Reference ID: 3847805: Interaction
Reference ID: 3847805: Interaction
Reference ID: 3847805: Interaction
Noxafil delayed-release tablets and oral suspension are not to be used interchangeably due to the
differences in the dosing of each formulation [see Dosage and Administration (2.3, 2.4, 2.5)].
Noxafil injection
• Administer via a central venous line, including a central venous catheter or peripherally inserted
central catheter (PICC), by slow intravenous infusion over approximately 90 minutes [see Dosage
and Administration (2.2)].
• If a central venous catheter is not available, Noxafil injection may be administered through a
peripheral venous catheter by slow intravenous infusion over 30 minutes only as a single dose in
advance of central venous line placement or to bridge the period during which a central venous line is
replaced or is in use for other intravenous treatment.
• When multiple dosing is required, the infusion should be done via a central venous line.
• Never administer Noxafil injection as an intravenous bolus injection.
Noxafil delayed-release tablets
• Swallow tablets whole. Do not divide, crush, or chew.
• Administer with food [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].
Noxafil oral suspension
• Administer with a full meal or with a liquid nutritional supplement or an acidic carbonated beverage
(e.g., ginger ale) in patients who cannot eat a full meal [see Dosage and Administration (2.4)]
• Co-administration of drugs that can decrease the plasma concentrations of posaconazole should
generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients
should be monitored closely for breakthrough fungal infections [see Drug Interactions (7.6, 7.7, 7.8,
7.9, 7.13)]
Dosage:
Preparation:
A study was conducted to evaluate physical compatibility of Noxafil injection with injectable drug products
and commonly used intravenous diluents during simulated Y-site infusion. Compatibility was determined
through visual observations, measurement of particulate matter and turbidity. Compatible diluents and
drug products are listed in Tables 2 and 3 below. Any diluents or drug products not listed in the tables
below should not be co-administered through the same intravenous line (or cannula).
• Noxafil injection can be infused at the same time through the same intravenous line (or cannula) with
the following compatible diluents:
• Noxafil injection can be infused at the same time through the same intravenous line (or cannula) with
the following drug products prepared in 5% dextrose in water or sodium chloride 0.9%. Co-
administration of drug products prepared in other diluents may result in particulate formation.
Incompatible Diluents:
Administration:
Prophylaxis of invasive Aspergillus and Loading dose: 300 mg (three 100 mg delayed-release tablets) twice a
Candida infections day on the first day.
Dosage:
Prophylaxis of invasive Aspergillus 200 mg (5 mL) three times a day. The duration of therapy is based on
and Candida infections recovery from neutropenia or immunosuppression.
Oropharyngeal Candidiasis Refractory 400 mg (10 mL) twice a day. Duration of therapy should be based on
to Itraconazole and/or Fluconazole the severity of the patient’s underlying disease and clinical response.
Figure 1: A measured dosing spoon is provided, marked for doses of 2.5 mL and 5 mL.
• Rinse the spoon with water after each administration and before storage.
• Administer each dose of Noxafil oral suspension during or immediately (i.e., within 20 minutes)
following a full meal to enhance the oral absorption of Noxafil and optimize plasma concentrations
[see Clinical Pharmacology (12.3)].
• For patients who cannot eat a full meal, Noxafil delayed-release tablets should be used instead of
Noxafil oral suspension. Noxafil delayed-release tablets should be used only for the prophylaxis
indication. Noxafil delayed-release tablets provide higher plasma drug exposures than Noxafil oral
suspension under fasted conditions [See Dosage and Administration (2.5)].
• In patients who cannot eat a full meal and for whom Noxafil delayed-release tablets or Noxafil
injection are not options, administer each dose of Noxafil oral suspension with a liquid nutritional
supplement or an acidic carbonated beverage (e.g., ginger ale).
• For patients who cannot eat a full meal or tolerate an oral nutritional supplement or an acidic
carbonated beverage and who do not have the option of taking Noxafil delayed-release tablets or
Noxafil injection, an alternative antifungal therapy should be considered or patients should be
monitored closely for breakthrough fungal infections.
4 CONTRAINDICATIONS
4.1 Hypersensitivity
Noxafil is contraindicated in persons with known hypersensitivity to posaconazole or other azole
antifungal agents.
4.2 Use with Sirolimus
Noxafil is contraindicated with sirolimus. Concomitant administration of Noxafil with sirolimus increases
the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity [see Drug
Interactions (7.1) and Clinical Pharmacology (12.3)].
4.3 QT Prolongation with Concomitant Use with CYP3A4 Substrates
Noxafil is contraindicated with CYP3A4 substrates that prolong the QT interval. Concomitant
administration of Noxafil with the CYP3A4 substrates, pimozide and quinidine may result in increased
plasma concentrations of these drugs, leading to QTc prolongation and cases of torsades de pointes [see
Warnings and Precautions (5.2) and Drug Interactions (7.2)].
4.4 HMG-CoA Reductase Inhibitors Primarily Metabolized Through CYP3A4
Coadministration with the HMG-CoA reductase inhibitors that are primarily metabolized through
CYP3A4 (e.g., atorvastatin, lovastatin, and simvastatin) is contraindicated since increased plasma
concentration of these drugs can lead to rhabdomyolysis [see Drug Interactions (7.3) and Clinical
Pharmacology (12.3)].
4.5 Use with Ergot Alkaloids
Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and
dihydroergotamine) which may lead to ergotism [see Drug Interactions (7.4)].
6 ADVERSE REACTIONS
6.1 Serious and Otherwise Important Adverse Reactions
The following serious and otherwise important adverse reactions are discussed in detail in another
section of the labeling:
• Hypersensitivity [see Contraindications (4.1)]
• Arrhythmias and QT Prolongation [see Warnings and Precautions (5.2)]
• Hepatic Toxicity [see Warnings and Precautions (5.3)]
6.2 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed
in clinical trials of Noxafil cannot be directly compared to rates in the clinical trials of another drug and
may not reflect the rates observed in practice. In clinical trials, the type of adverse reactions reported for
posaconazole injection and posaconazole delayed-release tablets were generally similar to that reported
in trials of posaconazole oral suspension.
Clinical Trial Experience with Posaconazole Injection
Multiple doses of posaconazole injection administered via a peripheral venous catheter were
associated with thrombophlebitis (60% incidence). Therefore, in subsequent studies, posaconazole
injection was administered via central venous catheter.
Table 6: Posaconazole Injection Study 1: Number (%) of Subjects Treated with Posaconazole
Injection 300 mg Daily Dose Reporting Treatment-Emergent Adverse Reactions: Frequency of
at Least 10%
Body System Posaconazole Posaconazole
Injection Injection
Preferred Term Treatment Phase Treatment Phase
n=237 (%)* or Subsequent
Oral Suspension
Treatment Phase
n=237(%)†
Gastrointestinal Disorders
Vascular Disorders
The most frequently reported adverse reactions with an onset during the posaconazole intravenous
phase of dosing with 300 mg once daily were diarrhea (32%), hypokalemia (22%), pyrexia (21%), and
nausea (19%). These adverse reactions were consistent with those seen in studies with Noxafil oral
suspension.
Clinical Trial Experience with Posaconazole Delayed-Release Tablets
The safety of posaconazole delayed-release tablets has been assessed in 230 patients in clinical
trials. Patients were enrolled in a non-comparative pharmacokinetic and safety trial of posaconazole
delayed-release tablets when given as antifungal prophylaxis (Delayed-Release Tablet Study 1). Patients
were immunocompromised with underlying conditions including hematological malignancy, neutropenia
post-chemotherapy, GVHD, and post HSCT. This patient population was 62% male, had a mean age of
51 years (range 19-78 years, 17% of patients were ≥65 years of age), and were 93% white and 16%
Hispanic. Posaconazole therapy was given for a median duration of 28 days. Twenty patients received
200 mg daily dose and 210 patients received 300 mg daily dose (following twice daily dosing on Day 1 in
each cohort). Table 7 presents treatment-emergent adverse reactions observed in patients treated with
300 mg daily dose at an incidence of ≥10% in posaconazole delayed-release tablet study.
Table 7: Posaconazole Delayed-Release Tablet Study 1: Number (%) of Subjects Treated with
300 mg Daily Dose Reporting Treatment-Emergent Adverse Reactions: Frequency of at Least 10%
Body System Posaconazole
delayed-release
Preferred Term tablet (300 mg)
(n=210)
Anemia 22 (10)
Thrombocytopenia 29 (14)
Gastrointestinal Disorders
Constipation 20 (10)
10
Nausea 56 (27)
Vomiting 28 (13)
Asthenia 20 (10)
Chills 22 (10)
Pyrexia 59 (28)
Hypokalemia 46 (22)
Hypomagnesemia 20 (10)
Headache 30 (14)
Cough 35 (17)
Epistaxis 30 (14)
Rash 34 (16)
Vascular Disorders
Hypertension 23 (11)
The most frequently reported adverse reactions (>25%) with posaconazole delayed-release tablets
300 mg once daily were diarrhea, pyrexia, and nausea.
The most common adverse reaction leading to discontinuation of posaconazole delayed-release
tablets 300 mg once daily was nausea (2%).
Clinical Trial Safety Experience with Posaconazole Oral Suspension
The safety of posaconazole oral suspension has been assessed in 1844 patients. This includes 605
patients in the active-controlled prophylaxis studies, 557 patients in the active-controlled OPC studies,
239 patients in refractory OPC studies, and 443 patients from other indications. This represents a
heterogeneous population, including immunocompromised patients, e.g., patients with hematological
malignancy, neutropenia post-chemotherapy, GVHD post HSCT, and HIV infection, as well as non
neutropenic patients. This patient population was 71% male, had a mean age of 42 years (range 8-84
years, 6% of patients were ≥65 years of age and 1% was <18 years of age), and were 64% white, 16%
Hispanic, and 36% non-white (including 14% black). Posaconazole therapy was given to 171 patients for
≥6 months, with 58 patients receiving posaconazole therapy for ≥12 months. Table 8 presents treatment-
emergent adverse reactions observed at an incidence of >10% in posaconazole prophylaxis studies.
Table 9 presents treatment-emergent adverse reactions observed at an incidence of at least 10% in the
OPC/rOPC studies.
Prophylaxis of Aspergillus and Candida: In the 2 randomized, comparative prophylaxis studies
(Oral Suspension Studies 1 and 2), the safety of posaconazole oral suspension 200 mg three times a day
was compared to fluconazole 400 mg once daily or itraconazole 200 mg twice a day in severely
immunocompromised patients.
11
Subjects Reporting any Adverse Reaction 595 (98) 531 (99) 58 (100)
12
Psychiatric Disorders
HIV Infected Subjects with OPC: In 2 randomized comparative studies in OPC, the safety of
posaconazole oral suspension at a dose of less than or equal to 400 mg QD in 557 HIV-infected patients
was compared to the safety of fluconazole in 262 HIV-infected patients at a dose of 100 mg QD.
An additional 239 HIV-infected patients with refractory OPC received posaconazole oral suspension in
2 non-comparative trials for refractory OPC (rOPC). Of these subjects, 149 received the 800-mg/day dose
and the remainder received the less than or equal to 400-mg QD dose.
In the OPC/rOPC studies, the most common adverse reactions were fever, diarrhea, nausea,
headache, vomiting, and coughing.
The most common adverse reactions that led to treatment discontinuation of posaconazole in the
Controlled OPC Pool included respiratory impairment (1%) and pneumonia (1%). In the refractory OPC
13
Table 9: Treatment-Emergent Adverse Reactions with Frequency of at Least 10% in OPC Studies
with Posaconazole Oral Suspension (Treated Population)
Number (%) of Subjects
Controlled OPC Pool Refractory OPC Pool
Body System Posaconazole Fluconazole Posaconazole
Preferred Term n=557 n=262 n=239
Subjects Reporting any Adverse Reaction* 356 (64) 175 (67) 221 (92)
Body as a Whole – General Disorders
Fever 34 (6) 22 (8) 82 (34)
Headache 44 (8) 23 (9) 47 (20)
Anorexia 10 (2) 4 (2) 46 (19)
Fatigue 18 (3) 12 (5) 31 (13)
Asthenia 9 (2) 5 (2) 31 (13)
Rigors 2 (<1) 4 (2) 29 (12)
Pain 4 (1) 2 (1) 27 (11)
Disorders of Blood and Lymphatic System
Neutropenia 21 (4) 8 (3) 39 (16)
Anemia 11 (2) 5 (2) 34 (14)
Gastrointestinal System Disorders
Diarrhea 58 (10) 34 (13) 70 (29)
Nausea 48 (9) 30 (11) 70 (29)
Vomiting 37 (7) 18 (7) 67 (28)
Abdominal Pain 27 (5) 17 (6) 43 (18)
Infection and Infestations
Candidiasis, Oral 3 (1) 1 (<1) 28 (12)
Herpes Simplex 16 (3) 8 (3) 26 (11)
Pneumonia 17 (3) 6 (2) 25 (10)
Metabolic and Nutritional Disorders
Weight Decrease 4 (1) 2 (1) 33 (14)
Dehydration 4 (1) 7 (3) 27 (11)
Psychiatric Disorders
Insomnia 8 (1) 3 (1) 39 (16)
Respiratory System Disorders
Coughing 18 (3) 11 (4) 60 (25)
Dyspnea 8 (1) 8 (3) 28 (12)
Skin and Subcutaneous Tissue Disorders
Rash 15 (3) 10 (4) 36 (15)
Sweating Increased 13 (2) 5 (2) 23 (10)
OPC=oropharyngeal candidiasis
* Number of subjects reporting treatment-emergent adverse reactions at least once during the study,
without regard to relationship to treatment. Subjects may have reported more than 1 event.
Adverse reactions were reported more frequently in the pool of patients with refractory OPC. Among
these highly immunocompromised patients with advanced HIV disease, serious adverse reactions (SARs)
were reported in 55% (132/239). The most commonly reported SARs were fever (13%) and neutropenia
(10%).
Less Common Adverse Reactions: Clinically significant adverse reactions reported during clinical
trials in prophylaxis, OPC/rOPC or other trials with posaconazole which occurred in less than 5% of
patients are listed below:
• Blood and lymphatic system disorders: hemolytic uremic syndrome, thrombotic
14
Table 10: Posaconazole Oral Suspension Study 1 and Study 2. Changes in Liver Function Test
Results from CTC Grade 0, 1, or 2 at Baseline to Grade 3 or 4
Number (%) of Patients With Change*
Oral Suspension Study 1
Posaconazole Fluconazole
Laboratory Parameter n=301 n=299
AST 11/266 (4) 13/266 (5)
ALT 47/271 (17) 39/272 (14)
Bilirubin 24/271 (9) 20/275 (7)
Alkaline Phosphatase 9/271 (3) 8/271 (3)
Oral Suspension Study 2
Posaconazole Fluconazole/Itraconazole
Laboratory Parameter (n=304) (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)
*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 11 (LFT abnormalities were present in some of these
patients prior to initiation of the study drug).
Table 11: Posaconazole Oral Suspension Studies: Clinically Significant Laboratory Test
Abnormalities without Regard to Baseline Value
Controlled Refractory
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)
15
7 DRUG INTERACTIONS
Posaconazole is primarily metabolized via UDP glucuronosyltransferase and is a substrate of p
glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect
posaconazole plasma concentrations. Coadministration of drugs that can decrease the plasma
concentrations of posaconazole should generally be avoided unless the benefit outweighs the risk. If such
drugs are necessary, patients should be monitored closely for breakthrough fungal infections.
Posaconazole is also a strong inhibitor of CYP3A4. Therefore, plasma concentrations of drugs
predominantly metabolized by CYP3A4 may be increased by posaconazole [see Clinical Pharmacology
(12.3)].
The following information was derived from data with posaconazole oral suspension or early tablet
formulation. All drug interactions with posaconazole oral suspension, except for those that affect the
absorption of posaconazole (via gastric pH and motility) are considered relevant to posaconazole
injection as well [see Drug Interactions (7.9) and (7.13)].
7.1 Immunosuppressants Metabolized by CYP3A4
Sirolimus: Concomitant administration of posaconazole with sirolimus increases the sirolimus blood
concentrations by approximately 9-fold and can result in sirolimus toxicity. Therefore, posaconazole is
contraindicated with sirolimus [see Contraindications (4.2) and Clinical Pharmacology (12.3)].
Tacrolimus: Posaconazole has been shown to significantly increase the Cmax and AUC of tacrolimus.
At initiation of posaconazole treatment, reduce the tacrolimus dose to approximately one-third of the
original dose. Frequent monitoring of tacrolimus whole blood trough concentrations should be performed
during and at discontinuation of posaconazole treatment and the tacrolimus dose adjusted accordingly
[see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
Cyclosporine: Posaconazole has been shown to increase cyclosporine whole blood concentrations in
heart transplant patients upon initiation of posaconazole treatment. It is recommended to reduce
cyclosporine dose to approximately three-fourths of the original dose upon initiation of posaconazole
treatment. Frequent monitoring of cyclosporine whole blood trough concentrations should be performed
during and at discontinuation of posaconazole treatment and the cyclosporine dose adjusted accordingly
[see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
7.2 CYP3A4 Substrates
Concomitant administration of posaconazole with CYP3A4 substrates such as pimozide and quinidine
may result in increased plasma concentrations of these drugs, leading to QTc prolongation and cases of
torsades de pointes. Therefore, posaconazole is contraindicated with these drugs [see Contraindications
(4.3) and Warnings and Precautions (5.2)].
7.3 HMG-CoA Reductase Inhibitors (Statins) Primarily Metabolized Through CYP3A4
Concomitant administration of posaconazole with simvastatin increases the simvastatin plasma
concentrations by approximately 10-fold. Therefore, posaconazole is contraindicated with HMG-CoA
reductase inhibitors primarily metabolized through CYP3A4 [see Contraindications (4.4) and Clinical
Pharmacology (12.3)].
7.4 Ergot Alkaloids
Most of the ergot alkaloids are substrates of CYP3A4. Posaconazole may increase the plasma
concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism.
Therefore, posaconazole is contraindicated with ergot alkaloids [see Contraindications (4.5)].
7.5 Benzodiazepines Metabolized by CYP3A4
Concomitant administration of posaconazole with midazolam increases the midazolam plasma
concentrations by approximately 5-fold. Increased plasma midazolam concentrations could potentiate and
prolong hypnotic and sedative effects. Concomitant use of posaconazole and other benzodiazepines
metabolized by CYP3A4 (e.g., alprazolam, triazolam) could result in increased plasma concentrations of
16
17
18
19
10 OVERDOSAGE
There is no experience with overdosage of posaconazole injection and delayed-release tablets.
During the clinical trials, some patients received posaconazole oral suspension up to 1600 mg/day
with no adverse reactions noted that were different from the lower doses. In addition, accidental overdose
was noted in one patient who took 1200 mg BID posaconazole oral suspension for 3 days. No related
adverse reactions were noted by the investigator.
Posaconazole is not removed by hemodialysis.
11 DESCRIPTION
Noxafil is an azole antifungal agent available as concentrated solution to be diluted before intravenous
administration, delayed-release tablet, or suspension for oral administration.
Posaconazole is designated chemically as 4-[4-[4-[4-[[ (3R,5R)-5- (2,4-difluorophenyl)tetrahydro-5
(1H-1,2,4-triazol-1-ylmethyl)-3-furanyl]methoxy]phenyl]-1-piperazinyl]phenyl]-2-[(1S,2S)-1-ethyl-2
hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one with an empirical formula of C37H42F2N8O4 and a
molecular weight of 700.8. The chemical structure is:
O
CH3
F F O N N N N
N OH
H3C
O
N N
20
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Posaconazole is an azole antifungal agent [see Clinical Pharmacology (12.4)].
12.2 Pharmacodynamics
Exposure Response Relationship: In clinical studies of neutropenic patients who were receiving
cytotoxic chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS) or
hematopoietic stem cell transplant (HSCT) recipients with Graft versus Host Disease (GVHD), a wide
range of plasma exposures to posaconazole was noted following administration of Noxafil oral
suspension. A pharmacokinetic-pharmacodynamic analysis of patient data revealed an apparent
association between average posaconazole concentrations (Cavg) and prophylactic efficacy (Table 12).
A lower Cavg may be associated with an increased risk of treatment failure, defined as treatment
discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive
fungal infections.
Table 12: Noxafil Oral Suspension Exposure Analysis (Cavg) in Prophylaxis Trials
Prophylaxis in AML/MDS* Prophylaxis in GVHD†
Cavg Range (ng/mL) Treatment Failure‡ (%) Cavg Range (ng/mL) Treatment Failure‡
(%)
12.3 Pharmacokinetics
General Pharmacokinetic Characteristics
Posaconazole Injection
Posaconazole injection exhibits dose proportional pharmacokinetics after single doses between 200
and 300 mg in healthy volunteers and patients. The mean pharmacokinetic parameters after single doses
with posaconazole injection in healthy volunteers and patients are shown in Table 13.
Table 13: Summary of Mean Pharmacokinetic Parameters (%CV) in Healthy Volunteers (30 minute
infusion via peripheral venous line) and Patients (90 minute infusion via central venous line) after
Dosing with Posaconazole Injection on Day 1
Dose (mg) n AUC0-∞ AUC0-12 Cmax t1/2 CL
(ng·hr/mL) (ng·hr/mL) (ng/mL) (hr) (L/hr)
Healthy 200 9 35400 (50) 8840 (20) 2250 (29) 23.6 (23) 6.5 (32)
Volunteers 300 9 46400 (26) 13000 (13) 2840 (30) 24.6 (20) 6.9 (27)
Patients 200 30 N/D 5570 (32) 954 (44) N/D N/D
21
Table 14: Arithmetic Mean (%CV) of PK Parameters in Serial PK-Evaluable Patients Following
Dosing of Posaconazole Injection (300 mg)*
Cmax Tmax† AUC0-24 Cav Cmin
Day N
(ng/mL) (hr) (ng*hr/mL) (ng/mL) (ng/mL)
10/14 49 3280 (74) 1.5 (0.98-4.0) 36100 (35) 1500 (35) 1090 (44)
AUC0-24 = area under the concentration-time curve over the dosing interval (i.e. 24 hours); Cav= time-averaged concentrations
(i.e., AUC0-24h/24hr);
Cmin = POS trough level immediately before a subject received the dose of POS on the day specified in the protocol; Cmax =
observed maximum plasma concentration; CV = coefficient of variation, expressed as a percent (%); Day = study day on
treatment; Tmax = time of observed maximum plasma concentration.
* 300 mg dose administered over 90 minutes once a day following BID dosing on Day 1
†
Median (minimum-maximum)
Table 15: Arithmetic Mean (%CV) of Steady State PK Parameters in Healthy Volunteers and
Patients Following Administration of Posaconazole Delayed-Release Tablets (300 mg)*
N AUC0-24 hr Cav† Cmax Cmin Tmax‡ t1/2 CL/F
(ng·hr/mL) (ng/mL) (ng/mL) (ng/mL) (hr) (hr) (L/hr)
Healthy 12 51618 2151 2764 1785 4 31 7.5
Volunteers (25) (25) (21) (29) (3-6) (40) (26)
Patients 50 37900 1580 2090 1310 4 (1.3-8.3) - 9.39
(42) (42) (38) (50) (45)
CV = coefficient of variation expressed as a percentage (%CV); AUC0-T = Area under the plasma
concentration-time curve from time zero to 24 hr; Cmax = maximum observed concentration; Cmin =
minimum observed plasma concentration; Tmax = time of maximum observed concentration; t½ = terminal
phase half-life; CL /F = Apparent total body clearance
*300 mg BID on Day 1, then 300 mg QD thereafter
†
Cav = time-averaged concentrations (i.e., AUC0-24 hr/24hr)
‡
Median (minimum-maximum)
22
Absorption:
Posaconazole Delayed-Release Tablets
When given orally in healthy volunteers, posaconazole delayed-release tablets are absorbed with a
median Tmax of 4 to 5 hours. Steady-state plasma concentrations are attained by Day 6 at the 300 mg
dose (QD after BID loading dose at Day 1). The absolute bioavailability of the oral delayed-release tablet
is approximately 54% under fasted conditions. The Cmax and AUC of posaconazole following
administration of posaconazole delayed-release tablets is increased 16% and 51%, respectively, when
given with a high fat meal compared to a fasted state (see Table 17). In order to enhance the oral
absorption of posaconazole and optimize plasma concentrations, posaconazole delayed-release tablets
should be administered with food.
23
↑6% ↑4%
Mylanta Ultimate strength liquid
25.4 meq/5 mL, 20 mL
(Increase in gastric pH)
(1.06; 0.90 -1.26)↑ (1.04; 0.90 -1.20)
↑2% ↑5%
Esomeprazole (Nexium) (Increase 40 mg (QAM 5 days, day -4 to
in gastric pH) 1)
(1.02; 0.88-1.17)↑ (1.05; 0.89 -1.24)
↓14% ↓7%
Metoclopramide (Reglan) (Increase 15 mg four times daily during 2
in gastric motility) days (Day -1 and 1)
(0.86, 0.73,1.02) (0.93, 0.803,1.07)
* Ratio Estimate is the ratio of coadministered drug plus posaconazole to posaconazole alone for Cmax or AUC0-last.
Single-Dose Oral Suspension Administration of 200 mg and 400 mg Under Fed and Fasted
Conditions
24
Table 20: The Effect of Varying Gastric Administration Conditions on the Cmax and AUC of
Posaconazole Oral Suspension in Healthy Volunteers*
Change in Cmax Change in AUC
(ratio estimate†; (ratio estimate†;
90% CI of the ratio 90% CI of the ratio
Study Description Administration Arms estimate) estimate)
↑96% ↑111%
5 minutes before high-fat meal
(1.96; 1.48-2.59) (2.11; 1.60-2.78)
400-mg single dose with a high-fat
↑339% ↑382%
meal relative to fasted state (n=12)
During high-fat meal
(4.39; 3.32-5.80) (4.82; 3.66-6.35)
↑333% ↑387%
20 minutes after high-fat meal
(4.33; 3.28-5.73) (4.87; 3.70-6.42)
↑136% ↑161%
Divided daily dose from 400 mg BID Fasted state
(2.36; 1.84-3.02) (2.61; 2.04-3.35)
to 200 mg QID for 7 days regardless
of fasted conditions or with BOOST
↑137% ↑157%
(n=12) With BOOST
(2.37; 1.86-3.04) (2.57; 2.00-3.30)
↑92% ↑70%
400-mg single dose with carbonated Ginger ale
(1.92; 1.51-2.44) (1.70; 1.43-2.03)
acidic beverage (ginger ale) and/or
proton pump inhibitor
↓32% ↓30%
(esomeprazole) (n=12) Esomeprazole
(0.68; 0.53-0.86) (0.70; 0.59-0.83)
↓21% ↓19%
400-mg single dose with a prokinetic With metoclopramide + BOOST
agent (metoclopramide 10 mg TID (0.79; 0.72-0.87) (0.81; 0.72-0.91)
for 2 days) + BOOST or an
antikinetic agent (loperamide 4-mg ↓3% ↑11%
single dose) + BOOST (n=12) With loperamide + BOOST
(0.97; 0.88-1.07) (1.11; 0.99-1.25)
25
Table 21: The Effect of Concomitant Medications that Affect the Gastric pH and Gastric Motility on
the Pharmacokinetics of Posaconazole Oral Suspension in Healthy Volunteers
Distribution:
The mean volume of distribution of posaconazole after intravenous solution administration was 261 L
and ranged from 226-295 L between studies and dose levels.
Posaconazole is highly bound to human plasma proteins (>98%), predominantly to albumin.
Metabolism:
Posaconazole primarily circulates as the parent compound in plasma. Of the circulating metabolites,
the majority are glucuronide conjugates formed via UDP glucuronidation (phase 2 enzymes).
Posaconazole does not have any major circulating oxidative (CYP450 mediated) metabolites. The
excreted metabolites in urine and feces account for ~17% of the administered radiolabeled dose.
Posaconazole is primarily metabolized via UDP glucuronidation (phase 2 enzymes) and is a substrate
for p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect
posaconazole plasma concentrations. A summary of drugs studied clinically with the oral suspension or
an early tablet formulation, which affect posaconazole concentrations, is provided in Table 22.
Table 22: Summary of the Effect of Coadministered Drugs on Posaconazole in Healthy Volunteers
26
In vitro studies with human hepatic microsomes and clinical studies indicate that posaconazole is an
inhibitor primarily of CYP3A4. A clinical study in healthy volunteers also indicates that posaconazole is a
strong CYP3A4 inhibitor as evidenced by a >5-fold increase in midazolam AUC. Therefore, plasma
concentrations of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole. A
summary of the drugs studied clinically, for which plasma concentrations were affected by posaconazole,
is provided in Table 23 [see Contraindications (4) and Drug Interactions (7.1) including
recommendations].
Table 23: Summary of the Effect of Posaconazole on Coadministered Drugs in Healthy Volunteers
and Patients
Effect on Bioavailability of
Coadministered Coadministered
Drug Drugs
(Postulated
Mechanism of Change in Mean
Interaction is Cmax
Inhibition of (ratio estimate*; Change in Mean AUC
CYP3A4 by Coadministered Drug Posaconazole Dose/ 90% CI of the ratio (ratio estimate*; 90%
posaconazole) Dose/Schedule Schedule estimate) CI of the ratio estimate)
Sirolimus 2-mg single oral dose 400 mg (oral suspension) ↑ 572% ↑ 788%
BID x 16 days (6.72; 5.62-8.03) (8.88; 7.26-10.9)
Cyclosporine Stable maintenance 200 mg (tablets) QD x 10
†
↑ cyclosporine whole blood trough
dose in heart transplant days concentrations
recipients Cyclosporine dose reductions of up to 29%
were required
Tacrolimus 0.05-mg/kg single oral 400 mg (oral suspension) ↑ 121% ↑ 358%
dose BID × 7 days (2.21; 2.01-2.42) (4.58; 4.03-5.19)
Simvastatin 40-mg single oral dose 100 mg (oral suspension) Simvastatin Simvastatin
QD x 13 days ↑ 841% ↑ 931%
(9.41, 7.13-12.44) (10.31, 8.40-12.67)
Simvastatin Acid Simvastatin Acid
↑ 817% ↑634%
(9.17, 7.36-11.43) (7.34, 5.82-9.25)
27
Additional clinical studies demonstrated that no clinically significant effects on zidovudine, lamivudine,
indinavir, or caffeine were observed when administered with posaconazole 200 mg QD; therefore, no
dose adjustments are required for these coadministered drugs when coadministered with posaconazole
200 mg QD.
Excretion:
Following administration of Noxafil oral suspension, posaconazole is predominantly eliminated in the
feces (71% of the radiolabeled dose up to 120 hours) with the major component eliminated as parent
drug (66% of the radiolabeled dose). Renal clearance is a minor elimination pathway, with 13% of the
radiolabeled dose excreted in urine up to 120 hours (<0.2% of the radiolabeled dose is parent drug).
Posaconazole injection is eliminated with a mean terminal half-life (t½) of 27 hours and a total body
clearance (CL) of 7.3 L/h.
Posaconazole delayed-release tablet is eliminated with a mean half-life (t½) ranging between 26 to 31
hours.
Posaconazole oral suspension is eliminated with a mean half-life (t½) of 35 hours (range: 20
66 hours).
12.4 Microbiology
Mechanism of Action:
Posaconazole blocks the synthesis of ergosterol, a key component of the fungal cell membrane,
through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14α-demethylase responsible
for the conversion of lanosterol to ergosterol in the fungal cell membrane. This results in an accumulation
of methylated sterol precursors and a depletion of ergosterol within the cell membrane thus weakening
the structure and function of the fungal cell membrane. This may be responsible for the antifungal activity
of posaconazole.
Activity in vitro:
Posaconazole has in vitro activity against Aspergillus fumigatus and Candida albicans, including
Candida albicans isolates from patients refractory to itraconazole or fluconazole or both drugs [see
Clinical Studies (14), Indications and Usage (1) and Dosage and Administration (2)]. However, correlation
between the results of susceptibility tests and clinical outcome has not been established. Posaconazole
interpretive criteria (breakpoints) have not been established for any fungus.
28
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No drug-related neoplasms were recorded in rats or mice treated with posaconazole for 2 years at
doses higher than the clinical dose. In a 2-year carcinogenicity study, rats were given posaconazole orally
at doses up to 20 mg/kg (females), or 30 mg/kg (males). These doses are equivalent to 3.9- or 3.5-times
the exposure achieved with a 400-mg BID oral suspension regimen, respectively, based on steady-state
AUC in healthy volunteers administered a high-fat meal (400-mg BID oral suspension regimen). In the
mouse study, mice were treated at oral doses up to 60 mg/kg/day or 4.8-times the exposure achieved
with a 400-mg BID oral suspension regimen.
Posaconazole was not genotoxic or clastogenic when evaluated in bacterial mutagenicity (Ames), a
chromosome aberration study in human peripheral blood lymphocytes, a Chinese hamster ovary cell
mutagenicity study, and a mouse bone marrow micronucleus study.
Posaconazole had no effect on fertility of male rats at a dose up to 180 mg/kg (1.7 x the 400-mg BID
oral suspension regimen based on steady-state plasma concentrations in healthy volunteers) or female
rats at a dose up to 45 mg/kg (2.2 x the 400-mg BID oral suspension regimen).
13.2 Animal Toxicology and/or Pharmacology
In a nonclinical study using intravenous administration of posaconazole in very young dogs (dosed
from 2 to 8 weeks of age), an increase in the incidence of brain ventricle enlargement was observed in
treated animals as compared with concurrent control animals. No difference in the incidence of brain
ventricle enlargement between control and treated animals was observed following the subsequent 5
month treatment-free period. There were no neurologic, behavioral or developmental abnormalities in the
dogs with this finding, and a similar brain finding was not seen with oral posaconazole administration to
juvenile dogs (4 days to 9 months of age).
The clinical significance of this finding is unknown; therefore, the use of posaconazole injection to
patients under 18 years of age is not recommended.
14 CLINICAL STUDIES
14.1 Prophylaxis of Aspergillus and Candida Infections with Posaconazole Oral Suspension
Two randomized, controlled studies were conducted using posaconazole as prophylaxis for the
prevention of invasive fungal infections (IFIs) among patients at high risk due to severely compromised
immune systems.
The first study (Oral Suspension Study 1) was a randomized, double-blind trial that compared
posaconazole oral suspension (200 mg three times a day) with fluconazole capsules (400 mg once daily)
as prophylaxis against invasive fungal infections in allogeneic hematopoietic stem cell transplant (HSCT)
recipients with Graft versus Host Disease (GVHD). Efficacy of prophylaxis was evaluated using a
composite endpoint of proven/probable IFIs, death, or treatment with systemic antifungal therapy
(patients may have met more than one of these criteria). This assessed all patients while on study
therapy plus 7 days and at 16 weeks post-randomization. The mean duration of therapy was comparable
between the 2 treatment groups (80 days, posaconazole; 77 days, fluconazole). Table 24 contains the
results from Oral Suspension Study 1.
Table 24: Results from Blinded Clinical Study in Prophylaxis of IFI in All Randomized Patients with
Hematopoietic Stem Cell Transplant (HSCT) and Graft-vs.-Host Disease (GVHD):
Oral Suspension Study 1
Posaconazole Fluconazole
n=301 n=299
On therapy plus 7 days
29
Through 16 weeks
Clinical Failure*,‡ 99 (33%) 110 (37%)
Failure due to:
Proven/Probable IFI 16 (5%) 27 (9%)
(Aspergillus) 7 (2%) 21 (7%)
(Candida) 4 (1%) 4 (1%)
(Other) 5 (2%) 2 (1%)
All Deaths 58 (19%) 59 (20%)
Proven/probable fungal 10 (3%) 16 (5%)
infection prior to death
SAF† 26 (9%) 30 (10%)
Event free lost to follow-up§ 24 (8%) 30 (10%)
* Patients may have met more than one criterion defining failure.
†
Use of systemic antifungal therapy (SAF) criterion is based on protocol
definitions (empiric/IFI usage >4 consecutive days).
‡
95% confidence interval (posaconazole-fluconazole) = (-11.5%, +3.7%).
§
Patients who are lost to follow-up (not observed for 112 days), and who did
not meet another clinical failure endpoint. These patients were considered
failures.
The second study (Oral Suspension Study 2) was a randomized, open-label study that compared
posaconazole oral suspension (200 mg 3 times a day) with fluconazole suspension (400 mg once daily)
or itraconazole oral solution (200 mg twice a day) as prophylaxis against IFIs in neutropenic patients who
were receiving cytotoxic chemotherapy for AML or MDS. As in Oral Suspension Study 1, efficacy of
prophylaxis was evaluated using a composite endpoint of proven/probable IFIs, death, or treatment with
systemic antifungal therapy (Patients might have met more than one of these criteria). This study
assessed patients while on treatment plus 7 days and 100 days postrandomization. The mean duration of
therapy was comparable between the 2 treatment groups (29 days, posaconazole; 25 days, fluconazole
or itraconazole). Table 25 contains the results from Oral Suspension Study 2.
Table 25: Results from Open-Label Clinical Study 2 in Prophylaxis of IFI in All Randomized
Posaconazole Fluconazole/Itraconazole
n=304 n=298
On therapy plus 7 days
Clinical Failure*,† 82 (27%) 126 (42%)
Failure due to:
Proven/Probable IFI 7 (2%) 25 (8%)
(Aspergillus) 2 (1%) 20 (7%)
(Candida) 3 (1%) 2 (1%)
(Other) 2 (1%) 3 (1%)
All Deaths 17 (6%) 25 (8%)
Proven/probable fungal 1 (<1%) 2 (1%)
infection prior to death
SAF‡ 67 (22%) 98 (33%)
30
In summary, 2 clinical studies of prophylaxis were conducted with the posaconazole oral suspension.
As seen in the accompanying tables (Tables 24 and 25), clinical failure represented a composite
endpoint of breakthrough IFI, mortality and use of systemic antifungal therapy. In Oral Suspension Study
1 (Table 24), the clinical failure rate of posaconazole (33%) was similar to fluconazole (37%), (95% CI for
the difference posaconazole–comparator -11.5% to 3.7%) while in Oral Suspension Study 2 (Table 25)
clinical failure was lower for patients treated with posaconazole (27%) when compared to patients treated
with fluconazole or itraconazole (42%), (95% CI for the difference posaconazole–comparator -22.9% to
7.8%).
All-cause mortality was similar at 16 weeks for both treatment arms in Oral Suspension Study 1 [POS
58/301 (19%) vs. FLU 59/299 (20%)]; all-cause mortality was lower at 100 days for posaconazole-treated
patients in Oral Suspension Study 2 [POS 44/304 (14%) vs. FLU/ITZ 64/298 (21%)]. Both studies
demonstrated substantially fewer breakthrough infections caused by Aspergillus species in patients
receiving posaconazole prophylaxis when compared to patients receiving fluconazole or itraconazole.
14.2 Treatment of Oropharyngeal Candidiasis with Posaconazole Oral Suspension
Posaconazole Oral Suspension Study 3 was a randomized, controlled, evaluator-blinded study in HIV-
infected patients with oropharyngeal candidiasis. Patients were treated with posaconazole or fluconazole
oral suspension (both posaconazole and fluconazole were given as follows: 100 mg twice a day for 1 day
followed by 100 mg once a day for 13 days).
Clinical and mycological outcomes were assessed after 14 days of treatment and at 4 weeks after the
end of treatment. Patients who received at least 1 dose of study medication and had a positive oral swish
culture of Candida species at baseline were included in the analyses (see Table 26). The majority of the
subjects had C. albicans as the baseline pathogen.
Clinical success at Day 14 (complete or partial resolution of all ulcers and/or plaques and symptoms)
and clinical relapse rates (recurrence of signs or symptoms after initial cure or improvement) 4 weeks
after the end of treatment were similar between the treatment arms (see Table 26).
Mycologic eradication rates (absence of colony forming units in quantitative culture at the end of
therapy, Day 14), as well as mycologic relapse rates (4 weeks after the end of treatment) were also
similar between the treatment arms (see Table 26).
Table 26: Posaconazole Oral Suspension Clinical Success, Mycological Eradication, and Relapse
Rates in Oropharyngeal Candidiasis
Posaconazole Fluconazole
Clinical Success at End of Therapy (Day 14) 155/169 (91.7%) 148/160 (92.5%)
Clinical Relapse (4 Weeks after End of Therapy) 45/155 (29.0%) 52/148 (35.1%)
Mycological Eradication (absence of CFU) at End of Therapy (Day 14) 88/169 (52.1%) 80/160 (50.0%)
Mycological Relapse (4 Weeks after End of Treatment) 49/88 (55.6%) 51/80 (63.7%)
Mycologic response rates, using a criterion for success as a posttreatment quantitative culture with
≤20 colony forming units (CFU/mL) were also similar between the two groups (posaconazole 68.0%,
fluconazole 68.1%). The clinical significance of this finding is unknown.
31
17.1 Administration
Noxafil Delayed-Release Tablets
Advise patients to take Noxafil delayed-release tablets with food.
Advise patients that Noxafil delayed-release tablets must be swallowed whole and not divided,
crushed, or chewed.
Instruct patients that if they miss a dose, they should take it as soon as they remember. If they do not
remember until it is within 12 hours of the next dose, they should be instructed to skip the missed dose
and go back to the regular schedule. Patients should not double their next dose or take more than the
prescribed dose.
Noxafil Oral Suspension
Advise patients to take each dose of Noxafil oral suspension during or immediately (i.e., within 20
minutes) following a full meal. In patients who cannot eat a full meal, each dose of Noxafil oral
suspension should be administered with a liquid nutritional supplement or an acidic carbonated beverage
(e.g., ginger ale) in order to enhance absorption.
32
Injection: Manuf. by: Schering-Plough (Brinny) Co., Brinny, Innishannon, County Cork, Ireland
Oral Suspension: Manuf. by: Patheon Inc., Whitby, Ontario, Canada L1N 5Z5
Copyright © 2006, 2010, 2013, 2014 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
All rights reserved.
uspi-mk5592-mf-1511r035
33
Noxafil delayed-release tablets and oral suspension are for adults and children over 13 years of age.
It is not known if Noxafil oral suspension and delayed-release tablets are safe and effective in children under 13 years of
age.
Who should not take Noxafil?
Do not take Noxafil if you:
• are allergic to posaconazole, any of the ingredients in Noxafil, or other azole antifungal medicines. See the end of
this leaflet for a complete list of ingredients in Noxafil.
• are taking any of the following medicines:
o sirolimus
o pimozide
o quinidine
o certain statin medicines that lower cholesterol (atorvastatin, lovastatin, simvastatin)
o ergot alkaloids (ergotamine, dihydroergotamine)
Ask your healthcare provider or pharmacist if you are not sure if you are taking any of these medicines.
Do not start taking a new medicine without talking to your healthcare provider or pharmacist.
What should I tell my healthcare provider before taking Noxafil?
Before you take Noxafil, tell your healthcare provider if you:
• are taking certain medicines that lower your immune system like cyclosporine or tacrolimus.
• are taking certain drugs for HIV infection, such as ritonavir, atazanavir, efavirenz, or fosamprenavir. Efavirenz and
fosamprenavir can cause a decrease in the Noxafil levels in your body. Efavirenz and fosamprenavir should not be
taken with Noxafil.
• are taking midazolam, a hypnotic and sedative medicine.
• have or had liver problems.
• have or had kidney problems.
• have or had an abnormal heart rate or rhythm, heart problems, or blood circulation problems.
• are pregnant or plan to become pregnant. It is not known if Noxafil will harm your unborn baby.
• are breastfeeding or plan to breastfeed. It is not known if Noxafil passes into your breast milk. You and your
34
Figure A
o Rinse the spoon with water after each dose of Noxafil oral suspension and before you store it away.
o If you miss a dose, take it as soon as you remember. However, if it is almost time for the next dose, skip
the missed dose and go back to the regular dosing schedule. Do not take a double dose to make up for
the forgotten dose.
Follow the instructions from your healthcare provider on how much Noxafil you should take and when to take it.
What are the possible side effects of Noxafil?
Noxafil may cause serious side effects, including:
35
If you take Noxafil delayed-release tablets or Noxafil oral suspension, tell your healthcare provider right away if you have
diarrhea or vomiting.
Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
These are not all the possible side effects of Noxafil. For more information, ask your healthcare provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store Noxafil?
•
Store Noxafil injection refrigerated at 36°F to 46°F (2°C to 8°C).
•
Store Noxafil delayed-release tablets and oral suspension at room temperature between 68°F to 77°F (20°C to
25°C).
• Do not freeze Noxafil oral suspension.
• Safely throw away medicine that is out of date or no longer needed.
Keep Noxafil and all medicines out of the reach of children.
General information about the safe and effective use of Noxafil.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use
Noxafil for a condition for which it was not prescribed. Do not give Noxafil to other people, even if they have the same
symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about
Noxafil that is written for health professionals.
What are the ingredients in Noxafil?
Active ingredient: posaconazole
Inactive ingredients:
Noxafil injection: Betadex Sulfobutyl Ether Sodium (SBECD), edetate sodium, hydrochloric acid, sodium hydroxide, and
water for injection.
36
usppi-mk5592-mf-1511r015
This Patient Informa ion has been approved by the U.S. Food and Drug Administration. Revised: 11/2015
37