Merck to Initiate Proof-of-Concept Study of Posaconazole for Chronic Chagas Disease, Recognized by WHO as One of the World

WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)-- Merck today announced plans to initiate a Phase II investigational proof-of-concept clinical study to evaluate its oral antifungal agent posaconazole for the treatment of chronic Chagas disease. Chagas disease results from infection with the parasite Trypanosoma cruzi that is spread by biting insects. The disease is estimated to affect approximately eight million people in Latin America, of whom approximately 30-40 percent will develop serious cardiac disease, digestive disease, or both as a result of this infection. Recognized by the World Health Organization (WHO) as a neglected tropical disease, Chagas disease also is becoming an emerging health problem in non-endemic areas through migration of infected populations from endemic areas. Currently, only two drugs are approved for treatment: benznidazole and nifurtimox.

“While significant progress has been made in recent years in the prevention of the transmission of this potentially life-threatening disease, no new drugs have been approved for the treatment of chronic Chagas disease in over three decades,” said Roger J. Pomerantz, M.D., F.A.C.P., global franchise head for infectious diseases and senior vice president, Merck Research Laboratories.

In planning the study to evaluate posaconazole, Merck has consulted with international agencies and research organizations to identify the current medical needs and reach consensus on a study design for posaconazole in asymptomatic chronic Chagas disease. The proposed study is a randomized, placebo-controlled Phase II study of posaconazole oral suspension (400 mg twice daily) given for 60 days, either as monotherapy or concomitantly with benznidazole. Benznidazole monotherapy will serve as an active control. The study is planned to enroll 160 adult patients with chronic Chagas disease at several sites in South America and follow them for a total of 360 days. The study will utilize polymerase chain reaction (PCR) to evaluate the levels of Trypanosoma cruzi in blood samples as the primary endpoint for response to treatment. Safety will be monitored by an external independent Data and Safety Monitoring Board (DSMB) on an ongoing basis and the DSMB will make recommendations as appropriate. Results from the study are expected in 2012. If successful, Phase III clinical studies with posaconazole would follow. Merck looks forward to working with interested partners to facilitate access if posaconazole is shown to be beneficial in the treatment of chronic Chagas disease.

About Chagas Disease

Chagas disease is caused by the protozoan parasite Trypanosoma cruzi, and was discovered in 1909 by the Brazilian physician Carlos Chagas (1879–1934). It continues to represent a serious social and economic problem in many Latin American countries, with approximately 20,000 deaths each year attributed to Chagas disease. Chagas disease is transmitted to humans mainly by insect bites, but also can be transmitted via blood transfusion, transplantation and vertically from mother to infant. Rarely, it can be contracted by ingestion of contaminated food or liquid. The initial phase of acute infection lasts for four-to-eight weeks and the chronic phase persists for the person’s lifespan. In most individuals, irrespective of the mode of transmission, acute Chagas infection is usually asymptomatic. The clinical outcome of the chronic phase of Chagas disease ranges from the absence of signs and symptoms of disease to severe illness and premature death. Typical clinical manifestations of the chronic phase are related to the pathological involvement of the heart, esophagus, colon, or a combination, and are grouped into three major forms: cardiac, digestive, and cardiodigestive. It may take more than 20 years from the time of the original infection to develop serious heart or digestive disease. Benznidazole and nifurtimox are the only drugs with proven efficacy against Chagas disease. Benznidazole is usually used for first-line treatment.

Merck’s Ongoing Commitment to Improving Global Health

Merck has a long history of engaging in public-private partnerships and research initiatives to develop and foster access to its medicines and vaccines worldwide. These efforts include:

  • Working with the Drugs for Neglected Diseases initiative (DNDi), Medicines for Malaria Venture (MMV) and other partners to advance the discovery and development of novel treatments for malaria, Chagas disease and other Neglected Tropical Diseases;
  • Fighting onchocerciasis (river blindness) and lymphatic filariasis (elephantiasis) through the MECTIZAN Donation Program, a diverse global partnership;
  • Partnering with the Government of Botswana and the Bill and Melinda Gates Foundation to support Botswana’s comprehensive national response to HIV and AIDS through the African Comprehensive HIV/AIDS Partnerships;
  • Collaborating with the Government of Nicaragua to demonstrate the feasibility and impact of rotavirus vaccine introduction in a GAVI-eligible country; and,Developing new and improved vaccines to address unmet medical needs in low-income countries by establishing, through a novel joint venture with the Wellcome Trust, the MSD Wellcome Trust Hilleman Laboratories.

About Posaconazole

Posaconazole is approved and marketed in the United States, European Union and several other countries as NOXAFIL® (posaconazole) oral suspension. In the U.S., NOXAFIL is indicated for prophylaxis of invasive Aspergillus and Candida infections in patients, 13 years of age and older, who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy. NOXAFIL also is indicated for the treatment of oropharyngeal candidiasis (OPC), including OPC refractory to itraconazole and/or fluconazole.

Selected Safety Information for NOXAFIL (posaconazole) Oral Suspension

Use in patients with hypersensitivity to the active substance or to any of the excipients is contraindicated. Coadministration with sirolimus or ergot alkaloids is contraindicated. Coadministration with the CYP3A4 substrates terfenadine, astemizole, cisapride, pimozide, halofantrine, or quinidine, is also contraindicated since this may result in increased plasma concentrations of these medicinal products, leading to QTc prolongation and rare occurrences of torsades de pointes.

NOXAFIL has been shown to interact with several medications, including drugs that suppress the immune system, and these reactions may be serious. The product label should be consulted when other drugs are prescribed with NOXAFIL.

Serious and rare fatal toxicity from cyclosporine has occurred when taken in combination with NOXAFIL and therefore reduction of the dose of drugs like cyclosporine or tacrolimus and frequent monitoring of drug levels of these medications are necessary when taking them in combination with NOXAFIL.

In clinical trials, there were infrequent cases of hepatic reactions (e.g., mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin, and/or clinical hepatitis). Rarely, more severe hepatic reactions including cholestasis or hepatic failure including fatalities were reported in patients with serious underlying medical conditions (e.g., hematologic malignancies) during treatment with posaconazole. Liver function tests should be monitored at the start of and during the course of therapy. Discontinuation of NOXAFIL must be considered in patients who experience symptoms consistent with liver disease that may be attributable to NOXAFIL. The safety and effectiveness of NOXAFIL in patients below the age of 13 years old have not been established.

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.

In the pooled prophylaxis safety analysis, fever, headache, anemia, diarrhea, nausea, vomiting, abdominal pain, hypokalemia, and thrombocytopenia were frequently reported treatment-emergent adverse events.

In clinical studies of OPC and refractory OPC, adverse events were reported more frequently in the pool of patients with refractory OPC. The most commonly reported serious adverse events in refractory OPC patients included fever (13%) and neutropenia (10%).

U.S. prescribing information for NOXAFIL is attached and also is available at http://www.spfiles.com/pinoxafil.pdf.

About Merck

Today's Merck is working to help the world be well. Through our medicines, vaccines, biologic therapies, and consumer and animal products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching programs that donate and deliver our products to the people who need them. Merck. Be Well. For more information, visit www.merck.com.

Forward-Looking Statement

This news release includes “forward-looking statements” within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Such statements may include, but are not limited to, statements about the benefits of the merger between Merck and Schering-Plough, including future financial and operating results, the combined company’s plans, objectives, expectations and intentions and other statements that are not historical facts. Such statements are based upon the current beliefs and expectations of Merck’s management and are subject to significant risks and uncertainties. Actual results may differ from those set forth in the forward-looking statements.

The following factors, among others, could cause actual results to differ from those set forth in the forward-looking statements: the possibility that the expected synergies from the merger of Merck and Schering-Plough will not be realized, or will not be realized within the expected time period; the impact of pharmaceutical industry regulation and health care legislation; the risk that the businesses will not be integrated successfully; disruption from the merger making it more difficult to maintain business and operational relationships; Merck’s ability to accurately predict future market conditions; dependence on the effectiveness of Merck’s patents and other protections for innovative products; the risk of new and changing regulation and health policies in the U.S. and internationally and the exposure to litigation and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck’s 2009 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

# # #

31153620T

PRODUCT INFORMATION

NOXAFIL®
(posaconazole) ORAL SUSPENSION

DESCRIPTION

NOXAFIL® (posaconazole) is a triazole antifungal agent available as a suspension for oral administration.

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

(Graphic Omitted)

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

Absorption

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

Following single-dose administration of 200 mg, the mean AUC and Cmax of posaconazole are approximately 3 times higher when administered with a nonfat meal and approximately 4 times higher when administered with a high-fat meal (~50 gm fat) relative to the fasted state. Following single-dose administration of 400 mg, the mean AUC and Cmax of posaconazole are approximately 3 times higher when administered with a liquid nutritional supplement (14 gm fat) relative to the fasted state (see Table 1). In order to assure attainment of adequate plasma concentrations, it is recommended to administer posaconazole with food or a nutritional supplement (see DOSAGE AND ADMINISTRATION).

TABLE 1: The Mean (%CV) [min-max] Posaconazole Pharmacokinetic Parameters Following Single-
Dose Suspension Administration of 200 mg and 400 mg Under Fed and Fasted Conditions

Dose (mg) Cmax
(ng/mL)
Tmaxa
(hr)
AUC (I)
(ng·hr/mL)
CL/F
(L/hr)

(hr)
200 mg fasted

(n=20)c

132 (50)
[45-267]
3.50
[1.5-36b]
4179 (31)
[2705-7269]
51 (25)
[28-74]
23.5 (25)
[15.3-33.7]
200 mg nonfat

(n=20) c

378 (43)
[131-834]
4 [3-5] 10,753 (35)
[4579-17,092]
21 (39)
[12-44]
22.2 (18)
[17.4-28.7]
200 mg high-fat

(54 gm fat)

(n=20) c

512 (34)
[241-1016]
5 [4-5] 15,059 (26)
[10,341-24,476]
14 (24)
[8.2-19]
23.0 (19)
[17.2-33.4]
400 mg fasted

(n=23) d

121 (75)
[27-366]
4 [2-12] 5258 (48)
[2834-9567]
91 (40)
[42-141]
27.3 (26)
[16.8-38.9]
400 mg with liquid nutritional supplement
(14 gm fat)

(n=23) d

355 (43)
[145-720]
5 [4-8] 11,295 (40)
[3865-20,592]
43 (56)
[19-103]
26.0 (19)
[18.2-35.0]
a Median [min-max]

b The subject with Tmax of 36 hrs had relatively constant plasma levels over 36 hrs (1.7 ng/mL difference between 4 hrs and 36 hrs)

c n=15 for AUC (I), CL/F and t1/2

d n=10 for AUC (I), CL/F and t1/2

 

In 12 healthy volunteers who received a single 400 mg dose of NOXAFIL Oral Suspension in the fasted state, 5 minutes before, during, and 20 minutes after a high-fat meal in a 4-way crossover design, the coadministration of NOXAFIL with a high fat meal significantly increased the extent of absorption of posaconazole compared to in the fasted state. However, the magnitude of the food effect varied with timing of the meals. When NOXAFIL was administered during a high-fat meal, the mean Cmax and AUC increased by 339% and 382% compared to in the fasted state, respectively. When NOXAFIL was administered 20 minutes after a high-fat meal, the mean Cmax and AUC also increased by 333% and 387% compared to in the fasted state, respectively. When NOXAFIL was administered 5 minutes before a high-fat meal, the mean Cmax and AUC increased by 96% and 111% compared to in the fasted state, respectively (See DOSAGE AND ADMINISTRATION).

In 12 healthy volunteers who received 400 mg BID and 200 mg QID of NOXAFIL Oral Suspension for 7 days in the fasted state and with liquid nutritional supplement (BOOST® Drink) in a 4-way crossover design, the administration of NOXAFIL 400 mg BID with BOOST increased the mean Cmax and AUC by 65% and 66%, respectively, compared to NOXAFIL 400 mg BID in the fasted state. However, when NOXAFIL 200 mg QID was administered with BOOST, the mean Cmax and AUC were not affected compared to NOXAFIL 200 mg QID in the fasted state.

In 12 healthy volunteers who received 400 mg BID and 200 mg QID of NOXAFIL Oral Suspension for 7 days in the fasted state and with liquid nutritional supplement (BOOST Drink) in a 4-way crossover design, the absorption of posaconazole was significantly increased when NOXAFIL was administered by dividing the total daily dose from 400 mg BID to 200 mg QID regardless of under fasted conditions or with liquid nutritional supplement. In the fasted state, the mean Cmax and AUC increased by 136% and 161%, respectively, when NOXAFIL was administered as 200 mg QID compared to 400 mg BID. When NOXAFIL was administered as 200 mg QID with BOOST, the mean Cmax and AUC increased by 44% and 54%, respectively, compared to 400 mg BID with BOOST.

In 12 healthy volunteers who received a single 400 mg dose of NOXAFIL Oral Suspension alone, or with ginger ale, or with esomeprazole, or both ginger ale and esomeprazole in the fasted state in a 4-way crossover design, the coadministration of NOXAFIL with ginger ale (carbonated acidic beverage) increased the mean Cmax and AUC by 92% and 70% compared to NOXAFIL alone, respectively. The coadministration of NOXAFIL with esomeprazole (proton pump inhibitor) decreased the mean Cmax and AUC by 46% and 32% compared to NOXAFIL alone, respectively. The coadministration of NOXAFIL with both ginger ale and esomeprazole decreased the mean Cmax and AUC by 33% and 21% compared to NOXAFIL alone, respectively (See CLINICAL PHARMACOLOGY, Drug Interactions, PRECAUTIONS, Drug Interactions, and DOSAGE AND ADMINISTRATION.

In 12 subjects who received single 400 mg dose of NOXAFIL Oral Suspension with BOOST, or with a prokinetic agent (metoclopramide 10 mg TID for 2 days) and BOOST, or with an anti-kinetic agent (loperamide 4 mg single dose) and BOOST in a 3-way crossover design, the coadministration of NOXAFIL with metoclopramide decreased the mean Cmax and AUC by 21% and 19%, respectively, compared to NOXAFIL alone. When NOXAFIL was coadministered with loperamide, the mean Cmax and AUC were decreased by 3% and increased by 11%, respectively, compared to NOXAFIL alone (See CLINICAL PHARMACOLOGY, Drug Interactions and PRECAUTIONS, Drug Interactions).

In 16 healthy volunteers who received a single 400 mg dose of NOXAFIL either orally or via an NG tube in a crossover design, the mean Cmax and AUC decreased by 19% and 23%, respectively, when NOXAFIL was administered via an NG tube compared to when POS was administered orally. In 5 subjects, the Cmax and AUC decreased substantially (range -27% to -53% and -33% to -51%, respectively) when NOXAFIL was administered via an NG tube compared to when NOXAFIL was administered orally. It is recommended to closely monitor patients for breakthrough fungal infections when NOXAFIL is administered via an NG tube because a lower plasma exposure may be associated with an increase risk of treatment failure (See CLINICAL PHARMACOLOGY, Exposure Response Relationship).

Distribution

Posaconazole has an apparent volume of distribution of 1774 L, suggesting extensive extravascular distribution and penetration into the body tissues.

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

Metabolism

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

Excretion

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

Summary of Pharmacokinetic Parameters

The mean (%CV) [min-max] posaconazole average steady-state plasma concentrations (Cav) and steady-state pharmacokinetic parameters in patients following administration of 200 mg TID and 400 mg BID of the oral suspension are provided in Table 2.

TABLE 2. The Mean (%CV) [min-max] Posaconazole Steady-State Pharmacokinetic Parameters in

Patients Following Oral Administration of Posaconazole 200 mg TID and 400 mg BID

Dosea Cav (ng/mL) AUCe (ng·hr/mL) CL/F (L/hr) V/F (L) t1/2 (hr)
200 mg TIDb

(n=252)

1103 (67)

[21.5– 3650]

NDf NDf NDf NDf
200 mg TIDc (n=215) 583 (65)

[89.7-2200]

15,900 (62)

[4100-56,100]

51.2 (54)

[10.7-146]

2425 (39)

[828-5702]

37.2 (39)

[19.1-148]

400 mg BIDd (n=23) 723 (86)

[6.70-2256]

9093 (80)

[1564-26,794]

76.1 (78)

[14.9-256]

3088 (84)

[407-13,140]

31.7 (42)

[12.4-67.3]

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

a Oral suspension administration

b Allogeneic hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease

c Neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia or

myelodysplastic syndromes

d Febrile neutropenic patients or patients with refractory invasive fungal infections, Cav n=24

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

f Not done

 

The variability in average plasma posaconazole concentrations in patients was relatively higher than that in healthy subjects.

Exposure Response Relationship

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

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

  • Each dose of NOXAFIL® Oral Suspension should be administered during or immediately (i.e. within 20 minutes) following a full meal or liquid nutritional supplement. For patients who cannot eat a full meal or tolerate an oral nutritional supplement, alternative antifungal therapy should be considered or patients should be monitored closely for breakthrough fungal infections.
  • Patients who have severe diarrhea or vomiting should be monitored closely for breakthrough fungal infections.
  • Co-administration of drugs that can decrease the plasma concentrations of posaconazole should generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections (see CLINICAL PHARMACOLOGY, Drug Interactions section).

Pharmacokinetics in Special Populations

Gender

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

Race

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

Geriatric

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

Pediatric

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

Hepatic Insufficiency

After a single oral dose of posaconazole 400 mg, the mean AUC was 43%, 27% and 21% higher in subjects with mild (Child-Pugh Class A, N=6), moderate (Child-Pugh Class B, N=6), and severe (Child-Pugh Class C, N=6) hepatic insufficiency, respectively, compared to subjects with normal hepatic function (N=18). Compared to subjects with normal hepatic function, the mean Cmax was 1% higher, 40% higher, and 34% lower in subjects with mild, moderate, and severe hepatic insufficiency, respectively. The mean apparent oral clearance (CL/F) was reduced by 18%, 36% and 28% in subjects with mild, moderate, and severe hepatic insufficiency, respectively, compared to subjects with normal hepatic function. The elimination half-life (t½) was 27 hours, 39 hours, 27 hours, and 43 hours in subjects with normal hepatic function, mild, moderate, and severe hepatic insufficiency, respectively.

It is recommended that no dose adjustment of NOXAFIL is needed in patients with mild to severe hepatic insufficiency (Child-Pugh Class A, B, and C) (See WARNINGS and DOSAGE AND ADMINISTRATION).

Renal Insufficiency

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

Electrocardiogram Evaluation

Multiple, time-matched ECGs collected over a 12-hour period were recorded at baseline and steady-state from 173 healthy male and female volunteers (18-85 years of age) administered posaconazole 400 mg BID with a high-fat meal. In this pooled analysis, the mean QTc (Fridericia) interval change from baseline was -5 msec following administration of the recommended clinical dose. A decrease in the QTc (F) interval (-3 msec) was also observed in a small number of subjects (n=16) administered placebo. The placebo-adjusted mean maximum QTc (F) interval change from baseline was <0 msec (-8 msec). No healthy subject administered posaconazole had a QTc (F) interval ≥500 msec or an increase ≥60 msec in their QTc (F) interval from baseline (see PRECAUTIONS).

Drug Interactions

Effect of Other Drugs on Posaconazole

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

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

Co-administered

Drug

(Postulated

Mechanism of

Interaction)

 

Co-administered

Drug

Dose/Schedule

 

Posaconazole

Dose/Schedule

 

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

(UDP-G

Induction)

  300 mg QD x 17 days   200 mg (tablets) QD × 10 days  

↓ 43% (0.57;

0.43-0.75)

 

↓ 49% (0.51; 0.37-0.71)

  Avoid concomitant use unless the benefit outweighs the risks.

Phenytoin

(UDP-G

Induction)

  200 mg QD x 10 days   200 mg (tablets) QD × 10 days  

↓ 41%

(0.59;

0.44-0.79)

 

↓ 50%

(0.50; 0.36-0.71)

  Avoid concomitant use unless the benefit outweighs the risks.

Cimetidine

(Alteration of

Gastric pH)

  400 mg BID × 10 days   200 mg (tablets) QD × 10 days  

↓ 39%

(0.61; 0.53-0.70)

 

↓ 39%

(0.61; 0.54-0.69)

  Avoid concomitant use unless the benefit outweighs the risks.

Efavirenz

(UDP-G

Induction)

  400 mg QD × 10 and 20 days   400 mg (oral suspension) BID × 10 and 20 days  

↓ 45% (0.55;

0.47-0.66)

 

↓ 50% (0.50; 0.43-0.60)

  Avoid concomitant use unless the benefit outweighs the risks.

Esomeprazole

(Increase in

gastric pH)

  40 mg QAM × 3 days   400 mg (oral suspension) single dose  

↓ 46% (0.54; 0.43-0.69)

 

↓ 32% (0.68; 0.57-0.81)

  Monitor closely for breakthrough fungal infections

Metoclopramide

(Increase in

gastric motility)

  10 mg TID × 2 days   400 mg (oral suspension) single dose  

↓ 21% (0.79; 0.72-0.87)

 

↓ 19% (0.81; 0.72-0.91)

  Monitor closely for breakthrough fungal infections

*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, loperamide, or H2 receptor antagonists other than cimetidine; therefore, no posaconazole dose adjustments are required when used concomitantly with these products.

Effect of Posaconazole on Other Drugs

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

volunteers also indicates that posaconazole is a strong CYP3A4 inhibitor as evidenced by a >5-fold increase in midazolam AUC. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole. A summary of the drugs studied clinically, for which plasma concentrations were affected by posaconazole, is provided in Table 4. (see CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS, Drug Interactions section).

TABLE 4. Summary of the Effect of Posaconazole on Co-administered Drugs in Healthy Volunteers and Patients

Coadministered

Drug (Postulated

Mechanism of Interaction)

 

Coadministered

Drug Dose/Schedule

  Posaconazole Dose/

Schedule

  Effect on Bioavailability of

Co-administered

Drugs

  Recommendations
     

Change in

Mean

Cmax

(ratio estimate*;

90% CI of the

ratio

estimate)

 

Change in

Mean AUC

(ratio

estimate*;

90% CI of the

ratio estimate)

 
Sirolimus

(Inhibition of CYP3A4 by posaconazole)

  2 mg single oral dose   400 mg (oral suspension) BID x 16 days  

↑ 572%

(6.72; 5.62-8.03)

 

↑ 788%

(8.88; 7.26-10.9)

 

Co-administration of

posaconazole with

sirolimus is

contraindicated (see

CONTRAINDICATIONS).

Cyclosporine

(Inhibition of CYP3A4 by posaconazole)

  Stable maintenance dose in heart transplant recipients   200 mg (tablets) QD x 10 days  

↑ cyclosporine whole blood trough concentrations

 

Cyclosporine dose reductions of up to 29% were required

 

At initiation of

posaconazole treatment,

reduce the cyclosporine

dose to approximately

three-fourths of the

original dose.

Frequent monitoring of

cyclosporine whole blood

trough concentrations

should be performed

during and at

discontinuation of

posaconazole treatment

and the cyclosporine

dose adjusted

accordingly.

Tacrolimus

(Inhibition of CYP3A4 by posaconazole)

  0.05 mg/kg single oral dose   400 mg (oral suspension) BID × 7 days  

↑ 121% (2.21; 2.01-2.42)

 

↑ 358%

(4.58; 4.03-5.19)

 

At initiation of

posaconazole treatment,

reduce the tacrolimus

dose to approximately

one-third of the original

dose.

Frequent monitoring of

tacrolimus whole blood

trough concentrations

should be performed

during and at

discontinuation of

posaconazole treatment

and the tacrolimus dose

adjusted accordingly.

Rifabutin

(Inhibition of CYP3A4 by posaconazole)

  300 mg QD x 17 days   200 mg (tablets) QD × 10 days  

↑ 31% (1.31; 1.10-1.57)

 

↑ 72%

(1.72;

1.51-1.95)

 

Avoid concomitant use

unless the benefit

outweighs the risks. If the

drugs are co-

administered, frequent

monitoring of rifabutin

adverse effects (eg,

uveitis, leukopenia)

should be performed.

Midazolam

(Inhibition of CYP3A4 by posaconazole)

 

Single 30 min

IV infusion of

0.05 mg/kg

 

0.4 mg single IV

dosea

 

 

2 mg single oral

dosea

 

 

0.4 mg single IV dosea

 

200 mg

(tablets) QD x

10 days

 

200 mg (oral

suspension)

BID x 7 days

 

200 mg (oral

suspension)

BID x 7 days

 

400 mg (oral

suspension)

BID x 7 days

 

NA**

 

 

 

↑ 30% (1.3;

1.13-1.48)

 

 

↑ 126%

(2.26; 2.02-

2.53)

 

↑ 62% (1.62;

1.41-1.86)

 

↑ 83% (1.83;

1.57-2.14)

 

 

↑ 362% (4.62;

4.02-5.3)

 

 

↑ 362% (4.59;

4.12-5.11)

 

 

↑ 524%

(6.24; 5.43-

7.16)

 

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

(Inhibition of CYP3A4 by posaconazole)

  200 mg QD PO x 10 days   200 mg (tablets) QD x 10 days  

↑ 16% (1.16; 0.85-1.57)

 

↑ 16%

(1.16; 0.84-1.59)

 

Frequent monitoring of

phenytoin concentrations

should be performed

while co-administered

with posaconazole and

dose reduction of

phenytoin should be

considered.

Ritonavir

(Inhibition of

CYP3A4 by

posaconazole)

  100 mg QD x

14 days

  400 mg (oral

suspension)

BID x 7 days

 

↑ 49%

(1.49;
1.04-2.15)

 

↑ 80%

(1.8;

1.39-2.31)

 

Frequent monitoring of

adverse effects and

toxicity of ritonavir should

be performed during co-

administration with

posaconazole.

Atazanavir (Inhibition of CYP3A4 by posaconazole)

 

 

Atazanavir/ ritonavir boosted regimen

(Inhibition of CYP3A4 by posaconazole)

 

300 mg QD x

14 days

 

 

 

 

300 mg/100 mg

QD x 14 days

 

400 mg (oral

suspension)

BID x 7 days

 

 

 

400 mg (oral

suspension)

BID x 7 days

 

↑ 155%

(2.55; 1.89-

3.45)

 

 

 

↑ 53% (1.53;

1.13-2.07)

 

↑ 268%

(3.68; 2.89-

4.70)

 

 

 

↑ 146%

(2.46; 1.93-

3.13)

 

Frequent monitoring of

adverse effects and

toxicity of Atazanavir

should be performed

during co-administration

with posaconazole.

*Ratio Estimate is the ratio of co-administered drug plus posaconazole to co-administered drug alone for Cmax or AUC.

**NA: Not applicable if administered as an IV.

a The mean terminal half-life of midazolam was increased from 3 hours to 8 to 10 hours during co-administration with posaconazole.

 

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

Posaconazole administration with glipizide does not require a dose adjustment in either drug; however, glucose concentrations decreased in some healthy volunteers administered the combination. Therefore, glucose concentrations should be monitored in accordance with the current standard of care for patients with diabetes when posaconazole is co-administered with glipizide.

MICROBIOLOGY

Mechanism of Action

As a triazole antifungal agent, posaconazole blocks the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of the enzyme lanosterol 14α-demethylase and accumulation of methylated sterol precursors.

Activity in vitro and in vivo

Posaconazole has shown in vitro activity against Aspergillus fumigatus and Candida albicans, including Candida albicans isolates from patients refractory to itraconazole or fluconazole or both drugs (see CLINICAL STUDIES and INDICATIONS AND USAGE).

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

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

Drug Resistance

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

CLINICAL STUDIES

Prophylaxis of Aspergillus and Candida Infections

Two randomized, controlled studies were conducted using posaconazole as prophylaxis for the prevention of invasive fungal infections (IFIs) among patients at high risk due to severely compromised immune systems.

The first study (Study 1) was a randomized, double-blind trial that compared posaconazole oral suspension (200 mg three times a day) with fluconazole capsules (400 mg once daily) as prophylaxis against invasive fungal infections in allogeneic hematopoietic stem cell transplant (HSCT) recipients with Graft versus Host Disease (GVHD). Efficacy of prophylaxis was evaluated using a composite endpoint of proven/probable IFIs, death, or treatment with systemic antifungal therapy (Patients may have met more than one of these criteria). Study 1 assessed all patients while on study therapy plus 7 days and at 16 weeks post-randomization. The mean duration of therapy was comparable between the two treatment groups (80 days, posaconazole; 77 days, fluconazole). Table 5 contains the results from Study 1.

TABLE 5. Results from Blinded Clinical Study 1 in Prophylaxis of IFI in All Randomized Patients with Hematopoietic Stem Cell Transplant (HSCT) and Graft-vs-Host Disease (GVHD)

         
    Posaconazole

n=301

  Fluconazole

n=299

On therapy plus 7 days

 Clinical Failurea

 

  50 (17%)

 

  55 (18%)

 
Failure due to:          
Proven/Probable IFI  

  7 (2%)

 

  22 (7%)

 
(Aspergillus)  

        3 (1%)

 

        17 (6%)

 
(Candida)  

        1 (<1%)

 

        3 (1%)

 
(Other)  

        3 (1%)

 

        2 (1%)

 
All Deaths  

  22 (7%)

 

  24 (8%)

Proven/probable
fungal infection
prior to death

 

      2 (1%)

 

      6 (2%)

 
SAFb  

  27 (9%)

 

  25 (8%)

 
           
Through 16 weeks  

 Clinical Failurea,c

 

  99 (33%)

 

  110 (37%)

 
Failure due to:          
Proven/Probable IFI  

  16 (5%)

 

  27 (9%)

 
(Aspergillus)  

        7 (2%)

 

        21 (7%)

 
(Candida)  

        4 (1%)

 

        4 (1%)

 
(Other)  

        5 (2%)

 

        2 (1%)

 
All Deaths

  58 (19%)

  59 (20%)

Proven/probable
fungal infection
prior to death

 

      10 (3%)

 

      16 (5%)

 
SAFb  

  26 (9%)

 

  30 (10%)

 

Event free lost to follow-upd

 

  24 (8%)

 

  30 (10%)

 

a Patients may have met more than one criterion 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.

 

The second study (Study 2) was a randomized, open-label study that compared posaconazole oral suspension (200 mg three times a day) with fluconazole suspension (400 mg once daily) or itraconazole oral solution (200 mg twice a day) as prophylaxis against IFIs in neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia or myelodysplastic syndromes. As in Study 1, efficacy of prophylaxis was evaluated using a composite endpoint of proven/probable IFIs, death, or treatment with systemic antifungal therapy (Patients might have met more than one of these criteria). Study 2 assessed patients while on treatment plus 7 days and 100 days post-randomization. The mean duration of therapy was comparable between the two treatment groups (29 days, posaconazole; 25 days, fluconazole or itraconazole). Table 6 contains the results from Study 2.

TABLE 6. Results from Open-Label Clinical Study 2 in Prophylaxis of IFI in All Randomized Patients with Hematologic Malignancy and Prolonged Neutropenia

         
    Posaconazole

n=304

  Fluconazole/Itraconazole

n=298

On therapy plus 7 days
Clinical Failurea,b  

  82 (27%)

 

  126 (42%)

Failure due to:        
Proven/Probable IFI  

  7 (2%)

 

  25 (8%)

(Aspergillus)  

        2 (1%)

 

        20 (7%)

(Candida)  

        3 (1%)

 

        2 (1%)

(Other)  

        2 (1%)

 

        3 (1%)

All Deaths  

  17 (6%)

 

  25 (8%)

 

Proven/probable
fungal infection
prior to death

 

      1 (1%)

 

      2 (1%)

SAFc  

  67 (22%)

 

  98 (33%)

         
Through 100 days post-randomization
Clinical Failureb  

  158 (52%)

 

  191 (64%)

Failure due to:        
Proven/Probable IFI  

  14 (5%)

 

  33 (11%)

(Aspergillus)  

        2 (1%)

 

        26 (9%)

(Candida)  

        10 (3%)

 

        4 (1%)

(Other)  

        2 (1%)

 

        3 (1%)

All Deaths

  44 (14%)

  64 (21%)

 

Proven/probable
fungal infection
prior to death

 

      2 (1%)

 

      16 (5%)

SAFc  

  98 (32%)

 

  125 (42%)

Event free lost to follow-upd

 

  34 (11%)

 

  24 (8%)

a 95% confidence interval (posaconazole-fluconazole/itraconazole) = (-22.9%, -7.8%).

b Patients may have met more than one criterion defining failure.

c Use of systemic antifungal therapy (SAF) criterion is based on protocol definitions (empiric/IFI usage >3 consecutive days).

d Patients who are lost to follow-up (not observed for 100 days), and who did not meet another clinical failure endpoint. These patients were considered failures.

 

In summary, two clinical studies of prophylaxis were conducted. As seen in the accompanying tables (Tables 5 and 6), clinical failure represented a composite endpoint of breakthrough IFI, mortality and use of systemic antifungal therapy. In Study 1 (Table 5), the clinical failure rate of posaconazole (33%) was similar to fluconazole (37%), (95% CI for the difference posaconazole–comparator -11.5% to 3.7%) while in Study 2 (Table 6) clinical failure was lower for patients treated with posaconazole (27%) when compared to patients treated with fluconazole or itraconazole (42%), (95% CI for the difference posaconazole–comparator -22.9% to -7.8%).

All-cause mortality was similar at 16 weeks for both treatment arms in Study 1 [POS 58/301 (19%) vs FLU 59/299 (20%)]; all-cause mortality was lower at 100 days for posaconazole-treated patients in Study 2 [POS 44/304 (14%) vs FLU/ITZ 64/298 (21%)]. Both studies demonstrated substantially fewer breakthrough infections caused by Aspergillus species in patients receiving posaconazole prophylaxis when compared to patients receiving fluconazole or itraconazole.

For information on a pharmacokinetic/pharmacodynamic analysis of patient data see CLINICAL PHARMACOLOGY, Exposure Response Relationship section.

Treatment of Oropharyngeal Candidiasis (OPC)

Study 3 was a randomized, controlled, evaluator-blinded study in HIV-infected patients with oropharyngeal candidiasis. Patients were treated with posaconazole or fluconazole oral suspension (both posaconazole and fluconazole were given as follows: 100 mg twice a day for 1 day followed by 100 mg once a day for 13 days).

Clinical and mycological outcomes were assessed after 14 days of treatment and at 4 weeks after the end of treatment. Patients who received at least one dose of study medication and had a positive oral swish culture of Candida species at baseline were included in the analyses (Table 7). The majority of the subjects had C. albicans as the baseline pathogen.

Clinical success at Day 14 (complete or partial resolution of all ulcers and/or plaques and symptoms) and clinical relapse rates (recurrence of signs or symptoms after initial cure or improvement) 4 weeks after the end of treatment were similar between the treatment arms (Table 7).

Mycologic eradication rates (absence of colony forming units in quantitative culture at the end of therapy, day 14), as well as mycologic relapse rates (4 weeks after the end of treatment) were also similar between the treatment arms (see Table 7).

TABLE 7. Clinical Success, Mycological Eradication, and Relapse Rates in Oropharyngeal

   

Candidiasis

   

Posaconazole

 

 

Fluconazole

 

Clinical Success at End of Therapy (Day 14)

 

155/169 (91.7%)

 

148/160 (92.5%)

Clinical Relapse (4 Weeks after End of Therapy)

 

45/155 (29.0%)

 

52/148 (35.1%)

         

Mycological Eradication (absence of CFU) at End of Therapy (Day 14)

 

88/169 (52.1%)

 

80/160 (50.0%)

Mycological Relapse (4 Weeks after End of Treatment)

 

49/88 (55.6%)

 

51/80 (63.7%)

   

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

Treatment of Oropharyngeal Candidiasis Refractory to Treatment with Fluconazole or Itraconazole

Study 4 was a non-comparative study of posaconazole oral suspension in HIV-infected subjects with OPC that was refractory to treatment with fluconazole or itraconazole. An episode of OPC was considered refractory if there was failure to improve or worsening of OPC after a standard course of therapy with fluconazole ≥ 100 mg/day for at least 10 consecutive days or itraconazole 200 mg/day for at least 10 consecutive days and treatment with either fluconazole or itraconazole had not been discontinued for more than 14 days prior to treatment with posaconazole. Of the 199 subjects enrolled in this study, eighty-nine subjects met these strict criteria for refractory infection.

Forty-five subjects with refractory OPC were treated with posaconazole 400 mg BID for three days, followed by 400 mg QD for 25 days with an option for further treatment during a 3-month maintenance period. Following a dosing amendment, a further 44 subjects were treated with posaconazole 400 mg BID for twenty-eight days. The efficacy of posaconazole was assessed by the clinical success (cure or improvement) rate after 4 weeks of treatment. The clinical success rate was 74.2% (66/89). The clinical success rates for both the original and the amended dosing regimens were similar (73.3% and 75.0%, respectively).

For information on a pharmacokinetic/pharmacodynamic analysis of patient data see CLINICAL PHARMACOLOGY, Exposure Response Relationship section.

INDICATIONS AND USAGE

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

NOXAFIL (posaconazole) is indicated for the treatment of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole (see MICROBIOLOGY and CLINICAL STUDIES).

CONTRAINDICATIONS

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

Co-administration of NOXAFIL® (posaconazole) with sirolimus is contraindicated. (see CLINICAL PHARMACOLOGY/Drug Interactions section, and PRECAUTIONS, Drug Interactions section).

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 In clinical trials, there were infrequent cases of hepatic reactions (eg, mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin, and/or clinical hepatitis). The elevations in liver function tests were generally reversible on discontinuation of therapy, and in some instances these tests normalized without drug interruption and rarely required drug discontinuation. Rarely, more severe hepatic reactions including cholestasis or hepatic failure including fatalities were reported in patients with serious underlying medical conditions (eg, hematologic malignancy) during treatment with posaconazole. These severe hepatic events were seen primarily in subjects receiving the 800 mg daily (400 mg BID or 200 mg QID) in another indication.

Monitoring of hepatic function Liver function tests should be evaluated at the start of and during the course of posaconazole therapy. Patients who develop abnormal liver function tests during posaconazole therapy should be monitored for the development of more severe hepatic injury. Patient management should include laboratory evaluation of hepatic function (particularly liver function tests and bilirubin). Discontinuation of posaconazole must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to posaconazole.

Cyclosporine drug interaction Cases of elevated cyclosporine levels resulting in rare serious adverse events, including nephrotoxicity and leukoencephalopathy, and death were reported in clinical efficacy studies. Dose reduction and more frequent clinical monitoring of cyclosporine and tacrolimus, should be performed when posaconazole therapy is initiated (see PRECAUTIONS, Drug Interactions section).

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 section; CONTRAINDICATIONS; and PRECAUTIONS, Drug Interactions section). Rigorous attempts to correct potassium, magnesium, and calcium should be made before starting posaconazole.

Information for Patients

Patients should be advised to:

  • Take each dose of NOXAFIL® Oral Suspension during or immediately (i.e. within 20 minutes) following a full meal or liquid nutritional supplement in order to enhance absorption.
  • Inform their physician if they develop severe diarrhea or vomiting as these conditions may decrease the plasma concentrations of posaconazole.
  • Inform their physician if they are taking other drugs or before they begin taking other drugs as certain drugs can decrease the plasma concentrations of posaconazole (see CLINICAL PHARMACOLOGY, Drug Interactions section).

Drug Interactions

A summary of significant drug interactions with posaconazole that have been studied clinically are provided in Tables 8 and 9. Appropriate precautions for the co-administration of these drugs with posaconazole are provided (see CLINICAL PHARMACOLOGY/Drug Interactions section, CONTRAINDICATIONS and WARNINGS).

TABLE 8. Summary of the Effect of Co-administered Drugs on Posaconazole

         
Co-administered Drug   Recommendations
 
Cimetidine   Avoid concomitant use unless the benefit outweighs the risks.
Rifabutin   Avoid concomitant use unless the benefit outweighs the risks.
Phenytoin   Avoid concomitant use unless the benefit outweighs the risks.
Efavirenz   Avoid concomitant use unless the benefit outweighs the risks.
Esomeprazole   Monitor closely for breakthrough fungal infections
Metoclopramide   Monitor closely for breakthrough fungal infections
 

Co-administration of these drugs listed in Table 8 with posaconazole may result in lower plasma concentrations of posaconazole.

 

   

 

 

TABLE 9. Summary of the Effect of Posaconazole on Co-administered Drugs

Co-administered Drug

Recommendations

Sirolimus     Co-administration of posaconazole with sirolimus is contraindicated (see CLINICAL PHARMACOLOGY, Drug Interactions section and CONTRAINDICATIONS).
Cyclosporine     Increased cyclosporine concentrations resulted in cyclosporine dose reductions in heart transplant patients co-administered posaconazole. At initiation of posaconazole treatment, reduce the cyclosporine dose to approximately three-fourths of the original dose. Frequent monitoring of cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the cyclosporine dose adjusted accordingly.
Tacrolimus     Posaconazole has been shown to increase Cmax and AUC of tacrolimus significantly. At initiation of posaconazole treatment, reduce the tacrolimus dose to approximately one-third of the original dose. Frequent monitoring of tacrolimus whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus dose adjusted accordingly.
Rifabutin     Concomitant use of posaconazole and rifabutin should be avoided unless the benefit to the patient outweighs the risk. However, if concomitant administration is required frequent monitoring of full blood counts and adverse events due to increased rifabutin levels (eg, uveitis, leukopenia) is recommended.
Midazolam     Frequent monitoring of adverse effects of benzodiazepines metabolized by CYP3A4 should be performed and dose reduction of these benzodiazepines should be considered during co-administration with posaconazole.
Phenytoin     Frequent monitoring of phenytoin concentrations should be performed while co-administered with posaconazole and dose reduction of phenytoin should be considered.
Atazanavir     Frequent monitoring of adverse effects and toxicity of atazanavir should be performed during co-administration with posaconazole.
Ritonavir     Frequent monitoring of adverse effects and toxicity of ritonavir should be performed during co-administration with posaconazole.
 

Although not studied in vitro or in vivo, posaconazole may affect the plasma concentrations of the drugs or drug classes described in Table 10. Appropriate precautions for the co-administration of these drugs with posaconazole are provided (see CONTRAINDICATIONS).

TABLE 10. Drugs Not Studied in vitro or in vivo but Likely to Result in Significant Drug Interactions

Drug or Drug Class (CYP3A4 Substrates)     Recommendations
Terfenadine, Astemizole, Pimozide, Cisapride, Quinidine, Halofantrine     Increased plasma concentrations of these drugs can lead to QT prolongation with rare occurrences of torsade de pointes. Co-administration with posaconazole is contraindicated (see CONTRAINDICATIONS).
Ergot Alkaloids     Posaconazole may increase the plasma concentration of ergot alkaloids (ergotamine and dihydroergotamine) which may lead 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.
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.
Digoxin     Increased plasma concentrations of digoxin have been reported in patients receiving digoxin and posaconazole. Therefore, monitoring of digoxin plasma concentrations is recommended during co-administration.
   

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

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

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

Pregnancy

Pregnancy Category C. Posaconazole has been shown to cause skeletal malformations (cranial malformations and missing ribs) in rats when given in doses ≥27 mg/kg (≥1.4 times the 400 mg BID regimen based on steady-state plasma concentrations of drug in healthy volunteers). The no-effect dose for malformations in rats was 9 mg/kg, which is 0.7 times the exposure achieved with the 400 mg BID regimen. No malformations were seen in rabbits at doses up to 80 mg/kg. In the rabbit, the no-effect dose was 20 mg/kg, while high doses of 40 mg/kg and 80 mg/kg, 2.9 or 5.2 times the exposure achieved with the 400 mg BID regimen, caused an increase in resorptions. In rabbits dosed at 80 mg/kg, a reduction in body weight gain of females and a reduction in litter size was seen. There are no adequate and well-controlled studies in pregnant women. Posaconazole should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Posaconazole is excreted in milk of lactating rats. The excretion of posaconazole in human breast milk has not been investigated. NOXAFIL should not be used by nursing mothers unless the benefit to the mother clearly outweighs the potential risk to the infant.

Pediatric Use

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

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

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 section).

ADVERSE REACTIONS

The safety of posaconazole therapy has been assessed in 1844 patients. This includes 605 patients in the prophylaxis studies, 796 in OPC/rOPC studies, and over 400 patients treated for other indications. Posaconazole therapy was given to 171 patients for ≥ 6 months, with 58 patients receiving posaconazole therapy for ≥ 12 months.

Prophylaxis of Aspergillus and Candida

Table 11 presents treatment-emergent adverse events observed at an incidence >10% in posaconazole prophylaxis studies.

 

TABLE 11. Study 1 and Study 2. Number (%) of Randomized Subjects Reporting Treatment-Emergent
          Adverse Events: Frequency of at Least 10% in the Posaconazole or Fluconazole Treatment
          Groups (Pooled Prophylaxis Safety Analysis)

      Posaconazole
(n=605)
    Fluconazole
(n=539)
    Itraconazole
(n=58)
Subjects Reporting any Adverse Event     595   (98)     531   (99)     58   (100)
Body as a Whole - General Disorders                  
Fever 274 (45) 254 (47) 32 (55)
Headache 171 (28) 141 (26) 23 (40)
Rigors 122 (20) 87 (16) 17 (29)
Fatigue 101 (17) 98 (18) 5 (9)
Edema Legs 93 (15) 67 (12) 11 (19)
Anorexia 92 (15) 94 (17) 16 (28)
Dizziness 64 (11) 56 (10) 5 (9)
Edema 54 (9) 68 (13) 8 (14)
Weakness     51   (8)     52   (10)     2   (3)
Cardiovascular Disorders, General
Hypertension 106 (18) 88 (16) 3 (5)
Hypotension     83   (14)     79   (15)     10   (17)
Disorders of Blood and Lymphatic System
Anemia 149 (25) 124 (23) 16 (28)
Neutropenia 141 (23) 122 (23) 23 (40)
Febrile Neutropenia     118   (20)     85   (16)     23   (40)
Disorders of the Reproductive System and Breast
Vaginal Hemorrhagea     24   (10)     20   (9)     3   (12)
Gastrointestinal System Disorders
Diarrhea 256 (42) 212 (39) 35 (60)
Nausea 232 (38) 198 (37) 30 (52)
Vomiting 174 (29) 173 (32) 24 (41)
Abdominal Pain 161 (27) 147 (27) 21 (36)
Constipation 126 (21) 94 (17) 10 (17)
Mucositis NOS 105 (17) 68 (13) 15 (26)
Dyspepsia     61   (10)     50   (9)     6   (10)
Heart Rate and Rhythm Disorders
Tachycardia     72   (12)     75   (14)     3   (5)
Infection and Infestations
Bacteremia 107 (18) 98 (18) 16 (28)
Herpes Simplex 88 (15) 61 (11) 10 (17)
Cytomegalovirus Infection 82 (14) 69 (13) 0
Pharyngitis 71 (12) 60 (11) 12 (21)
Upper Respiratory Tract Infection     44   (7)     54   (10)     5   (9)
Liver and Biliary System Disorders
Bilirubinemia     59   (10)     51   (9)     11   (19)
Metabolic and Nutritional Disorders
Hypokalemia 181 (30) 142 (26) 30 (52)
Hypomagnesemia 110 (18) 84 (16) 11 (19)
Hyperglycemia 68 (11) 76 (14) 2 (3)
Hypocalcemia     56   (9)     55   (10)     5   (9)
Musculoskeletal System Disorders
Musculoskeletal Pain 95 (16) 82 (15) 9 (16)
Arthralgia 69 (11) 67 (12) 5 (9)
Back Pain     63   (10)     66   (12)     4   (7)
Platelet, Bleeding and Clotting Disorders
Thrombocytopenia 175 (29) 146 (27) 20 (34)
Petechiae     64   (11)     54   (10)     9   (16)
Psychiatric Disorders
Insomnia 103 (17) 92 (17) 11 (19)
Anxiety     52   (9)     61   (11)     9   (16)
Respiratory System Disorders
Coughing 146 (24) 130 (24) 14 (24)
Dyspnea 121 (20) 116 (22) 15 (26)
Epistaxis     82   (14)     73   (14)     12   (21)
Skin and Subcutaneous Tissue Disorders
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.

 

Tables 12 and 13 present treatment-related adverse events observed at an incidence ≥2% in the posaconazole prophylaxis studies.

TABLE 12. Study 1. Treatment-Related Adverse Events, Occurring in Greater Than or Equal to 2% of

Patients in Posaconazole or Fluconazole Treatment Group

    Posaconazole
N=301
    Fluconazole
N=299
n (%)     n (%)
Body System/Preferred Term            
Subjects Reporting Any Adverse Event     107 (36)     115 (38)
Body as a Whole – General Disorders    
Drug Level Altered 5 (2) 2 (1)
Dizziness 4 (1) 5 (2)
Fatigue 4 (1) 6 (2)
Anorexia 3 (1) 7 (2)
Headache 3 (1) 8 (3)
Weakness     3 (1)     5 (2)
Cardiovascular Disorders, General
Hypertension     2 (1)     5 (2)
Central and Peripheral Nervous System Disorders
Tremor     4 (1)     6 (2)
Disorders of the Eye
Vision Blurred     3 (1)     5 (2)
Gastrointestinal System Disorders
Nausea 22 (7) 28 (9)
Vomiting 13 (4) 15 (5)
Diarrhea 8 (3) 12 (4)
Abdominal Pain 4 (1) 7 (2)
Dyspepsia 3 (1) 6 (2)
Constipation     1 (<1)     5 (2)
Liver and Biliary System Disorders
SGPT Increased 9 (3) 4 (1)
GGT Increased 9 (3) 7 (2)
Bilirubinemia 8 (3) 5 (2)
Hepatic Enzymes Increased 8 (3) 7 (2)
SGOT Increased     8 (3)     3 (1)
Metabolic and Nutritional Disorders
Phosphatase Alkaline Increased     5 (2)     5 (2)
Renal and Urinary System Disorders
Blood Creatinine Increased     6 (2)     5 (2)
Special Senses, Other Disorders
Taste Perversion     3 (1)     5 (2)
GGT = gamma-glutamyl transpeptidase; SGOT = serum glutamic oxaloacetic transaminase; SGPT = serum glutamic pyruvic transaminase.
 

TABLE 13. Study 2. Treatment-Related Adverse Events, Occurring in Greater Than or Equal to 2% of

Patients in Posaconazole or Fluconazole/Itraconazole Treatment Group

  Number (%) of Patients
Posaconazole
(n=304)
  Fluconazole/
Itraconazole
(n=298)
  Fluconazole
(n=240)
  Itraconazole
(n=58)
Body System/Preferred Term                
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 Disorders
Nausea 22 (7) 25 (8) 17 (7) 8 (14)
Diarrhea 20 (7) 21 (7) 12 (5) 9 (16)
Vomiting 14 (5) 20 (7) 14 (6) 6 (10)
Abdominal Pain 9 (3) 9 (3) 8 (3) 1 (2)
Mucositis NOS 7 (2) 0 0 0
Dyspepsia 5 (2) 3 (1) 3 (1) 0
Constipation   3 (1)   7 (2)   7 (3)   0
Heart Rate and Rhythm Disorders
QT/QTc Prolongation   12 (4)   9 (3)   5 (2)   4 (7)
Liver and Biliary System Disorders
Bilirubinemia 7 (2) 8 (3) 5 (2) 3 (5)
Hepatic Enzymes Increased 7 (2) 3 (1) 3 (1) 0
SGPT Increased 7 (2) 5 (2) 4 (2) 1 (2)
SGOT Increased 6 (2) 5 (2) 4 (2) 1 (2)
GGT Increased   5 (2)   2 (1)   1 (<1)   1 (2)
Metabolic and Nutritional Disorders
Hypokalemia   9 (3)   6 (2)   5 (2)   1 (2)
Skin and 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.

Overview of Adverse Events in HIV-infected subjects with OPC

In two randomized comparative studies in OPC, the safety of posaconazole at a dose of ≤ 400 mg QD in 557 HIV-infected patients was compared to the safety of fluconazole in 262 HIV-infected patients at a dose of 100 mg QD.

An additional 239 HIV-infected patients with refractory OPC received posaconazole in 2 non-comparative trials for refractory OPC (rOPC). Of these subjects, 149 received the 800 mg/day dose and the remainder received the ≤400 mg QD dose.

Table 14 presents Treatment-Emergent Adverse Events of Clinical Significance in the comparative and non-comparative studies of OPC.

TABLE 14. Treatment-Emergent Adverse Events of Clinical Significance in OPC studies

    Number (%) of Subjects      
Controlled OPC Pool     Refractory OPC Pool
Posaconazole   Fluconazole     Posaconazole
      n=557   n=262     n=239
Subjects Reporting any Adverse Eventa     356 (64)   175 (67)     221 (92)
Body as a Whole - General Disorders                
Fever 34 (6) 22 (8) 82 (34)
Headache 44 (8) 23 (9) 47 (20)
Anorexia 10 (2) 4 (2) 46 (19)
Fatigue 18 (3) 12 (5) 31 (13)
Asthenia 9 (2) 5 (2) 31 (13)
Rigors 2 (<1) 4 (2) 29 (12)
Pain     4 (1)   2 (1)     27 (11)
Disorders of Blood and Lymphatic System                
Neutropenia 21 (4) 8 (3) 39 (16)
Anemia 11 (2) 5 (2) 34 (14)
Neutropenia Aggravated     0   0     5 (2)
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)
Liver and Biliary System Disorders                
Bilirubinemia 6 (1) 2 (1) 6 (3)
Hepatic Enzymes Increased 1 (<1) 1 (<1) 8 (3)
Hepatic Function Abnormal 8 (1) 4 (2) 0
Hepatitis 3 (1) 0 5 (2)
Hepatomegaly 0 0 8 (3)
Jaundice 0 0 4 (2)
SGOT Increased 8 (1) 5 (2) 6 (3)
SGPT Increased     6 (1)   5 (2)     6 (3)
Metabolic and Nutritional Disorders                
Weight Decrease 4 (1) 2 (1) 33 (14)
Dehydration 4 (1) 7 (3) 27 (11)
Hypokalemia     6 (1)   3 (1)     15 (6)
Platelet, Bleeding, and Clotting Disorders                
Thrombocytopenia     4 (1)   1 (<1)     12 (5)
Psychiatric Disorders                
Insomnia     8 (1)   3 (1)     39 (16)
Renal & Urinary System Disorders                
Renal Failure Acute     0   0     7 (3)
Respiratory System Disorders                
Coughing 18 (3) 11 (4) 60 (25)
Dyspnea     8 (1)   8 (3)     28 (12)
Skin and Subcutaneous Tissue Disorders                
Rash 15 (3) 10 (4) 36 (15)
Sweating Increased     13 (2)   5 (2)     23 (10)

OPC=oropharyngeal candidiasis;

SGOT=serum glutamic oxaloacetic transaminase (same as AST); SGPT=serum glutamic pyruvic transaminase (same as ALT).

a Number of subjects reporting treatment-emergent adverse events at least once during the study, without regard to

relationship to treatment. Subjects may have reported more than one event.

 

Treatment-related, treatment-emergent events observed in patients with OPC at an incidence of ≥2% are shown in Table 15.

TABLE 15. Treatment-Related Adverse Events (Any Grade) ≥ 2%

      Number (%) of Subjects      
Controlled OPC Pool     Refractory OPC Pool
Posaconazole   Fluconazole     Posaconazole
Adverse Event       n=557   n=262     n=239
Subjects Reporting any Adverse Eventa       150 (27)   70 (27)     135 (56)
Headache 16 (3)   5 (2)     18 (8)
Anorexia 6 (1) 1 (<1) 7 (3)
Asthenia 4 (1) 2 (1) 6 (3)
Dizziness 9 (2) 5 (2) 8 (3)
Fatigue 8 (1) 5 (2) 7 (3)
Fever       10 (2)   1 (<1)     6 (3)
Central and Periph Nerv System                  
Somnolence       4 (1)   5 (2)     3 (1)
Disorders of Blood and Lymphatic System                  
Neutropenia 10 (2) 4 (2) 20 (8)
Anemia       2 (<1)   0     6 (3)
Gastrointestinal System Disorders                  
Diarrhea 19 (3) 13 (5) 26 (11)
Nausea 27 (5) 18 (7) 20 (8)
Vomiting 20 (4) 4 (2) 16 (7)
Abdominal Pain 10 (2) 8 (3) 12 (5)
Flatulence 6 (1) 0 11 (5)
Mouth Dry       7 (1)   6 (2)     5 (2)
Liver and Biliary System Disorders                  
Hepatic Enzymes Increased 1 (<1) 0 5 (2)
Hepatic Function Abnormal       3 (1)   4 (2)     0
Metabolic and Nutritional Disorders                  
Phosphatase Alkaline Increased       3 (1)   3 (1)     5 (2)
Musculoskeletal System Disorders                  
Myalgia       1 (<1)   0     4 (2)
Platelet, Bleeding, and Clotting Disorders                  
Thrombocytopenia       3 (1)   0     4 (2)
Psychiatric Disorders                  
Insomnia       3 (1)   0     6 (3)
Skin and Subcutaneous Tissue Disorders                  
Rash 8 (1) 4 (2) 10 (4)
Pruritus       6 (1)   2 (1)     5 (2)

OPC=oropharyngeal candidiasis;

SGOT=serum glutamic oxaloacetic transaminase (same as AST); SGPT=serum glutamic pyruvic transaminase (same as ALT).

a Number of subjects reporting treatment-related adverse events at least once during the study, without regard to

relationship to treatment. Subjects may have reported more than one event.

 

Adverse events were reported more frequently in the pool of patients with refractory OPC. Among these highly immunocompromised patients with advanced HIV disease, serious adverse events (SAEs) were reported in 55% (132/239). The most commonly reported SAEs were fever (13%) and neutropenia (10%).

Treatment-related SAEs were reported for 14% (34/239) of these patients and included neutropenia (5%) and abdominal pain (2%). Posaconazole was discontinued in two patients who developed neutropenia that was considered serious and treatment-related. All other reported treatment-related SAEs occurred in ≤ 1% of subjects on posaconazole.

Uncommon and rare treatment related serious or medically significant adverse events reported during clinical trials in prophylaxis, OPC/rOPC or other indications with posaconazole have included adrenal insufficiency, allergic and/or hypersensitivity reactions.

Rare cases of hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, and pulmonary embolus have been reported primarily among patients who had been receiving concomitant cyclosporine or tacrolimus for management of transplant rejection or graft-vs-host disease.

During clinical development there was a single case of torsade de pointes in a patient taking posaconazole. This report involved a seriously ill patient with multiple confounding, potentially contributory risk factors, such as a history of palpitations, recent cardiotoxic chemotherapy, hypokalemia, and hypomagnesemia.

Additionally, in another indication, 428 patients were treated with ≥800 mg/day with a similar AE profile.

Clinical Laboratory Values

In healthy volunteers and patients, elevation of liver function test values did not appear to be associated with higher plasma concentrations of posaconazole. The majority of abnormal liver function test results were minor, transient, and did not lead to discontinuation of therapy.

For the prophylaxis studies, the number of patients with changes in liver function tests from Common Toxicity Criteria (CTC) Grade 0, 1, or 2 at baseline to Grade 3 or 4 during the study is presented in Table 16.

   

TABLE 16. Study 1 and Study 2. Changes in Liver Function Test Results from CTC Grade 0, 1, or 2 at

Baseline to Grade 3 or 4

Number (%) of Patients With Changea
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 Aminotransferase.

 

The number of patients treated for OPC with clinically significant liver function test (LFT) abnormalities at any time during the studies is provided in Table 17 (LFT abnormalities were present in some of these patients prior to initiation of the study drug).

 

TABLE 17. Clinically Significant Laboratory Test Abnormalities Without Regard to Baseline Value

Laboratory Test     Controlled     Refractory
    Posaconazole   Fluconazole     Posaconazole
      n= 557   n=262     n=239
ALT > 3.0 x ULN     16/537 (3)   13/254 (5)     25/226 (11)
AST > 3.0 x ULN     33/537 (6)   26/254 (10)     39/223 (17)
Total Bilirubin > 1.5 x ULN     15/536 (3)   5/254 (2)     9/197 (5)
Alkaline Phosphatase > 3.0 x ULN     17/535 (3)   15/253 (6)     24/190 (13)
ALT= Alanine Aminotransferase; AST= Aspartate Aminotransferase.
 

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

     
Indication   Dose and Duration of therapy
Prophylaxis of Invasive Fungal Infections   200 mg (5 mL) three times a day. The duration of therapy is based on recovery from neutropenia or immunosuppression.
Oropharyngeal Candidiasis   Loading dose of 100 mg (2.5 mL) twice a day on the first day, then 100 mg (2.5 mL) once a day for 13 days.
Oropharyngeal Candidiasis Refractory to itraconazole and/or fluconazole   400 mg (10 mL) twice a day. Duration of therapy should be based on the severity of the patient’s underlying disease and clinical response.
 

Each dose of NOXAFIL® should be administered with a full meal or with a liquid nutritional supplement in patients who cannot eat a full meal (see CLINICAL PHARMACOLOGY).

Alternatively, NOXAFIL may be taken with an acidic carbonated beverage (e.g. ginger ale).

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

  • Each dose of NOXAFIL Oral Suspension should be administered during or immediately (i.e. within 20 minutes) following a full meal or liquid nutritional supplement. For patients who cannot eat a full meal or tolerate an oral nutritional supplement, alternative antifungal therapy should be considered or patients should be monitored closely for breakthrough fungal infections.
  • Patients who have severe diarrhea or vomiting should be monitored closely for breakthrough fungal infections.
  • Co-administration of drugs that can decrease the plasma concentrations of posaconazole should generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections (see CLINICAL PHARMACOLOGY, Drug Interactions section).

Shake NOXAFIL® Oral Suspension well before use.

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

(Graphic Omitted)

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

Renal Insufficiency

No dose adjustment is recommended for patients with renal dysfunction. However, the range of the posaconazole AUC estimates was highly variable (CV=96%) in subjects with severe renal insufficiency as compared to that in the other renal impairment groups (CV<40%). Due to the variability in exposure, patients with severe renal impairment should be monitored closely for breakthrough IFIs (see CLINICAL PHARMACOLOGY).

Hepatic Insufficiency

No dose adjustment of NOXAFIL is needed in patients with mild to severe hepatic insufficiency (Child-Pugh Class A, B, and C). (See CLINICAL PHARMACOLOGY/Pharmacokinetics in Special Populations).

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 15-30oC (59-86oF) [see USP Controlled Room Temperature]. DO NOT FREEZE.

 
Schering-Plough
Kenilworth, NJ 07033 USA
 
Copyright © 2006, 2008, Schering Corporation. All rights reserved.
U.S. Patent Nos. 5,661,151; 5,703,079; and 6,958,337.
 
BOOST® Drink is a registered trademark of Nestlé Healthcare Nutrition, Inc.
31153620T

2/09

 
 

31157528T

PATIENT INFORMATION

NOXAFIL®
(posaconazole) ORAL SUSPENSION

Read the Patient Information that comes with NOXAFIL® before you start taking it and each time you get a refill. There may be new information. This information does not replace talking with your doctor about your condition or treatment. Only your doctor can prescribe NOXAFIL and determine if it is right for you.

What is NOXAFIL?

-   NOXAFIL® is a prescription medicine that is used to prevent invasive fungal infections (infections that can spread throughout the body) caused by Aspergillus or Candida in patients with weak immune systems because of medicines or diseases [such as stem cell transplantation with graft versus host disease or chemotherapy for hematologic malignancy (blood cancers)].
- NOXAFIL is also used to treat fungal infections in the mouth or throat area (known as “thrush”) caused by fungi called Candida. NOXAFIL can be used as initial treatment or as a treatment after itraconazole and/or fluconazole have failed.
 

NOXAFIL is for adults and children over 13 years of age.

What should I tell my doctor before taking NOXAFIL?

Tell your doctor about all your health conditions, including if you:

- are taking certain drugs that suppress your immune system like cyclosporine (Neoral®), tacrolimus (Prograf®), or sirolimus (Rapamune®). Serious and rare fatal toxicity from cyclosporine has occurred when taken in combination with posaconazole and, therefore, reduction of the dose of drugs like cyclosporine, tacrolimus, or atazanavir and frequent monitoring of drug levels of these medicines is necessary when taking them in combination with posaconazole.

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

- are taking any other medicines, including prescription and non-prescription medicines, vitamins, and herbal supplements.

- have, or have had liver problems. Your doctor may do blood tests to make sure you should take NOXAFIL®.

- have, or have had an abnormal heart rate or rhythm.

- are, or think you are pregnant. Do not use NOXAFIL during pregnancy unless specifically advised by your doctor. You should use effective birth control while you are taking NOXAFIL if you are a woman who could become pregnant.

Contact your doctor immediately if you become pregnant while being treated with NOXAFIL.

Do not breast-feed while being treated with NOXAFIL, unless specifically advised by your doctor.

Who should not take NOXAFIL?

-

 

Do NOT take NOXAFIL® if you are taking any of the medicines listed below.

If any of these medicines are taken together with NOXAFIL, serious or life-threatening side effects from these medicines, or a decrease in the effect of NOXAFIL can occur. Tell your doctor right away if you are taking any of these medicines:
  • sirolimus
  • ergot alkaloids (ergotamine, dihydroergotamine, methylsergide, methylergonovine, ergonovine or bromocriptine)
  • terfenadine
  • astemizole
  • cisapride
  • pimozide
  • halofantrine
  • quinidine
  • rifabutin
  • phenytoin
  • cimetidine

-

If you have questions or are uncertain about your medicines, talk with your doctor or pharmacist.

-

Do not take NOXAFIL if you are allergic to anything in it. There is a list of what is in NOXAFIL at the end of this leaflet.

 

Can I take other medicines with NOXAFIL?

NOXAFIL® and many medicines can interact with each other and some must not be taken together (See “Who should not take NOXAFIL?”). The dose of other medicines may need to be adjusted when taken with NOXAFIL [for example, cyclosporine (Neoral®)*, tacrolimus (Prograf®)*, ritonavir, or atazanavir]. (See “What should I tell my doctor before taking NOXAFIL?”)

Knowing the medicines that you are taking is important. Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Keep a list of them with you to show your doctor or pharmacist. Do not take any new medicine without talking to your doctor.

What are possible side effects of NOXAFIL?

The most commonly reported side effects related to NOXAFIL® use were nausea, diarrhea, vomiting, headache, stomach pain, bloating, liver problems, low blood potassium, and decrease in neutrophils (certain type of white blood cells that fight infection).

Rarely, NOXAFIL may cause serious or life-threatening side effects. It may also cause severe drug interactions as discussed above. Call your doctor right away if you have any of the symptoms listed below.

Changes in heart rate or rhythm. People who have certain heart conditions or who take certain other medicines have a higher chance for this problem.

Rarely, very serious liver problems were reported in patients with serious underlying medical conditions. Your doctor may test your liver function while you are taking NOXAFIL. Call your doctor if you have any of these symptoms, as these may be signs of liver problems: you have itching, your eyes or skin turn yellow, you feel more tired than usual or feel like you have the flu, or you have nausea or vomiting.

Rarely, an increase in blood clots may occur in patients with blood cancers or post stem cell transplantation. These events may or may not be further increased in patients also on posaconazole and primarily occurred in patients also receiving cyclosporine or tacrolimus. If you notice swelling of one leg or shortness of breath, notify your doctor immediately.

These are not all the side effects associated with NOXAFIL. For more information, ask your doctor or pharmacist. If you experience any unusual effects while taking NOXAFIL, contact your doctor immediately.

How do I take NOXAFIL?

  • NOXAFIL® comes in cherry-flavored liquid form. Shake NOXAFIL Oral Suspension well before use.
  • Take NOXAFIL for as long as your doctor tells you. Take each dose of NOXAFIL during or immediately (i.e. within 20 minutes) following a full meal, or with a liquid nutritional supplement if you are unable to eat a full meal. Alternatively, NOXAFIL may be taken with an acidic carbonated beverage (e.g. ginger ale).
  • Follow your doctor’s instructions on when and how much of NOXAFIL you should take.

If you miss a dose of NOXAFIL, take it as soon as you remember.

  • If you take too much NOXAFIL, call your doctor or poison control center immediately.
  • Tell your doctor right away if you develop severe diarrhea or vomiting.

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

(Graphic Omitted)

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

How do I store NOXAFIL?

  • Store at 25oC (77oF); excursions permitted to 15-30oC (59-86oF) [see USP Controlled Room Temperature]. DO NOT FREEZE. Keep all containers tightly closed.
  • Keep NOXAFIL®, as well as other medicines, out of the reach of children.

General information about NOXAFIL

Doctors can prescribe medicines for conditions that are not in this leaflet. Use NOXAFIL® only as directed by your doctor. Do not give it to other people, even if they have the same symptoms as you. It may harm them.

This leaflet gives the most important information about NOXAFIL. For more information, talk to your doctor. You can ask your doctor or pharmacist for information about NOXAFIL that is written for health care professionals.

What is in NOXAFIL?

Active ingredient: posaconazole

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.

 
Schering Corporation
Kenilworth, NJ 07033 USA
 

Rx only

 
*Trademarks are the property of their respective owners.
 
Copyright © 2006, 2008 Schering Corporation. All rights reserved.
U.S. Patents 5,661,151; 5,703,079; and 6,958,337.
 

31157528T

Rev 02/09

 



CONTACT:

Merck
Media:
Ian McConnell, 908-423-3046
Robert Consalvo, 908-423-6595
or
Investors:
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