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NOXAFIL (Suspension)

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NOXAFIL (Suspension)
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Each dose of NOXAFIL should be administered with a full meal or with a liquid nutritional supplement in patients who can not eat a full meal. To enhance the oral absorption of posaconazole and optimize plasma concentrations: Shake NOXAFIL Oral Suspension well before use. A measured dosing spoon is provided, marked for doses of 2.5 mL and 5 mL. It is recommended that the spoon is rinsed with water after each administration and before storage.<br/>Renal Insufficiency: No dose adjustment is recommended for patients with renal dysfunction. However, the range of the posaconazole AUC estimates was highly variable (CV=96%) in subjects with severe renal insufficiency as compared to that in the other renal impairment groups (CV<40%). Due to the variability in exposure, patients with severe renal impairment should be monitored closely for breakthrough IFIs.<br/>Hepatic Insufficiency: The pharmacokinetic data in subjects with hepatic impairment was not sufficient to determine if dose adjustment is necessary in patients with hepatic dysfunction. It is recommended that posaconazole be used with caution in patients with hepatic impairment.
dailymed-instance:descripti...
NOXAFIL (posaconazole) is a triazole antifungal agent available as a suspension for oral administration. 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 CHFNOand a molecular weight of 700.8. The structural formula is: Posaconazole is a white powder and is insoluble in water. NOXAFIL Oral Suspension is a white, cherry-flavored immediate-release suspension containing 40 mg of posaconazole per mL and the following inactive ingredients: polysorbate 80, simethicone, sodium benzoate, sodium citrate dihydrate, citric acid monohydrate, glycerin, xanthan gum, liquid glucose, titanium dioxide, artificialcherry flavor, and purified water.
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Pharmacokinetics:<br/>Absorption: Posaconazole is absorbed with a median Tof ~3 to 5 hours. Dose proportional increases in plasma exposure (AUC) to posaconazole were observed following single oral doses from 50 mg to 800 mg and following multiple-dose administration from 50 mg BID to 400 mg BID. No further increases in exposure were observed when the dose was increased from 400 mg BID to 600 mg BID in febrile neutropenic patientsor those with refractory invasive fungal infections. 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 Cof posaconazole are approximately 3 times higher when 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 400 mg, the mean AUC and Cof posaconazole are approximately 3 times higher when administered with a liquid nutritional supplement (14 gm fat) relative to the fasted state (see TABLE 1). In order to assure attainment of adequate plasma concentrations, it is recommended to administer posaconazole with food or a nutritional supplement.<br/>Distribution: Posaconazole has an apparent volume of distribution of 1774 L, suggesting extensive extravascular distribution and penetration into the body tissues. Posaconazole is highly protein bound (>98%), predominantly to albumin.<br/>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.<br/>Excretion: Posaconazole is eliminated with a mean half-life (t) of 35 hours (range 20 to 66 hours) and a total body clearance (CL/F) of 32 L/hr. 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).<br/>Summary of Pharmacokinetic Parameters: The mean (%CV) [min���max] posaconazole average steady-state plasma concentrations (Cav) and steady-state pharmacokinetic parameters in patients following administration of 200 mg TID and 400 mg BID of the oral suspension are provided in TABLE 2. The variability in average plasma posaconazole concentrations in patients was relatively higher than that in healthy subjects.<br/>Exposure Response Relationship: In clinical studies of immunocompromised patients, a wide range of plasma exposures to posaconazole was noted. A pharmacokinetic-pharmacodynamic analysis of patient data revealed an apparent association between average posaconazole concentrations (Cav) and prophylactic efficacy. A lower Cav may be associated with an increased risk of treatment failure [defined in the study as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or invasive fungal infections (IFI)]. To enhance the oral absorption of posaconazole and optimize plasma concentrations:<br/>Pharmacokinetics in Special Populations:<br/>Gender: The pharmacokinetics of posaconazole are comparable in men and women. No adjustment in the dosage of NOXAFIL is necessary based on gender.<br/>Race: The pharmacokinetic profile of posaconazole is not significantly affected by race. No adjustment in the dosage of NOXAFIL is necessary based on race.<br/>Geriatric: The pharmacokinetics of posaconazole are comparable in young and elderly subjects (���65 years of age). No adjustment in the dosage of NOXAFIL is necessary in elderly patients (���65 years of age) based on age.<br/>Pediatric: In the prophylaxis studies, the mean steady-state posaconazole average concentration (Cav) was similar among ten adolescents (13���17 years of age) and adults (���18 years of age). This is consistent with pharmacokinetic data from another study in which mean steady-state posaconazole Cav from 12 adolescent patients (8���17 years of age) was similar to that in the adults (���18 years of age).<br/>Hepatic Insufficiency: The pharmacokinetic data in subjects with hepatic impairment was not sufficient to determine if dose adjustment is necessary in patients with hepatic dysfunction. It is recommended that posaconazole be used with caution in patients with hepatic impairment.<br/>Renal Insufficiency: Following single-dose administration of 400 mg of the oral suspension, there was no significant effect of mild (CLcr: 50���80 mL/min/1.73m, n=6) and moderate (CLcr: 20���49 mL/min/1.73m, n=6) renal insufficiency on posaconazole pharmacokinetics; therefore, no dose adjustment is required in patients with mild to moderate renal impairment. In subjects with severe renal insufficiency (CLcr:<20 mL/min/1.73m), the mean plasma exposure (AUC) was similar to that in patients with normal renal function (CLcr:>80 mL/min/1.73m); however, the range of the AUC estimates was highly variable (CV=96%) in these subjects with severe renal insufficiency as compared to that in the other renal impairment groups (CV<40%). Due to the variability in exposure, patients with severe renal impairment should be monitored closely for breakthrough fungal infections.<br/>Electrocardiogram Evaluation: 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���85 years of age) administered posaconazole 400 mg BID 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.<br/>Drug Interactions:<br/>Effect of Other Drugs on Posaconazole: 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, which affect posaconazole concentrations, is provided in TABLE 3. . Co-administration of these drugs listed in TABLE 3 with posaconazole may result in lower plasma concentrations of posaconazole. No clinically relevant effect on posaconazole bioavailability and/or plasma concentrations was observed when administered with an antacid, glipizide, ritonavir, H2 receptor antagonists other than cimetidine, or proton pump inhibitors; therefore, no posaconazole dose adjustments are required when used concomitantly with these products.<br/>Effect of Posaconazole on Other Drugs: In vitro studies with human hepatic microsomes and clinical studies indicate that posaconazole is an inhibitor primarily of CYP3A4. 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 4. Additional clinical studies demonstrated that no clinically significant effects on zidovudine, lamivudine, ritonavir, indinavir, or caffeine were observed when administered with posaconazole 200 mg QD; therefore, no dose adjustments are required for these co-administered drugs when co-administered with posaconazole 200 mgQD. Posaconazole administration with glipizide does not require a dose adjustment in either drug; however, glucose concentrations decreased in some healthy volunteers administered the combination. Therefore, glucose concentrations should be monitored in accordance with the current standard of care for patients with diabetes when posaconazole is co-administered with glipizide.
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Hypersensitivity to the active substance or to any of the excipients. Co-administration of NOXAFIL (posaconazole) with sirolimus is contraindicated. . Co-administration with ergot alkaloids. Co-administration with the CYP3A4 substrates terfenadine, astemizole, cisapride, pimozide, halofantrine, or quinidine since this may result in increased plasma concentrations of these medicinal products, leading to QTc prolongation and rare occurrences of torsades de pointes.
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NOXAFIL (posaconazole) Oral Suspension is available in 4-ounce (123 mL) amber glass bottles with child-resistant closures (NDC 0085-1328-01) containing 105 mL of suspension (40 mg of posaconazole per mL). Supplied with each bottle is a plastic dosing spoon calibrated for measuring 2.5-mL and 5-mL doses. Store at 25��C (77��F); excursions permitted to 15���30��C (59���86��F) [see USP Controlled Room Temperature]. DO NOT FREEZE.
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Arrhythmias and QT prolongation: Some azoles, including posaconazole, have been associated with prolongation of the QT interval on the electrocardiogram. Results from a multiple time-matched ECG analysis in healthy volunteers did not show any increase in the mean of the QTc interval. During clinical development there was one case of torsades de pointes ina patient taking posaconazole. This patient was seriously ill with multiple confounding risk factors including a history of cardiotoxic chemotherapy, hypokalemia, and concomitant medications that may have been contributory. Posaconazole should be administered with caution to patients with potentially proarrhythmic conditions and should not be administered with drugs that are known to prolong the QTc interval and are metabolized through CYP3A4. Rigorous attempts to correct potassium, magnesium, and calcium should be made before starting posaconazole.<br/>Information for Patients: Patients should be advised to:<br/>Drug Interactions: A summary of significant drug interactions with posaconazole that have been studied clinically are provided in TABLES 8 and 9. Appropriate precautions for the co-administration of these drugs with posaconazole are provided. Co-administration of these drugs listed in TABLE 8 with posaconazole may result in lower plasma concentrations of posaconazole. Although not studied in vitro or in vivo, posaconazole may affect the plasma concentrations of the drugs or drug classes described in TABLE 10. Appropriate precautions for the co-administration of these drugs with posaconazole are provided.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: No drug-related neoplasms were recorded in rats or mice treated with posaconazole for two years at doses below the maximum tolerated dose. In a two-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 BID regimen, respectively, based on steady-state AUC in healthy volunteers administered a high fat meal (400 mg BID regimen). In the mouse study, mice were treated at oral doses up to 60 mg/kg/dayor 4.8 times the exposure achieved with a 400 mg BID regimen. 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. Posaconazole had no effect on fertility of male rats at a dose up to 180 mg/kg (1.7��the 400 mg BID 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 BID regimen).<br/>Pregnancy:<br/>Pregnancy Category C: Posaconazole has been shown to cause skeletal malformations (cranial malformations and missing ribs) in rats when given in doses���27 mg/kg (���1.4 times the 400 mg BID regimen based on steady-state plasma concentrations of drug in healthy volunteers). The no-effect dose for malformations in rats was 9 mg/kg, which is 0.7 times the exposure achieved with the 400 mg BID regimen. No malformations were seen in rabbits at doses up to 80 mg/kg. In the rabbit, the no-effect dose was 20 mg/kg, while high doses of 40 mg/kg and 80 mg/kg, 2.9 or 5.2 times the exposure achieved with the 400 mg BID regimen, 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 was seen. There are no adequate and well-controlled studies in pregnant women. Posaconazole should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.<br/>Nursing Mothers: Posaconazole is excreted in milk of lactating rats. The excretion of posaconazole in human breast milk has not been investigated. NOXAFIL should not be used by nursing mothers unless the benefit to the mother clearly outweighs the potential risk to the infant.<br/>Pediatric Use: A total of 12 patients 13 to 17 years of age received 600 mg/day (200 mg three times a day) for prophylaxis of invasive fungal infections. The safety profile in these patients<18 years of age appears similar to the safety profile observed in adults. Based on pharmacokinetic data in 10 of these pediatric patients, the mean steady-state average posaconazole concentration (Cav) was similar between these patients and adults (���18 years of age). A total of 16 patients 8 to 17 years of age were treated with 800 mg/day (400 mg twice a day or 200 mg four times a day) in a study for another indication. Based on pharmacokinetic data in 12 of these pediatric patients, the mean steady-state average posaconazole concentration (Cav) was similar between these patients and adults (���18 years of age). Safety and effectiveness of posaconazole in pediatric patients below the age of 13 years have not been established.<br/>Geriatric Use: Of the 605 patients randomized to posaconazole in the prophylaxis clinical trials, 63 (10%) were���65 years of age. In addition, 48 patients treated with���800 mg/day posaconazole in another indication were���65 years of age. No overall differences in safety were observed between the geriatric patients and younger patients; therefore, no dosage adjustment is recommended for geriatric patients.
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During the clinical trials, some patients received posaconazole up to 1600 mg/day with no adverse events noted that were different from the lower doses. In addition, accidental overdose was noted in one patient who took 1200 mg BID for 3 days. No related adverse events were noted by the investigator. Posaconazole is not removed by hemodialysis.
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posaconazole
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NOXAFIL (Suspension)
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The safety of posaconazole therapy has been assessed in 1844 patients. This includes 605 patients in the prophylaxis studies, 796 in OPC/rOPC studies, and over 400 patients treated for other indications. Posaconazole therapy was given to 171 patients for���6 months, with 58 patients receiving posaconazole therapy for���12 months.<br/>Prophylaxis of Aspergillus and Candida: TABLE 11 presents treatment-emergent adverse events observed at an incidence>10% in posaconazole prophylaxis studies. TABLES 12 and 13 present treatment-related adverse events observed at an incidence���2% in the posaconazole prophylaxis studies. The most common treatment-related serious adverse events (1% each) in the combined prophylaxis studies were bilirubinemia, increased hepatic enzymes, hepatocellular damage, nausea, and vomiting.<br/>Overview of Adverse Events in HIV infected subjects with OPC: In two randomized comparative studies in OPC, the safety of posaconazole at a dose of���400 mg QD in 557 HIV infected patients was compared to the safety of fluconazole in 262 HIV infected patients at a dose of 100 mg QD. An additional 239 HIV infected patients with refractory OPC received posaconazole in 2 non-comparative trials for refractory OPC (rOPC). Of these subjects, 149 received the 800 mg/day dose and the remainder received the���400 mg QD dose. TABLE 14 presents Treatment-Emergent Adverse Events of Clinical Significance in the comparative and non-comparative studies of OPC. Treatment-related, treatment-emergent events observed in patients with OPC at an incidence of���2% are shown in TABLE 15. Adverse events were reported more frequently in the pool of patients with refractory OPC. Among these highly immunocompromised patients with advanced HIV disease, serious adverse events (SAEs) were reported in 55% (132/239). The most commonly reported SAEs were fever (13%) and neutropenia (10%). Treatment-related SAEs were reported for 14% (34/239) of these patients and included neutropenia (5%) and abdominal pain (2%). Posaconazole was discontinued in two patients who developed neutropenia that was considered serious and treatment-related. All other reported treatment-related SAEs occurred in���1% of subjects on posaconazole. Uncommon and rare treatment related serious or medically significant adverse events reported during clinical trials in prophylaxis, OPC/rOPC or other indications with posaconazole have included adrenal insufficiency, allergic and/or hypersensitivity reactions. Rare cases of hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, and pulmonary embolus have been reported primarily among patients who had been receiving concomitant cyclosporine or tacrolimus for management of transplant rejection or graft-vs-host disease. During clinical development there was a single case of torsade de pointes in a patient taking posaconazole. This report involved a seriously ill patient with multiple confounding, potentially contributory risk factors, such as a history of palpitations, recent cardiotoxic chemotherapy, hypokalemia, and hypomagnesemia. Additionally, in another indication, 428 patients were treated with���800 mg/day with a similar AE profile.<br/>Clinical Laboratory Values: In healthy volunteers and patients, elevation of liver function test values did not appear to be associated with higher plasma concentrations of posaconazole. The majority of abnormal liver function tests were minor, transient, and did not lead to discontinuation of therapy. For the prophylaxis studies, the number of patients with changes in liver function tests from Common Toxicity Criteria (CTC) Grade 0, 1, or 2 at baseline to Grade 3 or 4 during the study is presented in TABLE 16. The number of patients treated for OPC with clinically significant liver function test (LFT) abnormalities at any time during the studies is provided in TABLE 17 (LFT abnormalities were present in some of these patients prior to initiation of the study drug).
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Hypersensitivity: There is no information regarding cross-sensitivity between NOXAFIL and other azole antifungal agents. Caution should be used when prescribing NOXAFIL to patients with hypersensitivity to other azoles.<br/>Hepatic Toxicity: In clinical trials, there were infrequent cases of hepatic reactions (eg, mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin, and/or clinical hepatitis). The elevations in liver function tests were generally reversible on discontinuation of therapy, and in some instances these tests normalized without drug interruption and rarely required drug discontinuation. Rarely, more severe hepatic reactions including cholestasis or hepatic failure including fatalities were reported in patients with serious underlying medical conditions (eg, hematologic malignancy) during treatment with posaconazole. These severe hepatic events were seen primarily in subjects receiving the 800 mg daily (400 mg BID or 200mg QID) in another indication.<br/>Monitoring of hepatic function: Liver function tests should be evaluated at the start of and during the course of posaconazole therapy. Patients who develop abnormal liver function 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 function 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.<br/>Cyclosporine drug interaction: Cases of elevated cyclosporine levels resulting in rare serious adverse events, including nephrotoxicity and leukoencephalopathy, and death were reported in clinical efficacy studies. Dose reduction and more frequent clinical monitoring of cyclosporine, and tacrolimus, should be performed when posaconazole therapy is initiated.
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NOXAFIL (posaconazole) Oral Suspension is indicated for prophylaxis of invasive Aspergillus and Candida infections in 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. NOXAFIL (posaconazole) is indicated for the treatment of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole .
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NOXAFIL