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NOXAFIL ORAL SUSPENSION(泊沙康唑口服混悬剂)

2014-05-15 23:45:13  作者:新特药房  来源:互联网  浏览次数:1576  文字大小:【】【】【
简介: 抗真菌药泊沙康唑静脉剂型获批 近日,默克公司(Merck)的三唑抗真菌药泊沙康唑(posaconazole,Noxafil)静脉注射剂获得美国食品和药物管理局(FDA)批准,有望于4月中旬发售。 此前,Noxafil的缓释 ...

抗真菌药泊沙康唑静脉剂型获批
近日,默克公司(Merck)的三唑抗真菌药泊沙康唑(posaconazole,Noxafil)静脉注射剂获得美国食品和药物管理局(FDA)批准,有望于4月中旬发售。
此前,Noxafil的缓释片剂型已于2013年11月获FDA批准。目前有两种剂型,分别为100mg缓释片和40mg/ml口服混悬液。据了解,缓释片和口服混悬液剂型适用于13岁以上患者,而使用新的静脉用剂型患者要在18岁以上。
“Noxafil静脉剂型特别适用于需要静脉给药或者不能口服用药的患者。而且,部分患者可在初始治疗时选用Noxafil注射剂,之后逐渐转为口服剂型等。” Merck传染病研究室执行董事Nicholas Kartsonis表示。
据介绍,Noxafil三种剂型均适用于免疫功能严重低下能够感染侵袭性曲霉菌和假丝酵母菌感染的高风险人群,比如:接受造血干细胞移植后,易患移植物抗宿主病的患者;因化疗导致中性粒细胞减少的恶性血液病患者。
临床医师需要注意的是,对Noxafil或其他抗真菌药物过敏者禁用该药;同时,Noxafil必须避免该药与西罗莫司、匹莫齐特、奎尼丁、阿托伐他汀、洛伐他汀、辛伐他汀和麦角生物碱同时使用。
而且,应避免给患者同时使用降低Noxafil血药浓度的药物。如须同用,需要对患者进行密切监测,谨防突破性真菌感染。比如,环孢素和他克莫司与Noxafil同时给药时,需要调整这些药物的剂量,并经常监测血药浓度,否则环孢素或他克莫司的血药浓度增加会产生严重不良反应,包括肾毒性、脑白质病变甚至死亡。
此外,Noxafil注射剂给药方法为:在治疗第一天的负荷剂量为300mg(300mg/瓶),一天2次;从治疗的第二天开始,维持剂量为300mg(300mg/瓶),一天1次。制剂混合后要立刻使用,通过中央静脉缓慢滴注90分钟左右,否则应置于在2℃~8℃冷藏保存。Noxafil静脉注射剂在临床试验中所表现出的不良反应与口服混悬液大体相似,给药过程中常见的一过性副作用包括:腹泻(32%)、低钾血症(22%)、发热(21%)和恶心(19%)。
NOXAFIL®(泊沙康唑)口服混悬液40毫克/毫升
美国首次批准:2006
目前的主要变动
禁忌症,过敏
禁忌症,使用辛伐他汀
警告和注意事项,使用与咪达唑仑
适应症
NOXAFIL是一种三唑类抗真菌药表示为:
•侵袭性曲霉菌和念珠菌感染的患者中, 13岁及以上,谁在发展这些感染,由于受到严重免疫功能低下,如造血干细胞移植受者移植物抗宿主或那些与恶性血液病与化疗延长中性粒细胞减少高风险预防。
•治疗口咽念珠菌病( OPC ) ,包括OPC耐火材料( ROPC ),伊曲康唑和/或氟康唑。
剂量与用法
适应症剂量和治疗时间
侵袭性真菌感染的预防200毫克( 5毫升) ,一天三次。治疗持续时间是基于来自嗜中性白血球或免疫抑制的恢复。
口咽念珠菌病( OPC )装载的100毫克( 2.5毫升)的剂量每天两次的第一天,然后100毫克(2.5毫升),每日一次,连续13天。
OPC耐火材料( ROPC ),以伊曲康唑和/或氟康唑400毫克(10毫升) ,每日两次。治疗持续时间,应根据患者的潜在疾病的严重性和临床反应。
剂型和规格
每毫升NOXAFIL口服混悬液40毫克.
禁忌
•切勿管理与已知的过敏泊沙康唑, NOXAFIL的任何组件或其他唑类抗真菌药人.
•请勿共同使用NOXAFIL与下列药物; NOXAFIL增加浓度:
◦西罗莫司:可导致雷帕霉素毒性.
◦ CYP3A4底物(匹莫齐特,奎尼丁) :可能导致QT间期延长和TdP的罕见事件.
◦辛伐他汀:可导致横纹肌溶解症.
◦麦角生物碱:可导致麦角中毒
警告和注意事项
•钙调磷酸酶抑制剂毒性:环孢素或他克莫司NOXAFIL浓度增加;经常减少环孢素和他克莫司和监控浓度的剂量。
•心律失常及QT间期延长: NOXAFIL已经显示出延长QT间期和心动过速引起的罕见事件。管理慎用给患者带来潜在的致心律失常的条件。不管理与已知延长QT间期,并通过CYP3A4代谢的药物。正确的K + ,镁+ +和Ca + +开始NOXAFIL之前。
•肝毒性:在海拔肝功(一般是可逆的停药)可能发生。应停药谁在治疗期间出现肝功异常或监测肝功能试验的患者可以考虑。
•蓝精灵: NOXAFIL能延长催眠/镇静作用。监测病人和苯二氮受体拮抗剂应该可用。
不良反应
•常见的治疗出现不良反应( > 30 % )的预防研究是发热,腹泻和恶心。
•常见的治疗出现不良反应( > 5%)控制的OPC游泳池腹泻,恶心,头痛,呕吐等。常见的不良反应( > 20 % )在耐火材料的OPC池有发热,腹泻,恶心,呕吐。
药物相互作用
相互作用药物相互作用
利福布汀,苯妥英,依非韦伦,西咪替丁,奥美拉唑避免联合用药,除非胜过风险的利益
由CYP3A代谢的其他药物(他克莫司,环孢霉素,长春花生物碱类,钙通道阻滞剂)考虑调整剂量并监测不良反应和毒性.
地高辛监视器高辛血药浓度.
霉菌感染胃复安监控.
特殊人群中使用
•妊娠:根据动物数据,可能对胎儿造成伤害。
•哺乳母亲:请停止药物或哺乳期​​,同时在考虑到药物的重要性母亲。
•严重肾功能损害:密切留意突破真菌感染。


FULL PRESCRIBING INFORMATION

1. INDICATIONS AND USAGE

1.1 Prophylaxis of Invasive Fungal Infection

NOXAFIL Oral Suspension is indicated for prophylaxis of invasive Aspergillus and Candida infections in patients, 13 years of age and older, who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy.

1.2 Treatment of Oropharyngeal Candidiasis Including Oropharyngeal Candidiasis Refractory to Itraconazole and/or Fluconazole

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

2. DOSAGE AND ADMINISTRATION

2.1 Dosage

Indication Dose and Duration of Therapy
Prophylaxis of Invasive Fungal 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 of 100 mg (2.5 mL) twice a day on the first day, then 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.
2.2 Administration Instructions

Shake NOXAFIL Oral Suspension well before use.

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

It is recommended that the spoon is rinsed with water after each administration and before storage.

Each dose of NOXAFIL should be administered with a full meal or with a liquid nutritional supplement or an acidic carbonated beverage (e.g. ginger ale) in patients who cannot eat a full meal.

To enhance the oral absorption of posaconazole and optimize plasma concentrations:

  • Each dose of NOXAFIL should be administered during or immediately (i.e. within 20 minutes) following a full meal. In patients who cannot eat a full meal, each dose of NOXAFIL should be administered with a liquid nutritional supplement or an acidic carbonated beverage. For patients who cannot eat a full meal or tolerate an oral nutritional supplement or an acidic carbonated beverage, alternative antifungal therapy should be considered or patients should be monitored closely for breakthrough fungal infections.
  • Patients who have severe diarrhea or vomiting should be monitored closely for breakthrough fungal infections.
  • 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)].

3. DOSAGE FORMS AND STRENGTHS

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).

4. CONTRAINDICATIONS

4.1 Hypersensitivity

NOXAFIL is contraindicated in persons with known hypersensitivity to posaconazole, any component of NOXAFIL, or other azole antifungal agents.

4.2 Use With Sirolimus

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

4.3 QT Prolongation With Concomitant Use With CYP3A4 Substrates

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

4.4 Use With Simvastatin

Concomitant administration of NOXAFIL with simvastatin increases the simvastatin plasma concentrations by approximately 10 fold. Increased plasma statin concentrations can be associated with rhabdomyolysis [see Drug Interactions (7.3) and Clinical Pharmacology (12.3)].

4.5 Use With Ergot Alkaloids

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

5. WARNINGS AND PRECAUTIONS

5.1 Calcineurin-Inhibitor Drug Interactions

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 isolated deaths) have been reported in clinical efficacy studies in patients with elevated cyclosporine concentrations. Frequent monitoring of tacrolimus or cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus or cyclosporine dose adjusted accordingly.

5.2 Arrhythmias and QT Prolongation

Some azoles, including posaconazole, have been associated with prolongation of the QT interval on the electrocardiogram. In addition, rare 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 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.

5.3 Hepatic Toxicity

Hepatic reactions (e.g., mild to moderate elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin, and/or clinical hepatitis) have been reported in clinical trials. The elevations in liver function tests were generally reversible on discontinuation of therapy, and in some instances these tests normalized without drug interruption and rarely required drug discontinuation. Isolated 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 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.

5.4 Use with Midazolam

Concomitant administration of NOXAFIL with midazolam increases the midazolam plasma concentrations by approximately 5 fold. Increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects. Patients must be monitored closely for adverse effects associated with high plasma concentrations of midazolam and benzodiazepine receptor antagonists must be available to reverse these effects [see Drug Interactions (7.5) and Clinical Pharmacology (12.3)].

6. ADVERSE REACTIONS

6.1 Serious and Otherwise Important Adverse Reactions

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)]

6.2 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of NOXAFIL cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of posaconazole therapy has been assessed in 1844 patients in clinical trials. 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, graft vs. host disease post hematopoietic stem cell transplant, 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 1 presents treatment-emergent adverse reactions observed at an incidence of >10% in posaconazole prophylaxis studies. Table 2 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, the safety of posaconazole 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 1: Study 1 and Study 2. Number (%) of Randomized Subjects Reporting Treatment-Emergent Adverse Reactions: Frequency of at Least 10% in the Posaconazole or Fluconazole Treatment Groups (Pooled Prophylaxis Safety Analysis)
Body System
  Preferred Term
Posaconazole
(n=605)
Fluconazole
(n=539)
Itraconazole
(n=58)
Subjects Reporting any Adverse Reaction 595 (98) 531 (99) 58 (100)
NOS = not otherwise specified.
*
Percentages of sex-specific adverse reactions are based on the number of males/females.
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)
  Febrile Neutropenia 118 (20) 85 (16) 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)
  Mucositis NOS 105 (17) 68 (13) 15 (26)
  Dyspepsia 61 (10) 50 (9) 6 (10)
Heart Rate and Rhythm Disorders
  Tachycardia 72 (12) 75 (14) 3 (5)
Infection and Infestations
  Bacteremia 107 (18) 98 (18) 16 (28)
  Herpes Simplex 88 (15) 61 (11) 10 (17)
  Cytomegalovirus Infection 82 (14) 69 (13) 0
  Pharyngitis 71 (12) 60 (11) 12 (21)
  Upper Respiratory Tract Infection 44 (7) 54 (10) 5 (9)
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)
  Anxiety 52 (9) 61 (11) 9 (16)
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 at a dose of ≤400 mg QD in 557 HIV-infected patients was compared to the safety of fluconazole in 262 HIV-infected patients at a dose of 100 mg QD.

An additional 239 HIV-infected patients with refractory OPC received posaconazole in 2 non-comparative trials for refractory OPC (rOPC).

Of these subjects, 149 received the 800-mg/day dose and the remainder received the ≤400-mg QD dose.

In the OPC/rOPC studies, the most common adverse reactions were fever, diarrhea, nausea, headache, and vomiting.

The most common adverse reactions that led to treatment discontinuation of posaconazole in the Controlled OPC Pool included respiratory insufficiency (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 insufficiency (3%).

TABLE 2: Treatment-Emergent Adverse Reactions With Frequency of at Least 10% in OPC Studies (Treated Population)
Number (%) of Subjects
Controlled OPC Pool Refractory OPC Pool
Posaconazole Fluconazole Posaconazole
Body System
  Preferred Term n=557 n=262 n=239
Subjects Reporting any Adverse Reaction* 356 (64) 175 (67) 221 (92)
OPC=oropharyngeal candidiasis; SGOT=serum glutamic oxaloacetic transaminase (same as AST); SGPT=serum glutamic pyruvic transaminase (same as ALT).
*
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.
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
  • Liver and Biliary System Disorders: bilirubinemia, hepatic enzymes increased, hepatic function abnormal, hepatitis, hepatomegaly, jaundice, SGOT Increased, SGPT 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. The majority of abnormal liver function tests were minor, transient, and did not lead to discontinuation of therapy.

For the prophylaxis studies, the number of patients with changes in liver function tests from Common Toxicity Criteria (CTC) Grade 0, 1, or 2 at baseline to Grade 3 or 4 during the study is presented in Table 3.

TABLE 3: 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.
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)
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 4. (LFT abnormalities were present in some of these patients prior to initiation of the study drug).

TABLE 4: Clinically Significant Laboratory Test Abnormalities Without Regard to Baseline Value
Controlled Refractory
Posaconazole Fluconazole Posaconazole
Laboratory Test 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)

6.3 Postmarketing Experience

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

7. DRUG INTERACTIONS

Posaconazole is primarily metabolized via UDP glucuronidation and is a substrate of p-glycoprotein efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. 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)].

7.1 Immunosuppressants Metabolized by CYP3A4

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)].

7.2 CYP3A4 Substrates

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

7.3 HMG-CoA reductase Inhibitors (Statins) Metabolized Through CYP3A4

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

Although not studied clinically with statins other than simvastatin, posaconazole may increase the plasma concentrations of statins that are metabolized by CYP3A4. Increased plasma statin concentrations can be associated with rhabdomyolysis. It is recommended that patients be monitored for adverse events and dose reduction of the statin be considered during co-administration with posaconazole.

7.4 Ergot Alkaloids

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

7.5 Benzodiazepines Metabolized by CYP3A4

Concomitant administration of posaconazole with midazolam increases the midazolam plasma concentrations by approximately 5 fold. Increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects. Concomitant use of posaconazole and other benzodiazepines metabolized by CYP3A4 (e.g., alprazolam, triazolam) could result in increased plasma concentrations of these benzodiazepines. Patients must be monitored closely for adverse effects associated with high plasma concentrations of benzodiazepines metabolized by CYP3A4 and benzodiazepine receptor antagonists must be available to reverse these effects. [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)].

7.6 Anti-HIV Drugs

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 and dosage adjustments of ritonavir and atazanavir should be performed during co-administration with posaconazole.

7.7 Rifabutin

Rifabutin induces UDP-glucuronidase and decreases posaconazole plasma concentrations. Rifabutin is also metabolized by CYP3A4. Therefore, Co-administration 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 of 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.

7.8 Phenytoin

Phenytoin induces UDP-glucuronidase and decreases posaconazole plasma concentrations. Phenytoin is also metabolized by CYP3A4. Therefore, co-administration 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 of breakthrough fungal infections is recommended and frequent monitoring of phenytoin concentrations should be performed while co-administered with posaconazole and dose reduction of phenytoin should be considered.

7.9 Gastric Acid Suppressors/Neutralizers

Cimetidine (an H2-receptor antagonist) and esomeprazole (a proton pump inhibitor) decrease posaconazole plasma concentrations [see Clinical Pharmacology (12.3)]. It is recommended to avoid concomitant use of cimetidine and esomeprazole with posaconazole unless the benefit outweighs the risks. However, if concomitant administration is required, close monitoring of breakthrough fungal infections is recommended.

No clinically relevant effects were observed when posaconazole is concomitantly used with antiacids and H2-receptor antagonists other than cimetidine. No dosage adjustment of posaconazole is required when posaconazole is concomitantly used with antacids and H2-receptor antagonists other than cimetidine.

7.10 Vinca Alkaloids

Most of the vinca alkaloids are substrates of CYP3A4. Posaconazole may increase the plasma concentrations of vinca alkaloids (e.g., vincristine and vinblastine) which may lead to neurotoxicity. Therefore, it is recommended that dose adjustment of the vinca alkaloid be considered.

7.11 Calcium Channel Blockers Metabolized by CYP3A4

Posaconazole may increase the plasma concentrations of calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, diltiazem, nifedipine, nicardipine, felodipine). Frequent monitoring for adverse reactions and toxicity related to calcium channel blockers is recommended during co-administration. Dose reduction of calcium channel blockers may be needed.

7.12 Digoxin

Increased plasma concentrations of digoxin have been reported in patients receiving digoxin and posaconazole. Therefore, monitoring of digoxin plasma concentrations is recommended during co-administration.

7.13 Gastrointestinal Motility Agents

Metoclopramide decreases posaconazole plasma concentrations [see Clinical Pharmacology (12.3)]. If metoclopramide is concomitantly administered, it is recommended to closely monitor for breakthrough fungal infections.

Loperamide does not affect posaconazole plasma concentrations [see Clinical Pharmacology (12.3)]. No dosage adjustment of posaconazole is required when loperamide and posaconazole are used concomitantly.

7.14 Glipizide

Although no dosage adjustment of glipizide is required, it is recommended to monitor glucose concentrations when posaconazole and glipizide are concomitantly used.

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C: 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 regimen based on steady-state plasma concentrations of drug in healthy volunteers). The no-effect dose for malformations in rats was 9 mg/kg, which is 0.7 times the exposure achieved with the 400-mg BID regimen. No malformations were seen in rabbits at doses up to 80 mg/kg. In the rabbit, the no-effect dose was 20 mg/kg, while high doses of 40 mg/kg and 80 mg/kg, 2.9 or 5.2 times the exposure achieved with the 400-mg BID regimen, caused an increase in resorptions. In rabbits dosed at 80 mg/kg, a reduction in body weight gain of females and a reduction in litter size were seen.

8.3 Nursing Mothers

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.

8.4 Pediatric Use

The safety and effectiveness of posaconazole have been established in the age groups 13 to 17 years of age. The safety and effectiveness of posaconazole in pediatric patients below the age of 13 years have not been established. Use of posaconazole in these age groups is supported by evidence from adequate and well-controlled studies of posaconazole in adults with additional data.

A total of 12 patients 13 to 17 years of age received 600 mg/day (200 mg three times a day) for prophylaxis of invasive fungal infections. The safety profile in these patients <18 years of age appears similar to the safety profile observed in adults. Based on pharmacokinetic data in 10 of these pediatric patients, the mean steady-state average posaconazole concentration (Cav) was similar between these patients and adults (≥18 years of age).

A total of 16 patients 8 to 17 years of age were treated with 800 mg/day (400 mg twice a day or 200 mg four times a day) in a study for another indication. Based on pharmacokinetic data in 12 of these pediatric patients, the mean steady-state average posaconazole concentration (Cav) was similar between these patients and adults (≥18 years of age).

In the prophylaxis studies, the mean steady-state posaconazole average concentration (Cav) was similar among ten adolescents (13 to 17 years of age) and adults (≥18 years of age). This is consistent with pharmacokinetic data from another study in which mean steady-state posaconazole Cav from 12 adolescent patients (8–17 years of age) was similar to that in the adults (≥18 years of age).

8.5 Geriatric Use

Of the 605 patients randomized to posaconazole in the prophylaxis clinical trials, 63 (10%) were ≥65 years of age. In addition, 48 patients treated with ≥800-mg/day posaconazole in another indication were ≥65 years of age. No overall differences in safety were observed between the geriatric patients and younger patients; therefore, no dosage adjustment is recommended for geriatric patients.

The pharmacokinetics of posaconazole are comparable in young and elderly subjects (≥65 years of age). No adjustment in the dosage of NOXAFIL is necessary in elderly patients (≥65 years of age) based on age.

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.

8.6 Renal Insufficiency

Following single-dose administration of 400 mg of the oral suspension, there was no significant effect of mild (CLcr: 50–80 mL/min/1.73m2, n=6) and moderate (CLcr: 20–49 mL/min/1.73m2, n=6) renal insufficiency on posaconazole pharmacokinetics; therefore, no dose adjustment is required in patients with mild to moderate renal impairment. In subjects with severe renal insufficiency (CLcr: <20 mL/min/1.73m2), the mean plasma exposure (AUC) was similar to that in patients with normal renal function (CLcr: >80 mL/min/1.73m2); however, the range of the AUC estimates was highly variable (CV=96%) in these subjects with severe renal insufficiency as compared to that in the other renal impairment groups (CV<40%). Due to the variability in exposure, patients with severe renal impairment should be monitored closely for breakthrough fungal infections [see Dosage and Administration (2)].

8.7 Hepatic Insufficiency

After a single oral dose of posaconazole 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), and severe (Child-Pugh Class C, N=6) hepatic insufficiency, 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, and severe hepatic insufficiency, respectively. The mean apparent oral clearance (CL/F) was reduced by 18%, 36%, and 28% in subjects with mild, moderate, and severe hepatic insufficiency, 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, and severe hepatic insufficiency, respectively.

It is recommended that no dose adjustment of NOXAFIL is needed in patients with mild to severe hepatic insufficiency (Child-Pugh Class A, B, and C) [see Dosage and Administration (2), and Warnings and Precautions (5)].

8.8 Gender

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

8.9 Race

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

10. OVERDOSAGE

During the clinical trials, some patients received posaconazole 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 for 3 days. No related adverse reactions were noted by the investigator.

Posaconazole is not removed by hemodialysis.

11. DESCRIPTION

NOXAFIL is a triazole antifungal agent available as a suspension for oral administration.

Posaconazole is designated chemically as 4-[4-[4-[4-[[ (3R,5R)-5- (2,4-difluorophenyl)tetrahydro-5- (1H-1,2,4-triazol-1-ylmethyl)-3-furanyl]methoxy]phenyl]-1-piperazinyl]phenyl]-2-[ (1S,2S)-1-ethyl-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one with an empirical formula of C37H42F2N8O4 and a molecular weight of 700.8. The chemical structure is:

Posaconazole is a white powder and is insoluble in water.

NOXAFIL Oral Suspension is a white, cherry-flavored immediate-release suspension containing 40 mg of posaconazole per mL and the following inactive ingredients: polysorbate 80, simethicone, sodium benzoate, sodium citrate dihydrate, citric acid monohydrate, glycerin, xanthan gum, liquid glucose, titanium dioxide, artificial cherry flavor, and purified water.

12. CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Posaconazole is a triazole antifungal agent [see Clinical pharmacology (12.4)].

12.2 Pharmacodynamics

Exposure Response Relationship: In clinical studies of immunocompromised patients, a wide range of plasma exposures to posaconazole was noted. A pharmacokinetic-pharmacodynamic analysis of patient data revealed an apparent association between average posaconazole concentrations (Cav) and prophylactic efficacy. A lower Cav may be associated with an increased risk of treatment failure [defined in the study as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or invasive fungal infections (IFI)].

To enhance the oral absorption of posaconazole and optimize plasma concentrations:

  • Each dose of NOXAFIL should be administered during or immediately (i.e. within 20 minutes) following a full meal. In patients who cannot eat a full meal, each dose of NOXAFIL should be administered with a liquid nutritional supplement or an acidic carbonated beverage. For patients who cannot eat a full meal or tolerate an oral nutritional supplement or an acidic carbonated beverage, alternative antifungal therapy should be considered or patients should be monitored closely for breakthrough fungal infections.
  • Patients who have severe diarrhea or vomiting should be monitored closely for breakthrough fungal infections.
  • 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 (7.2)].

12.3 Pharmacokinetics

Absorption: In clinical studies of immunocompromised patients, a wide range of plasma exposures to posaconazole was noted. A pharmacokinetic-pharmacodynamic analysis of patient data revealed an apparent association between average posaconazole concentrations (Cav) and prophylactic efficacy. A lower Cav may be associated with an increased risk of treatment failure [defined in the study as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or invasive fungal infections (IFI)].

Posaconazole is absorbed with a median Tmax of ~3 to 5 hours. Dose proportional increases in plasma exposure (AUC) to posaconazole were observed following single oral doses from 50 mg to 800 mg and following multiple-dose administration from 50 mg BID to 400 mg BID. No further increases in exposure were observed when the dose was increased from 400 mg BID to 600 mg BID in febrile neutropenic patients or those with refractory invasive fungal infections. Steady-state plasma concentrations are attained at 7 to 10 days following multiple-dose administration.

Following single-dose administration of 200 mg, the mean AUC and Cmax of posaconazole are approximately 3 times higher when administered with a nonfat meal and approximately 4 times higher when administered with a high-fat meal (~50 gm fat) relative to the fasted state. Following single dose administration of 400 mg, the mean AUC and 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 5). In order to assure attainment of adequate plasma concentrations, it is recommended to administer posaconazole with food or a nutritional supplement.

TABLE 5: The Mean (%CV) [min-max] Posaconazole Pharmacokinetic Parameters Following Single-Dose 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)

(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 6: The Effect of Varying Gastric Administration Conditions on the Cmax and AUC of Posaconazole 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)
*
Ratio Estimate is the ratio of co-administered drug plus posaconazole to co-administered drug alone for Cmax or AUC.
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 increase risk of treatment failure.
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 a 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)
The mean (%CV) [min-max] posaconazole average steady-state plasma concentrations (Cav) and steady-state pharmacokinetic parameters in patients following administration of 200 mg TID and 400 mg BID of the oral suspension are provided in Table 7.

TABLE 7: The Mean (%CV) [min-max] Posaconazole Steady-State Pharmacokinetic Parameters in Patients Following Oral Administration of Posaconazole 200 mg TID and 400 mg BID
Dose Cav (ng/mL) AUC† (ng∙hr/mL) CL/F (L/hr) V/F (L) t½ (hr)
Note: Cav based on observed data; other pharmacokinetic parameters based on estimates from population pharmacokinetic analyses
*
Oral suspension administration
AUC (0–24 hr) for 200 mg TID and AUC (0–12 hr) for 400 mg BID
 
Allogeneic hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease
 
Not done
The variability in average plasma posaconazole concentrations in patients was relatively higher than that in healthy subjects.
 
Neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia or myelodysplastic syndromes
 
Febrile neutropenic patients or patients with refractory invasive fungal infections, Cav 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]
Distribution: Posaconazole has an apparent volume of distribution of 1774 L, suggesting extensive extravascular distribution and penetration into the body tissues.

Posaconazole is highly protein bound (>98%), predominantly to albumin.

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, which affect posaconazole concentrations, is provided in Table 8.

TABLE 8: Summary of the Effect of Co-administered Drugs on Posaconazole in Healthy Volunteers
Effect on Bioavailability of Posaconazole
Co-administered Drug (Postulated Mechanism of Interaction) Co-administered Drug Dose/Schedule Posaconazole Dose/Schedule 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 co-administered drug plus posaconazole to posaconazole alone for Cmax or AUC.
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)
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)
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)
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 9 [see Contraindications (4), and Drug Interactions (7.1) including recommendations].

TABLE 9: Summary of the Effect of Posaconazole on Co-administered 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 Co-administered 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 co-administered drug plus posaconazole to co-administered drug alone for Cmax or AUC.
 
The mean terminal half-life of midazolam was increased from 3 hours to 7 to 11 hours during co-administration 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)
Cyclosporin 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 IV 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 IV 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 co-administered drugs when co-administered with posaconazole 200 mg QD.

Excretion: Posaconazole is eliminated with a mean half-life (t½) of 35 hours (range: 20–66 hours) and a total body clearance (CL/F) of 32 L/hr. Posaconazole is predominantly eliminated in the feces (71% of the radiolabeled dose up to 120 hours) with the major component eliminated as parent drug (66% of the radiolabeled dose). Renal clearance is a minor elimination pathway, with 13% of the radiolabeled dose excreted in urine up to 120 hours (<0.2% of the radiolabeled dose is parent drug).

12.4 Microbiology

Mechanism of Action: Posaconazole blocks the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of the enzyme lanosterol 14α-demethylase and accumulation of methylated sterol precursors.

Activity in vitro and in vivo: Posaconazole has shown in vitro activity against Aspergillus fumigatus and Candida albicans, including Candida albicans isolates from patients refractory to itraconazole or fluconazole or both drugs [see Clinical Studies (14), Indications (1), and Dosage and Administration (2)].

In vitro susceptibility testing was performed according to the Clinical and Laboratory Standards Institute (CLSI) methods (M27-A2, M27-A, M38-A, M38-P). However, correlation between the results of susceptibility studies and clinical outcome has not been established. Posaconazole interpretive criteria/ breakpoints have not been established for any fungi.

In immunocompetent and/or immunocompromised mice and rabbits with pulmonary or disseminated infection with A. fumigatus, posaconazole administered prophylactically was effective in prolonging survival and reducing mycological burden. Prophylactic posaconazole also prolonged survival of immunocompetent mice challenged with C. albicans or A. flavus.

Drug Resistance: Clinical isolates of Candida albicans and Candida glabrata with decreases in posaconazole susceptibility 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.

13. NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No drug-related neoplasms were recorded in rats or mice treated with posaconazole for 2 years at doses higher than the clinical dose. In a 2-year carcinogenicity study, rats were given posaconazole orally at doses up to 20 mg/kg (females), or 30 mg/kg (males). These doses are equivalent to 3.9 or 3.5 times the exposure achieved with a 400-mg BID regimen, respectively, based on steady-state AUC in healthy volunteers administered a high-fat meal (400-mg BID regimen). In the mouse study, mice were treated at oral doses up to 60 mg/kg/day or 4.8 times the exposure achieved with a 400-mg BID regimen.

Posaconazole was not genotoxic or clastogenic when evaluated in bacterial mutagenicity (Ames), a chromosome aberration study in human peripheral blood lymphocytes, a Chinese hamster ovary cell mutagenicity study, and a mouse bone marrow micronucleus study.

Posaconazole had no effect on fertility of male rats at a dose up to 180 mg/kg (1.7 × the 400-mg BID regimen based on steady-state plasma concentrations in healthy volunteers) or female rats at a dose up to 45 mg/kg (2.2 × the 400-mg BID regimen).

13.2 Animal Toxicology and/or Pharmacology

In immunocompetent and/or immunocompromised mice and rabbits with pulmonary or disseminated infection with A. fumigatus, posaconazole administered prophylactically was effective in prolonging survival and reducing mycological burden. Prophylactic posaconazole also prolonged survival of immunocompetent mice challenged with C. albicans or A. flavus [see Clinical Studies (14)].

14. CLINICAL STUDIES

14.1 Prophylaxis of Aspergillus and Candida Infections

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 (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). Study 1 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 10 contains the results from Study 1.

TABLE 10: Results From Blinded Clinical Study 1 in Prophylaxis of IFI in All Randomized Patients With Hematopoietic Stem Cell Transplant (HSCT) and Graft-vs.-Host Disease (GVHD)
Posaconazole
n=301
Fluconazole
n=299
On therapy plus 7 days
*
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.
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 (Study 2) was a randomized, open-label study that compared posaconazole oral suspension (200 mg three 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 acute myelogenous leukemia or myelodysplastic syndromes. As in 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). Study 2 assessed patients while on treatment plus 7 days and 100 days post-randomization. The mean duration of therapy was comparable between the two treatment groups (29 days, posaconazole; 25 days, fluconazole or itraconazole). Table 11 contains the results from Study 2.

TABLE 11: Results From Open-Label Clinical Study 2 in Prophylaxis of IFI in All Randomized Patients With Hematologic Malignancy and Prolonged Neutropenia
Posaconazole
n=304
Fluconazole/Itraconazole
n=298
On therapy plus 7 days
*
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.
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 post-randomization
Clinical Failure† 158 (52%) 191 (64%)
  Failure due to:
    Proven/Probable IFI 14 (5%) 33 (11%)
(Aspergillus) 2 (1%) 26 (9%)
(Candida) 10 (3%) 4 (1%)
(Other) 2 (1%) 3 (1%)
  All Deaths 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. As seen in the accompanying tables (Tables 10 and 11), clinical failure represented a composite endpoint of breakthrough IFI, mortality and use of systemic antifungal therapy. In Study 1 (Table 10), 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 Study 2 (Table 11) 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 Study 1 [POS 58/301 (19%) vs. FLU 59/299 (20%)]; all-cause mortality was lower at 100 days for posaconazole-treated patients in 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.

14.2 Treatment of Oropharyngeal Candidiasis

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 (Table 12). 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 (Table 12).

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 12).

TABLE 12: 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 post-treatment quantitative culture with ≤20 colony forming units (CFU/mL) were also similar between the two groups (posaconazole 68.0%, fluconazole 68.1%). The clinical significance of this finding is unknown.

14.3 Treatment of Oropharyngeal Candidiasis Refractory to Treatment With Fluconazole or Itraconazole

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 ≥ 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 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).

16. HOW SUPPLIED/STORAGE AND HANDLING

Supplied with each bottle is a plastic dosing spoon calibrated for measuring 2.5-mL and 5-mL doses.

Store at 25°C (77°F); excursions permitted to 15°–30°C (59°–86°F). DO NOT FREEZE.
-------------------------------------------------
产地国家: 德国
原产地英文商品名:
NOXAFIL ORAL SUSPENSION 40mg/ml 105mls/bottle
原产地英文药品名:
POSACONAZOLE
中文参考商品译名:
NOXAFIL口服混悬剂 40毫克/毫升 105毫升/瓶
中文参考药品译名:
泊沙康唑
生产厂家中文参考译名:
默克
生产厂家英文名:
MSD Sharp & Dohme GmbH

责任编辑:admin


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