These highlights do not include all the information needed to use NOXAFIL ORAL SUSPENSION safely and effectively. See full prescribing information for NOXAFIL ORAL SUSPENSION.
NOXAFIL® (Posaconazole) ORAL SUSPENSION 40 mg/mL
Initial U.S. Approval: 2006
RECENT MAJOR CHANGES
Contraindications, Hypersensitivity (4.1)
9/2010
Contraindications, Use with Simvastatin (4.4)
9/2010
Warnings and Precautions, Use with Midazolam (5.4)
9/2010
INDICATIONS AND USAGE
NOXAFIL is a triazole antifungal agent 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 HSCT recipients with GVHD or those with hematologic malignancies with prolonged neutropenia from chemotherapy. (1.1)
the treatment of oropharyngeal candidiasis (OPC), including OPC refractory (rOPC) to itraconazole and/or fluconazole. (1.2)
DOSAGE AND ADMINISTRATION
Indication
Dose and Duration of therapy
Prophylaxis of Invasive Fungal Infections
200 mg (5 mL) three times a day. Duration of therapy is based on recovery from neutropenia or immunosuppression. (2.1)
Oropharyngeal Candidiasis (OPC)
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. (2.1)
OPC Refractory (rOPC) to Itraconazole and/or Fluconazole
400 mg (10 mL) twice a day. Duration of therapy should be based on the severity of the patient's underlying disease and clinical response. (2.1)
DOSAGE FORMS AND STRENGTHS
NOXAFIL Oral Suspension 40 mg per mL (3)
CONTRAINDICATIONS
Do not administer to persons with known hypersensitivity to posaconazole, any component of NOXAFIL, or other azole antifungal agents (4.1)
Do not coadminister NOXAFIL with the following drugs; NOXAFIL increases concentrations of:
Sirolimus: can result in sirolimus toxicity (4.2, 7.1)
CYP3A4 substrates (pimozide, quinidine): can result in QTc interval prolongation and rare occurrences of TdP (4.3, 7.2)
Simvastatin: can result in rhabdomyolysis (4.4, 7.3)
Ergot alkaloids: can result in ergotism (4.5, 7.4)
WARNINGS AND PRECAUTIONS
Calcineurin Inhibitor Toxicity: NOXAFIL increases concentrations of cyclosporine or tacrolimus; reduce dose of cyclosporine and tacrolimus and monitor concentrations frequently. (5.1)
Arrhythmias and QTc Prolongation: NOXAFIL has been shown to prolong the QTc interval and cause rare occurrences of TdP. Administer with caution to patients with potentially proarrhythmic conditions. Do not administer with drugs known to prolong QTc interval and metabolized through CYP3A4. Correct K+, Mg++, and Ca++ before starting NOXAFIL. (5.2)
Hepatic Toxicity: elevations in LFTs (generally reversible on discontinuation) may occur. Discontinuation should be considered in patients who develop abnormal LFTs or monitor LFTs during treatment. (5.3)
Midazolam: NOXAFIL can prolong hypnotic/sedative effects. Monitor patients and benzodiazepine receptor antagonists should be available. (5.4, 7.5)
ADVERSE REACTIONS
Common treatment-emergent adverse reactions (>30%) in prophylaxis studies are fever, diarrhea and nausea.(6.2)
Common treatment-emergent adverse reactions (>5%) in controlled OPC pool are diarrhea, nausea, headache, and vomiting. Common adverse reactions (>20%) in the refractory OPC pool are fever, diarrhea, nausea, and vomiting (6.2).
To report SUSPECTED ADVERSE REACTIONS, contact Schering Corporation, a subsidiary of Merck & Co., Inc., at 800-526-4099 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Avoid co-administration unless the benefit outweighs the risks (7.6, 7.7, 7.8, 7.9)
Other drugs metabolized by CYP3A ( tacrolimus, cyclosporine, vinca alkaloids, calcium channel blockers)
Consider dosage adjustment and monitor for adverse effects and toxicity (7.1,7.10, 7.11)
Digoxin
Monitor digoxin plasma concentrations (7.12)
Metoclopramide
Monitor for breakthrough fungal infections (7.13)
USE IN SPECIFIC POPULATIONS
Pregnancy: Based on animal data, may cause fetal harm. (8.1)
Nursing Mothers: Discontinue drug or nursing, taking in to consideration the importance of drug to the mother. (8.3)
Severe renal impairment: Monitor closely for breakthrough fungal Infections. (8.6)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling
Revised: 09/2010
Back to Highlights and Tabs
FULL PRESCRIBING INFORMATION: CONTENTS*
*Sections or subsections omitted from the full prescribing information are not listed
1.INDICATIONS AND USAGE
1.1 Prophylaxis of Invasive Fungal Infection
1.2 Treatment of Oropharyngeal Candidiasis Including Oropharyngeal Candidiasis Refractory to Itraconazole and/or Fluconazole
2.DOSAGE AND ADMINISTRATION
2.1 Dosage
2.2 Administration Instructions
3.DOSAGE FORMS AND STRENGTHS
4.CONTRAINDICATIONS
4.1 Hypersensitivity
4.2 Use With Sirolimus
4.3 QT Prolongation With Concomitant Use With CYP3A4 Substrates
4.4 Use With Simvastatin
4.5 Use With Ergot Alkaloids
5.WARNINGS AND PRECAUTIONS
5.1 Calcineurin-Inhibitor Drug Interactions
5.2 Arrhythmias and QT Prolongation
5.3 Hepatic Toxicity
5.4 Use with Midazolam
6.ADVERSE REACTIONS
6.1 Serious and Otherwise Important Adverse Reactions
6.2 Clinical Trials Experience
6.3 Postmarketing Experience
7.DRUG INTERACTIONS
7.1 Immunosuppressants Metabolized by CYP3A4
7.2 CYP3A4 Substrates
7.3 HMG-CoA reductase Inhibitors (Statins) Metabolized Through CYP3A4
7.4 Ergot Alkaloids
7.5 Benzodiazepines Metabolized by CYP3A4
7.6 Anti-HIV Drugs
7.7 Rifabutin
7.8 Phenytoin
7.9 Gastric Acid Suppressors/Neutralizers
7.10 Vinca Alkaloids
7.11 Calcium Channel Blockers Metabolized by CYP3A4
7.12 Digoxin
7.13 Gastrointestinal Motility Agents
7.14 Glipizide
8.USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Insufficiency
8.7 Hepatic Insufficiency
8.8 Gender
8.9 Race
10.OVERDOSAGE
11. DESCRIPTION
12.CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
12.4 Microbiology
13. NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
14. CLINICAL STUDIES
14.1 Prophylaxis of Aspergillus and Candida Infections
14.2 Treatment of Oropharyngeal Candidiasis
14.3 Treatment of Oropharyngeal Candidiasis Refractory to Treatment With Fluconazole or Itraconazole
16.HOW SUPPLIED/STORAGE AND HANDLING
17.PATIENT COUNSELING INFORMATION
17.1 Administration with Food
17.2 Drug Interactions
17.3 Serious and Potentially Serious Adverse Reactions
17.4 See Accompanying FDA-Approved Patient Labeling
FULL PRESCRIBING INFORMATION
1.INDICATIONS AND USAGE
1.1 Prophylaxis of Invasive Fungal Infection
NOXAFIL Oral Suspension is indicated for prophylaxis of invasive Aspergillus and Candida infections in patients, 13 years of age and older, who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy.
1.2 Treatment of Oropharyngeal Candidiasis Including Oropharyngeal Candidiasis Refractory to Itraconazole and/or Fluconazole
NOXAFIL is indicated for the treatment of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole.
2.DOSAGE AND ADMINISTRATION
2.1 Dosage
Indication
Dose and Duration of Therapy
Prophylaxis of Invasive Fungal Infections
200 mg (5 mL) three times a day. The duration of therapy is based on recovery from neutropenia or immunosuppression.
Oropharyngeal Candidiasis
Loading dose of 100 mg (2.5 mL) twice a day on the first day, then 100 mg (2.5 mL) once a day for 13 days.
Oropharyngeal Candidiasis Refractory to itraconazole and/or fluconazole
400 mg (10 mL) twice a day. Duration of therapy should be based on the severity of the patient's underlying disease and clinical response.
2.2 Administration Instructions
Shake NOXAFIL Oral Suspension well before use.
Figure 1: A measured dosing spoon is provided, marked for doses of 2.5 mL and 5 mL.
It is recommended that the spoon is rinsed with water after each administration and before storage.
Each dose of NOXAFIL should be administered with a full meal or with a liquid nutritional supplement or an acidic carbonated beverage (e.g. ginger ale) in patients who cannot eat a full meal.
To enhance the oral absorption of posaconazole and optimize plasma concentrations:
Each dose of NOXAFIL should be administered during or immediately (i.e. within 20 minutes) following a full meal. In patients who cannot eat a full meal, each dose of NOXAFIL should be administered with a liquid nutritional supplement or an acidic carbonated beverage. For patients who cannot eat a full meal or tolerate an oral nutritional supplement or an acidic carbonated beverage, alternative antifungal therapy should be considered or patients should be monitored closely for breakthrough fungal infections.
Patients who have severe diarrhea or vomiting should be monitored closely for breakthrough fungal infections.
Co-administration of drugs that can decrease the plasma concentrations of posaconazole should generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections [See Drug Interactions (7.6, 7.7, 7.8, 7.9, 7.13)].
3.DOSAGE FORMS AND STRENGTHS
NOXAFIL Oral Suspension is available in 4-ounce (123 mL) amber glass bottles with child-resistant closures (NDC 0085-1328-01) containing 105 mL of suspension (40 mg of posaconazole per mL).
4.CONTRAINDICATIONS
4.1 Hypersensitivity
NOXAFIL is contraindicated in persons with known hypersensitivity to posaconazole, any component of NOXAFIL, or other azole antifungal agents.
4.2 Use With Sirolimus
NOXAFIL is contraindicated with sirolimus. Concomitant administration of NOXAFIL with sirolimus increases the sirolimus blood concentrations by approximately 9 fold and can result in sirolimus toxicity [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
4.3 QT Prolongation With Concomitant Use With CYP3A4 Substrates
NOXAFIL is contraindicated with CYP3A4 substrates that prolong the QT interval. Concomitant administration of NOXAFIL with the CYP3A4 substrates, pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and rare occurrences of torsades de pointes [see Warnings and Precautions (5.2) and Drug Interactions (7.2)].
4.4 Use With Simvastatin
Concomitant administration of NOXAFIL with simvastatin increases the simvastatin plasma concentrations by approximately 10 fold. Increased plasma statin concentrations can be associated with rhabdomyolysis [see Drug Interactions (7.3) and Clinical Pharmacology (12.3)].
4.5 Use With Ergot Alkaloids
Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism [see Drug Interactions (7.4)].
5.WARNINGS AND PRECAUTIONS
5.1 Calcineurin-Inhibitor Drug Interactions
Concomitant administration of NOXAFIL with cyclosporine or tacrolimus increases the whole blood trough concentrations of these calcineurin-inhibitors [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. Nephrotoxicity and leukoencephalopathy (including isolated deaths) have been reported in clinical efficacy studies in patients with elevated cyclosporine concentrations. Frequent monitoring of tacrolimus or cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus or cyclosporine dose adjusted accordingly.
5.2 Arrhythmias and QT Prolongation
Some azoles, including posaconazole, have been associated with prolongation of the QT interval on the electrocardiogram. In addition, rare cases of torsades de pointes have been reported in patients taking posaconazole.
Results from a multiple time-matched ECG analysis in healthy volunteers did not show any increase in the mean of the QTc interval. Multiple, time-matched ECGs collected over a 12-hour period were recorded at baseline and steady-state from 173 healthy male and female volunteers (18–85 years of age) administered posaconazole 400 mg BID with a high-fat meal. In this pooled analysis, the mean QTc (Fridericia) interval change from baseline was –5 msec following administration of the recommended clinical dose. A decrease in the QTc (F) interval (–3 msec) was also observed in a small number of subjects (n=16) administered placebo. The placebo-adjusted mean maximum QTc (F) interval change from baseline was <0 msec (–8 msec). No healthy subject administered posaconazole had a QTc (F) interval ≥500 msec or an increase ≥60 msec in their QTc (F) interval from baseline.
Posaconazole should be administered with caution to patients with potentially proarrhythmic conditions. Do not administer with drugs that are known to prolong the QTc interval and are metabolized through CYP3A4 [see Contraindications (4.3) and Drug Interactions (7.2)]. Rigorous attempts to correct potassium, magnesium, and calcium should be made before starting posaconazole.
5.3 Hepatic Toxicity
Hepatic reactions (e.g., mild to moderate elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin, and/or clinical hepatitis) have been reported in clinical trials. The elevations in liver function tests were generally reversible on discontinuation of therapy, and in some instances these tests normalized without drug interruption and rarely required drug discontinuation. Isolated cases of more severe hepatic reactions including cholestasis or hepatic failure including deaths have been reported in patients with serious underlying medical conditions (e.g., hematologic malignancy) during treatment with posaconazole. These severe hepatic reactions were seen primarily in subjects receiving the 800 mg daily (400 mg BID or 200 mg QID) in clinical trials.
Liver function tests should be eva luated 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 eva luation of hepatic function (particularly liver function tests and bilirubin). Discontinuation of posaconazole must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to posaconazole.
5.4 Use with Midazolam
Concomitant administration of NOXAFIL with midazolam increases the midazolam plasma concentrations by approximately 5 fold. Increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects. Patients must be monitored closely for adverse effects associated with high plasma concentrations of midazolam and benzodiazepine receptor antagonists must be available to reverse these effects [see Drug Interactions (7.5) and Clinical Pharmacology (12.3)].
6.ADVERSE REACTIONS
6.1 Serious and Otherwise Important Adverse Reactions
The following serious and otherwise important adverse reactions are discussed in detail in another section of the labeling:
Hypersensitivity [see Contraindications (4.1)]
Arrhythmias and QT Prolongation [see Warnings and Precautions (5.2)]
Hepatic Toxicity [see Warnings and Precautions (5.3)]
6.2 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of NOXAFIL cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of posaconazole therapy has been assessed in 1844 patients in clinical trials. This includes 605 patients in the active-controlled prophylaxis studies, 557 patients in the active-controlled OPC studies, 239 patients in refractory OPC studies, and 443 patients from other indications. This represents a heterogeneous population, including immunocompromised patients, e.g., patients with hematological malignancy, neutropenia post-chemotherapy, graft vs. host disease post hematopoietic stem cell transplant, and HIV infection, as well as non-neutropenic patients. This patient population was 71% male, had a mean age of 42 years (range 8–84 years, 6% of patients were ≥65 years of age and 1% was <18 years of age), and were 64% white, 16% Hispanic, and 36% non-white (including 14% black). Posaconazole therapy was given to 171 patients for ≥6 months, with 58 patients receiving posaconazole therapy for ≥12 months. Table 1 presents treatment-emergent adverse reactions observed at an incidence of >10% in posaconazole prophylaxis studies. Table 2 presents treatment-emergent adverse reactions observed at an incidence of at least 10% in the OPC/rOPC studies.
Prophylaxis of Aspergillus and Candida: In the 2 randomized, comparative prophylaxis studies, the safety of posaconazole 200 mg three times a day was compared to fluconazole 400 mg once daily or itraconazole 200 mg twice a day in severely immunocompromised patients.
The most frequently reported adverse reactions (>30%) in the prophylaxis clinical trials were fever, diarrhea and nausea.
The most common adverse reactions leading to discontinuation of posaconazole in the prophylaxis studies were associated with GI disorders, specifically, nausea (2%), vomiting (2%), and hepatic enzymes increased (2%).
TABLE 1: Study 1 and Study 2. Number (%) of Randomized Subjects Reporting Treatment-Emergent Adverse Reactions: Frequency of at Least 10% in the Posaconazole or Fluconazole Treatment Groups (Pooled Prophylaxis Safety Analysis)
Body System
Preferred Term
Posaconazole
(n=605)
Fluconazole
(n=539)
Itraconazole
(n=58)
Subjects Reporting any Adverse Reaction
595
(98)
531
(99)
58
(100)
NOS = not otherwise specified.
*
Percentages of sex-specific adverse reactions are based on the number of males/females.
