NOXAFIL

Posaconazole is a triazole antifungal drug that is used to treat invasive infections by Candida species and Aspergillus species in severely immunocompromised patients.

For prophylaxis of invasive Aspergillus and

Candida infections in patients, 13 years of age and older, who are at high risk of developing these infections due to being severely immunocompromised as a result of procedures such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD), or due to hematologic malignancies with prolonged neutropenia from chemotherapy.

Also for the treatment of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole.

Posaconazole is used as an alternative treatment for invasive aspergillosis, Fusarium infections, and zygomycosis in patients who are intolerant of, or whose disease is refractory to, other antifungals.

Posaconazole is an antifungal agent structurally related to itraconazole.

It is a drug derived from itraconzaole through the replacement of the chlorine substituents with flourine in the phenyl ring, as well as hydroxylation of the triazolone side chain.

These modifications enhance the potency and spectrum of activity of the drug.

Posaconazole can be either fungicial or fungistatic in action.

Posaconazole is absorbed with a median

Tmax of approximately 3-5 hours.

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.

The excreted metabolites in urine and feces account for ~17% of the administered radiolabeled dose.

Posaconazole is eliminated with a mean half-life (t½) of 35 hours (range 20-66 hours).

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During the clinical trials, some patients received posaconazole up to 1600 mg/day with no adverse events noted that were different from the lower doses.

In addition, accidental overdose was noted in one patient who took 1200 mg BID for 3 days.

No related adverse events were noted by the investigator.

Known hypersensitivity to posaconazole or other azole antifungal agents.

Coadministration of posaconazole with the following drugs is contraindicated; posaconazole increases concentrations and toxicities of: Sirolimus CYP3A4 substrates (pimozide, quinidine): can result in QTc interval prolongation and cases of torsades de pointes (TdP) HMG-CoA Reductase Inhibitors Primarily Metabolized through CYP3A4 Ergot alkaloids Venetoclax: In patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) at initiation and during the ramp-up phase 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. 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. 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. 4.5 Use with Ergot Alkaloids Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism. 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.

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.

Therefore, follow the specific dosage recommendations for each of the formulations.

Administer posaconazole delayed-release tablets with or without food.

Table 1: Recommended Dosage in Adult Patients Indication Dosage Form, Dose, and Duration of Therapy Prophylaxis of invasive Aspergillus and Candida infections Delayed-Release Tablets: 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.

For pediatric patients, see the Full Prescribing Information for dosing recommendations for posaconazole delayed-release tablets 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.Therefore, follow the specific dosage recommendations for each of the formulations.

Posaconazole delayed-release tablets

Swallow tablets whole.

Do not divide, crush, or chew.

Administer with or without food.

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, and therefore is the preferred oral formulation for the prophylaxis indication. 2.2 Dosing Regimen in Adult Patients Table 1: Dosing Regimens in Adult Patients Indication D ose and Frequency D uration of Therapy Prophylaxis of invasive Aspergillus and Cand ida infections Load ingdose: 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. Load ingdose: 1 day Maintenance dose: Duration of therapy is based on recovery from neutropenia or immunosuppression. 2.3 Dosing Regimen in Pediatric Patients (ages to less than 18 years of age) The recommended dosing regimen of posaconazole for pediatric patients to less than 18 years of age is shown in Tables 2.

Table 2: Posaconazole Delayed-Release Tablet Dosing Regimens for Pediatric Patients (ages to less than 18 years of age) Rec ommended Pediatric Dosage and Formulation Indication Weight/Age Delayed-Release Tablet D uration of therapy Prophylaxis of invasive A spergillus and Candida infections Less than or equal to 40 kg (2 to less than 18 years of age) Greater than 40 kg (2 to less than 18 years of age) Not Applicable Load ing dose: 300 mg twice daily on the first day Maintenance dose: 300 mg once daily Duration of therapy is based on recovery from neutropenia or immunosuppression. 2.5 Administration Instructions for Posaconazole Delayed-Release Tablets Swallow tablets whole.

Administer posaconazole delayed-release tablets with or without food. 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.

Therefore, follow the specific dosage recommendations for each of the formulations. 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.

Posaconazole delayed-release tablets are available as yellow colored, capsule shaped, textured, biconvex film-coated tablets debossed with 'MP 1' on one side and plain on other side containing 100 mg of posaconazole.

Bottles with child-resistant closures of 60 delayed-release tablets (NDC 72205-168-60). 16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F), excursions permitted to 15° to 30°C (59° to 86°F) .

Based on findings from animal data, posaconazole may cause fetal harm when administered to pregnant women.

Available data for use of posaconazole in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

In animal reproduction studies, skeletal malformations (cranial malformations and missing ribs) and maternal toxicity (reduced food consumption and reduced body weight gain) were observed when posaconazole was dosed orally to pregnant rats during organogenesis at doses ≥1.4 times the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations of posaconazole in healthy volunteers.

In pregnant rabbits dosed orally during organogenesis, increased resorptions, reduced litter size, and reduced body weight gain of females were seen at doses 5 times the exposure achieved with the 400 mg twice daily oral suspension regimen.

Doses of ≥ 3 times the clinical exposure caused an increase in resorptions in these rabbits.

Based on animal data, advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and to 20%, respectively.

Posaconazole resulted in maternal toxicity (reduced food consumption and reduced body weight gain) and skeletal malformations (cranial malformations and missing ribs) when given orally to pregnant rats during organogenesis (Gestational Days 6 through 15) at doses ≥27 mg/kg (≥1.4 times the 400 mg twice daily oral suspension regimen based on steady-state plasma concentrations of drug in healthy volunteers).

The no-effect dose for malformations and maternal toxicity in rats was 9 mg/kg, which is 0.7 times the exposure achieved with the 400 mg twice daily oral suspension regimen.

No malformations were seen in rabbits dosed during organogenesis (Gestational Days 7 through 19) at doses up to 80 mg/kg (5 times the exposure achieved with the 400 mg twice daily oral suspension regimen).

In the rabbit, the no-effect dose was 20 mg/kg, while high doses of 40 mg/kg and 80 mg/kg (3 or 5 times the clinical exposure) 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.

The safety and effectiveness of posaconazole delayed-release tablets for the prophylaxis of invasive Aspergillus and Candida infections have been established in pediatric patients aged and older who are at high risk of developing these infections due to being severely immunocompromised, such as HSCT recipients with GVHD or those with hematologic malignancies with prolonged neutropenia from chemotherapy.

Use of posaconazole in these age groups is supported by evidence from adequate and well-controlled studies of posaconazole in adult and pediatric patients and additional pharmacokinetic and safety data in pediatric patients 2 years of age and older.

The safety and effectiveness of posaconazole have not been established in pediatric patients younger than 2 years of age.

No overall differences in the safety of posaconazole delayed-release tablets were observed between geriatric patients and younger adult patients in the clinical trials; therefore, no dosage adjustment is recommended for any formulation of posaconazole in geriatric patients.

No clinically meaningful differences in the pharmacokinetics of posaconazole were observed in geriatric patients compared to younger adult patients during clinical trials.

Of the 230 patients treated with posaconazole delayed-release tablets, 38 (17%) were greater than 65 years of age.

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.