Noxafil
NOXAFIL®
(posaconazole) Oral Suspension
DRUG DESCRIPTION
NOXAFIL® (posaconazole) is a triazole antifungal agent available as a suspension for oral administration.
Posaconazole is designated chemically as 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-ylmethyl)-3-furanyl]methoxy]phenyl]-1-piperazinyl]phenyl]-2-[(1S,2S)-1-ethyl-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3- one with an empirical formula of C37H42F2N8O4 and a molecular weight of 700.8. The structural formula is:
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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.
INDICATIONS
NOXAFIL (posaconazole) 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. (See Microbiology and Clinical Studies)
NOXAFIL (posaconazole) is indicated for the treatment of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole (See Microbiology and Clinical Studies).
DOSAGE AND ADMINISTRATION
| 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 toitraconazole 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. |
Each dose of NOXAFIL should be administered with a full meal or with a liquid nutritional supplement in patients who can not eat a full meal. (See CLINICAL PHARMACOLOGY)
To enhance the oral absorption of posaconazole and optimize plasma concentrations:
- Each dose of NOXAFIL Oral Suspension should be administered with a full meal or liquid nutritional supplement. For patients who can not eat a full meal or tolerate an oral nutritional supplement, 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 CLINICAL PHARMACOLOGY, Drug Interactions.)
Shake NOXAFIL Oral Suspension well before use.
A measured dosing spoon is provided, marked for doses of 2.5 mL and 5 mL.
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It is recommended that the spoon is rinsed with water after each administration and before storage.
Renal Insufficiency
No dose adjustment is recommended for patients with renal dysfunction. However, the range of the posaconazole AUC estimates was highly variable (CV=96%) in subjects with severe renal insufficiency as compared to that in the other renal impairment groups (CV<40%). Due to the variability in exposure, patients with severe renal impairment should be monitored closely for breakthrough IFIs. (See CLINICAL PHARMACOLOGY.)
Hepatic Insufficiency
The pharmacokinetic data in subjects with hepatic impairment was not sufficient to determine if dose adjustment is necessary in patients with hepatic dysfunction. It is recommended that posaconazole be used with caution in patients with hepatic impairment. (See CLINICAL PHARMACOLOGY and WARNINGS.)
HOW SUPPLIED
NOXAFIL (posaconazole) Oral Suspension is available in 4-ounce (123 mL) amber glass bottles with child-resistant closures (NDC 0085-1328-01) containing 105 mL of suspension (40 mg of posaconazole per mL).
Supplied with each bottle is a plastic dosing spoon calibrated for measuring 2.5- mL and 5-mL doses.
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. DO NOT FREEZE.
Schering Corporation, Kenilworth, NJ 07033, USA. Manufactured for Schering Corporation by Patheon, Inc., Canada. FDA Rev date: 05/20/08
SIDE EFFECTS
The safety of posaconazole therapy has been assessed in 1844 patients. This includes 605 patients in the prophylaxis studies, 796 in OPC/rOPC studies and over 400 patients treated for other indications. Posaconazole therapy was given to 171 patients for ≥6 months, with 58 patients receiving posaconazole therapy for ≥12 months.
Prophylaxis of Aspergillus and Candida
TABLE 11 presents treatment-emergent adverse events observed at an incidence >10% in posaconazole prophylaxis studies.
TABLE 11: Study 1 and Study 2. Number (%) of Randomized Subjects
Reporting Treatment-Emergent Adverse Events: Frequency of at Least 10% in the
POS or FLU Treatment Groups (Pooled Prophylaxis Safety Analysis)
| Posaconazole (n=605) |
Fluconazole (n=539) |
Itraconazole (n=58) |
|
| Subjects Reporting any Adverse Event | 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) |
| Febrile Neutropenia | 118 (20) | 85 (16) | 23 (40) |
| Disorders of the Reproductive Systema nd Breast | |||
| Vaginal Hemorrhagea | 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 TissueDisorders | |||
| Rash | 113 (19) | 96 (18) | 25 (43) |
| Pruritus | 69 (11) | 62 (12) | 11 (19) |
| a Percentages of sex-specific
adverse events are based on the number of males/females. NOS = not otherwise specified. |
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TABLES 12 and 13 present treatment-related adverse events observed at an incidence ≥2% in the posaconazole prophylaxis studies.
TABLE 12: Study 1. Treatment-Related Adverse Events, Occurring
in Greater Than or Equal to 2% of Patients in Posaconazole or Fluconazole Treatment
Group
| Body System/Preferred Term | Posaconazole N=301 |
Fluconazole N=299 |
| n (%) | n (%) | |
| Subjects Reporting Any Adverse Event | 107 (36) | 115 (38) |
| Body as a Whole - General Disorders | ||
| Drug Level Altered | 5 (2) | 2 (1) |
| Dizziness | 4 (1) | 5 (2) |
| Fatigue | 4 (1) | 6 (2) |
| Anorexia | 3 (1) | 7 (2) |
| Headache | 3 (1) | 8 (3) |
| Weakness | 3 (1) | 5 (2) |
| Cardiovascular Disorders, General | ||
| Hypertension | 2 (1) | 5 (2) |
| Central and Peripheral Nervous System Disorders | ||
| Tremor | 4 (1) | 6 (2) |
| Disorders of the Eye | ||
| Vision Blurred | 3 (1) | 5 (2) |
| Gastrointestinal System Disorders | ||
| Nausea | 22 (7) | 28 (9) |
| Vomiting | 13 (4) | 15 (5) |
| Diarrhea | 8 (3) | 12 (4) |
| Abdominal Pain | 4 (1) | 7 (2) |
| Dyspepsia | 3 (1) | 6 (2) |
| Constipation | 1 (<1) | 5 (2) |
| Liver and Biliary System Disorders | ||
| SGPT Increased | 9 (3) | 4 (1) |
| GGT Increased | 9 (3) | 7 (2) |
| Bilirubinemia | 8 (3) | 5 (2) |
| Hepatic Enzymes Increased | 8 (3) | 7 (2) |
| SGOT Increased | 8 (3) | 3 (1) |
| Metabolic and Nutritional Disorders | ||
| Phosphatase Alkaline Increased | 5 (2) | 5 (2) |
| Renal and Urinary System Disorders | ||
| Blood Creatinine Increased | 6 (2) | 5 (2) |
| Special Senses, Other Disorders | ||
| Taste Perversion | 3 (1) | 5 (2) |
| GGT = gamma-glutamyl transpeptidase; SGOT = serum glutamic oxaloacetic transaminase; SGPT = serum glutamic pyruvic transaminase. | ||
TABLE 13: Study 2. Treatment-Related Adverse Events, Occurring
in Greater Than or Equal to 2% of Patients in Posaconazole or Fluconazole/Itraconazole
Treatment Group
| Body System/Preferred Term | Number (%) of Patients | |||
| Posaconazole (n=304) |
Fluconazole/ Itraconazole (n=298) |
Fluconazole (n=240) |
Itraconazole (n=58) |
|
| Subjects Reporting Any Adverse Event | 102 (34) | 101 (34) | 71 (30) | 30 (52) |
| Body as a Whole - General Disorders | ||||
| Headache | 5 (2) | 1 (<1) | 0 | 1 (2) |
| Gastrointestinal System Term Disorders | ||||
| Nausea | 22 (7) | 25 (8) | 17 (7) | 8 (14) |
| Diarrhea | 20 (7) | 21 (7) | 12 (5) | 9 (16) |
| Vomiting | 14 (5) | 20 (7) | 14 (6) | 6 (10) |
| Abdominal Pain | 9 (3) | 9 (3) | 8 (3) | 1 (2) |
| Mucositis NOS | 7 (2) | 0 | 0 | 0 |
| Dyspepsia | 5 (2) | 3 (1) | 3 (1) | 0 |
| Constipation | 3 (1) | 7 (2) | 7 (3) | 0 |
| Heart Rate and Rhythm Disorders | ||||
| QT/QTc Prolongation | 12 (4) | 9 (3) | 5 (2) | 4 (7) |
| Liver and Biliary System Disorders | ||||
| Bilirubinemia | 7 (2) | 8 (3) | 5 (2) | 3 (5) |
| Hepatic Enzymes Increased | 7 (2) | 3 (1) | 3 (1) | 0 |
| SGPT Increased | 7 (2) | 5 (2) | 4 (2) | 1 (2) |
| SGOT Increased | 6 (2) | 5 (2) | 4 (2) | 1 (2) |
| GGT Increased | 5 (2) | 2 (1) | 1 (<1) | 1 (2) |
| Metabolic and Nutritional Disorders | ||||
| Hypokalemia | 9 (3) | 6 (2) | 5 (2) | 1 (2) |
| Skin and SubcutaneousTissue Disorders | ||||
| Rash | 9 (3) | 11 (4) | 10 (4) | 1 (2) |
| GGT = gamma-glutamyl transpeptidase; NOS = not otherwise specified; SGOT = serum glutamic oxaloacetic transaminase; SGPT = serum glutamic pyruvic transaminase. | ||||
The most common treatment-related serious adverse events (1% each) in the combined prophylaxis studies were bilirubinemia, increased hepatic enzymes, hepatocellular damage, nausea, and vomiting.
Overview of Adverse Events in HIV infected subjects with OPC
In two randomized comparative studies in OPC, the safety of posaconazole at a dose of ≤400 mg QD in 557 HIV infected patients was compared to the safety of fluconazole in 262 HIV-infected patients at a dose of 100 mg QD.
An additional 239 HIV infected patients with refractory OPC received posaconazole in 2 non-comparative trials for refractory OPC (rOPC). 149 of these subjects received the 800 mg/day dose and the remainder received the ≤400 QD dose.
TABLE 14 presents Treatment Emergent Adverse Events of Clinical Significance in the comparative and non-comparative studies of OPC.
TABLE 14: Treatment Emergent Adverse Events of Clinical Significance
in OPC studies
| Number (%) of Subjects Controlled OPC Pool | Refractory OPC Pool | ||
| POS n=557 |
FLZ n=262 |
POS n=239 |
|
| Subjects Reporting any Adverse Eventa | 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) |
| Neutropenia Aggravated | 0 | 0 | 5 (2) |
| Gastro-Intestinal 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) |
| Liver and Biliary System Disorders | |||
| Bilirubinemia | 6 (1) | 2 (1) | 6 (3) |
| Hepatic Enzymes Increased | 1 (<1) | 1 (<1) | 8 (3) |
| Hepatic Function Abnormal | 8 (1) | 4 (2) | 0 |
| Hepatitis | 3 (1) | 0 | 5 (2) |
| Hepatomegaly | 0 | 0 | 8 (3) |
| Jaundice | 0 | 0 | 4 (2) |
| SGOT Increased | 8 (1) | 5 (2) | 6 (3) |
| SGPT Increased | 6 (1) | 5 (2) | 6 (3) |
| Metabolic and Nutritional Disorders | |||
| Weight Decrease | 4 (1) | 2 (1) | 33 (14) |
| Dehydration | 4 (1) | 7 (3) | 27 (11) |
| Hypokalemia | 6 (1) | 3 (1) | 15 (6) |
| Platelet, Bleeding and Clotting Disorders | |||
| Thrombocytopenia | 4 (1) | 1 (<1) | 12 (5) |
| Psychiatric Disorders | |||
| Insomnia | 8 (1) | 3 (1) | 39 (16) |
| Renal & Urinary System Disorders | |||
| Renal Failure Acute | 0 | 0 | 7 (3) |
| 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) |
| OPC=oropharyngeal candidiasis; POS=posaconazole;
FLZ= fluconazole; SGOT=serum glutamic oxaloacetic transaminase (sameas
AST); SGPT= serum glutamic pyruvic transaminase (same as ALT). a: Number of subjects reporting treatment-emergent adverse events at least once during the study, without regard to relationship to treatment. Subjects may have reported more than one event. |
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Treatment related, treatment emergent events observed in patients with OPC at an incidence of ≥2% are shown in TABLE 15.
TABLE 15: Treatment Related, Adverse Events (Any Grade) ≥2%
| Adverse Event | Number (%) of Subjects Controlled OPC Pool | Refractory OPC Pool | |
| POS n=557 |
FLZ n=262 |
POS n=239 |
|
| Subjects Reporting any Adverse Eventa | 150 (27) | 70 (27) | 135 (56) |
| Body As A Whole - General Disorders | |||
| Headache | 16 (3) | 5 (2) | 18 (8) |
| Anorexia | 6 (1) | 1 (<1) | 7 (3) |
| Asthenia | 4 (1) | 2 (1) | 6 (3) |
| Dizziness | 9 (2) | 5 (2) | 8 (3) |
| Fatigue | 8 (1) | 5 (2) | 7 (3) |
| Fever | 10 (2) | 1 (<1) | 6 (3) |
| Central and Periph Nerv System | |||
| Somnolence | 4 (1) | 5 (2) | 3 (1) |
| Disorders of Blood and Lymphatic System | |||
| Neutropenia | 10 (2) | 4 (2) | 20 (8) |
| Anemia | 2 (<1) | 0 | 6 (3) |
| Gastro-Intestinal System Disorders | |||
| Diarrhea | 19 (3) | 13 (5) | 26 (11) |
| Nausea | 27 (5) | 18 (7) | 20 (8) |
| Vomiting | 20 (4) | 4 (2) | 16 (7) |
| Abdominal Pain | 10 (2) | 8 (3) | 12 (5) |
| Flatulence | 6 (1) | 0 | 11 (5) |
| Mouth Dry | 7 (1) | 6 (2) | 5 (2) |
| Liver and Biliary System Disorders | |||
| Hepatic Enzymes Increased | 1 (<1) | 0 | 5 (2) |
| Hepatic Function Abnormal | 3 (1) | 4 (2) | 0 |
| Metabolic and Nutritional Disorders | |||
| Phosphatase AlkalineIncreased | 3 (1) | 3 (1) | 5 (2) |
| Musculo-Skeletal System Disorders | |||
| Myalgia | 1 (<1) | 0 | 4 (2) |
| Platelet, Bleeding and Clotting Disorders | |||
| Thrombocytopenia | 3 (1) | 0 | 4 (2) |
| Psychiatric Disorders | |||
| Insomnia | 3 (1) | 0 | 6 (3) |
| Skin and Subcutaneous Tissue Disorders | |||
| Rash | 8 (1) | 4 (2) | 10 (4) |
| Pruritus | 6 (1) | 2 (1) | 5 (2) |
| OPC= oropharyngeal candidiasis; POS=posaconazole;
FLZ=fluconazole; SGOT=serum glutamic oxaloacetic transaminase (same as
AST); SGPT=serumglutamic pyruvic transaminase (same as ALT). a: Number of subjects reporting treatment-related adverse events at least once during the study, without regard to relationship to treatment. Subjects may have reported more than one event. |
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Adverse events were reported more frequently in the pool of patients with refractory OPC Among these highly immunocompromised patients with advanced HIV disease, serious adverse events (SAEs) were reported in 55% (132/239). The most commonly reported SAEs were fever (13%) and neutropenia (10%).
Treatment-related SAEs were reported for 14% (34/239) of these patients and included neutropenia (5%) and abdominal pain (2%). Posaconazole was discontinued in two patients who developed neutropenia that was considered serious and treatment-related. All other reported treatment-related SAEs occurred in 1% of subjects on posaconazole.
Uncommon and rare treatment related serious or medically significant adverse events reported during clinical trials in prophylaxis, OPC/rOPC or other indications with posaconazole have included adrenal insufficiency, allergic and/or hypersensitivity reactions.
Rare cases of hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, and pulmonary embolus have been reported primarily among patients who had been receiving concomitant cyclosporine or tacrolimus for management of transplant rejection or graft-vs-host disease.
During clinical development there was a single case of torsade de pointes in a patient taking posaconazole. This report involved a seriously ill patient with multiple confounding, potentially contributory risk factors, such as a history of palpitations, recent cardiotoxic chemotherapy, hypokalemia, and hypomagnesemia.
Additionally, in another indication, 428 patients were treated with >800 mg/day with a similar AE profile.
Clinical Laboratory Values
In healthy volunteers and patients, elevation of liver function test values did not appear to be associated with higher plasma concentrations of posaconazole. The majority of abnormal liver function tests were minor, transient, and did not lead to discontinuation of therapy.
For the prophylaxis studies, the number of patients with changes in liver function tests from Common Toxicity Criteria (CTC) Grade 0, 1, or 2 at baseline to Grade 3 or 4 during the study is presented in TABLE 16.
TABLE 16: 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
| Laboratory Parameter | Number (%) of Patients With Changea | |
| Study 1 | ||
| 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 | ||
| 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) |
| a 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. CTC = Common Toxicity Criteria; AST= Aspartate Aminotransferase; ALT= Alanine Aminotransferase. |
||
The number of patients treated for OPC with clinically significant liver function test (LFT) abnormalities at any time during the studies is provided in TABLE 17 (LFT abnormalities were present in some of these patients prior to initiation of the study drug).
TABLE 17: Clinically Significant Laboratory Test Abnormalities
Without Regard to Baseline Value
| Laboratory Test | Controlled | Refractory | |
| POS | FLZ | POS | |
| N = 557 | N = 262 | N = 239 | |
| ALT > 3.0 x ULN | 16/537(3) | 13/254(5) | 25/226(11) |
| AST > 3.0 x ULN | 33/537(6) | 26/254(10) | 39/223(17) |
| Total Bilirubin > 1.5 x ULN | 15/536(3) | 5/254(2) | 9/197(5) |
| Alkaline Phosphatase> 3.0 x ULN | 17/535(3) | 15/253(6) | 24/190(13) |
| ALT= Alanine Aminotransferase; AST= AspartateAminotransferase | |||
DRUG INTERACTIONS
A summary of significant drug interactions with posaconazole that have been studied clinically are provided in TABLES 8 and 9. Appropriate precautions for the co-administration of these drugs with posaconazole are provided. (See CLINICAL PHARMACOLOGY, Drug Interactions and WARNINGS.)
TABLE 8: Summary of the Effect of Co-administered Drugs on
Posaconazole
| Co-administered Drug | Recommendations |
| Cimetidine | Avoid concomitant use unless the benefit outweighs the risks. |
| Rifabutin | Avoid concomitant use unless the benefit outweighs the risks. |
| Phenytoin | Avoid concomitant use unless the benefit outweighs the risks. |
| Efavirenz | Avoid concomitant use unless the benefit outweighs the risks. |
Co-administration of these drugs listed in TABLE 8 with posaconazole may result in lower plasma concentrations of posaconazole.
TABLE 9: Summary of the Effect of Posaconazole on Co-administered
Drugs
| Co-administered | Recommendations |
| Sirolimus | Co-administration of posaconazole with sirolimus is contraindicated. (See CLINICAL PHARMACOLOGY/Drug Interactions and CONTRAINDICATIONS.) |
| Cyclosporine | Increased cyclosporine concentrations resulted in cyclosporine dose reductions in heart transplant patients co-administered posaconazole. At initiation of posaconazole treatment, reduce the cyclosporine dose to approximately three fourths of the original dose. Frequent monitoring of cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the cyclosporine dose adjusted accordingly. |
| Tacrolimus | Posaconazole has been shown to increase Cmax and AUC of tacrolimus significantly. 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. |
| Rifabutin | Concomitant use of posaconazole and rifabutin should be avoided unless the benefit to the patient outweighs the risk. However, if concomitant administration is required frequent monitoring of full blood counts and adverse events due to increased rifabutin levels (eg, uveitis) is recommended. |
| Midazolam | Frequent monitoring of adverse effects of benzodiazepines metabolized by CYP3A4 should be performed and dose reduction of these benzodiazepines should be considered during co-administration with posaconazole. |
| Phenytoin | Frequent monitoring of phenytoin concentrations should be performed while co-administered with posaconazole and dose reduction of phenytoin should be considered. |
| Atazanavir | Frequent monitoring of adverse effects and toxicity of atazanavir should be performed during co-administration with posaconazole. |
| Ritonavir | Frequent monitoring of adverse effects and toxicity of ritonavir should be performed during co-administration with posaconazole. |
Although not studied in vitro or in vivo, posaconazole may affect the plasma concentrations of the drugs or drug classes described in TABLE 10. Appropriate precautions for the co-administration of these drugs with posaconazole are provided. (See CONTRAINDICATIONS.)
TABLE 10: Drugs Not Studied in vitro or in vivo
but Likely to Result in Significant Drug Interactions
| Drug or DrugClass (CYP3A4 Substrates) | Recommendations |
| Terfenadine, Astemizole, Pimozide, Cisapride, Quinidine,Halofantrine | Increased plasma concentrations of these drugs can lead to QT prolongation with rare occurrences of torsade de pointes . Co-administration with posaconazole is contraindicated. (See CONTRAINDICATIONS.) |
| Ergot Alkaloids | Posaconazole may increase the plasma concentration of ergot alkaloids (ergotamine and dihydroergotamine) which may lead toergotism. Co-administration of posaconazole with ergotalkaloids is contraindicated. (See CONTRAINDICATIONS.) |
| Vinca Alkaloids | Posaconazole may increase the plasma concentrations of vincaalkaloids (eg, vincristine and vinblastine) which may lead toneurotoxicity. Therefore, it is recommended that the dose adjustment of the vinca alkaloid be considered. |
| HMG-Co Areductase inhibitors (statins) metabolized through CYP3A4 | It is recommended that dose reduction of statins be considered during co-administration. Increased statin concentrations in plasma can be associated with rhabdomyolysis. |
| Calcium Channel Blockers metabolized through CYP3A4 | Frequent monitoring for adverse events and toxicity related to calcium channel blockers is recommended during co-administration. Dose reduction of calcium channel blockers may beneeded. |
| 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. |
WARNINGS
Hypersensitivity
There is no information regarding cross-sensitivity between NOXAFIL and other azole antifungal agents. Caution should be used when prescribing NOXAFIL to patients with hypersensitivity to other azoles.
Hepatic Toxicity
In clinical trials, there were infrequent cases of hepatic reactions (eg, mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin, and/or clinical hepatitis). The elevations in liver function tests were generally reversible on discontinuation of therapy, and in some instances these tests normalized without drug interruption and rarely required drug discontinuation. Rarely, more severe hepatic reactions including cholestasis or hepatic failure including fatalities were reported in patients with serious underlying medical conditions (eg, hematologic malignancy) during treatment with posaconazole. These severe hepatic events were seen primarily in subjects receiving the 800 mg daily (400 mg BID or 200 mg QID) in another indication.
Monitoring of hepatic function
Liver function tests should be evaluated at the start of and during the course of posaconazole therapy. Patients who develop abnormal liver function tests during posaconazole therapy should be monitored for the development of more severe hepatic injury. Patient management should include laboratory evaluation of hepatic function (particularly liver function tests and bilirubin). Discontinuation of posaconazole must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to posaconazole.
Cyclosporine drug interaction
Cases of elevated cyclosporine levels resulting in rare serious adverse events, including nephrotoxicity and leukoencephalopathy, and death were reported in clinical efficacy studies. Dose reduction and more frequent clinical monitoring of cyclosporine and tacrolimus should be performed when posaconazole therapy is initiated. (See PRECAUTIONS: DRUG INTERACTIONS)
PRECAUTIONS
Arrhythmias and QT prolongation
Some azoles, including posaconazole, have been associated with prolongation of the QT interval on the electrocardiogram. Results from a multiple time-matched ECG analysis in healthy volunteers did not show any increase in the mean of the QTc interval. During clinical development there was one case of torsades de pointes in a patient taking posaconazole. This patient was seriously ill with multiple confounding risk factors including a history of cardiotoxic chemotherapy, hypokalemia, and concomitant medications that may have been contributory.
Posaconazole should be administered with caution to patients with potentially proarrhythmic conditions and should not be administered with drugs that are known to prolong the QTc interval and are metabolized through CYP3A4. (See CLINICAL PHARMACOLOGY, Electrocardiogram Evaluation; CONTRAINDICATIONS; and PRECAUTIONS: DRUG INTERACTIONS) Rigorous attempts to correct potassium, magnesium, and calcium should be made before starting posaconazole.
Information for Patients
Patients should be advised to:
- Take each dose of NOXAFIL Oral Suspension with a full meal or liquid nutritional supplement in order to enhance absorption.
- Inform their physician if they develop severe diarrhea or vomiting as these conditions may decrease the plasma concentrations of posaconazole.
- Inform their physician if they are taking other drugs or before they begin taking other drugs as certain drugs can decrease the plasma concentrations of posaconazole. (See CLINICAL PHARMACOLOGY, Drug Interactions.)
Carcinogenesis, Mutagenesis, Impairment of Fertility
No drug-related neoplasms were recorded in rats or mice treated with posaconazole for two years at doses below the maximum tolerated dose. In a two-year carcinogenicity study, rats were given posaconazole orally at doses up to 20 mg/kg (females), or 30 mg/kg (males). These doses are equivalent to 3.9 or 3.5 times the exposure achieved with a 400 mg BID regimen, respectively, based on steady-state AUC in healthy volunteers administered a high fat meal (400 mg BID regimen). In the mouse study, mice were treated at oral doses up to 60 mg/kg/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 x 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 x the 400 mg BID regimen).
Pregnancy
Pregnancy Category C
Posaconazole has been shown to cause skeletal malformations (cranial malformations and missing ribs) in rats when given in doses ≥27 mg/kg (≥1.4 times the 400 mg BID regimen based on steady-state plasma concentrations of drug in healthy volunteers). The no-effect dose for malformations in rats was 9 mg/kg, which is 0.7 times the exposure achieved with the 400 mg BID regimen. No malformations were seen in rabbits at doses up to 80 mg/kg. In the rabbit, the no-effect dose was 20 mg/kg, while high doses of 40 mg/kg and 80 mg/kg, 2.9 or 5.2 times the exposure achieved with the 400 mg BID regimen, caused an increase in resorptions. In rabbits dosed at 80 mg/kg, a reduction in body weight gain of females and a reduction in litter size was seen. There are no adequate and well-controlled studies in pregnant women. Posaconazole should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
Posaconazole is excreted in milk of lactating rats. The excretion of posaconazole in human breast milk has not been investigated. NOXAFIL should not be used by nursing mothers unless the benefit to the mother clearly outweighs the potential risk to the infant.
Pediatric Use
A total of 12 patients 13 to 17 years of age received 600 mg/day (200 mg three times a day) for prophylaxis of invasive fungal infections. The safety profile in these patients <18 years of age appears similar to the safety profile observed in adults. Based on pharmacokinetic data in 10 of these pediatric patients, the mean steady-state average posaconazole concentration (Cav) was similar between these patients and adults (≥18 years of age).
A total of 16 patients 8 to 17 years of age were treated with 800 mg/day (400 mg twice a day or 200 mg four times a day) in a study for another indication. Based on pharmacokinetic data in 12 of these pediatric patients, the mean steady-state average posaconazole concentration (Cav) was similar between these patients and adults (≥18 years of age). (See CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations , Pediatric.)
Safety and effectiveness of posaconazole in pediatric patients below the age of 13 years have not been established.
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. (See CLINICAL PHARMACOLOGY ,Pharmacokinetics in Special Populations, Geriatric.)
OVERDOSE
During the clinical trials, some patients received posaconazole up to 1600 mg/day with no adverse events noted that were different from the lower doses. In addition, accidental overdose was noted in one patient who took 1200 mg BID for 3 days. No related adverse events were noted by the investigator. Posaconazole is not removed by hemodialysis.
CONTRAINDICATIONS
Hypersensitivity to the active substance or to any of the excipients.
Co-administration of NOXAFIL® (posaconazole) with sirolimus is contraindicated (See CLINICAL PHARMACOLOGY/Drug Interactions and PRECAUTIONS: DRUG INTERACTIONS).
Co-administration with ergot alkaloids. (See PRECAUTIONS: DRUG INTERACTIONS)
Co-administration with the CYP3A4 substrates terfenadine, astemizole, cisapride, pimozide, halofantrine, or quinidine since this may result in increased plasma concentrations of these medicinal products, leading to QTc prolongation and rare occurrences of torsades de pointes. (See CLINICAL PHARMACOLOGY, Drug Interactions and PRECAUTIONS: DRUG INTERACTIONS)
CLINICAL PHARMACOLOGY
Pharmacokinetics
Absorption
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 1). In order to assure attainment of adequate plasma concentrations, it is recommended to administer posaconazole with food or a nutritional supplement. (See DOSAGE AND ADMINISTRATION.)
TABLE 1: 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) | Tmaxa (hr) | AUC(I) (ng·hr/mL) |
CL/F (L/hr) | t1/2 (hr) |
| 200 mg fasted (n=20)c |
132 (50) [45-267] |
3.50 [1.5-36b] |
4179 (31) [2705-7269] |
51 (25) [28-74] |
23.5 (25) [15.3-33.7] |
| 200 mg nonfat (n=20) c |
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) c |
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) d |
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) d |
355 (43) [145-720] |
5 [4-8] | 11,295 (40) [3865-20,592] |
43 (56) [19-103] |
26.0 (19) [18.2-35.0] |
| a: Median [min-max] b: 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) c: n=15 for AUC (I), CL/F and t1/2 d: n=10 for AUC(I), CL/F and t1/2 |
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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.
Excretion
Posaconazole is eliminated with a mean half-life (t½) of 35 hours (range 20 to 66 hours) and a total body clearance (CL/F) of 32 L/hr. Posaconazole is predominantly eliminated in the feces (71% of the radiolabeled dose up to 120 hours) with the major component eliminated as parent drug (66% of the radiolabeled dose). Renal clearance is a minor elimination pathway, with 13% of the radiolabeled dose excreted in urine up to 120 hours (<0.2% of the radiolabeled dose is parent drug).
Summary of Pharmacokinetic Parameters
The mean (% CV) [min-max] posaconazole average steady-state plasma concentrations (Cav) and steady-state pharmacokinetic parameters in patients following administration of 200 mg TID and 400 mg BID of the oral suspension are provided in TABLE 2.
TABLE 2: The Mean (%CV) [Min-Max] Posaconazole Steady-State
Pharmacokinetic Parameters in Patients Following Oral Administration of Posaconazole
200 Mg TID And 400 mg BID
| Dosea | Cav (ng/mL) | AUCe (ng·hr/mL) |
CL/F (L/hr) | V/F (L) | t1/2 (hr) |
| 200 mg TIDb (n=252) |
1103 (67) [21.5-3,650] |
NDf | NDf | NDf | NDf |
| 200 mg TIDc (n=215) |
583 (65) [89.7-2,200] |
15,900 (62) [4100 -56,100] |
51.2 (54) [10.7 -146] |
2425 (39) [828 -5702] |
37.2 (39) [19.1 -148] |
| 400 mg BIDd (n=23) |
723 (86) [6.70 -2,256] |
9093 (80) [1564 -26,794] |
76.1 (78) [14.9 - 256] |
3088 (84) [407-13,140] |
31.7 (42) [12.4-67.3] |
| Note: Cav based on observed data; other pharmacokinetic parameters
based on estimates from population pharmacokinetic analyses a: Oral suspension administration b: Allogeneic hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease c: Neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia or myelodysplastic syndromes d: Febrile neutropenic patients or patients with refractory invasive fungal infections, Cav n=24 e: AUC (0-24 hr) for 200 mg TID and AUC (0-12 hr) for 400 mg BID f: Not done |
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The variability in average plasma posaconazole concentrations in patients was relatively higher than that in healthy subjects.
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 Oral Suspension should be administered with a full meal or liquid nutritional supplement. For patients who can not eat a full meal or tolerate an oral nutritional supplement, 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 CLINICAL PHARMACOLOGY, Drug Interactions.)
Pharmacokinetics in Special Populations
Gender
The pharmacokinetics of posaconazole are comparable in men and women. No adjustment in the dosage of NOXAFIL is necessary based on gender.
Race
The pharmacokinetic profile of posaconazole is not significantly affected by race. No adjustment in the dosage of NOXAFIL is necessary based on race.
Geriatric
The pharmacokinetics of posaconazole are comparable in young and elderly subjects (≥65 years of age). No adjustment in the dosage of NOXAFIL is necessary in elderly patients (≥65 years of age) based on age.
Pediatric
In the prophylaxis studies, the mean steady-state posaconazole average concentration (Cav) was similar among ten adolescents (13-17 years of age) and adults (≥18 years of age). This is consistent with pharmacokinetic data from another study in which mean steady-state posaconazole Cav from 12 adolescent patients (8-17 years of age) was similar to that in the adults (≥18 years of age).
Hepatic Insufficiency
The pharmacokinetic data in subjects with hepatic impairment was not sufficient to determine if dose adjustment is necessary in patients with hepatic dysfunction. It is recommended that posaconazole be used with caution in patients with hepatic impairment. (See WARNINGS and DOSAGE AND ADMINISTRATION.)
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.)
Electrocardiogram Evaluation
Multiple, time-matched ECGs collected over a 12-hour period were recorded at baseline and steady-state from 173 healthy male and female volunteers (18-85 years of age) administered posaconazole 400 mg BID with a high fat meal. In this pooled analysis, the mean QTc (Fridericia) interval change from baseline was -5 msec following administration of the recommended clinical dose. A decrease in the QTc(F) interval (-3 msec) was also observed in a small number of subjects (n=16) administered placebo. The placebo-adjusted mean maximum QTc(F) interval change from baseline was <0 msec (-8 msec). No healthy subject administered posaconazole had a QTc(F) interval 500 msec or an increase 60 msec in their QTc(F) interval from baseline. (See PRECAUTIONS.)
Drug Interactions
Effect of Other Drugs on Posaconazole
Posaconazole is primarily metabolized via UDP glucuronidation (phase 2 enzymes) and is a substrate for p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. A summary of drugs studied clinically, which affect posaconazole concentrations, is provided in TABLE3. (See PRECAUTIONS: DRUG INTERACTIONS)
TABLE 3: Summary of the Effect of Co-administered Drugs on
Posaconazole in Healthy Volunteers
| Co-administered Drug (Postulated Mechanism of Interaction) | Co-administered Drug Dose/Schedule | Posaconazole Dose/Schedule | Effecton Bioavailability of Posaconazole | Recommendations | |
| Change in Mean Cmax (ratio estimate*; 90% CI of the ratio estimate) | Change in Mean AUC (ratio estimate*; 90% CI of the ratio estimate) | ||||
| Rifabutin (UDP-G Induction) | 300 mg QD x 17 days |
200 mg (tablets) QD × 10 days | ↓43% (0.57;0.43-0.75) |
↓49% (0.51;0.37-0.71) |
Avoid concomitant use unless the benefit out weighs the risks. |
| Phenytoin (UDP-G Induction) | 200 mg QD x 10 days |
200 mg (tablets) QD× 10 days | ↓41% (0.59;0.44-0.79) |
↓50% (0.50;0.36-0.71) |
Avoid concomitant use unless the benefit outweighs the risks. |
| 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) |
Avoid concomitant use unless the benefit outweighs the risks. |
| 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) |
Avoid concomitant use unless the benefit out weighs the risks. |
| * Ratio Estimate is the ratio of co-administered drug plus posaconazoleto posaconazole alone for Cmax or AUC. | |||||
Co-administration of these drugs listed in TABLE 3 with posaconazole may result in lower plasma concentrations of posaconazole.
No clinically relevant effect on posaconazole bioavailability and/or plasma concentrations was observed when administered with an antacid, glipizide, ritonavir, H2 receptor antagonists other than cimetidine, or proton pump inhibitors; therefore, no posaconazole dose adjustments are required when used concomitantly with these products.
Effect of Posaconazole on Other Drugs
In vitro studies with human hepatic microsomes and clinical studies indicate that posaconazole is an inhibitor primarily of CYP3A4. A clinical study in healthy volunteers also indicates that posaconazole is a strong CYP3A4 inhibitor as evidenced by a >5-fold increase in midazolam AUC. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole. A summary of the drugs studied clinically, for which plasma concentrations were affected by posaconazole, is provided in TABLE 4. (See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: DRUG INTERACTIONS)
TABLE 4: Summary of the Effect of Posaconazole on Co-administered
Drugs in Healthy Volunteers and Patients
| Co-administered Drug (Postulated Mechanism of Interaction) | Co-administered Drug Dose/Schedule | Posaconazole Dose/Schedule | Effect on Bioavailability of Co-administered Drugs | Recommendations | |
| Change in Mean Cmax (ratio estimate*; 90% CI of the ratio estimate) | Change in Mean AUC (ratio estimate*; 90% CI of the ratio estimate) | ||||
| Sirolimus (Inhibition of CYP3A4 by posaconazole) | 2 mg single oral dose |
400 mg (oral suspension) BID x 16 days | ↑572% (6.72;5.62-8.03) |
↑788% (8.88;7.26-10.9 |
Coadministration of posaconazole with sirolimus is contraindicated (see CONTRAINDICATIONS). |
| Cyclosporine (Inhibition of CYP3A4 by posaconazole) | Stable maintenance dose in heart transplant recipients | 200 mg (tablets) QD x 10 days | ↑cyclosporine whole blood
trough concentrations Cyclosporine dose reductions of up to 29% were required |
At initiation of posaconazole treatment, reduce the cyclosporine
dose to approximately three-fourths of the original dose. Frequent monitoring of cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the cyclosporine dose adjusted accordingly. |
|
| Tacrolimus (Inhibition of CYP3A4 by posaconazole) | 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) |
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. |
| Rifabutin (Inhibition of CYP3A4 by posaconazole) | 300 mg QD x 17 days |
200 mg (tablets) QD × 10 days | ↑31% (1.31;1.10-1.57) |
↑72% (1.72;1.51-1.95) |
Avoid concomitant use unless the benefit outweighs the risks. If the drugs are co-administered, frequent monitoring of rifabutin adverse effects (eg,uveitis, leukopenia) should be performed. |
| Midazolam (Inhibition of CYP3A4 by posaconazole) | Single 30 min IV infusion of 0.05 mg/kg | 200 mg (tablets) QD x 10 days | NA** | ↑83% (1.83;1.57-2.14) |
Frequent monitoring ofadverse effects of benzodiazepines metabolized by CYP3A4 should be performed and dose reduction of the sebenzodiazepines should be considered during co-administration with posaconazole. |
| 0.4 mg single IV dosea |
200 mg (oral suspension) BID x 7 days | ↑30% (1.3;1.13-1.48) |
↑362% (4.62;4.02-5.3) |
||
| 2 mg single oral dosea |
200 mg (oral suspension) BID x 7 days | ↑126% (2.26;2.02-2.53) |
↑362% (4.59;4.12-5.11) |
||
| 0.4 mg single IV dosea | 400 mg (oral suspension) BID x 7 days | ↑62% (1.62;1.41-1.86) |
↑524% (6.24;5.43-7.16) |
||
| Phenytoin (Inhibition of CYP3A4 by posaconazole) | 200 mg QD PO x 10 days |
200 mg (tablets) QD x10 days | ↑16% (1.16;0.85-1.57) |
↑16% (1.16;0.84-1.59) |
Frequent monitoring of phenytoin concentrations should be performed while co-administered with posaconazole and dose reduction of phenytoin should be considered. |
| Ritonavir (Inhibition of CYP3A4 by posaconazole) | 100 mg QD x 14 days |
400 mg (oral suspension) BID x 7 days | ↑49% (1.49;1.04-2.15) |
↑80% (1.8;1.39-2.31) |
Frequent monitoring of adverse effects and toxicity of ritonavir should be performed during co-administration with posaconazole. |
| Atazanavir (Inhibition of CYP3A4 by posaconazole) | 300 mg QD x 14 days |
400 mg (oral suspension) BID x 7 days | ↑155% (2.55;1.89-3.45) |
↑268% (3.68;2.89-4.70) |
Frequent monitoring of adverse effects andtoxicity of Atazanavir should be performed during co-administration with posaconazole. |
| Atazanavir/ritonavir boosted regimen (Inhibition of CYP3A4 by posaconazole) | 300 mg/100 mg QD x 14 days |
400 mg (oral suspension) BID x 7 days | ↑53% (153;1.13-2.07) |
↑146% (2.46;1.93-3.13) |
|
| *Ratio Estimate is the ratio of co-administered
drug plus posaconazole to co-administered drug alone for Cmax or AUC. **NA: Not applicable if administered as an IV a The mean terminal half-life of midazolam was increased from 3 hours to 8 to 10 hours during co-administration with posaconazole. |
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Additional clinical studies demonstrated that no clinically significant effects on zidovudine, lamivudine, ritonavir, indinavir, or caffeine were observed when administered with posaconazole 200 mg QD; therefore, no dose adjustments are required for these co-administered drugs when co-administered with posaconazole 200 mg QD.
Posaconazole administration with glipizide does not require a dose adjustment in either drug; however, glucose concentrations decreased in some healthy volunteers administered the combination. Therefore, glucose concentrations should be monitored in accordance with the current standard of care for patients with diabetes when posaconazole is co-administered with glipizide.
Microbiology
Mechanism of Action
As a triazole antifungal agent, 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 and INDICATIONS.)
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. (See Clinical Studies.)
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.
Clinical Studies
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 two treatment groups (80 days, posaconazole; 77 days, fluconazole). TABLE 5 contains the results from Study 1.
TABLE 5: 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 plus7 days | ||
| Clinical Failurea | 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 Proven /probable fungal infection prior to death | 22 (7%) 2 (<1%) |
24 (8%) 6 (2%) |
| SAF,b | 27 (9%) | 25 (8%) |
| Through 16 weeks | ||
| Clinical Failurea,c | 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 Proven/probable fungal infection prior to death | 58 (19%) 10 (3%) |
59 (20%) 16 (5%) |
| SAFb | 26 (9%) | 30 (10%) |
| Event free lost tofollow- upd | 24 (8%) | 30 (10%) |
| a: Patients may have met more
than one criterion defining failure. b: SAF - systemic antifungal therapy (SAF) criterion is based on protocol definitions (empiric/IFI usage >4 consecutive days). c: 95% confidence interval (posaconazole-fluconazole)= (-11.5%,+3.7%) d: Patients who are lost to follow-up (not observed for 112 days), and who did not meet another clinical failure end point. These patients were considered failures. |
||
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 6 contains the results from Study 2.
TABLE 6: 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 | ||
| Clinical Failurea,b | 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 Proven/probable fungal infection prior to death | 17 (6%) 1 (<1%) |
25 (8%) 2 (1%) |
| SAFc | 67 (22%) | 98 (33%) |
| Through 100 days post-randomization | ||
| Clinical Failure b | 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 Proven /probable fungal infection prior to death | 44 (14%) 2 (1%) |
64 (21%) 16 (5%) |
| SAFc | 98 (32%) | 125 (42%) |
| Event free lost to follow-upd | 34 (11%) | 24 (8%) |
| a: 95% confidence interval (posaconazole-fluconazole/itraconazole)
= (-22.9%, -7.8%). b: Patients may have met morethan one criteriondefining failure. c: Use of systemic antifungal therapy (SAF) criterion is based on protocol definitions (empiric/IFI usage >3 consecutive days). d: Patients who are lost to follow-up (not observed for 100 days), and who did not meet another clinical failure end point. These patients were considered failures. |
||
In summary, two clinical studies of prophylaxis were conducted. As seen in the accompanying tables (TABLES 5 and 6), clinical failure represented a composite endpoint of breakthrough IFI, mortality and use of systemic antifungal therapy. In Study 1 (TABLE 5), 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 6) 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.
For information on a pharmjacokinetic/pharmacodynamic analysis of patient data see CLINICAL PHARMACOLOGY, Exposure Response Relationship.
Treatment of Oropharyngeal Candidiasis (OPC)
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 one dose of study medication and had a positive oral swish culture of Candida species at baseline were included in the analyses (TABLE 7). 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 7).
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 7).
TABLE 7: 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.
Treatment of Oropharyngeal Candidiasis Refractory to Treatment with Fluconazole or Itraconazole
Study 4 was a non-comparative 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, eighty-nine subjects met these strict criteria for refractory infection.
Forty-five subjects with refractory OPC were treated with posaconazole 400 mg BID for three 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 twenty-eight 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).
For information on a pharmacokinetic / pharmacodynamic analysis of patient data see CLINICAL PHARMACOLOGY, Exposure Response Relationship.
PATIENT INFORMATION
NOXAFIL®
(posaconazole) ORAL SUSPENSION
Read the Patient Information that comes with NOXAFIL® Oral Suspension before you start taking it and each time you get a refill. There may be new information. This information does not replace talking with your doctor about your condition or treatment. Only your doctor can prescribe NOXAFIL and determine if it is right for you.
What is NOXAFIL®?
- NOXAFIL is a prescription medicine that is used to prevent invasive fungal infections (infections that can spread throughout the body) caused by Aspergillus or Candida in patients with weak immune systems because of medicines or diseases [such as stem cell transplantation with graft-versus-host disease or chemotherapy for hematologic malignancy (blood cancers)].
- NOXAFIL is also used to treat fungal infections in the mouth or throat area (known as "thrush") caused by fungi called Candida. NOXAFIL can be used as initial treatment or as a treatment after itraconazole and/or fluconazole have failed.
NOXAFIL is for adults and children over 13 years of age.
What should I tell my doctor before taking NOXAFIL®?
Tell your doctor about all your health conditions, including if you:
- are taking certain drugs that suppress your immune system like cyclosporine (Neoral®), tacrolimus (Prograf®), or sirolimus (Rapamune®). Serious and rare fatal toxicity from cyclosporine has occurred when taken in combination with posaconazole and, there-fore, reduction of the dose of drugs like cyclosporine, tacrolimus, or atazanavir and frequent monitoring of drug levels of these medicines is necessary when taking them in combination with posaconazole.
- have ever had an allergic reaction to other antifungal medicines such as ketoconazole, fluconazole, itraconazole, or voriconazole.
- are taking any other medicines, including prescription and non-prescription medicines, vitamins, and herbal supplements.
- have, or have had liver problems. Your doctor may do blood tests to make sure you should take NOXAFIL.
- have, or have had an abnormal heart rate or rhythm.
- are, or think you are pregnant. Do not use NOXAFIL during pregnancy unless specifically advised by your doctor. You should use effective birth control while you are taking NOXAFIL if you are a woman who could become pregnant.
Contact your doctor immediately if you become pregnant while being treated with NOXAFIL.
Do not breastfeed while being treated with NOXAFIL, unless specifically advised by your doctor.
Who should not take NOXAFIL®?
Do NOT take NOXAFIL if you are taking any of the medicines listed below.
If any of these medicines are taken together with NOXAFIL, serious or life-threatening side effects from these medicines, or a decrease in the effect of NOXAFIL can occur. Tell your doctor right away if you are taking any of these medicines:
- sirolimus
- ergot alkaloids (ergotamine, dihydroergotamine, methylsergide, methylergonovine, ergonovine, or bromocriptine)
- terfenadine
- astemizole
- cisapride
- pimozide
- halofantrine
- quinidine
- rifabutin
- phenytoin
- cimetidine
If you have questions or are uncertain about your medicines, talk with your doctor or pharmacist.
Do not take NOXAFIL if you are allergic to anything in it. There is a list of what is in NOXAFIL at the end of this leaflet.
Can I take other medicines with NOXAFIL®?
NOXAFIL and many medicines can interact with each other and some must not be taken together (see "Who should not take NOXAFIL?"). The dose of other medicines may need to be adjusted when taken with NOXAFIL [for example, cyclosporine (Neoral®), tacrolimus (Prograf®), ritonavir, or atazanavir]. (See "What should I tell my doctor before taking NOXAFIL?")
Knowing the medicines that you are taking is important. Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Keep a list of them with you to show your doctor or pharmacist. Do not take any new medicine without talking to your doctor.
What are possible side effects of NOXAFIL®?
The most commonly reported side effects related to NOXAFIL use were nausea, diarrhea, vomiting, headache, stomach pain, bloating, liver problems, low blood potassium, and decrease in neutrophils (certain type of white blood cells that fight infection).
Rarely, NOXAFIL may cause serious or life-threatening side effects. It may also cause severe drug interactions as discussed above. Call your doctor right away if you have any of the symptoms listed below.
Changes in heart rate or rhythm. People who have certain heart conditions or who take certain other medicines have a higher chance for this problem.
Rarely, very serious liver problems were reported in patients with serious underlying medical conditions. Your doctor may test your liver function while you are taking NOXAFIL. Call your doctor if you have any of these symptoms, as these may be signs of liver problems: you have itching, your eyes or skin turn yellow, you feel more tired than usual or feel like you have the flu, or you have nausea or vomiting.
Rarely, an increase in blood clots may occur in patients with blood cancers or post-stem cell transplantation. These events may or may not be further increased in patients also on posaconazole and primarily occurred in patients also receiving cyclosporine or tacrolimus. If