{ "meta": { "disclaimer": "Do not rely on openFDA to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. We may limit or otherwise restrict your access to the API in line with our Terms of Service.", "terms": "https://open.fda.gov/terms/", "license": "https://open.fda.gov/license/", "last_updated": "2026-09-23", "results": { "skip": 0, "limit": 1, "total": 1 } }, "results": [ { "spl_product_data_elements": [ "posaconazole posaconazole POSACONAZOLE POSACONAZOLE POLYOXYL 35 CASTOR OIL SODIUM BENZOATE TRISODIUM CITRATE DIHYDRATE CITRIC ACID MONOHYDRATE GLYCERIN SORBITOL TITANIUM DIOXIDE WATER HYDROXYETHYL CELLULOSE (2000 MPA.S AT 1%) DIMETHICONE, UNSPECIFIED CHERRY BRANDY" ], "recent_major_changes": [ "Dosage and Administration ( 2 ) 1/2026" ], "indications_and_usage": [ "1 INDICATIONS AND USAGE Posaconazole is an azole antifungal indicated as follows: • Posaconazole is indicated for the prophylaxis of invasive Aspergillus and Candida infections in adults and pediatric patients 13 years of age and older 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. ( 1.2 ) • Posaconazole oral suspension is indicated for the treatment of oropharyngeal candidiasis (OPC), including OPC refractory (rOPC) to itraconazole and/or fluconazole in adults and pediatric patients aged 13 years and older. ( 1.3 ) 1.2 Prophylaxis of Invasive Aspergillus and Candida Infections Posaconazole is indicated for the prophylaxis of invasive Aspergillus and Candida infections in adults and pediatric patients 13 years of age and older 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. 1.3 Treatment of Oropharyngeal Candidiasis Including Oropharyngeal Candidiasis Refractory to Itraconazole and/or Fluconazole Posaconazole oral suspension is indicated for the treatment of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole in adults and pediatric patients 13 years of age and older." ], "dosage_and_administration": [ "2 DOSAGE AND ADMINISTRATION • Posaconazole formulations are supplied in different dose strengths of posaconazole, are approved for different indications, age groups, and weights, have different dosages and duration of therapy; and have different preparation and administration instructions. ( 2.1 ) • Posaconazole oral suspension is not substitutable with posaconazole delayed-release tablets or posaconazole powder 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 oral suspension with a full meal. ( 2.1 ) • See the full prescribing information for important administration instructions for posaconazole oral suspension ( 2.8 ) • For adult and pediatric patients aged 13 years of age and older, see the Full Prescribing Information for dosing recommendations for posaconazole oral suspension based on the indication, age, and weight associated with the dosage form. ( 1.2 , 1.3 , 2.1 , 2.2 , 2.3 , 2.4 ) 2.1 Important Administration Instructions Posaconazole injection, posaconazole delayed-release tablets, posaconazole oral suspension and posaconazole PowderMix for delayed-release oral suspension are supplied in different dose strengths of posaconazole, are approved for different indications, age groups and weights; have different dosages and duration of therapy; and have different preparation and administration instructions. Therefore, select the recommended dosage form based on the indication, age group, and weight and carefully follow the recommended dosage, preparation and administration instructions described for each product [see Dosage and Administration ( 2.2 to 2.11 )] , and the following important administration instructions described below. Non-substitutable: Posaconazole oral suspension is not substitutable with posaconazole delayed-release tablets or posaconazole powder 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 oral suspension : • Administer with a full meal or with a liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale) in patients who cannot eat a full meal [see Dosage and Administration 2.8 )] . 2.2 Recommended Dosage of Posaconazole Oral Suspension in Adult Patients The recommended dosage of Posaconazole oral suspension in adult patients for the treatment of invasive aspergillosis, prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised, or for the treatment of oropharyngeal candidiasis (OPC) is shown in Table 1 [see Dosage and Administration ( 2.8 , 2.9 ) and Clinical Pharmacology ( 12.3 )]. Table 1: Recommended Dosage of Posaconazole Oral Suspension in Adult Patients Dosage Duration of Therapy Prophylaxis of Invasive Aspergillus and Candida Infections Posaconazole Oral Suspension: 200 mg (5 mL) three times a day. Maintenance dose : Duration of therapy is based on recovery from neutropenia or immunosuppression. Oropharyngeal Candidiasis (OPC) Posaconazole Oral Suspension: Loading dose : 100 mg (2.5 mL) twice a day on the first day. Maintenance dose : 100 mg (2.5 mL) once a day thereafter. Loading dose : 1 day Maintenance dose : 13 days OPC Refractory (rOPC) to Itraconazole and/or Fluconazole Posaconazole Oral Suspension: 400 mg (10 mL) twice a day. Duration of therapy is based on the severity of the patient’s underlying disease and clinical response. 2.3 Recommended Dosage of Posaconazole Oral Suspension for the Prophylaxis of Invasive Aspergillus and Candida Infections in Pediatric Patients 13 Years of Age and Older The recommended dosage of posaconazole oral suspension for pediatric patients ages 13 years of age and older for the prophylaxis of invasive Aspergillus and Candida infections is shown in Table 3 . Table 3: Recommended Dosage of Posaconazole Oral Suspension for the Prophylaxis of Invasive Aspergillus and Candida Infections in Pediatric Patients (13 Years of Age and Older) Recommended Pediatric Dosage of Posaconazole Oral Suspension Duration of Therapy 200 mg (5 mL) three times a day Duration of therapy is based on recovery from neutropenia or immunosuppression . 2.4 Recommended Dosage of Posaconazole Oral Suspension for the Treatment of Oropharyngeal Candidiasis in Pediatric Patients 13 Years of Age and Older The recommended dosage of posaconazole oral suspension for the treatment of oropharyngeal candidiasis (OPC) and OPC refractory (rOPC) to itraconazole and/or fluconazole in pediatric patients 13 years of age and older is shown in Table 6. The posaconazole injection, posaconazole delayed-release tablets, and posaconazole PowderMix for delayed-release oral suspension products are not approved for the treatment of oropharyngeal candidiasis in pediatric patients. Table 6: Recommended Dosage of Posaconazole Oral Suspension for the Treatment of OPC and rOPC in Pediatric Patients (13 Years of Age and Older) Recommended Pediatric Dosage of Posaconazole Oral Suspension Duration of Therapy Oropharyngeal Candidiasis (OPC) Loading dose : 100 mg (2.5 mL) twice daily on the first day Maintenance dose : 100 mg (2.5 mL) once daily Loading dose : 1 day Maintenance dose : 13 days OPC Refractory (rOPC) to Itraconazole and/or Fluconazole 400 mg (10 mL) twice daily Duration of therapy is based on the severity of the patient’s underlying disease and clinical response. 2.8 Administration Instructions for Posaconazole Oral Suspension Administer posaconazole oral suspension with a full meal or with a liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale) in patients who cannot eat a full meal. For patients who cannot eat a full meal, use posaconazole delayed-release tablets instead of the posaconazole oral suspension for the prophylaxis of invasive Aspergillus and Candida infections in those who are at high risk of developing these infections due to being severely immunocompromised. This is because posaconazole delayed-release tablets provide higher plasma drug exposures than posaconazole oral suspension under fasted condition [see Dosage and Administration ( 2.1 )] . For those patients using the posaconazole oral suspension: • Shake posaconazole oral suspension well before use. • Administer with measured dosing spoon provided in the package (see Figure 1). Figure 1: Measured dosing spoon provided in the package marked for doses of 2.5 mL and 5 mL. • Administer each dose of posaconazole oral suspension during or immediately (i.e., within 20 minutes) following a full meal [see Clinical Pharmacology ( 12.3 )] . • In patients who cannot eat a full meal and for whom posaconazole delayed-release tablets or posaconazole injection are not options, administer each dose of posaconazole oral suspension with a liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale). If these patients cannot tolerate an oral nutritional supplement or an acidic carbonated beverage either use: o An alternative antifungal therapy, or o Posaconazole oral suspension and closely monitor patients for breakthrough fungal infections. • Rinse the spoon with water after each administration and before storage. Figure 1 - Measured dosing spoon 2.9 Non-substitutability between Posaconazole Oral Suspension and Other Formulations Posaconazole oral suspension is not substitutable with posaconazole delayed-release tablets or posaconazole powder 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 )] . 2.11 Dosage Modifications in Patients with Renal Impairment The recommended dosage of posaconazole oral suspension is the same in patients with renal impairment compared to those with normal renal function." ], "dosage_and_administration_table": [ "
DosageDuration of Therapy
Prophylaxis of Invasive Aspergillus and Candida Infections
Posaconazole Oral Suspension: 200 mg (5 mL) three times a day.Maintenance dose:Duration of therapy is based on recovery from neutropenia or immunosuppression.
Oropharyngeal Candidiasis (OPC)
Posaconazole Oral Suspension:Loading dose: 100 mg (2.5 mL) twice a day on the first day.Maintenance dose: 100 mg (2.5 mL) once a day thereafter. Loading dose: 1 day Maintenance dose: 13 days
OPC Refractory (rOPC) to Itraconazole and/or Fluconazole
Posaconazole Oral Suspension: 400 mg (10 mL) twice a day.Duration of therapy is based on the severity of the patient’s underlying disease and clinical response.
", "
Recommended Pediatric Dosage of Posaconazole Oral SuspensionDuration of Therapy
200 mg (5 mL) three times a dayDuration of therapy is based on recovery from neutropenia or immunosuppression.
", "
Recommended Pediatric Dosage of Posaconazole Oral SuspensionDuration of Therapy
Oropharyngeal Candidiasis (OPC)
Loading dose:100 mg (2.5 mL) twice daily on the first dayMaintenance dose:100 mg (2.5 mL) once dailyLoading dose:1 dayMaintenance dose:13 days
OPC Refractory (rOPC) to Itraconazole and/or Fluconazole
400 mg (10 mL) twice dailyDuration of therapy is based on the severity of the patient’s underlying disease and clinical response.
" ], "dosage_forms_and_strengths": [ "3 DOSAGE FORMS AND STRENGTHS 4,200 mg/105 mL (40 mg/mL) of posaconazole: White to off-white, cherry brandy flavored suspension in amber glass bottles with child-resistant closures. Posaconazole oral suspension: 40 mg per mL ( 3 )" ], "contraindications": [ "4 CONTRAINDICATIONS • Known hypersensitivity to posaconazole or other azole antifungal agents. ( 4.1 ) • Coadministration of posaconazole with the following drugs is contraindicated; posaconazole increases concentrations and toxicities of: • Sirolimus ( 4.2 , 7.2 ) • 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 , 7.2 ) • Ergot alkaloids ( 4.5 , 7.2 ) • Venetoclax: In patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) at initiation and during the ramp-up phase ( 4.6 , 5.11 , 7.2 ) 4.1 Hypersensitivity Posaconazole is contraindicated in persons with known hypersensitivity to posaconazole or other azole antifungal agents. 4.2 Use with Sirolimus Posaconazole is contraindicated with sirolimus. Concomitant administration of posaconazole with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity [see Drug Interactions ( 7.2 ) and Clinical Pharmacology ( 12.3 )] . 4.3 QT Prolongation with Concomitant Use with CYP3A4 Substrates Posaconazole is contraindicated with CYP3A4 substrates that prolong the QT interval. Concomitant administration of posaconazole with the CYP3A4 substrates, pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and cases of torsades de pointes [see Warnings and Precautions ( 5.2 ) and Drug Interactions ( 7.2 )] . 4.4 HMG-CoA Reductase Inhibitors Primarily Metabolized Through CYP3A4 Coadministration with the HMG-CoA reductase inhibitors that are primarily metabolized through CYP3A4 (e.g., atorvastatin, lovastatin, and simvastatin) is contraindicated since increased plasma concentration of these drugs can lead to rhabdomyolysis [see Drug Interactions ( 7.2 ) 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 ( 7.2 )] . 4.6 Use with Venetoclax Coadministration of posaconazole with venetoclax at initiation and during the ramp-up phase is contraindicated in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) due to the potential for increased risk of tumor lysis syndrome [see Warnings and Precautions ( 5.11 ) and Drug Interactions ( 7.2 )] ." ], "warnings_and_cautions": [ "5 WARNINGS AND PRECAUTIONS • Calcineurin-Inhibitor Toxicity : Posaconazole increases concentrations of cyclosporine or tacrolimus; reduce dose of cyclosporine and tacrolimus and monitor concentrations frequently. ( 5.1 ) • Arrhythmias and QTc Prolongation : Posaconazole has been shown to prolong the QTc interval and cause cases of TdP. Administer with caution to patients with potentially proarrhythmic conditions. Do not administer with drugs known to prolong QTc interval and metabolized through CYP3A4. ( 5.2 , 7.2 ) • Electrolyte Disturbances : Monitor and correct, especially those involving potassium (K + ), magnesium (Mg ++ ), and calcium (Ca ++ ), before and during posaconazole therapy. ( 5.3 ) • Pseudoaldosteronism : Manifested by the onset or worsening of hypertension, and abnormal laboratory findings. Monitor blood pressure and potassium levels, and manage as necessary. ( 5.4 ) • Hepatic Toxicity : Elevations in liver tests may occur. Discontinuation should be considered in patients who develop abnormal liver tests or monitor liver tests during treatment. ( 5.5 ) • Concomitant Use with Midazolam : Posaconazole can prolong hypnotic/sedative effects. Monitor patients and benzodiazepine receptor antagonists should be available. ( 5.7 , 7.2 ) • Vincristine Toxicity : Concomitant administration of azole antifungals, including posaconazole, with vincristine has been associated with neurotoxicity and other serious adverse reactions; reserve azole antifungals, including posaconazole, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options. ( 5.8 , 7.2 ) • Breakthrough Fungal Infections : Monitor patients with severe diarrhea or vomiting when receiving posaconazole oral suspension. ( 5.10 ) • Venetoclax Toxicity : Concomitant administration of posaconazole with venetoclax may increase venetoclax toxicities, including the risk of tumor lysis syndrome, neutropenia, and serious infections; monitor for toxicity and reduce venetoclax dose. ( 4.6 , 5.11 , 7.2 ) 5.1 Calcineurin-Inhibitor Toxicity Concomitant administration of posaconazole with cyclosporine or tacrolimus increases the whole blood trough concentrations of these calcineurin-inhibitors [see Drug Interactions ( 7.2 ) and Clinical Pharmacology ( 12.3 )]. Nephrotoxicity and leukoencephalopathy (including deaths) have been reported in clinical efficacy studies in patients with elevated cyclosporine or tacrolimus concentrations. Frequent monitoring of tacrolimus or cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus or cyclosporine dose adjusted accordingly. 5.2 Arrhythmias and QT Prolongation Some azoles, including posaconazole, have been associated with prolongation of the QT interval on the electrocardiogram. In addition, cases of torsades de pointes have been reported in patients taking posaconazole. Results from a multiple time-matched ECG analysis in healthy volunteers did not show any increase in the mean of the QTc interval. Multiple, time-matched ECGs collected over a 12-hour period were recorded at baseline and steady-state from 173 healthy male and female volunteers (18 to 85 years of age) administered posaconazole oral suspension 400 mg twice daily with a high-fat meal. In this pooled analysis, the mean QTc (Fridericia) interval change from baseline was –5 msec following administration of the recommended clinical dose. A decrease in the QTc(F) interval (–3 msec) was also observed in a small number of subjects (n=16) administered placebo. The placebo-adjusted mean maximum QTc(F) interval change from baseline was <0 msec (–8 msec). No healthy subject administered posaconazole had a QTc(F) interval ≥500 msec or an increase ≥60 msec in their QTc(F) interval from baseline. Posaconazole should be administered with caution to patients with potentially proarrhythmic conditions. Do not administer with drugs that are known to prolong the QTc 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 Pseudoaldosteronism Pseudoaldosteronism, manifested by the onset of hypertension or worsening of hypertension, and abnormal laboratory findings (hypokalemia, low serum renin and aldosterone, and elevated 11-deoxycortisol), has been reported with posaconazole use in the postmarket setting. Monitor blood pressure and potassium levels and manage as necessary. Management of pseudoaldosteronism may include discontinuation of posaconazole, substitution with an appropriate antifungal drug that is not associated with pseudoaldosteronism, or use of aldosterone receptor antagonists. 5.5 Hepatic Toxicity Hepatic reactions (e.g., mild to moderate elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin, and/or clinical hepatitis) have been reported in clinical trials. The elevations in liver tests were generally reversible on discontinuation of therapy, and in some instances these tests normalized without drug interruption. Cases of more severe hepatic reactions including cholestasis or hepatic failure including deaths have been reported in patients with serious underlying medical conditions (e.g., hematologic malignancy) during treatment with posaconazole. These severe hepatic reactions were seen primarily in subjects receiving the posaconazole oral suspension 800 mg daily (400 mg twice daily or 200 mg four times a day) in clinical trials. Liver tests should be evaluated at the start of and during the course of posaconazole therapy. Patients who develop abnormal liver tests during posaconazole therapy should be monitored for the development of more severe hepatic injury. Patient management should include laboratory evaluation of hepatic function (particularly liver tests and bilirubin). Discontinuation of posaconazole must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to posaconazole. 5.6 Renal Impairment Due to the variability in exposure with posaconazole oral suspension, patients with severe renal impairment should be monitored closely for breakthrough fungal infections [see Dosage and Administration ( 2.11 ) and Use in Specific Populations ( 8.6 )]. 5.7 Midazolam Toxicity Concomitant administration of posaconazole with midazolam increases the midazolam plasma concentrations by approximately 5-fold. Increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects. Patients must be monitored closely for adverse effects associated with high plasma concentrations of midazolam and benzodiazepine receptor antagonists must be available to reverse these effects [see Drug Interactions ( 7.2 ) and Clinical Pharmacology ( 12.3 )] . 5.8 Vincristine Toxicity Concomitant administration of azole antifungals, including posaconazole, with vincristine has been associated with neurotoxicity and other serious adverse reactions, including seizures, peripheral neuropathy, syndrome of inappropriate antidiuretic hormone secretion, and paralytic ileus. Reserve azole antifungals, including posaconazole, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options [see Drug Interactions ( 7.2 )] . 5.10 Breakthrough Fungal Infections Patients who have severe diarrhea or vomiting should be monitored closely for breakthrough fungal infections when receiving posaconazole. 5.11 Venetoclax Toxicity Concomitant administration of posaconazole, a strong CYP3A4 inhibitor, with venetoclax may increase venetoclax toxicities, including the risk of tumor lysis syndrome (TLS), neutropenia, and serious infections. In patients with CLL/SLL, administration of posaconazole during initiation and the ramp-up phase of venetoclax is contraindicated [see Contraindications ( 4.6 )] . Refer to the venetoclax labeling for safety monitoring and dose reduction in the steady daily dosing phase in CLL/SLL patients. For patients with acute myeloid leukemia (AML), dose reduction and safety monitoring are recommended across all dosing phases when coadministering posaconazole with venetoclax [see Drug Interactions ( 7.2 )] . Refer to the venetoclax prescribing information for dosing instructions." ], "adverse_reactions": [ "6 ADVERSE REACTIONS The following serious and otherwise important adverse reactions are discussed in detail in another section of the labeling: • Arrhythmias and QT Prolongation [see Warnings and Precautions ( 5.2 )] • Electrolyte Disturbances [see Warnings and Precautions ( 5.3 )] • Pseudoaldosteronism [see Warnings and Precautions ( 5.4 )] • Hepatic Toxicity [see Warnings and Precautions ( 5.5 )] • Adult Patients: Common adverse reactions in studies with posaconazole in adults are diarrhea, nausea, fever, vomiting, headache, coughing, and hypokalemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of posaconazole cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials Safety Experience with Posaconazole Oral Suspension: The safety of posaconazole oral suspension has been assessed in 1,844 patients, including: • 605 patients in the active-controlled studies for the prophylaxis of invasive Aspergillus and Candida infections • 557 patients in the active-controlled OPC studies (not refractory to itraconazole or fluconazole) • 239 patients in refractory OPC studies (refractory to itraconazole or fluconazole) (rOPC), and • 443 patients in other patient populations These studies included immunocompromised patients (e.g., patients with hematological malignancy, neutropenia post-chemotherapy, GVHD post HSCT, and HIV infection), as well as non-neutropenic patients. This patient population was 71% male, had a mean age of 42 years (range 8 to 84 years, 6% of patients were ≥65 years of age and 1% was <18 years of age), and were 64% White, 14% Black, 16% Hispanic. Posaconazole oral suspension therapy was given to 171 patients for ≥6 months, including 58 patients who received posaconazole oral suspension therapy for ≥12 months. Table 10 presents adverse reactions observed at an incidence of >10% in the studies for prophylaxis of invasive Aspergillus and Candida infections. Table 11 presents adverse reactions observed at an incidence of at least 10% in the OPC/rOPC studies. Prophylaxis of Invasive Aspergillus and Candida Infections (posaconazole oral suspension) : In the two randomized, comparative studies for prophylaxis Aspergillus and Candida infections in those at high risk of developing these infections due to being severely immunocompromised (Posaconazole Oral Suspension Study 1 and 2), the safety of posaconazole oral suspension 200 mg three times a day was compared to fluconazole 400 mg once daily or itraconazole 200 mg twice a day in severely immunocompromised patients. The most frequently reported adverse reactions (>30%) in these trials were fever, diarrhea, and nausea. The most common adverse reactions leading to discontinuation of posaconazole oral suspension were GI adverse reactions, specifically, nausea (2%), vomiting (2%), and increased hepatic enzymes (2%). Table 10: Adverse Reactions in at least 10% of Patients Receiving Posaconazole Oral Suspension for the Prophylaxis of Invasive Aspergillus and Candida Infections Adverse Reactions Posaconazole Oral Suspension n=605 (%) Fluconazole n=539 (%) Itraconazole n=58 (%) Percentage of Patients Reporting any Adverse Reaction 98 99 100 Fever 45 47 55 Diarrhea 42 39 60 Nausea 38 37 52 Hypokalemia 30 26 52 Thrombocytopenia 29 27 34 Vomiting 29 32 41 Headache 28 26 40 Abdominal Pain 27 27 36 Anemia 25 23 28 Coughing 24 24 24 Neutropenia 23 23 40 Constipation 21 17 17 Dyspnea 20 22 26 Rigors 20 16 29 Rash 19 18 43 Hypertension 18 16 5 Hypomagnesemia 18 16 19 Fatigue 17 18 9 Insomnia 17 17 19 Musculoskeletal Pain 16 15 16 Anorexia 15 17 28 Edema Legs 15 12 19 Epistaxis 14 14 21 Hypotension 14 15 17 Pharyngitis 12 11 21 Tachycardia 12 14 5 Arthralgia 11 12 9 Dizziness 11 10 9 Hyperglycemia 11 14 3 Petechiae 11 10 16 Pruritus 11 12 19 Back Pain 10 12 7 Bilirubinemia 10 9 19 Dyspepsia 10 9 10 Vaginal Hemorrhage Percentage of sex-specific adverse reactions are based on the number of males/females. 10 9 12 Treatment of Nonrefractory OPC and Refractory OPC (posaconazole oral suspension) In two randomized comparative studies for the treatment of nonrefractory OPC, the safety of posaconazole oral suspension (less than or equal to 400 mg once daily) in 557 HIV-infected patients was compared to the safety of fluconazole (100 mg once daily) in 262 HIV-infected patients. An additional 239 HIV-infected patients with refractory OPC (rOPC) received posaconazole oral suspension in two non-comparative trials for rOPC. Of these patients, 149 received the 800 mg/day dosage and the remainder received the less than or equal to 400 mg once daily dosage. In the nonrefractory OPC and rOPC studies, the most common adverse reactions in patients treated with posaconazole oral suspension were fever, diarrhea, nausea, headache, vomiting, and coughing. Adverse reactions were reported more frequently in the studies of patients with refractory OPC. Among these highly immunocompromised patients with advanced HIV disease, serious adverse reactions were reported in 55% (132/239) of posaconazole oral suspension-treated patients. The most commonly reported serious adverse reactions were fever (13%) and neutropenia (10%). Table 11: Adverse Reactions in at least 10% of Patients Receiving Posaconazole Oral Suspension for the Treatment of Nonrefractory and Refractory OPC Adverse Reactions Controlled OPC Pool Refractory OPC Pool Posaconazole Oral Suspension Fluconazole Posaconazole Oral Suspension n=557 (%) n=262 (%) n=239 (%) Percentage of Patients that Reported any Adverse Reaction Based on patients reporting adverse reactions at least once during the study, without regard to relationship to treatment. Patients may have reported more than 1 adverse reaction. 64 67 92 Diarrhea 10 13 29 Nausea 9 11 29 Headache 8 9 20 Vomiting 7 7 28 Fever 6 8 34 Abdominal Pain 5 6 18 Neutropenia 4 3 16 Coughing 3 4 25 Fatigue 3 5 13 Herpes Simplex 3 3 11 Pneumonia 3 2 10 Rash 3 4 15 Anemia 2 2 14 Anorexia 2 2 19 Asthenia 2 2 13 Sweating Increased 2 2 10 Candidiasis, Oral 1 <1 12 Dehydration 1 3 11 Dyspnea 1 3 12 Insomnia 1 1 16 Pain 1 1 11 Weight Decrease 1 <1 14 Rigors <1 2 12 OPC=oropharyngeal candidiasis Additional Adverse Reactions Reported in Less Than 5% of Posaconazole-Treated Patients in Clinical Trials Other clinically significant adverse reactions reported in less than 5% of patients in clinical trials of posaconazole are listed below: • Blood and Lymphatic System Disorders: hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, neutropenia aggravated • Endocrine Disorders: adrenal insufficiency • Nervous System Disorders: paresthesia • Immune System Disorders: allergic reaction [see Contraindications ( 4.1 )] • Cardiac Disorders: torsades de pointes [see Warnings and Precautions ( 5.2 )] • Vascular Disorders: pulmonary embolism • Gastrointestinal Disorders: pancreatitis • Liver and Biliary System Disorders: hepatic enzymes increased, hepatic function abnormal, hepatitis, hepatomegaly, jaundice • Renal & Urinary System Disorders: renal failure acute Liver Test Abnormalities in the Clinical Trials of Posaconazole Oral Suspension Liver Test Abnormalities in the Clinical Trials with Posaconazole Oral Suspension for Prophylaxis of Invasive Aspergillus and Candida Infections In the prophylaxis of invasive Aspergillus and Candida infections studies, the number and percentage of patients with changes in liver tests from Common Toxicity Criteria (CTC) Grade 0, 1, or 2 at baseline to Grade 3 or 4 at the end of the studies is presented in Table 12. Table 12: Changes in Liver Test Results from CTC Grade 0, 1, or 2 at Baseline to Grade 3 or 4 in Prophylaxis of Invasive Aspergillus and Candida Infections Studies (Posaconazole Oral Suspension Study 1 and Study 2). Number (%) of Patients with Change Change from Grade 0 to 2 at baseline to Grade 3 or 4 during the study. These data are presented in the form X/Y, where X represents the number of patients who met the criterion as indicated, and Y represents the number of patients who had a baseline observation and at least one post-baseline observation. Posaconazole Oral Suspension Study 1 Laboratory Parameter Posaconazole Oral Suspension n=301 Fluconazole n=299 AST 11/266 (4) 13/266 (5) ALT 47/271 (17) 39/272 (14) Bilirubin 24/271 (9) 20/275 (7) Alkaline Phosphatase 9/271 (3) 8/271 (3) Posaconazole Oral Suspension Study 2 Laboratory Parameter Posaconazole Oral Suspension (n=304) Fluconazole/Itraconazole (n=298) AST 9/286 (3) 5/280 (2) ALT 18/289 (6) 13/284 (5) Bilirubin 20/290 (7) 25/285 (9) Alkaline Phosphatase 4/281 (1) 1/276 (<1) Liver Test Abnormalities in the Clinical Trials with Posaconazole Oral Suspension for the Treatment of OPC The number and percentage of patients treated for OPC with clinically significant liver test abnormalities at any time during the studies is provided in Table 13 (liver test abnormalities were present in some of these patients prior to initiation of the study drug). Table 13: Clinically Significant Liver Test Abnormalities without Regard to Baseline Value (Posaconazole Oral Suspension Studies for the Treatment of OPC) Laboratory Test Nonrefractory OPC Refractory OPC Posaconazole Oral Suspension Fluconazole Posaconazole Oral Suspension n=557 (%) n=262 (%) n=239 (%) ALT > 3.0 × ULN 16/537 (3) 13/254 (5) 25/226 (11) AST > 3.0 × ULN 33/537 (6) 26/254 (10) 39/223 (17) Total Bilirubin > 1.5 × ULN 15/536 (3) 5/254 (2) 9/197 (5) Alkaline Phosphatase > 3.0 × ULN 17/535 (3) 15/253 (6) 24/190 (13) ALT= Alanine Aminotransferase; AST= Aspartate Aminotransferase. Liver Test Abnormalities in the Clinical Trials with Posaconazole Oral Suspension for the Treatment of Invasive Aspergillosis The number and percentage of patients treated for invasive aspergillosis with clinically significant liver test abnormalities at any time during the Aspergillosis Treatment Study is provided in Table 14 . Liver test abnormalities present prior to the initiation of study drug included: ALT (22% of the patients), AST (13% of the patients), and bilirubin (13% of the patients). Table 14: Changes in Liver Test Results from CTC Grade 0, 1, or 2 at Baseline to Grade 3 or 4 (Aspergillosis Treatment Study) Number (%) of Patients with Change Change from Grade 0 to 2 at baseline to Grade 3 or 4 during the study. These data are presented in the form n/N, where n represents the number of patients who met the criterion as indicated, and N represents the number of patients who had a baseline observation and at least one post-baseline observation. Laboratory Parameter Posaconazole n/N (%) Voriconazole n/N (%) AST 22/281 (8) 21/285 (7) ALT 29/281 (10) 23/282 (8) Bilirubin 26/280 (9) 25/284 (9) Alkaline Phosphatase 12/282 (4) 20/284 (7) In healthy volunteers and patients, elevation of liver test values did not appear to be associated with higher plasma posaconazole concentrations. 6.2 Postmarketing Experience The following adverse reaction has been identified during the post-approval use of posaconazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Endocrine Disorders: Pseudoaldosteronism" ], "adverse_reactions_table": [ "Posaconazole Oral Suspension n=605 (%)Fluconazole n=539(%)
Adverse Reactions
Itraconazolen=58(%)
Percentage of Patients Reporting any Adverse Reaction9899100
Fever454755
Diarrhea423960
Nausea383752
Hypokalemia302652
Thrombocytopenia292734
Vomiting293241
Headache282640
Abdominal Pain272736
Anemia252328
Coughing242424
Neutropenia232340
Constipation211717
Dyspnea202226
Rigors201629
Rash191843
Hypertension18165
Hypomagnesemia181619
Fatigue17189
Insomnia171719
Musculoskeletal Pain161516
Anorexia151728
Edema Legs151219
Epistaxis141421
Hypotension141517
Pharyngitis121121
Tachycardia12145
Arthralgia11129
Dizziness11109
Hyperglycemia11143
Petechiae111016
Pruritus111219
Back Pain10127
Bilirubinemia10919
Dyspepsia10910
Vaginal HemorrhagePercentage of sex-specific adverse reactions are based on the number of males/females.10912
", "Adverse ReactionsControlled OPC PoolRefractory OPC PoolPosaconazole Oral SuspensionFluconazolePosaconazole Oral Suspension n=557(%)n=262(%)n=239 (%)646792Diarrhea101329Nausea91129Headache8920Vomiting7728Fever6834Abdominal Pain5618Neutropenia4316Coughing3425Fatigue3513Herpes Simplex3311Pneumonia3210Rash3415Anemia2214Anorexia2219Asthenia2213Sweating Increased2210Candidiasis, Oral1<112Dehydration1311Dyspnea1312Insomnia1116Pain1111Weight Decrease1<114Rigors<1212OPC=oropharyngeal candidiasis
Percentage of Patients that Reported any Adverse ReactionBased on patients reporting adverse reactions at least once during the study, without regard to relationship to treatment. Patients may have reported more than 1 adverse reaction.
", "
Number (%) of Patients with ChangeChange from Grade 0 to 2 at baseline to Grade 3 or 4 during the study. These data are presented in the form X/Y, where X represents the number of patients who met the criterion as indicated, and Y represents the number of patients who had a baseline observation and at least one post-baseline observation.
Posaconazole Oral Suspension Study 1
Laboratory ParameterPosaconazole Oral Suspension n=301Fluconazole n=299
AST11/266 (4)13/266 (5)
ALT47/271 (17)39/272 (14)
Bilirubin24/271 (9)20/275 (7)
Alkaline Phosphatase9/271 (3)8/271 (3)
Posaconazole Oral Suspension Study 2
Laboratory ParameterPosaconazole Oral Suspension (n=304)Fluconazole/Itraconazole (n=298)
AST9/286 (3)5/280 (2)
ALT18/289 (6)13/284 (5)
Bilirubin20/290 (7)25/285 (9)
Alkaline Phosphatase4/281 (1)1/276 (<1)
", "
Laboratory TestNonrefractory OPCRefractory OPC
Posaconazole Oral SuspensionFluconazolePosaconazole Oral Suspension
n=557 (%)n=262 (%)n=239 (%)
ALT > 3.0 × ULN16/537 (3)13/254 (5)25/226 (11)
AST > 3.0 × ULN33/537 (6)26/254 (10)39/223 (17)
Total Bilirubin > 1.5 × ULN15/536 (3)5/254 (2)9/197 (5)
Alkaline Phosphatase > 3.0 × ULN17/535 (3)15/253 (6)24/190 (13)
ALT= Alanine Aminotransferase; AST= Aspartate Aminotransferase.
", "
Number (%) of Patients with ChangeChange from Grade 0 to 2 at baseline to Grade 3 or 4 during the study. These data are presented in the form n/N, where n represents the number of patients who met the criterion as indicated, and N represents the number of patients who had a baseline observation and at least one post-baseline observation.
Laboratory ParameterPosaconazole n/N (%)Voriconazole n/N (%)
AST22/281 (8)21/285 (7)
ALT29/281 (10)23/282 (8)
Bilirubin26/280 (9)25/284 (9)
Alkaline Phosphatase12/282 (4)20/284 (7)
" ], "drug_interactions": [ "7 DRUG INTERACTIONS Table 15 and Table 17 include drugs with clinically important drug interactions when administered concomitantly with posaconazole and posaconazole PowderMix and instructions for preventing or managing them. Table 16 includes important drug interactions specific to the absorption of posaconazole administered as either posaconazole oral suspension or posaconazole PowderMix. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious adverse reactions or loss of efficacy [see Clinical Pharmacology ( 12.3 )] . The following information was derived from data with posaconazole oral suspension or another posaconazole tablet formulation unless otherwise noted. All clinically important drug interactions with posaconazole oral suspension, except for those that affect the absorption of posaconazole (via gastric pH and motility), are considered relevant to clinically important drug interactions with posaconazole injection, posaconazole delayed-release tablets, and posaconazole PowderMix for delayed-release oral suspension [Clinical Pharmacology ( 12.3 )] . Consult the labeling of concomitantly used drugs to obtain further information about interactions with posaconazole. Interaction Drug Interaction Rifabutin, phenytoin, efavirenz, cimetidine, esomeprazole Avoid coadministration unless the benefit outweighs the risks ( 7.1 , 7.2 ) Other drugs metabolized by CYP3A4 Consider dosage adjustment and monitor for adverse effects and toxicity ( 7.2 ) Digoxin Monitor digoxin plasma concentrations ( 7.2 ) Fosamprenavir, metoclopramide Monitor for breakthrough fungal infections ( 7.3 , 12.3 ) 7.1 Effects of Other Drugs on Posaconazole Posaconazole is primarily metabolized via UDP-glucuronosyltransferase and is a substrate of p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. Concomitant use of posaconazole with drugs that can decrease the plasma posaconazole concentrations should generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections. Table 15: Drug Interactions Affecting Posaconazole When Administered Concomitantly with Other Drugs UDP-Glucuronidase Inducers Mechanism and Clinical Effect(s) Posaconazole is a UDP-glucuronosyltransferase substrate. Concomitant use of posaconazole with UDP-glucuronidase inducers may decrease posaconazole exposure [see Clinical Pharmacology ( 12.3 )], which may reduce the effectiveness of posaconazole. Prevention or Management Efavirenz Avoid concomitant use of posaconazole with efavirenz, unless the benefit outweighs the risks. Rifabutin Avoid concomitant use of posaconazole with rifabutin unless the benefit to the patient outweighs the risk. If concomitant use is needed, monitor closely for breakthrough fungal infections. See Table 17 for rifabutin monitoring considerations when posaconazole affects rifabutin via CYP3A4 inhibition. Phenytoin Avoid concomitant use of posaconazole with phenytoin unless the benefit to the patient outweighs the risk. If concomitant use is needed, monitor for breakthrough fungal infections. See Table 17 for phenytoin monitoring considerations when posaconazole affects phenytoin via CYP3A4 inhibition. Fosamprenavir Mechanism and Clinical Effect(s) Concomitant use of posaconazole with fosamprenavir may lead to decreased posaconazole plasma concentrations [see Clinical Pharmacology ( 12.3 )], which may reduce effectiveness of posaconazole. Prevention or Management If concomitant use of posaconazole with fosamprenavir is needed, monitor closely for breakthrough fungal infections. Table 16: Drug Interactions Affecting Posaconazole Oral Suspension Absorption When Administered Concomitantly with Other Drugs Posaconazole Oral Suspension Cimetidine and Esomeprazole Mechanism and Clinical Effect(s) Concomitant use of posaconazole oral suspension with cimetidine or esomeprazole resulted in decreased posaconazole plasma concentrations [see Clinical Pharmacology ( 12.3 )], which may reduce effectiveness of posaconazole. Prevention or Management Avoid concomitant use of posaconazole oral suspension with cimetidine or esomeprazole unless the benefit outweighs the risks. If concomitant use is needed, monitor closely for breakthrough fungal infections. Metoclopramide Mechanism and Clinical Effect(s) Concomitant use of posaconazole oral suspension with metoclopramide decreased posaconazole plasma concentrations [see Clinical Pharmacology ( 12.3 )], which may reduce effectiveness of posaconazole oral suspension. Prevention or Management If posaconazole oral suspension is concomitantly administered with metoclopramide, closely monitor for breakthrough fungal infections. 7.2 Effects of Posaconazole on Other Drugs Posaconazole is a strong CYP3A4 inhibitor. Therefore, concomitant use of posaconazole may increase plasma concentrations of drugs that are CYP3A4 substrates [see Clinical Pharmacology (12.3)] . Table 17: Drug Interactions Affecting Drugs Administered Concomitantly with Posaconazole Digoxin Clinical Effect(s) Increased digoxin plasma concentrations have been reported in patients who received concomitant posaconazole and digoxin. Prevention or Management Monitor digoxin plasma concentrations during concomitant use of posaconazole. Glipizide Clinical Effect(s) No dosage modification of glipizide is needed when used concomitantly with posaconazole. However, glucose concentrations decrease in some patients concomitantly administered posaconazole and glipizide. Prevention or Management Increase monitoring of glucose concentrations when used concomitantly. CYP3A Substrates Immunosuppressants that are CYP3A4 Substrates Mechanism and Clinical Effect(s) Posaconazole is a strong CYP3A4 inhibitor. Therefore, plasma concentrations of CYP3A4 substrates may be increased by posaconazole use [see Clinical Pharmacology (12.3)]. Prevention or Management Sirolimus Posaconazole is contraindicated with sirolimus [see Clinical Pharmacology ( 12.3 )] . Tacrolimus • At initiation of posaconazole treatment, reduce the tacrolimus dosage to approximately one-third of the original tacrolimus dosage. • Frequent monitoring of tacrolimus whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus dosage should be modified accordingly [see Warnings and Precautions (5.1) and Clinical Pharmacology ( 12.3 )] . Cyclosporine • At initiation of posaconazole treatment reduce the cyclosporine dosage to approximately three-fourths of the original dosage. • Frequent monitoring of cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the cyclosporine dosage should be modified accordingly [see Warnings and Precautions (5.1) and Clinical Pharmacology ( 12.3 )] . CYP3A4 Substrates that Prolong QTc Interval Mechanism and Clinical Effect(s) Concomitant use of posaconazole with CYP3A4 substrates such as pimozide and quinidine may result in increased plasma concentrations of the CYP3A4 substrates leading to QTc interval prolongation and torsades de pointes [see Warnings and Precautions ( 5.2 )]. Prevention or Management Pimozide Concomitant use with posaconazole is contraindicated. Quinidine HMG-CoA Reductase Inhibitors (Statins) that are CYP3A4 Substrates Mechanism and Clinical Effect(s) Concomitant use of posaconazole with simvastatin increased simvastatin plasma concentrations which can lead to rhabdomyolysis [see Clinical Pharmacology ( 12.3 )]. Prevention or Management Atorvastatin, Lovastatin, Simvastatin Concomitant use with posaconazole is contraindicated. Benzodiazepines that are CYP3A4 Substrates Mechanism and Clinical Effect(s) Concomitant use of posaconazole with midazolam increased midazolam plasma concentrations which could potentiate and prolong hypnotic and sedative effects [see Clinical Pharmacology ( 12.3 )] . Prevention or Management Midazolam, Alprazolam, Triazolam Closely monitor for adverse reactions associated with high plasma concentrations of benzodiazepines that are CYP3A4 substrates during concomitant use, and a benzodiazepine receptor antagonist should be available to reverse effects [see Warnings and Precautions (5.7)]. Calcium Channel Blockers that are CYP3A4 Substrates Mechanism and Clinical Effect(s) Posaconazole may increase the plasma concentrations of calcium channel blockers that are substrates of CYP3A4. Prevention or Management Verapamil, Diltiazem, Nifedipine, Nicardipine, Felodipine Monitor frequently for adverse reactions and toxicity with concomitant use of posaconazole with calcium channel blockers that are CYP3A4 substrates. Dosage reduction of the calcium channel blocker may be needed. Anti-HIV Drugs that are CYP3A4 Substrates Mechanism and Clinical Effect(s) Ritonavir and atazanavir are CYP3A4 substrates and posaconazole increased plasma concentrations of these drugs [see Clinical Pharmacology ( 12.3 )]. Prevention or Management Ritonavir and Atazanavir Monitor frequently for adverse reactions and toxicity of ritonavir and atazanavir during concomitant use. Antineoplastic Drugs that are CYP3A4 Substrates Mechanism and Clinical Effect(s) Posaconazole may increase plasma concentrations of oncology drugs that are CYP3A4 substrates, which may increase the risk of serious adverse reactions. Prevention or Management Venetoclax CLL/SLL patients : Concomitant use of posaconazole with venetoclax during initiation and ramp-up phase is contraindicated. AML patients : With concomitant use, venetoclax dosage reduction and safety monitoring is recommended across all dosing phases [see Warnings and Precautions ( 5.11 )] . Vinca alkaloids (e.g., vincristine, vinblastine) Reserve concomitant use for patients with no alternative antifungal treatment options [see Warnings and Precautions ( 5.8 )]. Ergot Alkaloids Mechanism and Clinical Effect(s) Most of the ergot alkaloids are CYP3A4 substrates. Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism. Prevention or Management Ergotamine, Dihydroergotamine Concomitant use with posaconazole is contraindicated. Phenytoin Mechanism and Clinical Effect(s) Phenytoin is a CYP3A4 substrate. Concomitant use of posaconazole with phenytoin increased phenytoin plasma concentrations [see Clinical Pharmacology ( 12.3 )]. Prevention or Management Avoid concomitant use of posaconazole with phenytoin unless the benefit outweighs the risk. frequently monitor phenytoin concentrations and consider a dosage reduction of phenytoin. See Table 15 for additional monitoring considerations when phenytoin affects posaconazole via UDP-glucuronosyltransferase inhibition. Rifabutin Mechanism and Clinical Effect(s) Rifabutin is a CYP3A4 substrate. Concomitant use of posaconazole with rifabutin increased rifabutin plasma concentrations [see Clinical Pharmacology ( 12.3 )]. Prevention or Management Avoid concomitant use of posaconazole with rifabutin unless the benefit outweighs the risk. Frequent monitoring of full blood counts and adverse reactions due to increased rifabutin plasma concentrations (e.g., uveitis, leukopenia) during concomitant use are recommended. See Table 15 for additional monitoring considerations when rifabutin affects posaconazole via UDP-glucuronosyltransferase inhibition. 7.3 Absence of Clinically Important Interaction with Posaconazole Additional clinical studies demonstrated that no clinically important 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 drugs when coadministered with posaconazole 200 mg once daily. No clinically relevant effects on the pharmacokinetics of posaconazole oral suspension were observed during concomitant use with antacids, H 2 -receptor antagonists (other than cimetidine), and loperamide [see Clinical Pharmacology ( 12.3 )] . No dosage adjustment of posaconazole oral suspension is required during concomitant use with these drugs (other than cimetidine)." ], "drug_interactions_table": [ "
Interaction DrugInteraction
Rifabutin, phenytoin, efavirenz, cimetidine, esomeprazoleAvoid coadministration unless the benefit outweighs the risks (7.1,7.2)
Other drugs metabolized by CYP3A4Consider dosage adjustment and monitor for adverse effects and toxicity (7.2)
DigoxinMonitor digoxin plasma concentrations (7.2)
Fosamprenavir, metoclopramideMonitor for breakthrough fungal infections (7.3, 12.3)
", "UDP-Glucuronidase InducersPosaconazole is a UDP-glucuronosyltransferase substrate. Concomitant use of posaconazole with UDP-glucuronidase inducers may decrease posaconazole exposure [see Clinical Pharmacology (12.3)], which may reduce the effectiveness of posaconazole.EfavirenzAvoid concomitant use of posaconazole with rifabutin unless the benefit to the patient outweighs the risk. If concomitant use is needed, monitor closely for breakthrough fungal infections. See Table 17 for rifabutin monitoring considerations when posaconazole affects rifabutin via CYP3A4 inhibition.
Mechanism and Clinical Effect(s)
Prevention or Management
Avoid concomitant use of posaconazole with efavirenz, unless the benefit outweighs the risks.
Rifabutin
PhenytoinAvoid concomitant use of posaconazole with phenytoin unless the benefit to the patient outweighs the risk. If concomitant use is needed, monitor for breakthrough fungal infections. See Table 17 for phenytoin monitoring considerations when posaconazole affects phenytoin via CYP3A4 inhibition.
Fosamprenavir
Mechanism and Clinical Effect(s)Concomitant use of posaconazole with fosamprenavir may lead to decreased posaconazole plasma concentrations [see Clinical Pharmacology (12.3)], which may reduce effectiveness of posaconazole.
Prevention or ManagementIf concomitant use of posaconazole with fosamprenavir is needed, monitor closely for breakthrough fungal infections.
", "Concomitant use of posaconazole oral suspension with cimetidine or esomeprazole resulted in decreased posaconazole plasma concentrations [see Clinical Pharmacology (12.3)], which may reduce effectiveness of posaconazole.Avoid concomitant use of posaconazole oral suspension with cimetidine or esomeprazole unless the benefit outweighs the risks. If concomitant use is needed, monitor closely for breakthrough fungal infections.Concomitant use of posaconazole oral suspension with metoclopramide decreased posaconazole plasma concentrations [see Clinical Pharmacology (12.3)], which may reduce effectiveness of posaconazole oral suspension.If posaconazole oral suspension is concomitantly administered with metoclopramide, closely monitor for breakthrough fungal infections.
Posaconazole Oral Suspension
Cimetidine and Esomeprazole
Mechanism and Clinical Effect(s)
Prevention or Management
Metoclopramide
Mechanism and Clinical Effect(s)
Prevention or Management
", "Clinical Effect(s)Increased digoxin plasma concentrations have been reported in patients who received concomitant posaconazole and digoxin.Prevention or ManagementMonitor digoxin plasma concentrations during concomitant use of posaconazole.GlipizideClinical Effect(s)No dosage modification of glipizide is needed when used concomitantly with posaconazole. However, glucose concentrations decrease in some patients concomitantly administered posaconazole and glipizide.Prevention or ManagementIncrease monitoring of glucose concentrations when used concomitantly.Posaconazole is a strong CYP3A4 inhibitor. Therefore, plasma concentrations of CYP3A4 substrates may be increased by posaconazole use [see Clinical Pharmacology (12.3)].Prevention or ManagementSirolimusPosaconazole is contraindicated with sirolimus [see Clinical Pharmacology (12.3)].Tacrolimus At initiation of posaconazole treatment, reduce the tacrolimus dosage to approximately one-third of the original tacrolimus dosage. Frequent monitoring of tacrolimus whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus dosage should be modified accordingly [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].Cyclosporine At initiation of posaconazole treatment reduce the cyclosporine dosage to approximately three-fourths of the original dosage. Frequent monitoring of cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the cyclosporine dosage should be modified accordingly [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].Mechanism and Clinical Effect(s)Concomitant use of posaconazole with CYP3A4 substrates such as pimozide and quinidine may result in increased plasma concentrations of the CYP3A4 substrates leading to QTc interval prolongation and torsades de pointes [see Warnings and Precautions (5.2)].Prevention or ManagementPimozideQuinidineHMG-CoA Reductase Inhibitors (Statins) that are CYP3A4 SubstratesMechanism and Clinical Effect(s)Concomitant use of posaconazole with simvastatin increased simvastatin plasma concentrations which can lead to rhabdomyolysis [see Clinical Pharmacology (12.3)].Prevention or ManagementAtorvastatin,Lovastatin, SimvastatinBenzodiazepines that are CYP3A4 SubstratesMechanism and Clinical Effect(s)Concomitant use of posaconazole with midazolam increased midazolam plasma concentrations which could potentiate and prolong hypnotic and sedative effects [seeClinical Pharmacology (12.3)].Prevention or ManagementMidazolam, Alprazolam, TriazolamClosely monitor for adverse reactions associated with high plasma concentrations of benzodiazepines that are CYP3A4 substrates during concomitant use, and a benzodiazepine receptor antagonistshould be available to reverse effects [see Warnings and Precautions (5.7)].Calcium Channel Blockers that are CYP3A4 SubstratesMechanism and Clinical Effect(s)Posaconazole may increase the plasma concentrations of calcium channel blockers that are substrates of CYP3A4.Prevention or ManagementVerapamil, Diltiazem, Nifedipine, Nicardipine, FelodipineMonitor frequently for adverse reactions and toxicity with concomitant use of posaconazole with calcium channel blockers that are CYP3A4 substrates. Dosage reduction of the calcium channel blocker may be needed.Anti-HIV Drugs that are CYP3A4 SubstratesMechanism and Clinical Effect(s)Ritonavir and atazanavir are CYP3A4 substrates and posaconazole increased plasma concentrations of these drugs [see Clinical Pharmacology (12.3)].Prevention or ManagementRitonavir and AtazanavirMonitor frequently for adverse reactions and toxicity of ritonavir and atazanavir during concomitant use.Antineoplastic Drugs that are CYP3A4 SubstratesMechanism and Clinical Effect(s)Posaconazole may increase plasma concentrations of oncology drugs that are CYP3A4 substrates, which may increase the risk of serious adverse reactions.Prevention or ManagementVenetoclaxCLL/SLL patients: Concomitant use of posaconazole with venetoclax during initiation and ramp-up phase is contraindicated.AML patients: With concomitant use, venetoclax dosage reduction and safety monitoring is recommended across all dosing phases [see Warnings and Precautions (5.11)].Vinca alkaloids (e.g.,vincristine, vinblastine)Reserve concomitant use for patients with no alternative antifungal treatment options [see Warnings and Precautions (5.8)].Ergot AlkaloidsMechanism and Clinical Effect(s)Most of the ergot alkaloids are CYP3A4 substrates. Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism.Prevention or ManagementErgotamine,Dihydroergotamine Concomitant use with posaconazole is contraindicated.PhenytoinMechanism and Clinical Effect(s)Phenytoin is a CYP3A4 substrate. Concomitant use of posaconazole with phenytoin increased phenytoin plasma concentrations [see Clinical Pharmacology (12.3)].Prevention or ManagementAvoid concomitant use of posaconazole with phenytoin unless the benefit outweighs the risk. frequently monitor phenytoin concentrations and consider a dosage reduction of phenytoin. See Table 15 for additional monitoring considerations when phenytoin affects posaconazole via UDP-glucuronosyltransferase inhibition.RifabutinMechanism and Clinical Effect(s)Rifabutin is a CYP3A4 substrate. Concomitant use of posaconazole with rifabutin increased rifabutin plasma concentrations [see Clinical Pharmacology (12.3)].
Digoxin
CYP3A Substrates
Immunosuppressants that are CYP3A4 Substrates
Mechanism and Clinical Effect(s)
••
••
CYP3A4 Substrates that Prolong QTc Interval
Concomitant use with posaconazole is contraindicated.
Concomitant use with posaconazole is contraindicated.
Prevention or ManagementAvoid concomitant use of posaconazole with rifabutin unless the benefit outweighs the risk. Frequent monitoring of full blood counts and adverse reactions due to increased rifabutin plasma concentrations (e.g., uveitis, leukopenia) during concomitant use are recommended. See Table 15 for additional monitoring considerations when rifabutin affects posaconazole via UDP-glucuronosyltransferase inhibition.
" ], "use_in_specific_populations": [ "8 USE IN SPECIFIC POPULATIONS • Pregnancy: Based on animal data, may cause fetal harm. ( 8.1 ) • Pediatrics: Safety and effectiveness in patients younger than 13 years of age have not been established. ( 8.4 ) • Severe Renal Impairment: Monitor closely for breakthrough fungal infections. ( 8.6 ) 8.1 Pregnancy Risk Summary: Based on findings from animal data, posaconazole may cause fetal harm when administered to pregnant women. Available data for use of posaconazole in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, skeletal malformations were observed when posaconazole was dosed orally to pregnant rats during organogenesis at doses ≥1.4 times the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations of posaconazole in healthy volunteers. In pregnant rabbits dosed orally during organogenesis, doses of ≥ 3 times the clinical exposure caused an increase in resorptions (see Data) . Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data: Animal Data: Posaconazole resulted in maternal toxicity (reduced food consumption and reduced body weight gain) and skeletal malformations (cranial malformations and missing ribs) when given orally to pregnant rats during organogenesis (Gestational Days 6 through 15) at doses ≥27 mg/kg (≥1.4 times the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations of drug in healthy volunteers). The no-effect dose for malformations and maternal toxicity in rats was 9 mg/kg, which is 0.7 times the exposure achieved with the 400 mg twice daily oral suspension regimen. No malformations were seen in rabbits dosed during organogenesis (Gestational Days 7 through 19) at doses up to 80 mg/kg (5 times the exposure achieved with the 400 mg twice daily oral suspension regimen). In the rabbit, the no-effect dose was 20 mg/kg, while high doses of 40 mg/kg and 80 mg/kg (3 or 5 times the clinical exposure) caused an increase in resorptions. In rabbits dosed at 80 mg/kg, a reduction in body weight gain of females and a reduction in litter size were seen. 8.2 Lactation Risk Summary: There are no data on the presence of posaconazole in human milk, the effects on the breastfed infant, or the effects on milk production. Posaconazole is excreted in the milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for posaconazole and any potential adverse effects on the breastfed child from posaconazole or from the underlying maternal condition. 8.4 Pediatric Use The three dosage forms (injection, delayed-release tablets, oral suspension) and one posaconazole PowderMix (for delayed-release oral suspension) dosage form are different products; are approved for different pediatric indications, age groups, and weights; have different dosing regimens; and have different preparation and administration instructions. Therefore, select the recommended dosage form based on the pediatric indication, age group, and weight [see Dosage and Administration ( 2.1 )] . Prophylaxis of Invasive Aspergillus and Candida Infections The safety and effectiveness of posaconazole oral suspension have been established for the prophylaxis of invasive Aspergillus and Candida infections in pediatric patients 13 years of age and older who are at high risk of developing these infections due to being severely immunocompromised. Use of posaconazole for these pediatric indications is supported by adequate and well controlled studies of posaconazole in adults and pediatric patients aged 13 years of age and older [see Clinical Pharmacology ( 12.3 ) and Clinical studies ( 14 )] . The safety and effectiveness of posaconazole and posaconazole PowderMix have not been established in pediatric patients less than 2 years of age. Treatment of Oropharyngeal Candidiasis, including Refractory to Itraconazole and/or Fluconazole The safety and effectiveness of posaconazole oral suspension have been established for the treatment of oropharyngeal candidiasis (OPC), including OPC refractory (rOPC) to itraconazole and/or fluconazole in pediatric patients 13 years of age and older. Use of posaconazole oral suspension for this pediatric indication is supported by adequate and well controlled studies in adults and pediatric patients 13 years of age and older [see Clinical studies ( 14.4 )]. The posaconazole injection, posaconazole delayed-release tablets, and posaconazole PowderMix products are not approved for the treatment of oropharyngeal candidiasis in pediatric patients. Posaconazole Oral Suspension is the only dosage form approved for the treatment of OPC and rOPC in pediatric patients [see Dosage and Administration ( 2.4 )]. The safety and effectiveness of posaconazole oral suspension for the treatment of OPC and rOPC have not been established in pediatric patients less than 13 years of age. 8.5 Geriatric Use No overall differences in the safety or effectiveness of posaconazole oral suspension were observed between geriatric patients and younger adult patients in the clinical trials; therefore, the recommended dosage in geriatric patients is the same as that for younger adult patients. No clinically meaningful differences in posaconazole pharmacokinetics were observed in posaconazole-treated geriatric patients compared to posaconazole-treated younger adult patients during clinical trials [see Clinical Pharmacology ( 12.3 )] . • Of the 605 patients treated with posaconazole oral suspension in posaconazole Oral Suspension Study 1 and Study 2 (prophylaxis of invasive Aspergillus and Candida infections in those at high risk of developing these infections due to being severely immunocompromised), 63 (10%) patients were ≥65 years of age. • In studies of posaconazole for an unapproved indication, 48 patients treated with posaconazole oral suspension (greater than or equal to 800 mg/day (eight times the maximum recommended maintenance dosage for the treatment of OPC)) were ≥65 years of age. 8.6 Renal Impairment Posaconazole Oral Suspension No dosage adjustment is required for patients with eGFR 20 mL/minute/1.73 m 2 or higher. Due to variability in posaconazole exposure, closely monitor patients with eGFR less than 20 mL/minute/1.73 m 2 for breakthrough fungal infections. [see Clinical Pharmacology ( 12.3 )] . 8.7 Hepatic Impairment No dosage adjustment is recommended for posaconazole oral suspension in patients with mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, or C, respectively) [see Clinical Pharmacology ( 12.3 )] . 8.8 Sex No adjustment in the dosage of posaconazole is necessary based on sex. 8.9 Race No adjustment in the dosage of posaconazole is necessary based on race. 8.10 Weight Pharmacokinetic modeling suggests that patients who weigh greater than 120 kg may have lower posaconazole plasma drug exposure. Therefore, consider closely monitoring for breakthrough fungal infections particularly when using posaconazole oral suspension in patients weighing greater than 120 kg [see Clinical Pharmacology ( 12.3 )] ." ], "pregnancy": [ "8.1 Pregnancy Risk Summary: Based on findings from animal data, posaconazole may cause fetal harm when administered to pregnant women. Available data for use of posaconazole in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, skeletal malformations were observed when posaconazole was dosed orally to pregnant rats during organogenesis at doses ≥1.4 times the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations of posaconazole in healthy volunteers. In pregnant rabbits dosed orally during organogenesis, doses of ≥ 3 times the clinical exposure caused an increase in resorptions (see Data) . Based on animal data, advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data: Animal Data: Posaconazole resulted in maternal toxicity (reduced food consumption and reduced body weight gain) and skeletal malformations (cranial malformations and missing ribs) when given orally to pregnant rats during organogenesis (Gestational Days 6 through 15) at doses ≥27 mg/kg (≥1.4 times the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations of drug in healthy volunteers). The no-effect dose for malformations and maternal toxicity in rats was 9 mg/kg, which is 0.7 times the exposure achieved with the 400 mg twice daily oral suspension regimen. No malformations were seen in rabbits dosed during organogenesis (Gestational Days 7 through 19) at doses up to 80 mg/kg (5 times the exposure achieved with the 400 mg twice daily oral suspension regimen). In the rabbit, the no-effect dose was 20 mg/kg, while high doses of 40 mg/kg and 80 mg/kg (3 or 5 times the clinical exposure) caused an increase in resorptions. In rabbits dosed at 80 mg/kg, a reduction in body weight gain of females and a reduction in litter size were seen." ], "nursing_mothers": [ "8.2 Lactation Risk Summary: There are no data on the presence of posaconazole in human milk, the effects on the breastfed infant, or the effects on milk production. Posaconazole is excreted in the milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for posaconazole and any potential adverse effects on the breastfed child from posaconazole or from the underlying maternal condition." ], "pediatric_use": [ "8.4 Pediatric Use The three dosage forms (injection, delayed-release tablets, oral suspension) and one posaconazole PowderMix (for delayed-release oral suspension) dosage form are different products; are approved for different pediatric indications, age groups, and weights; have different dosing regimens; and have different preparation and administration instructions. Therefore, select the recommended dosage form based on the pediatric indication, age group, and weight [see Dosage and Administration ( 2.1 )] . Prophylaxis of Invasive Aspergillus and Candida Infections The safety and effectiveness of posaconazole oral suspension have been established for the prophylaxis of invasive Aspergillus and Candida infections in pediatric patients 13 years of age and older who are at high risk of developing these infections due to being severely immunocompromised. Use of posaconazole for these pediatric indications is supported by adequate and well controlled studies of posaconazole in adults and pediatric patients aged 13 years of age and older [see Clinical Pharmacology ( 12.3 ) and Clinical studies ( 14 )] . The safety and effectiveness of posaconazole and posaconazole PowderMix have not been established in pediatric patients less than 2 years of age. Treatment of Oropharyngeal Candidiasis, including Refractory to Itraconazole and/or Fluconazole The safety and effectiveness of posaconazole oral suspension have been established for the treatment of oropharyngeal candidiasis (OPC), including OPC refractory (rOPC) to itraconazole and/or fluconazole in pediatric patients 13 years of age and older. Use of posaconazole oral suspension for this pediatric indication is supported by adequate and well controlled studies in adults and pediatric patients 13 years of age and older [see Clinical studies ( 14.4 )]. The posaconazole injection, posaconazole delayed-release tablets, and posaconazole PowderMix products are not approved for the treatment of oropharyngeal candidiasis in pediatric patients. Posaconazole Oral Suspension is the only dosage form approved for the treatment of OPC and rOPC in pediatric patients [see Dosage and Administration ( 2.4 )]. The safety and effectiveness of posaconazole oral suspension for the treatment of OPC and rOPC have not been established in pediatric patients less than 13 years of age." ], "geriatric_use": [ "8.5 Geriatric Use No overall differences in the safety or effectiveness of posaconazole oral suspension were observed between geriatric patients and younger adult patients in the clinical trials; therefore, the recommended dosage in geriatric patients is the same as that for younger adult patients. No clinically meaningful differences in posaconazole pharmacokinetics were observed in posaconazole-treated geriatric patients compared to posaconazole-treated younger adult patients during clinical trials [see Clinical Pharmacology ( 12.3 )] . • Of the 605 patients treated with posaconazole oral suspension in posaconazole Oral Suspension Study 1 and Study 2 (prophylaxis of invasive Aspergillus and Candida infections in those at high risk of developing these infections due to being severely immunocompromised), 63 (10%) patients were ≥65 years of age. • In studies of posaconazole for an unapproved indication, 48 patients treated with posaconazole oral suspension (greater than or equal to 800 mg/day (eight times the maximum recommended maintenance dosage for the treatment of OPC)) were ≥65 years of age." ], "overdosage": [ "10 OVERDOSAGE During the clinical trials, some patients received posaconazole oral suspension up to 1,600 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 1,200 mg twice daily posaconazole oral suspension for 3 days. No related adverse reactions were noted by the investigator. Posaconazole is not removed by hemodialysis." ], "description": [ "11 DESCRIPTION Posaconazole is 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 C 37 H 42 F 2 N 8 O 4 and a molecular weight of 700.8. The chemical structure is: Posaconazole is a white to off-white powder that is practically insoluble in water. Posaconazole oral suspension is a white to off-white, cherry-brandy flavored immediate-release suspension containing 40 mg of posaconazole per mL and the following inactive ingredients: cherry-brandy flavor, citric acid monohydrate, hydroxyethyl cellulose, glycerin, polyoxyl 35 castor oil, simethicone emulsion, sodium benzoate, sodium citrate, sorbitol solution, titanium dioxide, and water. chemical-structure" ], "clinical_pharmacology": [ "12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Posaconazole is an azole antifungal agent [see Clinical Pharmacology ( 12.4 )] . 12.2 Pharmacodynamics Exposure Response Relationship: Prophylaxis of Invasive Aspergillus and Candida Infections in Adults Who Are at High Risk of Developing These Infections Due to Being Severely Immunocompromised : 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), a wide range of plasma posaconazole exposures was noted following administration of posaconazole oral suspension. A pharmacokinetic-pharmacodynamic analysis of patient data revealed an apparent association between average posaconazole concentrations (Cavg) and prophylactic efficacy ( Table 18 ). A 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 18: Posaconazole Oral Suspension Exposure Analysis (Cavg) in Prophylaxis Trials Prophylaxis in AML/MDS Neutropenic patients who were receiving cytotoxic chemotherapy for AML or MDS Prophylaxis in GVHD HSCT recipients with GVHD Cavg Range (ng/mL) Treatment Failure Defined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections (%) Cavg Range (ng/mL) Treatment Failure (%) Quartile 1 90 to 322 54.7 22 to 557 44.4 Quartile 2 322 to 490 37.0 557 to 915 20.6 Quartile 3 490 to 734 46.8 915 to 1,563 17.5 Quartile 4 734 to 2,200 27.8 1,563 to 3,650 17.5 Cavg = the average posaconazole concentration when measured at steady state Exposure Response Relationship Treatment of Invasive Aspergillosis in Adult and Adolescent Patients Across a range of posaconazole plasma minimum concentrations (C min , range: 244 to 5,663 ng/mL) following administration of posaconazole injection and posaconazole delayed-release tablets in adult and pediatric patients aged 14 years and older treated for invasive aspergillosis in Aspergillosis Treatment Study, there was no association between posaconazole C min and treatment efficacy [see Clinical Pharmacology ( 12.3 )] . Similarly, across a range of population pharmacokinetic model-predicted steady-state plasma average concentrations (Cavg, range: 589 to 6,315 ng/mL), there was no association between posaconazole Cavg and treatment efficacy. 12.3 Pharmacokinetics General Pharmacokinetic Characteristics Dose-proportional increases in plasma exposure (AUC) to posaconazole oral suspension were observed following single oral doses from 50 mg to 800 mg and following multiple-dose administration from 50 mg twice daily to 400 mg twice daily in healthy volunteers. No further increases in exposure were observed when the dose of the oral suspension increased from 400 mg twice daily to 600 mg twice daily in febrile neutropenic patients or those with refractory invasive fungal infections. The mean (%CV) [min-max] posaconazole oral suspension average steady-state plasma concentrations (Cavg) and steady-state pharmacokinetic parameters in patients following administration of 200 mg three times a day and 400 mg twice daily of the oral suspension are provided in Table 22. Table 22: The Mean (%CV) [min-max] Posaconazole Steady-State Pharmacokinetic Parameters in Patients Following Oral Administration of Posaconazole Oral Suspension 200 mg Three Times a Day and 400 mg Twice Daily Dose Oral suspension administration Cavg (ng/mL) AUC AUC (0 to 24 hr) for 200 mg three times a day and AUC (0 to 12 hr) for 400 mg twice daily (ng∙hr/mL) CL/F (L/hr) V/F (L) t ½ (hr) 200 mg three times a day HSCT recipients with GVHD (n=252) 1,103 (67) [21.5 to 3,650] ND Not done ND ND ND 200 mg three times a day Neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia or myelodysplastic syndromes (n=215) 583 (65) [89.7 to 2,200] 15,900 (62) [4,100 to 56,100] 51.2 (54) [10.7 to 146] 2425 (39) [828 to 5,702] 37.2 (39) [19.1 to 148] 400 mg twice daily Febrile neutropenic patients or patients with refractory invasive fungal infections, Cavg n=24 (n=23) 723 (86) [6.70 to 2,256] 9093 (80) [1,564 to 26,794] 76.1 (78) [14.9 to 256] 3,088 (84) [407 to 13,140] 31.7 (42) [12.4 to 67.3] Cavg = the average posaconazole concentration when measured at steady state Absorption: Posaconazole oral suspension is absorbed with a median T max of ~3 to 5 hours. Steady-state plasma concentrations are attained at 7 to 10 days following multiple-dose administration. Following single-dose administration of 200 mg, the mean AUC and C max of posaconazole are approximately 3 times higher when the oral suspension is administered with a nonfat meal and approximately 4 times higher when administered with a high-fat meal (~50 gm fat) relative to the fasted state. Following single-dose administration of posaconazole oral suspension 400 mg, the mean AUC and C max of posaconazole are approximately 3 times higher when administered with a liquid nutritional supplement (14 gm fat) relative to the fasted state (see Table 24 ). In addition, the effects of varying gastric administration conditions on the C max and AUC of posaconazole oral suspension in healthy volunteers have been investigated and are shown in Table 25 . To assure attainment of adequate plasma concentrations, it is recommended to administer posaconazole oral suspension during or immediately following a full meal. In patients who cannot eat a full meal, posaconazole oral suspension should be taken with a liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale). Table 24: The Mean (%CV) [min-max] Posaconazole Pharmacokinetic Parameters Following Single-Dose Oral Suspension Administration of 200 mg and 400 mg Under Fed and Fasted Conditions Dose (mg) C max (ng/mL) T max Median [min-max]. (hr) AUC (I) (ng∙hr/mL) CL/F (L/hr) t ½ (hr) 200 mg fasted (n=20) n=15 for AUC (I), CL/F, and t 1/2 132 (50) [45 to 267] 3.50 [1.5 to 36 The subject with T max of 36 hrs had relatively constant plasma levels over 36 hrs (1.7 ng/mL difference between 4 hrs and 36 hrs). ] 4179 (31) [2,705 to 7,269] 51 (25) [28 to 74] 23.5 (25) [15.3 to 33.7] 200 mg nonfat (n=20) 378 (43) [131 to 834] 4 [3 to 5] 10,753 (35) [4,579 to 17,092] 21 (39) [12 to 44] 22.2 (18) [17.4 to 28.7] 200 mg high fat (54 gm fat) (n=20) 512 (34) [241 to 1,016] 5 [4 to 5] 15,059 (26) [10,341 to 24,476] 14 (24) [8.2 to 19] 23.0 (19) [17.2 to 33.4] 400 mg fasted (n=23) n=10 for AUC (I), CL/F, and t 1/2 121 (75) [27 to 366] 4 [2 to 12] 5258 (48) [2,834 to 9,567] 91 (40) [42 to 141] 27.3 (26) [16.8 to 38.9] 400 mg with liquid nutritional supplement (14 gm fat) (n=23) 355 (43) [145 to 720] 5 [4 to 8] 11,295 (40) [3,865 to 20,592] 43 (56) [19 to 103] 26.0 (19) [18.2 to 35.0] Table 25: The Effect of Varying Gastric Administration Conditions on the C max and AUC of Posaconazole Oral Suspension in Healthy Volunteers In 5 subjects, the C max and AUC decreased substantially (range: -27% to -53% and -33% to -51%, respectively) when posaconazole was administered via an NG tube compared to when posaconazole was administered orally. It is recommended to closely monitor patients for breakthrough fungal infections when posaconazole is administered via an NG tube because a lower plasma exposure may be associated with an increased risk of treatment failure. Study Description Administration Arms Change in C max (ratio estimate Ratio Estimate is the ratio of coadministered drug plus posaconazole to coadministered drug alone for C max or AUC. ; 90% CI of the ratio estimate) Change in AUC (ratio estimate ; 90% CI of the ratio estimate) 400 mg single dose with a high-fat meal relative to fasted state (n=12) 5 minutes before high-fat meal ↑96% (1.96; 1.48 to 2.59) ↑111% (2.11; 1.60 to 2.78) During high-fat meal ↑339% (4.39; 3.32 to 5.80) ↑382% (4.82; 3.66 to 6.35) 20 minutes after high-fat meal ↑333% (4.33; 3.28 to 5.73) ↑387% (4.87; 3.70 to 6.42) 400 mg twice daily and 200 mg four times daily for 7 days in fasted state and with liquid nutritional supplement (BOOST ® ) (n=12) 400 mg twice daily with BOOST ↑65% (1.65; 1.29 to 2.11) ↑66% (1.66; 1.30 to 2.13) 200 mg four times daily with BOOST No Effect No Effect Divided daily dose from 400 mg twice daily to 200 mg four times daily for 7 days regardless of fasted conditions or with BOOST (n=12) Fasted state ↑136% (2.36; 1.84 to 3.02) ↑161% (2.61; 2.04 to 3.35) With BOOST ↑137% (2.37; 1.86 to 3.04) ↑157% (2.57; 2.00 to 3.30) 400 mg single dose with carbonated acidic beverage (ginger ale) and/or proton pump inhibitor (esomeprazole) (n=12) Ginger ale ↑92% (1.92; 1.51 to 2.44) ↑70% (1.70; 1.43 to 2.03) Esomeprazole ↓32% (0.68; 0.53 to 0.86) ↓30% (0.70; 0.59 to 0.83) 400 mg single dose with a prokinetic agent (metoclopramide 10 mg three times a day for 2 days) + BOOST or an antikinetic agent (loperamide 4 mg single dose) + BOOST (n=12) With metoclopramide + BOOST ↓21% (0.79; 0.72 to 0.87) ↓19% (0.81; 0.72 to 0.91) With loperamide + BOOST ↓3% (0.97; 0.88 to 1.07) ↑11% (1.11; 0.99 to 1.25) 400 mg single dose either orally with BOOST or via an NG tube with BOOST (n=16) Via NG tube NG = nasogastric ↓19% (0.81; 0.71 to 0.91) ↓23% (0.77; 0.69 to 0.86) Distribution: The mean volume of distribution of posaconazole after intravenous solution administration was 261 L and ranged from 226 to 295 L 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 2 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 a substrate for p-glycoprotein (P-gp) efflux. In vitro studies with human hepatic microsomes and clinical studies indicate that posaconazole is an inhibitor primarily of CYP3A4. Excretion: Following administration of posaconazole 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 a 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 oral suspension is eliminated with a mean half-life (t ½ ) of 35 hours (range: 20 to 66 hours). Specific Populations: No clinically significant differences in the pharmacokinetics of posaconazole were observed based on age, sex, renal impairment, and indication (prophylaxis or treatment). Patients with Renal Impairment: After posaconazole oral administration, there were no significant differences in the posaconazole pharmacokinetics in patients with eGFR 20 mL/minute/1.73 m 2 or higher compared to those with eGFR>80 mL/minute/1.73 m 2 . Although the mean posaconazole plasma exposure (AUC) was similar in patients with eGFR less than 20 mL/minute/1.73 m 2 treated with posaconazole oral suspension to those with eGFR >80 mL/minute/1.73 m 2 treated with posaconazole oral suspension, the range of the AUC estimates was highly variable (CV=96%) in patients with eGFR less than 20 mL/minute/1.73 m 2 compared to those with eGFR>80 mL/minute/1.73 m 2 (CV<40%). Patients with Hepatic Impairment: After a single oral dose of posaconazole 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 [see Use in Specific Populations ( 8.7 )]. Race/Ethnicity: In a 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 [see Use in Specific Populations ( 8.9 )] . Patients Weighing More Than 120 kg: Weight has a 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 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 Patients: A total of 12 patients 13 to 17 years of age received 600 mg/day (200 mg three times a day) of posaconazole 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 a study of 136 neutropenic pediatric patients 11 months to less than 18 years treated with posaconazole oral suspension, the exposure target of steady-state posaconazole Cavg between 500 ng/mL and less than 2500 ng/mL was attained in approximately 50% of patients instead of the prespecified 90% of patients. Drug Interaction Studies: Posaconazole is primarily metabolized via UDP glucuronidation (phase 2 enzymes) and is a substrate for p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. A summary of drugs studied clinically with the oral suspension or another tablet formulation, which affect posaconazole concentrations, is provided in Table 28 . Table 29 include a summary of the drug effects of concomitant medications that may impact the absorption of posaconazole when administered as either the oral suspension or delayed-release tablets. A clinical study in healthy volunteers also indicates that posaconazole is a strong CYP3A4 inhibitor as evidenced by a >5-fold increase in midazolam AUC. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole. A summary of the drugs studied clinically, for which plasma concentrations were affected by posaconazole, is provided in Table 31 [see Contraindications ( 4 ) and Drug Interactions ( 7.2 ) including recommendations] . Effects of Other Drugs on Posaconazole: Table 28: Summary of the Effects of Coadministered Drugs on Posaconazole in Healthy Volunteers Coadministered Drug (Postulated Mechanism of Interaction) Coadministered Drug Dose/Schedule Posaconazole Dose/Schedule Effect on Bioavailability of Posaconazole Change in Mean C max (ratio estimate Ratio Estimate is the ratio of coadministered drug plus posaconazole to posaconazole alone for C max 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 and 20 days 400 mg (oral suspension) twice daily × 10 and 20 days ↓ 45% (0.55; 0.47 to 0.66) ↓ 50% (0.50; 0.43 to 0.60) Fosamprenavir (unknown mechanism) 700 mg twice daily × 10 days 200 mg once daily on the 1 st day, 200 mg twice daily on the 2 nd day, then 400 mg twice daily × 8 days ↓ 21% 0.79 (0.71 to 0.89) ↓ 23% 0.77 (0.68 to 0.87) Rifabutin (UDP-G Induction) 300 mg once daily × 17 days 200 mg (tablets) once daily × 10 days The tablet refers to a non-commercial tablet formulation without polymer. ↓ 43% (0.57; 0.43 to 0.75) ↓ 49% (0.51; 0.37 to 0.71) Phenytoin (UDP-G Induction) 200 mg once daily × 10 days 200 mg (tablets) once daily × 10 days ↓ 41% (0.59; 0.44 to 0.79) ↓ 50% (0.50; 0.36 to 0.71) Posaconazole Oral Suspension: Concomitant administration of posaconazole oral suspension with drugs affecting gastric pH or gastric motility results in lower posaconazole exposure. (see Table 29 .) Table 29: The Effects of Concomitant Medications that Affect the Gastric pH and Gastric Motility on the Pharmacokinetics of Posaconazole Oral Suspension in Healthy Volunteers Coadministered Drug (Postulated Mechanism of Interaction) Coadministered Drug Dose/Schedule Posaconazole Dose/Schedule Effect on Bioavailability of Posaconazole Change in Mean C max (ratio estimate Ratio Estimate is the ratio of coadministered drug plus posaconazole to coadministered drug alone for C max or AUC. ; 90% CI of the ratio estimate) Change in Mean AUC (ratio estimate ; 90% CI of the ratio estimate) Cimetidine (Alteration of gastric pH) 400 mg twice daily × 10 days 200 mg (tablets) once daily × 10 days The tablet refers to a non-commercial tablet formulation without polymer. ↓ 39% (0.61; 0.53 to 0.70) ↓ 39% (0.61; 0.54 to 0.69) Esomeprazole (Increase in gastric pH) The drug interactions associated with the oral suspension are also relevant for the delayed-release tablet with the exception of Esomeprazole and Metoclopramide. 40 mg every morning × 3 days 400 mg (oral suspension) single dose ↓ 46% (0.54; 0.43 to 0.69) ↓ 32% (0.68; 0.57 to 0.81) Metoclopramide (Increase in gastric motility) 10 mg three times a day × 2 days 400 mg (oral suspension) single dose ↓ 21% (0.79; 0.72 to 0.87) ↓ 19% (0.81; 0.72 to 0.91) Effects of Posaconazole on Other Drugs: Table 31: Summary of the Effects of Posaconazole on Coadministered Drugs in Healthy Adult Volunteers and Patients Coadministered Drug (Postulated Mechanism of Interaction is Inhibition of CYP3A4 by posaconazole) Coadministered Drug Dose/Schedule Posaconazole Dose/Schedule Effect on Bioavailability of Coadministered Drugs Change in Mean C max (ratio estimate Ratio Estimate is the ratio of coadministered drug plus posaconazole to coadministered drug alone for C max or AUC. ; 90% CI of the ratio estimate) Change in Mean AUC (ratio estimate ; 90% CI of the ratio estimate) Sirolimus 2 mg single oral dose 400 mg (oral suspension) twice daily × 16 days ↑ 572% (6.72; 5.62 to 8.03) ↑ 788% (8.88; 7.26 to 10.9) Cyclosporine Stable maintenance dose in heart transplant recipients 200 mg (tablets) once daily × 10 days ↑ Cyclosporine whole blood trough concentrations Cyclosporine dose reductions of up to 29% were required Tacrolimus 0.05 mg/kg single oral dose 400 mg (oral suspension) twice daily × 7 days ↑ 121% (2.21; 2.01 to 2.42) ↑ 358% (4.58; 4.03 to 5.19) Simvastatin 40 mg single oral dose 100 mg (oral suspension) once daily × 13 days Simvastatin ↑ 841% (9.41, 7.13 to 12.44) Simvastatin Acid ↑ 817% (9.17, 7.36 to 11.43) Simvastatin ↑ 931% (10.31, 8.40 to 12.67) Simvastatin Acid ↑634% (7.34, 5.82 to 9.25) 200 mg (oral suspension) once daily × 13 days Simvastatin ↑ 1041% (11.41, 7.99 to 16.29) Simvastatin Acid ↑ 851% (9.51, 8.15 to 11.10) Simvastatin ↑ 960% (10.60, 8.63 to 13.02) Simvastatin Acid ↑ 748% (8.48, 7.04 to 10.23) Midazolam 0.4 mg single intravenous dose The mean terminal half-life of midazolam was increased from 3 hours to 7 to 11 hours during coadministration with posaconazole. 200 mg (oral suspension) twice daily × 7 days ↑ 30% (1.3; 1.13 to 1.48) ↑ 362% (4.62; 4.02 to 5.3) 0.4 mg single intravenous dose 400 mg (oral suspension) twice daily × 7 days ↑ 62% (1.62; 1.41 to 1.86) ↑ 524% (6.24; 5.43 to 7.16) 2 mg single oral dose 200 mg (oral suspension) once daily × 7 days ↑ 169% (2.69; 2.46 to 2.93) ↑ 470% (5.70; 4.82 to 6.74) 2 mg single oral dose 400 mg (oral suspension) twice daily × 7 days ↑ 138% (2.38; 2.13 to 2.66) ↑ 397% (4.97; 4.46 to 5.54) Rifabutin 300 mg once daily × 17 days 200 mg (tablets) once daily × 10 days The tablet refers to a non-commercial tablet formulation without polymer. ↑ 31% (1.31; 1.10 to 1.57) ↑ 72% (1.72; 1.51 to 1.95) Phenytoin 200 mg once daily PO × 10 days 200 mg (tablets) once daily × 10 days ↑ 16% (1.16; 0.85 to 1.57) ↑ 16% (1.16; 0.84 to 1.59) Ritonavir 100 mg once daily × 14 days 400 mg (oral suspension) twice daily × 7 days ↑ 49% (1.49; 1.04 to 2.15) ↑ 80% (1.8; 1.39 to 2.31) Atazanavir 300 mg once daily × 14 days 400 mg (oral suspension) twice daily × 7 days ↑ 155% (2.55; 1.89 to 3.45) ↑ 268% (3.68; 2.89 to 4.70) Atazanavir/ ritonavir boosted regimen 300 mg/100 mg once daily × 14 days 400 mg (oral suspension) twice daily × 7 days ↑ 53% (1.53; 1.13 to 2.07) ↑ 146% (2.46; 1.93 to 3.13) 12.4 Microbiology Mechanism of Action: Posaconazole blocks the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14α-demethylase responsible for the conversion of lanosterol to ergosterol in the fungal cell membrane. This results in an accumulation of methylated sterol precursors and a 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 a 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_pharmacology_table": [ "
Prophylaxis in AML/MDSNeutropenic patients who were receiving cytotoxic chemotherapy for AML or MDSProphylaxis 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 to 32254.722 to 55744.4
Quartile 2322 to 49037.0557 to 91520.6
Quartile 3490 to 73446.8915 to 1,56317.5
Quartile 4734 to 2,20027.81,563 to 3,65017.5
Cavg = the average posaconazole concentration when measured at steady state
", "
DoseOral suspension administrationCavg (ng/mL)AUCAUC (0 to 24 hr) for 200 mg three times a day and AUC (0 to 12 hr) for 400 mg twice daily (ng∙hr/mL)CL/F (L/hr)V/F (L)t½ (hr)
200 mg three times a dayHSCT recipients with GVHD (n=252)1,103 (67) [21.5 to 3,650]NDNot doneNDNDND
200 mg three times a dayNeutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia or myelodysplastic syndromes (n=215)583 (65) [89.7 to 2,200]15,900 (62) [4,100 to 56,100]51.2 (54) [10.7 to 146]2425 (39) [828 to 5,702]37.2 (39) [19.1 to 148]
400 mg twice dailyFebrile neutropenic patients or patients with refractory invasive fungal infections, Cavg n=24 (n=23)723 (86) [6.70 to 2,256]9093 (80) [1,564 to 26,794]76.1 (78) [14.9 to 256]3,088 (84) [407 to 13,140]31.7 (42) [12.4 to 67.3]
Cavg = the average posaconazole concentration when measured at steady state
", "
Dose (mg)Cmax (ng/mL)TmaxMedian [min-max]. (hr)AUC (I) (ng∙hr/mL)CL/F (L/hr)t½ (hr)
200 mg fasted (n=20)n=15 for AUC (I), CL/F, and t1/2132 (50) [45 to 267]3.50 [1.5 to 36The subject with Tmax of 36 hrs had relatively constant plasma levels over 36 hrs (1.7 ng/mL difference between 4 hrs and 36 hrs).]4179 (31) [2,705 to 7,269]51 (25) [28 to 74]23.5 (25) [15.3 to 33.7]
200 mg nonfat (n=20)378 (43) [131 to 834]4 [3 to 5]10,753 (35) [4,579 to 17,092]21 (39) [12 to 44]22.2 (18) [17.4 to 28.7]
200 mg high fat (54 gm fat) (n=20)512 (34) [241 to 1,016]5 [4 to 5]15,059 (26) [10,341 to 24,476]14 (24) [8.2 to 19]23.0 (19) [17.2 to 33.4]
400 mg fasted (n=23)n=10 for AUC (I), CL/F, and t1/2121 (75) [27 to 366]4 [2 to 12]5258 (48) [2,834 to 9,567]91 (40) [42 to 141]27.3 (26) [16.8 to 38.9]
400 mg with liquid nutritional supplement (14 gm fat) (n=23)355 (43) [145 to 720]5 [4 to 8]11,295 (40) [3,865 to 20,592]43 (56) [19 to 103]26.0 (19) [18.2 to 35.0]
", "
Table 25: The Effect of Varying Gastric Administration Conditions on the Cmax and AUC of Posaconazole Oral Suspension in Healthy VolunteersIn 5 subjects, the Cmax and AUC decreased substantially (range: -27% to -53% and -33% to -51%, respectively) when posaconazole was administered via an NG tube compared to when posaconazole was administered orally. It is recommended to closely monitor patients for breakthrough fungal infections when posaconazole is administered via an NG tube because a lower plasma exposure may be associated with an increased risk of treatment failure.
Study DescriptionAdministration ArmsChange in 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 AUC (ratio estimate; 90% CI of the ratio estimate)
400 mg single dose with a high-fat meal relative to fasted state (n=12) 5 minutes before high-fat meal↑96% (1.96; 1.48 to 2.59)↑111% (2.11; 1.60 to 2.78)
During high-fat meal↑339% (4.39; 3.32 to 5.80)↑382% (4.82; 3.66 to 6.35)
20 minutes after high-fat meal↑333% (4.33; 3.28 to 5.73)↑387% (4.87; 3.70 to 6.42)
400 mg twice daily and 200 mg four times daily for 7 days in fasted state and with liquid nutritional supplement (BOOST®) (n=12)400 mg twice daily with BOOST↑65% (1.65; 1.29 to 2.11)↑66% (1.66; 1.30 to 2.13)
200 mg four times daily with BOOSTNo EffectNo Effect
Divided daily dose from 400 mg twice daily to 200 mg four times daily for 7 days regardless of fasted conditions or with BOOST (n=12)Fasted state↑136% (2.36; 1.84 to 3.02)↑161% (2.61; 2.04 to 3.35)
With BOOST↑137% (2.37; 1.86 to 3.04)↑157% (2.57; 2.00 to 3.30)
400 mg single dose with carbonated acidic beverage (ginger ale) and/or proton pump inhibitor (esomeprazole) (n=12)Ginger ale↑92% (1.92; 1.51 to 2.44)↑70% (1.70; 1.43 to 2.03)
Esomeprazole↓32% (0.68; 0.53 to 0.86)↓30% (0.70; 0.59 to 0.83)
400 mg single dose with a prokinetic agent (metoclopramide 10 mg three times a day for 2 days) + BOOST or an antikinetic agent (loperamide 4 mg single dose) + BOOST (n=12)With metoclopramide + BOOST↓21% (0.79; 0.72 to 0.87)↓19% (0.81; 0.72 to 0.91)
With loperamide + BOOST↓3% (0.97; 0.88 to 1.07)↑11% (1.11; 0.99 to 1.25)
400 mg single dose either orally with BOOST or via an NG tube with BOOST (n=16)Via NG tubeNG = nasogastric↓19% (0.81; 0.71 to 0.91)↓23% (0.77; 0.69 to 0.86)
", "
Coadministered Drug (Postulated Mechanism of Interaction)Coadministered Drug Dose/SchedulePosaconazole Dose/ScheduleEffect on Bioavailability of Posaconazole
Change 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 and 20 days400 mg (oral suspension) twice daily × 10 and 20 days↓ 45% (0.55; 0.47 to 0.66)↓ 50% (0.50; 0.43 to 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 days↓ 21% 0.79 (0.71 to 0.89)↓ 23% 0.77 (0.68 to 0.87)
Rifabutin (UDP-G Induction)300 mg once daily × 17 days200 mg (tablets) once daily × 10 daysThe tablet refers to a non-commercial tablet formulation without polymer.↓ 43% (0.57; 0.43 to 0.75)↓ 49% (0.51; 0.37 to 0.71)
Phenytoin(UDP-G Induction)200 mg once daily × 10 days200 mg (tablets) once daily × 10 days↓ 41% (0.59; 0.44 to 0.79)↓ 50% (0.50; 0.36 to 0.71)
", "
Coadministered Drug (Postulated Mechanism of Interaction)Coadministered Drug Dose/SchedulePosaconazole Dose/ScheduleEffect on Bioavailability of Posaconazole
Change 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)
Cimetidine (Alteration of gastric pH)400 mg twice daily × 10 days200 mg (tablets) once daily × 10 daysThe tablet refers to a non-commercial tablet formulation without polymer.↓ 39% (0.61; 0.53 to 0.70)↓ 39% (0.61; 0.54 to 0.69)
Esomeprazole (Increase in gastric pH)The drug interactions associated with the oral suspension are also relevant for the delayed-release tablet with the exception of Esomeprazole and Metoclopramide.40 mg every morning × 3 days400 mg (oral suspension) single dose↓ 46% (0.54; 0.43 to 0.69)↓ 32% (0.68; 0.57 to 0.81)
Metoclopramide (Increase in gastric motility)10 mg three times a day × 2 days400 mg (oral suspension) single dose↓ 21% (0.79; 0.72 to 0.87)↓ 19% (0.81; 0.72 to 0.91)
", "
Coadministered Drug (Postulated Mechanism of Interaction is Inhibition of CYP3A4 by posaconazole)Coadministered Drug Dose/SchedulePosaconazole Dose/ScheduleEffect on Bioavailability of Coadministered Drugs
Change 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 (oral suspension) twice daily × 16 days↑ 572% (6.72; 5.62 to 8.03)↑ 788% (8.88; 7.26 to 10.9)
CyclosporineStable maintenance dose in heart transplant recipients200 mg (tablets) once daily × 10 days↑ Cyclosporine whole blood trough concentrations Cyclosporine dose reductions of up to 29% were required
Tacrolimus0.05 mg/kg single oral dose400 mg (oral suspension) twice daily × 7 days↑ 121% (2.21; 2.01 to 2.42)↑ 358% (4.58; 4.03 to 5.19)
Simvastatin40 mg single oral dose100 mg (oral suspension) once daily × 13 daysSimvastatin ↑ 841% (9.41, 7.13 to 12.44) Simvastatin Acid ↑ 817% (9.17, 7.36 to 11.43)Simvastatin ↑ 931% (10.31, 8.40 to 12.67) Simvastatin Acid ↑634% (7.34, 5.82 to 9.25)
200 mg (oral suspension) once daily × 13 daysSimvastatin ↑ 1041% (11.41, 7.99 to 16.29) Simvastatin Acid ↑ 851% (9.51, 8.15 to 11.10)Simvastatin ↑ 960% (10.60, 8.63 to 13.02) Simvastatin Acid ↑ 748% (8.48, 7.04 to 10.23)
Midazolam0.4 mg single intravenous doseThe mean terminal half-life of midazolam was increased from 3 hours to 7 to 11 hours during coadministration with posaconazole.200 mg (oral suspension) twice daily × 7 days↑ 30% (1.3; 1.13 to 1.48)↑ 362% (4.62; 4.02 to 5.3)
0.4 mg single intravenous dose400 mg (oral suspension) twice daily × 7 days↑ 62% (1.62; 1.41 to 1.86)↑ 524% (6.24; 5.43 to 7.16)
2 mg single oral dose200 mg (oral suspension) once daily × 7 days↑ 169% (2.69; 2.46 to 2.93)↑ 470% (5.70; 4.82 to 6.74)
2 mg single oral dose400 mg (oral suspension) twice daily × 7 days↑ 138% (2.38; 2.13 to 2.66)↑ 397% (4.97; 4.46 to 5.54)
Rifabutin300 mg once daily × 17 days200 mg (tablets) once daily × 10 daysThe tablet refers to a non-commercial tablet formulation without polymer.↑ 31% (1.31; 1.10 to 1.57)↑ 72% (1.72; 1.51 to 1.95)
Phenytoin200 mg once daily PO × 10 days200 mg (tablets) once daily × 10 days↑ 16% (1.16; 0.85 to 1.57)↑ 16% (1.16; 0.84 to 1.59)
Ritonavir100 mg once daily × 14 days400 mg (oral suspension) twice daily × 7 days↑ 49% (1.49; 1.04 to 2.15)↑ 80% (1.8; 1.39 to 2.31)
Atazanavir300 mg once daily × 14 days400 mg (oral suspension) twice daily × 7 days↑ 155% (2.55; 1.89 to 3.45)↑ 268% (3.68; 2.89 to 4.70)
Atazanavir/ ritonavir boosted regimen300 mg/100 mg once daily × 14 days400 mg (oral suspension) twice daily × 7 days↑ 53% (1.53; 1.13 to 2.07)↑ 146% (2.46; 1.93 to 3.13)
" ], "mechanism_of_action": [ "12.1 Mechanism of Action Posaconazole is an azole antifungal agent [see Clinical Pharmacology ( 12.4 )] ." ], "pharmacodynamics": [ "12.2 Pharmacodynamics Exposure Response Relationship: Prophylaxis of Invasive Aspergillus and Candida Infections in Adults Who Are at High Risk of Developing These Infections Due to Being Severely Immunocompromised : 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), a wide range of plasma posaconazole exposures was noted following administration of posaconazole oral suspension. A pharmacokinetic-pharmacodynamic analysis of patient data revealed an apparent association between average posaconazole concentrations (Cavg) and prophylactic efficacy ( Table 18 ). A 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 18: Posaconazole Oral Suspension Exposure Analysis (Cavg) in Prophylaxis Trials Prophylaxis in AML/MDS Neutropenic patients who were receiving cytotoxic chemotherapy for AML or MDS Prophylaxis in GVHD HSCT recipients with GVHD Cavg Range (ng/mL) Treatment Failure Defined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections (%) Cavg Range (ng/mL) Treatment Failure (%) Quartile 1 90 to 322 54.7 22 to 557 44.4 Quartile 2 322 to 490 37.0 557 to 915 20.6 Quartile 3 490 to 734 46.8 915 to 1,563 17.5 Quartile 4 734 to 2,200 27.8 1,563 to 3,650 17.5 Cavg = the average posaconazole concentration when measured at steady state Exposure Response Relationship Treatment of Invasive Aspergillosis in Adult and Adolescent Patients Across a range of posaconazole plasma minimum concentrations (C min , range: 244 to 5,663 ng/mL) following administration of posaconazole injection and posaconazole delayed-release tablets in adult and pediatric patients aged 14 years and older treated for invasive aspergillosis in Aspergillosis Treatment Study, there was no association between posaconazole C min and treatment efficacy [see Clinical Pharmacology ( 12.3 )] . Similarly, across a range of population pharmacokinetic model-predicted steady-state plasma average concentrations (Cavg, range: 589 to 6,315 ng/mL), there was no association between posaconazole Cavg and treatment efficacy." ], "pharmacodynamics_table": [ "
Prophylaxis in AML/MDSNeutropenic patients who were receiving cytotoxic chemotherapy for AML or MDSProphylaxis 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 to 32254.722 to 55744.4
Quartile 2322 to 49037.0557 to 91520.6
Quartile 3490 to 73446.8915 to 1,56317.5
Quartile 4734 to 2,20027.81,563 to 3,65017.5
Cavg = the average posaconazole concentration when measured at steady state
" ], "pharmacokinetics": [ "12.3 Pharmacokinetics General Pharmacokinetic Characteristics Dose-proportional increases in plasma exposure (AUC) to posaconazole oral suspension were observed following single oral doses from 50 mg to 800 mg and following multiple-dose administration from 50 mg twice daily to 400 mg twice daily in healthy volunteers. No further increases in exposure were observed when the dose of the oral suspension increased from 400 mg twice daily to 600 mg twice daily in febrile neutropenic patients or those with refractory invasive fungal infections. The mean (%CV) [min-max] posaconazole oral suspension average steady-state plasma concentrations (Cavg) and steady-state pharmacokinetic parameters in patients following administration of 200 mg three times a day and 400 mg twice daily of the oral suspension are provided in Table 22. Table 22: The Mean (%CV) [min-max] Posaconazole Steady-State Pharmacokinetic Parameters in Patients Following Oral Administration of Posaconazole Oral Suspension 200 mg Three Times a Day and 400 mg Twice Daily Dose Oral suspension administration Cavg (ng/mL) AUC AUC (0 to 24 hr) for 200 mg three times a day and AUC (0 to 12 hr) for 400 mg twice daily (ng∙hr/mL) CL/F (L/hr) V/F (L) t ½ (hr) 200 mg three times a day HSCT recipients with GVHD (n=252) 1,103 (67) [21.5 to 3,650] ND Not done ND ND ND 200 mg three times a day Neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia or myelodysplastic syndromes (n=215) 583 (65) [89.7 to 2,200] 15,900 (62) [4,100 to 56,100] 51.2 (54) [10.7 to 146] 2425 (39) [828 to 5,702] 37.2 (39) [19.1 to 148] 400 mg twice daily Febrile neutropenic patients or patients with refractory invasive fungal infections, Cavg n=24 (n=23) 723 (86) [6.70 to 2,256] 9093 (80) [1,564 to 26,794] 76.1 (78) [14.9 to 256] 3,088 (84) [407 to 13,140] 31.7 (42) [12.4 to 67.3] Cavg = the average posaconazole concentration when measured at steady state Absorption: Posaconazole oral suspension is absorbed with a median T max of ~3 to 5 hours. Steady-state plasma concentrations are attained at 7 to 10 days following multiple-dose administration. Following single-dose administration of 200 mg, the mean AUC and C max of posaconazole are approximately 3 times higher when the oral suspension is administered with a nonfat meal and approximately 4 times higher when administered with a high-fat meal (~50 gm fat) relative to the fasted state. Following single-dose administration of posaconazole oral suspension 400 mg, the mean AUC and C max of posaconazole are approximately 3 times higher when administered with a liquid nutritional supplement (14 gm fat) relative to the fasted state (see Table 24 ). In addition, the effects of varying gastric administration conditions on the C max and AUC of posaconazole oral suspension in healthy volunteers have been investigated and are shown in Table 25 . To assure attainment of adequate plasma concentrations, it is recommended to administer posaconazole oral suspension during or immediately following a full meal. In patients who cannot eat a full meal, posaconazole oral suspension should be taken with a liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale). Table 24: The Mean (%CV) [min-max] Posaconazole Pharmacokinetic Parameters Following Single-Dose Oral Suspension Administration of 200 mg and 400 mg Under Fed and Fasted Conditions Dose (mg) C max (ng/mL) T max Median [min-max]. (hr) AUC (I) (ng∙hr/mL) CL/F (L/hr) t ½ (hr) 200 mg fasted (n=20) n=15 for AUC (I), CL/F, and t 1/2 132 (50) [45 to 267] 3.50 [1.5 to 36 The subject with T max of 36 hrs had relatively constant plasma levels over 36 hrs (1.7 ng/mL difference between 4 hrs and 36 hrs). ] 4179 (31) [2,705 to 7,269] 51 (25) [28 to 74] 23.5 (25) [15.3 to 33.7] 200 mg nonfat (n=20) 378 (43) [131 to 834] 4 [3 to 5] 10,753 (35) [4,579 to 17,092] 21 (39) [12 to 44] 22.2 (18) [17.4 to 28.7] 200 mg high fat (54 gm fat) (n=20) 512 (34) [241 to 1,016] 5 [4 to 5] 15,059 (26) [10,341 to 24,476] 14 (24) [8.2 to 19] 23.0 (19) [17.2 to 33.4] 400 mg fasted (n=23) n=10 for AUC (I), CL/F, and t 1/2 121 (75) [27 to 366] 4 [2 to 12] 5258 (48) [2,834 to 9,567] 91 (40) [42 to 141] 27.3 (26) [16.8 to 38.9] 400 mg with liquid nutritional supplement (14 gm fat) (n=23) 355 (43) [145 to 720] 5 [4 to 8] 11,295 (40) [3,865 to 20,592] 43 (56) [19 to 103] 26.0 (19) [18.2 to 35.0] Table 25: The Effect of Varying Gastric Administration Conditions on the C max and AUC of Posaconazole Oral Suspension in Healthy Volunteers In 5 subjects, the C max and AUC decreased substantially (range: -27% to -53% and -33% to -51%, respectively) when posaconazole was administered via an NG tube compared to when posaconazole was administered orally. It is recommended to closely monitor patients for breakthrough fungal infections when posaconazole is administered via an NG tube because a lower plasma exposure may be associated with an increased risk of treatment failure. Study Description Administration Arms Change in C max (ratio estimate Ratio Estimate is the ratio of coadministered drug plus posaconazole to coadministered drug alone for C max or AUC. ; 90% CI of the ratio estimate) Change in AUC (ratio estimate ; 90% CI of the ratio estimate) 400 mg single dose with a high-fat meal relative to fasted state (n=12) 5 minutes before high-fat meal ↑96% (1.96; 1.48 to 2.59) ↑111% (2.11; 1.60 to 2.78) During high-fat meal ↑339% (4.39; 3.32 to 5.80) ↑382% (4.82; 3.66 to 6.35) 20 minutes after high-fat meal ↑333% (4.33; 3.28 to 5.73) ↑387% (4.87; 3.70 to 6.42) 400 mg twice daily and 200 mg four times daily for 7 days in fasted state and with liquid nutritional supplement (BOOST ® ) (n=12) 400 mg twice daily with BOOST ↑65% (1.65; 1.29 to 2.11) ↑66% (1.66; 1.30 to 2.13) 200 mg four times daily with BOOST No Effect No Effect Divided daily dose from 400 mg twice daily to 200 mg four times daily for 7 days regardless of fasted conditions or with BOOST (n=12) Fasted state ↑136% (2.36; 1.84 to 3.02) ↑161% (2.61; 2.04 to 3.35) With BOOST ↑137% (2.37; 1.86 to 3.04) ↑157% (2.57; 2.00 to 3.30) 400 mg single dose with carbonated acidic beverage (ginger ale) and/or proton pump inhibitor (esomeprazole) (n=12) Ginger ale ↑92% (1.92; 1.51 to 2.44) ↑70% (1.70; 1.43 to 2.03) Esomeprazole ↓32% (0.68; 0.53 to 0.86) ↓30% (0.70; 0.59 to 0.83) 400 mg single dose with a prokinetic agent (metoclopramide 10 mg three times a day for 2 days) + BOOST or an antikinetic agent (loperamide 4 mg single dose) + BOOST (n=12) With metoclopramide + BOOST ↓21% (0.79; 0.72 to 0.87) ↓19% (0.81; 0.72 to 0.91) With loperamide + BOOST ↓3% (0.97; 0.88 to 1.07) ↑11% (1.11; 0.99 to 1.25) 400 mg single dose either orally with BOOST or via an NG tube with BOOST (n=16) Via NG tube NG = nasogastric ↓19% (0.81; 0.71 to 0.91) ↓23% (0.77; 0.69 to 0.86) Distribution: The mean volume of distribution of posaconazole after intravenous solution administration was 261 L and ranged from 226 to 295 L 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 2 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 a substrate for p-glycoprotein (P-gp) efflux. In vitro studies with human hepatic microsomes and clinical studies indicate that posaconazole is an inhibitor primarily of CYP3A4. Excretion: Following administration of posaconazole 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 a 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 oral suspension is eliminated with a mean half-life (t ½ ) of 35 hours (range: 20 to 66 hours). Specific Populations: No clinically significant differences in the pharmacokinetics of posaconazole were observed based on age, sex, renal impairment, and indication (prophylaxis or treatment). Patients with Renal Impairment: After posaconazole oral administration, there were no significant differences in the posaconazole pharmacokinetics in patients with eGFR 20 mL/minute/1.73 m 2 or higher compared to those with eGFR>80 mL/minute/1.73 m 2 . Although the mean posaconazole plasma exposure (AUC) was similar in patients with eGFR less than 20 mL/minute/1.73 m 2 treated with posaconazole oral suspension to those with eGFR >80 mL/minute/1.73 m 2 treated with posaconazole oral suspension, the range of the AUC estimates was highly variable (CV=96%) in patients with eGFR less than 20 mL/minute/1.73 m 2 compared to those with eGFR>80 mL/minute/1.73 m 2 (CV<40%). Patients with Hepatic Impairment: After a single oral dose of posaconazole 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 [see Use in Specific Populations ( 8.7 )]. Race/Ethnicity: In a 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 [see Use in Specific Populations ( 8.9 )] . Patients Weighing More Than 120 kg: Weight has a 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 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 Patients: A total of 12 patients 13 to 17 years of age received 600 mg/day (200 mg three times a day) of posaconazole 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 a study of 136 neutropenic pediatric patients 11 months to less than 18 years treated with posaconazole oral suspension, the exposure target of steady-state posaconazole Cavg between 500 ng/mL and less than 2500 ng/mL was attained in approximately 50% of patients instead of the prespecified 90% of patients. Drug Interaction Studies: Posaconazole is primarily metabolized via UDP glucuronidation (phase 2 enzymes) and is a substrate for p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. A summary of drugs studied clinically with the oral suspension or another tablet formulation, which affect posaconazole concentrations, is provided in Table 28 . Table 29 include a summary of the drug effects of concomitant medications that may impact the absorption of posaconazole when administered as either the oral suspension or delayed-release tablets. A clinical study in healthy volunteers also indicates that posaconazole is a strong CYP3A4 inhibitor as evidenced by a >5-fold increase in midazolam AUC. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole. A summary of the drugs studied clinically, for which plasma concentrations were affected by posaconazole, is provided in Table 31 [see Contraindications ( 4 ) and Drug Interactions ( 7.2 ) including recommendations] . Effects of Other Drugs on Posaconazole: Table 28: Summary of the Effects of Coadministered Drugs on Posaconazole in Healthy Volunteers Coadministered Drug (Postulated Mechanism of Interaction) Coadministered Drug Dose/Schedule Posaconazole Dose/Schedule Effect on Bioavailability of Posaconazole Change in Mean C max (ratio estimate Ratio Estimate is the ratio of coadministered drug plus posaconazole to posaconazole alone for C max 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 and 20 days 400 mg (oral suspension) twice daily × 10 and 20 days ↓ 45% (0.55; 0.47 to 0.66) ↓ 50% (0.50; 0.43 to 0.60) Fosamprenavir (unknown mechanism) 700 mg twice daily × 10 days 200 mg once daily on the 1 st day, 200 mg twice daily on the 2 nd day, then 400 mg twice daily × 8 days ↓ 21% 0.79 (0.71 to 0.89) ↓ 23% 0.77 (0.68 to 0.87) Rifabutin (UDP-G Induction) 300 mg once daily × 17 days 200 mg (tablets) once daily × 10 days The tablet refers to a non-commercial tablet formulation without polymer. ↓ 43% (0.57; 0.43 to 0.75) ↓ 49% (0.51; 0.37 to 0.71) Phenytoin (UDP-G Induction) 200 mg once daily × 10 days 200 mg (tablets) once daily × 10 days ↓ 41% (0.59; 0.44 to 0.79) ↓ 50% (0.50; 0.36 to 0.71) Posaconazole Oral Suspension: Concomitant administration of posaconazole oral suspension with drugs affecting gastric pH or gastric motility results in lower posaconazole exposure. (see Table 29 .) Table 29: The Effects of Concomitant Medications that Affect the Gastric pH and Gastric Motility on the Pharmacokinetics of Posaconazole Oral Suspension in Healthy Volunteers Coadministered Drug (Postulated Mechanism of Interaction) Coadministered Drug Dose/Schedule Posaconazole Dose/Schedule Effect on Bioavailability of Posaconazole Change in Mean C max (ratio estimate Ratio Estimate is the ratio of coadministered drug plus posaconazole to coadministered drug alone for C max or AUC. ; 90% CI of the ratio estimate) Change in Mean AUC (ratio estimate ; 90% CI of the ratio estimate) Cimetidine (Alteration of gastric pH) 400 mg twice daily × 10 days 200 mg (tablets) once daily × 10 days The tablet refers to a non-commercial tablet formulation without polymer. ↓ 39% (0.61; 0.53 to 0.70) ↓ 39% (0.61; 0.54 to 0.69) Esomeprazole (Increase in gastric pH) The drug interactions associated with the oral suspension are also relevant for the delayed-release tablet with the exception of Esomeprazole and Metoclopramide. 40 mg every morning × 3 days 400 mg (oral suspension) single dose ↓ 46% (0.54; 0.43 to 0.69) ↓ 32% (0.68; 0.57 to 0.81) Metoclopramide (Increase in gastric motility) 10 mg three times a day × 2 days 400 mg (oral suspension) single dose ↓ 21% (0.79; 0.72 to 0.87) ↓ 19% (0.81; 0.72 to 0.91) Effects of Posaconazole on Other Drugs: Table 31: Summary of the Effects of Posaconazole on Coadministered Drugs in Healthy Adult Volunteers and Patients Coadministered Drug (Postulated Mechanism of Interaction is Inhibition of CYP3A4 by posaconazole) Coadministered Drug Dose/Schedule Posaconazole Dose/Schedule Effect on Bioavailability of Coadministered Drugs Change in Mean C max (ratio estimate Ratio Estimate is the ratio of coadministered drug plus posaconazole to coadministered drug alone for C max or AUC. ; 90% CI of the ratio estimate) Change in Mean AUC (ratio estimate ; 90% CI of the ratio estimate) Sirolimus 2 mg single oral dose 400 mg (oral suspension) twice daily × 16 days ↑ 572% (6.72; 5.62 to 8.03) ↑ 788% (8.88; 7.26 to 10.9) Cyclosporine Stable maintenance dose in heart transplant recipients 200 mg (tablets) once daily × 10 days ↑ Cyclosporine whole blood trough concentrations Cyclosporine dose reductions of up to 29% were required Tacrolimus 0.05 mg/kg single oral dose 400 mg (oral suspension) twice daily × 7 days ↑ 121% (2.21; 2.01 to 2.42) ↑ 358% (4.58; 4.03 to 5.19) Simvastatin 40 mg single oral dose 100 mg (oral suspension) once daily × 13 days Simvastatin ↑ 841% (9.41, 7.13 to 12.44) Simvastatin Acid ↑ 817% (9.17, 7.36 to 11.43) Simvastatin ↑ 931% (10.31, 8.40 to 12.67) Simvastatin Acid ↑634% (7.34, 5.82 to 9.25) 200 mg (oral suspension) once daily × 13 days Simvastatin ↑ 1041% (11.41, 7.99 to 16.29) Simvastatin Acid ↑ 851% (9.51, 8.15 to 11.10) Simvastatin ↑ 960% (10.60, 8.63 to 13.02) Simvastatin Acid ↑ 748% (8.48, 7.04 to 10.23) Midazolam 0.4 mg single intravenous dose The mean terminal half-life of midazolam was increased from 3 hours to 7 to 11 hours during coadministration with posaconazole. 200 mg (oral suspension) twice daily × 7 days ↑ 30% (1.3; 1.13 to 1.48) ↑ 362% (4.62; 4.02 to 5.3) 0.4 mg single intravenous dose 400 mg (oral suspension) twice daily × 7 days ↑ 62% (1.62; 1.41 to 1.86) ↑ 524% (6.24; 5.43 to 7.16) 2 mg single oral dose 200 mg (oral suspension) once daily × 7 days ↑ 169% (2.69; 2.46 to 2.93) ↑ 470% (5.70; 4.82 to 6.74) 2 mg single oral dose 400 mg (oral suspension) twice daily × 7 days ↑ 138% (2.38; 2.13 to 2.66) ↑ 397% (4.97; 4.46 to 5.54) Rifabutin 300 mg once daily × 17 days 200 mg (tablets) once daily × 10 days The tablet refers to a non-commercial tablet formulation without polymer. ↑ 31% (1.31; 1.10 to 1.57) ↑ 72% (1.72; 1.51 to 1.95) Phenytoin 200 mg once daily PO × 10 days 200 mg (tablets) once daily × 10 days ↑ 16% (1.16; 0.85 to 1.57) ↑ 16% (1.16; 0.84 to 1.59) Ritonavir 100 mg once daily × 14 days 400 mg (oral suspension) twice daily × 7 days ↑ 49% (1.49; 1.04 to 2.15) ↑ 80% (1.8; 1.39 to 2.31) Atazanavir 300 mg once daily × 14 days 400 mg (oral suspension) twice daily × 7 days ↑ 155% (2.55; 1.89 to 3.45) ↑ 268% (3.68; 2.89 to 4.70) Atazanavir/ ritonavir boosted regimen 300 mg/100 mg once daily × 14 days 400 mg (oral suspension) twice daily × 7 days ↑ 53% (1.53; 1.13 to 2.07) ↑ 146% (2.46; 1.93 to 3.13)" ], "pharmacokinetics_table": [ "
DoseOral suspension administrationCavg (ng/mL)AUCAUC (0 to 24 hr) for 200 mg three times a day and AUC (0 to 12 hr) for 400 mg twice daily (ng∙hr/mL)CL/F (L/hr)V/F (L)t½ (hr)
200 mg three times a dayHSCT recipients with GVHD (n=252)1,103 (67) [21.5 to 3,650]NDNot doneNDNDND
200 mg three times a dayNeutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia or myelodysplastic syndromes (n=215)583 (65) [89.7 to 2,200]15,900 (62) [4,100 to 56,100]51.2 (54) [10.7 to 146]2425 (39) [828 to 5,702]37.2 (39) [19.1 to 148]
400 mg twice dailyFebrile neutropenic patients or patients with refractory invasive fungal infections, Cavg n=24 (n=23)723 (86) [6.70 to 2,256]9093 (80) [1,564 to 26,794]76.1 (78) [14.9 to 256]3,088 (84) [407 to 13,140]31.7 (42) [12.4 to 67.3]
Cavg = the average posaconazole concentration when measured at steady state
", "
Dose (mg)Cmax (ng/mL)TmaxMedian [min-max]. (hr)AUC (I) (ng∙hr/mL)CL/F (L/hr)t½ (hr)
200 mg fasted (n=20)n=15 for AUC (I), CL/F, and t1/2132 (50) [45 to 267]3.50 [1.5 to 36The subject with Tmax of 36 hrs had relatively constant plasma levels over 36 hrs (1.7 ng/mL difference between 4 hrs and 36 hrs).]4179 (31) [2,705 to 7,269]51 (25) [28 to 74]23.5 (25) [15.3 to 33.7]
200 mg nonfat (n=20)378 (43) [131 to 834]4 [3 to 5]10,753 (35) [4,579 to 17,092]21 (39) [12 to 44]22.2 (18) [17.4 to 28.7]
200 mg high fat (54 gm fat) (n=20)512 (34) [241 to 1,016]5 [4 to 5]15,059 (26) [10,341 to 24,476]14 (24) [8.2 to 19]23.0 (19) [17.2 to 33.4]
400 mg fasted (n=23)n=10 for AUC (I), CL/F, and t1/2121 (75) [27 to 366]4 [2 to 12]5258 (48) [2,834 to 9,567]91 (40) [42 to 141]27.3 (26) [16.8 to 38.9]
400 mg with liquid nutritional supplement (14 gm fat) (n=23)355 (43) [145 to 720]5 [4 to 8]11,295 (40) [3,865 to 20,592]43 (56) [19 to 103]26.0 (19) [18.2 to 35.0]
", "
Table 25: The Effect of Varying Gastric Administration Conditions on the Cmax and AUC of Posaconazole Oral Suspension in Healthy VolunteersIn 5 subjects, the Cmax and AUC decreased substantially (range: -27% to -53% and -33% to -51%, respectively) when posaconazole was administered via an NG tube compared to when posaconazole was administered orally. It is recommended to closely monitor patients for breakthrough fungal infections when posaconazole is administered via an NG tube because a lower plasma exposure may be associated with an increased risk of treatment failure.
Study DescriptionAdministration ArmsChange in 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 AUC (ratio estimate; 90% CI of the ratio estimate)
400 mg single dose with a high-fat meal relative to fasted state (n=12) 5 minutes before high-fat meal↑96% (1.96; 1.48 to 2.59)↑111% (2.11; 1.60 to 2.78)
During high-fat meal↑339% (4.39; 3.32 to 5.80)↑382% (4.82; 3.66 to 6.35)
20 minutes after high-fat meal↑333% (4.33; 3.28 to 5.73)↑387% (4.87; 3.70 to 6.42)
400 mg twice daily and 200 mg four times daily for 7 days in fasted state and with liquid nutritional supplement (BOOST®) (n=12)400 mg twice daily with BOOST↑65% (1.65; 1.29 to 2.11)↑66% (1.66; 1.30 to 2.13)
200 mg four times daily with BOOSTNo EffectNo Effect
Divided daily dose from 400 mg twice daily to 200 mg four times daily for 7 days regardless of fasted conditions or with BOOST (n=12)Fasted state↑136% (2.36; 1.84 to 3.02)↑161% (2.61; 2.04 to 3.35)
With BOOST↑137% (2.37; 1.86 to 3.04)↑157% (2.57; 2.00 to 3.30)
400 mg single dose with carbonated acidic beverage (ginger ale) and/or proton pump inhibitor (esomeprazole) (n=12)Ginger ale↑92% (1.92; 1.51 to 2.44)↑70% (1.70; 1.43 to 2.03)
Esomeprazole↓32% (0.68; 0.53 to 0.86)↓30% (0.70; 0.59 to 0.83)
400 mg single dose with a prokinetic agent (metoclopramide 10 mg three times a day for 2 days) + BOOST or an antikinetic agent (loperamide 4 mg single dose) + BOOST (n=12)With metoclopramide + BOOST↓21% (0.79; 0.72 to 0.87)↓19% (0.81; 0.72 to 0.91)
With loperamide + BOOST↓3% (0.97; 0.88 to 1.07)↑11% (1.11; 0.99 to 1.25)
400 mg single dose either orally with BOOST or via an NG tube with BOOST (n=16)Via NG tubeNG = nasogastric↓19% (0.81; 0.71 to 0.91)↓23% (0.77; 0.69 to 0.86)
", "
Coadministered Drug (Postulated Mechanism of Interaction)Coadministered Drug Dose/SchedulePosaconazole Dose/ScheduleEffect on Bioavailability of Posaconazole
Change 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 and 20 days400 mg (oral suspension) twice daily × 10 and 20 days↓ 45% (0.55; 0.47 to 0.66)↓ 50% (0.50; 0.43 to 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 days↓ 21% 0.79 (0.71 to 0.89)↓ 23% 0.77 (0.68 to 0.87)
Rifabutin (UDP-G Induction)300 mg once daily × 17 days200 mg (tablets) once daily × 10 daysThe tablet refers to a non-commercial tablet formulation without polymer.↓ 43% (0.57; 0.43 to 0.75)↓ 49% (0.51; 0.37 to 0.71)
Phenytoin(UDP-G Induction)200 mg once daily × 10 days200 mg (tablets) once daily × 10 days↓ 41% (0.59; 0.44 to 0.79)↓ 50% (0.50; 0.36 to 0.71)
", "
Coadministered Drug (Postulated Mechanism of Interaction)Coadministered Drug Dose/SchedulePosaconazole Dose/ScheduleEffect on Bioavailability of Posaconazole
Change 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)
Cimetidine (Alteration of gastric pH)400 mg twice daily × 10 days200 mg (tablets) once daily × 10 daysThe tablet refers to a non-commercial tablet formulation without polymer.↓ 39% (0.61; 0.53 to 0.70)↓ 39% (0.61; 0.54 to 0.69)
Esomeprazole (Increase in gastric pH)The drug interactions associated with the oral suspension are also relevant for the delayed-release tablet with the exception of Esomeprazole and Metoclopramide.40 mg every morning × 3 days400 mg (oral suspension) single dose↓ 46% (0.54; 0.43 to 0.69)↓ 32% (0.68; 0.57 to 0.81)
Metoclopramide (Increase in gastric motility)10 mg three times a day × 2 days400 mg (oral suspension) single dose↓ 21% (0.79; 0.72 to 0.87)↓ 19% (0.81; 0.72 to 0.91)
", "
Coadministered Drug (Postulated Mechanism of Interaction is Inhibition of CYP3A4 by posaconazole)Coadministered Drug Dose/SchedulePosaconazole Dose/ScheduleEffect on Bioavailability of Coadministered Drugs
Change 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 (oral suspension) twice daily × 16 days↑ 572% (6.72; 5.62 to 8.03)↑ 788% (8.88; 7.26 to 10.9)
CyclosporineStable maintenance dose in heart transplant recipients200 mg (tablets) once daily × 10 days↑ Cyclosporine whole blood trough concentrations Cyclosporine dose reductions of up to 29% were required
Tacrolimus0.05 mg/kg single oral dose400 mg (oral suspension) twice daily × 7 days↑ 121% (2.21; 2.01 to 2.42)↑ 358% (4.58; 4.03 to 5.19)
Simvastatin40 mg single oral dose100 mg (oral suspension) once daily × 13 daysSimvastatin ↑ 841% (9.41, 7.13 to 12.44) Simvastatin Acid ↑ 817% (9.17, 7.36 to 11.43)Simvastatin ↑ 931% (10.31, 8.40 to 12.67) Simvastatin Acid ↑634% (7.34, 5.82 to 9.25)
200 mg (oral suspension) once daily × 13 daysSimvastatin ↑ 1041% (11.41, 7.99 to 16.29) Simvastatin Acid ↑ 851% (9.51, 8.15 to 11.10)Simvastatin ↑ 960% (10.60, 8.63 to 13.02) Simvastatin Acid ↑ 748% (8.48, 7.04 to 10.23)
Midazolam0.4 mg single intravenous doseThe mean terminal half-life of midazolam was increased from 3 hours to 7 to 11 hours during coadministration with posaconazole.200 mg (oral suspension) twice daily × 7 days↑ 30% (1.3; 1.13 to 1.48)↑ 362% (4.62; 4.02 to 5.3)
0.4 mg single intravenous dose400 mg (oral suspension) twice daily × 7 days↑ 62% (1.62; 1.41 to 1.86)↑ 524% (6.24; 5.43 to 7.16)
2 mg single oral dose200 mg (oral suspension) once daily × 7 days↑ 169% (2.69; 2.46 to 2.93)↑ 470% (5.70; 4.82 to 6.74)
2 mg single oral dose400 mg (oral suspension) twice daily × 7 days↑ 138% (2.38; 2.13 to 2.66)↑ 397% (4.97; 4.46 to 5.54)
Rifabutin300 mg once daily × 17 days200 mg (tablets) once daily × 10 daysThe tablet refers to a non-commercial tablet formulation without polymer.↑ 31% (1.31; 1.10 to 1.57)↑ 72% (1.72; 1.51 to 1.95)
Phenytoin200 mg once daily PO × 10 days200 mg (tablets) once daily × 10 days↑ 16% (1.16; 0.85 to 1.57)↑ 16% (1.16; 0.84 to 1.59)
Ritonavir100 mg once daily × 14 days400 mg (oral suspension) twice daily × 7 days↑ 49% (1.49; 1.04 to 2.15)↑ 80% (1.8; 1.39 to 2.31)
Atazanavir300 mg once daily × 14 days400 mg (oral suspension) twice daily × 7 days↑ 155% (2.55; 1.89 to 3.45)↑ 268% (3.68; 2.89 to 4.70)
Atazanavir/ ritonavir boosted regimen300 mg/100 mg once daily × 14 days400 mg (oral suspension) twice daily × 7 days↑ 53% (1.53; 1.13 to 2.07)↑ 146% (2.46; 1.93 to 3.13)
" ], "microbiology": [ "12.4 Microbiology Mechanism of Action: Posaconazole blocks the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14α-demethylase responsible for the conversion of lanosterol to ergosterol in the fungal cell membrane. This results in an accumulation of methylated sterol precursors and a 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 a 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": [ "13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: No drug-related neoplasms were recorded in rats or mice treated with posaconazole for 2 years at doses higher than the clinical dose. In a 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 a 400 mg twice daily oral suspension regimen, respectively, based on steady-state AUC in healthy volunteers administered a high-fat meal (400 mg twice daily 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 a 400 mg twice daily oral suspension regimen. Mutagenesis: Posaconazole was not genotoxic or clastogenic when evaluated in bacterial mutagenicity (Ames), a chromosome aberration study in human peripheral blood lymphocytes, a Chinese hamster ovary cell mutagenicity study, and a mouse bone marrow micronucleus study. Impairment of Fertility: Posaconazole had no effect on fertility of male rats at a dose up to 180 mg/kg (1.7 × the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations in healthy volunteers) or female rats at a dose up to 45 mg/kg (2.2 × the 400 mg twice daily oral suspension regimen)." ], "carcinogenesis_and_mutagenesis_and_impairment_of_fertility": [ "13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: No drug-related neoplasms were recorded in rats or mice treated with posaconazole for 2 years at doses higher than the clinical dose. In a 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 a 400 mg twice daily oral suspension regimen, respectively, based on steady-state AUC in healthy volunteers administered a high-fat meal (400 mg twice daily 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 a 400 mg twice daily oral suspension regimen. Mutagenesis: Posaconazole was not genotoxic or clastogenic when evaluated in bacterial mutagenicity (Ames), a chromosome aberration study in human peripheral blood lymphocytes, a Chinese hamster ovary cell mutagenicity study, and a mouse bone marrow micronucleus study. Impairment of Fertility: Posaconazole had no effect on fertility of male rats at a dose up to 180 mg/kg (1.7 × the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations in healthy volunteers) or female rats at a dose up to 45 mg/kg (2.2 × the 400 mg twice daily oral suspension regimen)." ], "clinical_studies": [ "14 CLINICAL STUDIES 14.2 Prophylaxis of Aspergillus and Candida Infections with Posaconazole 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 (Posaconazole Oral Suspension Study 1) was a randomized, double-blind trial that compared posaconazole oral suspension (200 mg three times a 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 a 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 7 days and at 16 weeks post-randomization. The mean duration of therapy was comparable between the 2 treatment groups (80 days, posaconazole oral suspension; 77 days, fluconazole). Table 34 contains the results from Posaconazole Oral Suspension Study 1. Table 34: Results from Blinded Clinical Study in Prophylaxis of IFI in All Randomized Patients with Hematopoietic Stem Cell Transplant (HSCT) and Graft-vs.-Host Disease (GVHD): Posaconazole Oral Suspension Study 1 Posaconazole n=301 Fluconazole n=299 On therapy plus 7 days Clinical Failure Patients may have met more than one criterion defining failure. 50 (17%) 55 (18%) Failure due to: Proven/Probable IFI 7 (2%) 22 (7%) ( Aspergillus ) 3 (1%) 17 (6%) ( Candida ) 1 (<1%) 3 (1%) (Other) 3 (1%) 2 (1%) All Deaths Proven/probable fungal infection prior to death 22 (7%) 2 (<1%) 24 (8%) 6 (2%) SAF Use of systemic antifungal therapy (SAF) criterion is based on protocol definitions (empiric/IFI usage >4 consecutive days). 27 (9%) 25 (8%) Through 16 weeks Clinical Failure 95% confidence interval (posaconazole-fluconazole) = (-11.5%, +3.7%). 99 (33%) 110 (37%) Failure due to: Proven/Probable IFI 16 (5%) 27 (9%) ( Aspergillus ) 7 (2%) 21 (7%) ( Candida ) 4 (1%) 4 (1%) (Other) 5 (2%) 2 (1%) All Deaths Proven/probable fungal infection prior to death 58 (19%) 10 (3%) 59 (20%) 16 (5%) SAF 26 (9%) 30 (10%) Event free lost to follow-up Patients 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 (Posaconazole Oral Suspension Study 2) was a randomized, open-label study that compared posaconazole oral suspension (200 mg 3 times a day) with fluconazole suspension (400 mg once daily) or itraconazole oral solution (200 mg twice a day) as prophylaxis against IFIs in neutropenic patients who were receiving cytotoxic chemotherapy for AML or MDS. As in Posaconazole Oral Suspension Study 1, efficacy of prophylaxis was evaluated using a 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 7 days and 100 days post-randomization. The mean duration of therapy was comparable between the 2 treatment groups (29 days, posaconazole; 25 days, fluconazole or itraconazole). Table 35 contains the results from Posaconazole Oral Suspension Study 2. Table 35: Results from Open-Label Clinical Study 2 in Prophylaxis of IFI in All Randomized Patients with Hematologic Malignancy and Prolonged Neutropenia: Posaconazole Oral Suspension Study 2 Posaconazole n=304 Fluconazole/Itraconazole n=298 On therapy plus 7 days Clinical Failure 95% 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 IFI 7 (2%) 25 (8%) ( Aspergillus ) 2 (1%) 20 (7%) ( Candida ) 3 (1%) 2 (1%) (Other) 2 (1%) 3 (1%) All Deaths Proven/probable fungal infection prior to death 17 (6%) 1 (<1%) 25 (8%) 2 (1%) SAF Use 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-randomization Clinical Failure 158 (52%) 191 (64%) Failure due to: Proven/Probable IFI 14 (5%) 33 (11%) ( Aspergillus ) 2 (1%) 26 (9%) ( Candida ) 10 (3%) 4 (1%) (Other) 2 (1%) 3 (1%) All Deaths Proven/probable fungal infection prior to death 44 (14%) 2 (1%) 64 (21%) 16 (5%) SAF 98 (32%) 125 (42%) Event free lost to follow-up Patients 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, 2 clinical studies of prophylaxis were conducted with the posaconazole oral suspension. As seen in the accompanying tables ( Tables 34 and 35 ), clinical failure represented a composite endpoint of breakthrough IFI, mortality and use of systemic antifungal therapy. In Posaconazole Oral Suspension Study 1 ( Table 34 ), 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 Posaconazole Oral Suspension Study 2 ( Table 35 ) 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 Posaconazole Oral Suspension Study 1 [POS 58/301 (19%) vs. FLU 59/299 (20%)]; all-cause mortality was lower at 100 days for posaconazole-treated patients in Posaconazole Oral Suspension Study 2 [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. 14.3 Treatment of Oropharyngeal Candidiasis with Posaconazole Oral Suspension Posaconazole Oral Suspension Study 3 was a randomized, controlled, evaluator-blinded study in HIV-infected patients with oropharyngeal candidiasis. Patients were treated with posaconazole or fluconazole oral suspension (both posaconazole and fluconazole were given as follows: 100 mg twice a day for 1 day followed by 100 mg once a day for 13 days). Clinical and mycological outcomes were assessed after 14 days of treatment and at 4 weeks after the end of treatment. Patients who received at least 1 dose of study medication and had a positive oral swish culture of Candida species at baseline were included in the analyses (see Table 36 ). The majority of the subjects had C. albicans as the baseline pathogen. Clinical success at Day 14 (complete or partial resolution of all ulcers and/or plaques and symptoms) and clinical relapse rates (recurrence of signs or symptoms after initial cure or improvement) 4 weeks after the end of treatment were similar between the treatment arms (see Table 36 ). Mycologic eradication rates (absence of colony forming units in quantitative culture at the end of therapy, Day 14), as well as mycologic relapse rates (4 weeks after the end of treatment) were also similar between the treatment arms (see Table 36 ). Table 36: Posaconazole Oral Suspension Clinical Success, Mycological Eradication, and Relapse Rates in Oropharyngeal Candidiasis Posaconazole Fluconazole Clinical Success at End of Therapy (Day 14) 155/169 (91.7%) 148/160 (92.5%) Clinical Relapse (4 Weeks after End of Therapy) 45/155 (29.0%) 52/148 (35.1%) Mycological Eradication (Absence of CFU) at End of Therapy (Day 14) 88/169 (52.1%) 80/160 (50.0%) Mycological Relapse (4 Weeks after End of Treatment) 49/88 (55.6%) 51/80 (63.7%) Mycologic response rates, using a criterion for success as a posttreatment quantitative culture with ≤20 colony forming units (CFU/mL) were also similar between the two groups (posaconazole 68.0%, fluconazole 68.1%). The clinical significance of this finding is unknown. 14.4 Posaconazole Oral Suspension Treatment of Oropharyngeal Candidiasis Refractory to Treatment with Fluconazole or Itraconazole Posaconazole Oral Suspension Study 4 was a noncomparative study of posaconazole oral suspension in HIV-infected subjects with OPC that was refractory to treatment with fluconazole or itraconazole. An episode of OPC was considered refractory if there was failure to improve or worsening of OPC after a standard course of therapy with fluconazole greater than or equal to 100 mg/day for at least 10 consecutive days or itraconazole 200 mg/day for at least 10 consecutive days and treatment with either fluconazole or itraconazole had not been discontinued for more than 14 days prior to treatment with posaconazole. Of the 199 subjects enrolled in this study, 89 subjects met these strict criteria for refractory infection. Forty-five subjects with refractory OPC were treated with posaconazole oral suspension 400 mg twice daily for 3 days, followed by 400 mg once daily for 25 days with an option for further treatment during a 3-month maintenance period. Following a dosing amendment, a further 44 subjects were treated with posaconazole 400 mg twice daily for 28 days. The efficacy of posaconazole was assessed by the clinical success (cure or improvement) rate after 4 weeks of treatment. The clinical success rate was 74.2% (66/89). The clinical success rates for both the original and the amended dosing regimens were similar (73.3% and 75.0%, respectively)." ], "clinical_studies_table": [ "
Posaconazole n=301Fluconazole n=299
On therapy plus 7 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 DeathsProven/probable fungal infection prior to death22 (7%)2 (<1%)24 (8%)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 weeks
Clinical Failure95% 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 DeathsProven/probable fungal infection prior to death58 (19%) 10 (3%)59 (20%)16 (5%)
SAF26 (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%)
", "
Posaconazole n=304Fluconazole/Itraconazole n=298
On therapy plus 7 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 DeathsProven/probable fungal infection prior to death17 (6%)1 (<1%)25 (8%)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-randomization
Clinical Failure158 (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 DeathsProven/probable fungal infection prior to death44 (14%)2 (1%)64 (21%)16 (5%)
SAF98 (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%)
", "
PosaconazoleFluconazole
Clinical Success at End of Therapy (Day 14)155/169 (91.7%)148/160 (92.5%)
Clinical Relapse (4 Weeks after End of Therapy)45/155 (29.0%)52/148 (35.1%)
Mycological Eradication (Absence of CFU) at End of Therapy (Day 14)88/169 (52.1%)80/160 (50.0%)
Mycological Relapse (4 Weeks after End of Treatment)49/88 (55.6%)51/80 (63.7%)
" ], "how_supplied": [ "16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Posaconazole Oral Suspension Posaconazole oral suspension is a white to off-white, cherry brandy flavored oral suspension in 4-ounce (120 mL) amber glass bottles with child-resistant closures containing 105 mL of suspension (40 mg of posaconazole per mL). Supplied with each oral suspension bottle is a plastic dosing spoon calibrated for measuring 2.5 mL and 5 mL doses. NDC 0054-0449-49: Bottle of 105 mL 16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F); [See USP Controlled Room Temperature.] DO NOT FREEZE.", "16.1 How Supplied Posaconazole Oral Suspension Posaconazole oral suspension is a white to off-white, cherry brandy flavored oral suspension in 4-ounce (120 mL) amber glass bottles with child-resistant closures containing 105 mL of suspension (40 mg of posaconazole per mL). Supplied with each oral suspension bottle is a plastic dosing spoon calibrated for measuring 2.5 mL and 5 mL doses. NDC 0054-0449-49: Bottle of 105 mL" ], "storage_and_handling": [ "16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F); [See USP Controlled Room Temperature.] DO NOT FREEZE." ], "information_for_patients": [ "17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Important Administration Instructions Advise patients to take each dose of posaconazole oral suspension during or immediately (i.e., within 20 minutes) following a full meal. In patients who cannot eat a full meal, each dose of posaconazole oral suspension should be administered with a liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale) in order to enhance absorption. Instruct patients that if they miss a dose, they should take it as soon as they remember. However, if it is almost time for 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 Interactions Advise 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 a 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 Reactions Advise patients to inform their physician immediately if they: • notice a change in heart rate or heart rhythm, or have a 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. The trademarks referenced herein are owned by their respective companies. Distributed by: Hikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07922 C50000256/07 Revised May 2026" ], "spl_patient_package_insert": [ "Patient Information Posaconazole Oral Suspension (poe’ sa kon’ a zole) Rx only What is posaconazole oral suspension? Posaconazole oral suspension is a prescription medicine used in adults and children 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 is used in people who have an increased chance of getting these infections due to a weak immune system. These include people who have had a hematopoietic stem cell transplantation (bone marrow transplant) with graft versus host disease or those with a low white blood cell count due to chemotherapy for blood cancers (hematologic malignancies). Posaconazole oral suspension is used for: • prevention of fungal infections in adults and children 13 years of age and older. Posaconazole oral suspension is also used to treat a fungal infection called \"thrush\" caused by Candida in your mouth or throat area. Posaconazole oral suspension can be used as the first treatment for thrush, or as another treatment for thrush after itraconazole or fluconazole treatment has not worked. Posaconazole oral suspension is for adults and children 13 years of age and older. It is not known if Posaconazole oral suspension is safe and effective in children under 13 years of age for the treatment of thrush as the first treatment for thrush, or as another treatment for thrush after itraconazole or fluconazole treatment has not worked. Do not take posaconazole if you: • are allergic to posaconazole, any of the ingredients in posaconazole, or other azole antifungal medicines. See the end of this Patient Information leaflet for a complete list of ingredients in posaconazole. • are taking any of the following medicines: o sirolimus o pimozide o quinidine o certain statin medicines that lower cholesterol (atorvastatin, lovastatin, simvastatin) o 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 a new medicine without talking to your healthcare provider or pharmacist. Before you take posaconazole tell your healthcare provider about all of your medical conditions, including 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 a decrease in the posaconazole levels in your body. Efavirenz and fosamprenavir should not be taken with posaconazole. • are taking midazolam, a hypnotic and sedative medicine. • are taking vincristine, vinblastine and other “vinca alkaloids” (medicines used to treat cancer). • are taking venetoclax, a 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 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 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 can affect the way other medicines work, and other medicines can affect the way posaconazole works, 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 oral suspension. • cimetidine or esomeprazole. If you are taking these medicines, you should not take posaconazole oral suspension. Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure. Know the medicines you take. Keep a list of them with you to show your healthcare provider or pharmacist when you get a new medicine. How should I take posaconazole oral suspension? • Do not switch between posaconazole oral suspension and posaconazole delayed-release tablets or posaconazole powder for delayed-release oral suspension. • Take posaconazole exactly as your healthcare provider tells you to take it. • Your healthcare provider will tell you how much posaconazole to take and when to take it. • Take posaconazole for as long as your healthcare provider tells you to take it. • If you take too much posaconazole, call your healthcare provider or go to the nearest hospital emergency room right away. • Posaconazole oral suspension: o Shake posaconazole oral suspension well before use. o Take each dose of posaconazole oral suspension during or within 20 minutes after a full meal. If you cannot eat a full meal, take each dose of posaconazole oral suspension with a liquid nutritional supplement or an acidic carbonated beverage, like ginger ale. o A measured dosing spoon comes with your posaconazole oral suspension and is marked for doses of 2.5 mL and 5 mL . See Figure A and B. Figure A Figure B o Rinse the spoon with water after each dose of posaconazole oral suspension and before you store it away. o If you miss a dose, take it as soon as you remember. However, if it is almost time for the next dose, skip the missed dose and go back to the regular dosing schedule. Do not take a double dose to make up for the missed dose or take more than your prescribed dose. Follow the instructions from your healthcare provider on how much posaconazole you should take and when to take it. What are the possible side effects of posaconazole oral suspension? Posaconazole may cause serious side effects, including: • drug interactions with cyclosporine or tacrolimus. If you take posaconazole 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. 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 oral suspension, may cause heart rhythm problems. People who have certain heart problems or who take certain medicines have a 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. • new or worsening high blood pressure and low potassium levels in your blood (pseudoaldosteronism). Your healthcare provider should check your blood pressure and potassium levels. • 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. Your healthcare provider should do blood tests to check your liver while you are taking posaconazole. Call your healthcare provider right away if you have any of the following symptoms of liver problems: o itchy skin o feeling very tired o nausea or vomiting o flu-like symptoms o yellowing of your eyes or skin • increased amounts of midazolam in your blood. If you take posaconazole with midazolam, posaconazole 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. The most common side effects of posaconazole in adults include: • diarrhea • headache • nausea • coughing • fever • low potassium levels in the blood • vomiting If you take posaconazole oral suspension, 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. 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 I store posaconazole oral suspension? • Store posaconazole oral suspension at room temperature between 68°F to 77°F (20°C to 25°C). • Do not freeze posaconazole oral suspension. Safely throw away medicine that is out of date or no longer needed. Keep posaconazole and all medicines out of the reach of children. General information about the safe and effective use of posaconazole. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use posaconazole for a condition for which it was not prescribed. Do not give posaconazole 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 that is written for health professionals. What are the ingredients in posaconazole oral suspension? Active ingredient: posaconazole Inactive ingredients: cherry-brandy flavor, citric acid monohydrate, hydroxyethyl cellulose, glycerin, polyoxyl 35 castor oil, simethicone emulsion, sodium benzoate, sodium citrate, sorbitol solution, titanium dioxide, and water. The trademarks depicted in this piece are owned by their respective companies. This Patient Information has been approved by the U.S. Food and Drug Administration. Distributed by: Hikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07922 C50000256/07 Revised May 2026 Figure A - Dosing Spoon Figure B - Dosing Spoon Measures" ], "spl_patient_package_insert_table": [ "itchy skinfeeling very tirednausea or vomitingflu-like symptomsyellowing of your eyes or skin
o
o
o
o
o
", "diarrheaheadachenauseacoughingfeverlow potassium levels in the bloodvomiting
•
•
•
•
•
•
•
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