posaconazole (Rx)

>10%

Fever (45%)

Diarrhea (42%)

Nausea (38%)

Hypokalemia (30%)

Headache (28%)

Abd pain (27%)

Anemia (25%)

Cough (24%)

Nausea (38%)

Thrombocytopenia (29%)

Constipation (21%)

Dyspnea (20%)

Febrile neutropenia (20%)

Rigors (20%)

Rash (19%)

Bacteremia (18%)

HTN (18%)

Hypomagnesemia (18%)

Fatigue (17%)

Insomnia (17%)

Mucositis (17%)

Musculoskeletal pain (16%)

Anorexia (15%)

Herpes simplex (15%)

Leg edema (15%)

CMV infection (14%)

Epistaxis (14%)

Hypotension (14%)

Pharyngitis (12%)

Arthralgia (11%)

Dizziness (11%)

Hypoglycemia (11%)

Petechiae (11%)

Pruritus (11%)

Back pain (10%)

Dyspepsia (10%)

Vaginal hemorrhage (10%)

1-10%

Anxiety (9%)

Edema (9%)

Hypocalcemia (9%)

Weakness (8%)

URI (7%)

Postmarketing Reports

Prolonged QT interval (up to 4% )

Hyperbilirubinemia (2% to 3% )

Increased liver enzymes (1% to 3% )

Liver damage (1% )

Adrenal insufficiency

Cholestasis

Liver failure (rare )

Seizure

Pancreatitis

Endocrine disorders: Pseudoaldosteronism

Contraindications

Hypersensitivity to posaconazole or other azoles

Coadministration with sirolimus; increases sirolimus blood concentrations by ~9-fold

CYP3A4 substrates that prolong the QT interval (eg, pimozide, quinidine); posaconazole inhibits CYP3A4 isoenzyme

Coadministration with the HMG-CoA reductase inhibitors (statins) that are primarily metabolized through CYP3A4 (eg, atorvastatin, lovastatin, simvastatin); increased statin plasma concentration can lead to rhabdomyolysis

May increase plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism

Cautions

Coadministration with calcineurin inhibitors (eg, cyclosporine, tacrolimus); increases whole concentrations of calcineurin inhibitors

Coadministration with midazolam increases midazolam plasma concentrations by ~5-fold; increased risk of prolonged hypnotic and sedative effects

May prolong QT interval; cases of torsades de pointes reported

Hepatic reactions reported including mild-to-moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin, and clinical hepatitis; consider discontinuing therapy in patients who develop abnormal LFTs or monitor LFTs during treatment

Coadministration with azole antifungals 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, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options

Electrolyte disturbances, especially those involving potassium, magnesium or calcium levels, should be monitored and corrected as necessary before and during posaconazole therapy

Pregnancy

Available data in pregnant women are insufficient to establish a drug- associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes; based on findings from animal data, therapy may cause fetal harm when administered to pregnant women

Animal data

• Skeletal malformations (cranial malformations and missing ribs) and maternal toxicity (reduced food consumption and reduced body weight gain) observed when dosed orally to pregnant rats; during organogenesis at doses greater than or equal to 1.4 times the 400 mg twice daily oral suspension regimen recommended in humans; 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 potential risk to a fetus

Lactation

There are no data on presence of drug in human milk, effects on breastfed infant, or on milk production; drug is excreted in milk of lactating rats; when a drug is present in animal milk, it is likely that the drug will be present in human milk; developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for drug and any potential adverse effects on breastfed child from drug or from underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Inhibits fungal cell membrane sterol biosynthesis

Absorption

Increased by food

Peak plasma time: 3-5 hr (oral susp); 3-4 hr (tablet); 1.5 hr (IV)

Peak plasma concentration: 1590 ng/mL (IV)

Distribution

Protein bound: >98%

Vd: 287 L (oral); 261 L (IV)

Metabolism

Metabolized primarily by glucuronide conjugates

Strong CYP3A4 inhibitor

Elimination

Half-life: 35 hr (oral susp); 26-31 hr (tablet); 24.6 hr (IV)

Total body clearance: 51.2 L/hr (oral susp); 9.39 L/hr (tablet); 7.3 L/hr (IV)

Excretion: 71% feces; 13% urine

IV Compatibility

IV solutions

• Dextrose 5% in water
• 0.9% NaCl

Y-site administration

• Amikacin
• Caspofungin, ciprofloxacine
• Daptomycin, dobutamine
• Famotidine
• Gentamicin
• Hydromorphone
• Levofloxacin, lorazepam
• Meropenem, micafungin, morphine
• Norepinephrine
• Potassium chloride
• Vancomycin

IV Preparation

Equilibrate the refrigerated vial to room temperature

Aseptically transfer 16.7 mL (300 mg) of solution to an IV bag/bottle containing approximately 150 mL of 5% dextrose in water or sodium chloride 0.9%

Should only be administered with these diluents; use of other infusion solutions may result in particulate formation

Posaconazole injection is a single dose sterile solution without preservatives; once admixed, the product should be used immediately

The diluted solution ranges from colorless to yellow

IV Administration

Must be administered through a 0.22 micron polyethersulfone (PES) or polyvinylidene difluoride (PVDF) filter

Should be administered via a central venous line, including a central venous catheter or peripherally inserted central catheter (PICC), by slow IV infusion over ~90 minutes

If a central venous catheter is not available, may administer through a peripheral venous catheter by slow IV infusion over 30 minutes only as a single dose in advance of central venous line placement or to bridge the period during which a central venous line is replaced or is in use for other IV treatment

When multiple dosing is required, the infusion should be done via a central venous line

Not for IV bolus injection

Oral Administration

Tablets and oral suspension are not interchangeable because of differences in dosing for each formulation

Tablets

• Take tablets with food
• Tablets: Swallow whole; do not divide, crush, or chew

Oral suspension

• Oral suspension should be taken with a full meal or liquid nutritional supplement or an acidic carbonated beverage (eg, ginger ale) in patients unable to eat a full meal

Storage

Unopened vials: Store refrigerated at 2-8°C (36-46°F)

Diluted solution

• Posaconazole injection is a single dose sterile solution without preservatives; once admixed, the product should be used immediately
• If not used immediately, refrigerate for up to 24 hr between 2-8°C (36-46°F)