posaconazole (Rx)

>10%

Injection

• Diarrhea (10-42%)
• Pyrexia (21-31%)
• Nausea (19-30%)
• Hypokalemia (22-28%)
• Rash (15-24%)
• Headache (14-21%)
• Vomiting (12-19%)
• Epistaxis (14-17%)
• Abdominal pain (13-17%)
• Peripheral edema (12-15%)
• Cough (9-13%)
• Constipation (8-13%)
• Hypomagnesemia (11-13%)
• Decreased appetite (10-12%)
• Hypertension (8-11%)
• Thrombocytopenia (7-11%)
• Upper abdominal pain (6-11%)

Oral suspension

• Fever (6-45%)
• Nausea (9-38%)
• Hypokalemia (30%)
• Thrombocytopenia (29%)
• Vomiting (7-29%)
• Headache (8-28%)
• Abdominal pain (5-27%)
• Coughing (3-25%)
• Anemia (2-25%)
• Neutropenia (4-23%)
• Constipation (21%)
• Dyspnea (1-20%)
• Rigors (<20%)
• Anorexia (2-19%)
• Rash (3-19%)
• Hypomagnesemia (18%)
• Hypertension (18%)
• ALT increased, Grade 3 or 4 (6-17%)
• AST >3x ULN (6-17%)
• Fatigue (2-17%)
• Insomnia (1-17%)
• Musculoskeletal pain (16%)
• Edema legs (15%)
• Epistaxis (14%)
• Hypotension (14%)
• Decrease weight (1-14%)
• Tachycardia (12%)
• Pharyngitis (12%)
• Oral candidiasis (<12%)
• Hyperglycemia (11%)
• Pruritus (11%)
• Petechiae (11%)
• Dizziness (11%)
• Arthralgia (11%)
• Herpes simplex (3-11%)
• ALT >3x ULN (3-11%)
• Pain (1-11%)
• Dehydration (1-11%)

Tablets

• Diarrhea (29%)
• Pyrexia (28%)
• Nausea (27%)
• Hypokalemia (22%)
• Cough (17%)
• Rash (16%)
• Peripheral edema (16%)
• Epistaxis (14%)
• Headache (14%)
• Mucosal inflammation (14%)
• Thrombocytopenia (14%)
• Vomiting (13%)
• Alkaline phosphatase >3x ULN (3-13%)
• Abdominal pain (11%)
• Hypertension 23 (11%)

1-10%

Injection

• Petechiae (8-10%)
• Anemia (7-10%)
• Dyspnea (7-10%)

Tablets

• Anemia (10%)
• Constipation (10%)
• Asthenia (10%)
• Chills (10%)
• Hypomagnesemia (10%)

Oral suspension

• Back pain (10%)
• Bilirubinemia (10%)
• Vaginal hemorrhage (10%)
• Dyspepsia (10%)
• Pneumonia (3-10%)
• Sweating increased (2-10%)
• Edema (9%)
• Hypocalcemia (9%)
• Bilirubin increased, Grade 3 or 4 (7-9%)
• Weakness (8%)
• Hemolytic uremic syndrome (<5%)
• Thrombotic thrombocytopenic purpura (<5%)
• Neutropenia aggravated (<5%)
• Adrenal insufficiency (<5%)
• Paresthesia (<5%)
• Allergic reaction (<5%)
• Torsades de pointes (<5%)
• Pulmonary embolism (<5%)
• Pancreatitis (<5%)
• Bilirubinemia (<5%)
• Hepatic enzymes increased (<5%)
• Hepatic function abnormal (<5%)
• Hepatitis (<5%)
• Hepatomegaly (<5%)
• Jaundice (<5%)
• AST/ALT increased (<5%)
• Hypokalemia (<5%)
• Thrombocytopenia (<5%)
• Renal failure acute (<5%)
• Total bilirubin > 1.5x ULN (3-5%)
• AST, Grade 3 or 4 (3-4%)
• Alkaline phosphatase, Grade 3 or 4 (1-3%)

Postmarketing Reports

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)

Coadministration with the HMG-CoA reductase inhibitors (statins) that are primarily metabolized through CYP3A4 (eg, atorvastatin, lovastatin, simvastatin)

Concurrent use with ergot alkaloids

Coadministration with venetoclax in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)

Use of delayed-release oral suspension in patients with known or suspected hereditary fructose intolerance (HFI)

Delayed-release oral suspension only

• Patients with known or suspected hereditary fructose intolerance (HFI)

Cautions

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

Closely monitor patients with severe renal impairment for breakthrough fungal infections due to the variability in exposure of the delayed-release tablets and oral suspension; avoid use of injection in patients with moderate or severe renal impairment (eGFR <50 mL/min); unless benefit outweighs risks

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

Closely monitor patients who have severe diarrhea or vomiting for breakthrough fungal infections when receiving delayed-release tablets, oral suspension, or delayed-release oral suspension

Use of delayed-release oral suspension in patients with HFI

• Delayed-release oral suspension contains sorbitol, an inactive ingredient, and may precipitate a metabolic crisis that may include, but is not limited to life-threatening hypoglycemia, hypophosphatemia, lactic acidosis, and hepatic failure in patients with HFI
• Review patient history of HFI symptoms (nausea, vomiting, abdominal pain) with sorbitol/fructose/sucrose exposure before using the delayed-release oral suspension
• Diagnosis of HFI may not yet be established in pediatric patients

Drug interactions overview

Posaconazole is a P-gp substrate and a strong CYP3A4 inhibitor; metabolized by UDP-glucuronidase

• Rifabutin and phenytoin

  • Avoid unless benefit outweighs risks
  • Rifabutin and phenytoin may decrease posaconazole plasma concentrations by inducing UDP-glucuronidase
  • Posaconazole may also increase rifabutin and phenytoin levels by inhibiting CYP3A4

• Antiretroviral agents

  • Efavirenz may induce UDP-glucuronidase and significantly decrease posaconazole plasma levels; avoid use
  • Ritonavir and atazanavir are CYP3A4 substrates; posaconazole may increase plasma concentrations of these drugs; closely monitor for posaconazole-related toxicities if concurrently used
  • Fosamprenavir may decrease posaconazole plasma concentration; closely monitor for breakthrough fungal infections

• Benzodiazepines metabolized by CYP3A4

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

• CYP3A4 substrates that cause QT prolongation

  • Contraindicated
  • Coadministration with CYP3A4 substrates may result in increased plasma concentrations of these drugs, leading to QTc prolongation and cases of torsades de pointes

• Immunosuppressants metabolized by CYP3A4

  • Coadministration posaconazole with calcineurin inhibitors (eg, sirolimus, tacrolimus, cyclosporine) increases blood concentrations pf calcineurin inhibitors
  • Sirolimus: Contraindicated
  • Tacrolimus: Reduce tacrolimus dose to ~1/3 of original dose when initiating posaconazole; closely monitor tacrolimus trough concentrations during and at discontinuation of posaconazole treatment and adjust tacrolimus dose accordingly
  • Cyclosporine: Reduce cyclosporine dose to ~ 3/4 of original dose when initiating cyclosporine; closely monitor tacrolimus trough concentrations during and at discontinuation of posaconazole treatment and adjust tacrolimus dose accordingly

• HMG-CoA reductase inhibitors primarily metabolized through CYP3A4

  • Contraindicated
  • May increase plasma concentrations of simvastatin by ~10-fold

• Ergot alkaloids

  • Contraindicated
  • May increase the plasma concentrations of ergot alkaloids which may lead to ergotism

• Cimetidine and esomeprazole

  • Oral suspension: Cimetidine (an H2-receptor antagonist) and esomeprazole (a proton pump inhibitor) decreased posaconazole plasma concentrations; avoid use of cimetidine and esomeprazole unless the benefit outweighs the risks

• Vinca alkaloids

  • Use with vinca alkaloids (eg, vinblastine, vincristine) may increase the plasma concentrations of vinca alkaloids and risks of neurotoxicity and other serious adverse reactions
  • Reserve azole antifungals for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options

• Calcium channel blockers

  • May increase the plasma concentrations of calcium channel blockers metabolized by CYP3A4 (eg, verapamil, diltiazem, nifedipine, nicardipine, felodipine)
  • Closely monitor for adverse reactions and toxicity related to calcium channel blockers; consider dose reduction of calcium channel blockers

• Digoxin

  • Increased plasma concentrations of digoxin reported in patients receiving digoxin and posaconazole; closely monitor digoxin levels

• Venetoclax toxicity

  • Concomitant administration of Noxafil, a strong CYP3A4 inhibitor, with venetoclax may increase venetoclax toxicities, including the risk of tumor lysis syndrome (TLS), neutropenia, and serious infections; in patients with CLL/SLL, administration of Noxafil during initiation and the ramp-up phase of venetoclax is contraindicated; refer to the venetoclax labeling for safety monitoring and dose reduction in the steady daily dosing phase in CLL/SLL patients
  • For patients with acute myeloid leukemia (AML), dose reduction and safety monitoring are recommended across all dosing phases when coadministering Noxafil with venetoclax; refer to the venetoclax prescribing information for dosing instructions

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 Incompatibilities

Lactated ringer (LR)

Dextrose 5% (D5W) with LR

4.2% sodium bicarbonate

IV Compatibility

IV solutions

• 0.45% NaCl
• 0.9% NaCl
• D5W
• D5W 0.45% NaCl
• D5W 0.9% NaCl
• D5W and 20 mEq potassium chloride

Y-site administration

• Drugs

  • Amikacin
  • Caspofungin
  • Ciprofloxacin
  • Daptomycin
  • Dobutamine
  • Famotidine
  • Gentamicin
  • Hydromorphone
  • Levofloxacin
  • Lorazepam
  • Meropenem
  • Micafungin
  • Morphine
  • Norepinephrine
  • Potassium chloride
  • Vancomycin

IV Preparation

Equilibrate refrigerated vial to room temperature

Aseptically transfer 16.7 mL (300 mg) of solution to an IV bag/bottle containing ~150 mL of a compatible admixture diluent; final concentration of diluted IV bag is 1-2 mg/mL

Use of other infusion solutions may result in particulate formation

Injection is a single dose sterile solution without preservatives; once admixed, use product immediately; if not used immediately, refrigerate for up to 24 hours at 2-8ºC (36-46ºF)

Visually inspect product for particulate matter prior to administration; diluted solution ranges from colorless to yellow

IV Administration

IV infusion only; not for IV bolus injection

Administer through a 0.22 micron polyethersulfone (PES) or polyvinylidene difluoride (PVDF) filter

Administer 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 required, infusion should be done via central venous line

Oral Preparation

Oral suspension H4

• Shake well before use
• Administer with measured dosing spoon (marked doses of 2.5 mL and 5 mL)
• Rinse spoon with water after each administration and before storage
• Administer each dose during or immediately (ie, within 20 min) following a full meal to enhance absorption of the oral suspension

Delayed-release oral suspension

• Do not open packet in kit until ready to prepare
• Remove 9 mL of mixing liquid using the provided BLUE syringe
• ONLY use the mixing liquid in the kit to prepare delayed-release oral suspension
• Using the provided mixing cup, combine 9 mL of mixing liquid and the entire contents of one packet in the kit and mix
• Each single-use packet in the kit contains 300 mg of posaconazole to be suspended in 9 mL of mixing liquid giving a final concentration of ~30 mg/mL
• Shake mixing cup vigorously for 45 sec to mix powder and mixing liquid from kit; check to make sure the powder is mixed; mixture should look cloudy and free of clumps
• Reconstituted suspension must be used within 1 hr; discard unused portion of the prepared drug product

Oral Administration

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

Tablets

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

Oral suspension

• Take with a full meal or liquid nutritional supplement or an acidic carbonated beverage (eg, ginger ale) in patients unable to eat a full meal
• If unable to eat a full meal or tolerate an oral nutritional supplement or an acidic carbonated beverage and who do not have the option of taking delayed-release tablets or injection, consider an alternative antifungal therapy or closely monitor for breakthrough fungal infections

Delayed-release oral suspension

• Take with food
• Use 3-mL syringe (green) for doses ≤3 mL
• Use 10-mL syringe (blue) for doses >3 mL
• Administer dose orally within 1 r of mixing
• Not all the mixture in the mixing cup will be used
• Maximum dose that can be accurately withdrawn from mixing cup after reconstitution is 240 mg (8 mL)
• To ensure delivery of the correct dose, ONLY provided notched tip syringes must be used for preparation and administration
• Discard any remaining suspension; mixing cup and notched tip syringes may be hand washed and reused
• Alternatively, mixing cup may be discarded, and a similar mixing cup with a lid may be used for subsequent doses
• For additional supply, a separate box of notched tip syringes is provided with the kit

Missed dose

• >12 hr of next dose: Take as soon as possible
• <12 hr of next dose: Skip missed dose; go back to regular schedule; do not double dose

Storage

Unopened vials: Refrigerate at 2-8ºC (36-46ºF)

Tablets

• Store at 20-25ºC (36-46ºF), excursions permitted to 15-30ºC (59-86ºF)

Oral suspension

• Store at 25ºC (36-46ºF), excursions permitted to 15-30ºC (59-86ºF)
• Do not freeze

Delayed-release oral suspension

• Store entire kit at 20-25ºC (36-46ºF), excursions permitted to 15-30ºC (59-86ºF) in a clean, dry place
• Do not open foil packet containing delayed-release oral suspension until ready for use
• Once mixed, use within 1 hr; discard any unused drug

Diluted solution

• Vial is a single dose sterile solution without preservatives; once admixed, use immediately
• If not used immediately, refrigerate for up to 24 hr at 2-8ºC (36-46ºF)