Posaconazole: uses, dosing, side effects & brands

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 Noxafil in adults are diarrhea, nausea, fever, vomiting, headache, coughing, and hypokalemia. ( 6.1 ) Pediatric Patients: Common adverse reactions (incidence >20% receiving 6 mg/kg Noxafil injection and Noxafil PowderMix for delayed-release oral suspension) in a study in pediatric patients are pyrexia, febrile neutropenia, vomiting, mucosal inflammation, pruritus, hypertension, hypokalemia, and stomatitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme LLC at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of Noxafil cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Treatment of Invasive Aspergillosis in Adults and Adolescents (Noxafil injection and Noxafil Delayed-Release Tablets) The…

Known hypersensitivity to posaconazole or other azole antifungal agents. ( 4.1 ) Coadministration of Noxafil with the following drugs is contraindicated; Noxafil 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 ) Noxafil PowderMix for delayed-release oral suspension is contraindicated in patients with known or suspected Hereditary Fructose Intolerance (HFI). ( 4.7 , 5.9 , 8.4 ) 4.1 Hypersensitivity Noxafil is contraindicated in persons with known hypersensitivity to posaconazole or other azole antifungal agents. 4.2 Use with Sirolimus Noxafil is contraindicated with sirolimus. Concomitant administration of Noxafil 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 Noxafil is contraindicated with CYP3A4 substrates that prolong the QT interval. Concomitant administration of Noxafil 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 Noxafil 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 Noxafil 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) ]. 4.7 Use of Noxafil PowderMix for Delayed-Release Oral Suspension in Patients with Hereditary Fructose Intolerance Noxafil PowderMix for delayed-release oral suspension is contraindicated in patients with known or suspected hereditary fructose intolerance (HFI) [see Warnings and Precautions (5.9) and Use in Specific Populations (8.4) ] .

Table 15 and Table 17 include drugs with clinically important drug interactions when administered concomitantly with Noxafil and Noxafil PowderMix and instructions for preventing or managing them. Table 16 includes important drug interactions specific to the absorption of posaconazole administered as either Noxafil oral suspension or Noxafil 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 Noxafil oral suspension or another posaconazole tablet formulation unless otherwise noted. All clinically important drug interactions with Noxafil 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 Noxafil injection, Noxafil delayed-release tablets, and Noxafil PowderMix for delayed-release oral suspension [see 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 The drug interactions with esomeprazole and metoclopramide do not apply to Noxafil tablets or Noxafil PowderMix ( 7.3 , 12.3 ). 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 ( 7.1 ) 7.1 Effects of Other Drugs on Noxafil and Noxafil PowderMix 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 Noxafil 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 Noxafil and Noxafil PowderMix When Administered Concomitantly with Other Drugs UDP-Glucuronidase Inducers Mechanism and Clinical Effect(s) Posaconazole is a UDP-glucuronosyltransferase substrate. Concomitant use of Noxafil 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 Noxafil 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 Noxafil Oral Suspension and Noxafil PowderMix Absorption When Administered Concomitantly with Other Drugs Noxafil Oral Suspension Cimetidine and Esomeprazole Mechanism and Clinical Effect(s) Concomitant use of Noxafil oral suspension with cimetidine or esomeprazole resulted in decreased posaconazole plasma concentrations [see Clinical Pharmacology (12.3) ], which may reduce effectiveness of Noxafil. Prevention or Management Avoid concomitant use of Noxafil 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 Noxafil oral suspension with metoclopramide decreased posaconazole plasma concentrations [see Clinical Pharmacology (12.3) ], which may reduce effectiveness of Noxafil oral suspension. Prevention or Management If Noxafil oral suspension is concomitantly administered with metoclopramide, closely monitor for breakthrough fungal infections. Noxafil Oral PowderMix Alcohol Mechanism and Clinical Effect(s) Posaconazole releases faster from Noxafil PowderMix in the presence of alcohol, which may interfere with Noxafil PowderMix’s delayed-release characteristics [see Clinical Pharmacology (12.3) ]. Prevention or Management Administration of Noxafil PowderMix with alcohol is not recommended. 7.2 Effects of Noxafil and Noxafil PowderMix on Other Drugs Posaconazole is a strong CYP3A4 inhibitor. Therefore, concomitant use of Noxafil may increase plasma concentrations of drugs that are CYP3A4 substrates [see Clinical Pharmacology (12.3) ] . Table 17: Drug Interactions Affecting Drugs Administered Concomitantly with Noxafil and Noxafil PowderMix 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 Noxafil. 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 Noxafil and Noxafil PowderMix Additional clinical studies demonstrated that no clinically important effects on zidovudine, lamivudine, indinavir, or caffeine were observed when administered with Noxafil 200 mg once daily; therefore, no dose adjustments are required for these drugs when coadministered with Noxafil 200 mg once daily. No clinically relevant effects on the pharmacokinetics of Noxafil delayed-release tablets were observed during concomitant use with antacids, H 2 -receptor antagonists and proton pump inhibitors, and metoclopramide [see Clinical Pharmacology (12.3) ] . No dosage adjustment of Noxafil delayed-release tablets or Noxafil PowderMix for delayed-release oral suspension is required during concomitant use with these drugs. No clinically relevant effects on the pharmacokinetics of Noxafil 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 Noxafil oral suspension is required during concomitant use with these drugs (other than cimetidine).