxafil(R) 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(R) Oral Suspension for days. No related adverse reactions were noted by the investigator.Posaconazole is not removed by hemodialysis.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 100 mg Label. NDC 0406-7711-60 60 TABLETS PosaconazoleDelayed-Release Tablets100 mgRx onlyATTENTION: Noxafil(TM) Oral Suspension and Posaconazole Delayed-Release Tablets are NOT interchangeable due to differences in the dosing of each formulation.PHARMACIST: Dispense the Patient Information provided separately to each patient.Mallinckrodt(TM)L00P34Rev 05/2022. PRINCIPAL DISPLAY PANEL 100 mg Label.

SPL PATIENT PACKAGE INSERT SECTION.

Patient InformationPosaconazole (poe sa kon zole) delayed-release tabletsWhat are posaconazole delayed-release tabletsPosaconazole delayed-release tablets are prescription medicine used in adults and children 13 years of age and older to help prevent or treat fungal infections that can spread throughout your body (invasive fungal infections). These infections are caused by fungi called Aspergillus or Candida. Posaconazole delayed-release tablets are used in people who have an increased chance of getting these infections due to weak immune system. These include people who have had hematopoietic stem cell transplantation (bone marrow transplant) with graft-versus-host disease or those with low white blood cell count due to chemotherapy for blood cancers (hematologic malignancies).Posaconazole delayed-release tablets are used for:prevention of fungal infections in adults and children 13 years of age and older who weigh greater than 88 lbs (40 kg). It is not known if posaconazole delayed-release tablets are safe and effective in children under years of age.Who should not take posaconazole delayed-release tabletsDo not take posaconazole delayed-release tablets if you:are allergic to posaconazole, any of the ingredients in posaconazole delayed-release tablets, or other azole antifungal medicines. See the end of this leaflet for complete list of ingredients in posaconazole delayed-release tablets.are taking any of the following medicines:sirolimuspimozidequinidinecertain statin medicines that lower cholesterol (atorvastatin, lovastatin, simvastatin)ergot alkaloids (ergotamine, dihydroergotamine) have chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) and you have just started taking venetoclax or your venetoclax dose is being slowly increased.Ask your healthcare provider or pharmacist if you are not sure if you are taking any of these medicines. Do not start taking new medicine without talking to your healthcare provider or pharmacist.What should tell my healthcare provider before taking posaconazole delayed-release tabletsBefore you take posaconazole delayed-release tablets, tell your healthcare provider if you:are taking certain medicines that lower your immune system like cyclosporine or tacrolimus.are taking certain drugs for HIV infection, such as ritonavir, atazanavir, efavirenz, or fosamprenavir. Efavirenz and fosamprenavir can cause decrease in the posaconazole levels in your body. Efavirenz and fosamprenavir should not be taken with posaconazole delayed-release tablets.are taking midazolam, hypnotic and sedative medicine.are taking vincristine, vinblastine and other vinca alkaloids (medicines used to treat cancer).are taking venetoclax, medicine used to treat cancer.have or had liver problems.have or had kidney problems.have or had an abnormal heart rate or rhythm, heart problems, or blood circulation problems.are pregnant or plan to become pregnant. It is not known if posaconazole delayed-release tablets will harm your unborn baby.are breastfeeding or plan to breastfeed. It is not known if posaconazole passes into your breast milk. You and your healthcare provider should decide if you will take posaconazole delayed-release tablets or breastfeed. You should not do both.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Posaconazole delayed-release tablets can affect the way other medicines work, and other medicines can affect the way posaconazole delayed-release tablets work, and can cause serious side effects.Especially tell your healthcare provider if you take:rifabutin or phenytoin. If you are taking these medicines, you should not take posaconazole delayed-release tablets.Ask your healthcare provider or pharmacist for list of these medicines if you are not sure.Know the medicines you take. Keep list of them with you to show your healthcare provider or pharmacist when you get new medicine. How will take posaconazole delayed-release tabletsDo not switch between taking posaconazole delayed-release tablets and Noxafil(R) Oral Suspension.Take posaconazole delayed-release tablets exactly as your healthcare provider tells you to take them.Your healthcare provider will tell you how many posaconazole delayed-release tablets to take and when to take them.Take posaconazole delayed-release tablets for as long as your healthcare provider tells you to take them.If you take too many posaconazole delayed-release tablets, call your healthcare provider or go to the nearest hospital emergency room right away.Posaconazole delayed-release tablets:Take posaconazole delayed-release tablets with or without food.Take posaconazole delayed-release tablets whole. Do not break, crush, or chew posaconazole delayed-release tablets before swallowing. If you cannot swallow posaconazole delayed-release tablets whole, tell your healthcare provider. You may need different medicine.If you miss dose, take it as soon as you remember and then take your next scheduled dose at its regular time. If it is within 12 hours of your next dose, do not take the missed dose. Skip the missed dose and go back to your regular schedule. Do not double your next dose or take more than your prescribed dose.Follow the instructions from your healthcare provider on how many posaconazole delayed-release tablets you should take and when to take them.What are the possible side effects of posaconazole delayed-release tabletsPosaconazole delayed-release tablets may cause serious side effects, including:drug interactions with cyclosporine or tacrolimus. If you take posaconazole delayed-release tablets with cyclosporine or tacrolimus, your blood levels of cyclosporine or tacrolimus may increase. Serious side effects can happen in your kidney or brain if you have high levels of cyclosporine or tacrolimus in your blood. Your healthcare provider should do blood tests to check your levels of cyclosporine or tacrolimus if you are taking these medicines while taking posaconazole delayed-release tablets. Tell your healthcare provider right away if you have swelling in your arm or leg or shortness of breath.problems with the electrical system of your heart (arrhythmias and QTc prolongation). Certain medicines used to treat fungus called azoles, including posaconazole, the active ingredient in posaconazole delayed-release tablets, may cause heart rhythm problems. People who have certain heart problems or who take certain medicines have higher chance for this problem. Tell your healthcare provider right away if your heartbeat becomes fast or irregular.changes in body salt (electrolytes) levels in your blood. Your healthcare provider should check your electrolytes while you are taking posaconazole delayed-release tablets.liver problems. Some people who also have other serious medical problems may have severe liver problems that may lead to death, especially if you take certain doses of posaconazole delayed-release tablets. Your healthcare provider should do blood tests to check your liver while you are taking posaconazole delayed-release tablets. Call your healthcare provider right away if you have any of the following symptoms of liver problems:itchy skinnausea or vomitingyellowing of your eyes or skinfeeling very tiredflu-like symptomsincreased amounts of midazolam in your blood. If you take posaconazole delayed-release tablets with midazolam, posaconazole delayed-release tablets increases the amount of midazolam in your blood. This can make your sleepiness last longer. Your healthcare provider should check you closely for side effects if you take midazolam with posaconazole delayed-release tablets.The most common side effects of posaconazole delayed-release tablets include:diarrheanauseafevervomitingheadachecoughinglow potassium levels in the bloodIf you take posaconazole delayed-release tablets, tell your healthcare provider right away if you have diarrhea or vomiting.Tell your healthcare provider if you have any side effect that bothers you or that does not go away.These are not all the possible side effects of posaconazole delayed-release tablets. For more information, ask your healthcare provider or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store posaconazole delayed-release tabletsStore posaconazole delayed-release tablets at room temperature between 68F to 77F (20C to 25C).Safely throw away medicine that is out of date or no longer needed.Keep posaconazole delayed-release tablets and all medicines out of the reach of children.General information about the safe and effective use of posaconazole delayed-release tablets.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use posaconazole delayed-release tablets for condition for which they were not prescribed. Do not give posaconazole delayed-release tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about posaconazole delayed-release tablets that is written for health professionals.What are the ingredients in posaconazole delayed-release tabletsActive ingredient: posaconazole Inactive ingredients: Hypromellose Acetate Succinate, Microcrystalline Cellulose, Hydroxypropyl Cellulose, Croscarmellose Sodium, Silicon Dioxide, and Magnesium Stearate. The color coating contains (Polyvinyl Alcohol, Titanium Dioxide, Polyethylene Glycol, Talc, Ferric Oxide Yellow, and Ferrosoferric Oxide).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.SpecGx LLCWebster Groves, MO 63119 USA www.mallinckrodt.com or call 1-800-778-7898Mallinckrodt(TM)This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: 04/2022X30000254. prevention of fungal infections in adults and children 13 years of age and older who weigh greater than 88 lbs (40 kg). are allergic to posaconazole, any of the ingredients in posaconazole delayed-release tablets, or other azole antifungal medicines. See the end of this leaflet for complete list of ingredients in posaconazole delayed-release tablets.. are taking any of the following medicines:sirolimuspimozidequinidinecertain statin medicines that lower cholesterol (atorvastatin, lovastatin, simvastatin)ergot alkaloids (ergotamine, dihydroergotamine) sirolimus. pimozide. quinidine. certain statin medicines that lower cholesterol (atorvastatin, lovastatin, simvastatin). ergot alkaloids (ergotamine, dihydroergotamine). have chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) and you have just started taking venetoclax or your venetoclax dose is being slowly increased.. are taking certain medicines that lower your immune system like cyclosporine or tacrolimus.. are taking certain drugs for HIV infection, such as ritonavir, atazanavir, efavirenz, or fosamprenavir. Efavirenz and fosamprenavir can cause decrease in the posaconazole levels in your body. Efavirenz and fosamprenavir should not be taken with posaconazole delayed-release tablets.. are taking midazolam, hypnotic and sedative medicine.. are taking vincristine, vinblastine and other vinca alkaloids (medicines used to treat cancer).. are taking venetoclax, medicine used to treat cancer.. have or had liver problems.. have or had kidney problems.. have or had an abnormal heart rate or rhythm, heart problems, or blood circulation problems.. are pregnant or plan to become pregnant. It is not known if posaconazole delayed-release tablets will harm your unborn baby.. are breastfeeding or plan to breastfeed. It is not known if posaconazole passes into your breast milk. You and your healthcare provider should decide if you will take posaconazole delayed-release tablets or breastfeed. You should not do both.. rifabutin or phenytoin. If you are taking these medicines, you should not take posaconazole delayed-release tablets.. Do not switch between taking posaconazole delayed-release tablets and Noxafil(R) Oral Suspension.. Take posaconazole delayed-release tablets exactly as your healthcare provider tells you to take them.. Your healthcare provider will tell you how many posaconazole delayed-release tablets to take and when to take them.. Take posaconazole delayed-release tablets for as long as your healthcare provider tells you to take them.. If you take too many posaconazole delayed-release tablets, call your healthcare provider or go to the nearest hospital emergency room right away.. Posaconazole delayed-release tablets:Take posaconazole delayed-release tablets with or without food.Take posaconazole delayed-release tablets whole. Do not break, crush, or chew posaconazole delayed-release tablets before swallowing. If you cannot swallow posaconazole delayed-release tablets whole, tell your healthcare provider. You may need different medicine.If you miss dose, take it as soon as you remember and then take your next scheduled dose at its regular time. If it is within 12 hours of your next dose, do not take the missed dose. Skip the missed dose and go back to your regular schedule. Do not double your next dose or take more than your prescribed dose.. Take posaconazole delayed-release tablets with or without food.. Take posaconazole delayed-release tablets whole. Do not break, crush, or chew posaconazole delayed-release tablets before swallowing. If you cannot swallow posaconazole delayed-release tablets whole, tell your healthcare provider. You may need different medicine.. If you miss dose, take it as soon as you remember and then take your next scheduled dose at its regular time. If it is within 12 hours of your next dose, do not take the missed dose. Skip the missed dose and go back to your regular schedule. Do not double your next dose or take more than your prescribed dose.. drug interactions with cyclosporine or tacrolimus. If you take posaconazole delayed-release tablets with cyclosporine or tacrolimus, your blood levels of cyclosporine or tacrolimus may increase. Serious side effects can happen in your kidney or brain if you have high levels of cyclosporine or tacrolimus in your blood. Your healthcare provider should do blood tests to check your levels of cyclosporine or tacrolimus if you are taking these medicines while taking posaconazole delayed-release tablets. Tell your healthcare provider right away if you have swelling in your arm or leg or shortness of breath.. problems with the electrical system of your heart (arrhythmias and QTc prolongation). Certain medicines used to treat fungus called azoles, including posaconazole, the active ingredient in posaconazole delayed-release tablets, may cause heart rhythm problems. People who have certain heart problems or who take certain medicines have higher chance for this problem. Tell your healthcare provider right away if your heartbeat becomes fast or irregular.. changes in body salt (electrolytes) levels in your blood. Your healthcare provider should check your electrolytes while you are taking posaconazole delayed-release tablets.. liver problems. Some people who also have other serious medical problems may have severe liver problems that may lead to death, especially if you take certain doses of posaconazole delayed-release tablets. Your healthcare provider should do blood tests to check your liver while you are taking posaconazole delayed-release tablets. Call your healthcare provider right away if you have any of the following symptoms of liver problems:itchy skinnausea or vomitingyellowing of your eyes or skinfeeling very tiredflu-like symptoms. itchy skin. nausea or vomiting. yellowing of your eyes or skin. feeling very tired. flu-like symptoms. increased amounts of midazolam in your blood. If you take posaconazole delayed-release tablets with midazolam, posaconazole delayed-release tablets increases the amount of midazolam in your blood. This can make your sleepiness last longer. Your healthcare provider should check you closely for side effects if you take midazolam with posaconazole delayed-release tablets.. diarrhea. nausea. fever. vomiting. headache. coughing. low potassium levels in the blood. Store posaconazole delayed-release tablets at room temperature between 68F to 77F (20C to 25C).. Safely throw away medicine that is out of date or no longer needed.

ADVERSE REACTIONS SECTION.

6ADVERSE 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)] 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 Mallinckrodt at 1-800-778-7898 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Common adverse reactions in studies with posaconazole are diarrhea, nausea, fever, vomiting, headache, coughing, and hypokalemia. (6.1). 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of posaconazole delayed-release tablets 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 AdultsClinical Trial Experience with Posaconazole Delayed-Release Tablets for ProphylaxisThe safety of posaconazole delayed-release tablets has been assessed in 230 patients in clinical trials. Patients were enrolled in 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 postchemotherapy, GVHD, and post HSCT. This patient population was 62% male, had 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 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 in each cohort). Table 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 DoseBody SystemPosaconazole delayed-release tablet (300 mg)n=210 (%)Subjects Reporting any Adverse Reaction207(99)Blood and Lymphatic System DisorderAnemia22(10)Thrombocytopenia29(14)Gastrointestinal DisordersAbdominal Pain23(11)Constipation20(10)Diarrhea61(29)Nausea56(27)Vomiting28(13)General Disorders and Administration Site ConditionsAsthenia20(10)Chills22(10)Mucosal Inflammation29(14)Edema Peripheral33(16)Pyrexia59(28)Metabolism and Nutrition DisordersHypokalemia46(22)Hypomagnesemia20(10)Nervous System DisordersHeadache30(14)Respiratory, Thoracic and Mediastinal DisordersCough35(17)Epistaxis30(14)Skin and Subcutaneous Tissue DisordersRash34(16)Vascular DisordersHypertension23(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) delayed-release tablets. 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 population of uncertain size, it is not always possible to reliably estimate their frequency.Endocrine Disorders: Pseudoaldosteronism.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology. In nonclinical study using intravenous administration of posaconazole in very young dogs (dosed from to weeks of age), an increase in the incidence of brain ventricle enlargement was observed in treated animals as compared with concurrent control animals. No difference in the incidence of brain ventricle enlargement between control and treated animals was observed following the subsequent 5-month treatment-free period. There were no neurologic, behavioral or developmental abnormalities in the dogs with this finding, and similar brain finding was not seen with oral posaconazole administration to juvenile dogs (4 days to months of age). There were no drug-related increases in the incidence of brain ventricle enlargement when treated and control animals were compared in separate study of 10-week old dogs dosed with intravenous posaconazole for 13 weeks with 9-week recovery period or follow-up study of 31-week old dogs dosed for months.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisNo drug-related neoplasms were recorded in rats or mice treated with posaconazole for years at doses higher than the clinical dose. In 2-year carcinogenicity study, rats were given posaconazole orally at doses up to 20 mg/kg (females), or 30 mg/kg (males). These doses are equivalent to 3.9- or 3.5-times the exposure achieved with 400-mg twice daily Noxafil(R) Oral Suspension regimen, respectively, based on steady-state AUC in healthy volunteers administered high-fat meal (400-mg twice daily Noxafil(R) Oral Suspension regimen). In the mouse study, mice were treated at oral doses up to 60 mg/kg/day or 4.8-times the exposure achieved with 400-mg twice daily Noxafil(R) Oral Suspension regimen.MutagenesisPosaconazole was not genotoxic or clastogenic when evaluated in bacterial mutagenicity (Ames), chromosome aberration study in human peripheral blood lymphocytes, Chinese hamster ovary cell mutagenicity study, and mouse bone marrow micronucleus study.Impairment of FertilityPosaconazole had no effect on fertility of male rats at dose up to 180 mg/kg (1.7 the 400-mg twice daily Noxafil(R) Oral Suspension regimen based on steady-state plasma concentrations in healthy volunteers) or female rats at dose up to 45 mg/kg (2.2 the 400-mg twice daily Noxafil(R) Oral Suspension regimen).

CLINICAL PHARMACOLOGY SECTION.

12CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Posaconazole is an azole antifungal agent [see Clinical Pharmacology (12.4)].. 12.2 Pharmacodynamics. Exposure Response Relationship Prophylaxis: In clinical studies of neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS) or hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD), wide range of plasma exposures to posaconazole was noted following administration of Noxafil(R) Oral Suspension. pharmacokinetic-pharmacodynamic analysis of patient data revealed an apparent association between average posaconazole concentrations (Cavg) and prophylactic efficacy (Table 17). lower Cavg may be associated with an increased risk of treatment failure, defined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections.Table 17: Noxafil(R) Oral Suspension Exposure Analysis (Cavg) in Prophylaxis Trials Prophylaxis in AML/MDSNeutropenic patients who were receiving cytotoxic chemotherapy for AML or MDS Prophylaxis in GVHDHSCT recipients with GVHD Cavg Range (ng/mL) Treatment FailureDefined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections(%) Cavg Range (ng/mL) Treatment Failure(%)Quartile 190-32254.722-55744.4Quartile 2322-49037.0557-91520.6Quartile 3490-73446.8915-156317.5Quartile 4734-220027.81563-365017.5Cavg the average posaconazole concentration when measured at steady state. 12.3 Pharmacokinetics. General Pharmacokinetic Characteristics. Posaconazole delayed-release tablets exhibit dose proportional pharmacokinetics after single and multiple dosing up to 300 mg. The mean pharmacokinetic parameters of posaconazole at steady state following administration of posaconazole delayed-release tablets 300 mg twice daily on Day 1, then 300 mg once daily thereafter in healthy volunteers and in neutropenic patients who are receiving cytotoxic chemotherapy for AML or MDS or HSCT recipients with GVHD are shown in Table 20.Table 20: Arithmetic Mean (%CV) of Steady State PK Parameters in Healthy Volunteers and Patients Following Administration of Posaconazole Delayed-Release Tablets (300 mg)300 mg twice daily on Day 1, then 300 mg once daily thereafter AUC0-24 hr CavCav time-averaged concentrations (i.e., AUC0-24 hr/24hr) Cmax Cmin Tmax Median (minimum-maximum) (hr)t1/2 CL/F (ng.hr/mL)(ng/mL)(ng/mL)(ng/mL) (hr)(L/hr)Healthy12516182151276417854317.5Volunteers (25)(25)(21)(29)(3-6)(40)(26)Patients 50379001580209013104 (1.3-8.3)-9.39 (42)(42)(38)(50) (45)CV coefficient of variation expressed as percentage (%CV); AUC0-T Area under the plasma concentration-time curve from time zero to 24 hr; Cmax maximum observed concentration; Cmin minimum observed plasma concentration; Tmax time of maximum observed concentration; 1/2 terminal phase half-life; CL/F Apparent total body clearance. Absorption: . When given orally in healthy volunteers, posaconazole delayed-release tablets are absorbed with median Tmax of to hours. Steady-state plasma concentrations are attained by Day at the 300 mg dose (once daily after twice daily loading dose at Day 1). The absolute bioavailability of the oral delayed-release tablet is approximately 54% under fasted conditions. The Cmax and AUC of posaconazole following administration of posaconazole delayed-release tablets is increased 16% and 51%, respectively, when given with high-fat meal compared to fasted state (see Table 22). Table 22: Statistical Comparison of Plasma Pharmacokinetics of Posaconazole Following Single Oral Dose Administration of 300 mg Posaconazole Delayed-Release Tablet to Healthy Subjects under Fasting and Fed Conditions Fasting ConditionsFed Conditions(High-Fat Meal)48.5 fat Fed/FastingPharmacokinetic ParameterNMean (%CV)NMean (%CV)GMR (90% CI)Cmax (ng/mL)14 935 (34)161060 (25)1.16 (0.96, 1.41)AUC0-72hr (hrng/mL)1426200 (28)1638400 (18)1.51 (1.33, 1.72)Tmax Median (Min, Max) reported for Tmax (hr)145.00(3.00, 8.00)166.00(5.00, 24.00) N/AGMR=Geometric least-squares mean ratio; CI=Confidence interval. Concomitant administration of posaconazole delayed-release tablets with drugs affecting gastric pH or gastric motility did not demonstrate any significant effects on posaconazole pharmacokinetic exposure (see Table 23).Table 23: The Effect of Concomitant Medications that Affect the Gastric pH and Gastric Motility on the Pharmacokinetics of Posaconazole Delayed-Release Tablets in Healthy VolunteersCoadministered DrugAdministration ArmsChange in Cmax (ratio estimateRatio Estimate is the ratio of coadministered drug plus posaconazole to posaconazole alone for Cmax or AUC0-last. ;90% CI of the ratio estimate)Change in AUC0-last (ratio estimate;90% CI of the ratio estimate)Mylanta(R) Ultimate strength liquid (Increase in gastric pH)25.4 meq/5 mL, 20 mL6%(1.06; 0.90-1.26)4%(1.04; 0.90-1.20)Ranitidine (Zantac(R)) (Alteration in gastric pH) 150 mg (morning dose of 150 mg Ranitidine twice daily)4%(1.04; 0.88-1.23)3%(0.97; 0.84-1.12)Esomeprazole (Nexium(R)) (Increase in gastric pH)40 mg (every morning for days, Day -4 to 1)2%(1.02; 0.88-1.17)5%(1.05; 0.89-1.24)Metoclopramide (Reglan(R)) (Increase in gastric motility)15 mg four times daily for days (Day -1 and 1)14%(0.86, 0.73,1.02)7%(0.93, 0.803,1.07). Distribution:The mean volume of distribution of posaconazole after intravenous solution administration was 261 and ranged from 226-295 between studies and dose levels.Posaconazole is highly bound to human plasma proteins (>98%), predominantly to albumin.. Metabolism:Posaconazole primarily circulates as the parent compound in plasma. Of the circulating metabolites, the majority are glucuronide conjugates formed via UDP glucuronidation (phase enzymes). Posaconazole does not have any major circulating oxidative (CYP450 mediated) metabolites. The excreted metabolites in urine and feces account for ~17% of the administered radiolabeled dose.Posaconazole is primarily metabolized via UDP glucuronidation (phase enzymes) and is substrate for p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. summary of drugs studied clinically with the Noxafil(R) Oral Suspension or an early tablet formulation, which affect posaconazole concentrations, is provided in Table 27.Table 27: Summary of the Effect of Coadministered Drugs on Posaconazole in Healthy VolunteersCoadministered Drug (Postulated Mechanism of Interaction)Coadministered Drug Dose/SchedulePosaconazole Dose/ScheduleEffect on Bioavailability of PosaconazoleChange in Mean Cmax (ratio estimateRatio Estimate is the ratio of coadministered drug plus posaconazole to posaconazole alone for Cmax or AUC.; 90% CI of the ratio estimate)Change in Mean AUC(ratio estimate; 90% CI of the ratio estimate)Efavirenz(UDP-G Induction)400 mg once daily 10 and20 days400 mg (Noxafil(R) Oral Suspension) twice daily 10 and 20 days45% (0.55; 0.47-0.66)50%(0.50; 0.43-0.60)Fosamprenavir(unknown mechanism)700 mg twice daily 10 days200 mg once daily on the 1st day, 200 mg twice daily on the 2nd day, then 400 mg twice daily 8 Days21%0.79 (0.71-0.89)23%0.77 (0.68-0.87)Rifabutin(UDP-G Induction)300 mg once daily 17 days200 mg (tablets) once dailyx 10 daysThe tablet refers to non-commercial tablet formulation without polymer. 43%(0.57; 0.43-0.75)49%(0.51; 0.37-0.71)Phenytoin(UDP-G Induction)200 mg once daily 10 days200 mg (tablets) once dailyx 10 days 41%(0.59; 0.44-0.79)50%(0.50; 0.36-0.71). In vitro studies with human hepatic microsomes and clinical studies indicate that posaconazole is an inhibitor primarily of CYP3A4. clinical study in healthy volunteers also indicates that posaconazole is strong CYP3A4 inhibitor as evidenced by >5-fold increase in midazolam AUC. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole. summary of the drugs studied clinically, for which plasma concentrations were affected by posaconazole, is provided in Table 28 [see Contraindications (4) and Drug Interactions (7.1) including recommendations].Table 28: Summary of the Effect of Posaconazole on Coadministered Drugs in Healthy Adult Volunteers and PatientsCoadministered Drug(Postulated Mechanism of Interaction is Inhibition of CYP3A4 by posaconazole)Coadministered Drug Dose/SchedulePosaconazole Dose/ScheduleEffect on Bioavailability of Coadministered DrugsChange in Mean Cmax (ratio estimateRatio Estimate is the ratio of coadministered drug plus posaconazole to coadministered drug alone for Cmax or AUC.; 90% CI of the ratio estimate)Change in Mean AUC(ratio estimate; 90% CI of the ratio estimate)Sirolimus2-mg single oral dose400 mg (Noxafil(R) Oral Suspension) twice daily 16 days572%(6.72; 5.62-8.03)788%(8.88; 7.26-10.9)CyclosporineStable maintenance dose in heart transplant recipients200 mg (tablets) once daily 10 daysThe tablet refers to non-commercial tablet formulation without polymer. cyclosporine whole blood trough concentrationsCyclosporine dose reductions of up to 29% were requiredTacrolimus0.05-mg/kg single oral dose400 mg (Noxafil(R) Oral Suspension) twice daily 7 days121%(2.21; 2.01-2.42)358%(4.58; 4.03-5.19)Simvastatin 40-mg single oral dose 100 mg (Noxafil(R) Oral Suspension) once daily 13 daysSimvastatin841%(9.41, 7.13-12.44)Simvastatin Acid817%(9.17, 7.36-11.43)Simvastatin931%(10.31, 8.40-12.67)Simvastatin Acid634%(7.34, 5.82-9.25)200 mg (Noxafil(R) Oral Suspension) once daily 13 daysSimvastatin1041%(11.41, 7.99-16.29)Simvastatin Acid851%(9.51, 8.15-11.10)Simvastatin960%(10.60, 8.63-13.02)Simvastatin Acid748%(8.48, 7.04-10.23)Midazolam 0.4-mg single intravenous doseThe mean terminal half-life of midazolam was increased from hours to to 11 hours during coadministration with posaconazole. 200 mg (Noxafil(R) Oral Suspension) twice daily 7 days30%(1.3; 1.13-1.48)362%(4.62; 4.02-5.3)0.4-mg single intravenous dose 400 mg (Noxafil(R) Oral Suspension) twice daily 7 days62%(1.62; 1.41-1.86)524%(6.24; 5.43-7.16)2-mg single oral dose 200 mg (Noxafil(R) Oral Suspension) once daily 7 days169%(2.69; 2.46-2.93)470%(5.70; 4.82-6.74)2-mg single oral dose 400 mg (Noxafil(R) Oral Suspension) twice daily 7 days138%(2.38; 2.13-2.66)397%(4.97; 4.46-5.54)Rifabutin300 mg once daily 17 days200 mg (tablets) once daily 10 days 31%(1.31; 1.10-1.57)72%(1.72;1.51-1.95)Phenytoin200 mg once daily PO 10 days200 mg (tablets) once daily 10 days 16%(1.16; 0.85-1.57)16%(1.16; 0.84-1.59)Ritonavir100 mg once daily 14 days400 mg (Noxafil(R) Oral Suspension)twice daily 7 days49%(1.49; 1.04-2.15)80%(1.8;1.39-2.31)Atazanavir300 mg once daily 14 days400 mg (Noxafil(R) Oral Suspension) twice daily 7 days155%(2.55; 1.89-3.45)268%(3.68; 2.89-4.70)Atazanavir/ ritonavir boosted regimen300 mg/100 mg once daily 14 days400 mg (Noxafil(R) Oral Suspension) twice daily 7 days53%(1.53; 1.13-2.07)146%(2.46; 1.93-3.13)Additional clinical studies demonstrated that no clinically significant effects on zidovudine, lamivudine, indinavir, or caffeine were observed when administered with posaconazole 200 mg once daily; therefore, no dose adjustments are required for these coadministered drugs when coadministered with posaconazole 200 mg once daily.. Excretion:Following administration of Noxafil(R) Oral Suspension, posaconazole is predominantly eliminated in the feces (71% of the radiolabeled dose up to 120 hours) with the major component eliminated as parent drug (66% of the radiolabeled dose). Renal clearance is minor elimination pathway, with 13% of the radiolabeled dose excreted in urine up to 120 hours (<0.2% of the radiolabeled dose is parent drug).Posaconazole delayed-release tablet is eliminated with mean half-life (t 1/2 ranging between 26 to 31 hours.Specific Populations No clinically significant differences in the pharmacokinetics of posaconazole were observed based on age, sex, renal impairment, and indication.Race/Ethnicity:In population pharmacokinetic analysis of posaconazole, AUC was found to be 25% higher in Chinese patients relative to patients from other races/ethnicities. This higher exposure is not expected to be clinically relevant given the expected variability in posaconazole exposure.Patients Weighing More Than 120 kg:Weight has clinically significant effect on posaconazole clearance. Relative to 70 kg patients, the Cavg is decreased by 25% in patients greater than 120 kg. Patients administered posaconazole delayed-release tablets weighing more than 120 kg may be at higher risk for lower posaconazole plasma concentrations compared to lower weight patients [see Use in Specific Populations (8.10)].Pediatric PatientsA total of 12 patients 13 to 17 years of age received 600 mg/day (200 mg three times day) of Noxafil(R) Oral Suspension for prophylaxis of invasive fungal infections. Based on pharmacokinetic data in 10 of these pediatric patients, the mean steady-state Cav was similar between these patients and adults (>=18 years of age). In study of 136 neutropenic pediatric patients 11 months to less than 18 years treated with Noxafil(R) Oral Suspension, the exposure target of steady-state posaconazole Cavg between 500 ng/mL and less than 2,500 ng/mL was attained in approximately 50% of patients instead of the pre-specified 90% of patients.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.. 12.4 Microbiology. Mechanism of Action:Posaconazole blocks the synthesis of ergosterol, key component of the fungal cell membrane, through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14-demethylase responsible for the conversion of lanosterol to ergosterol in the fungal cell membrane. This results in an accumulation of methylated sterol precursors and depletion of ergosterol within the cell membrane thus weakening the structure and function of the fungal cell membrane. This may be responsible for the antifungal activity of posaconazole.. Resistance:Clinical isolates of Candida albicans and Candida glabrata with decreased susceptibility to posaconazole were observed in oral swish samples taken during prophylaxis with posaconazole and fluconazole, suggesting potential for development of resistance. These isolates also showed reduced susceptibility to other azoles, suggesting cross-resistance between azoles. The clinical significance of this finding is not known.. Antimicrobial Activity:Posaconazole has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1)].. Microorganisms:Aspergillus spp. and Candida spp. . Susceptibility Testing:For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.2 Prophylaxis of Aspergillus and Candida Infections with Noxafil(R) Oral Suspension. Two randomized, controlled studies were conducted using posaconazole as prophylaxis for the prevention of invasive fungal infections (IFIs) among patients at high risk due to severely compromised immune systems.The first study (Noxafil(R) Oral Suspension Study 1) was randomized, double-blind trial that compared Noxafil(R) Oral Suspension (200 mg three times day) with fluconazole capsules (400 mg once daily) as prophylaxis against invasive fungal infections in allogeneic hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD). Efficacy of prophylaxis was evaluated using composite endpoint of proven/probable IFIs, death, or treatment with systemic antifungal therapy (patients may have met more than one of these criteria). This assessed all patients while on study therapy plus days and at 16 weeks post-randomization. The mean duration of therapy was comparable between the treatment groups (80 days, posaconazole; 77 days, fluconazole). Table 32 contains the results from Noxafil(R) Oral Suspension Study 1.Table 32: Results from Blinded Clinical Study in Prophylaxis of IFI in All Randomized Patients with Hematopoietic Stem Cell Transplant (HSCT) and Graft-Versus-Host Disease (GVHD): Noxafil(R) Oral Suspension Study Posaconazole n=301 Fluconazole n=299 On therapy plus days Clinical FailurePatients may have met more than one criterion defining failure. 50 (17%) 55 (18%) Failure due to: Proven/Probable IFI7 (2%)22 (7%)(Aspergillus)3 (1%)17 (6%)(Candida)1 (<1%)3 (1%)(Other)3 (1%)2 (1%)All Deaths22 (7%)24 (8%) Proven/probable fungal infection prior to death2 (<1%)6 (2%)SAFUse of systemic antifungal therapy (SAF) criterion is based on protocol definitions (empiric/IFI usage >4 consecutive days). 27 (9%)25 (8%) Through 16 weeksClinical Failure 95% confidence interval (posaconazole-fluconazole) (-11.5%, +3.7%). 99 (33%)110 (37%)Failure due to:Proven/Probable IFI16 (5%)27 (9%)(Aspergillus)7 (2%)21 (7%)(Candida)4 (1%)4 (1%)(Other)5 (2%)2 (1%)All Deaths58 (19%)59 (20%)Proven/probable fungal infection prior to death 10 (3%)16 (5%)SAF 26 (9%)30 (10%)Event free lost to follow-upPatients who are lost to follow-up (not observed for 112 days), and who did not meet another clinical failure endpoint. These patients were considered failures. 24 (8%)30 (10%)The second study (Noxafil(R) Oral Suspension Study 2) was randomized, open-label study that compared Noxafil(R) Oral Suspension (200 mg times day) with fluconazole suspension (400 mg once daily) or itraconazole oral solution (200 mg twice day) as prophylaxis against IFIs in neutropenic patients who were receiving cytotoxic chemotherapy for AML or MDS. As in Noxafil(R) Oral Suspension Study 1, efficacy of prophylaxis was evaluated using composite endpoint of proven/probable IFIs, death, or treatment with systemic antifungal therapy (patients might have met more than one of these criteria). This study assessed patients while on treatment plus days and 100 days post-randomization. The mean duration of therapy was comparable between the treatment groups (29 days, posaconazole; 25 days, fluconazole or itraconazole). Table 33 contains the results from Noxafil(R) Oral Suspension Study 2.Table 33: Results from Open-Label Clinical Study in Prophylaxis of IFI in All Randomized Patients with Hematologic Malignancy and Prolonged Neutropenia: Noxafil(R) Oral Suspension Study Posaconazole n=304 Fluconazole n=298 On therapy plus days Clinical Failure95% confidence interval (posaconazole-fluconazole/itraconazole) (-22.9%, -7.8%). Patients may have met more than one criterion defining failure. 82 (27%)126 (42%) Failure due to: Proven/Probable IFI7 (2%)25 (8%)(Aspergillus)2 (1%)20 (7%)(Candida)3 (1%)2 (1%)(Other)2 (1%)3 (1%)All Deaths17 (6%)25 (8%) Proven/probable fungal infection prior to death1 (<1%)2 (1%)SAFUse of systemic antifungal therapy (SAF) criterion is based on protocol definitions (empiric/IFI usage >3 consecutive days). 67 (22%)98 (33%) Through 100 days post-randomizationClinical Failure 158 (52%)191 (64%)Failure due to:Proven/Probable IFI14 (5%)33 (11%)(Aspergillus)2 (1%)26 (9%)(Candida)10 (3%)4 (1%)(Other)2 (1%)3 (1%)All Deaths44 (14%)64 (21%)Proven/probable fungal infection prior to death (1%)16 (5%)SAF 98 (32%)125 (42%)Event free lost to follow-upPatients who are lost to follow-up (not observed for 100 days), and who did not meet another clinical failure endpoint. These patients were considered failures. 34 (11%)24 (8%)In summary, clinical studies of prophylaxis were conducted with the Noxafil(R) Oral Suspension. As seen in the accompanying tables (Tables 32 and 33), clinical failure represented composite endpoint of breakthrough IFI, mortality and use of systemic antifungal therapy. In Noxafil(R) Oral Suspension Study (Table 32), the clinical failure rate of posaconazole (33%) was similar to fluconazole (37%), (95% CI for the difference posaconazole-comparator -11.5% to 3.7%) while in Noxafil(R) Oral Suspension Study (Table 33) clinical failure was lower for patients treated with posaconazole (27%) when compared to patients treated with fluconazole or itraconazole (42%), (95% CI for the difference posaconazole-comparator -22.9% to -7.8%).All-cause mortality was similar at 16 weeks for both treatment arms in Noxafil(R) Oral Suspension Study [POS 58/301 (19%) vs. FLU 59/299 (20%)]; all-cause mortality was lower at 100 days for posaconazole-treated patients in Noxafil(R) Oral Suspension Study [POS 44/304 (14%) vs. FLU/ITZ 64/298 (21%)]. Both studies demonstrated fewer breakthrough infections caused by Aspergillus species in patients receiving posaconazole prophylaxis when compared to patients receiving fluconazole or itraconazole.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of posaconazole delayed-release tablets 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 AdultsClinical Trial Experience with Posaconazole Delayed-Release Tablets for ProphylaxisThe safety of posaconazole delayed-release tablets has been assessed in 230 patients in clinical trials. Patients were enrolled in 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 postchemotherapy, GVHD, and post HSCT. This patient population was 62% male, had 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 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 in each cohort). Table 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 DoseBody SystemPosaconazole delayed-release tablet (300 mg)n=210 (%)Subjects Reporting any Adverse Reaction207(99)Blood and Lymphatic System DisorderAnemia22(10)Thrombocytopenia29(14)Gastrointestinal DisordersAbdominal Pain23(11)Constipation20(10)Diarrhea61(29)Nausea56(27)Vomiting28(13)General Disorders and Administration Site ConditionsAsthenia20(10)Chills22(10)Mucosal Inflammation29(14)Edema Peripheral33(16)Pyrexia59(28)Metabolism and Nutrition DisordersHypokalemia46(22)Hypomagnesemia20(10)Nervous System DisordersHeadache30(14)Respiratory, Thoracic and Mediastinal DisordersCough35(17)Epistaxis30(14)Skin and Subcutaneous Tissue DisordersRash34(16)Vascular DisordersHypertension23(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) delayed-release tablets. However, due to Merck Sharp Dohme Corp.s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

CONTRAINDICATIONS SECTION.

4CONTRAINDICATIONS. Known hypersensitivity to posaconazole or other azole antifungal agents. (4.1)Coadministration of posaconazole delayed-release tablets with the following drugs is contraindicated; posaconazole delayed-release tablets increase 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, 5.10, 7.16) Known hypersensitivity to posaconazole or other azole antifungal agents. (4.1). Coadministration of posaconazole delayed-release tablets with the following drugs is contraindicated; posaconazole delayed-release tablets increase 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, 5.10, 7.16) 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, 5.10, 7.16) 4.1 Hypersensitivity. Posaconazole delayed-release tablets are contraindicated in persons with known hypersensitivity to posaconazole or other azole antifungal agents.. 4.2 Use with Sirolimus. Posaconazole delayed-release tablets are contraindicated with sirolimus. Concomitant administration of posaconazole delayed-release tablets 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 delayed-release tablets are contraindicated with CYP3A4 substrates that prolong the QT interval. Concomitant administration of posaconazole delayed-release tablets 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 delayed-release tablets 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 (5.10) and Drug Interactions (7.16)].

DESCRIPTION SECTION.

11 DESCRIPTION. Posaconazole delayed-release tablets are an azole antifungal agent.Posaconazole is designated chemically as 4-[4-[4-[4-[[ (3R,5R)-5- (2,4-difluorophenyl)tetrahydro-5- (1H-1,2,4-triazol-1-ylmethyl)-3-furanyl]methoxy]phenyl]-1-piperazinyl]phenyl]-2-[(1S,2S)-1-ethyl-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one with an empirical formula of C37H42F2N8O4 and molecular weight of 700.8. The chemical structure is:Posaconazole is white powder with low aqueous solubility.Posaconazole delayed-release tablets are yellow, modified, oval, convex tablets containing 100 mg of posaconazole. Each delayed-release tablet contains the inactive ingredients: Hypromellose Acetate Succinate, Microcrystalline Cellulose, Hydroxypropyl Cellulose, Croscarmellose Sodium, Silicon Dioxide, and Magnesium Stearate. The color coating contains (Polyvinyl Alcohol, Titanium Dioxide, Polyethylene Glycol, Talc, Ferric Oxide Yellow, and Ferrosoferric Oxide).. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2DOSAGE AND ADMINISTRATION. Posaconazole delayed-release tablets are not substitutable with Noxafil(R) Oral Suspension or Noxafil(R) 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 infectionsPosaconazole Delayed-Release Tablets:Loading dose: 300 mg (three 100 mg delayed-release tablets) twice day on the first day.Maintenance dose: 300 mg (three 100 mg delayed-release tablets) once day, starting on the second day. Duration of therapy is based on recovery from neutropenia or immunosuppression. (2.2, 2.3). Posaconazole delayed-release tablets are not substitutable with Noxafil(R) Oral Suspension or Noxafil(R) 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). 2.1Important Administration Instructions. Non-substitutablePosaconazole delayed-release tablets are not substitutable with Noxafil(R) Oral Suspension or Noxafil(R) 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 tabletsSwallow 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 full meal, posaconazole delayed-release tablets should be used instead of Noxafil(R) Oral Suspension for the prophylaxis indication. Posaconazole delayed-release tablets generally provide higher plasma drug exposures than Noxafil(R) Oral Suspension under both fed and fasted conditions.. 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 full meal, posaconazole delayed-release tablets should be used instead of Noxafil(R) Oral Suspension for the prophylaxis indication. Posaconazole delayed-release tablets generally provide higher plasma drug exposures than Noxafil(R) Oral Suspension under both fed and fasted conditions.. 2.2 Dosing Regimen in Adult Patients. Table 1: Dosing Regimens in Adult PatientsIndicationDose and FrequencyDuration of TherapyProphylaxis of invasive Aspergillus and Candida infectionsPosaconazole Delayed-Release Tablets:Loading dose: 300 mg (three 100 mg delayed-release tablets) twice day on the first day.Maintenance dose: 300 mg (three 100 mg delayed-release tablets) once day, starting on the second day.Loading dose:1 dayMaintenance dose:Duration of therapy is based on recovery from neutropenia or immunosuppression.. 2.3Dosing Regimen in Pediatric Patients (ages 13 to less than 18 years of age). The recommended dosing regimen of posaconazole delayed-release tablets for pediatric patients 13 to less than 18 years of age is shown in Table [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].Table 2: Posaconazole Delayed-Release Tablet Dosing Regimens for Pediatric Patients (ages 13 to less than 18 years of age)IndicationDelayed-Release TabletDuration of therapyProphylaxis of Invasive Aspergillus and Candida infectionsLoading dose:300 mg twice daily on the first dayMaintenance dose:300 mg once dailyDuration of therapy is based on recovery from neutropenia or immunosuppression.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.. 2.5Administration 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)].. 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(R) Oral Suspension and Other Formulations. Posaconazole delayed-release tablets are not substitutable with Noxafil(R) Oral Suspension or Noxafil(R) 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)]. 2.9 Dosage Adjustments in Patients with Renal Impairment. The pharmacokinetics of posaconazole delayed-release tablets are not significantly affected by renal impairment. Therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment.

GERIATRIC USE SECTION.

8.5 Geriatric Use. No overall differences in the safety of posaconazole delayed-release tablets were observed between geriatric patients and younger adult patients in the clinical trials; therefore, no dosage adjustment is recommended for any formulation of posaconazole in geriatric patients. No clinically meaningful differences in the pharmacokinetics of posaconazole were observed in geriatric patients compared to younger adult patients during clinical trials [see Clinical Pharmacology (12.3)].Of the 230 patients treated with posaconazole delayed-release tablets, 38 (17%) were greater than 65 years of age.No overall differences in the pharmacokinetics and safety were observed between elderly and young subjects during clinical trials, but greater sensitivity of some older individuals cannot be ruled out.

HEPATIC IMPAIRMENT SUBSECTION.

8.7 Hepatic Impairment. After single oral dose of Noxafil(R) Oral Suspension 400 mg, the mean AUC was 43%, 27%, and 21% higher in subjects with mild (Child-Pugh Class A, N=6), moderate (Child-Pugh Class B, N=6), or severe (Child-Pugh Class C, N=6) hepatic impairment, respectively, compared to subjects with normal hepatic function (N=18). Compared to subjects with normal hepatic function, the mean Cmax was 1% higher, 40% higher, and 34% lower in subjects with mild, moderate, or severe hepatic impairment, respectively. The mean apparent oral clearance (CL/F) was reduced by 18%, 36%, and 28% in subjects with mild, moderate, or severe hepatic impairment, respectively, compared to subjects with normal hepatic function. The elimination half-life (t 1/2 was 27 hours, 39 hours, 27 hours, and 43 hours in subjects with normal hepatic function and mild, moderate, or severe hepatic impairment, respectively.It is recommended that no dose adjustment of posaconazole is needed in patients with mild to severe hepatic impairment (Child-Pugh Class A, B, or C) [see Dosage and Administration (2) and Warnings and Precautions (5.4)]. However, specific study has not been conducted with the delayed-release tablets.

HOW SUPPLIED SECTION.

16HOW SUPPLIED/STORAGE AND HANDLING. 16.1 HowSupplied. Posaconazole delayed-release tablets are yellow, modified, oval, convex tablets debossed with logo M inside square on one side and 100 on the opposite side containing 100 mg of posaconazole. Bottles of 60 . . . . . . . NDC 0406-7711-60. 16.2 Storage and Handling. Store at 20 to 25C (68 to 77F), excursions permitted to 15 to 30C (59 to 86F) [see USP Controlled Room Temperature].Dispense in tight, light-resistant container (as defined in USP) with child-resistant closure.

INDICATIONS & USAGE SECTION.

1INDICATIONS AND USAGE. Posaconazole delayed-release tablets are an azole antifungal indicated as follows: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 as follows: (1.2)Posaconazole delayed-release tablets: adults and pediatric patients 13 years of age and older 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 as follows: (1.2)Posaconazole delayed-release tablets: adults and pediatric patients 13 years of age and older 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 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 13 years of age and olderAdditional 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.. Posaconazole delayed-release tablets: adults and pediatric patients 13 years of age and older.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere 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 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 mothers clinical need for posaconazole delayed-release tablets and any potential adverse effects on the breastfed child from posaconazole delayed-release tablets or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

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

MICROBIOLOGY SECTION.

12.4 Microbiology. Mechanism of Action:Posaconazole blocks the synthesis of ergosterol, key component of the fungal cell membrane, through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14-demethylase responsible for the conversion of lanosterol to ergosterol in the fungal cell membrane. This results in an accumulation of methylated sterol precursors and depletion of ergosterol within the cell membrane thus weakening the structure and function of the fungal cell membrane. This may be responsible for the antifungal activity of posaconazole.. Resistance:Clinical isolates of Candida albicans and Candida glabrata with decreased susceptibility to posaconazole were observed in oral swish samples taken during prophylaxis with posaconazole and fluconazole, suggesting potential for development of resistance. These isolates also showed reduced susceptibility to other azoles, suggesting cross-resistance between azoles. The clinical significance of this finding is not known.. Antimicrobial Activity:Posaconazole has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1)].. Microorganisms:Aspergillus spp. and Candida spp. . Susceptibility Testing:For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisNo drug-related neoplasms were recorded in rats or mice treated with posaconazole for years at doses higher than the clinical dose. In 2-year carcinogenicity study, rats were given posaconazole orally at doses up to 20 mg/kg (females), or 30 mg/kg (males). These doses are equivalent to 3.9- or 3.5-times the exposure achieved with 400-mg twice daily Noxafil(R) Oral Suspension regimen, respectively, based on steady-state AUC in healthy volunteers administered high-fat meal (400-mg twice daily Noxafil(R) Oral Suspension regimen). In the mouse study, mice were treated at oral doses up to 60 mg/kg/day or 4.8-times the exposure achieved with 400-mg twice daily Noxafil(R) Oral Suspension regimen.MutagenesisPosaconazole was not genotoxic or clastogenic when evaluated in bacterial mutagenicity (Ames), chromosome aberration study in human peripheral blood lymphocytes, Chinese hamster ovary cell mutagenicity study, and mouse bone marrow micronucleus study.Impairment of FertilityPosaconazole had no effect on fertility of male rats at dose up to 180 mg/kg (1.7 the 400-mg twice daily Noxafil(R) Oral Suspension regimen based on steady-state plasma concentrations in healthy volunteers) or female rats at dose up to 45 mg/kg (2.2 the 400-mg twice daily Noxafil(R) Oral Suspension regimen).. 13.2 Animal Toxicology and/or Pharmacology. In nonclinical study using intravenous administration of posaconazole in very young dogs (dosed from to weeks of age), an increase in the incidence of brain ventricle enlargement was observed in treated animals as compared with concurrent control animals. No difference in the incidence of brain ventricle enlargement between control and treated animals was observed following the subsequent 5-month treatment-free period. There were no neurologic, behavioral or developmental abnormalities in the dogs with this finding, and similar brain finding was not seen with oral posaconazole administration to juvenile dogs (4 days to months of age). There were no drug-related increases in the incidence of brain ventricle enlargement when treated and control animals were compared in separate study of 10-week old dogs dosed with intravenous posaconazole for 13 weeks with 9-week recovery period or follow-up study of 31-week old dogs dosed for months.

PATIENT COUNSELING INFORMATION.

17PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).Important Administration InstructionsPosaconazole Delayed-Release TabletsAdvise patients that posaconazole delayed-release tablets must be swallowed whole and not divided, crushed, or chewed.Instruct patients that if they miss dose, they should take it as soon as they remember. If they do not remember until it is within 12 hours of the next dose, they should be instructed to skip the missed dose and go back to the regular schedule. Patients should not double their next dose or take more than the prescribed dose.Drug InteractionsAdvise patients to inform their physician immediately if they:develop severe diarrhea or vomiting. are currently taking drugs that are known to prolong the QTc interval and are metabolized through CYP3A4.are currently taking cyclosporine or tacrolimus, or they notice swelling in an arm or leg or shortness of breath.are taking other drugs or before they begin taking other drugs as certain drugs can decrease or increase the plasma concentrations of posaconazole. Serious and Potentially Serious Adverse ReactionsAdvise patients to inform their physician immediately if they:notice change in heart rate or heart rhythm, or have heart condition or circulatory disease. Posaconazole can be administered with caution to patients with potentially proarrhythmic conditions.are pregnant, plan to become pregnant, or are nursing.have liver disease or develop itching, nausea or vomiting, their eyes or skin turn yellow, they feelmore tired than usual or feel like they have the flu.have ever had an allergic reaction to other antifungal medicines such as ketoconazole, fluconazole, itraconazole, or voriconazole.Mallinckrodt, the M brand mark and the Mallinckrodt Pharmaceuticals logo are trademarks of Mallinckrodt company. (C) 2022 Mallinckrodt.Mylanta, Zantac, Nexium, and Reglan are trademarks of their respective owners.SpecGx LLCWebster Groves, MO 63119 USAwww.mallinckrodt.com or call 1-800-778-7898L20P21Revised: 05/2022Mallinckrodt(TM)PharmaceuticalsPHARMACIST: Dispense separate Patient Information to each patient. Patient Information available at: www.mallinckrodt.com/medguide/X30000254 or call 1-800-778-7898. develop severe diarrhea or vomiting. are currently taking drugs that are known to prolong the QTc interval and are metabolized through CYP3A4.. are currently taking cyclosporine or tacrolimus, or they notice swelling in an arm or leg or shortness of breath.. are taking other drugs or before they begin taking other drugs as certain drugs can decrease or increase the plasma concentrations of posaconazole.. notice change in heart rate or heart rhythm, or have heart condition or circulatory disease. Posaconazole can be administered with caution to patients with potentially proarrhythmic conditions.. are pregnant, plan to become pregnant, or are nursing.. have liver disease or develop itching, nausea or vomiting, their eyes or skin turn yellow, they feel. more tired than usual or feel like they have the flu.. have ever had an allergic reaction to other antifungal medicines such as ketoconazole, fluconazole, itraconazole, or voriconazole.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of posaconazole delayed-release tablets for the prophylaxis of invasive Aspergillus and Candida infections have been established in pediatric patients aged 13 years and older who are at high risk of developing these infections due to being severely immunocompromised, such as HSCT recipients with GVHD or those with hematologic malignancies with prolonged neutropenia from chemotherapy.Use of posaconazole in these age groups is supported by evidence from adequate and well controlled studies of posaconazole in adult and pediatric patients and additional pharmacokinetic and safety data in pediatric patients 13 years of age and older [see Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14)].The safety and effectiveness of posaconazole have not been established in pediatric patients younger than years of age.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.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Exposure Response Relationship Prophylaxis: In clinical studies of neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS) or hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD), wide range of plasma exposures to posaconazole was noted following administration of Noxafil(R) Oral Suspension. pharmacokinetic-pharmacodynamic analysis of patient data revealed an apparent association between average posaconazole concentrations (Cavg) and prophylactic efficacy (Table 17). lower Cavg may be associated with an increased risk of treatment failure, defined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections.Table 17: Noxafil(R) Oral Suspension Exposure Analysis (Cavg) in Prophylaxis Trials Prophylaxis in AML/MDSNeutropenic patients who were receiving cytotoxic chemotherapy for AML or MDS Prophylaxis in GVHDHSCT recipients with GVHD Cavg Range (ng/mL) Treatment FailureDefined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections(%) Cavg Range (ng/mL) Treatment Failure(%)Quartile 190-32254.722-55744.4Quartile 2322-49037.0557-91520.6Quartile 3490-73446.8915-156317.5Quartile 4734-220027.81563-365017.5Cavg the average posaconazole concentration when measured at steady state.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. General Pharmacokinetic Characteristics. Posaconazole delayed-release tablets exhibit dose proportional pharmacokinetics after single and multiple dosing up to 300 mg. The mean pharmacokinetic parameters of posaconazole at steady state following administration of posaconazole delayed-release tablets 300 mg twice daily on Day 1, then 300 mg once daily thereafter in healthy volunteers and in neutropenic patients who are receiving cytotoxic chemotherapy for AML or MDS or HSCT recipients with GVHD are shown in Table 20.Table 20: Arithmetic Mean (%CV) of Steady State PK Parameters in Healthy Volunteers and Patients Following Administration of Posaconazole Delayed-Release Tablets (300 mg)300 mg twice daily on Day 1, then 300 mg once daily thereafter AUC0-24 hr CavCav time-averaged concentrations (i.e., AUC0-24 hr/24hr) Cmax Cmin Tmax Median (minimum-maximum) (hr)t1/2 CL/F (ng.hr/mL)(ng/mL)(ng/mL)(ng/mL) (hr)(L/hr)Healthy12516182151276417854317.5Volunteers (25)(25)(21)(29)(3-6)(40)(26)Patients 50379001580209013104 (1.3-8.3)-9.39 (42)(42)(38)(50) (45)CV coefficient of variation expressed as percentage (%CV); AUC0-T Area under the plasma concentration-time curve from time zero to 24 hr; Cmax maximum observed concentration; Cmin minimum observed plasma concentration; Tmax time of maximum observed concentration; 1/2 terminal phase half-life; CL/F Apparent total body clearance. Absorption: . When given orally in healthy volunteers, posaconazole delayed-release tablets are absorbed with median Tmax of to hours. Steady-state plasma concentrations are attained by Day at the 300 mg dose (once daily after twice daily loading dose at Day 1). The absolute bioavailability of the oral delayed-release tablet is approximately 54% under fasted conditions. The Cmax and AUC of posaconazole following administration of posaconazole delayed-release tablets is increased 16% and 51%, respectively, when given with high-fat meal compared to fasted state (see Table 22). Table 22: Statistical Comparison of Plasma Pharmacokinetics of Posaconazole Following Single Oral Dose Administration of 300 mg Posaconazole Delayed-Release Tablet to Healthy Subjects under Fasting and Fed Conditions Fasting ConditionsFed Conditions(High-Fat Meal)48.5 fat Fed/FastingPharmacokinetic ParameterNMean (%CV)NMean (%CV)GMR (90% CI)Cmax (ng/mL)14 935 (34)161060 (25)1.16 (0.96, 1.41)AUC0-72hr (hrng/mL)1426200 (28)1638400 (18)1.51 (1.33, 1.72)Tmax Median (Min, Max) reported for Tmax (hr)145.00(3.00, 8.00)166.00(5.00, 24.00) N/AGMR=Geometric least-squares mean ratio; CI=Confidence interval. Concomitant administration of posaconazole delayed-release tablets with drugs affecting gastric pH or gastric motility did not demonstrate any significant effects on posaconazole pharmacokinetic exposure (see Table 23).Table 23: The Effect of Concomitant Medications that Affect the Gastric pH and Gastric Motility on the Pharmacokinetics of Posaconazole Delayed-Release Tablets in Healthy VolunteersCoadministered DrugAdministration ArmsChange in Cmax (ratio estimateRatio Estimate is the ratio of coadministered drug plus posaconazole to posaconazole alone for Cmax or AUC0-last. ;90% CI of the ratio estimate)Change in AUC0-last (ratio estimate;90% CI of the ratio estimate)Mylanta(R) Ultimate strength liquid (Increase in gastric pH)25.4 meq/5 mL, 20 mL6%(1.06; 0.90-1.26)4%(1.04; 0.90-1.20)Ranitidine (Zantac(R)) (Alteration in gastric pH) 150 mg (morning dose of 150 mg Ranitidine twice daily)4%(1.04; 0.88-1.23)3%(0.97; 0.84-1.12)Esomeprazole (Nexium(R)) (Increase in gastric pH)40 mg (every morning for days, Day -4 to 1)2%(1.02; 0.88-1.17)5%(1.05; 0.89-1.24)Metoclopramide (Reglan(R)) (Increase in gastric motility)15 mg four times daily for days (Day -1 and 1)14%(0.86, 0.73,1.02)7%(0.93, 0.803,1.07). Distribution:The mean volume of distribution of posaconazole after intravenous solution administration was 261 and ranged from 226-295 between studies and dose levels.Posaconazole is highly bound to human plasma proteins (>98%), predominantly to albumin.. Metabolism:Posaconazole primarily circulates as the parent compound in plasma. Of the circulating metabolites, the majority are glucuronide conjugates formed via UDP glucuronidation (phase enzymes). Posaconazole does not have any major circulating oxidative (CYP450 mediated) metabolites. The excreted metabolites in urine and feces account for ~17% of the administered radiolabeled dose.Posaconazole is primarily metabolized via UDP glucuronidation (phase enzymes) and is substrate for p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. summary of drugs studied clinically with the Noxafil(R) Oral Suspension or an early tablet formulation, which affect posaconazole concentrations, is provided in Table 27.Table 27: Summary of the Effect of Coadministered Drugs on Posaconazole in Healthy VolunteersCoadministered Drug (Postulated Mechanism of Interaction)Coadministered Drug Dose/SchedulePosaconazole Dose/ScheduleEffect on Bioavailability of PosaconazoleChange in Mean Cmax (ratio estimateRatio Estimate is the ratio of coadministered drug plus posaconazole to posaconazole alone for Cmax or AUC.; 90% CI of the ratio estimate)Change in Mean AUC(ratio estimate; 90% CI of the ratio estimate)Efavirenz(UDP-G Induction)400 mg once daily 10 and20 days400 mg (Noxafil(R) Oral Suspension) twice daily 10 and 20 days45% (0.55; 0.47-0.66)50%(0.50; 0.43-0.60)Fosamprenavir(unknown mechanism)700 mg twice daily 10 days200 mg once daily on the 1st day, 200 mg twice daily on the 2nd day, then 400 mg twice daily 8 Days21%0.79 (0.71-0.89)23%0.77 (0.68-0.87)Rifabutin(UDP-G Induction)300 mg once daily 17 days200 mg (tablets) once dailyx 10 daysThe tablet refers to non-commercial tablet formulation without polymer. 43%(0.57; 0.43-0.75)49%(0.51; 0.37-0.71)Phenytoin(UDP-G Induction)200 mg once daily 10 days200 mg (tablets) once dailyx 10 days 41%(0.59; 0.44-0.79)50%(0.50; 0.36-0.71). In vitro studies with human hepatic microsomes and clinical studies indicate that posaconazole is an inhibitor primarily of CYP3A4. clinical study in healthy volunteers also indicates that posaconazole is strong CYP3A4 inhibitor as evidenced by >5-fold increase in midazolam AUC. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole. summary of the drugs studied clinically, for which plasma concentrations were affected by posaconazole, is provided in Table 28 [see Contraindications (4) and Drug Interactions (7.1) including recommendations].Table 28: Summary of the Effect of Posaconazole on Coadministered Drugs in Healthy Adult Volunteers and PatientsCoadministered Drug(Postulated Mechanism of Interaction is Inhibition of CYP3A4 by posaconazole)Coadministered Drug Dose/SchedulePosaconazole Dose/ScheduleEffect on Bioavailability of Coadministered DrugsChange in Mean Cmax (ratio estimateRatio Estimate is the ratio of coadministered drug plus posaconazole to coadministered drug alone for Cmax or AUC.; 90% CI of the ratio estimate)Change in Mean AUC(ratio estimate; 90% CI of the ratio estimate)Sirolimus2-mg single oral dose400 mg (Noxafil(R) Oral Suspension) twice daily 16 days572%(6.72; 5.62-8.03)788%(8.88; 7.26-10.9)CyclosporineStable maintenance dose in heart transplant recipients200 mg (tablets) once daily 10 daysThe tablet refers to non-commercial tablet formulation without polymer. cyclosporine whole blood trough concentrationsCyclosporine dose reductions of up to 29% were requiredTacrolimus0.05-mg/kg single oral dose400 mg (Noxafil(R) Oral Suspension) twice daily 7 days121%(2.21; 2.01-2.42)358%(4.58; 4.03-5.19)Simvastatin 40-mg single oral dose 100 mg (Noxafil(R) Oral Suspension) once daily 13 daysSimvastatin841%(9.41, 7.13-12.44)Simvastatin Acid817%(9.17, 7.36-11.43)Simvastatin931%(10.31, 8.40-12.67)Simvastatin Acid634%(7.34, 5.82-9.25)200 mg (Noxafil(R) Oral Suspension) once daily 13 daysSimvastatin1041%(11.41, 7.99-16.29)Simvastatin Acid851%(9.51, 8.15-11.10)Simvastatin960%(10.60, 8.63-13.02)Simvastatin Acid748%(8.48, 7.04-10.23)Midazolam 0.4-mg single intravenous doseThe mean terminal half-life of midazolam was increased from hours to to 11 hours during coadministration with posaconazole. 200 mg (Noxafil(R) Oral Suspension) twice daily 7 days30%(1.3; 1.13-1.48)362%(4.62; 4.02-5.3)0.4-mg single intravenous dose 400 mg (Noxafil(R) Oral Suspension) twice daily 7 days62%(1.62; 1.41-1.86)524%(6.24; 5.43-7.16)2-mg single oral dose 200 mg (Noxafil(R) Oral Suspension) once daily 7 days169%(2.69; 2.46-2.93)470%(5.70; 4.82-6.74)2-mg single oral dose 400 mg (Noxafil(R) Oral Suspension) twice daily 7 days138%(2.38; 2.13-2.66)397%(4.97; 4.46-5.54)Rifabutin300 mg once daily 17 days200 mg (tablets) once daily 10 days 31%(1.31; 1.10-1.57)72%(1.72;1.51-1.95)Phenytoin200 mg once daily PO 10 days200 mg (tablets) once daily 10 days 16%(1.16; 0.85-1.57)16%(1.16; 0.84-1.59)Ritonavir100 mg once daily 14 days400 mg (Noxafil(R) Oral Suspension)twice daily 7 days49%(1.49; 1.04-2.15)80%(1.8;1.39-2.31)Atazanavir300 mg once daily 14 days400 mg (Noxafil(R) Oral Suspension) twice daily 7 days155%(2.55; 1.89-3.45)268%(3.68; 2.89-4.70)Atazanavir/ ritonavir boosted regimen300 mg/100 mg once daily 14 days400 mg (Noxafil(R) Oral Suspension) twice daily 7 days53%(1.53; 1.13-2.07)146%(2.46; 1.93-3.13)Additional clinical studies demonstrated that no clinically significant effects on zidovudine, lamivudine, indinavir, or caffeine were observed when administered with posaconazole 200 mg once daily; therefore, no dose adjustments are required for these coadministered drugs when coadministered with posaconazole 200 mg once daily.. Excretion:Following administration of Noxafil(R) Oral Suspension, posaconazole is predominantly eliminated in the feces (71% of the radiolabeled dose up to 120 hours) with the major component eliminated as parent drug (66% of the radiolabeled dose). Renal clearance is minor elimination pathway, with 13% of the radiolabeled dose excreted in urine up to 120 hours (<0.2% of the radiolabeled dose is parent drug).Posaconazole delayed-release tablet is eliminated with mean half-life (t 1/2 ranging between 26 to 31 hours.Specific Populations No clinically significant differences in the pharmacokinetics of posaconazole were observed based on age, sex, renal impairment, and indication.Race/Ethnicity:In population pharmacokinetic analysis of posaconazole, AUC was found to be 25% higher in Chinese patients relative to patients from other races/ethnicities. This higher exposure is not expected to be clinically relevant given the expected variability in posaconazole exposure.Patients Weighing More Than 120 kg:Weight has clinically significant effect on posaconazole clearance. Relative to 70 kg patients, the Cavg is decreased by 25% in patients greater than 120 kg. Patients administered posaconazole delayed-release tablets weighing more than 120 kg may be at higher risk for lower posaconazole plasma concentrations compared to lower weight patients [see Use in Specific Populations (8.10)].Pediatric PatientsA total of 12 patients 13 to 17 years of age received 600 mg/day (200 mg three times day) of Noxafil(R) Oral Suspension for prophylaxis of invasive fungal infections. Based on pharmacokinetic data in 10 of these pediatric patients, the mean steady-state Cav was similar between these patients and adults (>=18 years of age). In study of 136 neutropenic pediatric patients 11 months to less than 18 years treated with Noxafil(R) Oral Suspension, the exposure target of steady-state posaconazole Cavg between 500 ng/mL and less than 2,500 ng/mL was attained in approximately 50% of patients instead of the pre-specified 90% of patients.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.

POSTMARKETING EXPERIENCE SECTION.

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 population of uncertain size, it is not always possible to reliably estimate their frequency.Endocrine Disorders: Pseudoaldosteronism.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on findings from animal data, posaconazole delayed-release tablets may cause fetal harm when administered to pregnant women. Available data for use of posaconazole delayed-release tablets in pregnant women are insufficient to establish 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 Noxafil(R) Oral Suspension regimen based on steady-state plasma concentrations of posaconazole delayed-release tablets 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 times the exposure achieved with the 400 mg twice daily Noxafil(R) Oral Suspension regimen. Doses of >= 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 fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 to 4% and 15 to 20%, respectively.. Data Animal DataPosaconazole 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 through 15) at doses >=27 mg/kg (>=1.4 times the 400 mg twice daily Noxafil(R) 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 mg/kg, which is 0.7 times the exposure achieved with the 400 mg twice daily Noxafil(R) Oral Suspension regimen. No malformations were seen in rabbits dosed during organogenesis (Gestational Days through 19) at doses up to 80 mg/kg (5 times the exposure achieved with the 400 mg twice daily Noxafil(R) 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 times the clinical exposure) caused an increase in resorptions. In rabbits dosed at 80 mg/kg, reduction in body weight gain of females and reduction in litter size were seen.

RECENT MAJOR CHANGES SECTION.

Indications and Usage (1)06/2021 Dosage and Administration (2)06/2021 Warnings and Precautions (5)06/2021. Indications and Usage (1)06/2021 Dosage and Administration (2)06/2021 Contraindications (4)01/2022 Warnings and Precautions (5)01/2022.

RENAL IMPAIRMENT SUBSECTION.

8.6 Renal Impairment. Following single-dose administration of 400 mg of the Noxafil(R) Oral Suspension, there was no significant effect of mild (eGFR: 50-80 mL/min/1.73 m2, n=6) or moderate (eGFR: 20-49 mL/min/1.73 m2, n=6) renal impairment on posaconazole pharmacokinetics; therefore, no dose adjustment is required in patients with mild to moderate renal impairment. In subjects with severe renal impairment (eGFR: <20 mL/min/1.73 m2), the mean plasma exposure (AUC) was similar to that in patients with normal renal function (eGFR: >80 mL/min/1.73 m2); however, the range of the AUC estimates was highly variable (CV=96%) in these subjects with severe renal impairment as compared to that in the other renal impairment groups (CV<40%). Due to the variability in exposure, patients with severe renal impairment should be monitored closely for breakthrough fungal infections [see Dosage and Administration (2)]. Similar recommendations apply to posaconazole delayed-release tablets; however, specific study has not been conducted with the delayed-release tablets.

SPL UNCLASSIFIED SECTION.

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 13 years of age and olderAdditional 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.. Posaconazole delayed-release tablets: adults and pediatric patients 13 years of age and older.

USE IN SPECIFIC POPULATIONS SECTION.

8USE IN SPECIFIC POPULATIONS. Pregnancy: Based on animal data, may cause fetal harm. (8.1)Pediatrics: Safety and effectiveness in patients younger than years of age have not been established. (8.4)Severe renal impairment: Monitor closely for breakthrough fungal infections. (8.6). Pregnancy: Based on animal data, may cause fetal harm. (8.1). Pediatrics: Safety and effectiveness in patients younger than years of age have not been established. (8.4). Severe renal impairment: Monitor closely for breakthrough fungal infections. (8.6). 8.1 Pregnancy. Risk SummaryBased on findings from animal data, posaconazole delayed-release tablets may cause fetal harm when administered to pregnant women. Available data for use of posaconazole delayed-release tablets in pregnant women are insufficient to establish 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 Noxafil(R) Oral Suspension regimen based on steady-state plasma concentrations of posaconazole delayed-release tablets 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 times the exposure achieved with the 400 mg twice daily Noxafil(R) Oral Suspension regimen. Doses of >= 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 fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 to 4% and 15 to 20%, respectively.. Data Animal DataPosaconazole 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 through 15) at doses >=27 mg/kg (>=1.4 times the 400 mg twice daily Noxafil(R) 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 mg/kg, which is 0.7 times the exposure achieved with the 400 mg twice daily Noxafil(R) Oral Suspension regimen. No malformations were seen in rabbits dosed during organogenesis (Gestational Days through 19) at doses up to 80 mg/kg (5 times the exposure achieved with the 400 mg twice daily Noxafil(R) 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 times the clinical exposure) caused an increase in resorptions. In rabbits dosed at 80 mg/kg, reduction in body weight gain of females and reduction in litter size were seen.. 8.2 Lactation. Risk SummaryThere 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 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 mothers clinical need for posaconazole delayed-release tablets and any potential adverse effects on the breastfed child from posaconazole delayed-release tablets or from the underlying maternal condition.. 8.4 Pediatric Use. The safety and effectiveness of posaconazole delayed-release tablets for the prophylaxis of invasive Aspergillus and Candida infections have been established in pediatric patients aged 13 years and older who are at high risk of developing these infections due to being severely immunocompromised, such as HSCT recipients with GVHD or those with hematologic malignancies with prolonged neutropenia from chemotherapy.Use of posaconazole in these age groups is supported by evidence from adequate and well controlled studies of posaconazole in adult and pediatric patients and additional pharmacokinetic and safety data in pediatric patients 13 years of age and older [see Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14)].The safety and effectiveness of posaconazole have not been established in pediatric patients younger than years of age.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.. 8.5 Geriatric Use. No overall differences in the safety of posaconazole delayed-release tablets were observed between geriatric patients and younger adult patients in the clinical trials; therefore, no dosage adjustment is recommended for any formulation of posaconazole in geriatric patients. No clinically meaningful differences in the pharmacokinetics of posaconazole were observed in geriatric patients compared to younger adult patients during clinical trials [see Clinical Pharmacology (12.3)].Of the 230 patients treated with posaconazole delayed-release tablets, 38 (17%) were greater than 65 years of age.No overall differences in the pharmacokinetics and safety were observed between elderly and young subjects during clinical trials, but greater sensitivity of some older individuals cannot be ruled out.. 8.6 Renal Impairment. Following single-dose administration of 400 mg of the Noxafil(R) Oral Suspension, there was no significant effect of mild (eGFR: 50-80 mL/min/1.73 m2, n=6) or moderate (eGFR: 20-49 mL/min/1.73 m2, n=6) renal impairment on posaconazole pharmacokinetics; therefore, no dose adjustment is required in patients with mild to moderate renal impairment. In subjects with severe renal impairment (eGFR: <20 mL/min/1.73 m2), the mean plasma exposure (AUC) was similar to that in patients with normal renal function (eGFR: >80 mL/min/1.73 m2); however, the range of the AUC estimates was highly variable (CV=96%) in these subjects with severe renal impairment as compared to that in the other renal impairment groups (CV<40%). Due to the variability in exposure, patients with severe renal impairment should be monitored closely for breakthrough fungal infections [see Dosage and Administration (2)]. Similar recommendations apply to posaconazole delayed-release tablets; however, specific study has not been conducted with the delayed-release tablets.. 8.7 Hepatic Impairment. After single oral dose of Noxafil(R) Oral Suspension 400 mg, the mean AUC was 43%, 27%, and 21% higher in subjects with mild (Child-Pugh Class A, N=6), moderate (Child-Pugh Class B, N=6), or severe (Child-Pugh Class C, N=6) hepatic impairment, respectively, compared to subjects with normal hepatic function (N=18). Compared to subjects with normal hepatic function, the mean Cmax was 1% higher, 40% higher, and 34% lower in subjects with mild, moderate, or severe hepatic impairment, respectively. The mean apparent oral clearance (CL/F) was reduced by 18%, 36%, and 28% in subjects with mild, moderate, or severe hepatic impairment, respectively, compared to subjects with normal hepatic function. The elimination half-life (t 1/2 was 27 hours, 39 hours, 27 hours, and 43 hours in subjects with normal hepatic function and mild, moderate, or severe hepatic impairment, respectively.It is recommended that no dose adjustment of posaconazole is needed in patients with mild to severe hepatic impairment (Child-Pugh Class A, B, or C) [see Dosage and Administration (2) and Warnings and Precautions (5.4)]. However, specific study has not been conducted with the delayed-release tablets.. 8.8 Gender. The pharmacokinetics of posaconazole are comparable in males and females. No adjustment in the dosage of posaconazole delayed-release tablets is necessary based on gender.. 8.9 Race. The pharmacokinetic profile of posaconazole is not significantly affected by race. No adjustment in the dosage of posaconazole delayed-release tablets is necessary based on race.. 8.10 Weight. Pharmacokinetic modeling suggests that patients weighing greater than 120 kg may have lower posaconazole plasma drug exposure. It is, therefore, suggested to closely monitor for breakthrough fungal infections [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5WARNINGS AND PRECAUTIONS. Calcineurin-Inhibitor Toxicity: Posaconazole delayed-release tablets increase concentrations of cyclosporine or tacrolimus; reduce dose of cyclosporine and tacrolimus and monitor concentrations frequently. (5.1)Arrhythmias and QTc Prolongation: Posaconazole delayed-release tablets have 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 delayed-release tablets 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 delayed-release tablets 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 delayed-release tablets, with vincristine has been associated with neurotoxicity and other serious adverse reactions; reserve azole antifungals, including posaconazole delayed-release tablets, for patients receiving 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. (5.9)Venetoclax Toxicity: Concomitant administration of posaconazole delayed-release tablets with venetoclax may increase venetoclax toxicities, including the risk of tumor lysis syndrome, neutropenia, and serious infections; monitor for toxicity and reduce venetoclax dose. (4.6, 5.10, 7.16). Calcineurin-Inhibitor Toxicity: Posaconazole delayed-release tablets increase concentrations of cyclosporine or tacrolimus; reduce dose of cyclosporine and tacrolimus and monitor concentrations frequently. (5.1). Arrhythmias and QTc Prolongation: Posaconazole delayed-release tablets have 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 delayed-release tablets 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 delayed-release tablets 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 delayed-release tablets, with vincristine has been associated with neurotoxicity and other serious adverse reactions; reserve azole antifungals, including posaconazole delayed-release tablets, for patients receiving 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. (5.9). Venetoclax Toxicity: Concomitant administration of posaconazole delayed-release tablets with venetoclax may increase venetoclax toxicities, including the risk of tumor lysis syndrome, neutropenia, and serious infections; monitor for toxicity and reduce venetoclax dose. (4.6, 5.10, 7.16). 5.1 Calcineurin-Inhibitor Toxicity. Concomitant administration of posaconazole delayed-release tablets 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 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 12-hour period were recorded at baseline and steady-state from 173 healthy male and female volunteers (18-85 years of age) administered Noxafil(R) Oral Suspension 400 mg twice daily with 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. decrease in the QTc(F) interval (-3 msec) was also observed in 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 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 Noxafil(R) Oral Suspension 800 mg daily (400 mg twice daily or 200 mg four times 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.. 5.5Renal Impairment. Due to the variability in exposure with posaconazole delayed-release tablets, Noxafil(R) Oral Suspension, and Noxafil(R) PowderMix for Delayed-Release Oral Suspension, patients with severe renal impairment should be monitored closely for breakthrough fungal infections [see Dosage and Administration (2.9) and Use in Specific Populations (8.6)].. 5.6 Midazolam Toxicity. Concomitant administration of posaconazole delayed-release tablets 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)].. 5.7Vincristine Toxicity. Concomitant administration of azole antifungals, including posaconazole delayed-release tablets, 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 delayed-release tablets, for patients receiving vinca alkaloid, including vincristine, who have no alternative antifungal treatment options [see Drug Interactions (7.10)].. 5.9 Breakthrough Fungal Infections. Patients who have severe diarrhea or vomiting should be monitored closely for breakthrough fungal infections when receiving posaconazole delayed-release tablets. 5.10 Venetoclax Toxicity. Concomitant administration of posaconazole delayed-release tablets, 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 delayed-release tablets 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 delayed-release tablets with venetoclax [see Drug Interactions (7.16)]. Refer to the venetoclax prescribing information for dosing instructions.