Prescription Drug Information: NOXAFIL (Page 2 of 9)

2.4 Dosage and Administration Instructions for Noxafil Oral Suspension

Dosage:

Table 5: Dosage for Noxafil Oral Suspension
Indication Dose and Duration of Therapy
Prophylaxis of invasive Aspergillus and Candida 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: 100 mg (2.5 mL) twice a day on the first day.
Maintenance dose: 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.

Administration Instructions for Noxafil Oral Suspension:

  • Shake Noxafil oral suspension well before use. Administer with measured dosing spoon (see Figure 1) provided.
Figure 1
(click image for full-size original)

Figure 1: A measured dosing spoon is provided, marked for doses of 2.5 mL and 5 mL.

  • Rinse the spoon with water after each administration and before storage.
  • Administer each dose of Noxafil oral suspension during or immediately (i.e., within 20 minutes) following a full meal to enhance the oral absorption of Noxafil and optimize plasma concentrations [see Clinical Pharmacology (12.3)].
  • For patients who cannot eat a full meal, Noxafil delayed-release tablets should be used instead of Noxafil oral suspension. Noxafil delayed-release tablets should be used only for the prophylaxis indication. Noxafil delayed-release tablets provide higher plasma drug exposures than Noxafil oral suspension under fasted conditions [see Dosage and Administration (2.5)].
  • In patients who cannot eat a full meal and for whom Noxafil delayed-release tablets or Noxafil injection are not options, administer each dose of Noxafil oral suspension with a liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale).
  • For patients who cannot eat a full meal or tolerate an oral nutritional supplement or an acidic carbonated beverage and who do not have the option of taking Noxafil delayed-release tablets or Noxafil injection, an alternative antifungal therapy should be considered or patients should be monitored closely for breakthrough fungal infections.
Figure 1

2.5 Non-Interchangeability between Noxafil Delayed-Release Tablets and Noxafil Oral Suspension

Noxafil delayed-release tablets and oral suspension are not to be used interchangeably due to the differences in the dosing of each formulation. Therefore, follow the specific dosage recommendations for each of the formulations [see Dosage and Administration (2.3, 2.4)].

2.6 Dosage Adjustments in Patients with Renal Impairment

The pharmacokinetics of Noxafil oral suspension and delayed-release tablets are not significantly affected by renal impairment. Therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment.

  • Noxafil injection should be avoided in patients with moderate or severe renal impairment (eGFR <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of Noxafil injection.
  • In patients with moderate or severe renal impairment (estimated glomerular filtration rate (eGFR) <50 mL/min), receiving the Noxafil injection, accumulation of the intravenous vehicle, Betadex Sulfobutyl Ether Sodium (SBECD), is expected to occur. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral Noxafil therapy.

3 DOSAGE FORMS AND STRENGTHS

Noxafil injection is available in Type I glass vials closed with bromobutyl rubber stopper and aluminum seal containing 300 mg of posaconazole in 16.7 mL of solution (18 mg of posaconazole per mL).

Noxafil delayed-release tablets are available as yellow, coated, oblong tablets, debossed with “100″ on one side containing 100 mg of posaconazole.

Noxafil oral suspension is available in 4-ounce (123 mL) amber glass bottles with child-resistant closures 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 or other azole antifungal agents.

4.2 Use with Sirolimus

Noxafil is contraindicated with sirolimus. Concomitant administration of Noxafil with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

4.3 QT Prolongation with Concomitant Use with CYP3A4 Substrates

Noxafil is contraindicated with CYP3A4 substrates that prolong the QT interval. Concomitant administration of Noxafil with the CYP3A4 substrates, pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and cases of torsades de pointes [see Warnings and Precautions (5.2) and Drug Interactions (7.2)].

4.4 HMG-CoA Reductase Inhibitors Primarily Metabolized Through CYP3A4

Coadministration with the HMG-CoA reductase inhibitors that are primarily metabolized through CYP3A4 (e.g., atorvastatin, lovastatin, and simvastatin) is contraindicated since increased plasma concentration of these drugs can lead to rhabdomyolysis [see Drug Interactions (7.3) and Clinical Pharmacology (12.3)].

4.5 Use with Ergot Alkaloids

Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism [see Drug Interactions (7.4)].

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 deaths) have been reported in clinical efficacy studies in patients with elevated cyclosporine or tacrolimus 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, 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 oral suspension 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)].

5.3 Electrolyte Disturbances

Electrolyte disturbances, especially those involving potassium, magnesium or calcium levels, should be monitored and corrected as necessary before and during posaconazole therapy.

5.4 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. 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 posaconazole oral suspension 800 mg daily (400 mg BID or 200 mg QID) in clinical trials.

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.

5.5 Renal Impairment

Due to the variability in exposure with Noxafil delayed-release tablets and oral suspension, patients with severe renal impairment should be monitored closely for breakthrough fungal infections [see Dosage and Administration (2.6) and Use in Specific Populations (8.6)].

Noxafil injection should be avoided in patients with moderate or severe renal impairment (eGFR <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of Noxafil injection. In patients with moderate or severe renal impairment (eGFR <50 mL/min), receiving the Noxafil injection, accumulation of the intravenous vehicle, SBECD, is expected to occur. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral Noxafil therapy [see Dosage and Administration (2.6) and Use in Specific Populations (8.6)].

5.6 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)].

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