Posanol

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Posanol uses

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Posanol reviews

1 INDICATIONS AND USAGE

Posanol is an azole antifungal agent indicated for:

injection, delayed-release tablets, and oral suspension

• prophylaxis of invasive Aspergillus and Candida infections in patients 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.

Oral suspension

• treatment of oropharyngeal candidiasis (OPC), including OPC refractory (rOPC) to itraconazole and/or fluconazole. (1.2)

1.1 Prophylaxis of Invasive Aspergillus and Candida Infections

Posanol^® injection, delayed-release tablets, and oral suspension are indicated for prophylaxis of invasive Aspergillus and Candida infections in patients 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.

Posanol injection is indicated in patients 18 years of age and older.

Posanol delayed-release tablets and oral suspension are indicated in patients 13 years of age and older.

1.2 Treatment of Oropharyngeal Candidiasis Including Oropharyngeal Candidiasis Refractory to Itraconazole and/or Fluconazole

Posanol oral suspension is indicated for the treatment of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole.

2 DOSAGE AND ADMINISTRATION

Posanol delayed-release tablets and oral suspension are not interchangeable due to the differences in the dosing of each formulation. Therefore, follow the specific dosage recommendations for each of the formulations.

Indication	Dose and Duration of Therapy
Prophylaxis of invasive Aspergillus and Candida infections	InjectionPosanol injection must be administered through an in-line filter. Administer by intravenous infusion over approximately 90 minutes via a central venous line. Never give Posanol injection as an intravenous bolus injection. (2):
	Loading dose: 300 mg Posanol injection intravenously twice a day on the first day.
	Maintenance dose: 300 mg Posanol injection intravenously once a day thereafter. Duration of therapy is based on recovery from neutropenia or immunosuppression. (2.1)
	Delayed-Release Tablets Posanol delayed-release tablets should be taken with food. (2) :
	Loading dose: 300 mg (three 100 mg delayed-release tablets) twice a day on the first day.
	Maintenance dose: 300 mg (three 100 mg delayed-release tablets) once a day, starting on the second day. Duration of therapy is based on recovery from neutropenia or immunosuppression. (2.2)
	Oral Suspension Posanol oral suspension should be taken with a full meal. (2) : 200 mg (5 mL) three times a day. Duration of therapy is based on recovery from neutropenia or immunosuppression. (2.3)
Oropharyngeal Candidiasis (OPC)	Oral Suspension :
	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. (2.3)
OPC Refractory (rOPC) to Itraconazole and/or Fluconazole	Oral Suspension : 400 mg (10 mL) twice a day. Duration of therapy is based on the severity of the patient's underlying disease and clinical response. (2.3)

2.1 Important Administration Instructions for Posanol Injection, Posanol Delayed-Release Tablets and Posanol Oral Suspension

Posanol delayed-release tablets and oral suspension are not to be used interchangeably due to the differences in the dosing of each formulation .

Posanol injection

• Administer via a central venous line, including a central venous catheter or peripherally inserted central catheter (PICC), by slow intravenous infusion over approximately 90 minutes .
• If a central venous catheter is not available, Posanol injection may be administered through a peripheral venous catheter by slow intravenous infusion over 30 minutes only as a single dose in advance of central venous line placement or to bridge the period during which a central venous line is replaced or is in use for other intravenous treatment.
• When multiple dosing is required, the infusion should be done via a central venous line.
• Never administer Posanol injection as an intravenous bolus injection.

Posanol delayed-release tablets

• Swallow tablets whole. Do not divide, crush, or chew.
• Administer with food .

Posanol oral suspension

• Administer with a full meal or with a liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale) in patients who cannot eat a full meal
• Co-administration of drugs that can decrease the plasma concentrations of Posanol should generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections

Posanol delayed-release tablets and Posanol oral suspension

• Patients who have severe diarrhea or vomiting should be monitored closely for breakthrough fungal infections when receiving Posanol delayed-release tablets or oral suspension.

2.2 Dosage, Preparation, Intravenous Line Compatibility and Administration of Posanol Injection

Dosage:

Indication	Dose and Duration of Therapy
Prophylaxis of invasive Aspergillus and Candida infections	Loading dose: 300 mg Posanol injection intravenously twice a day on the first day.
	Maintenance dose: 300 mg Posanol injection intravenously once a day, starting on the second day. Duration of therapy is based on recovery from neutropenia or immunosuppression.

Preparation:

• Equilibrate the refrigerated vial of Posanol injection to room temperature.
• To prepare the required dose, aseptically transfer one vial (16.7 mL) of Posanol injection (containing 300 mg of Posanol in solution) to an intravenous bag (or bottle) of a compatible admixture diluent (as described in Table 2), to achieve a final concentration of Posanol that is between 1 mg/mL and 2 mg/mL. Use of other diluents is not recommended because they may result in particulate formation.
• Posanol injection is a single dose sterile solution without preservatives. Once admixed, the product should be used immediately. If not used immediately, the solution can be stored up to 24 hours refrigerated 2-8°C (36-46°F). Posanol injection is for single use only and any unused solution should be discarded.
• Parenteral drug products should be inspected visually for particulate matter prior to administration, whenever solution and container permit. Once admixed, the solution of Posanol ranges from colorless to yellow. Variations of color within this range do not affect the quality of the product.

Intravenous Line Compatibility:

A study was conducted to evaluate physical compatibility of Posanol injection with injectable drug products and commonly used intravenous diluents during simulated Y-site infusion. Compatibility was determined through visual observations, measurement of particulate matter and turbidity. Compatible diluents and drug products are listed in Tables 2 and 3 below. Any diluents or drug products not listed in the tables below should not be co-administered through the same intravenous line (or cannula).

• Posanol injection can be infused at the same time through the same intravenous line (or cannula) with the following compatible diluents:

0.45% sodium chloride

0.9% sodium chloride

5% dextrose in water

5% dextrose and 0.45% sodium chloride

5% dextrose and 0.9% sodium chloride

5% dextrose and 20 mEq potassium chloride

• Posanol injection can be infused at the same time through the same intravenous line (or cannula) with the following drug products prepared in 5% dextrose in water or sodium chloride 0.9%. Co-administration of drug products prepared in other diluents may result in particulate formation.

Amikacin sulfate

Caspofungin

Ciprofloxacin

Daptomycin

Dobutamine hydrochloride

Famotidine

Filgrastim

Gentamicin sulfate

Hydromorphone hydrochloride

Levofloxacin

Lorazepam

Meropenem

Micafungin

Morphine sulfate

Norepinephrine bitartrate

Potassium chloride

Vancomycin hydrochloride

Incompatible Diluents:

Posanol injection must not be diluted with the following diluents:

Lactated Ringer's solution

5% dextrose with Lactated Ringer's solution

4.2% sodium bicarbonate

Administration:

• Posanol injection must be administered through a 0.22 micron polyethersulfone (PES) or polyvinylidene difluoride (PVDF) filter.
• Administer via a central venous line, including a central venous catheter or PICC by slow infusion over approximately 90 minutes. Posanol injection is not for bolus administration.
• If a central venous catheter is not available, Posanol injection may be administered through a peripheral venous catheter only as a single dose in advance of central venous line placement or to bridge the period during which a central venous line is replaced or is in use for other treatment.
• When multiple dosing is required, the infusion should be done via a central venous line. When administered through a peripheral venous catheter, the infusion should be administered over approximately 30 minutes. Note: In clinical trials, multiple peripheral infusions given through the same vein resulted in infusion site reactions .

2.3 Dosage and Administration Instructions for Posanol Delayed-Release Tablets

Dosage:

Indication	Dose and Duration of Therapy
Prophylaxis of invasive Aspergillus and Candida infections	Loading dose: 300 mg (three 100 mg delayed-release tablets) twice a day on the first day.
	Maintenance dose: 300 mg (three 100 mg delayed-release tablets) once a day, starting on the second day. Duration of therapy is based on recovery from neutropenia or immunosuppression.

Administration Instructions for Posanol Delayed-Release Tablets:

• Swallow tablets whole. Do not divide, crush, or chew.
• Administer Posanol delayed-release tablets with food to enhance the oral absorption of Posanol and optimize plasma concentrations .
• Posanol delayed-release tablets should be used only for the prophylaxis indication.
• Posanol delayed-release tablets generally provide higher plasma drug exposures than Posanol oral suspension under both fed and fasted conditions, and therefore is the preferred oral formulation for the prophylaxis indication.

2.4 Dosage and Administration Instructions for Posanol Oral Suspension

Dosage:

Indication	Dose and Duration of Therapy
Prophylaxis of invasive Aspergillus and Candida infections	200 mg 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 Posanol Oral Suspension:

• Shake Posanol oral suspension well before use. Administer with measured dosing spoon provided.

• Rinse the spoon with water after each administration and before storage.
• Administer each dose of Posanol oral suspension during or immediately (i.e., within 20 minutes) following a full meal to enhance the oral absorption of Posanol and optimize plasma concentrations .
• For patients who cannot eat a full meal, Posanol delayed-release tablets should be used instead of Posanol oral suspension. Posanol delayed-release tablets should be used only for the prophylaxis indication. Posanol delayed-release tablets provide higher plasma drug exposures than Posanol oral suspension under fasted conditions .
• In patients who cannot eat a full meal and for whom Posanol delayed-release tablets or Posanol injection are not options, administer each dose of Posanol 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 Posanol delayed-release tablets or Posanol 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 Posanol Delayed-Release Tablets and Posanol Oral Suspension

Posanol 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 .

2.6 Dosage Adjustments in Patients with Renal Impairment

The pharmacokinetics of Posanol 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.

• Posanol 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 Posanol injection.
• In patients with moderate or severe renal impairment (estimated glomerular filtration rate (eGFR) <50 mL/min), receiving the Posanol 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 Posanol therapy.

3 DOSAGE FORMS AND STRENGTHS

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

Posanol 100 mg delayed-release tablets are available as yellow, coated, oblong tablets, debossed with "100" on one side.

Posanol oral suspension is available in 4-ounce (123 mL) amber glass bottles with child-resistant closures containing 105 mL of suspension (40 mg of Posanol per mL).

• Posanol injection: 300 mg per 16.7 mL (18 mg per mL) (3)
• Posanol delayed-release tablet 100 mg (3)
• Posanol oral suspension 40 mg per mL (3)

4 CONTRAINDICATIONS

• Do not administer to persons with known hypersensitivity to Posanol or other azole antifungal agents.
• Do not coadminister Posanol with the following drugs; Posanol increases concentrations of:
  • Sirolimus: can result in sirolimus toxicity (4.2, 7.1)
  • CYP3A4 substrates (pimozide, quinidine): can result in QTc interval prolongation and cases of TdP (4.3, 7.2)
  • HMG-CoA Reductase Inhibitors Primarily Metabolized Through CYP3A4: can lead to rhabdomyolysis (4.4, 7.3)
  • Ergot alkaloids: can result in ergotism (4.5, 7.4)

4.1 Hypersensitivity

Posanol is contraindicated in persons with known hypersensitivity to Posanol or other azole antifungal agents.

4.2 Use with Sirolimus

Posanol is contraindicated with sirolimus. Concomitant administration of Posanol with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity .

4.3 QT Prolongation with Concomitant Use with CYP3A4 Substrates

Posanol is contraindicated with CYP3A4 substrates that prolong the QT interval. Concomitant administration of Posanol 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 .

4.4 HMG-CoA Reductase Inhibitors Primarily Metabolized Through CYP3A4

Coadministration with the HMG-CoA reductase inhibitors that are primarily metabolized through CYP3A4 is contraindicated since increased plasma concentration of these drugs can lead to rhabdomyolysis .

4.5 Use with Ergot Alkaloids

Posanol may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism .

5 WARNINGS AND PRECAUTIONS

• Calcineurin Inhibitor Toxicity: Posanol increases concentrations of cyclosporine or tacrolimus; reduce dose of cyclosporine and tacrolimus and monitor concentrations frequently.
• Arrhythmias and QTc Prolongation: Posanol has been shown to prolong the QTc interval and cause cases 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 Posanol. (5.2)
• Hepatic Toxicity: Elevations in LFTs may occur. Discontinuation should be considered in patients who develop abnormal LFTs or monitor LFTs during treatment. (5.3)
• Posanol injection should be avoided in patients with moderate or severe renal impairment (creatinine clearance <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of Posanol injection. (5.4, 8.6)
• Midazolam: Posanol can prolong hypnotic/sedative effects. Monitor patients and benzodiazepine receptor antagonists should be available. (5.5, 7.5)
• Vincristine Toxicity: Concomitant administration of azole antifungals, including Posanol, with vincristine has been associated with neurotoxicity and other serious adverse reactions; reserve azole antifungals, including Posanol, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options. (5.6, 7.10)

5.1 Calcineurin-Inhibitor Drug Interactions

Concomitant administration of Posanol with cyclosporine or tacrolimus increases the whole blood trough concentrations of these calcineurin-inhibitors . 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 Posanol treatment and the tacrolimus or cyclosporine dose adjusted accordingly.

5.2 Arrhythmias and QT Prolongation

Some azoles, including Posanol, 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 Posanol.

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 administered Posanol 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 Posanol had a QTc(F) interval ≥500 msec or an increase ≥60 msec in their QTc(F) interval from baseline.

Posanol 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 . Rigorous attempts to correct potassium, magnesium, and calcium should be made before starting Posanol.

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. 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 Posanol. These severe hepatic reactions were seen primarily in subjects receiving the Posanol 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 Posanol therapy. Patients who develop abnormal liver function tests during Posanol 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 Posanol must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to Posanol.

5.4 Renal Impairment

Due to the variability in exposure with Posanol delayed-release tablets and oral suspension, patients with severe renal impairment should be monitored closely for breakthrough fungal infections .

Posanol 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 Posanol injection. In patients with moderate or severe renal impairment (eGFR <50 mL/min), receiving the Posanol 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 Posanol therapy .

5.5 Use with Midazolam

Concomitant administration of Posanol 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 .

5.6 Vincristine Toxicity

Concomitant administration of azole antifungals, including Posanol, with vincristine has been associated with neurotoxicity and other serious adverse reactions, including seizures, peripheral neuropathy, syndrome of inappropriate antidiuretic hormone secretion, and paralytic ileus. Reserve azole antifungals, including Posanol, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options .

6 ADVERSE REACTIONS

• Common treatment-emergent adverse reactions in studies with Posanol are diarrhea, nausea, fever, vomiting, headache, coughing, and hypokalemia.

To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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
• Arrhythmias and QT Prolongation
• Hepatic Toxicity

6.2 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of Posanol cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trials, the type of adverse reactions reported for Posanol injection and Posanol delayed-release tablets were generally similar to that reported in trials of Posanol oral suspension.

Clinical Trial Experience with Posanol Injection

Multiple doses of Posanol injection administered via a peripheral venous catheter were associated with thrombophlebitis. Therefore, in subsequent studies, Posanol injection was administered via central venous catheter.

The safety of Posanol injection has been assessed in 268 patients in a clinical trial. Patients were enrolled in a non-comparative pharmacokinetic and safety trial of Posanol injection when given as antifungal prophylaxis (Posaconazole Injection Study 1). Patients were immunocompromised with underlying conditions including hematological malignancy, neutropenia post-chemotherapy, GVHD, and post HSCT. This patient population was 55% male, had a mean age of 51 years (range 18-82 years, 19% of patients were ≥65 years of age), and were 95% white and 8% Hispanic. Ten patients received a single dose of 200 mg Posanol injection, 21 patients received 200 mg daily dose for a median of 14 days, and 237 patients received 300 mg daily dose for a median of 9 days.

Table 6 presents treatment-emergent adverse reactions observed in patients treated with Posanol injection 300 mg daily dose in the Posanol injection study. Each patient received a loading dose, 300 mg twice on Day 1. Following Posanol intravenous therapy, patients received Posanol oral suspension to complete 28 days of total Posanol therapy.

Body System Preferred Term	Posanol Injection Treatment Phase n=237 (%)Adverse reactions reported in patients with an onset during the Posanol intravenous dosing phase of the study.		Posanol Injection Treatment Phase or Subsequent Oral Suspension Treatment Phase n=237(%)Adverse reactions reported with an onset at any time during the study in patients who were treated for up to 28 days of Posanol therapy.
Subjects Reporting any Adverse Reaction	220	(93)	235	(99)
Blood and Lymphatic System Disorder
Anemia	16	(7)	23	(10)
Thrombocytopenia	17	(7)	25	(11)
Gastrointestinal Disorders
Abdominal Pain Upper	15	(6)	25	(11)
Abdominal Pain	30	(13)	41	(17)
Constipation	18	(8)	31	(13)
Diarrhea	75	(32)	93	(39)
Nausea	46	(19)	70	(30)
Vomiting	29	(12)	45	(19)
General Disorders and Administration Site Conditions
Fatigue	19	(8)	24	(10)
Chills	28	(12)	38	(16)
Edema Peripheral	28	(12)	35	(15)
Pyrexia	49	(21)	73	(31)
Metabolism and Nutrition Disorders
Decreased appetite	23	(10)	29	(12)
Hypokalemia	51	(22)	67	(28)
Hypomagnesemia	25	(11)	30	(13)
Nervous System Disorders
Headache	33	(14)	49	(21)
Respiratory, Thoracic and Mediastinal Disorders
Cough	21	(9)	31	(13)
Dyspnea	16	(7)	24	(10)
Epistaxis	34	(14)	40	(17)
Skin and Subcutaneous Tissue Disorders
Petechiae	20	(8)	24	(10)
Rash	35	(15)	56	(24)
Vascular Disorders
Hypertension	20	(8)	26	(11)

The most frequently reported adverse reactions with an onset during the Posanol intravenous phase of dosing with 300 mg once daily were diarrhea (32%), hypokalemia (22%), pyrexia (21%), and nausea (19%). These adverse reactions were consistent with those seen in studies with Posanol oral suspension.

Clinical Trial Experience with Posanol Delayed-Release Tablets

The safety of Posanol delayed-release tablets has been assessed in 230 patients in clinical trials. Patients were enrolled in a non-comparative pharmacokinetic and safety trial of Posanol delayed-release tablets when given as antifungal prophylaxis (Delayed-Release Tablet Study 1). Patients were immunocompromised with underlying conditions including hematological malignancy, neutropenia post-chemotherapy, GVHD, and post HSCT. This patient population was 62% male, had a mean age of 51 years (range 19-78 years, 17% of patients were ≥65 years of age), and were 93% white and 16% Hispanic. Posanol therapy was given for a median duration of 28 days. Twenty patients received 200 mg daily dose and 210 patients received 300 mg daily dose (following twice daily dosing on Day 1 in each cohort). Table 7 presents treatment-emergent adverse reactions observed in patients treated with 300 mg daily dose at an incidence of ≥10% in Posanol delayed-release tablet study.

Body System Preferred Term	Posanol delayed-release tablet (300 mg) (n=210)
Subjects Reporting any Adverse Reaction	201	(99)
Blood and Lymphatic System Disorder
Anemia	22	(10)
Thrombocytopenia	29	(14)
Gastrointestinal Disorders
Abdominal Pain	23	(11)
Constipation	20	(10)
Diarrhea	61	(29)
Nausea	56	(27)
Vomiting	28	(13)
General Disorders and Administration Site Conditions
Asthenia	20	(10)
Chills	22	(10)
Mucosal Inflammation	29	(14)
Edema Peripheral	33	(16)
Pyrexia	59	(28)
Metabolism and Nutrition Disorders
Hypokalemia	46	(22)
Hypomagnesemia	20	(10)
Nervous System Disorders
Headache	30	(14)
Respiratory, Thoracic and Mediastinal Disorders
Cough	35	(17)
Epistaxis	30	(14)
Skin and Subcutaneous Tissue Disorders
Rash	34	(16)
Vascular Disorders
Hypertension	23	(11)

The most frequently reported adverse reactions (>25%) with Posanol delayed-release tablets 300 mg once daily were diarrhea, pyrexia, and nausea.

The most common adverse reaction leading to discontinuation of Posanol delayed-release tablets 300 mg once daily was nausea (2%).

Clinical Trial Safety Experience with Posanol Oral Suspension

The safety of Posanol oral suspension has been assessed in 1844 patients. This includes 605 patients in the active-controlled prophylaxis studies, 557 patients in the active-controlled OPC studies, 239 patients in refractory OPC studies, and 443 patients from other indications. This represents a heterogeneous population, including immunocompromised patients, e.g., patients with hematological malignancy, neutropenia post-chemotherapy, GVHD post HSCT, and HIV infection, as well as non-neutropenic patients. This patient population was 71% male, had a mean age of 42 years (range 8-84 years, 6% of patients were ≥65 years of age and 1% was <18 years of age), and were 64% white, 16% Hispanic, and 36% non-white (including 14% black). Posanol therapy was given to 171 patients for ≥6 months, with 58 patients receiving Posanol therapy for ≥12 months. Table 8 presents treatment-emergent adverse reactions observed at an incidence of >10% in Posanol prophylaxis studies. Table 9 presents treatment-emergent adverse reactions observed at an incidence of at least 10% in the OPC/rOPC studies.

Prophylaxis of Aspergillus and Candida: In the 2 randomized, comparative prophylaxis studies (Oral Suspension Studies 1 and 2), the safety of Posanol oral suspension 200 mg three times a day was compared to fluconazole 400 mg once daily or itraconazole 200 mg twice a day in severely immunocompromised patients.

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 Posanol in the prophylaxis studies were associated with GI disorders, specifically, nausea (2%), vomiting (2%), and hepatic enzymes increased (2%).

Body System Preferred Term	Posanol (n=605)		Fluconazole (n=539)		Itraconazole (n=58)
Subjects Reporting any Adverse Reaction	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)
Disorders of the Reproductive System and Breast
Vaginal HemorrhagePercentages of sex-specific adverse reactions are based on the number of males/females.	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)
Dyspepsia	61	(10)	50	(9)	6	(10)
Heart Rate and Rhythm Disorders
Tachycardia	72	(12)	75	(14)	3	(5)
Infection and Infestations
Pharyngitis	71	(12)	60	(11)	12	(21)
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)
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)

HIV Infected Subjects with OPC : In 2 randomized comparative studies in OPC, the safety of Posanol oral suspension at a dose of less than or equal to 400 mg QD in 557 HIV-infected patients was compared to the safety of fluconazole in 262 HIV-infected patients at a dose of 100 mg QD.

An additional 239 HIV-infected patients with refractory OPC received Posanol oral suspension in 2 non-comparative trials for refractory OPC (rOPC). Of these subjects, 149 received the 800-mg/day dose and the remainder received the less than or equal to 400-mg QD dose.

In the OPC/rOPC studies, the most common adverse reactions were fever, diarrhea, nausea, headache, vomiting, and coughing.

The most common adverse reactions that led to treatment discontinuation of Posanol in the Controlled OPC Pool included respiratory impairment (1%) and pneumonia (1%). In the refractory OPC pool, the most common adverse reactions that led to treatment discontinuation of Posanol were AIDS (7%) and respiratory impairment (3%).

Body System Preferred Term	Number (%) of Subjects
	Controlled OPC Pool		Refractory OPC Pool
	Posanol	Fluconazole	Posanol
	n=557	n=262	n=239
OPC=oropharyngeal candidiasis
Subjects Reporting any Adverse ReactionNumber of subjects reporting treatment-emergent adverse reactions at least once during the study, without regard to relationship to treatment. Subjects may have reported more than 1 event.	356 (64)	175 (67)	221 (92)
Body as a Whole – General Disorders
Fever	34 (6)	22 (8)	82 (34)
Headache	44 (8)	23 (9)	47 (20)
Anorexia	10 (2)	4 (2)	46 (19)
Fatigue	18 (3)	12 (5)	31 (13)
Asthenia	9 (2)	5 (2)	31 (13)
Rigors	2 (<1)	4 (2)	29 (12)
Pain	4 (1)	2 (1)	27 (11)
Disorders of Blood and Lymphatic System
Neutropenia	21 (4)	8 (3)	39 (16)
Anemia	11 (2)	5 (2)	34 (14)
Gastrointestinal System Disorders
Diarrhea	58 (10)	34 (13)	70 (29)
Nausea	48 (9)	30 (11)	70 (29)
Vomiting	37 (7)	18 (7)	67 (28)
Abdominal Pain	27 (5)	17 (6)	43 (18)
Infection and Infestations
Candidiasis, Oral	3 (1)	1 (<1)	28 (12)
Herpes Simplex	16 (3)	8 (3)	26 (11)
Pneumonia	17 (3)	6 (2)	25 (10)
Metabolic and Nutritional Disorders
Weight Decrease	4 (1)	2 (1)	33 (14)
Dehydration	4 (1)	7 (3)	27 (11)
Psychiatric Disorders
Insomnia	8 (1)	3 (1)	39 (16)
Respiratory System Disorders
Coughing	18 (3)	11 (4)	60 (25)
Dyspnea	8 (1)	8 (3)	28 (12)
Skin and Subcutaneous Tissue Disorders
Rash	15 (3)	10 (4)	36 (15)
Sweating Increased	13 (2)	5 (2)	23 (10)

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

Less Common Adverse Reactions: Clinically significant adverse reactions reported during clinical trials in prophylaxis, OPC/rOPC or other trials with Posanol which occurred in less than 5% of patients are listed below:

• Blood and lymphatic system disorders: hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, neutropenia aggravated
• Endocrine disorders: adrenal insufficiency
• Nervous system disorders: paresthesia
• Immune system disorders: allergic reaction
• Cardiac disorders: torsades de pointes
• Vascular disorders: pulmonary embolism
• Gastrointestinal disorders: pancreatitis
• Liver and Biliary System Disorders: bilirubinemia, hepatic enzymes increased, hepatic function abnormal, hepatitis, hepatomegaly, jaundice, AST Increased, ALT Increased
• Metabolic and Nutritional Disorders: hypokalemia
• Platelet, Bleeding, and Clotting Disorders: thrombocytopenia
• Renal & Urinary System Disorders: renal failure acute

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 Posanol.

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 10.

Number (%) of Patients With ChangeChange 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.
Oral Suspension Study 1
Laboratory Parameter	Posanol 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)
Oral Suspension Study 2
Laboratory Parameter	Posanol (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)

The number of patients treated for OPC with clinically significant liver function test (LFT) abnormalities at any time during the studies is provided in Table 11 (LFT abnormalities were present in some of these patients prior to initiation of the study drug).

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

6.3 Postmarketing Experience

No clinically significant postmarketing adverse reactions were identified that have not previously been reported during clinical trials experience.

7 DRUG INTERACTIONS

Posanol is primarily metabolized via UDP glucuronosyltransferase and is a substrate of p-glycoprotein efflux. Therefore, inhibitors or inducers of these clearance pathways may affect Posanol plasma concentrations. Coadministration of drugs that can decrease the plasma concentrations of Posanol should generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections.

Posanol is also a strong inhibitor of CYP3A4. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by Posanol .

The following information was derived from data with Posanol oral suspension or early tablet formulation. All drug interactions with Posanol oral suspension, except for those that affect the absorption of Posanol (via gastric pH and motility) are considered relevant to Posanol injection as well .

Interaction Drug	Interaction
Rifabutin, phenytoin, efavirenz, cimetidine, esomeprazoleThe drug interactions with esomeprazole and metoclopramide do not apply to Posanol tablets.	Avoid coadministration unless the benefit outweighs the risks (7.6, 7.7, 7.8, 7.9)
Other drugs metabolized by CYP3A4	Consider dosage adjustment and monitor for adverse effects and toxicity (7.1, 7.10, 7.11)
Digoxin	Monitor digoxin plasma concentrations (7.12)
Fosamprenavir, metoclopramide	Monitor for breakthrough fungal infections (7.6, 7.13)

7.1 Immunosuppressants Metabolized by CYP3A4

Sirolimus: Concomitant administration of Posanol with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity. Therefore, Posanol is contraindicated with sirolimus .

Tacrolimus: Posanol has been shown to significantly increase the C_max and AUC of tacrolimus. At initiation of Posanol 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 Posanol treatment and the tacrolimus dose adjusted accordingly .

Cyclosporine: Posanol has been shown to increase cyclosporine whole blood concentrations in heart transplant patients upon initiation of Posanol treatment. It is recommended to reduce cyclosporine dose to approximately three-fourths of the original dose upon initiation of Posanol treatment. Frequent monitoring of cyclosporine whole blood trough concentrations should be performed during and at discontinuation of Posanol treatment and the cyclosporine dose adjusted accordingly .

7.2 CYP3A4 Substrates

Concomitant administration of Posanol with CYP3A4 substrates such as pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and cases of torsades de pointes. Therefore, Posanol is contraindicated with these drugs .

7.3 HMG-CoA Reductase Inhibitors (Statins) Primarily Metabolized Through CYP3A4

Concomitant administration of Posanol with simvastatin increases the simvastatin plasma concentrations by approximately 10-fold. Therefore, Posanol is contraindicated with HMG-CoA reductase inhibitors primarily metabolized through CYP3A4 .

7.4 Ergot Alkaloids

Most of the ergot alkaloids are substrates of CYP3A4. Posanol may increase the plasma concentrations of ergot alkaloids which may lead to ergotism. Therefore, Posanol is contraindicated with ergot alkaloids .

7.5 Benzodiazepines Metabolized by CYP3A4

Concomitant administration of Posanol with midazolam increases the midazolam plasma concentrations by approximately 5-fold. Increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects. Concomitant use of Posanol and other benzodiazepines metabolized by CYP3A4 (e.g., alprazolam, triazolam) could result in increased plasma concentrations of these benzodiazepines. Patients must be monitored closely for adverse effects associated with high plasma concentrations of benzodiazepines metabolized by CYP3A4 and benzodiazepine receptor antagonists must be available to reverse these effects .

7.6 Anti-HIV Drugs

Efavirenz: Efavirenz induces UDP-glucuronidase and significantly decreases Posanol plasma concentrations . It is recommended to avoid concomitant use of efavirenz with Posanol unless the benefit outweighs the risks.

Ritonavir and Atazanavir: Ritonavir and atazanavir are metabolized by CYP3A4 and Posanol increases plasma concentrations of these drugs . Frequent monitoring of adverse effects and toxicity of ritonavir and atazanavir should be performed during coadministration with Posanol.

Fosamprenavir: Combining fosamprenavir with Posanol may lead to decreased Posanol plasma concentrations. If concomitant administration is required, close monitoring for breakthrough fungal infections is recommended .

7.7 Rifabutin

Rifabutin induces UDP-glucuronidase and decreases Posanol plasma concentrations. Rifabutin is also metabolized by CYP3A4. Therefore, coadministration of rifabutin with Posanol increases rifabutin plasma concentrations . Concomitant use of Posanol and rifabutin should be avoided unless the benefit to the patient outweighs the risk. However, if concomitant administration is required, close monitoring for breakthrough fungal infections as well as frequent monitoring of full blood counts and adverse reactions due to increased rifabutin plasma concentrations (e.g., uveitis, leukopenia) are recommended.

7.8 Phenytoin

Phenytoin induces UDP-glucuronidase and decreases Posanol plasma concentrations. Phenytoin is also metabolized by CYP3A4. Therefore, coadministration of phenytoin with Posanol increases phenytoin plasma concentrations . Concomitant use of Posanol and phenytoin should be avoided unless the benefit to the patient outweighs the risk. However, if concomitant administration is required, close monitoring for breakthrough fungal infections is recommended and frequent monitoring of phenytoin concentrations should be performed while coadministered with Posanol and dose reduction of phenytoin should be considered.

7.9 Gastric Acid Suppressors/Neutralizers

Posanol Delayed-Release Tablet:

No clinically relevant effects on the pharmacokinetics of Posanol were observed when Posanol delayed-release tablets are concomitantly used with antacids, H₂-receptor antagonists and proton pump inhibitors . No dosage adjustment of Posanol delayed-release tablets is required when Posanol delayed-release tablets are concomitantly used with antacids, H₂-receptor antagonists and proton pump inhibitors.

Posanol Oral Suspension:

Cimetidine (an H₂-receptor antagonist) and esomeprazole (a proton pump inhibitor) when given with Posanol oral suspension results in decreased Posanol plasma concentrations . It is recommended to avoid concomitant use of cimetidine and esomeprazole with Posanol oral suspension unless the benefit outweighs the risks. However, if concomitant administration is required, close monitoring for breakthrough fungal infections is recommended.

No clinically relevant effects were observed when Posanol oral suspension is concomitantly used with antacids and H₂-receptor antagonists other than cimetidine. No dosage adjustment of Posanol oral suspension is required when Posanol oral suspension is concomitantly used with antacids and H₂-receptor antagonists other than cimetidine.

7.10 Vinca Alkaloids

Most of the vinca alkaloids are substrates of CYP3A4. Concomitant administration of azole antifungals, including Posanol, with vincristine has been associated with serious adverse reactions . Posanol may increase the plasma concentrations of vinca alkaloids which may lead to neurotoxicity and other serious adverse reactions. Therefore, reserve azole antifungals, including Posanol, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options.

7.11 Calcium Channel Blockers Metabolized by CYP3A4

Posanol may increase the plasma concentrations of calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, diltiazem, nifedipine, nicardipine, felodipine). Frequent monitoring for adverse reactions and toxicity related to calcium channel blockers is recommended during coadministration. Dose reduction of calcium channel blockers may be needed.

7.12 Digoxin

Increased plasma concentrations of digoxin have been reported in patients receiving digoxin and Posanol. Therefore, monitoring of digoxin plasma concentrations is recommended during coadministration.

7.13 Gastrointestinal Motility Agents

Posanol Delayed-Release Tablet:

Concomitant administration of metoclopramide with Posanol delayed-release tablets did not affect the pharmacokinetics of Posanol . No dosage adjustment of Posanol delayed-release tablets is required when given concomitantly with metoclopramide.

Posanol Oral Suspension:

Metoclopramide, when given with Posanol oral suspension, decreases Posanol plasma concentrations . If metoclopramide is concomitantly administered with Posanol oral suspension, it is recommended to closely monitor for breakthrough fungal infections.

Loperamide does not affect Posanol plasma concentrations after Posanol oral suspension administration. No dosage adjustment of Posanol is required when loperamide and Posanol are used concomitantly.

7.14 Glipizide

Although no dosage adjustment of glipizide is required, it is recommended to monitor glucose concentrations when Posanol and glipizide are concomitantly used.

8 USE IN SPECIFIC POPULATIONS

• Pregnancy: Based on animal data, may cause fetal harm.
• 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)

8.1 Pregnancy

There are no adequate and well-controlled studies in pregnant women. Posanol should be used in pregnancy only if the potential benefit outweighs the potential risk to the fetus.

Posanol 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 oral suspension 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 oral suspension 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 oral suspension 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 were seen.

8.3 Nursing Mothers

Posanol is excreted in milk of lactating rats. It is not known whether Posanol is excreted in human milk. Because of the potential for serious adverse reactions from Posanol in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

The safety and effectiveness of Posanol injection in pediatric patients below the age of 18 years of age has not been established. Posanol injection should not be used in pediatric patients because of nonclinical safety concerns .

The safety and effectiveness of Posanol oral suspension and Posanol delayed-release tablets have been established in the age groups 13 to 17 years of age. Use of Posanol in these age groups is supported by evidence from adequate and well-controlled studies of Posanol in adults. The safety and effectiveness of Posanol in pediatric patients below the age of 13 years (birth to 12 years) have not been established.

A total of 12 patients 13 to 17 years of age received 600 mg/day (200 mg three times a day) of Posanol oral suspension 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 Posanol concentration (Cavg) was similar between these patients and adults (≥18 years of age). In a study of 136 neutropenic pediatric patients 11 months to less than 18 years treated with Posanol oral suspension, the exposure target of steady-state Posanol Cavg between 500 ng/mL and less than 2500 ng/mL was attained in approximately 50% of patients instead of the pre-specified 90% of patients.

8.5 Geriatric Use

Of the 279 patients treated with Posanol injection, 52 (19%) were greater than 65 years of age. The pharmacokinetics of Posanol injection are comparable in young and elderly subjects. No overall differences in safety were observed between the geriatric patients and younger patients; therefore, no dosage adjustment is recommended for Posanol injection in geriatric patients.

Of the 230 patients treated with Posanol delayed-release tablets, 38 (17%) were greater than 65 years of age. The pharmacokinetics of Posanol delayed-release tablets are comparable in young and elderly subjects. No overall differences in safety were observed between the geriatric patients and younger patients; therefore, no dosage adjustment is recommended for geriatric patients.

Of the 605 patients randomized to Posanol oral suspension in the prophylaxis clinical trials, 63 (10%) were ≥65 years of age. In addition, 48 patients treated with greater than or equal to 800-mg/day Posanol in another indication were ≥65 years of age. No overall differences in safety were observed between the geriatric patients and younger patients.

The pharmacokinetics of Posanol oral suspension are comparable in young and elderly subjects (≥65 years of age); therefore no adjustment in the dosage of Posanol oral suspension is necessary in geriatric patients.

No overall differences in the pharmacokinetics and safety were observed between elderly and young subjects during clinical trials, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Renal Impairment

Following single-dose administration of 400 mg of the oral suspension, there was no significant effect of mild or moderate (eGFR: 20-49 mL/min/1.73 m², n=6) renal impairment on Posanol pharmacokinetics; therefore, no dose adjustment is required in patients with mild to moderate renal impairment. In subjects with severe renal impairment (eGFR: <20 mL/min/1.73 m²), the mean plasma exposure (AUC) was similar to that in patients with normal renal function (eGFR: >80 mL/min/1.73 m²); however, the range of the AUC estimates was highly variable (CV=96%) in these subjects with severe renal impairment 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 . Similar recommendations apply to Posanol delayed-release tablets; however, a specific study has not been conducted with the delayed-release tablets.

Posanol 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 Posanol injection. In patients with moderate or severe renal impairment (eGFR <50 mL/min), receiving the Posanol 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 Posanol therapy .

8.7 Hepatic Impairment

After a single oral dose of Posanol oral suspension 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), or severe (Child-Pugh Class C, N=6) hepatic impairment, respectively, compared to subjects with normal hepatic function (N=18). Compared to subjects with normal hepatic function, the mean C_max was 1% higher, 40% higher, and 34% lower in subjects with mild, moderate, or severe hepatic impairment, respectively. The mean apparent oral clearance (CL/F) was reduced by 18%, 36%, and 28% in subjects with mild, moderate, or severe hepatic impairment, respectively, compared to subjects with normal hepatic function. The elimination half-life (t_½) was 27 hours, 39 hours, 27 hours, and 43 hours in subjects with normal hepatic function and mild, moderate, or severe hepatic impairment, respectively.

It is recommended that no dose adjustment of Posanol is needed in patients with mild to severe hepatic impairment (Child-Pugh Class A, B, or C) [see Dosage and Administration (2) and Warnings and Precautions (5.3)]. Similar recommendations apply to Posanol delayed-release tablets; however, a specific study has not been conducted with the delayed-release tablets.

Similar recommendations apply to Posanol injection; however, a specific study has not been conducted with the Posanol injection.

8.8 Gender

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

8.9 Race

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

8.10 Weight

Pharmacokinetic modeling suggests that patients weighing greater than 120 kg may have lower Posanol plasma drug exposure. It is, therefore, suggested to closely monitor for breakthrough fungal infections.

10 OVERDOSAGE

There is no experience with overdosage of Posanol injection and delayed-release tablets.

During the clinical trials, some patients received Posanol oral suspension up to 1600 mg/day with no adverse reactions noted that were different from the lower doses. In addition, accidental overdose was noted in one patient who took 1200 mg BID Posanol oral suspension for 3 days. No related adverse reactions were noted by the investigator.

Posanol is not removed by hemodialysis.

11 DESCRIPTION

Posanol is an azole antifungal agent available as concentrated solution to be diluted before intravenous administration, delayed-release tablet, or suspension for oral administration.

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

Rinse the spoon with water after each dose of Posanol oral suspension and before you store it away.

If you miss a dose, take it as soon as you remember. However, if it is almost time for the next dose, skip the missed dose and go back to the regular dosing schedule. Do not take a double dose to make up for the forgotten dose.

Follow the instructions from your healthcare provider on how much Posanol you should take and when to take it.

What are the possible side effects of Posanol?

Posanol may cause serious side effects, including:

• drug interactions with cyclosporine or tacrolimus. If you take Posanol with cyclosporine or tacrolimus, your blood levels of cyclosporine or tacrolimus may increase. Serious side effects can happen in your kidney or brain if you have high levels of cyclosporine or tacrolimus in your blood. Your healthcare provider should do blood tests to check your levels of cyclosporine or tacrolimus if you are taking these medicines while taking Posanol. Tell your healthcare provider right away if you have swelling in your arm or leg or shortness of breath.
• problems with the electrical system of your heart (arrhythmias and QTc prolongation). Certain medicines used to treat fungus called azoles, including Posanol, the active ingredient in Posanol, may cause heart rhythm problems. People who have certain heart problems or who take certain medicines have a higher chance for this problem. Tell your healthcare provider right away if your heartbeat becomes fast or irregular.
• liver problems. Some people who also have other serious medical problems may have severe liver problems that may lead to death, especially if you take certain doses of Posanol. Your healthcare provider should do blood tests to check your liver while you are taking Posanol. Call your healthcare provider right away if you have any of the following symptoms of liver problems:

  itchy skin nausea or vomiting yellowing of your eyes

  feeling very tired flu-like symptoms

• increased amounts of midazolam in your blood. If you take Posanol with midazolam, Posanol increases the amount of midazolam in your blood. This can make your sleepiness last longer. Your healthcare provider should check you closely for side effects if you take midazolam with Posanol.

The most common side effects of Posanol include:

• diarrhea
• nausea
• fever
• vomiting

• headache
• coughing
• low potassium levels in the blood

If you take Posanol delayed-release tablets or Posanol oral suspension, tell your healthcare provider right away if you have diarrhea or vomiting.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Posanol. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Posanol?

• Store Posanol injection refrigerated at 36°F to 46°F (2°C to 8°C).
• Store Posanol delayed-release tablets and oral suspension at room temperature between 68°F to 77°F (20°C to 25°C).
• Do not freeze Posanol oral suspension.
• Safely throw away medicine that is out of date or no longer needed.

Keep Posanol and all medicines out of the reach of children.

General information about the safe and effective use of Posanol.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Posanol for a condition for which it was not prescribed. Do not give Posanol to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about Posanol that is written for health professionals.

What are the ingredients in Posanol?

Active ingredient: Posanol

Inactive ingredients:

Posanol injection: Betadex Sulfobutyl Ether Sodium (SBECD), edetate sodium, hydrochloric acid, sodium hydroxide, and water for injection.

Posanol delayed-release tablets: hypromellose acetate succinate, microcrystalline cellulose, hydroxypropylcellulose, silicon dioxide, croscarmellose sodium, magnesium stearate, and Opadry® II Yellow (consists of the following ingredients: polyvinyl alcohol partially hydrolyzed, Macrogol/PEG 3350, titanium dioxide, talc, and iron oxide yellow)

Posanol oral suspension: polysorbate 80, simethicone, sodium benzoate, sodium citrate dihydrate, citric acid monohydrate, glycerin, xanthan gum, liquid glucose, titanium dioxide, artificial cherry flavor, and purified water

Manuf. for: Merck Sharp & Dohme Corp., a subsidiary of

MERCK & CO., INC., Whitehouse Station, NJ 08889, USA

Injection: MSD International GmbH, Brinny, Innishannon, County Cork, Ireland

Delayed-Release Tablets: Manuf. by: N. V. Organon, Kloosterstraat 6, 5349 AB Oss, Netherlands

Oral Suspension: Manuf. by: Patheon Inc., Whitby, Ontario, Canada L1N 5Z5

For patent information: www.merck.com/product/patent/home.html

The trademarks depicted in this piece are owned by their respective companies.

Copyright © 2006-2017 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

All rights reserved.

usppi-mk5592-mf-1703r017

For more information, go to www.noxafil.com or call 1-800-672-6372.

Figure A

Posanol pharmaceutical active ingredients containing related brand and generic drugs:

• Posaconazole

Posanol available forms, composition, doses:

• POSANOL 40MG/ML ORAL SUSPENSION
• Suspension; Oral; Posaconazole 40 mg / ml

Posanol destination | category:

• Human:
• Azoles

Posanol Anatomical Therapeutic Chemical codes:

• J02AC04 - Posaconazole

Posanol pharmaceutical companies:

• Merck
• Schering-Plough

References

1. Dailymed."NOXAFIL (POSACONAZOLE) SUSPENSION NOXAFIL (POSACONAZOLE) TABLET, COATED NOXAFIL (POSACONAZOLE) SOLUTION [MERCK SHARP & DOHME CORP.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
2. Dailymed."POSACONAZOLE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
3. "Posaconazole". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Posanol?

Depending on the reaction of the Posanol after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Posanol not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Posanol addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

Review

sdrugs.com conducted a study on Posanol, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Posanol consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology