NOXAFIL(r) (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:

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.

CLINICAL PHARMACOLOGY

Pharmacokinetics

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

Posaconazole has an apparent volume of distribution of 1,774 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 eliminated with a mean half-life (t1/2) 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

Note: Cav based on observed data; other pharmacokinetic parameters based on estimates from population pharmacokinetic analyses

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 (0-24hr) for 200 mg TID and AUC (0-12hr) for 400 mg BID

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:

Pharmacokinetics in Special Populations

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

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

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.

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 to 17 years of age) was similar to that in the adults (>= 18 years of age).

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)

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 to 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

Posaconazole is primarily metabolized via UDP glucuronidation (phase 2 enzymes) and is a substrate for p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. A summary of drugs studied clinically, which affect posaconazole concentrations, is provided in TABLE 3. (See PRECAUTIONS, Drug Interactions)

TABLE 3. Summary of the Effect of Co-administered Drugs on Posaconazole in Healthy Volunteers

Ratio Estimate is the ratio of co-administered drug plus posaconazole to 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.

In vitro studies with human hepatic microsomes and clinical studies indicate that posaconazole is an inhibitor primarily of CYP3A4. 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

Additional clinical studies demonstrated that no clinically significant effects on zidovudine, lamivudine, ritonavir, indinavir, or caffeine were observed when administered with posaconazole; therefore, no dose adjustments are required for these co-administered drugs. 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 14a-demethylase and accumulation of methylated sterol precursors.

Activity in vitro and in vivo

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 anti-fungal 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)

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 anti-fungal 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

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 pharmacokinetic / pharmacodynamic analysis of patient data see CLINICAL PHARMACOLOGY, Exposure Response Relationship.

CONTRAINDICATIONS

Hypersensitivity to the active substance or to any of the excipients. 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)

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 .,

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 (e.g., 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 PRECAUTIONS, Drug Interactions

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, tacrolimus, and sirolimus should be performed when posaconazole therapy is initiated. (See

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

Drug Interactions

A summary of significant drug interactions with posaconazole that have been studied clinically are provided in TABLES 7 and 8. Appropriate precautions for

the co-administration of these drugs with posaconazole are provided. (See CLINICAL PHARMACOLOGY, Drug Interactions and WARNINGS)

Co-administration of these drugs listed in TABLE 7 with posaconazole may result in lower plasma concentrations of posaconazole.

Although not studied in vitro or in vivo, posaconazole may affect the plasma concentrations of the drugs or drug classes described in TABLE 9. Appropriate precautions for the co-administration of these drugs with posaconazole are provided. (See CONTRAINDICATIONS)

TABLE 9. Drugs Not Studied in vitro or in vivo but Likely to Result in Significant 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, 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 13-17 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 8-17 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)

ADVERSE REACTIONS

The safety of posaconazole therapy has been assessed in 1,844 patients. This includes 605 patients in the prophylaxis studies and 1,239 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 10

presents treatment-emergent adverse events observed at an incidence >10% in the posaconazole prophylaxis studies.

TABLE 10. 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	274	(45)	254	(47)	32	(55)
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	106	(18)	88	(16)	3	(5)
Hypertension	106	(18)	88	(16)	3	(5)
Hypotension	83	(14)	79	(15)	10	(17)
Disorders of Blood and Lymphatic System	149	(25)	124	(23)	16	(28)
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 a	24	(10)	20	(9)	3	(12)

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	Posaconazole n=605		Fluconazole n=539		Itraconazole n=58
Gastro-Intestinal System Disorders	256	(42)	212	(39)	35	(60)
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	107	(18)	98	(18)	16	(28)
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	181	(30)	142	(26)	30	(52)
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)
Musculo-Skeletal System Disorders	95	(16)	82	(15)	9	(16)
Musculo-Skeletal 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	175	(29)	146	(27)	20	(34)
Thrombocytopenia	175	(29)	146	(27)	20	(34)
Petechiae	64	(11)	54	(10)	9	(16)
Psychiatric Disorders	103	(17)	92	(17)	11	(19)
Insomnia	103	(17)	92	(17)	11	(19)
Anxiety	52	(9)	61	(11)	9	(16)
Respiratory System Disorders	146	(24)	130	(24)	14	(24)
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	113	(19)	96	(18)	25	(43)
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 11 and 12

present treatment-related adverse events observed at an incidence >= 2% in the posaconazole prophylaxis studies.

TABLE 11. 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	5 (2)	2 (1)
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	22 (7)	28 (9)
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	9 (3)	4 (1)
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.

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TABLE 12. 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	22 (7)	25 (8)	17 (7)	8 (14)
Disorders
Nausea
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 Hepatic Enzymes Increased SGPT Increased SGOT Increased GGT Increased	7 (2) 7 (2) 7 (2) 6 (2) 5 (2)	8 (3) 3 (1) 5 (2) 5 (2) 2 (1)	5 (2) 3 (1) 4 (2) 4 (2) 1 (<1)	3 (5) 0 1 (2) 1 (2) 1 (2)
Metabolic and Nutritional Disorders Hypokalemia	9 (3)	6 (2)	5 (2)	1 (2)
Skin and Subcutaneous Tissue 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. Uncommon and rare treatment related serious or medically significant adverse events reported during clinical trials with posaconazole have included adrenal insufficiency, allergic and/or hypersensitivity reactions.

SCH 56592 (POSACONAZOLE) ORAL SUSPENSION MODULE 1

1.5.2 LABELING

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. 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 13 for the prophylaxis studies.

TABLE 13. 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 a
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
	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

SCH 56592 (POSACONAZOLE) ORAL SUSPENSION MODULE 1

LABELING

Aminotransferase.

Number (%) of Patients With Changea

OVERDOSAGE

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.

DOSAGE AND ADMINISTRATION

NOXAFIL Oral Suspension should be administered 200 mg (5 mL) three times a day. 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. The duration of therapy is based on recovery from neutropenia or immunosuppression. (See CLINICAL PHARMACOLOGY) To enhance the oral absorption of posaconazole and optimize plasma concentrations:

Shake NOXAFIL Oral Suspension well before use. A measured dosing spoon is provided, marked for doses of 2.5 mL and 5 mL.

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

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)

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 25oC (77oF); excursions permitted to 15o-30oC (59o-86oF) [see USP Controlled Room Temperature]. DO NOT FREEZE. Schering Corporation Kenilworth, NJ 07033 USA U.S. Patents 5,703,079, 5,661,151, 6,713,481 and 5,703,236. Copyright (c) 2006 Schering Corporation. All rights reserved. Manufactured for Schering Corporation by Patheon, Inc., Canada. B-xxxxxxxx . x/xx

Dose (mg)	Cmax (ng/mL)	Tmax a (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 [1.5-36 b ]	4,179 (31) [2,705-7,269]	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) [4,579-17,092]	21 (39) [12-44]	22.2 (18) [17.4-28.7]
200 mg high fat	512 (34)	5 [4-5]	15,059 (26)	14 (24)	23.0 (19)
(54 gm fat)	[241-1,016]		[10,341-24,476]	[8.2-19]	[17.2-33.4]
(n=20) c	[241-1,016]		[10,341-24,476]	[8.2-19]	[17.2-33.4]
400 mg fasted	121 (75)	4 [2-12]	5,258 (48)	91 (40)	27.3 (26)
(n=23) d	[27-366]	4 [2-12]	[2,834-9,567]	[42-141]	[16.8-38.9]
400 mg with liquid	355 (43)	5 [4-8]	11,295 (40)	43 (56)	26.0 (19)
nutritional supplement	[145-720]		[3,865-20,592]	[19-103]	[18.2-35.0]
(14 gm fat)
(n=23) d
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

Dose a	Cav (ng/mL)	AUC e (ng *hr/mL)	CL/F (L/hr)	V/F (L)	t1/2 (hr)
200 mg TID b (n=252)	1,103 (67) [21.5- 3,650]	ND f	ND f	ND f	ND f
200 mg TID c	583 (65)	15,900 (62)	51.2 (54)	2,425 (39)	37.2 (39)
(n=215)	[89.7-2,200]	[4,100 -56,100]	[10.7 -146]	[828 -5,702]	[19.1 -148]
400 mg BID d	723 (86)	9,093 (80)	76.1 (78)	3,088 (84)	31.7 (42)
(n=23)	[6.70 - 2,256]	[1,564 -26,794]	[14.9 - 256]	[407-13,140]	[12.4-67.3]

Co-administered Drug (Postulated Mechanism of Interaction)	Co-administered Drug Dose/Schedule	Posaconazole Dose/Schedule	Effect on 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	300 mg QD x 17	200 mg	\| 43%	\| 49%	Avoid concomitant use
(UDP-G	days	(tablets) QD x	(0.57;	(0.51;	unless the benefit
Induction)		10 days	0.43-	0.37-	outweighs the risks.
			0.75)	0.71)
Phenytoin (UDP- G Induction)	200 mg QD x 10 days	200 mg (tablets) QD x	\| 41% (0.59;	\| 50% (0.50;	Avoid concomitant use unless the benefit
		10 days	0.44-	0.36-	outweighs the risks.
			0.79)	0.71)
Cimetidine (Alteration of	400 mg BID x 10 days	200 mg (tablets) QD x	\| 39% (0.61;	\| 39% (0.61;	Avoid concomitant use unless the benefit
Gastric pH)		10 days	0.53-	0.54-	outweighs the risks.
			0.70)	0.69)

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)
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.

Co- administered Drug (Postulated Mechanism of Interaction)	Co-administered Drug Dose/Schedule	Posaconazole Dose/ Schedule	Effect on Bioavailability of Co-administered Drugs		Recommendations
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)	Recommendations
Tacrolimus	0.05 mg/kg single	400 mg (oral	\| 121%	\| 358%	At initiation of
(Inhibition of CYP3A4 by posaconazole)	oral dose	suspension) BID x 7 days	(2.21; 2.01- 2.42)	(4.58; 4.03- 5.19)	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	300 mg QD x 17	200 mg	\| 31%	\| 72%	Avoid concomitant use
(Inhibition of CYP3A4 by	days	(tablets) QD x 10 days	(1.31; 1.10-	(1.72; 1.51-	unless the benefit outweighs the risks. If the
posaconazole)			1.57)	1.95)	drugs are co-administered,
					frequent monitoring of
					rifabutin adverse effects
					(e.g. uveitis, leukopenia)
					should be performed.
Midazolam	Single 30 min IV	200 mg	NA * *	\| 83%	Frequent monitoring of
(Inhibition of	infusion of 0.05	(tablets) QD x		(1.83;	adverse effects of
CYP3A4 by	mg/kg	10 days		1.57-	benzodiazepines
posaconazole)				2.14)	metabolized by CYP3A4
					should be performed and
					dose reduction of these
					benzodiazepines should
					be considered during co-
					administration with
					posaconazole.
Phenytoin	200 mg QD PO x	200 mg	\| 16%	\| 16%	Frequent monitoring of
(Inhibition of	10 days	(tablets) QD x	(1.16;	(1.16;	phenytoin concentrations
CYP3A4 by		10 days	0.85-	0.84-	should be performed while
posaconazole)			1.57)	1.59)	co-administered with
					posaconazole and dose
					reduction of phenytoin
					should be considered.
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

F-xxxxxxxx

NOXAFIL(r) PRODUCT INFORMATION

(posaconazole) ORAL SUSPENSION DESCRIPTION

CLINICAL PHARMACOLOGY

Pharmacokinetics

Summary of Pharmacokinetic Parameters

Exposure Response Relationship

Pharmacokinetics in Special Populations

Electrocardiogram Evaluation

Drug Interactions

MICROBIOLOGY

Mechanism of Action

Activity in vitro and in vivo

Drug Resistance

CLINICAL STUDIES

Prophylaxis of Aspergillus and Candida Infections

INDICATIONS AND USAGE

CONTRAINDICATIONS

WARNINGS

Hypersensitivity

Hepatic Toxicity .,

Monitoring of hepatic function

Cyclosporine drug interaction PRECAUTIONS, Drug Interactions

PRECAUTIONS

Arrhythmias and QT prolongation

Information for Patients

Drug Interactions

Carcinogenesis, Mutagenesis, Impairment of Fertility

Pregnancy

Nursing Mothers

Pediatric Use

Geriatric Use

ADVERSE REACTIONS

Prophylaxis of Aspergillus and Candida

TABLE 10

TABLES 11 and 12

Clinical Laboratory Values

OVERDOSAGE

DOSAGE AND ADMINISTRATION

HOW SUPPLIED

	Posaconazole n =301		Fluconazole n = 299
On therapy plus 7 days
Clinical Failure a	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		2 (<1%)	6 (2%)
prior to death
SAF b	27 (9%)		25 (8%)

Through 16 weeks
Clinical Failure a,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	58 (19%)		59 (20%)

Proven / probable fungal infection prior to death	10 (3%)	16 (5%)
SAF b	26 (9%)	30 (10%)
Event free lost to follow- up d	24 (8%)	30 (10%)
a: Patients may have met more than one criteria defining failure. b: Use of 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 endpoint. These patients were considered failures.

	Posaconazole n =304		Fluconazole/Itraconazole n = 298
On therapy plus 7 days
Clinical Failure a,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	17 (6%)		25 (8%)
Proven / probable		1 (<1%)	2 (1%)
fungal infection
prior to death
SAF c	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	44 (14%)		64 (21%)
Proven / probable	2 (1%)		16 (5%)
fungal infection
prior to death

SAF c	98 (32%)	125 (42%)
Event free lost to follow- up d	34 (11%)	24 (8%)
a: 95% confidence interval (posaconazole-fluconazole/ itraconazole) = (-22.9%, - 7.8%). b: Patients may have met more than one criteria defining failure. c: Use of systemic antifungal therapy (SAF) criterion is based on protocol definition (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 endpoint. These patients were considered failures.

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

Co-administered Drug	Recommendations
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 (e.g., 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.

Drug or Drug Class (CYP3A4 Substrates)	Recommendations
Terfenadine, Astemizole, Pimozide, Cisapride, Quinidine	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 to ergotism. Co- administration of posaconazole with ergot alkaloids is contraindicated . (See CONTRAINDICATIONS )
Vinca Alkaloids	Posaconazole may increase the plasma concentrations of vinca alkaloids (eg, vincristine and vinblastine) which may lead to neurotoxicity. Therefore, it is recommended that the dose adjustment of the vinca alkaloid be considered.
Sirolimus	Frequent monitoring of sirolimus whole blood trough concentrations should be performed upon initiation, during co-administration, and at discontinuation of posaconazole treatment, with sirolimus doses reduced accordingly.
HMG-CoA reductase 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 be needed.