FDA Label for Posaconazole

Recent Major Changes

1.2 Prophylaxis Of Invasive Aspergillus And Candida Infections

Posaconazole delayed-release tablets are indicated for the 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 [see Clinical Studies (14.2)] as follows

• Posaconazole delayed-release tablets: Adults and pediatric patients 13 years of age and older.

Additional Pediatric Use information is approved for Merck Sharp & Dohme Corp.’s NOXAFIL (posaconazole delayed-release tablets). However, due to Merck Sharp & Dohme Corp.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

2.1 Important Administration Instructions

Non-substitutable

Noxafil oral suspension is not substitutable with posaconazole delayed-release tablets or Noxafil PowderMix for delayed-release oral suspension due to the differences in the dosing of each formulation.

Posaconazole delayed-release tablets.

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

•Administer with or without food [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].

•For patients who cannot eat a full meal, Posaconazole delayed-release tablets should be used instead of Noxafil oral suspension for the prophylaxis indication. Posaconazole delayed-release tablets generally provide higher plasma drug exposures than Noxafil oral suspension under both fed and fasted conditions.

2.2 Dosing Regimen In Adult Patients

Table 1: Dosing Regimen in Adult Patients

2.3 Dosing Regimen In Pediatric Patients (Ages 13 To Less Than 18 Years Of Age)

The recommended dosing regimen of Posaconazole delayed-release tablets for pediatric patients 13 to less than 18 years of age is shown in Table 3 [see Dosage and Administration (2.5,) and Clinical Pharmacology (12.3)].

Table 2: Posaconazole Delayed-Release Tablet Dosing Regimens for Pediatric Patients (ages 13 to less than 18 years of age)

Additional Pediatric Use information is approved for Merck Sharp & Dohme Corp.’s NOXAFIL (posaconazole delayed-release tablets). However, due to Merck Sharp & Dohme Corp.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

2.5 Administration Instructions For Posaconazole Delayed-Release Tablets

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

•Administer posaconazole delayed-release tablets with or without food [see Clinical Pharmacology (12.3)].

2.7 Non-Substitutability Between Noxafil Oral Suspension And Other Formulations

Noxafil oral suspension is not substitutable with posaconazole delayed-release tablets or Noxafil PowderMix for delayed-release oral suspension due to the differences in the dosing of each formulation.

2.9 Dosage Adjustments In Patients With Renal Impairment

The pharmacokinetics of posaconazole 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.

3 Dosage Forms And Strengths

Posaconazole delayed-release tablets are available as pale yellow to yellow, oval, biconvex, film coated tablets debossed with ‘B100’ on one side and plain on the other side.

4.1 Hypersensitivity

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

4.2 Use With Sirolimus

Posaconazole is contraindicated with sirolimus. Concomitant administration of posaconazole 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

Posaconazole is contraindicated with CYP3A4 substrates that prolong the QT interval. Concomitant administration of posaconazole 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)].

4.6 Use With Venetoclax

Coadministration of posaconazole with venetoclax at initiation and during the ramp-up phase is contraindicated in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) due to the potential for increased risk of tumor lysis syndrome [see Warnings and Precautions (5.10) and Drug Interactions (7.16)].

5.1 Calcineurin-Inhibitor Toxicity

Concomitant administration of posaconazole 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 to 85 years of age) administered Noxafil oral suspension 400 mg twice daily 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 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 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 Noxafil oral suspension 800 mg daily (400 mg twice daily or 200 mg four times a day) in clinical trials.

Liver tests should be evaluated at the start of and during the course of posaconazole therapy. Patients who develop abnormal liver 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 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 posaconazole delayed-release tablets, Noxafil oral suspension, and Noxafil PowderMix for delayed-release oral suspension, patients with severe renal impairment should be monitored closely for breakthrough fungal infections [see Dosage and Administration (2.9) and Use in Specific Populations (8.6)].

5.6 Midazolam Toxicity

Concomitant administration of posaconazole with midazolam increases the midazolam plasma concentrations by approximately 5-fold. Increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects. 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)].

5.7 Vincristine Toxicity

Concomitant administration of azole antifungals, including posaconazole, 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 posaconazole, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options [see Drug Interactions (7.10)].

5.9 Breakthrough Fungal Infections

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

5.10 Venetoclax Toxicity

Concomitant administration of posaconazole, a strong CYP3A4 inhibitor, with venetoclax may increase venetoclax toxicities, including the risk of tumor lysis syndrome (TLS), neutropenia, and serious infections. In patients with CLL/SLL, administration of posaconazole during initiation and the ramp-up phase of venetoclax is contraindicated [see Contraindications (4.6)]. Refer to the venetoclax labeling for safety monitoring and dose reduction in the steady daily dosing phase in CLL/SLL patients.

For patients with acute myeloid leukemia (AML), dose reduction and safety monitoring are recommended across all dosing phases when coadministering posaconazole with venetoclax [see Drug Interactions (7.16)]. Refer to the venetoclax prescribing information for dosing instructions.

Other

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 (5.4)]

Clinical Trial Experience in Adults

Clinical Trial Experience with Posaconazole Delayed-Release Tablets for Prophylaxis

The safety of posaconazole delayed-release tablets has been assessed in 230 patients in clinical trials. Patients were enrolled in a non-comparative pharmacokinetic and safety trial of posaconazole delayed-release tablets when given as antifungal prophylaxis (Posaconazole Delayed-Release Tablet Study). 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 to 78 years, 17% of patients were ≥65 years of age), and were 93% white and 16% Hispanic. Posaconazole therapy was given for a median duration of 28 days. Twenty patients received 200 mg daily dose and 210 patients received 300 mg daily dose (following twice daily dosing on Day 1 in each cohort). Table 9 presents adverse reactions observed in patients treated with 300 mg daily dose at an incidence of ≥10% in posaconazole delayed-release tablet study.
Table 9: Posaconazole Delayed-Release Tablet Study: Adverse Reactions in at Least 10% of Subjects Treated with 300 mg Daily Dose

Body System	Posaconazole delayed-release tablet (300 mg) (n=210)
Subjects Reporting any Adverse Reaction	207	(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 posaconazole delayed-release tablets 300 mg once daily were diarrhea, pyrexia, and nausea.

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


Additional Pediatric Use information is approved for Merck Sharp & Dohme Corp.’s NOXAFIL (posaconazole delayed-release tablets). However, due to Merck Sharp & Dohme Corp.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Sirolimus: Concomitant administration of posaconazole with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity. Therefore, posaconazole is contraindicated with sirolimus [see Contraindications (4.2) and Clinical Pharmacology (12.3)].

Tacrolimus: Posaconazole has been shown to significantly increase the C_max and AUC of tacrolimus. At initiation of posaconazole treatment, reduce the tacrolimus dose to approximately one-third of the original dose. Frequent monitoring of tacrolimus whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus dose adjusted accordingly [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

Cyclosporine: Posaconazole has been shown to increase cyclosporine whole blood concentrations in heart transplant patients upon initiation of posaconazole treatment. It is recommended to reduce cyclosporine dose to approximately three-fourths of the original dose upon initiation of posaconazole treatment. Frequent monitoring of cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the cyclosporine dose adjusted accordingly [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

Efavirenz: Efavirenz induces UDP-glucuronidase and significantly decreases posaconazole plasma concentrations [see Clinical Pharmacology(12.3)]. It is recommended to avoid concomitant use of efavirenz with posaconazole unless the benefit outweighs the risks.

Ritonavir and Atazanavir: Ritonavir and atazanavir are metabolized by CYP3A4 and posaconazole increases plasma concentrations of these drugs [see Clinical Pharmacology (12.3)]. Frequent monitoring of adverse effects and toxicity of ritonavir and atazanavir should be performed during coadministration with posaconazole.

Fosamprenavir: Combining fosamprenavir with posaconazole may lead to decreased posaconazole plasma concentrations. If concomitant administration is required, close monitoring for breakthrough fungal infections is recommended [see Clinical Pharmacology (12.3)].

No clinically relevant effects on the pharmacokinetics of posaconazole were observed when posaconazole delayed-release tablets are concomitantly used with antacids, H ₂ -receptor antagonists and proton pump inhibitors [see Clinical Pharmacology (12.3)] . No dosage adjustment of posaconazole delayed-release tablets is required when concomitantly used with antacids, H ₂ -receptor antagonists and proton pump inhibitors.

Concomitant administration of metoclopramide with posaconazole delayed-release tablets did not affect the pharmacokinetics of posaconazole [see Clinical Pharmacology (12.3)]. No dosage adjustment of posaconazole delayed-release tablets is required when given concomitantly with metoclopramide.

Exposure Response Relationship Prophylaxis: In clinical studies of neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS) or hematopoietic stem cell transplant (HSCT) recipients with Graft versus Host Disease (GVHD), a wide range of plasma exposures to posaconazole was noted following administration of Noxafil oral suspension. A pharmacokinetic-pharmacodynamic analysis of patient data revealed an apparent association between average posaconazole concentrations (Cavg) and prophylactic efficacy (Table 17). A lower Cavg may be associated with an increased risk of treatment failure, defined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections.

Table 17: Noxafil Oral Suspension Exposure Analysis (C_avg) in Prophylaxis Trials

	Prophylaxis in AML/MDS*		Prophylaxis in GVHD†
	Cavg Range (ng/mL)	Treatment Failure‡ (%)	Cavg Range (ng/mL)	Treatment Failure‡ (%)
Quartile 1	90 to 322	54.7	22 to 557	44.4
Quartile 2	322 to 490	37.0	557 to 915	20.6
Quartile 3	490 to 734	46.8	915 to 1563	17.5
Quartile 4	734 to 2200	27.8	1563 to 3650	17.5
Cavg = the average posaconazole concentration when measured at steady state * Neutropenic patients who were receiving cytotoxic chemotherapy for AML or MDS † HSCT recipients with GVHD ‡ Defined as treatment discontinuation, use of empiric systemic antifungal therapy (SAF), or occurrence of breakthrough invasive fungal infections

Absorption:

When given orally in healthy volunteers, posaconazole delayed-release tablets are absorbed with a median Tmax of 4 to 5 hours. Steady-state plasma concentrations are attained by Day 6 at the 300 mg dose (once daily after twice daily loading dose at Day 1). The absolute bioavailability of the oral delayed-release tablet is approximately 54% under fasted conditions. The Cmax and AUC of posaconazole following administration of posaconazole delayed-release tablets is increased 16% and 51%, respectively, when given with a high fat meal compared to a fasted state (see Table 22).


Table 22: Statistical Comparison of Plasma Pharmacokinetics of Posaconazole Following Single Oral Dose Administration of 300 mg Posaconazole Delayed-Release Tablet to Healthy Subjects under Fasting and Fed Conditions

	Fasting Conditions		Fed Conditions (High Fat Meal)*		Fed/Fasting
Pharmacokinetic Parameter	N	Mean (%CV)	N	Mean (%CV)	GMR (90% CI)
Cmax (ng/mL)	14	935 (34)	16	1060 (25)	1.16 (0.96, 1.41)
AUC0-72hr(hr∙ng/mL)	14	26200 (28)	16	38400 (18)	1.51 (1.33, 1.72)
Tmax† (hr)	14	5.00 (3.00, 8.00)	16	6.00 (5.00, 24.00)	N/A
GMR=Geometric least-squares mean ratio; CI=Confidence interval* 48.5 g fat† Median (Min, Max) reported for Tmax Concomitant administration of posaconazole delayed-release tablets with drugs affecting gastric pH or gastric motility did not demonstrate any significant effects on posaconazole pharmacokinetic exposure (see Table 23). Table 23: The Effect of Concomitant Medications that Affect the Gastric pH and Gastric Motility on the Pharmacokinetics of Posaconazole Delayed-Release Tablets in Healthy Volunteers

Coadministered Drug	Administration Arms	Change in Cmax (ratio estimate*; 90% CI of the ratio estimate)	Change in AUC0-last (ratio estimate*; 90% CI of the ratioestimate)
Mylanta® Ultimate strength liquid (Increase in gastric pH)	25.4 meq/5 mL, 20 mL	↑6%(1.06; 0.90 to 1.26)↑	↑4%(1.04; 0.90 to 1.20)
Ranitidine (Zantac®) (Alteration in gastric pH)	150 mg (morning dose of 150 mg Ranitidine twice daily)	↑4%(1.04; 0.88 to 1.23)↑	↓3%(0.97; 0.84 to 1.12)
Esomeprazole (Nexium®) (Increase in gastric pH)	40 mg (every morning for 5 days, day -4 to 1)	↑2%(1.02; 0.88 to 1.17)↑	↑5%(1.05; 0.89 to 1.24)
Metoclopramide (Reglan®) (Increase in gastric motility)	15 mg four times daily for 2 days (Day -1 and 1)	↓14% (0.86, 0.73,1.02)	↓7%(0.93,0.803,1.07)
* Ratio Estimate is the ratio of coadministered drug plus posaconazole to posaconazole alone for Cmax or AUC0-last.

Distribution:

The mean volume of distribution of posaconazole after intravenous solution administration was 261 L and ranged from 226 to 295 L between studies and dose levels.

Posaconazole is highly bound to human plasma proteins (>98%), predominantly to albumin.

Metabolism:

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

Posaconazole is primarily metabolized via UDP glucuronidation (phase 2 enzymes) and is a substrate for p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. A summary of drugs studied clinically with the oral suspension or an early tablet formulation, which affect posaconazole concentrations, is provided in Table 27.

Table 27: Summary of the Effect of Coadministered Drugs on Posaconazole in Healthy Volunteers

Coadministered Drug (Postulated Mechanism of Interaction)	Coadministered Drug Dose/ Schedule	Posaconazole Dose/Schedule	Effect on Bioavailability of Posaconazole
			Change in Mean Cmax(ratio estimate*; 90% CI of the ratio estimate)	Change in Mean AUC(ratio estimate*; 90% CI of the ratio estimate)
Efavirenz(UDP-g induction)	400 mg once daily × 10 and 20 days	400 mg (oral suspension) twice daily × 10 and 20 days	↓45% (0.55; 0.47 to 0.66)	↓ 50%(0.50; 0.43 to 0.60)
Fosamprenavir (unknown mechanism)	700 mg twice daily x 10 days	200 mg once daily on the 1st day, 200 mg twice daily onthe 2ndday, then 400 mg twice daily x 8 days	↓21%0.79 (0.71 to 0.89)	↓23%0.77 (0.68 to 0.87)
Rifabutin(UDP-g induction)	300 mg once daily x 17 days	200 mg (tablets) once daily × 10 days †	↓43%(0.57; 0.43 to 0.75)	↓49%(0.51; 0.37 to 0.71)
Phenytoin(UDP-g induction)	200 mg once daily x 10 days	200 mg (tablets) once daily × 10 days†	↓ 41%(0.59; 0.44 to 0.79)	↓ 50%(0.50; 0.36 to 0.71)
* Ratio Estimate is the ratio of coadministered drug plus posaconazole to posaconazole alone for Cmax or AUC.† The tablet refers to a non-commercial tablet formulation without polymer.

In vitro studies with human hepatic microsomes and clinical studies indicate that posaconazole is an inhibitor primarily of CYP3A4. A clinical study in healthy volunteers also indicates that posaconazole is a strong CYP3A4 inhibitor as evidenced by a >5-fold increase in midazolam AUC. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole. A summary of the drugs studied clinically, for which plasma concentrations were affected by posaconazole, is provided in Table 28 [see Contraindications (4) and Drug Interactions (7.1) including recommendations].

Table 28: Summary of the Effect of Posaconazole on Coadministered Drugs in Healthy Volunteers and Patients

Coadministered Drug(Postulated Mechanism of Interaction is Inhibition of CYP3A4 by posaconazole)	Coadministered Drug Dose/Schedule	Posaconazole Dose/Schedule	Effect on Bioavailability of Coadministered Drugs
			Change inMean Cmax(ratio estimate*; 90% CI of the ratio estimate)	Change in Mean AUC (ratio estimate*; 90% CI of the ratio estimate)
Sirolimus	2-mg single oral dose	400 mg (oral suspension) twice daily × 16 days	↑ 572%(6.72; 5.62 to 8.03)	↑ 788%(8.88; 7.26 to 10.9)
Cyclosporine	stable maintenance dose in heart transplant recipients	200 mg (tablets) once daily x 10 days†	↑ cyclosporine whole blood trough concentrations. Cyclosporine dose reductions of up to 29% were required
Tacrolimus	0.05-mg/kg single oral dose	400 mg (oral suspension) twice daily × 7 days	↑ 121%(2.21; 2.01 to 2.42)	↑ 358%(4.58; 4.03 to 5.19)
Simvastatin	40-mg single oral dose	100 mg (oral suspension) once daily× 13 days	Simvastatin↑ 841%(9.41, 7.13 to 12.44) Simvastatin Acid↑ 817%(9.17, 7.36 to11.43)	Simvastatin↑ 931%(10.31, 8.40 to 12.67) Simvastatin Acid↑634%(7.34, 5.82 to9.25)
		200 mg (oral suspension)once daily × 13 days	Simvastatin↑ 1,041%(11.41, 7.99 to 16.29) Simvastatin Acid↑851%(9.51, 8.15 to 11.10)	Simvastatin↑ 960%(10.60, 8.63 to 13.02) Simvastatin Acid↑748%(8.48, 7.04 to 10.23)
Midazolam	0.4-mg single intravenous dose‡ 0.4-mg single intravenous dose‡ 2-mg single oral dose‡ 2-mg single oral dose‡	200 mg (oral suspension) twice daily × 7 days 400 mg (oral suspension) twice daily × 7 days 200 mg (oral suspension) once daily × 7 days 400 mg (oral suspension) twice daily × 7 days	↑ 30%(1.3; 1.13 to 1.48) ↑62% (1.62; 1.41 to 1.86) ↑ 169%(2.69; 2.46 to 2.93) ↑ 138%(2.38; 2.13 to 2.66)	↑ 362%(4.62; 4.02 to 5.3) ↑524% (6.24; 5.43 to 7.16) ↑ 470%(5.70; 4.82 to 6.74) ↑ 397%(4.97; 4.46 to 5.54)
Rifabutin	300 mg once daily× 17days	200 mg (tablets) once daily × 10 days†	↑ 31%(1.31; 1.10 to 1.57)	↑ 72%(1.72;1.51 to 1.95)
Phenytoin	200 mg once daily PO × 10 days	200 mg (tablets) once daily × 10 days†	↑ 16%(1.16; 0.85 to 1.57)	↑ 16%(1.16; 0.84 to 1.59)
Ritonavir	100 mg once daily× 14days	400 mg (oral suspension) twice daily × 7 days	↑ 49%(1.49; 1.04 to 2.15)	↑ 80%(1.8;1.39 to 2.31)
Atazanavir	300 mg once daily × 14days	400 mg (oral suspension) twice daily × 7 days	↑ 155%(2.55; 1.89 to 3.45)	↑ 268%(3.68; 2.89 to 4.70)
Atazanavir/ritonavirboosted regimen	300 mg/100 mg once daily x 14 days	400 mg (oral suspension) twice daily × 7 days	↑ 53%(1.53; 1.13 to 2.07)	↑ 146%(2.46; 1.93 to 3.13)
* Ratio Estimate is the ratio of coadministered drug plus posaconazole to coadministered drug alone for Cmax or AUC. †The tablet refers to a non- commercial tablet formulation without polymer. ‡ The mean terminal half- life of midazolam was increased from 3 hours to 7 to 11 hours during coadministration with posaconazole.

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

Excretion:

Following administration of Noxafil oral suspension, posaconazole is predominantly eliminated in the feces (71% of the radiolabeled dose up to 120 hours) with the major component eliminated as parent drug (66% of the radiolabeled dose). Renal clearance is a minor elimination pathway, with 13% of the radiolabeled dose excreted in urine up to 120 hours (<0.2% of the radiolabeled dose is parent drug).Posaconazole delayed-release tablet is eliminated with a mean half-life (t_½) ranging between 26 to 31 hours.

Specific Populations

No clinically significant differences in the pharmacokinetics of posaconazole were observed based on age, sex, renal impairment, and indication.

Race/Ethnicity:

In a population pharmacokinetic analysis of posaconazole, AUC was found to be 25% higher in Chinese patients relative to patients from other races/ethnicities. This higher exposure is not expected to be clinically relevant given the expected variability in posaconazole exposure.

Patients Weighing More Than 120 kg:

Weight has a clinically significant effect on posaconazole clearance. Relative to 70 kg patients, the Cavg is decreased by 25% in patients greater than 120 kg. Patients administered posaconazole delayed-release tablets weighing more than 120 kg may be at higher risk for lower posaconazole plasma concentrations compared to lower weight patients [see Use in Specific Populations (8.10)].

Pediatric Patients

A total of 12 patients 13 to 17 years of age received 600 mg/day (200 mg three times a day) of Noxafil® oral suspension for prophylaxis of invasive fungal infections. Based on pharmacokinetic data in 10 of these pediatric patients, the mean steady-state Cav 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 Noxafil® oral suspension, the exposure target of steady-state posaconazole Cavg between 500 ng/mL and less than 2,500 ng/mL was attained in approximately 50% of patients instead of the pre-specified 90% of patients.

Additional Pediatric Use information is approved for Merck Sharp & Dohme Corp.’s NOXAFIL (posaconazole delayed-release tablets). However, due to Merck Sharp & Dohme Corp.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Mechanism of Action:

Posaconazole blocks the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14α-demethylase responsible for the conversion of lanosterol to ergosterol in the fungal cell membrane. This results in an accumulation of methylated sterol precursors and a depletion of ergosterol within the cell membrane thus weakening the structure and function of the fungal cell membrane. This may be responsible for the antifungal activity of posaconazole.


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

Antimicrobial Activity:
Posaconazole has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1)].


Microorganisms:
Aspergillus spp. and Candida spp.


Susceptibility Testing
For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

Phenytoin induces UDP-glucuronidase and decreases posaconazole plasma concentrations. Phenytoin is also metabolized by CYP3A4. Therefore, coadministration of phenytoin with posaconazole increases phenytoin plasma concentrations [see Clinical Pharmacology (12.3)]. Concomitant use of posaconazole 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 posaconazole and dose reduction of phenytoin should be considered.

structure - structure

Posaconazole is a white to off white powder with a low aqueous solubility. Posaconazole delayed-release tablet is pale yellow to yellow, oval, biconvex, film coated tablets debossed with ‘B100’ on one side and plain on the other side. Each delayed-release tablet contains the inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hydroxy propyl cellulose, hypromellose acetate succinate, magnesium stearate, microcrystalline cellulose, and Opadry^® II yellow (consists of following ingredients: ferrosoferric oxide, iron Oxide yellow, macrogol/PEG 3350, polyvinyl alcohol partially hydrolyzed, talc and titanium Dioxide).

12.1 Mechanism Of Action

Posaconazole is an azole antifungal agent [see Clinical Pharmacology (12.4)].

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

No drug-related neoplasms were recorded in rats or mice treated with posaconazole for 2 years at doses higher than the clinical dose. In a 2-year carcinogenicity study, rats were given posaconazole orally at doses up to 20 mg/kg (females), or 30 mg/kg (males). These doses are equivalent to 3.9- or 3.5-times the exposure achieved with a 400-mg twice daily oral suspension regimen, respectively, based on steady-state AUC in healthy volunteers administered a high-fat meal (400-mg twice daily oral suspension regimen). In the mouse study, mice were treated at oral doses up to 60 mg/kg/day or 4.8-times the exposure achieved with a 400-mg twice daily oral suspension regimen.

Mutagenesis

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

Impairment of Fertility

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

13.2 Animal Toxicology And/Or Pharmacology

In a nonclinical study using intravenous administration of posaconazole in very young dogs (dosed from 2 to 8 weeks of age), an increase in the incidence of brain ventricle enlargement was observed in treated animals as compared with concurrent control animals. No difference in the incidence of brain ventricle enlargement between control and treated animals was observed following the subsequent 5-month treatment-free period. There were no neurologic, behavioral or developmental abnormalities in the dogs with this finding, and a similar brain finding was not seen with oral posaconazole administration to juvenile dogs (4 days to 9 months of age).

There were no drug-related increases in the incidence of brain ventricle enlargement when treated and control animals were compared in a separate study of 10-week old dogs dosed with intravenous posaconazole for 13 weeks with a 9-week recovery period or a follow-up study of 31-week old dogs dosed for 3 months.

14.2 Prophylaxis Of Aspergillus And Candida Infections With Noxafil Oral Suspension

Two randomized, controlled studies were conducted using posaconazole as prophylaxis for the prevention of invasive fungal infections (IFIs) among patients at high risk due to severely compromised immune systems. The first study (Noxafil Oral Suspension Study 1) was a randomized, double-blind trial that compared Noxafil oral suspension (200 mg three times a day) with fluconazole capsules (400 mg once daily) as prophylaxis against invasive fungal infections in allogeneic hematopoietic stem cell transplant (HSCT) recipients with Graft versus Host Disease (GVHD). Efficacy of prophylaxis was evaluated using a composite endpoint of proven/probable IFIs, death, or treatment with systemic antifungal therapy (patients may have met more than one of these criteria). This assessed all patients while on study therapy plus 7 days and at 16 weeks post-randomization. The mean duration of therapy was comparable between the 2 treatment groups (80 days, Noxafil oral suspension; 77 days, fluconazole). Table 32 contains the results from Noxafil Oral Suspension Study 1.

Table 32: Results from Blinded Clinical Study in Prophylaxis of IFI in All Randomized Patients with Hematopoietic Stem Cell Transplant (HSCT) and Graft-vs.-Host Disease (GVHD): Noxafil Oral Suspension Study 1

The second study (Noxafil Oral Suspension Study 2) was a randomized, open-label study that compared Noxafil oral suspension (200 mg 3 times a day) with fluconazole suspension (400 mg once daily) or itraconazole oral solution (200 mg twice a day) as prophylaxis against IFIs in neutropenic patients who were receiving cytotoxic chemotherapy for AML or MDS. As in Noxafil Oral Suspension Study 1, efficacy of prophylaxis was evaluated using a composite endpoint of proven/probable IFIs, death, or treatment with systemic antifungal therapy (Patients might have met more than one of these criteria). This study assessed patients while on treatment plus 7 days and 100 days postrandomization. The mean duration of therapy was comparable between the 2 treatment groups (29 days, posaconazole; 25 days, fluconazole or itraconazole). Table 33 contains the results from Noxafil Oral Suspension Study 2.

Table 33: Results from Open-Label Clinical Study 2 in Prophylaxis of IFI in All Randomized Patients with Hematologic Malignancy and Prolonged Neutropenia: Noxafil Oral Suspension Study 2

In summary, 2 clinical studies of prophylaxis were conducted with the Noxafil oral suspension. As seen in the accompanying tables (Tables 32 and 33), clinical failure represented a composite endpoint of breakthrough IFI, mortality and use of systemic antifungal therapy. In Noxafil Oral Suspension Study 1 (Table 32), the clinical failure rate of posaconazole (33%) was similar to fluconazole (37%), (95% CI for the difference posaconazole–comparator -11.5% to 3.7%) while in Noxafil Oral Suspension Study 2 (Table 33) clinical failure was lower for patients treated with posaconazole (27%) when compared to patients treated with fluconazole or itraconazole (42%), (95% CI for the difference posaconazole–comparator - 22.9% to -7.8%).

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

16.1 How Supplied

Posaconazole delayed-release tablets are available as pale yellow to yellow, oval, biconvex, film coated tablets debossed with ‘B100’ on one side and plain on the other side containing 100 mg of posaconazole. Bottles with child-resistant closures of 60 delayed-release tablets (NDC 70377-038-11).

16.2 Storage And Handling

Store at 20°C to 25°C (68°F to 77°F) with excursions between 15°C and 30°C (59°F and 86°F) permitted [see USP Controlled Room Temperature].

17 Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Important Administration Instructions

Advise patients that Posaconazole delayed-release tablets must be swallowed whole and not divided, crushed, or chewed. Instruct patients that if they miss a dose, they should take it as soon as they remember. If they do not remember until it is within 12 hours of the next dose, they should be instructed to skip the missed dose and go back to the regular schedule. Patients should not double their next dose or take more than the prescribed dose.

Drug Interactions Advise patients to inform their physician immediately if they:

•develop severe diarrhea or vomiting.

•are currently taking drugs that are known to prolong the QTc interval and are metabolized through CYP3A4.

• are currently taking a cyclosporine or tacrolimus, or they notice swelling in an arm or leg or shortness of breath.

• are taking other drugs or before they begin taking other drugs as certain drugs can decrease or increase the plasma concentrations of posaconazole.

Serious and Potentially Serious Adverse ReactionsAdvise patients to inform their physician immediately if they:

•notice a change in heart rate or heart rhythm, or have a heart condition or circulatory disease. Posaconazole can be administered with caution to patients with potentially proarrhythmic conditions.

•are pregnant, plan to become pregnant, or are nursing.

•have liver disease or develop itching, nausea or vomiting, their eyes or skin turn yellow, they feel more tired than usual or feel like they have the flu.

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

Manufactured by:

Biocon Pharma Limited,

Bengaluru, India.

Manufactured for:

Biocon Pharma Inc.

Iselin, New Jersey,USA .

The trademarks referenced herein are owned by their respective companies.

Patient Information

Principal Display Panel - 60 Tablet Bottle Label

NDC 70377-038-11

Posaconazole Delayed-Release Tablets

100 mg

Attention: Noxafil^® Oral Suspension and Posaconazole Delayed-
Release Tablets are NOT interchangeable due to
differences in the dosing of each formulation.

Rx only     60 Tablets

60-tab-label - 60 tab label