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泊沙康唑口服液

美国FDA近日已批准Noxafil (posaconazole，泊沙康唑) 上市，用于治疗13岁以上人群的曲霉菌、假丝酵母菌的入侵性感染。入侵性真菌感染能威胁生命，通常发生在免疫力受抑制的病人中，如：器官移植病人，干细胞移植及接受化疗的癌症患者。

Noxafil是FDA首次批准用于治疗由曲霉菌引起的入侵性真菌感染的抗真菌药物。Noxafil由先灵葆雅公司研发，在2005年10月已欧洲获得批准用于成人严重入侵性真菌感染。

NOXAFIL®（泊沙康唑）注射液，用于静脉使用
NOXAFIL®（泊沙康唑）缓释片，供口服使用

初始美国批准：2006
近期主要变化
剂量和管理 11/2015
警告和注意事项，长春新碱毒性   09/2016
行动机制
泊沙康唑是唑类抗真菌剂[参见Clinical Pharmacology]。

适应症和用法
Noxafil是一种唑类抗真菌剂，适用于：
  延迟释放片剂  

预防由于严重免疫受损而发生这些感染的高风险的患者中的侵袭性曲霉菌和念珠菌感染，例如具有GVHD的HSCT接受者或具有来自化学疗法的具有长期中性粒细胞减少的血液学恶性肿瘤的那些。
口服悬浮液
治疗口咽念珠菌病（OPC），包括对伊曲康唑和/或氟康唑的OPC难治性（rOPC）。
剂量和给药
由于每种制剂的给药方式不同，因此，延胡索缓释片和口服悬浮液是不可互换的。因此，请遵循每种制剂的具体剂量建议。
指征剂量和治疗时间
*必须通过在线过滤器施用Noxafil注射液。通过静脉输注在大约90分钟通过中心静脉管施用。切勿以静脉内快速浓注的形式给予Noxafil注射。延胡索缓释片应与食物一起服用。
诺卡塞口服悬浮液应与全餐一起服用。
侵入性曲霉和假丝酵母感染的预防注射：
装载剂量：在第一天静脉内注射300mg的Noxafil注射剂每天两次。
维持剂量：静脉内注射300mg诺沙非注射，一天一次。治疗的持续时间基于从中性粒细胞减少或免疫抑制的恢复。
延迟释放片：
装载剂量：300mg（三个100mg延迟释放片），在第一天每天两次。
维持剂量：300mg（三个100mg延迟释放片剂），每天一次，从第二天开始。治疗的持续时间基于从中性粒细胞减少或免疫抑制的恢复。
口服悬浮液：200 mg（5mL），每天三次。治疗的持续时间基于从中性粒细胞减少或免疫抑制的恢复。
口咽念珠菌病（OPC）口服悬浮液：
装载剂量：在第一天每天两次100mg（2.5mL）。
维持剂量：100mg（2.5mL），每天一次，持续13天。
OPC耐火剂（rOPC）至伊曲康唑和/或氟康唑口服悬浮液：400mg（10mL），每日两次。治疗的持续时间基于患者的基础疾病和临床反应的严重性。
剂量形式和强度
Noxafil注射：300mg/16.7mL（18mg/mL）
Noxafil缓释片剂100mg
Noxafil口服悬浮液40mg/mL
禁忌症
不要对已知对泊沙康唑或其他唑类抗真菌药过敏的人服用。
不要将Noxafil与以下药物共同使用： Noxafil增加的浓度：
西罗莫司：可导致西罗莫司毒性。
CYP3A4底物（匹莫齐，奎尼丁）：可导致QTc间期延长和TdP病例。
通过CYP3A4主要代谢的HMG-CoA还原酶抑制剂：可以导致横纹肌溶解。
麦角生物碱：可导致麦角生物。
警告和注意事项
钙调神经磷酸酶抑制剂毒性：Noxafil增加环孢菌素或他克莫司的浓度;减少环孢菌素和他克莫司的剂量并经常监测浓度。
心律失常和QTc延长：Noxafil已被证明可延长QTc间期并导致TdP病例。对可能致心律失常的患者谨慎使用。不要使用已知延长QTc间期并通过CYP3A4代谢的药物。在开始Noxafil之前校正K +，Mg和Ca。
肝毒性：可能发生LFT的升高。在治疗期间发展异常LFT或监测LFT的患者应考虑停药。
在中度或重度肾损伤（肌酐清除率<50 mL/min）的患者中应避免使用诺沙平注射，除非对患者的益处/风险评估证明使用诺沙福注射是合理的。
咪达唑仑：诺沙非可以延长催眠/镇静作用。监测患者和苯二氮卓受体拮抗剂应该是可用的。
长春新碱毒性：唑类抗真菌剂（包括Noxafil）与长春新碱的伴随施用已经与神经毒性和其他严重不良反应相关;储备唑类抗真菌剂，包括Noxafil，用于接受长春花生物碱的患者，包括长春新碱，其没有替代的抗真菌治疗选择。
不良反应
在使用泊沙康唑的研究中常见的治疗性紧急不良反应是腹泻，恶心，发热，呕吐，头痛，咳嗽和低钾血症。
要报告可疑的不良反应，请联系Merck Sharp＆Dohme。
药物相互作用
相互作用药物相互作用
药物与艾美拉唑和甲氧氯普胺的相互作用不适用于泊沙康唑片。
利福布汀，苯妥英，依法韦仑，西咪替丁，埃索美拉唑*避免联合给药，除非获益超过风险。
由CYP3A4代谢的其他药物考虑剂量调整和监测不良反应和毒性。
地高辛监测地高辛血浆浓度。
Fosamprenavir，metoclopramide *监测突破性真菌感染
在特定人群中使用
妊娠：根据动物数据，可能导致胎儿伤害。
护理母亲：停止使用药物或护理，考虑药物对母亲的重要性。
严重肾功能损害：密切监测突破性真菌感染。

 

Noxafil

Generic Name: posaconazole
Dosage Form: oral suspension; tablet, injection

 

 

Noxafil® 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.

Noxafil oral suspension is indicated for the treatment of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole.

 

Noxafil delayed-release tablets and oral suspension are not to be used interchangeably due to the differences in the dosing of each formulation [see Dosage and Administration (2.3, 2.4, 2.5)].

Noxafil injection

Administer via a central venous line, including a central venous catheter or peripherally inserted central catheter (PICC), by slow intravenous infusion over approximately 90 minutes [see Dosage and Administration (2.2)].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 administer Noxafil injection as an intravenous bolus injection.

Noxafil delayed-release tablets

Swallow tablets whole. Do not divide, crush, or chew.Administer with food [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

Noxafil oral suspension

Administer with a full meal or with a liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale) in patients who cannot eat a full meal [see Dosage and Administration (2.4)]Co-administration 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 [see Drug Interactions (7.6, 7.7, 7.8, 7.9, 7.13)]

 

 

 

 

 

 

 

 

 

 

 

Dosage:

Table 1: Dosage for Noxafil Injection
Indication	Dose and Duration of Therapy
Prophylaxis of invasive Aspergillus and Candidainfections	Loading dose: 300 mg Noxafil injection intravenously twice a day on the first day.
	Maintenance dose: 300 mg Noxafil injection intravenously once a day, starting on the second day. Duration of therapy is based on recovery from neutropenia or immunosuppression.

Preparation:

· Equilibrate the refrigerated vial of Noxafil (posaconazole) injection to room temperature.

· To prepare the required dose, aseptically transfer one vial (16.7 mL) of Noxafil injection (containing 300 mg of posaconazole in solution) to an intravenous bag (or bottle) of a compatible admixture diluent (as described in Table 2), to achieve a final concentration of posaconazole that is between 1 mg/mL and 2 mg/mL. Use of other diluents is not recommended because they 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). Noxafil injection 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. Compatible diluents and drug products are listed in Tables 2 and 3 below. Any diluents or drug products not listed in the tables below should not be co-administered through the same intravenous line (or cannula).

Noxafil injection can be infused at the same time through the same intravenous line (or cannula) with the following compatible diluents:

Table 2: Compatible Diluents

0.45% sodium chloride

0.9% sodium chloride

5% dextrose in water

5% dextrose and 0.45% sodium chloride

5% dextrose and 0.9% sodium chloride

5% dextrose and 20 mEq potassium chloride

Noxafil injection can be infused at the same time through the same intravenous line (or cannula) with the following drug products prepared in 5% dextrose in water or sodium chloride 0.9%. Co-administration of drug products prepared in other diluents may result in particulate formation.

Table 3: Compatible Drugs

Amikacin sulfate

Caspofungin

Ciprofloxacin

Daptomycin

Dobutamine hydrochloride

Famotidine

Filgrastim

Gentamicin sulfate

Hydromorphone hydrochloride

Levofloxacin

Lorazepam

Meropenem

Micafungin

Morphine sulfate

Norepinephrine bitartrate

Potassium chloride

Vancomycin hydrochloride

Incompatible Diluents:

Noxafil injection must not be diluted with the following diluents:

Lactated Ringer's solution
5% dextrose with Lactated Ringer's solution
4.2% sodium bicarbonate

Administration:

· 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 [see Adverse Reactions (6.2)].

Dosage:

Table 4: Dosage for Noxafil Delayed-Release Tablets
Indication	Dose and Duration of Therapy
Prophylaxis of invasive Aspergillus and Candidainfections	Loading dose: 300 mg (three 100 mg delayed-release tablets) twice a day on the first day.
	Maintenance dose: 300 mg (three 100 mg delayed-release tablets) once a day, starting on the second day. Duration of therapy is based on recovery from neutropenia or immunosuppression.

Administration Instructions for Noxafil Delayed-Release Tablets:

Swallow tablets whole. Do not divide, crush, or chew.Administer Noxafil delayed-release tablets with food to enhance the oral absorption of posaconazole and optimize plasma concentrations [see Clinical Pharmacology (12.3)].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.

Dosage:

Table 5: Dosage for Noxafil Oral Suspension
Indication	Dose and Duration of Therapy
Prophylaxis of invasive Aspergillus and Candida infections	200 mg (5 mL) three times a day. The duration of therapy is based on recovery from neutropenia or immunosuppression.
Oropharyngeal Candidiasis	Loading dose: 100 mg (2.5 mL) twice a day on the first day.
	Maintenance dose: 100 mg (2.5 mL) once a day for 13 days.
Oropharyngeal Candidiasis Refractory to Itraconazole and/or Fluconazole	400 mg (10 mL) twice a day. Duration of therapy should be based on the severity of the patient's underlying disease and clinical response.

Administration Instructions for Noxafil Oral Suspension:

Shake Noxafil oral suspension well before use. Administer with measured dosing spoon (see Figure 1) provided.

Figure 1: A measured dosing spoon is provided, marked for doses of 2.5 mL and 5 mL.

Rinse the spoon with water after each administration and before storage.Administer each dose of Noxafil oral suspension during or immediately (i.e., within 20 minutes) following a full meal to enhance the oral absorption of Noxafil and optimize plasma concentrations [see Clinical Pharmacology (12.3)].For patients who cannot eat a full meal, Noxafil delayed-release tablets should be used instead of Noxafil oral suspension. Noxafil delayed-release tablets should be used only for the prophylaxis indication. Noxafil delayed-release tablets provide higher plasma drug exposures than Noxafil oral suspension under fasted conditions [See Dosage and Administration (2.5)].In patients who cannot eat a full meal and for whom Noxafil delayed-release tablets or Noxafil injection are not options, administer each dose of Noxafil oral suspension with a liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale).For 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.

Noxafil delayed-release tablets and oral suspension are not to be used interchangeably due to the differences in the dosing of each formulation. Therefore, follow the specific dosage recommendations for each of the formulations [see Dosage and Administration (2.3, 2.4)].

The pharmacokinetics of Noxafil oral suspension and delayed-release tablets are not significantly affected by renal impairment. Therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment.

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.

Noxafil injection is available in Type I glass vials closed with bromobutyl rubber stopper and aluminum seal containing 300 mg per 16.7 mL of solution (18 mg of posaconazole per mL).

Noxafil 100 mg delayed-release tablets are available as yellow, coated, oblong tablets, debossed with "100" on one side.

Noxafil oral suspension is available in 4-ounce (123 mL) amber glass bottles with child-resistant closures containing 105 mL of suspension (40 mg of posaconazole per mL).

Noxafil is contraindicated in persons with known hypersensitivity to posaconazole or other azole antifungal agents.

Noxafil is contraindicated with sirolimus. Concomitant administration of Noxafil with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

Noxafil is contraindicated with CYP3A4 substrates that prolong the QT interval. Concomitant administration of Noxafil with the CYP3A4 substrates, pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and cases of torsades de pointes [see Warnings and Precautions (5.2) and Drug Interactions (7.2)]

 

 

Coadministration with the HMG-CoA reductase inhibitors that are primarily metabolized through CYP3A4 (e.g., atorvastatin, lovastatin, and simvastatin) is contraindicated since increased plasma concentration of these drugs can lead to rhabdomyolysis [see Drug Interactions (7.3) and Clinical Pharmacology (12.3)].

Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism [see Drug Interactions (7.4)].

Concomitant administration of Noxafil with cyclosporine or tacrolimus increases the whole blood trough concentrations of these calcineurin-inhibitors [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. Nephrotoxicity and leukoencephalopathy (including deaths) have been reported in clinical efficacy studies in patients with elevated cyclosporine or tacrolimus concentrations. Frequent monitoring of tacrolimus or cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus or cyclosporine dose adjusted accordingly.

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 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 [see Dosage and Administration (2.6) and Use in Specific Populations (8.6)].

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 [see Dosage and Administration (2.6) and Use in Specific Populations (8.6)].

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 [see Drug Interactions (7.5) and Clinical Pharmacology (12.3)]

 

 

 

Concomitant administration of azole antifungals, including Noxafil, with vincristine has been associated with neurotoxicity and other serious adverse reactions, including seizures, peripheral neuropathy, syndrome of inappropriate antidiuretic hormone secretion, and paralytic ileus. Reserve azole antifungals, including Noxafil, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options [see Drug Interactions (7.10)].

The following serious and otherwise important adverse reactions are discussed in detail in another section of the labeling:

· Hypersensitivity [see Contraindications (4.1)]

· Arrhythmias and QT Prolongation [see Warnings and Precautions (5.2)]

· Hepatic Toxicity [see Warnings and Precautions (5.3)]

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 6 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.

Table 6: Posaconazole Injection Study 1: Number (%) of Subjects Treated with Posaconazole Injection 300 mg Daily Dose Reporting Treatment-Emergent Adverse Reactions: Frequency of at Least 10%
Body System Preferred Term	Posaconazole Injection Treatment Phase n=237 (%)*		Posaconazole Injection Treatment Phase or Subsequent Oral Suspension Treatment Phase n=237(%)†
* Adverse reactions reported in patients with an onset during the posaconazole intravenous dosing phase of the study. † Adverse reactions reported with an onset at any time during the study in patients who were treated for up to 28 days of posaconazole therapy.
Subjects Reporting any Adverse Reaction	220	(93)	235	(99)
Blood and Lymphatic System Disorder
Anemia	16	(7)	23	(10)
Thrombocytopenia	17	(7)	25	(11)
Gastrointestinal Disorders
Abdominal Pain Upper	15	(6)	25	(11)
Abdominal Pain	30	(13)	41	(17)
Constipation	18	(8)	31	(13)
Diarrhea	75	(32)	93	(39)
Nausea	46	(19)	70	(30)
Vomiting	29	(12)	45	(19)
General Disorders and Administration Site Conditions
Fatigue	19	(8)	24	(10)
Chills	28	(12)	38	(16)
Edema Peripheral	28	(12)	35	(15)
Pyrexia	49	(21)	73	(31)
Metabolism and Nutrition Disorders
Decreased appetite	23	(10)	29	(12)
Hypokalemia	51	(22)	67	(28)
Hypomagnesemia	25	(11)	30	(13)
Nervous System Disorders
Headache	33	(14)	49	(21)
Respiratory, Thoracic and Mediastinal Disorders
Cough	21	(9)	31	(13)
Dyspnea	16	(7)	24	(10)
Epistaxis	34	(14)	40	(17)
Skin and Subcutaneous Tissue Disorders
Petechiae	20	(8)	24	(10)
Rash	35	(15)	56	(24)
Vascular Disorders
Hypertension	20	(8)	26	(11)

 

 

 

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 7 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.

Table 7: Posaconazole Delayed-Release Tablet Study 1: Number (%) of Subjects Treated with 300 mg Daily Dose Reporting Treatment-Emergent Adverse Reactions: Frequency of at Least 10%
Body System Preferred Term	Posaconazole delayed-release tablet (300 mg) (n=210)
Subjects Reporting any Adverse Reaction	201	(99)
Blood and Lymphatic System Disorder
Anemia	22	(10)
Thrombocytopenia	29	(14)
Gastrointestinal Disorders
Abdominal Pain	23	(11)
Constipation	20	(10)
Diarrhea	61	(29)
Nausea	56	(27)
Vomiting	28	(13)
General Disorders and Administration Site Conditions
Asthenia	20	(10)
Chills	22	(10)
Mucosal Inflammation	29	(14)
Edema Peripheral	33	(16)
Pyrexia	59	(28)
Metabolism and Nutrition Disorders
Hypokalemia	46	(22)
Hypomagnesemia	20	(10)
Nervous System Disorders
Headache	30	(14)
Respiratory, Thoracic and Mediastinal Disorders
Cough	35	(17)
Epistaxis	30	(14)
Skin and Subcutaneous Tissue Disorders
Rash	34	(16)
Vascular Disorders
Hypertension	23	(11)

The most frequently reported adverse reactions (>25%) with posaconazole delayed-release tablets 300 mg once daily were diarrhea, pyrexia, and nausea.

The most common adverse reaction leading to discontinuation of posaconazole delayed-release tablets 300 mg once daily was nausea (2%).

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 8 presents treatment-emergent adverse reactions observed at an incidence of >10% in posaconazole prophylaxis studies. Table 9 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%).

Table 8: Posaconazole Oral Suspension Study 1 and Study 2. Number (%) of Randomized Subjects Reporting Treatment-Emergent Adverse Reactions: Frequency of at Least 10% in the Posaconazole Oral Suspension or Fluconazole Treatment Groups (Pooled Prophylaxis Safety Analysis)
Body System Preferred Term	Posaconazole (n=605)		Fluconazole (n=539)		Itraconazole (n=58)
* Percentages of sex-specific adverse reactions are based on the number of males/females.
Subjects Reporting any Adverse Reaction	595	(98)	531	(99)	58	(100)
Body as a Whole - General Disorders
Fever	274	(45)	254	(47)	32	(55)
Headache	171	(28)	141	(26)	23	(40)
Rigors	122	(20)	87	(16)	17	(29)
Fatigue	101	(17)	98	(18)	5	(9)
Edema Legs	93	(15)	67	(12)	11	(19)
Anorexia	92	(15)	94	(17)	16	(28)
Dizziness	64	(11)	56	(10)	5	(9)
Edema	54	(9)	68	(13)	8	(14)
Weakness	51	(8)	52	(10)	2	(3)
Cardiovascular Disorders, General
Hypertension	106	(18)	88	(16)	3	(5)
Hypotension	83	(14)	79	(15)	10	(17)
Disorders of Blood and Lymphatic System
Anemia	149	(25)	124	(23)	16	(28)
Neutropenia	141	(23)	122	(23)	23	(40)
Disorders of the Reproductive System and Breast
Vaginal Hemorrhage*	24	(10)	20	(9)	3	(12)
Gastrointestinal System Disorders
Diarrhea	256	(42)	212	(39)	35	(60)
Nausea	232	(38)	198	(37)	30	(52)
Vomiting	174	(29)	173	(32)	24	(41)
Abdominal Pain	161	(27)	147	(27)	21	(36)
Constipation	126	(21)	94	(17)	10	(17)
Dyspepsia	61	(10)	50	(9)	6	(10)
Heart Rate and Rhythm Disorders
Tachycardia	72	(12)	75	(14)	3	(5)
Infection and Infestations
Pharyngitis	71	(12)	60	(11)	12	(21)
Liver and Biliary System Disorders
Bilirubinemia	59	(10)	51	(9)	11	(19)
Metabolic and Nutritional Disorders
Hypokalemia	181	(30)	142	(26)	30	(52)
Hypomagnesemia	110	(18)	84	(16)	11	(19)
Hyperglycemia	68	(11)	76	(14)	2	(3)
Hypocalcemia	56	(9)	55	(10)	5	(9)
Musculoskeletal System Disorders
Musculoskeletal Pain	95	(16)	82	(15)	9	(16)
Arthralgia	69	(11)	67	(12)	5	(9)
Back Pain	63	(10)	66	(12)	4	(7)
Platelet, Bleeding and Clotting Disorders
Thrombocytopenia	175	(29)	146	(27)	20	(34)
Petechiae	64	(11)	54	(10)	9	(16)
Psychiatric Disorders
Insomnia	103	(17)	92	(17)	11	(19)
Respiratory System Disorders
Coughing	146	(24)	130	(24)	14	(24)
Dyspnea	121	(20)	116	(22)	15	(26)
Epistaxis	82	(14)	73	(14)	12	(21)
Skin and Subcutaneous Tissue Disorders
Rash	113	(19)	96	(18)	25	(43)
Pruritus	69	(11)	62	(12)	11	(19)

 

 

 

 

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%).

Table 9: Treatment-Emergent Adverse Reactions with Frequency of at Least 10% in OPC Studies with Posaconazole Oral Suspension (Treated Population)
Body System   Preferred Term	Number (%) of Subjects
	Controlled OPC Pool		Refractory OPC Pool
	Posaconazole	Fluconazole	Posaconazole
	n=557	n=262	n=239
OPC=oropharyngeal candidiasis
* Number of subjects reporting treatment-emergent adverse reactions at least once during the study, without regard to relationship to treatment. Subjects may have reported more than 1 event.
Subjects Reporting any Adverse Reaction*	356 (64)	175 (67)	221 (92)
Body as a Whole – General Disorders
Fever	34 (6)	22 (8)	82 (34)
Headache	44 (8)	23 (9)	47 (20)
Anorexia	10 (2)	4 (2)	46 (19)
Fatigue	18 (3)	12 (5)	31 (13)
Asthenia	9 (2)	5 (2)	31 (13)
Rigors	2 (<1)	4 (2)	29 (12)
Pain	4 (1)	2 (1)	27 (11)
Disorders of Blood and Lymphatic System
Neutropenia	21 (4)	8 (3)	39 (16)
Anemia	11 (2)	5 (2)	34 (14)
Gastrointestinal System Disorders
Diarrhea	58 (10)	34 (13)	70 (29)
Nausea	48 (9)	30 (11)	70 (29)
Vomiting	37 (7)	18 (7)	67 (28)
Abdominal Pain	27 (5)	17 (6)	43 (18)
Infection and Infestations
Candidiasis, Oral	3 (1)	1 (<1)	28 (12)
Herpes Simplex	16 (3)	8 (3)	26 (11)
Pneumonia	17 (3)	6 (2)	25 (10)
Metabolic and Nutritional Disorders
Weight Decrease	4 (1)	2 (1)	33 (14)
Dehydration	4 (1)	7 (3)	27 (11)
Psychiatric Disorders
Insomnia	8 (1)	3 (1)	39 (16)
Respiratory System Disorders
Coughing	18 (3)	11 (4)	60 (25)
Dyspnea	8 (1)	8 (3)	28 (12)
Skin and Subcutaneous Tissue Disorders
Rash	15 (3)	10 (4)	36 (15)
Sweating Increased	13 (2)	5 (2)	23 (10)

 

 

 

 

 

 

 

 

 

 

 

 

 

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

· Endocrine disorders: adrenal insufficiency

· Nervous system disorders: paresthesia

· Immune system disorders: allergic reaction [see Contraindications (4.1)]

· Cardiac disorders: torsades de pointes [see Warnings and Precautions (5.2)]

· Vascular disorders: pulmonary embolism

· Gastrointestinal disorders: pancreatitis

· Liver and Biliary System Disorders: bilirubinemia, hepatic enzymes increased, hepatic function abnormal, hepatitis, hepatomegaly, jaundice, AST Increased, ALT Increased

· Metabolic and Nutritional Disorders: hypokalemia

· 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 10.

Table 10: Posaconazole Oral Suspension Study 1 and Study 2. Changes in Liver Function Test Results from CTC Grade 0, 1, or 2 at Baseline to Grade 3 or 4
Number (%) of Patients With Change*
CTC = Common Toxicity Criteria; AST= Aspartate Aminotransferase;
ALT= Alanine Aminotransferase.
* Change from Grade 0 to 2 at baseline to Grade 3 or 4 during the study. These data are presented in the form X/Y, where X represents the number of patients who met the criterion as indicated, and Y represents the number of patients who had a baseline observation and at least one post-baseline observation.
Oral Suspension Study 1
Laboratory Parameter	Posaconazole n=301	Fluconazole n=299
AST	11/266 (4)	13/266 (5)
ALT	47/271 (17)	39/272 (14)
Bilirubin	24/271 (9)	20/275 (7)
Alkaline Phosphatase	9/271 (3)	8/271 (3)
Oral Suspension Study 2
Laboratory Parameter	Posaconazole (n=304)	Fluconazole/Itraconazole (n=298)
AST	9/286 (3)	5/280 (2)
ALT	18/289 (6)	13/284 (5)
Bilirubin	20/290 (7)	25/285 (9)
Alkaline Phosphatase	4/281 (1)	1/276 (<1)

The number of patients treated for OPC with clinically significant liver function test (LFT) abnormalities at any time during the studies is provided in Table 11 (LFT abnormalities were present in some of these patients prior to initiation of the study drug).

Table 11: Posaconazole Oral Suspension Studies: Clinically Significant Laboratory Test Abnormalities without Regard to Baseline Value
Laboratory Test	Controlled		Refractory
	Posaconazole	Fluconazole	Posaconazole
	n=557(%)	n=262(%)	n=239(%)
ALT= Alanine Aminotransferase; AST= Aspartate Aminotransferase.
ALT > 3.0 × ULN	16/537 (3)	13/254 (5)	25/226 (11)
AST > 3.0 × ULN	33/537 (6)	26/254 (10)	39/223 (17)
Total Bilirubin > 1.5 × ULN	15/536 (3)	5/254 (2)	9/197 (5)
Alkaline Phosphatase > 3.0 × ULN	17/535 (3)	15/253 (6)	24/190 (13)

No clinically significant postmarketing adverse reactions were identified that have not previously been reported during clinical trials experience.

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 [see Clinical Pharmacology (12.3)].

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 [see Drug Interactions (7.9) and (7.13)].

Sirolimus: Concomitant administration of posaconazole with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity. Therefore, posaconazole is contraindicated with sirolimus [see Contraindications (4.2) and Clinical Pharmacology (12.3)].

Tacrolimus: Posaconazole has been shown to significantly increase the Cmax and AUC of tacrolimus. At initiation of posaconazole treatment, reduce the tacrolimus dose to approximately one-third of the original dose. Frequent monitoring of tacrolimus whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus dose adjusted accordingly [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

Cyclosporine: Posaconazole has been shown to increase cyclosporine whole blood concentrations in heart transplant patients upon initiation of posaconazole treatment. It is recommended to reduce cyclosporine dose to approximately three-fourths of the original dose upon initiation of posaconazole treatment. Frequent monitoring of cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the cyclosporine dose adjusted accordingly [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

Concomitant administration of posaconazole with CYP3A4 substrates such as pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and cases of torsades de pointes. Therefore, posaconazole is contraindicated with these drugs [see Contraindications (4.3) and Warnings and Precautions (5.2)].

Concomitant administration of posaconazole with simvastatin increases the simvastatin plasma concentrations by approximately 10-fold. Therefore, posaconazole is contraindicated with HMG-CoA reductase inhibitors primarily metabolized through CYP3A4 [see Contraindications (4.4) and Clinical Pharmacology (12.3)].

Most of the ergot alkaloids are substrates of CYP3A4. Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism. Therefore, posaconazole is contraindicated with ergot alkaloids [see Contraindications (4.5)].

Concomitant administration of posaconazole with midazolam increases the midazolam plasma concentrations by approximately 5-fold. Increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects. Concomitant use of posaconazole and other benzodiazepines metabolized by CYP3A4 (e.g., alprazolam, triazolam) could result in increased plasma concentrations of these benzodiazepines. Patients must be monitored closely for adverse effects associated with high plasma concentrations of benzodiazepines metabolized by CYP3A4 and benzodiazepine receptor antagonists must be available to reverse these effects [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)].

Efavirenz: Efavirenz induces UDP-glucuronidase and significantly decreases posaconazole plasma concentrations [see Clinical Pharmacology (12.3)]. It is recommended to avoid concomitant use of efavirenz with posaconazole unless the benefit outweighs the risks.

Ritonavir and Atazanavir: Ritonavir and atazanavir are metabolized by CYP3A4 and posaconazole increases plasma concentrations of these drugs [see Clinical Pharmacology (12.3)]. Frequent monitoring of adverse effects and toxicity of ritonavir and atazanavir should be performed during coadministration with posaconazole.

Fosamprenavir: Combining fosamprenavir with posaconazole may lead to decreased posaconazole plasma concentrations. If concomitant administration is required, close monitoring for breakthrough fungal infections is recommended [see Clinical Pharmacology (12.3)].

Rifabutin induces UDP-glucuronidase and decreases posaconazole plasma concentrations. Rifabutin is also metabolized by CYP3A4. Therefore, coadministration of rifabutin with posaconazole increases rifabutin plasma concentrations [see Clinical Pharmacology (12.3)]. Concomitant use of posaconazole and rifabutin should be avoided unless the benefit to the patient outweighs the risk. However, if concomitant administration is required, close monitoring for breakthrough fungal infections as well as frequent monitoring of full blood counts and adverse reactions due to increased rifabutin plasma concentrations (e.g., uveitis, leukopenia) are recommended.

Phenytoin induces UDP-glucuronidase and decreases posaconazole plasma concentrations. Phenytoin is also metabolized by CYP3A4. Therefore, coadministration of phenytoin with posaconazole increases phenytoin plasma concentrations [see Clinical Pharmacology (12.3)]. Concomitant use of posaconazole and phenytoin should be avoided unless the benefit to the patient outweighs the risk. However, if concomitant administration is required, close monitoring for breakthrough fungal infections is recommended and frequent monitoring of phenytoin concentrations should be performed while coadministered with posaconazole and dose reduction of phenytoin should be considered.

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 [see Clinical Pharmacology (12.3)]. No dosage adjustment of posaconazole delayed-release tablets is required when posaconazole delayed-release tablets are concomitantly used with antacids, H2-receptor antagonists and proton pump inhibitors.

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 [see Clinical Pharmacology (12.3)]. 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.

Most of the vinca alkaloids (e.g., vincristine and vinblastine) are substrates of CYP3A4. Concomitant administration of azole antifungals, including Noxafil, with vincristine has been associated with serious adverse reactions [see Warnings and Precautions (5.6)]. Posaconazole may increase the plasma concentrations of vinca alkaloids which may lead to neurotoxicity and other serious adverse reactions. Therefore, reserve azole antifungals, including Noxafil, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options.

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.

Posaconazole Delayed-Release Tablet:

Concomitant administration of metoclopramide with posaconazole delayed-release tablets did not affect the pharmacokinetics of posaconazole [see Clinical Pharmacology (12.3)]. No dosage adjustment of posaconazole delayed-release tablets is required when given concomitantly with metoclopramide.

Posaconazole Oral Suspension:

Metoclopramide, when given with posaconazole oral suspension, decreases posaconazole plasma concentrations [see Clinical Pharmacology (12.3)]. 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 [see Clinical Pharmacology (12.3)]. 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.

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.

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.

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 [see Nonclinical Toxicology (13.2)].

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 (birth to 12 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). In a study of 136 neutropenic pediatric patients 11 months to less than 18 years treated with posaconazole oral suspension, the exposure target of steady-state posaconazole Cavg between 500 ng/mL and less than 2500 ng/mL was attained in approximately 50% of patients instead of the pre-specified 90% of patients.

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.

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 [see Dosage and Administration (2)]. Similar recommendations apply to posaconazole delayed-release tablets; however, a specific study has not been conducted with the delayed-release tablets.

 

 

 

 

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 [see Dosage and Administration (2.6) and Warnings and Precautions (5.4)].

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) [see Dosage and Administration (2) and Warnings and Precautions (5.3)]. 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.

The pharmacokinetics of posaconazole are comparable in men and women. No adjustment in the dosage of Noxafil is necessary based on gender.

The pharmacokinetic profile of posaconazole is not significantly affected by race. No adjustment in the dosage of Noxafil is necessary based on race.

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.

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.

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.

Posaconazole is an azole antifungal agent [see Clinical Pharmacology (12.4)].

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 12). A lower Cavg may be associated with an increased risk of treatment failure, defined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections.

Table 12: Noxafil Oral Suspension Exposure Analysis (Cavg) in Prophylaxis Trials
	Prophylaxis in AML/MDS*		Prophylaxis in GVHD†
	Cavg Range (ng/mL)	Treatment Failure‡ (%)	Cavg Range (ng/mL)	Treatment Failure‡ (%)
Cavg = the average posaconazole concentration when measured at steady state
* Neutropenic patients who were receiving cytotoxic chemotherapy for AML or MDS † HSCT recipients with GVHD ‡ Defined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections
Quartile 1	90-322	54.7	22-557	44.4
Quartile 2	322-490	37.0	557-915	20.6
Quartile 3	490-734	46.8	915-1563	17.5
Quartile 4	734-2200	27.8	1563-3650	17.5

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 13.

Table 13: Summary of Mean Pharmacokinetic Parameters (%CV) in Healthy Volunteers (30 minute infusion via peripheral venous line) and Patients (90 minute infusion via central venous line) after Dosing with Posaconazole Injection on Day 1
	Dose (mg)	n	AUC0-∞ (ng∙hr/mL)	AUC0-12 (ng∙hr/mL)	Cmax (ng/mL)	t1/2 (hr)	CL (L/hr)
AUC0-∞ = Area under the plasma concentration-time curve from time zero to infinity; AUC0-12 = Area under the plasma concentration-time curve from time zero to 12 hr after the first dose on Day 1; Cmax = maximum observed concentration; t½= terminal phase half-life; CL = total body clearance; N/D = Not Determined
Healthy Volunteers	200	9	35400 (50)	8840 (20)	2250 (29)	23.6 (23)	6.5 (32)
	300	9	46400 (26)	13000 (13)	2840 (30)	24.6 (20)	6.9 (27)
Patients	200	30	N/D	5570 (32)	954 (44)	N/D	N/D
	300	22	N/D	8240 (26)	1590 (62)	N/D	N/D

Table 14 displays the pharmacokinetic parameters of posaconazole in patients following administration of posaconazole injection 300 mg taken once a day for 10 or 14 days following BID dosing on Day 1.

Table 14: Arithmetic Mean (%CV) of PK Parameters in Serial PK-Evaluable Patients Following Dosing of Posaconazole Injection (300 mg)*
Day	N	Cmax (ng/mL)	Tmax† (hr)	AUC0-24 (ng*hr/mL)	Cav (ng/mL)	Cmin (ng/mL)
AUC0-24 = area under the concentration-time curve over the dosing interval (i.e. 24 hours); Cav= time-averaged concentrations (i.e., AUC0-24h/24hr);
Cmin = POS trough level immediately before a subject received the dose of POS on the day specified in the protocol; Cmax = observed maximum plasma concentration; CV = coefficient of variation, expressed as a percent (%); Day = study day on treatment; Tmax = time of observed maximum plasma concentration.
* 300 mg dose administered over 90 minutes once a day following BID dosing on Day 1 † Median (minimum-maximum)
10/14	49	3280 (74)	1.5 (0.98-4.0)	36100 (35)	1500 (35)	1090 (44)

Posaconazole Delayed-Release Tablets

Noxafil delayed-release tablets exhibit dose proportional pharmacokinetics after single and multiple dosing up to 300 mg. The mean pharmacokinetic parameters of posaconazole at steady state following administration of Noxafil delayed-release tablets 300 mg twice daily (BID) on Day 1, then 300 mg once daily (QD) thereafter in healthy volunteers and in neutropenic patients who are receiving cytotoxic chemotherapy for AML or MDS or HSCT recipients with GVHD are shown in Table 15.

Table 15: Arithmetic Mean (%CV) of Steady State PK Parameters in Healthy Volunteers and Patients Following Administration of Posaconazole Delayed-Release Tablets (300 mg)*
	N	AUC0-24 hr (ng∙hr/mL)	Cav† (ng/mL)	Cmax (ng/mL)	Cmin (ng/mL)	Tmax‡ (hr)	t1/2 (hr)	CL/F (L/hr)
CV = coefficient of variation expressed as a percentage (%CV); AUC0-T = Area under the plasma concentration-time curve from time zero to 24 hr; Cmax = maximum observed concentration; Cmin = minimum observed plasma concentration; Tmax = time of maximum observed concentration; t½ = terminal phase half-life; CL /F = Apparent total body clearance
* 300 mg BID on Day 1, then 300 mg QD thereafter † Cav = time-averaged concentrations (i.e., AUC0-24 hr/24hr) ‡ Median (minimum-maximum)
Healthy Volunteers	12	51618 (25)	2151 (25)	2764 (21)	1785 (29)	4 (3-6)	31 (40)	7.5 (26)
Patients	50	37900 (42)	1580 (42)	2090 (38)	1310 (50)	4 (1.3-8.3)	-	9.39 (45)

Posaconazole Oral Suspension

Dose-proportional increases in plasma exposure (AUC) to posaconazole oral suspension were observed following single oral doses from 50 mg to 800 mg and following multiple-dose administration from 50 mg BID to 400 mg BID in healthy volunteers. No further increases in exposure were observed when the dose of the oral suspension increased from 400 mg BID to 600 mg BID in febrile neutropenic patients or those with refractory invasive fungal infections.

The mean (%CV) [min-max] posaconazole oral suspension average steady-state plasma concentrations (Cavg) and steady-state pharmacokinetic parameters in patients following administration of 200 mg TID and 400 mg BID of the oral suspension are provided in Table 16.

Table 16: The Mean (%CV) [min-max] Posaconazole Steady-State Pharmacokinetic Parameters in Patients Following Oral Administration of Posaconazole Oral Suspension 200 mg TID and 400 mg BID
Dose*	Cavg (ng/mL)	AUC† (ng∙hr/mL)	CL/F (L/hr)	V/F (L)	t½ (hr)
Cavg = the average posaconazole concentration when measured at steady state
The variability in average plasma posaconazole concentrations in patients was relatively higher than that in healthy subjects.
* Oral suspension administration † AUC (0-24 hr) for 200 mg TID and AUC (0-12 hr) for 400 mg BID ‡ HSCT recipients with GVHD § Not done ¶ Neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia or myelodysplastic syndromes # Febrile neutropenic patients or patients with refractory invasive fungal infections, Cavg n=24
200 mg TID‡ (n=252)	1103 (67) [21.5-3650]	ND§	ND§	ND§	ND§
200 mg TID¶ (n=215)	583 (65) [89.7-2200]	15,900 (62) [4100-56,100]	51.2 (54) [10.7-146]	2425 (39) [828-5702]	37.2 (39) [19.1-148]
400 mg BID# (n=23)	723 (86) [6.70-2256]	9093 (80) [1564-26,794]	76.1 (78) [14.9-256]	3088 (84) [407-13,140]	31.7 (42) [12.4-67.3]

Absorption:

Posaconazole Delayed-Release Tablets

When given orally in healthy volunteers, posaconazole delayed-release tablets are absorbed with a median Tmax of 4 to 5 hours. Steady-state plasma concentrations are attained by Day 6 at the 300 mg dose (QD after BID loading dose at Day 1). The absolute bioavailability of the oral delayed-release tablet is approximately 54% under fasted conditions. The Cmax and AUC of posaconazole following administration of posaconazole delayed-release tablets is increased 16% and 51%, respectively, when given with a high fat meal compared to a fasted state (see Table 17). In order to enhance the oral absorption of posaconazole and optimize plasma concentrations, posaconazole delayed-release tablets should be administered with food.

Table 17: Statistical Comparison of Plasma Pharmacokinetics of Posaconazole Following Single Oral Dose Administration of 300 mg Posaconazole Delayed-Release Tablet to Healthy Subjects under Fasting and Fed Conditions
	Fasting Conditions		Fed Conditions (High Fat Meal)*		Fed/Fasting
Pharmacokinetic Parameter	N	Mean (%CV)	N	Mean (%CV)	GMR (90% CI)
GMR=Geometric least-squares mean ratio; CI=Confidence interval
* 48.5 g fat † Median (Min, Max) reported for Tmax
Cmax (ng/mL)	14	935 (34)	16	1060 (25)	1.16 (0.96, 1.41)
AUC0-72hr (hr∙ng/mL)	14	26200 (28)	16	38400 (18)	1.51 (1.33, 1.72)
Tmax† (hr)	14	5.00 (3.00, 8.00)	16	6.00 (5.00, 24.00)	N/A

 

 

 

 

 

 

 

Concomitant administration of posaconazole delayed-release tablets with drugs affecting gastric pH or gastric motility did not demonstrate any significant effects on posaconazole pharmacokinetic exposure (see Table 18).

Table 18: The Effect of Concomitant Medications that Affect the Gastric pH and Gastric Motility on the Pharmacokinetics of Posaconazole Delayed-Release Tablets in Healthy Volunteers
Coadministered Drug	Administration Arms	Change in Cmax (ratio estimate*; 90% CI of the ratio estimate)	Change in AUC0-last (ratio estimate*; 90% CI of the ratio estimate)
* Ratio Estimate is the ratio of coadministered drug plus posaconazole to posaconazole alone for Cmax or AUC0-last.
Mylanta® Ultimate strength liquid (Increase in gastric pH)	25.4 meq/5 mL, 20 mL	↑6% (1.06; 0.90 -1.26)↑	↑4% (1.04; 0.90 -1.20)
Ranitidine (Zantac®) (Alteration in gastric pH)	150 mg (morning dose of 150 mg Ranitidine BID)	↑4% (1.04; 0.88 -1.23)↑	↓3% (0.97; 0.84 -1.12)
Esomeprazole (Nexium®) (Increase in gastric pH)	40 mg (QAM 5 days, day -4 to 1)	↑2% (1.02; 0.88-1.17)↑	↑5% (1.05; 0.89 -1.24)
Metoclopramide (Reglan®) (Increase in gastric motility)	15 mg four times daily during 2 days (Day -1 and 1)	↓14% (0.86, 0.73,1.02)	↓7% (0.93, 0.803,1.07)

Posaconazole Oral Suspension

Posaconazole oral suspension is absorbed with a median Tmax of ~3 to 5 hours. Steady-state plasma concentrations are attained at 7 to 10 days following multiple-dose administration.

Following single-dose administration of 200 mg, the mean AUC and Cmax of posaconazole are approximately 3-times higher when the oral suspension is administered with a nonfat meal and approximately 4-times higher when administered with a high-fat meal (~50 gm fat) relative to the fasted state. Following single-dose administration of posaconazole oral suspension 400 mg, the mean AUC and Cmax of posaconazole are approximately 3-times higher when administered with a liquid nutritional supplement (14 gm fat) relative to the fasted state (see Table 19). In addition, the effects of varying gastric administration conditions on the Cmax and AUC of posaconazole oral suspension in healthy volunteers have been investigated and are shown in Table 20.

In order to assure attainment of adequate plasma concentrations, it is recommended to administer Noxafil oral suspension during or immediately following a full meal. In patients who cannot eat a full meal, Noxafil oral suspension should be taken with a liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale).

Table 19: The Mean (%CV) [min-max] Posaconazole Pharmacokinetic Parameters Following Single-Dose Oral Suspension Administration of 200 mg and 400 mg Under Fed and Fasted Conditions
Dose (mg)	Cmax (ng/mL)	Tmax* (hr)		AUC (I) (ng∙hr/mL)		CL/F (L/hr)		t½ (hr)
* Median [min-max]. † n=15 for AUC (I), CL/F, and t ½ ‡ The subject with Tmax of 36 hrs had relatively constant plasma levels over 36 hrs (1.7 ng/mL difference between 4 hrs and 36 hrs). § n=10 for AUC (I), CL/F, and t ½
200 mg fasted (n=20)†	132 (50) [45-267]	3.50 [1.5-36‡]		4179 (31) [2705-7269]		51 (25) [28-74]		23.5 (25) [15.3-33.7]
200 mg nonfat (n=20)†	378 (43) [131-834]	4 [3-5]		10,753 (35) [4579-17,092]		21 (39) [12-44]		22.2 (18) [17.4-28.7]
200 mg high fat (54 gm fat) (n=20)†	512 (34) [241-1016]	5 [4-5]		15,059 (26) [10,341-24,476]		14 (24) [8.2-19]		23.0 (19) [17.2-33.4]
400 mg fasted (n=23)§	121 (75) [27-366]	4 [2-12]		5258 (48) [2834-9567]		91 (40) [42-141]		27.3 (26) [16.8-38.9]
400 mg with liquid nutritional supplement (14 gm fat) (n=23)§	355 (43) [145-720]	5 [4-8]		11,295 (40) [3865-20,592]		43 (56) [19-103]		26.0 (19) [18.2-35.0]
Table 20: The Effect of Varying Gastric Administration Conditions on the Cmax and AUC of Posaconazole Oral Suspension in Healthy Volunteers*
Study Description			Administration Arms		Change in Cmax (ratio estimate†; 90% CI of the ratio estimate)		Change in AUC (ratio estimate†; 90% CI of the ratio estimate)
* In 5 subjects, the Cmax and AUC decreased substantially (range: -27% to -53% and -33% to -51%, respectively) when Noxafil was administered via an NG tube compared to when Noxafil was administered orally. 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. † Ratio Estimate is the ratio of coadministered drug plus posaconazole to coadministered drug alone for Cmax or AUC. ‡ NG = nasogastric
400-mg single dose with a high-fat meal relative to fasted state (n=12)			5 minutes before high-fat meal		↑96% (1.96; 1.48-2.59)		↑111% (2.11; 1.60-2.78)
			During high-fat meal		↑339% (4.39; 3.32-5.80)		↑382% (4.82; 3.66-6.35)
			20 minutes after high-fat meal		↑333% (4.33; 3.28-5.73)		↑387% (4.87; 3.70-6.42)
400 mg BID and 200 mg QID for 7 days in fasted state and with liquid nutritional supplement (BOOST®) (n=12)			400 mg BID with BOOST		↑65% (1.65; 1.29-2.11)		↑66% (1.66; 1.30-2.13)
			200 mg QID with BOOST		No Effect		No Effect
Divided daily dose from 400 mg BID to 200 mg QID for 7 days regardless of fasted conditions or with BOOST (n=12)			Fasted state		↑136% (2.36; 1.84-3.02)		↑161% (2.61; 2.04-3.35)
			With BOOST		↑137% (2.37; 1.86-3.04)		↑157% (2.57; 2.00-3.30)
400-mg single dose with carbonated acidic beverage (ginger ale) and/or proton pump inhibitor (esomeprazole) (n=12)			Ginger ale		↑92% (1.92; 1.51-2.44)		↑70% (1.70; 1.43-2.03)
			Esomeprazole		↓32% (0.68; 0.53-0.86)		↓30% (0.70; 0.59-0.83)
400-mg single dose with a prokinetic agent (metoclopramide 10 mg TID for 2 days) + BOOST or an antikinetic agent (loperamide 4-mg single dose) + BOOST (n=12)			With metoclopramide + BOOST		↓21% (0.79; 0.72-0.87)		↓19% (0.81; 0.72-0.91)
			With loperamide + BOOST		↓3% (0.97; 0.88-1.07)		↑11% (1.11; 0.99-1.25)
400-mg single dose either orally with BOOST or via an NG tube with BOOST (n=16)			Via NG tube‡		↓19% (0.81; 0.71-0.91)		↓23% (0.77; 0.69-0.86)

Concomitant administration of posaconazole oral suspension with drugs affecting gastric pH or gastric motility results in lower posaconazole exposure. (See Table 21.)

Table 21: The Effect of Concomitant Medications that Affect the Gastric pH and Gastric Motility on the Pharmacokinetics of Posaconazole Oral Suspension in Healthy Volunteers
Coadministered Drug (Postulated Mechanism of Interaction)	Coadministered Drug Dose/Schedule	Posaconazole Dose/Schedule	Effect on Bioavailability of Posaconazole
			Change in Mean Cmax (ratio estimate*; 90% CI of the ratio estimate)	Change in Mean AUC (ratio estimate*; 90% CI of the ratio estimate)
* Ratio Estimate is the ratio of coadministered drug plus posaconazole to coadministered drug alone for Cmax or AUC. † The tablet refers to a non-commercial tablet formulation without polymer. ‡ The drug interactions associated with the oral suspension are also relevant for the delayed-release tablet with the exception of Esomeprazole and Metoclopramide.
Cimetidine (Alteration of gastric pH)	400 mg BID × 10 days	200 mg (tablets) QD × 10 days†	↓ 39% (0.61; 0.53-0.70)	↓ 39% (0.61; 0.54-0.69)
Esomeprazole (Increase in gastric pH)‡	40 mg QAM × 3 days	400 mg (oral suspension) single dose	↓ 46% (0.54; 0.43-0.69)	↓ 32% (0.68; 0.57-0.81)
Metoclopramide (Increase in gastric motility)‡	10 mg TID × 2 days	400 mg (oral suspension) single dose	↓ 21% (0.79; 0.72-0.87)	↓ 19% (0.81; 0.72-0.91)

Distribution:

The mean volume of distribution of posaconazole after intravenous solution administration was 261 L and ranged from 226-295 L between studies and dose levels.

Posaconazole is highly bound to human plasma proteins (>98%), predominantly to albumin.

Metabolism:

Posaconazole primarily circulates as the parent compound in plasma. Of the circulating metabolites, the majority are glucuronide conjugates formed via UDP glucuronidation (phase 2 enzymes). Posaconazole does not have any major circulating oxidative (CYP450 mediated) metabolites. The excreted metabolites in urine and feces account for ~17% of the administered radiolabeled dose.

Posaconazole is primarily metabolized via UDP glucuronidation (phase 2 enzymes) and is a substrate for p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. A summary of drugs studied clinically with the oral suspension or an early tablet formulation, which affect posaconazole concentrations, is provided in Table 22.

Table 22: Summary of the Effect of Coadministered Drugs on Posaconazole in Healthy Volunteers
Coadministered Drug (Postulated Mechanism of Interaction)	Coadministered Drug Dose/Schedule	Posaconazole Dose/Schedule	Effect on Bioavailability of Posaconazole
			Change in Mean Cmax (ratio estimate*; 90% CI of the ratio estimate)	Change in Mean AUC (ratio estimate*; 90% CI of the ratio estimate)
* Ratio Estimate is the ratio of coadministered drug plus posaconazole to posaconazole alone for Cmax or AUC. † The tablet refers to a non-commercial tablet formulation without polymer.
Efavirenz (UDP-G Induction)	400 mg QD × 10 and 20 days	400 mg (oral suspension) BID × 10 and 20 days	↓45% (0.55; 0.47-0.66)	↓ 50% (0.50; 0.43-0.60)
Fosamprenavir (unknown mechanism)	700 mg BID × 10 days	200 mg QD on the 1st day, 200 mg BID on the 2nd day, then 400 mg BID × 8 Days	↓21% 0.79 (0.71-0.89)	↓23% 0.77 (0.68-0.87)
Rifabutin (UDP-G Induction)	300 mg QD × 17 days	200 mg (tablets) QD × 10 days†	↓ 43% (0.57; 0.43-0.75)	↓ 49% (0.51; 0.37-0.71)
Phenytoin (UDP-G Induction)	200 mg QD × 10 days	200 mg (tablets) QD × 10 days†	↓ 41% (0.59; 0.44-0.79)	↓ 50% (0.50; 0.36-0.71)

In vitro studies with human hepatic microsomes and clinical studies indicate that posaconazole is an inhibitor primarily of CYP3A4. A clinical study in healthy volunteers also indicates that posaconazole is a strong CYP3A4 inhibitor as evidenced by a >5-fold increase in midazolam AUC. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole. A summary of the drugs studied clinically, for which plasma concentrations were affected by posaconazole, is provided in Table 23 [see Contraindications (4) and Drug Interactions (7.1) including recommendations].

Table 23: Summary of the Effect of Posaconazole on Coadministered Drugs in Healthy Volunteers and Patients
Coadministered Drug (Postulated Mechanism of Interaction is Inhibition of CYP3A4 by posaconazole)	Coadministered Drug Dose/Schedule	Posaconazole Dose/Schedule	Effect on Bioavailability of Coadministered Drugs
			Change in Mean Cmax (ratio estimate*; 90% CI of the ratio estimate)	Change in Mean AUC (ratio estimate*; 90% CI of the ratio estimate)
* Ratio Estimate is the ratio of coadministered drug plus posaconazole to coadministered drug alone for Cmax or AUC. † The tablet refers to a non-commercial tablet formulation without polymer. ‡ The mean terminal half-life of midazolam was increased from 3 hours to 7 to 11 hours during coadministration with posaconazole.
Sirolimus	2-mg single oral dose	400 mg (oral suspension) BID × 16 days	↑ 572% (6.72; 5.62-8.03)	↑ 788% (8.88; 7.26-10.9)
Cyclosporine	Stable maintenance dose in heart transplant recipients	200 mg (tablets) QD × 10 days†	↑ cyclosporine whole blood trough concentrations Cyclosporine dose reductions of up to 29% were required
Tacrolimus	0.05-mg/kg single oral dose	400 mg (oral suspension) BID × 7 days	↑ 121% (2.21; 2.01-2.42)	↑ 358% (4.58; 4.03-5.19)
Simvastatin	40-mg single oral dose	100 mg (oral suspension) QD × 13 days	Simvastatin ↑ 841% (9.41, 7.13-12.44) Simvastatin Acid ↑ 817% (9.17, 7.36-11.43)	Simvastatin ↑ 931% (10.31, 8.40-12.67) Simvastatin Acid ↑634% (7.34, 5.82-9.25)
		200 mg (oral suspension) QD × 13 days	Simvastatin ↑ 1041% (11.41, 7.99-16.29) Simvastatin Acid ↑851% (9.51, 8.15-11.10)	Simvastatin ↑ 960% (10.60, 8.63-13.02) Simvastatin Acid ↑748% (8.48, 7.04-10.23)
Midazolam	0.4-mg single intravenous dose‡	200 mg (oral suspension) BID × 7 days	↑ 30% (1.3; 1.13-1.48)	↑ 362% (4.62; 4.02-5.3)
	0.4-mg single intravenous dose‡	400 mg (oral suspension) BID × 7 days	↑62% (1.62; 1.41-1.86)	↑524% (6.24; 5.43-7.16)
	2-mg single oral dose‡	200 mg (oral suspension) QD × 7 days	↑ 169% (2.69; 2.46-2.93)	↑ 470% (5.70; 4.82-6.74)
	2-mg single oral dose‡	400 mg (oral suspension) BID × 7 days	↑ 138% (2.38; 2.13-2.66)	↑ 397% (4.97; 4.46-5.54)
Rifabutin	300 mg QD × 17 days	200 mg (tablets) QD × 10 days†	↑ 31% (1.31; 1.10-1.57)	↑ 72% (1.72;1.51-1.95)
Phenytoin	200 mg QD PO × 10 days	200 mg (tablets) QD × 10 days†	↑ 16% (1.16; 0.85-1.57)	↑ 16% (1.16; 0.84-1.59)
Ritonavir	100 mg QD × 14 days	400 mg (oral suspension) BID × 7 days	↑ 49% (1.49; 1.04-2.15)	↑ 80% (1.8;1.39-2.31)
Atazanavir	300 mg QD × 14 days	400 mg (oral suspension) BID × 7 days	↑ 155% (2.55; 1.89-3.45)	↑ 268% (3.68; 2.89-4.70)
Atazanavir/ ritonavir boosted regimen	300 mg/100 mg QD × 14 days	400 mg (oral suspension) BID × 7 days	↑ 53% (1.53; 1.13-2.07)	↑ 146% (2.46; 1.93-3.13)

Additional clinical studies demonstrated that no clinically significant effects on zidovudine, lamivudine, indinavir, or caffeine were observed when administered with posaconazole 200 mg QD; therefore, no dose adjustments are required for these coadministered drugs when coadministered with posaconazole 200 mg QD.

Excretion:

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).

Mechanism of Action:

Posaconazole blocks the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14α-demethylase responsible for the conversion of lanosterol to ergosterol in the fungal cell membrane. This results in an accumulation of methylated sterol precursors and a depletion of ergosterol within the cell membrane thus weakening the structure and function of the fungal cell membrane. This may be responsible for the antifungal activity of posaconazole.

Resistance:

Clinical isolates of Candida albicans and Candida glabrata with decreased susceptibility to posaconazole were observed in oral swish samples taken during prophylaxis with posaconazole and fluconazole, suggesting a potential for development of resistance. These isolates also showed reduced susceptibility to other azoles, suggesting cross-resistance between azoles. The clinical significance of this finding is not known.

Antimicrobial Activity:

Posaconazole has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1)].

Microorganisms:

Aspergillus spp. and Candida spp.

Susceptibility testing:

Posaconazole interpretive criteria (breakpoints) have not been established.

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).

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.

 

 

 

 

 

 

 

 

 

 

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 24contains the results from Oral Suspension Study 1.

Table 24: Results from Blinded Clinical Study in Prophylaxis of IFI in All Randomized Patients with Hematopoietic Stem Cell Transplant (HSCT) and Graft-vs.-Host Disease (GVHD): Oral Suspension Study 1
	Posaconazole n=301	Fluconazole n=299
* Patients may have met more than one criterion defining failure. † Use of systemic antifungal therapy (SAF) criterion is based on protocol definitions (empiric/IFI usage >4 consecutive days). ‡ 95% confidence interval (posaconazole-fluconazole) = (-11.5%, +3.7%). § Patients who are lost to follow-up (not observed for 112 days), and who did not meet another clinical failure endpoint. These patients were considered failures.
On therapy plus 7 days
Clinical Failure*	50 (17%)	55 (18%)
Failure due to:
Proven/Probable IFI	7 (2%)	22 (7%)
(Aspergillus)	3 (1%)	17 (6%)
(Candida)	1 (<1%)	3 (1%)
(Other)	3 (1%)	2 (1%)
All Deaths	22 (7%)	24 (8%)
Proven/probable fungal infection prior to death	2 (<1%)	6 (2%)
SAF†	27 (9%)	25 (8%)
Through 16 weeks
Clinical Failure*,‡	99 (33%)	110 (37%)
Failure due to:
Proven/Probable IFI	16 (5%)	27 (9%)
(Aspergillus)	7 (2%)	21 (7%)
(Candida)	4 (1%)	4 (1%)
(Other)	5 (2%)	2 (1%)
All Deaths	58 (19%)	59 (20%)
Proven/probable fungal infection prior to death	10 (3%)	16 (5%)
SAF†	26 (9%)	30 (10%)
Event free lost to follow-up§	24 (8%)	30 (10%)

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 25 contains the results from Oral Suspension Study 2.

Table 25: Results from Open-Label Clinical Study 2 in Prophylaxis of IFI in All Randomized Patients with Hematologic Malignancy and Prolonged Neutropenia: Oral Suspension Study 2
	Posaconazole n=304	Fluconazole/Itraconazole n=298
* 95% confidence interval (posaconazole-fluconazole/itraconazole) = (-22.9%, -7.8%). † Patients may have met more than one criterion defining failure. ‡ Use of systemic antifungal therapy (SAF) criterion is based on protocol definitions (empiric/IFI usage >3 consecutive days). § Patients who are lost to follow-up (not observed for 100 days), and who did not meet another clinical failure endpoint. These patients were considered failures.
On therapy plus 7 days
Clinical Failure*,†	82 (27%)	126 (42%)
Failure due to:
Proven/Probable IFI	7 (2%)	25 (8%)
(Aspergillus)	2 (1%)	20 (7%)
(Candida)	3 (1%)	2 (1%)
(Other)	2 (1%)	3 (1%)
All Deaths	17 (6%)	25 (8%)
Proven/probable fungal infection prior to death	1 (<1%)	2 (1%)
SAF‡	67 (22%)	98 (33%)
Through 100 days postrandomization
Clinical Failure†	158 (52%)	191 (64%)
Failure due to:
Proven/Probable IFI	14 (5%)	33 (11%)
(Aspergillus)	2 (1%)	26 (9%)
(Candida)	10 (3%)	4 (1%)
(Other)	2 (1%)	3 (1%)
All Deaths	44 (14%)	64 (21%)
Proven/probable fungal infection prior to death	2 (1%)	16 (5%)
SAF‡	98 (32%)	125 (42%)
Event free lost to follow-up§	34 (11%)	24 (8%)

In summary, 2 clinical studies of prophylaxis were conducted with the posaconazole oral suspension. As seen in the accompanying tables (Tables 24 and 25), clinical failure represented a composite endpoint of breakthrough IFI, mortality and use of systemic antifungal therapy. In Oral Suspension Study 1 (Table 24), 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 25) 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.

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 26). 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 26).

Mycologic eradication rates (absence of colony forming units in quantitative culture at the end of therapy, Day 14), as well as mycologic relapse rates (4 weeks after the end of treatment) were also similar between the treatment arms (see Table 26).

Table 26: Posaconazole Oral Suspension Clinical Success, Mycological Eradication, and Relapse Rates in Oropharyngeal Candidiasis
	Posaconazole	Fluconazole
Clinical Success at End of Therapy (Day 14)	155/169 (91.7%)	148/160 (92.5%)
Clinical Relapse (4 Weeks after End of Therapy)	45/155 (29.0%)	52/148 (35.1%)
Mycological Eradication (absence of CFU) at End of Therapy (Day 14)	88/169 (52.1%)	80/160 (50.0%)
Mycological Relapse (4 Weeks after End of Treatment)	49/88 (55.6%)	51/80 (63.7%)

Mycologic response rates, using a criterion for success as a posttreatment quantitative culture with ≤20 colony forming units (CFU/mL) were also similar between the two groups (posaconazole 68.0%, fluconazole 68.1%). The clinical significance of this finding is unknown.

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).

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).

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) [see USP Controlled Room Temperature]. DO NOT FREEZE.

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.

Advise patients that Noxafil delayed-release tablets must be swallowed whole and not divided, crushed, or chewed.

Instruct 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.

Instruct patients that if they miss a dose, they should take it as soon as they remember. However, if it is almost time for the next dose, they should be instructed to skip the missed dose and go back to the regular schedule. Patients should not double their next dose or take more than the prescribed dose.

Advise patients to inform their physician immediately if they:

· develop severe diarrhea or vomiting.

· are currently taking drugs that are known to prolong the QTc interval and are metabolized through CYP3A4.

· are currently taking a cyclosporine or tacrolimus, or they notice swelling in an arm or leg or shortness of breath.

· are taking other drugs or before they begin taking other drugs as certain drugs can decrease or increase the plasma concentrations of posaconazole.

Advise patients to inform their physician immediately if they:

· notice a change in heart rate or heart rhythm, or have a heart condition or circulatory disease. Posaconazole can be administered with caution to patients with potentially proarrhythmic conditions.

· are pregnant, plan to become pregnant, or are nursing.

· have liver disease or develop itching, nausea or vomiting, their eyes or skin turn yellow, they feel more tired than usual or feel like they have the flu.

· have ever had an allergic reaction to other antifungal medicines such as ketoconazole, fluconazole, itraconazole, or voriconazole.

Manuf. for: Merck Sharp & Dohme Corp., a subsidiary of
MERCK & CO., INC., Whitehouse Station, NJ 08889, USA

Injection: Manuf. by: MSD International GmbH, Brinny, Innishannon, County Cork, Ireland

Delayed-Release Tablets: Manuf. by: N. V. Organon, Kloosterstraat 6, 5349 AB Oss, Netherlands

Oral Suspension: Manuf. by: Patheon Inc., Whitby, Ontario, Canada L1N 5Z5

For patent information: www.merck.com/product/patent/home.html

The trademarks referenced herein are owned by their respective companies.

Copyright © 2006-2017 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
All rights reserved.

 

 

 

 

 

uspi-mk5592-mf-1709r039

This Patient Information has been approved by the U.S. Food and Drug Administration.                                                              Revised: 08/2017
Patient Information Noxafil® (NOX-a-fil) (posaconazole) injection Noxafil® (NOX-a-fil) (posaconazole) delayed-release tablets Noxafil® (NOX-a-fil) (posaconazole) oral suspension
What is Noxafil? Noxafil injection, delayed-release tablets, and oral suspension are prescription medicines used to help prevent fungal infections that can spread throughout your body (invasive fungal infections). These infections are caused by fungi called Aspergillus or Candida. Noxafil is used in people who have an increased chance of getting these infections due to a weak immune system. These include people who have: · had a hematopoietic stem cell transplantation (bone marrow transplant) with graft versus host disease · a low white blood cell count due to chemotherapy for blood cancers (hematologic malignancy) Noxafil oral suspension is also used to treat a fungal infection called "thrush" caused by Candida in your mouth or throat area. Noxafil oral suspension can be used as the first treatment for thrush, or as another treatment for thrush after itraconazole or fluconazole treatment has not worked. Noxafil injection is for adults over 18 years of age. It is not known if Noxafil injection is safe and effective in children under 18 years of age. Noxafil delayed-release tablets and oral suspension are for adults and children over 13 years of age. It is not known if Noxafil oral suspension and delayed-release tablets are safe and effective in children under 13 years of age.
Who should not take Noxafil? Do not take Noxafil if you: · are allergic to posaconazole, any of the ingredients in Noxafil, or other azole antifungal medicines. See the end of this leaflet for a complete list of ingredients in Noxafil. · are taking any of the following medicines: o      sirolimus o      pimozide o      quinidine o      certain statin medicines that lower cholesterol (atorvastatin, lovastatin, simvastatin) o      ergot alkaloids (ergotamine, dihydroergotamine) Ask your healthcare provider or pharmacist if you are not sure if you are taking any of these medicines. Do not start taking a new medicine without talking to your healthcare provider or pharmacist.
What should I tell my healthcare provider before taking Noxafil? Before you take Noxafil, tell your healthcare provider if you: · are taking certain medicines that lower your immune system like cyclosporine or tacrolimus. · are taking certain drugs for HIV infection, such as ritonavir, atazanavir, efavirenz, or fosamprenavir. Efavirenz and fosamprenavir can cause a decrease in the Noxafil levels in your body. Efavirenz and fosamprenavir should not be taken with Noxafil. · are taking midazolam, a hypnotic and sedative medicine. · are taking vincristine, vinblastine and other "vinca alkaloids" (medicines used to treat cancer). · have or had liver problems. · have or had kidney problems. · have or had an abnormal heart rate or rhythm, heart problems, or blood circulation problems. · are pregnant or plan to become pregnant. It is not known if Noxafil will harm your unborn baby. · are breastfeeding or plan to breastfeed. It is not known if Noxafil passes into your breast milk. You and your healthcare provider should decide if you will take Noxafil or breastfeed. You should not do both. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Noxafil can affect the way other medicines work, and other medicines can affect the way Noxafil works, and can cause serious side effects. Especially tell your healthcare provider if you take: · rifabutin or phenytoin. If you are taking these medicines, you should not take Noxafil delayed-release tablets or Noxafil oral suspension. · cimetidine or esomeprazole. If you are taking these medicines, you should not take Noxafil oral suspension. Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure. Know the medicines you take. Keep a list of them with you to show your healthcare provider or pharmacist when you get a new medicine.
How will I take Noxafil? · Do not switch between taking Noxafil delayed-release tablets and Noxafil oral suspension without talking to your healthcare provider. · Take Noxafil exactly as your healthcare provider tells you to take it. · Your healthcare provider will tell you how much Noxafil to take and when to take it. · Take Noxafil for as long as your healthcare provider tells you to take it. · If you take too much Noxafil, call your healthcare provider or go to the nearest hospital emergency room right away. · Noxafil injection is usually given over 30 to 90 minutes through a plastic tube placed in your vein. · Noxafil delayed-release tablets: o      Take Noxafil delayed-release tablets with food. o      Take Noxafil delayed-release tablets whole. Do not break, crush, or chew Noxafil delayed-release tablets before swallowing. If you cannot swallow Noxafil delayed-release tablets whole, tell your healthcare provider. You may need a different medicine. o      If you miss a dose, take it as soon as you remember and then take your next scheduled dose at its regular time. If it is within 12 hours of your next dose, do not take the missed dose. Skip the missed dose and go back to your regular schedule. Do not double your next dose or take more than your prescribed dose. · Noxafil oral suspension: o      Shake Noxafil oral suspension well before use. o      Take each dose of Noxafil oral suspension during or within 20 minutes after a full meal. If you cannot eat a full meal, take each dose of Noxafil oral suspension with a liquid nutritional supplement or an acidic carbonated beverage, like ginger ale. o      A measured dosing spoon comes with your Noxafil oral suspension and is marked for doses of 2.5 mL and 5 mL. See Figure A.                                                                                  Figure A o      Rinse the spoon with water after each dose of Noxafil oral suspension and before you store it away. o      If you miss a dose, take it as soon as you remember. However, if it is almost time for the next dose, skip the missed dose and go back to the regular dosing schedule. Do not take a double dose to make up for the forgotten dose. Follow the instructions from your healthcare provider on how much Noxafil you should take and when to take it.
What are the possible side effects of Noxafil? Noxafil may cause serious side effects, including: · drug interactions with cyclosporine or tacrolimus. If you take Noxafil with cyclosporine or tacrolimus, your blood levels of cyclosporine or tacrolimus may increase. Serious side effects can happen in your kidney or brain if you have high levels of cyclosporine or tacrolimus in your blood. Your healthcare provider should do blood tests to check your levels of cyclosporine or tacrolimus if you are taking these medicines while taking Noxafil. Tell your healthcare provider right away if you have swelling in your arm or leg or shortness of breath. · problems with the electrical system of your heart (arrhythmias and QTc prolongation). Certain medicines used to treat fungus called azoles, including posaconazole, the active ingredient in Noxafil, may cause heart rhythm problems. People who have certain heart problems or who take certain medicines have a higher chance for this problem. Tell your healthcare provider right away if your heartbeat becomes fast or irregular. · liver problems. Some people who also have other serious medical problems may have severe liver problems that may lead to death, especially if you take certain doses of Noxafil. Your healthcare provider should do blood tests to check your liver while you are taking Noxafil. Call your healthcare provider right away if you have any of the following symptoms of liver problems: o                                            itchy skin o                                            nausea or vomiting o                                            yellowing of your eyes o                                            feeling very tired o                                            flu-like symptoms ·
increased amounts of midazolam in your blood. If you take Noxafil with midazolam, Noxafil increases the amount of midazolam in your blood. This can make your sleepiness last longer. Your healthcare provider should check you closely for side effects if you take midazolam with Noxafil. The most common side effects of Noxafil include:
·                     diarrhea ·                     nausea ·                     fever ·                     vomiting	·                     headache ·                     coughing ·                     low potassium levels in the blood
If you take Noxafil delayed-release tablets or Noxafil oral suspension, tell your healthcare provider right away if you have diarrhea or vomiting. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Noxafil. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store Noxafil? · Store Noxafil injection refrigerated at 36°F to 46°F (2°C to 8°C). · Store Noxafil delayed-release tablets and oral suspension at room temperature between 68°F to 77°F (20°C to 25°C). · Do not freeze Noxafil oral suspension. · Safely throw away medicine that is out of date or no longer needed. Keep Noxafil and all medicines out of the reach of children.
General information about the safe and effective use of Noxafil. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Noxafil for a condition for which it was not prescribed. Do not give Noxafil to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about Noxafil that is written for health professionals.
What are the ingredients in Noxafil? Active ingredient: posaconazole Inactive ingredients: Noxafil injection: Betadex Sulfobutyl Ether Sodium (SBECD), edetate sodium, hydrochloric acid, sodium hydroxide, and water for injection. Noxafil delayed-release tablets: 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: polysorbate 80, simethicone, sodium benzoate, sodium citrate dihydrate, citric acid monohydrate, glycerin, xanthan gum, liquid glucose, titanium dioxide, artificial cherry flavor, and purified water
Manuf. for: Merck Sharp & Dohme Corp., a subsidiary of MERCK & CO., INC., Whitehouse Station, NJ 08889, USA Injection: MSD International GmbH, Brinny, Innishannon, County Cork, Ireland Delayed-Release Tablets: Manuf. by: N. V. Organon, Kloosterstraat 6, 5349 AB Oss, Netherlands Oral Suspension: Manuf. by: Patheon Inc., Whitby, Ontario, Canada L1N 5Z5 For patent information: www.merck.com/product/patent/home.html The trademarks depicted in this piece are owned by their respective companies. Copyright © 2006-2017 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. usppi-mk5592-mf-1703r017 For more information, go to www.Noxafil.com or call 1-800-672-6372.

This Patient Information has been approved by the U.S. Food and Drug Administration.                                                              Revised: 08/2017

 

 

 

 

NDC 0085-1328-01
105 mL

Noxafil®
(posaconazole)

Oral Suspension

200 mg/5 mL

Each mL contains: 40 mg posaconazole.

Attention: Noxafil Oral Suspension and
Delayed-Release Tablets are NOT
interchangeable due to differences in the
dosing of each formulation.

SHAKE WELL BEFORE EACH USE.

Take with a meal, or a nutritional supplement,
or an acidic carbonated beverage.

Carton contains measured dosing spoon.

Rx only

NDC 0085-4324-02

Noxafil®
(posaconazole)
delayed-release tablets

100 mg

Each tablet contains 100 mg posaconazole.

Attention: Noxafil Oral Suspension and Delayed-
Release Tablets are NOT interchangeable due to
differences in the dosing of each formulation.

Rx only

60 Tablets

NDC 0085-4331-01

Noxafil®
(posaconazole)
Injection

300 mg/16.7 mL
(18 mg/mL)

For Intravenous Use Only

Requires further dilution prior to infusion.

Rx only
Single-Dose Vial

Noxafil posaconazole suspension

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0085-1328 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength posaconazole (posaconazole) posaconazole 40 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength polysorbate 80   sodium benzoate   trisodium citrate dihydrate   citric acid monohydrate   glycerin   xanthan gum   anhydrous dextrose   titanium dioxide   water

Product Characteristics Color      Score      Shape   Size   Flavor CHERRY Imprint Code   Contains

Packaging # Item Code Package Description   1 NDC:0085-1328-01 1 BOTTLE, GLASS in 1 CARTON   1   105 mL in 1 BOTTLE, GLASS

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA022003 09/15/2006

Noxafil posaconazole tablet, coated

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0085-4324 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength posaconazole (posaconazole) posaconazole 100 mg

Inactive Ingredients Ingredient Name Strength HYPROMELLOSE ACETATE SUCCINATE 06081224 (3 MM2/S)   MICROCRYSTALLINE CELLULOSE   HYDROXYPROPYL CELLULOSE (1200000 MW)   SILICON DIOXIDE   CROSCARMELLOSE SODIUM   MAGNESIUM STEARATE   POLYVINYL ALCOHOL, UNSPECIFIED   POLYETHYLENE GLYCOL 3350   TITANIUM DIOXIDE   TALC   FERRIC OXIDE YELLOW

Product Characteristics Color YELLOW Score no score Shape OVAL (oblong) Size 17mm Flavor   Imprint Code 100 Contains

Packaging # Item Code Package Description   1 NDC:0085-4324-02 60 TABLET, COATED in 1 BOTTLE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA205053 11/25/2013

Noxafil posaconazole solution

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0085-4331 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength posaconazole (posaconazole) posaconazole 18 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength BETADEX SULFOBUTYL ETHER SODIUM   EDETATE DISODIUM   HYDROCHLORIC ACID   SODIUM HYDROXIDE   WATER

Packaging # Item Code Package Description   1 NDC:0085-4331-01 1 VIAL, GLASS in 1 CARTON   1   16.7 mL in 1 VIAL, GLASS

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA205596 03/13/2014

Labeler - Merck Sharp & Dohme Corp. (001317601)

Revised: 09/2017

 

Merck Sharp & Dohme Corp.