POSACONAZOLE tablet, delayed release

United States - English - NLM (National Library of Medicine)

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Active ingredient:
POSACONAZOLE (UNII: 6TK1G07BHZ) (POSACONAZOLE - UNII:6TK1G07BHZ)
Available from:
Lannett Company Inc.
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Posaconazole delayed-release tablets 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. Posaconazole delayed-release tablets 100 mg are indicated in patients 13 years of age and older. Posaconazole is contraindicated in persons with known hypersensitivity to posaconazole or other azole antifungal agents. 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)] . Posaconazole is contraindicated with CYP3A4 substrates that prolong the QT interval. Concomitant administration of posacona
Product summary:
Posaconazole delayed-release tablets are available as yellow, coated, oblong tablets, debossed with “100” on one side containing 100 mg of posaconazole. Bottles with child-resistant closures of 60 delayed-release tablets (NDC 0527-2133-35). Bottles with screw cap closures of 1,000 delayed-release tablets (NDC 0527-2133-43). Cartons of 24 delayed-release tablets (12 units/blister, 2 blisters/carton) (NDC  0527-2133-30). Store at 20° to 25°C (68° to 77°F), excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
Authorization status:
Abbreviated New Drug Application
Authorization number:
0527-2133-30, 0527-2133-35, 0527-2133-43

POSACONAZOLE- posaconazole tablet, delayed release

Lannett Company Inc.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use POSACONAZOLE DELAYED-RELEASE

TABLETS safely and effectively. See full prescribing information for POSACONAZOLE DELAYED-RELEASE

TABLETS.

POSACONAZOLE delayed-release tablets, for oral use

Initial U.S. Approval: 2006

RECENT MAJOR CHANGES

Warnings and Precautions, Electrolyte Disturbances (5.3) 2/2019

INDICATIONS AND USAGE

Posaconazole delayed-release tablets is an azole antifungal agent 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 HSCT recipients with GVHD or those with hematologic

malignancies with prolonged neutropenia from chemotherapy. (1.1)

DOSAGE AND ADMINISTRATION

Posaconazole delayed-release tablets and oral suspension are not interchangeable due to the differences in the dosing of

each formulation.

Indic atio n

Dose and Duration of Therapy

Prophylaxis of

invasive

Aspergillus

and Candida

Infe ctions

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. (2.3)

† Posaconazole delayed-release tablets should be taken with food. (2)

DOSAGE FORMS AND STRENGTHS

Posaconazole delayed-release tablet 100 mg (3)

CONTRAINDICATIONS

Do not administer to persons with known hypersensitivity to posaconazole or other azole antifungal agents. (4.1)

Do not coadminister posaconazole with the following drugs; posaconazole 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)

WARNINGS AND PRECAUTIONS

Calcineurin-Inhibitor Toxicity: Posaconazole increases concentrations of cyclosporine or tacrolimus; reduce dose of

cyclosporine and tacrolimus and monitor concentrations frequently. (5.1)

Arrhythmias and QTc Prolongation: Posaconazole 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. (5.2)

Electrolyte Disturbances: Monitor and correct, especially those involving potassium (K ), magnesium (Mg

), and

Calcium (Ca

) before and during posaconazole therapy. (5.3)

Hepatic Toxicity: Elevations in LFTs may occur. Discontinuation should be considered in patients who develop

abnormal LFTs or monitor LFTs during treatment. (5.4)

Midazolam: Posaconazole can prolong hypnotic/sedative effects. Monitor patients and benzodiazepine receptor

antagonists should be available. (5.6, 7.5)

Vincristine Toxicity: Concomitant administration of azole antifungals, including posaconazole, with vincristine has been

associated with neurotoxicity and other serious adverse reactions; reserve azole antifungals, including posaconazole,

for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options.

(5.7,7.10)

ADVERSE REACTIONS

Common treatment-emergent adverse reactions in studies with posaconazole are diarrhea, nausea, fever, vomiting,

headache, coughing, and hypokalemia. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Lannett Company, Inc. at 1-844-834-0530 or FDA at 1-

800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Interaction Drug

Interaction

Rifabutin, phenytoin, efavirenz, cimetidine

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)

Fosampre navir

Monitor for breakthrough fungal infections (7.6, 7.13)

USE IN SPECIFIC POPULATIONS

Pregnancy: Based on animal data, may cause fetal harm. (8.1)

Severe renal impairment: Monitor closely for breakthrough fungal infections. (8.6)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 6/2020

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

1.1 Prophylaxis of Invasive Aspergillus and Candida Infections

2 DOSAGE AND ADMINISTRATION

2.1 Important Administration Instructions for Posaconazole Delayed-Release Tablets

2.3 Dosage and Administration Instructions for Posaconazole Delayed-Release Tablets

2.5 Non-Interchangeability between posaconazole delayed-release tablets and posaconazole oral

suspension

2.6 Dosage Adjustments in Patients with Renal Impairment

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

4.1 Hypersensitivity

4.2 Use with Sirolimus

4.3 QT Prolongation with Concomitant Use with CYP3A4 Substrates

4.4 HMG-CoA Reductase Inhibitors Primarily Metabolized Through CYP3A4

4.5 Use with Ergot Alkaloids

5 WARNINGS AND PRECAUTIONS

5.1 Calcineurin-Inhibitor Drug Interactions

5.2 Arrhythmias and QT Prolongation

5.3 Electrolyte Disturbances

5.4 Hepatic Toxicity

5.5 Renal Impairment

5.6 Use with Midazolam

5.7 Vincristine Toxicity

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Immunosuppressants Metabolized by CYP3A4

7.2 CYP3A4 Substrates

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

7.4 Ergot Alkaloids

7.5 Benzodiazepines Metabolized by CYP3A4

7.6 Anti-HIV Drugs

7.7 Rifabutin

7.8 Phenytoin

7.9 Gastric Acid Suppressors/Neutralizers

7.10 Vinca Alkaloids

7.11 Calcium Channel Blockers Metabolized by CYP3A4

7.12 Digoxin

7.13 Gastrointestinal Motility Agents

7.14 Glipizide

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

8.8 Gender

8.9 Race

8.10 Weight

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

12.4 Microbiology

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

14.1 Prophylaxis of Aspergillus and Candida Infections with Posaconazole Oral Suspension

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

17.1 Administration

17.2 Drug Interactions

17.3 Serious and Potentially Serious Adverse Reactions

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Prophylaxis of Invasive Aspergillus and Candida Infections

Sections or subsections omitted from the full prescribing information are not listed.

Posaconazole delayed-release tablets 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.

Posaconazole delayed-release tablets 100 mg are indicated in patients 13 years of age and older.

2 DOSAGE AND ADMINISTRATION

2.1 Important Administration Instructions for Posaconazole Delayed-Release Tablets

Posaconazole delayed-release tablets and oral suspension are not to be used interchangeably due to the

differences in the dosing of each formulation [see Dosage and Administration (2.3), (2.5)].

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

Administer with food [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

Patients who have severe diarrhea or vomiting should be monitored closely for breakthrough fungal

infections when receiving posaconazole delayed-release tablets.

2.3 Dosage and Administration Instructions for Posaconazole Delayed-Release Tablets

Dos age:

Table 4: Dosage for Posaconazole Delayed-Release Tablets

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 Posaconazole Delayed-Release Tablets:

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

Administer posaconazole delayed-release tablets with food to enhance the oral absorption of

posaconazole and optimize plasma concentrations [see Clinical Pharmacology (12.3)].

Posaconazole delayed-release tablets should be used only for the prophylaxis indication.

Posaconazole delayed-release tablets generally provide higher plasma drug exposures than

posaconazole oral suspension under both fed and fasted conditions, and therefore is the preferred

oral formulation for the prophylaxis indication.

2.5 Non-Interchangeability between posaconazole delayed-release tablets and posaconazole oral

s us pens ion

Posaconazole delayed-release tablets and oral suspension are not to be used interchangeably due to the

differences in the dosing of each formulation. Therefore, follow the specific dosage recommendations

for each of the formulations [see Dosage and Administration (2.3)].

2.6 Dosage Adjustments in Patients with Renal Impairment

The pharmacokinetics of posaconazole delayed-release tablets is 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 yellow, coated, oblong tablets, debossed with

"100" on one side containing 100 mg of posaconazole.

4 CONTRAINDICATIONS

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)].

5 WARNINGS AND PRECAUTIONS

5.1 Calcineurin-Inhibitor Drug Interactions

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 posaconazole oral suspension 400 mg BID with a high-fat meal. In this pooled

analysis, the mean QTc (Fridericia) interval change from baseline was –5 msec following administration

of the recommended clinical dose. A decrease in the QTc(F) interval (–3 msec) was also observed in a

small number of subjects (n=16) administered placebo. The placebo-adjusted mean maximum QTc(F)

interval change from baseline was <0 msec (–8 msec). No healthy subject administered posaconazole

had a

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

Posaconazole should be administered with caution to patients with potentially proarrhythmic conditions.

Do not administer with drugs that are known to prolong the QTc interval and are metabolized through

CYP3A4 [see Contraindications (4.3) and Drug Interactions (7.2)].

5.3 Electrolyte Disturbances

Electrolyte disturbances, especially those involving potassium, magnesium or calcium levels, should

be monitored and corrected as necessary before and during posaconazole therapy.

5.4 Hepatic Toxicity

Hepatic reactions (e.g., mild to moderate elevations in alanine aminotransferase (ALT), aspartate

aminotransferase (AST), alkaline phosphatase, total bilirubin, and/or clinical hepatitis) have been

reported in clinical trials. The elevations in liver function tests were generally reversible on

discontinuation of therapy, and in some instances these tests normalized without drug interruption. Cases

of more severe hepatic reactions including cholestasis or hepatic failure including deaths have been

reported in patients with serious underlying medical conditions (e.g., hematologic malignancy) during

treatment with posaconazole. These severe hepatic reactions were seen primarily in subjects receiving

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

Liver function tests should be evaluated at the start of and during the course of posaconazole therapy.

Patients who develop abnormal liver function tests during posaconazole therapy should be monitored

for the development of more severe hepatic injury. Patient management should include laboratory

evaluation of hepatic function (particularly liver function tests and bilirubin). Discontinuation of

posaconazole must be considered if clinical signs and symptoms consistent with liver disease develop

that may be attributable to posaconazole.

5.5 Renal Impairment

Due to the variability in exposure with posaconazole delayed-release tablets, patients with severe renal

impairment should be monitored closely for breakthrough fungal infections [see Dosage and

Administration (2.6) and Use in Specific Populations (8.6)].

5.6 Use with Midazolam

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)].

6 ADVERSE REACTIONS

The following serious and otherwise important adverse reactions are discussed in detail in another

section of the labeling:

Hypersensitivity [see Contraindications (4.1)]

Arrhythmias and QT Prolongation [see Warnings and Precautions (5.2)]

Hepatic Toxicity [see Warnings and Precautions (5.4)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed

in clinical trials of posaconazole 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 posaconazole injection and posaconazole delayed-release tablets were generally similar to

that reported in trials of posaconazole oral suspension.

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 (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 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 7 presents treatment-emergent adverse reactions observed in patients treated with

300 mg daily dose at an incidence of ≥10% in posaconazole delayed-release tablet study.

Table 7: Posaconazole Delayed-Release Tablet Study 1: Number (%) of Subjects Treated with

300 mg Daily Dose Reporting Treatment-Emergent Adverse Reactions: Frequency of at Least

10%

Body System

Preferred Term

Posaconazole delayed-

release tablet (300

mg)

(n=210)

Subjects Reporting any Adverse Reaction

(99)

Blood and Lymphatic System Disorder

Anemia

(10)

Thrombocytopenia

(14)

Gastrointestinal Disorders

Abdominal Pain

(11)

Constipation

(10)

Diarrhea

(29)

Nausea

(27)

Vomiting

(13)

General Disorders and Administration Site Conditions

Asthenia

(10)

Chills

(10)

Mucosal Inflammation

(14)

Edema Peripheral

(16)

Pyrexia

(28)

Metabolism and Nutrition Disorders

Hypokalemia

(22)

Hypomagnesemia

(10)

Nervous System Disorders

Headache

(14)

Respiratory, Thoracic and Mediastinal Disorders

Cough

(17)

Epistaxis

(14)

Skin and Subcutaneous Tissue Disorders

Rash

(16)

Vascular Disorders

Hypertension

(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%).

6.2 Postmarketing Experience

The following adverse reaction has been identified during the post-approval use of

posaconazole. Because these reactions are reported voluntarily from a population of uncertain size, it is

not always possible to reliably estimate their frequency.

Endocrine Disorders: Pseudoaldosteronism [see Adverse Reactions (6.2)]

7 DRUG INTERACTIONS

Posaconazole is primarily metabolized via UDP glucuronosyltransferase and is a substrate of p-

glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect

posaconazole plasma concentrations. Coadministration of drugs that can decrease the plasma

concentrations of posaconazole should generally be avoided unless the benefit outweighs the risk. If

such drugs are necessary, patients should be monitored closely for breakthrough fungal infections.

Posaconazole is also a strong inhibitor of CYP3A4. Therefore, plasma concentrations of drugs

predominantly metabolized by CYP3A4 may be increased by posaconazole [see Clinical Pharmacology

(12.3)].

The following information was derived from data with posaconazole oral suspension or early tablet

formulation.

7.1 Immunosuppressants Metabolized by CYP3A4

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

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)].

7.2 CYP3A4 Substrates

Concomitant administration of posaconazole 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, posaconazole is contraindicated with these drugs [see Contraindications

(4.3) and Warnings and Precautions (5.2)].

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

Concomitant administration of posaconazole with simvastatin increases the simvastatin plasma

concentrations by approximately 10-fold. Therefore, posaconazole is contraindicated with HMG-CoA

reductase inhibitors primarily metabolized through CYP3A4 [see Contraindications (4.4) and Clinical

Pharmacology (12.3)].

7.4 Ergot Alkaloids

Most of the ergot alkaloids are substrates of CYP3A4. Posaconazole may increase the plasma

concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism.

Therefore, posaconazole is contraindicated with ergot alkaloids [see Contraindications (4.5)].

7.5 Benzodiazepines Metabolized by CYP3A4

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. Concomitant use of posaconazole 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 [see Warnings and Precautions (5.6) and Clinical

Pharmacology (12.3)].

7.6 Anti-HIV Drugs

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)].

7.7 Rifabutin

Rifabutin induces UDP-glucuronidase and decreases posaconazole plasma concentrations. Rifabutin is

also metabolized by CYP3A4. Therefore, coadministration of rifabutin with posaconazole increases

rifabutin plasma concentrations [see Clinical Pharmacology (12.3)]. Concomitant use of posaconazole

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 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.

7.9 Gastric Acid Suppressors/Neutralizers

No clinically relevant effects on the pharmacokinetics of posaconazole were observed when

posaconazole delayed-release tablets are concomitantly used with antacids, H -receptor antagonists and

proton pump inhibitors [see Clinical Pharmacology (12.3)]. No dosage adjustment of posaconazole

delayed-release tablets is required when posaconazole delayed-release tablets are concomitantly used

with antacids, H -receptor antagonists and proton pump inhibitors.

7.10 Vinca Alkaloids

Most of the vinca alkaloids (e.g., vincristine and vinblastine) are substrates of CYP3A4. Concomitant

administration of azole antifungals, including posaconazole, with vincristine has been associated with

serious adverse reactions [see Warnings and Precautions (5.7)]. Posaconazole may increase the plasma

concentrations of vinca alkaloids which may lead to neurotoxicity and other serious adverse reactions.

Therefore, reserve azole antifungals, including posaconazole, for patients receiving a vinca alkaloid,

including vincristine, who have no alternative antifungal treatment options.

7.11 Calcium Channel Blockers Metabolized by CYP3A4

Posaconazole 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

posaconazole. Therefore, monitoring of digoxin plasma concentrations is recommended during

coadministration.

7.13 Gastrointestinal Motility Agents

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.

7.14 Glipizide

Although no dosage adjustment of glipizide is required, it is recommended to monitor glucose

concentrations when posaconazole and glipizide are concomitantly used.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on findings from animal data, posaconazole l 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

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