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{{DrugProjectFormSinglePage |authorTag=Ammu Susheela, M.D. [1] |genericName=Posaconazole |aOrAn=an |drugClass=antifungal |indicationType=treatment |indication=Invasive Aspergillus (prophylaxis) and Candida infections, oropharyngeal Candidiasis including oropharyngeal candidiasis refractory to Itraconazole and/or Fluconazole |adverseReactions=hypokalemia, diarrhea, vomiting, headache, fever |blackBoxWarningTitle=ConditionName: |blackBoxWarningBody=ConditionName:
|fdaLIADAdult======Prophylaxis of Invasive Aspergillus and Candida Infections=====
Posaconazole injection, delayed-release tablets, and oral suspension are indicated for prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy.
Noxafil injection is indicated in patients 18 years of age and older.
Noxafil delayed-release tablets and oral suspension are indicated in patients 13 years of age and older.
1 Treatment of Oropharyngeal Candidiasis Including Oropharyngeal Candidiasis Refractory to Itraconazole and/or Fluconazole
3 Preparation
5 Administration Information
6 Use in Patients with Renal Impairment
7 Use with Sirolimus
8 QT Prolongation with Concomitant Use with CYP3A4 Substrates
9 HMG-CoA Reductase Inhibitors Primarily Metabolized Through CYP3A4
10 Use with Ergot Alkaloids
11 Arrhythmias and QT Prolongation
12 Hepatic Toxicity
13 Renal Impairment
14 Use with Midazolam
15 Clinical Trials Experience
16 Clinical Trial Experience with Posaconazole Injection
17 Clinical Trial Experience with Posaconazole Delayed-Release Tablets
18 Clinical Trial Safety Experience with Posaconazole Oral Suspension
19 Immunosuppressants Metabolized by CYP3A4
20 CYP3A4 Substrates
21 HMG-CoA Reductase Inhibitors (Statins) Primarily Metabolized Through CYP3A4
22 Ergot Alkaloids
23 Benzodiazepines Metabolized by CYP3A4
24 Anti-HIV Drugs
25 Rifabutin
26 Phenytoin
27 Gastric Acid Suppressors/Neutralizers
28 Vinca Alkaloids
29 Calcium Channel Blockers Metabolized by CYP3A4
30 Digoxin
31 Gastrointestinal Motility Agents
32 Glipizide
32.1 Posaconazole Injection
33 Excretion
34 Microbiology
35 Animal Toxicology and/or Pharmacology
36 Treatment of Oropharyngeal Candidiasis with Posaconazole Oral Suspension
37 Posaconazole Oral Suspension Treatment of Oropharyngeal Candidiasis Refractory to Treatment with Fluconazole or Itraconazole
38 Delayed-Release Tablets
39 Oral Suspension
40 Administration
40.1 Noxafil Delayed-Release Tablets
41 Noxafil Oral Suspension
42 Drug Interactions
43 Serious and Potentially Serious Adverse Reactions
Treatment of Oropharyngeal Candidiasis Including Oropharyngeal Candidiasis Refractory to Itraconazole and/or Fluconazole
Noxafil oral suspension is indicated for the treatment of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole.
The prescriber should follow the specific dosing instructions for each formulation.
Noxafil injection should be administered via a central venous line, including a central venous catheter or peripherally inserted central catheter (PICC), by slow intravenous infusion over approximately 90 minutes. If a central venous catheter is not available, Noxafil injection may be administered through a peripheral venous catheter by slow intravenous infusion over 30 minutes only as a single dose in advance of central venous line placement or to bridge the period during which a central venous line is replaced or is in use for other intravenous treatment. When multiple dosing is required, the infusion should be done via a central venous line. Never give Noxafil injection as an intravenous bolus injection.
The delayed-release tablet and oral suspension are not to be used interchangeably due to the differences in the dosing of each formulation.
Noxafil delayed-release tablets must be swallowed whole, and not be divided, crushed, or chewed. Noxafil delayed-release tablets should be taken with food.
Noxafil oral suspension should be administered 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.
Coadministration of drugs that can decrease the plasma concentrations of posaconazole should generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections.
Patients who have severe diarrhea or vomiting should be monitored closely for breakthrough fungal infections when receiving Noxafil delayed-release tablets or oral suspension.
This image is provided by the National Library of Medicine.
Equilibrate the refrigerated vial of posaconazole injection to room temperature.
Aseptically transfer 16.7 mL of posaconazole solution to an intravenous bag (or bottle) containing approximately 150 mL of 5% dextrose in water or sodium chloride 0.9%. Noxafil injection should only be administered with these diluents. Use of other infusion solutions may result in particulate formation.
Noxafil injection is a single dose sterile solution without preservatives. Once admixed, the product should be used immediately. If not used immediately, the solution can be stored up to 24 hours refrigerated 2-8°C (36-46°F). This medicinal product is for single use only and any unused solution should be discarded.
Parenteral drug products should be inspected visually for particulate matter prior to administration, whenever solution and container permit. Once admixed, the solution of Noxafil ranges from colorless to yellow. Variations of color within this range do not affect the quality of the product.
Intravenous Line Compatibility
A study was conducted to evaluate physical compatibility of Noxafil injection with injectable drug products and commonly used intravenous diluents during simulated Y-site infusion. Compatibility was determined through visual observations, measurement of particulate matter and turbidity.
Based on the results of the study, the following drug products and diluents can be infused at the same time through the same intravenous line (or cannula) as Noxafil injection. Co-administered drug products should be prepared in 5% dextrose in water or sodium chloride 0.9%. Co-administration of drug products prepared in other infusion solutions may result in particulate formation.
Any products or diluents not listed in the table above should not be coadministered through the same intravenous line (or cannula).
Noxafil injection must be administered through a 0.22 micron polyethersulfone (PES) or polyvinylidene difluoride (PVDF) filter.
Administer via a central venous line, including a central venous catheter or PICC by slow infusion over approximately 90 minutes. Noxafil injection is not for bolus administration.
If a central venous catheter is not available, Noxafil injection may be administered through a peripheral venous catheter only as a single dose in advance of central venous line placement or to bridge the period during which a central venous line is replaced or is in use for other treatment. When multiple dosing is required, the infusion should be done via a central venous line. When administered through a peripheral venous catheter, the infusion should be administered over approximately 30 minutes. Note: In clinical trials, multiple peripheral infusions given through the same vein resulted in infusion site reactions
It is recommended that the spoon is rinsed with water after each administration and before storage.
Administration Information
Noxafil delayed-release tablets:
Noxafil delayed-release tablets should be taken with food to enhance the oral absorption of posaconazole and optimize plasma concentrations.
Noxafil delayed-release tablets should be used only for the prophylaxis indication.
Noxafil delayed-release tablets generally provide higher plasma drug exposures than Noxafil oral suspension under both fed and fasted conditions, and therefore is the preferred oral formulation for the prophylaxis indication.
Noxafil oral suspension:
Each dose of Noxafil oral suspension should be administered during or immediately (i.e., within 20 minutes) following a full meal to enhance the oral absorption of posaconazole and optimize plasma concentrations.
In patients who cannot eat a full meal and for whom Noxafil delayed-release tablets or Noxafil injection are not options, each dose of Noxafil oral suspension should be administered with a liquid nutritional supplement or an acidic carbonated beverage.
In patients who cannot eat a full meal or tolerate an oral nutritional supplement or an acidic carbonated beverage and who do not have the option of taking Noxafil delayed-release tablets or Noxafil injection, an alternative antifungal therapy should be considered or patients should be monitored closely for breakthrough fungal infections.
Use in Patients with Renal Impairment
The pharmacokinetics of Noxafil oral suspension are not significantly affected by renal impairment. Therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment.
Noxafil injection should be avoided in patients with moderate or severe renal impairment (eGFR <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of Noxafil injection. In patients with moderate or severe renal impairment (estimated glomerular filtration rate (eGFR) <50 mL/min), receiving the Noxafil injection, accumulation of the intravenous vehicle, Betadex Sulfobutyl Ether Sodium (SBECD), is expected to occur. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral Noxafil therapy.
|offLabelAdultGuideSupport=* Allergic bronchopulmonary aspergillosis [1]
Aspergillosis, Invasive[1]
Aspergillosis, Invasive, in severely immunocompromised patients; Prophylaxis
Candidiasis of the esophagus, Recurrent; Prophylaxis - HIV infection
Candidiasis of the esophagus - HIV infection
|offLabelAdultNoGuideSupport=* Candidiasis of the esophagus[2]
Fusarium infection[3]
Mycosis
Necrotizing pulmonary aspergillosis, chronic, (Or cavitary)[2]
|fdaLIADPed=There is limited information regarding FDA-Labeled Use of Posaconazole in pediatric patients.
|offLabelPedGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Posaconazole in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding Off-Label Non–Guideline-Supported Use of Posaconazole in pediatric patients.
|contraindications======Hypersensitivity=====
Noxafil is contraindicated in persons with known hypersensitivity to posaconazole or other azole antifungal agents.
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.
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.
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.
Use with Ergot Alkaloids
Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism.
|warnings======Calcineurin-Inhibitor Drug Interactions=====
Concomitant administration of Noxafil with cyclosporine or tacrolimus increases the whole blood trough concentrations of these calcineurin-inhibitors.
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.
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 (18-85 years of age) administered posaconazole oral suspension 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.
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)]. Rigorous attempts to correct potassium, magnesium, and calcium should be made before starting posaconazole.
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 function 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 BID or 200 mg QID) in clinical trials.
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.
Due to the variability in exposure with Noxafil delayed-release tablets and oral suspension, patients with severe renal impairment should be monitored closely for breakthrough fungal infections.
Noxafil injection should be avoided in patients with moderate or severe renal impairment (eGFR <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of Noxafil injection. In patients with moderate or severe renal impairment (eGFR <50 mL/min), receiving the Noxafil injection, accumulation of the intravenous vehicle, SBECD, is expected to occur. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral Noxafil therapy.
Use with Midazolam
Concomitant administration of Noxafil 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.
|clinicalTrials======Serious and Otherwise Important Adverse Reactions=====
The following serious and otherwise important adverse reactions are reported.
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. In clinical trials, the type of adverse reactions reported for posaconazole injection and posaconazole delayed-release tablets were generally similar to that reported in trials of posaconazole oral suspension.
Clinical Trial Experience with Posaconazole Injection
Multiple doses of posaconazole injection administered via a peripheral venous catheter were associated with thrombophlebitis (60% incidence). Therefore, in subsequent studies, posaconazole injection was administered via central venous catheter.
The safety of posaconazole injection has been assessed in 268 patients in a clinical trial. Patients were enrolled in a non-comparative pharmacokinetic and safety trial of posaconazole injection when given as antifungal prophylaxis (Posaconazole Injection Study 1).
Patients were immunocompromised with underlying conditions including hematological malignancy, neutropenia post-chemotherapy, GVHD, and post HSCT. This patient population was 55% male, had a mean age of 51 years (range 18-82 years, 19% of patients were ≥65 years of age), and were 95% white and 8% Hispanic. Ten patients received a single dose of 200 mg posaconazole injection, 21 patients received 200 mg daily dose for a median of 14 days, and 237 patients received 300 mg daily dose for a median of 9 days.
Table 4 presents treatment-emergent adverse reactions observed in patients treated with posaconazole injection 300 mg daily dose in the posaconazole injection study. Each patient received a loading dose, 300 mg twice on Day 1. Following posaconazole intravenous therapy, patients received posaconazole oral suspension to complete 28 days of total posaconazole therapy.
The most frequently reported adverse reactions with an onset during the posaconazole intravenous phase of dosing with 300 mg once daily were diarrhea (32%), hypokalemia (22%), pyrexia (21%), and nausea (19%). These adverse reactions were consistent with those seen in studies with Noxafil oral suspension.
Clinical Trial Experience with Posaconazole Delayed-Release Tablets
The safety of posaconazole delayed-release tablets has been assessed in 230 patients in clinical trials. Patients were enrolled in a non-comparative pharmacokinetic and safety trial of posaconazole delayed-release tablets when given as antifungal prophylaxis (Delayed-Release Tablet Study 1). Patients were immunocompromised with underlying conditions including hematological malignancy, neutropenia post-chemotherapy, GVHD, and post HSCT. This patient population was 62% male, had a mean age of 51 years (range 19-78 years, 17% of patients were ≥65 years of age), and were 93% white and 16% Hispanic. Posaconazole therapy was given for a median duration of 28 days. Twenty patients received 200 mg daily dose and 210 patients received 300 mg daily dose (following twice daily dosing on Day 1 in each cohort).
Table 5 presents treatment-emergent adverse reactions observed in patients treated with 300 mg daily dose at an incidence of ≥10% in posaconazole delayed-release tablet study.
The most frequently reported adverse reactions (>25%) with posaconazole delayed-release tablets 300 mg once daily were diarrhea, pyrexia, and nausea.
The most common adverse reaction leading to discontinuation of posaconazole delayed-release tablets 300 mg once daily was nausea (2%).
Clinical Trial Safety Experience with Posaconazole Oral Suspension
The safety of posaconazole oral suspension has been assessed in 1844 patients. This includes 605 patients in the active-controlled prophylaxis studies, 557 patients in the active-controlled OPC studies, 239 patients in refractory OPC studies, and 443 patients from other indications.
This represents a heterogeneous population, including 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 8-84 years, 6% of patients were ≥65 years of age and 1% was <18 years of age), and were 64% white, 16% Hispanic, and 36% non-white (including 14% black). Posaconazole therapy was given to 171 patients for ≥6 months, with 58 patients receiving posaconazole therapy for ≥12 months. Table 6 presents treatment-emergent adverse reactions observed at an incidence of >10% in posaconazole prophylaxis studies. Table 7 presents treatment-emergent adverse reactions observed at an incidence of at least 10% in the OPC/rOPC studies.
Prophylaxis of Aspergillus and Candida
In the 2 randomized, comparative prophylaxis studies (Oral Suspension Studies 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 the prophylaxis clinical trials were fever, diarrhea, and nausea.
The most common adverse reactions leading to discontinuation of posaconazole in the prophylaxis studies were associated with GI disorders, specifically, nausea (2%), vomiting (2%), and hepatic enzymes increased (2%).
HIV Infected Subjects with OPC: In 2 randomized comparative studies in OPC, the safety of posaconazole oral suspension at a dose of less than or equal to 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 oral suspension in 2 non-comparative trials for refractory OPC (rOPC). Of these subjects, 149 received the 800-mg/day dose and the remainder received the less than or equal to 400-mg QD dose.
In the OPC/rOPC studies, the most common adverse reactions were fever, diarrhea, nausea, headache, vomiting, and coughing.
The most common adverse reactions that led to treatment discontinuation of posaconazole in the Controlled OPC Pool included respiratory impairment (1%) and pneumonia (1%). In the refractory OPC pool, the most common adverse reactions that led to treatment discontinuation of posaconazole were AIDS (7%) and respiratory impairment (3%).
Adverse reactions were reported more frequently in the pool of patients with refractory OPC. Among these highly immunocompromised patients with advanced HIV disease, serious adverse reactions (SARs) were reported in 55% (132/239). The most commonly reported SARs were fever (13%) and neutropenia (10%).
Less Common Adverse Reactions
Clinically significant adverse reactions reported during clinical trials in prophylaxis, OPC/rOPC or other trials with posaconazole which occurred in less than 5% of patients are listed below:
Blood and lymphatic system disorders
Hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, neutropenia aggravated
Vascular disorders
Liver and Biliary System Disorders
Bilirubinemia, hepatic enzymes increased, hepatic function abnormal, hepatitis, hepatomegaly, jaundice, AST Increased, ALT Increased
Metabolic and Nutritional Disorders
Platelet, Bleeding, and Clotting Disorders: thrombocytopenia Renal & Urinary System Disorders: renal failure acute 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.
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 8.
|postmarketing=No clinically significant postmarketing adverse reactions were identified that have not previously been reported during clinical trials experience. |drugInteractions=* Posaconazole is primarily metabolized via UDP glucuronosyltransferase and is a substrate of p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. Coadministration of drugs that can decrease the plasma concentrations of posaconazole should generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections.
Posaconazole is also a strong inhibitor of CYP3A4. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole.
The following information was derived from data with posaconazole oral suspension or early tablet formulation. All drug interactions with posaconazole oral suspension, except for those that affect the absorption of posaconazole (via gastric pH and motility) are considered relevant to posaconazole injection as well.
Immunosuppressants Metabolized by CYP3A4
Concomitant administration of posaconazole with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity. Therefore, posaconazole is contraindicated with sirolimus.
Posaconazole has been shown to significantly increase the Cmax and AUC of tacrolimus. At initiation of posaconazole treatment, reduce the tacrolimus dose to approximately one-third of the original dose. Frequent monitoring of tacrolimus whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus dose adjusted accordingly.
Posaconazole has been shown to increase cyclosporine whole blood concentrations in heart transplant patients upon initiation of posaconazole treatment. It is recommended to reduce cyclosporine dose to approximately three-fourths of the original dose upon initiation of posaconazole treatment. Frequent monitoring of cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the cyclosporine dose adjusted accordingly.
CYP3A4 Substrates
Concomitant administration of posaconazole with CYP3A4 substrates such as pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and cases of torsades de pointes. Therefore, posaconazole is contraindicated with these drugs.
HMG-CoA Reductase Inhibitors (Statins) Primarily Metabolized Through CYP3A4
Concomitant administration of posaconazole with simvastatin increases the simvastatin plasma concentrations by approximately 10-fold. Therefore, posaconazole is contraindicated with HMG-CoA reductase inhibitors primarily metabolized through CYP3A4.
Ergot Alkaloids
Most of the ergot alkaloids are substrates of CYP3A4. Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism. Therefore, posaconazole is contraindicated with ergot alkaloids.
Benzodiazepines Metabolized by CYP3A4
Concomitant administration of posaconazole with midazolam increases the midazolam plasma concentrations by approximately 5-fold. Increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects. Concomitant use of posaconazole and other benzodiazepines metabolized by CYP3A4 (e.g., alprazolam, triazolam) could result in increased plasma concentrations of these benzodiazepines. Patients must be monitored closely for adverse effects associated with high plasma concentrations of benzodiazepines metabolized by CYP3A4 and benzodiazepine receptor antagonists must be available to reverse these effects.
Anti-HIV Drugs
Efavirenz induces UDP-glucuronidase and significantly decreases posaconazole plasma concentrations. It is recommended to avoid concomitant use of efavirenz with posaconazole unless the benefit outweighs the risks.
Ritonavir and Atazanavir
Ritonavir and atazanavir are metabolized by CYP3A4 and posaconazole increases plasma concentrations of these drugs. Frequent monitoring of adverse effects and toxicity of ritonavir and atazanavir should be performed during coadministration with posaconazole.
Fosamprenavir
Combining fosamprenavir with posaconazole may lead to decreased posaconazole plasma concentrations. If concomitant administration is required, close monitoring for breakthrough fungal infections is recommended.
Rifabutin induces UDP-glucuronidase and decreases posaconazole plasma concentrations. Rifabutin is also metabolized by CYP3A4. Therefore, coadministration of rifabutin with posaconazole increases rifabutin plasma concentrations. Concomitant use of posaconazole and rifabutin should be avoided unless the benefit to the patient outweighs the risk. However, if concomitant administration is required, close monitoring for breakthrough fungal infections as well as frequent monitoring of full blood counts and adverse reactions due to increased rifabutin plasma concentrations (e.g., uveitis, leukopenia) are recommended.
Phenytoin induces UDP-glucuronidase and decreases posaconazole plasma concentrations. Phenytoin is also metabolized by CYP3A4. Therefore, coadministration of phenytoin with posaconazole increases phenytoin plasma concentrations. Concomitant use of posaconazole and phenytoin should be avoided unless the benefit to the patient outweighs the risk. However, if concomitant administration is required, close monitoring for breakthrough fungal infections is recommended and frequent monitoring of phenytoin concentrations should be performed while coadministered with posaconazole and dose reduction of phenytoin should be considered.
Gastric Acid Suppressors/Neutralizers
Posaconazole Delayed-Release Tablet
No clinically relevant effects on the pharmacokinetics of posaconazole were observed when posaconazole delayed-release tablets are concomitantly used with antacids, H2-receptor antagonists and proton pump inhibitors. No dosage adjustment of posaconazole delayed-release tablets is required when posaconazole delayed-release tablets are concomitantly used with antacids, H2-receptor antagonists and proton pump inhibitors.
Posaconazole Oral Suspension
Cimetidine (an H2-receptor antagonist) and esomeprazole (a proton pump inhibitor) when given with posaconazole oral suspension results in decreased posaconazole plasma concentrations. It is recommended to avoid concomitant use of cimetidine and esomeprazole with posaconazole oral suspension unless the benefit outweighs the risks. However, if concomitant administration is required, close monitoring for breakthrough fungal infections is recommended.
No clinically relevant effects were observed when posaconazole oral suspension is concomitantly used with antacids and H2-receptor antagonists other than cimetidine. No dosage adjustment of posaconazole oral suspension is required when posaconazole oral suspension is concomitantly used with antacids and H2-receptor antagonists other than cimetidine.
Vinca Alkaloids
Most of the vinca alkaloids are substrates of CYP3A4. Posaconazole may increase the plasma concentrations of vinca alkaloids (e.g., vincristine and vinblastine) which may lead to neurotoxicity. Therefore, it is recommended that dose adjustment of the vinca alkaloid be considered.
Calcium Channel Blockers Metabolized by CYP3A4
Posaconazole may increase the plasma concentrations of calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, diltiazem, nifedipine, nicardipine, felodipine). Frequent monitoring for adverse reactions and toxicity related to calcium channel blockers is recommended during coadministration. Dose reduction of calcium channel blockers may be needed.
Increased plasma concentrations of digoxin have been reported in patients receiving digoxin and posaconazole. Therefore, monitoring of digoxin plasma concentrations is recommended during coadministration.
Gastrointestinal Motility Agents
Concomitant administration of metoclopramide with posaconazole delayed-release tablets did not affect the pharmacokinetics of posaconazole. No dosage adjustment of posaconazole delayed-release tablets is required when given concomitantly with metoclopramide.
Metoclopramide, when given with posaconazole oral suspension, decreases posaconazole plasma concentrations. If metoclopramide is concomitantly administered with posaconazole oral suspension, it is recommended to closely monitor for breakthrough fungal infections.
Loperamide does not affect posaconazole plasma concentrations after posaconazole oral suspension administration. No dosage adjustment of posaconazole is required when loperamide and posaconazole are used concomitantly.
Although no dosage adjustment of glipizide is required, it is recommended to monitor glucose concentrations when posaconazole and glipizide are concomitantly used.
|FDAPregCat=C |useInPregnancyFDA=* There are no adequate and well-controlled studies in pregnant women. Noxafil should be used in pregnancy only if the potential benefit outweighs the potential risk to the fetus.
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 oral suspension 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 oral suspension 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 oral suspension 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 were seen.
|useInPregnancyAUS=* Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Posaconazole in women who are pregnant. |useInNursing=* Posaconazole is excreted in milk of lactating rats. It is not known whether Noxafil is excreted in human milk. Because of the potential for serious adverse reactions from Noxafil in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. |useInPed=* The safety and effectiveness of Noxafil injection in pediatric patients below the age of 18 years of age has not been established. Noxafil injection should not be used in pediatric patients because of nonclinical safety concerns.
The safety and effectiveness of posaconazole oral suspension and posaconazole delayed-release tablets have been established in the age groups 13 to 17 years of age. Use of posaconazole in these age groups is supported by evidence from adequate and well-controlled studies of posaconazole in adults. The safety and effectiveness of posaconazole in pediatric patients below the age of 13 years have not been established.
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. 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 (Cavg) 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) of posaconazole oral suspension in a study for another indication. Based on pharmacokinetic data in 12 of these pediatric patients, the mean steady-state average posaconazole concentration (Cavg) was similar between these patients and adults (≥18 years of age).
In the prophylaxis studies, the mean steady-state posaconazole average concentration (Cavg) was similar among ten adolescents (13 to 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 Cavg from 12 adolescent patients (8 to 17 years of age) was similar to that in the adults (≥18 years of age).
|useInGeri=* Of the 279 patients treated with posaconazole injection, 52 (19%) were greater than 65 years of age. The pharmacokinetics of posaconazole injection are comparable in young and elderly subjects. No overall differences in safety were observed between the geriatric patients and younger patients; therefore, no dosage adjustment is recommended for Noxafil injection in geriatric patients.
Of the 230 patients treated with posaconazole delayed-release tablets, 38 (17%) were greater than 65 years of age. The pharmacokinetics of posaconazole delayed-release tablets are comparable in young and elderly subjects. No overall differences in safety were observed between the geriatric patients and younger patients; therefore, no dosage adjustment is recommended for geriatric patients.
Of the 605 patients randomized to posaconazole oral suspension in the prophylaxis clinical trials, 63 (10%) were ≥65 years of age. In addition, 48 patients treated with greater than or equal to 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.
The pharmacokinetics of posaconazole oral suspension are comparable in young and elderly subjects (≥65 years of age); therefore no adjustment in the dosage of Noxafil oral suspension is necessary in geriatric patients.
No overall differences in the pharmacokinetics and safety were observed between elderly and young subjects during clinical trials, but greater sensitivity of some older individuals cannot be ruled out.
|useInGender=The pharmacokinetics of posaconazole are comparable in men and women. No adjustment in the dosage of Noxafil is necessary based on gender. |useInRace=The pharmacokinetic profile of posaconazole is not significantly affected by race. No adjustment in the dosage of Noxafil is necessary based on race. |useInRenalImpair=* Following single-dose administration of 400 mg of the oral suspension, there was no significant effect of mild (eGFR: 50-80 mL/min/1.73 m2, n=6) or moderate (eGFR: 20-49 mL/min/1.73 m2, n=6) renal impairment on posaconazole pharmacokinetics; therefore, no dose adjustment is required in patients with mild to moderate renal impairment. In subjects with severe renal impairment (eGFR: <20 mL/min/1.73 m2), the mean plasma exposure (AUC) was similar to that in patients with normal renal function (eGFR: >80 mL/min/1.73 m2); however, the range of the AUC estimates was highly variable (CV=96%) in these subjects with severe renal impairment as compared to that in the other renal impairment groups (CV<40%). Due to the variability in exposure, patients with severe renal impairment should be monitored closely for breakthrough fungal infections.
Similar recommendations apply to posaconazole delayed-release tablets; however, a specific study has not been conducted with the delayed-release tablets.
|useInHepaticImpair=* 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. The mean apparent oral clearance (CL/F) was reduced by 18%, 36%, and 28% in subjects with mild, moderate, or severe hepatic impairment, respectively, compared to subjects with normal hepatic function. The elimination half-life (t½) was 27 hours, 39 hours, 27 hours, and 43 hours in subjects with normal hepatic function and mild, moderate, or severe hepatic impairment, respectively.
It is recommended that no dose adjustment of Noxafil is needed in patients with mild to severe hepatic impairment (Child-Pugh Class A, B, or C). Similar recommendations apply to posaconazole delayed-release tablets; however, a specific study has not been conducted with the delayed-release tablets.
Similar recommendations apply to posaconazole injection; however, a specific study has not been conducted with the posaconazole injection.
|useInReproPotential=There is no FDA guidance on the use of Posaconazole in women of reproductive potentials and males. |useInImmunocomp=There is no FDA guidance one the use of Posaconazole in patients who are immunocompromised.
|othersTitle=Weight |useInOthers=* Pharmacokinetic modeling suggests that patients weighing greater than 120 kg may have lower posaconazole plasma drug exposure. It is, therefore, suggested to closely monitor for breakthrough fungal infections. |administration=* Oral
|monitoring=* It is recommended to closely monitor patients for breakthrough fungal infections when Noxafil is administered via an NG tube because a lower plasma exposure may be associated with an increased risk of treatment failure.
Noxafil increases concentrations of cyclosporine or tacrolimus; reduce dose of cyclosporine and tacrolimus and monitor concentrations frequently
Elevations in LFTs may occur. Discontinuation should be considered in patients who develop abnormal LFTs or monitor LFTs during treatment.
Patients who develop abnormal liver function tests during posaconazole therapy should be monitored for the development of more severe hepatic injury.
Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral Noxafil therapy.
|IVCompat=There is limited information regarding IV Compatibility of Posaconazole in the drug label.
|overdose=* There is no experience with overdosage of posaconazole injection and delayed-release tablets.
During the clinical trials, some patients received posaconazole oral suspension up to 1600 mg/day with no adverse reactions noted that were different from the lower doses. In addition, accidental overdose was noted in one patient who took 1200 mg BID posaconazole oral suspension for 3 days. No related adverse reactions were noted by the investigator.
Posaconazole is not removed by hemodialysis.
|drugBox={{Drugbox2 | Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 464210822 | IUPAC_name = 4-(4-(4-(4-(((3R,5R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl)oxolan-3-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-2-((2S,3S)-2-hydroxypentan-3-yl)-1,2,4-triazol-3-one | image = Posaconazole.png | width = 360 | image2 = Posaconazole3d.png
| tradename = Noxafil, Posanol | Drugs.com = Monograph | MedlinePlus = a607036 | licence_EU = Noxafil | licence_US = Posaconazole | pregnancy_AU = B3 | pregnancy_US = C | legal_US = Rx-only | routes_of_administration = Oral
| bioavailability = High | protein_bound = 98 to 99% | metabolism = Hepatic glucuronidation | elimination_half-life = 16 to 31 hours | excretion = Fecal (77%) and renal (14%)
| CASNo_Ref = Y | CAS_number_Ref = Y | CAS_number = 171228-49-2 | ATC_prefix = J02 | ATC_suffix = AC04 | PubChem = 147912 | ChEBI_Ref = N | ChEBI = 64355 | DrugBank_Ref = Y | DrugBank = DB01263 | ChemSpiderID_Ref = Y | ChemSpiderID = 130409 | UNII_Ref = Y | UNII = 6TK1G07BHZ | KEGG_Ref = Y | KEGG = D02555 | ChEMBL_Ref = N | ChEMBL = 1397
| C=37 | H=42 | F=2 | N=8 | O=4 | molecular_weight = 700.778 g/mol | smiles = O=C1N(/N=C\N1c2ccc(cc2)N7CCN(c6ccc(OCC3C[C@@](OC3)(c4ccc(F)cc4F)Cn5ncnc5)cc6)CC7)[C@@H](CC)[C@@H](O)C | InChI = 1/C37H42F2N8O4/c1-3-35(26(2)48)47-36(49)46(25-42-47)31-7-5-29(6-8-31)43-14-16-44(17-15-43)30-9-11-32(12-10-30)50-20-27-19-37(51-21-27,22-45-24-40-23-41-45)33-13-4-28(38)18-34(33)39/h4-13,18,23-27,35,48H,3,14-17,19-22H2,1-2H3/t26-,27?,35-,37-/m0/s1 | InChIKey = RAGOYPUPXAKGKH-AGDNISCABP | StdInChI_Ref = Y | StdInChI = 1S/C37H42F2N8O4/c1-3-35(26(2)48)47-36(49)46(25-42-47)31-7-5-29(6-8-31)43-14-16-44(17-15-43)30-9-11-32(12-10-30)50-20-27-19-37(51-21-27,22-45-24-40-23-41-45)33-13-4-28(38)18-34(33)39/h4-13,18,23-27,35,48H,3,14-17,19-22H2,1-2H3/t26-,27?,35-,37-/m0/s1 | StdInChIKey_Ref = Y | StdInChIKey = RAGOYPUPXAKGKH-AGDNISCASA-N | synonyms = 4-{4-[4-(4-{[(5R)-5-(2,4-difluorophenyl)-5-(1H-1,2,4-triazol-1-ylmethyl)oxolan-3-yl]methoxy}phenyl)piperazin-1-yl]phenyl}-1-[(2S,3S)-2-hydroxypentan-3-yl]-4,5-dihydro-1H-1,2,4-triazol-5-one }} |mechAction=* Posaconazole is an azole antifungal agent |structure=* Noxafil is an azole antifungal agent available as concentrated solution to be diluted before intravenous administration, delayed-release tablet, or 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 C37H42F2N8O4 and a molecular weight of 700.8. The chemical structure is:
Posaconazole is a white powder with a low aqueous solubility.
Noxafil injection is available as a clear colorless to yellow, sterile liquid essentially free of foreign matter. Each vial contains 300 mg of posaconazole and the following inactive ingredients: 6.68 g Betadex Sulfobutyl Ether Sodium (SBECD), 0.003 g edetate disodium, hydrochloric acid and sodium hydroxide to adjust the pH to 2.6, and water for injection.
Noxafil delayed-release tablet is a yellow, coated, oblong tablet containing 100 mg of posaconazole. Each delayed-release tablet contains the inactive ingredients: hypromellose acetate succinate, microcrystalline cellulose, hydroxypropylcellulose, silicon dioxide, croscarmellose sodium, magnesium stearate, and Opadry® II Yellow (consists of the following ingredients: polyvinyl alcohol partially hydrolyzed, Macrogol/PEG 3350, titanium dioxide, talc, and iron oxide yellow).
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, artificial cherry flavor, and purified water.
|PD======Exposure Response Relationship=====
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 exposures to posaconazole was noted following administration of Noxafil oral suspension. A pharmacokinetic-pharmacodynamic analysis of patient data revealed an apparent association between average posaconazole concentrations (Cavg) and prophylactic efficacy (Table 10). 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.
|PK======General Pharmacokinetic Characteristics=====
Posaconazole Injection
Posaconazole injection exhibits dose proportional pharmacokinetics after single doses between 200 and 300 mg in healthy volunteers and patients. The mean pharmacokinetic parameters after single doses with posaconazole injection in healthy volunteers and patients are shown in Table 11.
Additional clinical studies demonstrated that no clinically significant effects on zidovudine, lamivudine, indinavir, or caffeine were observed when administered with posaconazole 200 mg QD; therefore, no dose adjustments are required for these coadministered drugs when coadministered with posaconazole 200 mg QD.
Following administration of Noxafil 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 injection is eliminated with a mean terminal half-life (t½) of 27 hours and a total body clearance (CL) of 7.3 L/h.
Posaconazole delayed-release tablet is eliminated with a mean half-life (t½) ranging between 26 to 31 hours.
Posaconazole oral suspension is eliminated with a mean half-life (t½) of 35 hours (range: 20-66 hours).
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.
Activity in vitro
Posaconazole has in vitro activity against Aspergillus fumigatus and Candida albicans, including Candida albicans isolates from patients refractory to itraconazole or fluconazole or both drugs. However, correlation between the results of susceptibility tests and clinical outcome has not been established. Posaconazole interpretive criteria (breakpoints) have not been established for any fungus.
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.
|nonClinToxic======Carcinogenesis, Mutagenesis, Impairment of Fertility=====
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 BID oral suspension regimen, respectively, based on steady-state AUC in healthy volunteers administered a high-fat meal (400-mg BID 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 BID oral suspension 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 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 BID oral suspension regimen).
Animal Toxicology and/or Pharmacology
In a nonclinical study using intravenous administration of posaconazole in very young dogs (dosed from 2 to 8 weeks of age), an increase in the incidence of brain ventricle enlargement was observed in treated animals as compared with concurrent control animals. No difference in the incidence of brain ventricle enlargement between control and treated animals was observed following the subsequent 5-month treatment-free period. There were no neurologic, behavioral or developmental abnormalities in the dogs with this finding, and a similar brain finding was not seen with oral posaconazole administration to juvenile dogs (4 days to 9 months of age).
The clinical significance of this finding is unknown; therefore, the use of posaconazole injection to patients under 18 years of age is not recommended.
|clinicalStudies======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 (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; 77 days, fluconazole). Table 22 contains the results from Oral Suspension Study 1.[File:Posaconazole01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
The second study (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 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 postrandomization. The mean duration of therapy was comparable between the 2 treatment groups (29 days, posaconazole; 25 days, fluconazole or itraconazole). Table 23 contains the results from Oral Suspension Study 2.
File:Posaconazole01.png
In summary, 2 clinical studies of prophylaxis were conducted with the posaconazole oral suspension. As seen in the accompanying tables (Tables 22 and 23), clinical failure represented a composite endpoint of breakthrough IFI, mortality and use of systemic antifungal therapy. In Oral Suspension Study 1 (Table 22), 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 Oral Suspension Study 2 (Table 23) 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 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 Oral Suspension Study 2 [POS 44/304 (14%) vs. FLU/ITZ 64/298 (21%)]. Both studies demonstrated substantially fewer breakthrough infections caused by Aspergillus species in patients receiving posaconazole prophylaxis when compared to patients receiving fluconazole or itraconazole.
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 24). 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 24).
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
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.
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 BID for 3 days, followed by 400 mg QD 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 BID 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).
|howSupplied======Injection=====
Noxafil injection is available in Type I glass vials closed with bromobutyl rubber stopper and aluminum seal (NDC 0085-4331-01) containing 300 mg per 16.7 mL of solution (18 mg of posaconazole per mL). Store refrigerated at 2-8°C (36-46°F).
Delayed-Release Tablets
Noxafil 100 mg delayed-release tablets; yellow, coated, oblong, debossed with "100" on one side. Bottles with child-resistant closures of 60 delayed-release tablets (NDC 0085-4324-02). Store at 20-25°C (68-77°F), excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].
Oral Suspension
Noxafil 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).
|storage=* Supplied with each oral suspension 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). DO NOT FREEZE. |packLabel= |fdaPatientInfo=* Advise the patient to read the FDA-approved patient labeling (Patient Information).
Noxafil Delayed-Release Tablets
Advise patients to take Noxafil delayed-release tablets with food.
Physicians should instruct their patients that if they miss a dose, they should take it as soon as they remember. If they do not remember until it is within 12 hours of the next dose, they should be instructed to skip the missed dose and go back to the regular schedule. Patients should not double their next dose or take more than the prescribed dose.
Noxafil Oral Suspension
Advise patients to take each dose of Noxafil 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 Noxafil oral suspension should be administered with a liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale) in order to enhance absorption.
Patients should be advised to inform their physician immediately if they:
develop severe diarrhea or vomiting.
Patients 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
Patients should be advised 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.
|alcohol=* Alcohol-Posaconazole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=*Noxafil[4]
|drugShortage=
↑ 1.0 1.1 Walsh TJ, Anaissie EJ, Denning DW, Herbrecht R, Kontoyiannis DP, Marr KA; et al. (2008). "Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America". Clin Infect Dis. 46 (3): 327–60. doi:10.1086/525258. PMID 18177225 PMID: 18177225 Check |pmid= value (help). CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
↑ 2.0 2.1 Pappas PG, Kauffman CA, Andes D, Benjamin DK, Calandra TF, Edwards JE; et al. (2009). "Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America". Clin Infect Dis. 48 (5): 503–35. doi:10.1086/596757. PMID 19191635 PMID: 19191635 Check |pmid= value (help). CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
↑ Raad II, Graybill JR, Bustamante AB, Cornely OA, Gaona-Flores V, Afif C; et al. (2006). "Safety of long-term oral posaconazole use in the treatment of refractory invasive fungal infections". Clin Infect Dis. 42 (12): 1726–34. doi:10.1086/504328. PMID 16705579 PMID: 16705579 Check |pmid= value (help). CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
↑ "NOXAFIL- posaconazole suspension".
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text:
Look at what
a half-cent buys
One half of each local sales tax penny is spent on transportation to improve life in Orange County every day.
One half of each sales tax penny is spent on transportation to improve life in Orange County every day.
Through OC Go (also known as Measure M), half of each local sales tax penny is spent on transportation projects that improve life in Orange County every day. OC Go leverages funding to accelerate projects and save time and money. Check out the OC Go highlights for 2017. View More
During a 30-year term ending in 2041, OC Go is expected to provide $13.5 billion in improvements. A comprehensive review of all OC Go-implemented projects and programs is required every 10 years. The first review (2006-2016) was completed and determined that the program is on track. OCTA administers OC Go for the people of Orange County.
In November, the OCTA Board approved the Updated Next 10 Delivery Plan providing guidance for OC Go project and program delivery through 2026. The update addresses a recent reduction in sales tax revenue projections. A recent sales tax forecast decreased OC Go by $700 million (through 2041) to $13.5 billion. The Updated Next 10 Plan incorporates current revenue projections, bonding assumptions, project costs and schedules, and identifies adjustments needed to ensure continued delivery of the complete OC Go Plan.
OCTA rebranded Measure M as OC Go to raise awareness about Orange County's vital local sales tax for transportation improvements. The new OC Go name and logo is consistent with other OCTA brands including OC Bus, OC Streetcar, OC Bike, OC Vanpool and OC Metrolink.
I-5 SOUTH COUNTY IMPROVEMENTS
Contractors are in the final stages of a project to add six miles of carpool lanes in each direction of I-5 between San Juan Creek Road and Avenida Pico. The improvements, which include reconstruction of the Avenida Pico interchange, will help relieve congestion through the cities of San Clemente, Dana Point and San Juan Capistrano. The project has three segments; the middle segment (Avenida Vista Hermosa to Pacific Coast Highway) was completed in mid-2017. The added carpool lanes will be open to traffic when the remaining two segments (Avenida Pico to Avenida Vista Hermosa and PCH to San Juan Creek Road) are completed in spring 2018.
Enhanced Freeways
Completed one freeway project and continued construction on three freeway project segments.
Synchronized Streets
Approved five synchronized projects that will help drivers travel more efficiently by reducing stop-and-go traffic.
The OC Go freeway program includes 27 project segments that will remedy traffic chokepoints and relieve congestion on Orange County freeways. To date, 10 freeway segments have been completed.
I-405 Improvement Project
In January, the design-build contract was awarded to OC 405 Partners, and work began on preconstruction activities. Design-build is a project delivery method that allows for design work and construction to occur simultaneously. One contractor is hired to perform both functions, which increases the speed that a project can be delivered and saves money. The project is anticipated to be complete in 2023. This project will improve 16 miles in both directions of the I‐405 through the cities of Costa Mesa, Fountain Valley, Garden Grove, Huntington Beach, Los Alamitos, Seal Beach, and Westminster. Improvements include the addition of one general purpose lane, a second HOV lane to be combined with the existing HOV lane providing a dual express lane facility, and improved local interchanges along the corridor between SR-73 to I-605. The general purpose lane portion of the project is partially funded by OC Go and a combination of local, state and federal funds. The express lanes portion are being financed and primarily paid for by those who choose to pay a toll and use the 405 Express Lanes.
Driving through multiple cities stopping at red lights can be difficult and time consuming, in part because each city controls its own traffic signals. OC Go helps synchronize traffic lights across the county to improve the quality of your drive.
OCTA approved $2.5 million for five synchronization projects designed to reduce travel times, stops and delays, and emissions along Irvine Boulevard, Gilbert/Idaho streets, Camino Vera Cruz, Bear Street and Olympiad/Felipe roads. Additionally, OCTA completed 11 projects that synchronized 296 signals along 86.3 miles on Goldenwest Street, Los Alisos Boulevard, Antonio Parkway, Adams Avenue, Barranca Parkway, Jeronimo Road, State College Road, Trabuco Road, Alton Parkway, Newport Avenue/Boulevard and La Paz Road.
There are 32 projects planned or in progress through the Regional Traffic Signal Synchronization Program. To date, the program has resulted in:
63 signal projects completed
$89.17 million in funding awarded by the Board
Approximately 40 million in improvements along 582 miles and 2,212 signals
Travel time savings: 13%
Speed improvements: 15%
Stop reduction: 31%
Improved Local Streets
Allocated nearly $85.3 million for street improvements and completed the OC Bridges grade separation projects.
Streetcar Progress
Completed design and engineering on the OC Streetcar, which will connect activity and employment centers in Santa Ana.
Every trip begins with a local street or road, and keeping them in good shape is an important component of OC Go.
OCTA approved $32.24 million for 13 projects for the Regional Capacity Program, which funds intersection improvements and other street improvement projects to help reduce congestion. In addition, $53.1 million in OC Go Local Fair Share funds were distributed to cities and the County of Orange to preserve existing streets and roads and to provide other transportation improvements based on the priorities and infrastructure needs of local cities.
OCTA marked the completion of the final two underpasses in the OC Bridges program, which during the last five years built a total of seven bridges and underpasses to separate car and pedestrian traffic from the busy Burlington Northern Santa Fe (BNSF) freight rail line running through Fullerton, Anaheim and Placentia. By 2030, the number of daily freight trains is expected to nearly double from 70 to 130. The OC Bridges Program helps preserve quality of life by keeping motorists moving while allowing trains to transport goods. OC Go funded $168 million of the $663 million OC Bridges program and leveraged the remaining cost with state and federal contributions. Projects included:
Lakeview Avenue
Raymond Avenue
State College Boulevard
Orangethorpe Avenue
Tustin Avenue/Rose Drive
Placentia Avenue
Kraemer Boulevard
The OC Streetcar will start at the Santa Ana Regional Transportation Center and serve Santa Ana's historic downtown and Civic Center on the 4.5-mile route to Garden Grove.
It will connect directly with 18 OCTA bus routes, including the seven busiest routes in the county. In addition, the OC Streetcar is expected to support economic development and create jobs. More than half of the funding for the OC Streetcar is planned to come from the federal government with some state and local funding. Construction is anticipated to begin in late 2018, with service beginning two years later. By 2035, the OC Streetcar is estimated to carry more than 7,000 riders each day.
Traffic-free Travel
There were nearly 4.5 million car-free boardings on the three Metrolink train lines serving Orange County.
OC Go provided approximately $10.1 million in discounted fares for 14.3 million transit trips for seniors and persons with disabilities.
Each day, commuters and other travelers use convenient Metrolink trains to get to work or other destinations within Orange County or adjoining counties including Los Angeles, Riverside, San Bernardino and San Diego.
Orange County has 11 Metrolink stations and is served by three lines – Orange County Line (OC Line), Inland Empire Orange County Line (IEOC Line) and 91 Line.
Additionally, funding has been provided for rail line and station improvement projects to accommodate increased service. Currently the Fullerton Transportation Center Improvements and the Orange Transportation Center Parking Structure are under construction.
Three programs work together to provide efficient, cost-effective transportation for seniors and persons with disabilities.
The Senior Mobility Program fills the gap between local fixed-route buses and ACCESS service by providing transportation services to seniors in 31 cities in Orange County. OCTA and the participating cities contribute to the program. Another program supplements existing countywide senior non-emergency medical transportation services. The third program reduces fares for bus and ACCESS paratransit rides for seniors and persons with disabilities.
Protected Open Space
Funded a 12th restoration project and completed five stewardship plans for open space preserves.
Sixteen local agencies received a total of $3.1 million to improve water quality.
In exchange for expedited freeway projects, OCTA preserves and restores natural habitats.
A total of 1,300 acres has been permanently protected to enhance wildlife connectivity, safeguard sensitive species and preserve substantial parcels of valuable habitat. Preserves are located in Brea, Laguna Beach, Silverado Canyon and Trabuco Canyon. In addition, OC Go has funded 12 restoration projects that help remove invasive plants and restore approximately 350 acres of open space lands to its native habitat.
OC Go funded its 12th restoration project to remove multiple previously constructed dams. These actions improve existing aquatic habitat to help bring back native species.
The United States Fish and Wildlife Service and the California Department of Fish and Wildlife finalized environmental permits that will enable OCTA to streamline the biological resources permitting process for OC Go freeway projects. The agencies also signed an agreement which permanently protects natural habitat and wildlife on OCTA's Preserves.
The Army Corps of Engineers (Corps) issued a programmatic permit to OCTA and Caltrans. This is the first ever Corps-approved advanced mitigation permit for multiple mitigation sites and projects spanning numerous watersheds.
OCTA completed five of seven Preserve Resource Management Plans, which outline the stewardship and operations of each preserve.
The Environmental Cleanup Program uses OC Go funds to clean transportation-related pollutants from Orange County's waterways.
A total of $3.1 million was allocated to 16 local agencies to improve water quality. Since 2011, approximately $48 million has been awarded to more than 170 projects from 33 cities and the county. OCTA is expected to award approximately $300 million for water-quality projects during the 30-year life of OC Go.
Select an interest below and explore destinations.
Walking/Biking Trails
Urban Bicycle Outfitters
L.A. Union Station
ANAHEIM-ARTIC
Laguna Niguel / Mission Viejo
Select a Station L.A. Union Station Buena Park Station Fullerton Station Anaheim ARTIC Station Orange Station Santa Ana Station Tustin Station Irvine Station Laguna Niguel Station San Juan Capistrano Station San Clemente Station San Clemente Pier Station Oceanside Station

redpajama_set_name: RedPajamaCommonCrawl


text:
Allowed Uses of Taxpayer Info Widened
IRS Practice and Procedure
The IRS in late December issued temporary and proposed regulations under IRC § 7216 clarifying and expanding the ways in which tax return preparers may disclose or use certain tax return information without taxpayer consent (TD 9478 and REG-131028-09). The IRS also issued two revenue rulings approving several scenarios involving use or disclosure of tax return information. The temporary regulations amend final regulations that were issued in 2008 and took effect Jan. 1, 2009 (see "Disclosure Consent Under § 7216," JofA, Oct. 09, page 22).
IRC § 7216 provides a criminal penalty (along with the civil penalty of section 6713) for any tax return preparer who "knowingly or recklessly" discloses or uses tax return information, with those terms and others defined by the 2008 final regulations (TD 9375, amending Treas. Reg. §§ 301.7216-1 through 301.7216-3). Generally, preparers must obtain taxpayers' written permission to disclose or use their information, except for certain required or limited purposes.
One of those limited purposes is to compile and maintain a list of clients' names, addresses, e-mail addresses and phone numbers for the sole purpose of offering tax information or additional tax return preparation services to those taxpayers (Treas. Reg. § 301.7216-2(n)). The temporary regulations further allow practitioners to include in such a list taxpayers' entity classification or type, such as individual status, and their return form number (for example, 1040).
Another permitted limited purpose is for statistical compilations of taxpayer information (which generally are subject to the use and disclosure restrictions even when they do not identify any particular taxpayer) in connection with a sale or other disposition of a tax return preparation business (Treas. Reg. § 301.7216-2(o)). The temporary regulations clarify that "sale or other disposition" includes due diligence performed in contemplation of such a sale or disposition and add new allowed uses of statistical compilations. They also add as permissible uses of anonymous statistical compilations those that benefit taxpayers generally and inform tax policymakers. Return preparers may even use such compilations for advertising and marketing. However, they must not state even average or aggregate dollar amounts of tax refunds, credits or deductions realized.
The temporary regulations also state that individuals who meet the definition of a tax return preparer solely because they provide auxiliary services to another tax return preparer may not, under Treas. Reg. § 301.7216-2(n), use the tax return information they receive from the other preparer to compile and maintain a list of taxpayers for their own use.
In addition, the temporary regulations clarify that tax return preparers may use and disclose tax return information to the extent necessary to accomplish a conflict-of-interest review undertaken to comply with the requirements of any federal, state or local law, agency, board or commission, or by a professional association ethics committee or board.
The revenue rulings, 2010-4 and 2010-5, provide guidance to tax return preparers on situations in which they will not be liable for civil or criminal penalties for disclosing or using tax return information. Revenue Ruling 2010-4 states that a preparer may contact clients to inform them of changes in tax law that could affect returns that the preparer prepared previously or future return filing obligations, since in both instances, the information is "for the purpose of preparing a tax return" and "for the purpose of providing other legal or accounting services to the taxpayer," both of which are allowed by the regulations. The IRS notes, however, that a preparer cannot in this way use information of taxpayers who have informed the preparer that they do not wish to be contacted or will not be using his or her tax preparation services in the next filing season.
A third-party service provider that creates, publishes or distributes tax-focused newsletters, bulletins or similar publications or electronic communications may qualify as a provider of auxiliary services for whom disclosure and use is generally permitted under Treas. Reg. § 301.7216-1(b)(2)(i)(B). Accordingly, preparers may for that purpose share taxpayers' names and mailing or e-mail addresses with such third-party service providers that are located in the United States and whose services provided are not substantive determinations or advice affecting the tax liability reported by taxpayers.
Revenue Ruling 2010-5 allows disclosure of taxpayer names and type of services provided by a preparer to the extent necessary to obtain professional liability insurance coverage, including obtaining price quotes for coverage. Preparers may also convey taxpayer information, including copies of returns, to report a professional liability claim or potential claim or to obtain legal representation or advice under the terms of a policy.
TD 9478 and REG-131028-09, Revenue Rulings 2010-4 and 2010-5


By zwobbe, September 22, 2017 in What motorcycle should I buy?
Currently looking into buying a new bike this winter. Had the chance to ride a 2017 350xcf and then an older 350xcfw which brings me to my question. How is the 350xcf in tight technical woods? It seemed a lot more aggressive than the W and I'm concerned that I won't like it. I ride mainly tight goat trail like woods and race B class in Hare scrambles. I am coming off of a 250xcw and I'm pretty set on buying a 350 next.
Also noticed that all KTM discontinued the xcfw line for 2017, if I removed the blinkers, mirrors, etc. off of an excf would it be the same bike as the w?
I have a '16 350 XCF-W. I'm bummed they discontinued them. The EXC-F is basically the same bike I believe with some emissions stuff, turn signals, etc which I'm assuming can be removed pretty easily. I also suspect the final gearing is higher so you'd need sprockets and probably tires to make it just like the XCF-W. Unfortunately I think the EXC-F's come with a heftier price tag. I paid something like $7800 for my '16 XCF-W in November of '15.
The XCF-W has a completely different motor than the XC-F. It's designed with less total power but more low-end grunt and more flywheel mass. It's got a lower first gear than the XC-F. Since you are on a 250 XCF-W now you probably already know that the suspension is different and more geared towards rocks and roots compared to the XC-F which is stiffer, not as good on the rocks and roots but better for the high speed stuff like whoops.
If you are riding fast flowy trails the XC-F might be the ticket. If you are riding slower more technical stuff the XCF-W / EXC-F is the way to go. I've heard the XC-F is very stall prone at low RPM compared to the XCF-W / EXC-F.
I talked to two guys who owned both an XCF-W and XC-F. They both told me for the single track around here they both much preferred the XCF-W over the XC-F.
You rode both the XC-F and XCF-W, what was your impressions? I've not had the chance to ride the XC-F so everything I'm stating is based on talking to other people.
I did not get to get to get the full feel of the XCF because I only got the chance to ride it in the field next to the dealership. However, it felt very powerful compared to the XCW. Reminded me a lot of an MX bike and I think it might be a little bit too much for the tight technical riding I normally do. It was a lot of fun but I think I better stick with the exc or w model for the type of riding that I do.
Yeah the 350XC-F makes more power than a Honda CRF450R. I'm sure you could get used to the power. My concern would be with how stall resistant the motor is at low RPM and how well the suspension works for rocks and roots. I'm super impressed with how the XCF-W goes down rocky rooty washed out trails and never deflects. I know on MX bikes with stiffer suspension when I go down steep downhills with rocks, roots, eroded ledges, etc I feel like a pin ball. I've not ridden the XC-F but I know the suspension is stiffer than the XCF-W / EXC but I don't know if it still tracks well and eats up the rocks and roots like the XCF-W / EXC.
I'm hoping my XCF-W lasts me a long time. But when I'm ready for a new bike I'll probably go over to the two-stroke XC-W since they no longer make the XCF-W and I don't want to pay the premium price of the EXC only to have to rip off and replace a bunch stuff to make it the equivalent of an XCF-W.
If I were to buy an XCF and decided I didn't like it, is there anything I could do to it to make it more of my taste?


When will we be able to post photos and links?
Hi @AmberLee! Thanks for your questions.
The ability to add photos is now updated. You can insert an image by going to Photos then you can drag and drop an image or use an existing image URL. This also means that you can change your avatar to an image of your choosing.
To add a link, you can go to the Insert/Edit link icon (next to the emoji insert).
Please let us know if you have additional questions!
I see we can add photos to a Reply which is awesome. Was not able to figure out how to add a photo to our profile.
Hi @SandraA, to add a profile picture you can change your Avatar under My Setting > Avatars > then you'll select a photo to upload. Once uploaded, click Save and Continue to complete the profile image update.
Does the image need to go through an approval process?
I've uploaded my photo in place of the Avatar and saved it. The photo goes into my photos in my account. But it does not replace the Avatar.
Image approvals are not required. It might be the last save and continue option. Below is a screenshot of the settings for reference.
Please feel free to swing by our Community station at the SAP Concur booth in the expo hall if you have additional questions. We'd also love to meet you in person!
I am experiencing the same as Amber. I tried again today and its the same. The update of photo in Avatar is routed for approval.
Hi Meggie - I tried uploading my pic too and it says it is successful pending approval in a big green box.
I am also experiencing the 'once it's approved' message, but not with every image. I tried a small image (38x38, 4KB) and it uploaded it and saved it no problem. I switched back to a standard avatar and tried a larger image (150x150, 23KB). With the second one, it gave me the message that it would have to be approved.
Thanks, everyone! We'll look into this and will get back to you.


"It's very nice to be in this stadium with a lot of history," said Mathias 'Zanka' Jørgensen after agreeing to join PSV Eindhoven in the summer on a free transfer from FC København.
PSV Eindhoven have agreed the signing of Danish international defender Mathias 'Zanka' Jørgensen from FC København on a four-year contract.
The 21-year-old, who will be reunited with former København team-mate Atiba Hutchinson at the Eredivisie side, will join PSV on a free transfer this summer after five seasons with the Danish champions. He has helped FCK to three successive league titles from 2009 to 2011.
Jørgensen, who started out with Danish second-tier outfit Boldklubben 1893, has made 89 Superliga appearances for the Løverne, as well as four for Denmark's senior team. Although the centre-back has been limited to just eight top-flight outings this term after sustaining knee ligament damage in September, he hopes to recover in time for UEFA EURO 2012.
'Zanka', so called after a character in the 1993 film Cool Runnings, was presented with his shirt at the PSV Stadion by the Dutch club's former midfielder Willy van der Kuijlen. "It's very nice to be in this stadium with a lot of history and finally know I'm going to be a part of it this summer," said Jørgensen. "I am very happy. I have recovered from my knee injury and hope to make my comeback shortly."
PSV top the Eredivisie, level on points with AZ Alkmaar. Morten Olsen's Denmark face the Netherlands, Portugal and Germany in Group B at UEFA EURO 2012.


text:
Ventuari peut désigner :

Toponymes

Río Ventuari : un affluent du fleuve Orénoque ;
 Alto Ventuari : l'une des trois paroisses civiles de la municipalité de Manapiare dans l'État d'Amazonas ;
 Medio Ventuari : l'une des trois paroisses civiles de la municipalité de Manapiare dans l'État d'Amazonas ;
 Bajo Ventuari : l'une des trois paroisses civiles de la municipalité de Manapiare dans l'État d'Amazonas.

Homonymie de toponyme

redpajama_set_name: RedPajamaWikipedia


The last two weeks the only means i can obtain is if i reboot mycomputer. different sensible mp3explosive freezes therefore i have to ct...extra.
With this new characteristic you could "trouble paintings" and "resurrect artwork" for all of your mp3 recordsdata. solely bmp, jpg and png photos are allowed to stock as paintings, but you can use renewd paintingss for your participant, your smarphone or ipod.
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Remove DRM from Spotify Music! Is it doable to rescue MP3 information from Spotify music? Or is there MP3 NORMALIZER to obtain Spotify music for having fun with by the side of automotive player? Spotify users may sea cliff by means of such query. Here Sidify Music Cby the side ofverter for Spotify helps you solve the above issues. it might probably remove DRM from Spotify music as a result to design it better to enjoying music by the side of the go.
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2.- Multidomain login so I can connect to computers belonging to separate domains simultaneously. Here there could be an issue of address clash since different domains may use the same subnet, but it could be fixed by choosing different subnets.
3.- Add-ons/Services configurations per computer. Right now we have add-ons that once installed apply potentially to all computers in the exact same way even though sometimes it may not make sense, for example Remote Desktop Connection (RDC) to a Unix computer or puTTy to a Windows computer. Also specific customization maybe required, for example some computers may RDC in different ports than the default.
4.- I would like to easily configure commands for each computer or group of computers in the list. They may even be dependent on the Client OS I'm currently using or even the specific computer I'm using.
5.- It would be good to be able to add to the list devices that cannot actually use the NeoR Domain ip address like: Net cameras, printers or even computers that do not support NeoRouter. They can be assigned an ip address by the server and then a routing mechanism could be used to connect to them through one of the computers in the VPN.
6.- Finally there are computers that I interact with that I would like to include in the list of computers even though they are not in the NeoR VPN just to have something like a comprehensive directory of computers and services that I can potentially use from anywhere.
Thanks for your good suggestions. Some of them are in our plan already, some may not, but we will evaluate it.
BTW, your question (5) can be solved by the "Network Bridge" feature, which is implemented in the v0.9.9. What I want to explain is that for the security purpose, we don't want to mix the computers inside/outside of the virtual LAN, so when "Network Bridge" feature is enabled, ACL will be disabled. When the feature is disabled by default, ACL can control/protect each computer at port leval.
Thanks for your reply and let me congratulate you and your team for an excellent product.
Although it is technically possible to share local devices using the Network Bridge (I read the wiki description) it's very complicated. Network savvy users will be able to do it but not your average NeoRouter user.
You are right. Simplicity is the our purpose too. We will improve it in the future.


text:
"""
djangofy
========

"""

from io import (
    load_soup,
    dump_soup,
    load_json,
    dump_json
)

from translate import (
    translate
)

from update import (
    add_attr,
    insert_inside_nodes,
    insert_around_nodes,
    strip_nodes,
    strip_attrs
)

import utils

from version import __version__

redpajama_set_name: RedPajamaGithub


text:
Q: How to generate code after app initialization (JHipster)? I am a jhipster newbie and am trying out different things. Now I have created an app and changed a lot of things already. Everything is running fine. Unfortunately, I noticed only afterwards that I would like to have gatling tests. I did not select gatling during the initial app generation. But is there a way to generate tests like Gatling or Protractor afterwards? What is the intended procedure in terms of best practices?
With entities it is clearly regulated you can add new ones or re-import a .jdl file. Also I know how to add new languages with jhipster languages. But what about other frameworks?

A: Edit .yo-rc.json file, add "gatling" to testFrameworks property like below:
 "testFrameworks": ["gatling", "protractor"],

Then re-generate your project using jhipster --with-entities, using git diff to keep only the changes you want

redpajama_set_name: RedPajamaStackExchange


text:
Swindon Town badge - Link to home
Away Fans Info
TownPay
SINGLE SIGN ON HELP
The County Ground
STFC Community Foundation
STFC Customer Charter
Branding & Advertising Opportunities
Brilliant For Business Advertising Packages
First-Team Coaching Staff
Swindon Town Women
Vigouroux - We Go Again On Saturday
swindontownfc.co.uk
Lawrence Vigouroux was typically modest about his heroics during the 1-1 draw away at Southend United on Tuesday night and was just happy to have helped his side secure a vital point.
"I think I've played better than that but it was more important that we got the draw and we got a point at a tough place to come," he said.
"They are on a good run here and I'm really happy for the boys. They've dug in and I'm just really happy.
"It shows that we've got a lot of character. A lot of people have questioned our character but Tuesday showed that we can dig deep at tough places and get a point.
"Overall I'm really pleased for the boys and we go again on Saturday against Bradford.
"I don't really remember any saves to be honest, it is just a blur.
"I'm just happy that I did as much as I could to keep the ball out of the net and we go again on Saturday. It will be a tough game, they are a team in good form and we have to go and be confident and defend the way we did on Tuesday.
"If we do that then we'll always have a chance."
Vigouroux had a big hand in Town's equaliser against the Shrimpers and is confident the Reds' fortunes will now start to change for the better.
"It was a typical Swindon goal," he added.
"We played out from the back, luckily I got the ball to Conor Thomas and he turned and then he played a wonderful ball for Jon Obika who put it in the back of the net, which is what he does best.
"If I can help out the team in that way as well it is always a bonus but, first and foremost, I've got to keep the ball out the back of the net.
"Hopefully we can go again on Saturday and we can get three points.
"We've got a lot of players out injured at the minute and a lot of key players out injured in the form of Michael Doughty, Nathan Thompson and Yaser Kasim.
"They are key players for us and once they start to come back in and we have all the squad together again, we'll push on and we'll be a good force in this division.
"We've just been unlucky with the timing of injuries and it seems like we get one then another three follow, but it is something we've got to deal with.
"We've got a young group in there and I'm only 23 but I feel like one of the experienced players and I'm trying to offer as much advice and help as I can to help the boys through what was a tough period.
"Hopefully we can turn it around on Saturday."
CONOR MASTERSON SIGNS ON LOAN FROM QPR
Swindon Town are pleased to announce the signing of defender Conor Masterson from QPR on a short-term loan deal. The deal is subject to EFL and FA clearance.
GALLERY: SWINDON TOWN 1-2 DONCASTER ROVERS
CANCER DEADLINE DAY - DONATE NOW TOWN FANS
This transfer window, Swindon Town Football Club is calling on all fans, players, clubs and legends of the game to help give cancer the boot – by making a donation to help charities tackling the...
JOINT FA, PREMIER LEAGUE AND EFL STATEMENT
The Football Association, Premier League, EFL and Barclays Women's Super League have this week introduced enhanced COVID-19 measures and stressed their importance to everyone in the game.


The World Food Programme (WFP), the world's largest humanitarian organization addressing hunger and promoting food security, announced the disturbing news in a statement on Thursday, saying it was based on a survey, jointly conducted by Yemeni and international experts in October according to an international system for classifying food crises.
The organization also found that some 65,000 Yemenis were in a food "catastrophe" or near famine levels, mostly in conflict zones in the Arab Peninsula country, adding that the number could rise to 237,000 if desperately-needed aid did not get through.
Since the onset of aggression, the Yemeni army, backed by fighters from the country's popular Houthi Ansarullah movement, has been defending the impoverished nation against the invaders. The coalition is also resolute to crush the movement as another goal in its war on Yemen, which is teetering on the edge of famine.
The situation has worsened in Yemen in recent months due to a broad economic collapse after a full-scale offensive by UAE forces, backed by armed militia loyal to Hadi, was launched against the Houthi-held port city of Hudaydah in June.
The so-called liberation operation, however, failed to achieve its objective of overrunning the vital port and defeating Houthi fighters.
"The country with the biggest problem in 2019 is going to be Yemen."


The 18th Annual Screen Actors Guild Awards!
Things are starting to look magical here at the Shrine Auditorium in Los Angeles thanks to our fabulous team's hard work.
Take a look at some of the Behind-the-Scenes photos from today!
Make sure to follow SAG Awards' social media sites for live updates from our social media team. We have a very busy schedule leading up to the SAG Awards on this Sunday night and we'll keep you in the loop!
Tune in for more Behind-the-Scenes updates tomorrow!