Dosing and uses of Noxafil (posaconazole)
Adult dosage forms and strengths
oral suspension
- 40mg/mL (105mL)
tablet, delayed-release
- 100mg
injectable solution
- 18mg/mL (300mg/vial)
Invasive Aspergillus & Candida Infections
Oral suspension or 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 (eg, hematopoietic stem cell transplant recipients with GVHD, hematologic malignancies with prolonged neutropenia from chemotherapy)
Oral suspension: 200 mg (5 mL) PO TId
Tablet: 300 mg PO BID on Day 1, then 300 mg PO qDay
IV: 300 mg IV BID on Day 1, then 300 mg IV qDay (see IV preparation and administration)
Duration of therapy is based on recovery from neutropenia or immunosuppression
Oropharyngeal Candidiasis
Oral suspension is indicated for oropharyngeal candidiasis
100 mg (2.5 mL) PO BID on Day 1, then 100 mg PO qDay for 13 days
Refractory to itraconazole and/or fluconazole: 400 mg (10 mL) PO BID; duration based on severity of underlying disease and clinical response
Dosage modifications
Moderate-to-severe renal impairment (IV)
- eGFR <50 mL/min: Avoid IV administration unless benefit/risk assessment justifies use
- Accumulation of the IV vehicle, SBECD, is expected to occur
- Serum creatinine levels should be closely monitored; if increases occur, consideration should be given to changing to oral posaconazole therapy
Severe renal impairment (tablets or oral suspension)
- Variability of systemic exposure with tablets or oral suspension observed
- Monitored closely for breakthrough fungal infections
Orphan Designations
Treatment of invasive aspergillosis
Treatment of zygomycosis
Sponsor
- Merck, Sharp & Dohme Corp; 1 Merck Drive; Whitehouse Station, New Jersey 08889
Pediatric dosage forms and strengths
oral suspension
- 40mg/mL (105mL)
tablet, delayed-release
- 100mg
Invasive Aspergillus & Candida Infections
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 (eg, hematopoietic stem cell transplant recipients with GVHD, hematologic malignancies with prolonged neutropenia from chemotherapy)
<18 years (IV): Safety and efficacy not established
<13 years (tablets and oral suspension): Safety and efficacy not established
≥13 years
- Oral suspension: 200 mg (5 mL) TID
- Tablet: 300 mg PO BID on Day 1, then 300 mg PO qDay
- Duration of therapy is based on recovery from neutropenia or immunosuppression
Oropharyngeal Candidiasis
Oral suspension is indicated for oropharyngeal candidiasis
<13 years: Safety and efficacy not established
≥13 years
- Oral suspension: 100 mg (2.5 mL) PO BID on Day 1, then 100 mg PO qDay for 13 days
- Refractory to itraconazole and/or fluconazole: 400 mg (10 mL) PO BID; duration based on severity of underlying disease and clinical response
Noxafil (posaconazole) adverse (side) effects
>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
Warnings
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 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
Pregnancy and lactation
Pregnancy category: C
Lactation: unknown; weigh risk/benefit
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.
Pharmacology of Noxafil (posaconazole)
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
Administration
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)
