Posaconazole

Pronunciation: (POE-sa-KON-a-zole)
Class: Antifungal

Trade Names

Noxafil
- Suspension, oral 40 mg/mL

Spriafil (Canada)

Pharmacology

Blocks the synthesis of ergosterol, a key component of fungal cell membranes.

Pharmacokinetics

Absorption

T _max is approximately 3 to 5 h. Steady-state plasma concentrations are reached in 7 to 10 days. Food increases the mean AUC and C _max 3 to 4 times.

Distribution

Vd is 1,774 L. More than 98% protein bound, primarily to albumin.

Metabolism

Metabolism mainly involves glucuronide conjugation via uridine diphosphate glucuronidation.

Elimination

Elimination is approximately 71% in feces and 13% in urine in up to 120 h. The mean half-life is 35 h.

Special Populations

Renal Function Impairment

No significant effect of mild (CrCl 50 to 80 mL/min per 1.73 m ² ) and moderate (CrCl 20 to 49 mL/min per 1.73 m ² ) renal impairment. In severe renal impairment (CrCl less than 20 mL/min per 1.73 m ² ), AUC range estimates are highly variable.

Hepatic Function Impairment

In patients with mild, moderate, or severe hepatic insufficiency, C _max is 1% higher, 40% higher, and 34% lower; AUC is 43%, 27%, and 21% higher; and elimination half-life is 18%, 36%, and 28% lower, respectively.

Elderly

Pharmacokinetics are comparable in younger and elderly (65 y and older) patients.

Children

Pharmacokinetics similar between pediatric patients 8 to 17 y of age and adults.

Indications and Usage

Prophylaxis of invasive Aspergillus and Candida infections in patients 13 y and older who are at high risk of developing these infections because of being severely immunocompromised; treatment of oropharyngeal candidiasis refractory to itraconazole and/or fluconazole.

Contraindications

Coadministration of ergot derivatives, sirolimus, or simvastatin; coadministration with CYP3A4 substrates (eg, pimozide, quinidine); hypersensitivity to any component of the product or other azole antifungal agents.

Dosage and Administration

Prophylaxis of Invasive Fungal Infections
Adults and Children 13 y and older

PO 200 mg (5 mL) 3 times daily. The duration is based on recovery from neutropenia or immunosuppression.

Oropharyngeal Candidiasis
Adults and Children 13 y and older

PO Start with a loading dose of 100 mg (2.5 mL) twice daily on the first day, then 100 mg (2.5 mL) once daily for 13 days.

Oropharyngeal Candidiasis Refractory to Itraconazole and/or Fluconazole
Adults and Children 13 y and older

PO 400 mg (10 mL) twice daily. Duration based on severity of the underlying disease and clinical response.

General Advice

• Shake well before administering dose.
• Administer with a full meal (during or within 20 min), a liquid nutritional supplement, or an acidic carbonated beverage (eg, ginger ale).

Storage/Stability

Store between 59° and 86°F. Do not freeze.

Drug Interactions

Aripiprazole, iloperidone

Plasma concentrations and pharmacologic effects of these agents may be increased. The dose of these agents should be reduced by one-half when coadministered with posaconazole. If therapy with posaconazole is discontinued, the dose of these agents should be increased to the original dose.

Atazanavir, ritonavir

Atazanavir and ritonavir plasma concentrations may be increased. Closely monitor for adverse reactions and toxicity. Adjust the atazanavir and ritonavir dose as needed.

Benzodiazepines metabolized by CYP3A4 (eg, alprazolam, midazolam, triazolam)

Coadministration resulted in a 5-fold increase in midazolam plasma concentrations. Perform frequent monitoring for adverse reactions and consider dose reduction of these benzodiazepines during coadministration. A benzodiazepine receptor antagonist must be available to reverse these adverse effects.

Calcium channel blockers metabolized through CYP3A4 (eg, felodipine, nifedipine, nisoldipine)

Posaconazole may elevate plasma levels of these agents, increasing the risk of toxicity. Dose reduction of the calcium channel blocker may be needed.

Cimetidine, efavirenz, esomeprazole, phenytoin, rifabutin

Posaconazole plasma levels may be decreased; if possible, avoid coadministration.

Colchicine

Colchicine plasma concentrations may be increased. Life-threatening and fatal colchicine toxicity may occur. A colchicine dosing adjustment is required for patients also receiving posaconazole. Coadministration is contraindicated in patients with renal or hepatic impairment.

Cyclosporine, sirolimus, tacrolimus

Plasma levels of these drugs may be elevated by posaconazole, increasing the risk of serious adverse reactions, including nephrotoxicity. Reduce the dose of cyclosporine and tacrolimus by three-fourths and one-third of the original dose, respectively. Perform frequent clinical monitoring of cyclosporine and tacrolimus whole blood concentrations when posaconazole therapy is initiated and discontinued. Concurrent use of posaconazole and sirolimus is contraindicated.

CYP3A4 substrates (alpha-1 adrenergic blockers [eg, alfuzosin, silodosin, tamsulosin], buspirone, ciclesonide, cinacalcet, cisapride, conivaptan, cyclophosphamide, dofetilide, dronedarone, eletriptan, eplerenone, erlotinib, erythromycin, eszopiclone, everolimus, fentanyl, fluticasone, gefitinib, halofantrine, imatinib, ixabepilone, levomethadyl, nilotinib, phosphodiesterase type 5 inhibitors [eg, sildenafil], pimozide, quetiapine, quinidine, ranolazine, rifampin, telithromycin, temsirolimus, tolvaptan, tyrosine kinase receptor inhibitors [eg, dasatinib, lapatinib], zolpidem)

Plasma levels of these agents may be elevated by posaconazole, increasing the pharmacologic effects and risk of adverse reactions. Close clinical and laboratory monitoring is warranted. Avoid coadministration of posaconazole and dronedarone, erythromycin, everolimus, ixabepilone, nilotinib, tamsulosin, or temsirolimus. Coadministration of posaconazole and alfuzosin, cisapride, conivaptan, halofantrine, pimozide, quinidine, ranolazine, silodosin, or tolvaptan is contraindicated. Increased plasma concentrations of cisapride, halofantrine, pimozide, and quinidine can lead to QT prolongation with rare occurrences of torsades de pointes.

Digoxin

Increased plasma concentrations of digoxin may occur. Monitor digoxin concentrations and adjust the digoxin dose as needed.

Ergot derivatives

Plasma levels may be elevated by posaconazole, increasing the risk of ergotism. Coadministration with posaconazole is contraindicated.

Food

Posaconazole administration with a high-fat meal or non-fat meal increases posaconazole AUC and C _max compared with giving posaconazole in the fasted state. In addition, posaconazole AUC and C _max are higher when given with a liquid nutritional supplement (14 g fat) compared with the fasted state. To ensure attainment of adequate plasma concentrations, it is recommended to administer posaconazole with food or a nutritional supplement or acidic carbonated beverage (eg, ginger ale) in patients who cannot eat a full meal.

Glipizide

Although no dosage adjustment of glipizide is required, it is recommended that glucose concentrations be monitored during concurrent use.

HMG-CoA reductase inhibitors (statins) metabolized through CYP3A4 (eg, atorvastatin, simvastatin)

Posaconazole may elevate plasma levels of these agents, increasing the risk of adverse reactions (eg, rhabdomyolysis). Statin dose reduction is recommended. Concurrent use of posaconazole and simvastatin is contraindicated.

Maraviroc

Maraviroc plasma concentrations may be increased. A maraviroc dosing adjustment is recommended. Coadministration is contraindicated in patients with renal or hepatic impairment.

Metoclopramide

Posaconazole plasma concentrations may be reduced. Closely monitor for breakthrough fungal infections.

Muscarinic receptor antagonists metabolized by CYP3A4 (ie, darifenacin, fesoterodine, solifenacin, tolterodine)

Plasma concentrations and pharmacologic effects of these agents may be increased. The daily dose of darifenacin should not exceed 7.5 mg when coadministered with potent CYP3A4 inhibitors, such as posaconazole. Similarly, the dosage of solifenacin should not exceed 5 mg daily. The dosage of tolterodine, whether immediate-release or ER, should not exceed 2 mg/day. The dosage of fesoterodine should not exceed 4 mg daily.

Vinca alkaloids

Plasma concentrations may be elevated by posaconazole, increasing the risk of neurotoxicity. Consider dosage adjustment of the vinca alkaloid.

Adverse Reactions

Cardiovascular

Hypertension (18%); hypotension (14%); tachycardia (12%); pulmonary embolism, torsades de pointes (less than 5%); QT/QTc prolongation.

CNS

Headache (28%); fatigue, insomnia (17%); dizziness (11%); anxiety (9%); weakness (8%); paresthesia (less than 5%); asthenia (2%).

Dermatologic

Rash (19%); pruritus (11%); increased sweating (2%).

EENT

Pharyngitis (12%).

GI

Diarrhea (42%); nausea (38%); vomiting (29%); abdominal pain (27%); constipation (21%); mucositis (17%); anorexia (15%); dyspepsia (10%).

Genitourinary

Vaginal hemorrhage (10%); acute renal failure (less than 5%).

Hepatic

Increased ALT and/or AST (17%); alkaline phosphatase increased (13%); bilirubinemia (10%); hepatic enzymes increased, hepatic function abnormal, hepatitis, hepatomegaly, jaundice (less than 5%).

Hematologic-Lymphatic

Thrombocytopenia (29%); anemia (25%); neutropenia (23%); febrile neutropenia (20%); petechiae (11%); hemolytic uremic syndrome, neutropenia aggravated, thrombotic thrombocytopenic purpura (less than 5%).

Metabolic-Nutritional

Hypokalemia (30%); hypomagnesemia (18%); hyperglycemia (11%); hypocalcemia (9%); decreased weight, dehydration (1%).

Musculoskeletal

Rigors (20%); musculoskeletal pain (16%); arthralgia (11%); back pain (10%).

Respiratory

Coughing (24%); dyspnea (20%); epistaxis (14%); upper respiratory tract infection (7%); pneumonia (3%).

Miscellaneous

Fever (45%); bacteremia (18%); herpes simplex, leg edema (15%); cytomegalovirus infection (14%); edema (9%); adrenal insufficiency, allergic reaction (less than 5%); oral candidiasis, pain (1%).

Precautions

Monitor Monitor patients who have severe renal impairment, severe diarrhea, or vomiting for breakthrough fungal infections. Evaluate LFTs prior to and during therapy. Monitor patients who develop abnormal LFTs during therapy for development of more severe hepatic injury.

Pregnancy

Category C . It is best to avoid posaconazole during pregnancy, especially in the first trimester. However, if the woman's condition requires posaconazole, the benefit probably outweighs the unknown risk. The lowest possible dose should be used.

Lactation

Undetermined. The molecular weight (about 701), low metabolism (about 17%), and long elimination half-life (35 hours) suggest it will be excreted into breast milk.

Children

Safety and efficacy not established in patients younger than 13 y.

Arrhythmias and QT prolongation

Some azoles, including posaconazole, have been associated with QT interval prolongation. Rare cases of torsades de pointes have been reported. Administer with caution to patients with potentially proarrhythmic conditions.

Hepatic toxicity

Hepatic reactions (eg, mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin, and/or clinical hepatitis) have been reported.

Overdosage

Symptoms

No adverse reactions were noted with dosages up to 1,600 mg/day.

Patient Information

• Advise patient to read the patient information leaflet before using the product for the first time and with each refill.
• Instruct patients to take exactly as prescribed and not to change the dose or discontinue therapy unless advised by health care provider.
• Instruct patients to take this medication with a full meal (during or within 20 min), liquid nutritional supplement, or an acidic carbonated beverage (eg, ginger ale).
• Advise patients to inform health care provider immediately if severe diarrhea or vomiting develops because these conditions may change blood levels of the drug.
• Advise patient to inform their health care provider of all drugs taken, especially any drugs they are taking that prolong the QT interval, drugs that are metabolized through CYP3A4, or cyclosporine or tacrolimus.
• Advise patients to inform health care provider immediately if the following occur: shortness of breath, swelling in one leg, change in heart rate or heart rhythm, itching, yellowing of skin and eyes, feeling unusually tired, flu-like symptoms.
• Advise women to notify health care providers if they become pregnant or are breast-feeding.

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