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Posaconazole

Class: Azoles
Chemical Name: (1) 3H-1,2,4-Triazol-3-one, 4 - [4 - [4 - [4 - [[5 - (2,4 - difluorophenyl)tetrahydro - 5 - (1H - 1,2,4 - triazol - 1 - ylmethyl) - 3 - furanyl]methoxy]phenyl] - 1 - piperazinyl]phenyl] - 2 - (1 - ethyl - 2 - hydroxypropyl) - 2,4 - dihydro - , [3R-[3α(1S*,2S*),5α]]-; (2) 4 - [p - [4 - [p - [[(3R,5R) - 5 - (2,4 - Difluorophenyl)tetrahydro - 5 - (1H - 1,2,4 - triazol - 1 - ylmethyl) - 3 - furyl]methoxy]phenyl] - 1 - piperazinyl]phenyl] - 1 - [(1S,2S) - 1 - ethyl - 2 - hydroxypropyl] - Δ2 - 1,2,4 - triazolin - 5 - one
Molecular Formula: C37H42F2N8O4
CAS Number: CAS-171228-49-2
Brands: Noxafil

Introduction

Antifungal; azole (triazole derivative).1 2 3 4 5 6

Uses for Posaconazole

Prevention of Aspergillus and Candida Infections in Immunocompromised Individuals

Prevention of invasive Aspergillus and Candida infections in severely immunocompromised adults and adolescents ≥13 years of age, including hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host-disease (GVHD) and patients with hematologic malignancies and prolonged chemotherapy-associated neutropenia.1 2 4 5 6 11 16 425

For primary prophylaxis of invasive aspergillosis in immunocompromised individuals at high risk (i.e., neutropenic patients with acute myelogenous leukemia [AML] or myelodysplastic syndrome [MDS], HSCT recipients with GVHD), IDSA considers posaconazole the drug of choice;423 alternatives are itraconazole or micafungin.423

For primary prophylaxis of candidiasis in individuals with chemotherapy-induced neutropenia at risk, IDSA recommends fluconazole, posaconazole, or caspofungin.425

For primary prophylaxis of candidiaisis in HSCT recipients with neutropenia at risk, IDSA recommends fluconazole, posaconazole, or micafungin.425

Oropharyngeal Candidiasis

Treatment of oropharyngeal candidiasis in adults, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole.1 2 5 6 9 10 31 425 436 440

IDSA recommends topical treatment with clotrimazole lozenges or nystatin oral suspension for mild oropharyngeal candidiasis;425 oral fluconazole is recommended for moderate to severe disease.425 For refractory oropharyngeal candidiasis, including fluconazole-refractory infections, itraconazole oral solution, oral posaconazole, or oral voriconazole is recommended.425 An IV echinocandin (caspofungin, micafungin, anidulafungin) or IV amphotericin B also are recommended as alternatives for refractory infections.425

For treatment of oropharyngeal candidiasis in HIV-infected adults and adolescents, CDC, NIH, and IDSA recommend oral fluconazole as the preferred drug of choice for initial episodes;440 other drugs of choice are clotrimazole lozenges or nystatin oral suspension.440 Alternatives for initial episodes are itraconazole oral solution or oral posaconazole.440 For fluconazole-refractory infections in HIV-infected adults and adolescents, itraconazole oral solution or oral posaconazole is preferred;440 alternatives include IV amphotericin B, an IV echinocandin (caspofungin, micafungin, anidulafungin), or oral or IV voriconazole.440

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Although routine long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent relapse or recurrence is not usually recommended in patients adequately treated for oropharyngeal candidiasis, patients with frequent or severe recurrences of oropharyngeal candidiasis (including HIV-infected adults, adolescents, and children) may benefit from secondary prophylaxis with oral fluconazole or itraconazole oral solution; however, consider the potential for azole resistance.425 440 Patients with fluconazole-refractory oropharyngeal candidiasis who responded to treatment with an echinocandin should receive voriconazole or posaconazole for secondary prophylaxis until antiretroviral therapy produces immune reconstitution.440

Esophageal Candidiasis

Treatment of esophageal candidiasis in adults, including esophageal candidiasis refractory to oral itraconazole and/or fluconazole.9 425 436 440

Esophageal candidiasis requires treatment with a systemic antifungal (not a topical antifungal).425 440

IDSA recommends oral fluconazole as the preferred drug of choice for the treatment of esophageal candidiasis;425 if oral therapy is not tolerated, IV fluconazole, IV amphotericin B, or an IV echinocandin (caspofungin, micafungin, anidulafungin) is recommended.425 For fluconazole-refractory infections, preferred alternatives are itraconazole oral solution, oral posaconazole, or IV or oral voriconazole;425 other alternatives are an IV echinocandin (caspofungin, micafungin, anidulafungin) or IV amphotericin B.425

For treatment of esophageal candidiasis in HIV-infected adults and adolescents, CDC, NIH, and IDSA recommend oral or IV fluconazole as the preferred drug of choice and itraconazole oral solution as a preferred alternative.440 Other alternatives include an IV echinocandin (caspofungin, micafungin, anidulafungin), oral or IV voriconazole, oral posaconazole, or IV amphotericin B.440 For refractory esophageal candidiasis including fluconazole-refractory infections,in HIV-infected adults and adolescents, itraconazole oral solution or oral posaconazole is preferred;440 alternatives are IV amphotericin B, an IV echinocandin, or oral or IV voriconazole.440

Although routine long-term suppressive or maintenance therapy (secondary prophylaxis) to prevent relapse or recurrence is not usually recommended in patients adequately treated for esophageal candidiasis, patients with frequent or severe recurrences of esophageal candidiasis (including HIV-infected adults, adolescents, and children) may benefit from secondary prophylaxis with oral fluconazole or oral posaconazole; however, consider the potential for azole resistance.425 440 Patients with fluconazole-refractory esophageal candidiasis who responded to an echinocandin should receive voriconazole or posaconazole for secondary prophylaxis until antiretroviral therapy produces immune reconstitution.440

Aspergillosis

Alternative for treatment of invasive aspergillosis in patients intolerant of, or whose disease is refractory to, other antifungals (e.g., amphotericin B, voriconazole, itraconazole).4 20 21 53 423 436

IDSA considers voriconazole the drug of choice for primary treatment of invasive aspergillosis in most patients and IV amphotericin B the preferred alternative.423 For salvage therapy in patients refractory to or intolerant of primary antifungal therapy, IDSA recommends amphotericin B, caspofungin, micafungin, posaconazole, or itraconazole.423 For empiric or preemptive therapy, IDSA recommends amphotericin B, caspofungin, itraconazole, or voriconazole.423

For treatment of invasive aspergillosis in HIV-infected adults and adolescents, CDC, NIH, and IDSA recommend voriconazole as the drug of choice;440 IV amphotericin B, IV caspofungin, and oral posaconazole are recommended as alternatives.440

Primary prophylaxis against invasive aspergillosis in immunocompromised individuals at high risk.423 (See Prevention of Aspergillus and Candida Infections in Immunocompromised Individuals under Uses.)

Fusarium Infections

Has been used in some patients as salvage therapy for treatment of Fusarium infections.18 19 27 36 37 56 436

Although further study is needed, suggested as an alternative for treatment of Fusarium infections in patients intolerant of, or whose disease is refractory to, other antifungals.4 6 18 19 27

Zygomycosis

Has been used in some patients as salvage therapy for treatment of zygomycosis, including infections caused by Mucor or Rhizopus, in patients intolerant of, or whose disease is refractory to, other antifungals (e.g., amphotericin B).17 25 26 42 45 46 52 55 56

IV amphotericin B usually is considered the drug of first choice for treatment of zygomycosis (with or without surgical intervention).42 45 46 436 Some clinicians suggest oral posaconazole is a possible alternative for treatment of zygomycosis when IV amphotericin B is ineffective or cannot be used42 45 55 and for oral follow-up therapy after an initial response is obtained with IV amphotericin B.42 46 436

Posaconazole Dosage and Administration

Administration

Oral Administration

Administer orally during or immediately (i.e., within 20 minutes) following a full meal or liquid nutritional supplement.1 Alternatively, may be administered with an acidic beverage (e.g., ginger ale).1 (See Food under Pharmacokinetics.)

Consider alternative antifungal in patients unable to consume a full meal or liquid nutritional supplement;1 monitor closely for breakthrough fungal infections if use of posaconazole is considered necessary in such patients.1

Monitor patients with severe diarrhea or vomiting for breakthrough fungal infections since posaconazole plasma concentrations can be affected in such patients.1

Has been administered via nasogastric (NG) tube;1 39 closely monitor such patients for breakthrough fungal infections since systemic exposure may be lower and may be associated with an increased risk of treatment failure.1 39 (See Plasma Concentrations under Pharmacokinetics.)

Avoid concurrent therapy with drugs that can decrease plasma concentrations of posaconazole (e.g., cimetidine, phenytoin, rifabutin) unless benefits outweigh risks;1 monitor closely for breakthrough fungal infections if concurrent use of these drugs is considered necessary.1 (See Interactions.)

Shake suspension container well prior to each dose.1 Administer dose using the calibrated measuring spoon provided by the manufacturer; rinse spoon with water after each dose and before storage.1

Dosage

Pediatric Patients

Prevention of Aspergillus and Candida Infections in Immunocompromised Individuals
Oral

Children ≥13 years of age: 200 mg 3 times daily.1

Duration of prophylaxis based on patient’s recovery from immunosuppression or neutropenia.1 Prophylaxis continued for up to 112 days in clinical studies.11 16

Candida Infections
Treatment of Oropharyngeal Candidiasis
Oral

HIV-infected adolescents: 400 mg twice daily on day 1, followed by 400 mg once daily for 7–14 days.440

HIV-infected adolescents with fluconazole-refractory infections: 400 mg twice daily; a duration of 28 days has been effective in some patients.440

Treatment of Esophageal Candidiasis
Oral

HIV-infected adolescents: 400 mg twice daily for 14–21 days.440

HIV-infected adolescents with fluconazole-refractory infections: 400 mg twice daily; a duration of 28 days has been effective in some patients.440

Prevention of Recurrence (Secondary Prophylaxis) of Esophageal Candidiasis
Oral

HIV-infected adolescents: 400 mg twice daily.440

Secondary prophylaxis not usually recommended; use only if patient has frequent or severe recurrences.440 Consider discontinuing secondary prophylaxis if CD4+ T-cell count increases to ≥200/mm3 in response to antiretroviral therapy.440

Aspergillosis
Oral

Invasive aspergillosis in HIV-infected adolescents: 400 mg twice daily.440 Optimal duration not established; continue at least until CD4+ T-cell count increases to 200/mm3 as a result of potent antiretroviral therapy and there is evidence of clinical response.440

Adults

Prevention of Aspergillosis and Candida Infections in Immunocompromised Individuals
Oral

200 mg 3 times daily.1 423

Duration of prophylaxis based on patient’s recovery from immunosuppression or neutropenia.1 Prophylaxis continued for up to 112 days in clinical studies.11 16

Candida Infections
Treatment of Oropharyngeal Candidiasis
Oral

Manufacturer recommends 100 mg twice daily on day 1, followed by 100 mg once daily for 13 days.1 For infections refractory to itraconazole and/or fluconazole, manufacturer recommends 400 mg twice daily and states that the duration depends on clinical response and severity of underlying disease.1

For fluconazole-refractory infections, IDSA recommends 400 mg twice daily for 3 days, followed by 400 mg once daily for up to 28 days.425

HIV-infected adults: 400 mg twice daily on day 1, followed by 400 mg once daily for 7–14 days.440 For fluconazole-refractory infections, use 400 mg twice daily; a duration of 28 days has been effective in some patients.440

Treatment of Esophageal Candidiasis
Oral

Fluconazole-refractory infections: IDSA recommends 400 mg twice daily for 14–21 days.425

HIV-infected adults: 400 mg twice daily for 14–21 days.440 For fluconazole-refractory infections, use 400 mg twice daily; a duration of 28 days has been effective in some patients.440

Prevention of Recurrence (Secondary Prophylaxis) of Oropharyngeal Candidiasis
Oral

HIV-infected adults: 400 mg twice daily.440

Secondary prophylaxis not usually recommended; use only if patient has frequent or severe recurrences.440 Consider discontinuing secondary prophylaxis if CD4+ T-cell count increases to ≥200/mm3 in response to antiretroviral therapy.440

Aspergillosis
Oral

Salvage therapy: IDSA recommends 200 mg 4 times daily until disease stabilizes, followed by 400 mg twice daily thereafter.423 For salvage therapy in a clinical trial, 400 mg twice daily or 200 mg 4 times daily has been given for up to approximately 12 months.20

Invasive aspergillosis in HIV-infected adults: 400 mg twice daily.440 Optimal duration not established; continue at least until CD4+ T-cell count increases to 200/mm3 as a result of potent antiretroviral therapy and there is evidence of clinical response.440

Fusarium Infections
Oral

400 mg twice daily or 200 mg 4 times daily for up to 12 months or longer has been used for salvage therapy when other antifungals were ineffective or could not be used.18 27

Zygomycosis
Oral

400 mg twice daily or 200 mg 4 times daily has been used for salvage therapy when other antifungals were ineffective or could not be used.17 26

200 mg 3–4 times daily has been used for follow-up therapy in patients after an initial response was obtained with IV amphotericin B.42 436

Special Populations

Hepatic Impairment

Dosage adjustment not necessary in patients with hepatic impairment (Child-Pugh class A, B, or C).1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Dosage adjustment not necessary in patients with mild or moderate renal impairment.1 Monitor patients with severe renal impairment closely for breakthrough fungal infections since posaconazole AUCs are highly variable in these patients.1 (See Absorption: Special Populations under Pharmacokinetics.)

Not dialyzable;1 may administer without regard to timing of hemodialysis.4 6 31

Geriatric Patients

Dosage adjustments not necessary in adults ≥65 years of age based on age.1

Cautions for Posaconazole

Contraindications

  • Known hypersensitivity to posaconazole or any ingredient in the formulation.1

  • Concomitant use with sirolimus.1 (See Specific Drugs under Interactions.)

  • Concomitant use with ergot alkaloids (ergotamine, dihydroergotamine).1 (See Specific Drugs under Interactions.)

  • Concomitant use with drugs that are CYP3A4 substrates and for which elevated plasma concentrations may be associated with prolonged QT interval corrected for rate (QTc) and rare occurrences of torsades de pointes (e.g., terfenadine or astemizole [drugs no longer commercially available in the US], cisapride [currently commercially available in the US only under a limited-access protocol], pimozide, halofantrine [not commercially available in the US], quinidine).1 (See Drugs that Prolong QT Interval under Interactions.)

Warnings/Precautions

Warnings

Hepatic Effects

Serious hepatic effects, including cholestasis or hepatic failure (sometimes fatal), reported rarely in patients with serious underlying medical conditions (e.g., hematologic malignancy).1 Hepatic effects generally occurred in those receiving posaconazole dosage of 800 mg daily (400 mg twice daily or 200 mg 4 times daily).1

Less severe hepatic effects, including mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin, and/or clinical hepatitis, may occur.1 Elevated liver function tests were generally reversible after discontinuing posaconazole treatment, and in some cases test results returned to normal levels without interrupting therapy; posaconazole discontinuance rarely required.1 Elevated liver function tests not associated with increased plasma posaconazole concentrations.1

Monitor liver function (e.g., liver function tests, bilirubin) prior to and during posaconazole therapy.1 If abnormal liver function tests occur during therapy, monitor for development of more severe hepatic injury using appropriate laboratory tests.1 Consider discontinuing posaconazole if clinical signs and symptoms of liver disease occur.1

Sensitivity Reactions

Hypersensitivity Reactions

Allergic and hypersensitivity reactions reported rarely.1

Cross-hypersensitivity

Data regarding cross-sensitivity with other azole antifungals not available.1 Use with caution in patients hypersensitive to other azoles.1

General Precautions

Cardiovascular Effects

Prolonged QT interval reported with posaconazole and some other azoles (e.g., fluconazole, voriconazole).1 9 29 30 38 One case involved a seriously ill patient with multiple confounding risk factors that may have contributed (e.g., prior cardiotoxic chemotherapy, hypokalemia, concomitant drugs).1 5 11

Use with caution in patients with potentially proarrhythmic conditions.1 Do not use concomitantly with drugs metabolized by CYP3A4 that are known to prolong the QTc interval.1 (See Drugs that Prolong the QT Interval under Interactions.)

Rigorous attempts should be made to correct potassium, magnesium, and calcium imbalances before starting posaconazole.1

Specific Populations

Pregnancy

Category C.1

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Do not use in nursing women unless potential benefits outweigh risks to the infant.1

Pediatric Use

Safety and efficacy not established in children <13 years of age.1

CDC, NIH, and IDSA state that data are insufficient to date to make recommendations regarding use in HIV-infected infants and children.441

Has been used in a limited number of children ≥7 years of age without unusual adverse effects.17

Data from a limited number of pediatric patients 13–17 years of age who received oral posaconazole (200 mg 3 times daily) for prophylaxis of invasive fungal infections indicate a safety profile similar to that in adults.1

Comparison of pharmacokinetic data from a limited number of pediatric patients 8–17 years of age who received oral posaconazole (400 mg 2 times or 200 mg 4 times daily) for treatment of invasive fungal infections with pharmacokinetic data from adults indicates that mean steady-state plasma posaconazole concentrations in pediatric patients and adults are similar.1 31

Geriatric Use

Safety profile similar to that in younger adults.1 38

Hepatic Impairment

Careful monitoring recommended.1 Possible adverse hepatic effects.1 (See Hepatic Effects under Cautions.)

Although posaconazole pharmacokinetics are altered in individuals with hepatic impairment (see Absorption: Special Populations and also see Elimination under Pharmacokinetics),1 41 the manufacturer states that dosage adjustments are not considered necessary.1 (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Monitor patients with severe renal impairment closely for breakthrough fungal infections since posaconazole AUCs are highly variable in these patients.1

Common Adverse Effects

GI effects (nausea,1 2 5 8 9 10 vomiting,1 2 5 8 9 10 diarrhea,1 2 8 9 10 abdominal pain,1 2 5 8 9 10 anorexia,1 9 constipation,1 dry mouth,38 dyspepsia,1 flatulence1 5 9 ), fever,1 10 headache,1 2 5 8 9 10 38 increased sweating,1 rigors,1 dizziness,1 5 9 10 38 fatigue,1 8 9 edema (legs),1 asthenia,1 9 weakness,1 9 hypertension,1 hypotension,1 11 anxiety,1 vaginal hemorrhage,1 mucositis,1 tachycardia,1 bacteremia,1 pneumonia,1 herpes simplex,1 cytomegalovirus infection,1 pharyngitis,1 musculoskeletal pain,1 arthralgia,1 back pain,1 petechiae,1 insomnia,1 9 coughing,1 9 dyspnea,1 epistaxis,1 rash,1 2 8 9 10 pruritus.1 9 Also, anemia,1 neutropenia,1 5 9 11 febrile neutropenia,1 thrombocytopenia,1 9 hypocalcemia,1 hypokalemia,1 hypomagnesemia,1 hyperglycemia,1 increased AST,1 2 8 increased ALT,1 2 8 increased γ-glutamyltransferase (GGT, γ-glutamyl transpeptidase, GGPT),1 increased alkaline phosphatase,1 9 bilirubinemia.1 11

Interactions for Posaconazole

Inhibits CYP3A4.1 2 5

Principally metabolized via uridine diphosphate (UDP)-glucuronosyltransferase glucuronidation (UGT; phase 2 enzymes) and is a substrate of P-glycoprotein transport system.1 2

Drugs Metabolized by Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction with drugs metabolized by CYP3A4 (increased plasma concentrations of CYP3A4 substrates).1 2 5 56

Does not appear to inhibit CYP isoenzymes 1A2, 2C8/9, 2D6, or 2E1.62

Drugs that Prolong QT Interval

Risk of prolonged QT interval and torsades de pointes with CYP3A4 substrates that prolong the QTc.1 Concomitant use contraindicated.1 37 (See Contraindications under Cautions.)

Drugs Affecting or Affected by P-glycoprotein Transport

Substrate of the P-glycoprotein transport system.1 Potential pharmacokinetic interaction with drugs that are inhibitors or inducers of P-glycoprotein with possible increase or decrease in plasma posaconazole concentrations, respectively.1

Drugs Affecting Uridine Diphosphate-glucuronosyltransferase

Pharmacokinetic interactions likely with drugs that are inhibitors or inducers of uridine diphosphate-glucuronosyltransferase UDP glucuronidation (UGT; phase 2 enzymes) with possible increase or decrease in plasma posaconazole concentrations, respectively.1 5

Specific Drugs

Drug

Interaction

Comments

Amphotericin B

In vitro evidence of synergism against Aspergillus hyphae and indifference against Aspergillus conidia14

In vitro evidence of indifference against Rhizopus oryzae; no evidence of synergism or antagonism66

Clinical importance unclear14

Antacids

No clinically important pharmacokinetic interactions1 60

Dosage adjustments not needed1

Anticonvulsants (phenytoin)

Decreased posaconazole peak plasma concentrations and AUC; increased phenytoin peak plasma concentration and AUC1 24 40

Concomitant use not recommended unless benefits outweigh risks1 24 40 56

If used concomitantly, closely monitor phenytoin concentrations, consider reducing phenytoin dosage1 40

Antihistamines (astemizole, terfenadine)

Possible pharmacokinetic interaction and potential for serious or life-threatening reactions (e.g., prolonged QT interval, torsades de pointes) with astemizole or terfenadine (drugs no longer commercially available in the US)1

Concomitant use contraindicated1

Antimycobacterial agents (rifabutin)

Rifabutin: Decreased posaconazole peak plasma concentrations and AUC; increased rifabutin peak plasma concentrations and AUC;1 23 40 possible increased risk of rifabutin-associated adverse effects (e.g., uveitis, leukopenia)23

Rifabutin: Avoid concomitant use unless benefits outweigh risks;1 2 23 40 if used concomitantly, frequently monitor for rifabutin associated adverse effects (e.g., uveitis, leukopenia)1 23 40

Antiretrovirals, HIV protease inhibitors (PIs)

Atazanavir (with or without ritonavir): Increased atazanavir peak plasma concentrations and AUC1 44 431

Indinavir: No clinically important pharmacokinetic interactions1

Ritonavir (low dose): Increased ritonavir peak plasma concentration and AUC1

Atazanavir (with or without ritonavir): If used concomitantly, monitor frequently for atazanavir adverse effects and toxicity1 44 431

Indinavir: Dosage adjustment not needed when administered with posaconazole 200 mg daily1

Ritonavir: Dosage adjustment not needed when administered with posaconazole 200 mg daily;1 monitor frequently for ritonavir adverse effects and toxicity1

Antiretrovirals, nonnucleoside reverse transcriptase inhibitors (NNRTIs)

Efavirenz: Decreased posaconazole peak plasma concentrations and AUC1 44 431

Etravirine: Possible increased etravirine plasma concentrations;63 431 no change in posaconazole concentrations63

Efavirenz: Avoid concomitant use unless benefits outweigh risks;1 44 431 if concomitant use is necessary, consider monitoring plasma posaconazole concentrations431

Etravirine: Some clinicians state dosage adjustment not needed;431 manufacturer of etravirine states that dosage adjustment of posaconazole may be needed depending on other concomitantly administered drugs63

Antiretrovirals, nucleoside reverse transcriptase inhibitors (NRTIs)

Lamivudine: No clinically important pharmacokinetic interactions1

Zidovudine: No clinically important pharmacokinetic interactions1

Lamivudine: Dosage adjustment not needed when administered with posaconazole 200 mg daily1

Zidovudine: Dosage adjustment not needed when administered with posaconazole 200 mg daily1

Benzodiazepines (midazolam)

Midazolam: Increased peak plasma concentrations, AUC, and mean terminal half-life of midazolam1 37 40 49

Other benzodiazepines: Increased plasma concentrations of benzodiazepines metabolized by CYP3A4 1 5 49

Monitor frequently for benzodiazepine toxicity; consider reducing benzodiazepine dosage1 40 49

Caffeine

No clinically important pharmacokinetic interactions1

Dosage adjustment not needed when administered with posaconazole 200 mg daily1

Calcium-channel blocking agents

Possible increased concentrations of calcium-channel blockers metabolized by CYP3A41

Monitor for toxicity; dosage adjustment of the calcium-channel blocker may be necessary1

Cisapride (currently commercially available in US only under a limited access protocol)

Possible pharmacokinetic interaction and potential for serious or life-threatening reactions (e.g., prolonged QT interval, torsades de pointes) 1

Concomitant use contraindicated1

Digoxin

Increased digoxin plasma concentrations1

If used concomitantly, monitor digoxin plasma concentrations1

Ergot alkaloids (ergotamine, dihydroergotamine)

Possible pharmacokinetic interaction (increased plasma concentrations of ergot alkaloids resulting in ergotism)1

Concomitant use contraindicated1

Glipizide

No clinically important pharmacokinetic interactions; hypoglycemia reported1

Dosage adjustments not needed; monitor blood glucose concentrations according to current recommendations for patients with diabetes1

Halofantrine (not commercially available in US)

Possible pharmacokinetic interaction and potential for serious or life-threatening reactions (e.g., prolonged QT interval, torsades de pointes) 1

Concomitant use contraindicated1

Histamine H2-receptor antagonists (cimetidine)

Cimetidine: Decreased posaconazole peak plasma concentrations and AUC1 2 4 5 40

No pharmacokinetic interactions reported with other histamine H2-receptor antagonists 1

Cimetidine: Avoid concomitant use unless benefits outweigh risks1 40

HMG-CoA reductase inhibitors (statins)

Possible increased plasma concentrations of HMG-CoA reductase inhibitors metabolized by CYP3A41

Monitor for manifestations of toxicity (e.g., rhabdomyolysis) and reduce dosage of HMG-CoA reductase inhibitor as necessary1

Immunosuppressive agents (cyclosporine, sirolimus, tacrolimus)

Cyclosporine: Increased cyclosporine concentrations; serious adverse effects (e.g., nephrotoxicity, leukoencephalopathy, death) reported in heart transplant patients1 22

Sirolimus: Increased sirolimus peak plasma concentrations and AUC1

Tacrolimus: Increased tacrolimus peak concentrations and AUC1 22 40

Cyclosporine: Decrease cyclosporine dosage by 25% if initiating posaconazole;1 5 56 monitor cyclosporine trough concentrations during and after discontinuing posaconazole and adjust cyclosporine dosage as needed1 2 4 5 22 37

Sirolimus: Concomitant use contraindicated1

Tacrolimus: Decrease tacrolimus dosage by 66% if initiating posaconazole;1 monitor tacrolimus trough concentrations during and after discontinuing posaconazole and adjust tacrolimus dose as needed1 2 4 22 40

Loperamide

No clinically important pharmacokinetic interactions1

Dosage adjustments not needed1

Metoclopramide

Decreased posaconazole mean peak plasma concentrations and AUC1

Monitor closely for breakthrough fungal infections1

Pimozide

Possible pharmacokinetic interaction and potential for serious or life-threatening reactions (e.g., prolonged QT interval, torsades de pointes) 1

Concomitant use contraindicated1

Proton-pump inhibitors (esomeprazole, omeprazole)

Esomeprazole: Decreased posaconazole mean peak plasma concentrations and AUC1

Omeprazole: Decreased posaconazole trough concentrations50

Esomeprazole: Monitor closely for breakthrough fungal infections1

Omeprazole: Monitor plasma posaconazole concentrations or consider switching to an another antifungal50 56

Quinidine

Possible pharmacokinetic interaction and potential for serious or life-threatening reactions (e.g., prolonged QT interval, torsades de pointes) 1

Concomitant use contraindicated1

Vinca alkaloids

Possible increased plasma concentrations of vinca alkaloids (e.g., vincristine, vinblastine)1 37

Monitor for manifestations of vinca alkaloid toxicity (neurotoxicity) and adjust dosage as necessary1 37 56

Posaconazole Pharmacokinetics

Absorption

Displays dose-proportional increases in AUC when administered orally over a dosage range of 50 mg twice daily to 400 mg twice daily.1 In febrile neutropenic patients or those with refractory invasive fungal infections, no further increases in exposure occur if dosage is increased from 400 mg twice daily to 600 mg twice daily.1

Plasma Concentrations

Median time to peak plasma concentrations following oral administration is approximately 3–8 hours.1 15 61 71 72 73

Steady-state concentrations achieved following 7–10 days of twice-daily oral posaconazole.1

In a crossover study in healthy adults who received a single 400-mg dose of posaconazole oral suspension orally or via an NG tube after a liquid nutritional supplement (Boost Plus), the mean time to peak plasma concentrations of posaconazole was similar (4 hours) but mean peak plasma concentrations and AUC were 19 and 23% lower, respectively, when the dose was administered using an NG tube.1 39 In some patients, posaconazole peak plasma concentrations and AUC were reduced substantially (up to approximately 50%) when the drug was administered via an NG tube compared to when it was administered orally.1 39 (See Oral Administration under Dosage and Administration.)

Food

Food or a liquid nutritional supplement increases posaconazole plasma concentrations and AUC.1 15 60 71

Following oral administration of a single 200-mg dose of posaconazole oral suspension with a nonfat or high-fat meal (approximately 50 g of fat), both the mean AUC and peak plasma posaconazole concentrations were approximately threefold or fourfold higher, respectively, compared with those observed following administration in the fasted state.1 61

In a crossover study in healthy adults who received a single 400-mg dose of posaconazole oral suspension during or 20 minutes following a high-fat meal, mean peak plasma posaconazole concentrations and AUC were approximately threefold or fourfold higher, respectively, compared with those observed following administration in the fasted state.1 When the dose was administered 5 minutes prior to the high-fat meal, mean peak plasma posaconazole concentrations and AUC were similar to those observed when the drug is administered in the fasted state.1

Following oral administration of a single 400-mg dose of posaconazole with 240 mL of liquid nutritional supplement (Boost Plus; 360 calories, 14 g fat), mean peak plasma concentration and AUC were both approximately threefold higher than following administration in the fasted state.1 15 71 Bioavailability of posaconazole is lower if the posaconazole dose is administered with < 240 mL of the nutritional supplement;71 posaconazole bioavailability is about 20% lower if only 120 mL of the liquid nutritional supplement is used instead of 240 mL.71

Following oral administration of a single 400-mg dose of posaconazole with an acidic beverage (i.e., ginger ale) in healthy adults in the fasted state, mean peak plasma concentrations and AUC of posaconazole were increased by 92 and 70%, respectively, compared with those reported following administration of posaconazole alone in the fasted state.1

Special Populations

Data from a limited number of pediatric patients 13–17 years of age receiving oral posaconazole (200 mg 3 times daily) for prophylaxis of invasive fungal infections indicate that mean steady-state plasma posaconazole concentrations in this age group are similar to those reported in adults.1

Comparison of data from a limited number of pediatric patients 8–17 years of age who received oral posaconazole (400 mg 2 times or 200 mg 4 times daily) for treatment of invasive fungal infections with data from adults indicates that mean steady-state plasma posaconazole concentrations in pediatric patients and adults are similar.1 48 51

Compared with individuals with normal hepatic function, the mean AUC of posaconazole following a single 400-mg oral dose given after a high-fat meal in those with mild, moderate, or severe hepatic impairment was 43, 27, or 21% higher, respectively, and the mean peak plasma concentration was 1% higher, 40% higher, or 34% lower, respectively.1 41

Pharmacokinetics in individuals with mild or moderate renal impairment (Clcr 20–80 mL/minute per 1.73 m2) is similar to that reported in individuals with normal renal function.1 In individuals with severe renal insufficiency (Clcr <20 mL/minute per 1.73 m2), mean AUC is similar to that reported in individuals with normal renal function; however, the range of AUC estimates is highly variable compared with that in those with mild or moderate renal impairment.1

Distribution

Extent

Extensive extravascular distribution and penetration into body tissues is expected.1 Detected in skin72 and in pulmonary epithelial lining fluid and alveolar cell tissue following oral administration of posaconazole oral suspension.73

Distributed into milk in rats; not known whether distributed into milk in humans.1

Plasma Protein Binding

>98% (primarily albumin).1

Elimination

Metabolism

Principally metabolized via uridine diphosphate (UDP)-glucuronosyltransferase glucuronidation (UGT; phase 2 enzymes).1 2 40 51 Posaconazole circulates in plasma principally as the parent drug; the majority of circulating metabolites are glucuronide conjugates formed via UDP glucuronidation.1

No major circulating metabolites formed via CYP isoenzymes.1

Elimination Route

71% of a dose recovered in feces as parent drug over 120 hours;1 2 4 5 13% of a dose recovered in urine over 120 hours (<0.2% as parent drug).1 2 5 6 Metabolites recovered in urine and feces represent approximately 17% of a dose.1

Half-life

35 hours (range: 20–66 hours).1 15 39 61

Special Populations

Mean oral clearance decreased 18, 36, or 28% in individuals with mild, moderate, or severe hepatic impairment, respectively.1 Elimination half-life is 39, 27, or 43 hours in those with mild, moderate, or severe hepatic impairment, respectively.1

Stability

Storage

Oral

Suspension

25°C (may be exposed to 15–30°C); do not freeze.1

Actions and Spectrum

  • Triazole-derivative azole antifungal, structurally similar to itraconazole.1 2 3 4 5 6 51

  • Fungicidal or fungistatic in action.2 4 56

  • Exerts its antifungal activity by inhibiting the cytochrome P-450 dependent enzyme sterol 14-α-demethylase in fungi, thus inhibiting an essential step in fungal ergosterol biosynthesis.1 2 4 5 6

  • Candida: Active in vitro against C. albicans,1 68 C. dubliniensis,67 68 C. fumata,67 C. glabrata,68 C. guilliermondii,67 68 C. kefyr,67 C. krusei,68 C. lipolytica,67 C. lusitaniae,67 68 C. metapsilosis,67 C. orthopsilosis,67 C. parapsilosis,68 C. pelliculosa,67 C. rugosa,67 and C. tropicalis.68 Active in vitro against some fluconazole-resistant Candida1 4 54 68 and has been active against some strains obtained from patients with infections refractory to fluconazole and/or itraconazole therapy.1 9 51

  • Aspergillus: Active in vitro against A. fumigatus,1 14 66 68 A. flavus,14 66 68 A. niger,14 66 68 and A. terreus.14 66 68

  • Other fungi: Active in vitro against Blastomyces,68 Coccidioides,68 Cryptococcus neoformans,2 3 4 51 65 C. gattii,65 Histoplasma capsulatum,2 4 and some strains of Fusarium oxysporum and F. moniliforme.68 Some zygomycetes, including some strains of Rhizopus,46 64 66 68 69 Mucor,68 69 Absidia,68 69 Cunninghamella,68 69 and Apophysomyces68 69 are inhibited in vitro by posaconazole.

  • C. albicans and C. glabrata with decreased susceptibility to posaconazole have been reported.1 2 4 68

  • Posaconazole-resistant fungi may be cross-resistant to other azole antifungals (e.g., fluconazole, itraconazole).1 2 4

Advice to Patients

  • Importance of taking the drug exactly as prescribed, including taking each dose during or immediately (i.e., within 20 minutes) following a full meal or liquid nutritional supplement to ensure adequate GI absorption of the drug.1 7 Alternatively, may be taken with an acidic carbonated beverage (e.g., ginger ale).1 Advise patients to inform clinicians if they are unable to eat full meals or drink nutritional supplements.7

  • Importance of informing clinicians if severe diarrhea or vomiting develops during treatment.1 7

  • Importance of informing clinicians of a history of allergic reactions to other antifungals (e.g., fluconazole, itraconazole, ketoconazole, voriconazole).1 7

  • Importance of informing clinicians if any of the following symptoms develop during posaconazole therapy: Changes in heart rate or rhythm, itching, yellowing of skin or eyes, extreme fatigue or flu-like symptoms, nausea, swelling of one leg, or shortness of breath.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, and any concomitant illnesses (e.g., liver disease, heart disease).1 7

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 7 Importance of using contraceptive measures during posaconazole therapy.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Posaconazole

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Suspension

40 mg/mL

Noxafil (available with calibrated measuring spoon)

Schering

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions December 1, 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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