Noxafil

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

Before taking posaconazole,

• tell your doctor and pharmacist if you are allergic to posaconazole; other antifungal medications such as fluconazole (Diflucan), isavuconazonium (Cresemba), itraconazole (Onmel, Sporanox), ketoconazole (Extina, Nizoral, Xolegel), or voriconazole (Vfend); simethicone; any other medications; or any of the ingredients in posaconazole products. Ask your pharmacist for a list of the ingredients.
• tell your doctor if you taking any of the following medications: atorvastatin (Lipitor, in Caduet), ergot-type medications such as bromocriptine (Cycloset, Parlodel), cabergoline, dihydroergotamine (D.H.E. 45, Migranal), ergoloid mesylates (Hydergine), ergonovine, ergotamine (Ergomar, in Cafergot, in Migergot), and methylergonovine (Methergine); lovastatin (Altoprev, in Advicor); pimozide (Orap); quinidine (in Nuedexta); simvastatin (Zocor, in Simcor, in Vytorin); or sirolimus (Rapamune). Your doctor will probably tell you not to take posaconazole if you are taking one or more of these medications.
• tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: benzodiazepines such as alprazolam (Xanax), diazepam (Valium), midazolam, and triazolam (Halcion); calcium channel blockers such as diltiazem (Cardizem, Cartia, Tiazac, others), felodipine, nicardipine (Cardene), nifedipine (Adalat, Afeditab CR, Procardia), and verapamil (Calan, Covera, Verelan, others); cyclosporine (Gengraf, Neoral, Sandimmune); digoxin (Lanoxin); efavirenz (Sustiva, in Atripla); erythromycin (E.E.S., ERYC, Erythrocin, others), fosamprenavir (Lexiva); glipizide (Glucotrol); phenytoin (Dilantin, Phenytek); rifabutin (Mycobutin); ritonavir (Norvir) taken with atazanavir (Reyataz); tacrolimus (Astagraf, Envarsus XR, Prograf); vinblastine; and vincristine (Marquibo Kit). If you are taking the posaconazole oral suspension, also tell your doctor if you are taking cimetidine (Tagamet), esomeprazole (Nexium, in Vimovo), or metoclopramide (Reglan). Many other medications may also interact with posaconazole, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you have or have ever had a slow or irregular heartbeat; a prolonged QT interval (a rare heart problem that may cause irregular heartbeat, fainting, or sudden death); problems with blood circulation; low levels of calcium, magnesium, or potassium in your blood; or kidney, or liver disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking posaconazole, call your doctor.

Serious side effects have been reported. See "Drug Precautions" section.

The most common side effects of Noxafil delayed-release tablets include:

• diarrhea
• fever
• nausea

The most common side effects of Noxafil oral suspension include:

• diarrhea
• nausea
• headache
• vomiting
• fever

The most common side effects of Noxafil injection  include:

• anemia
• abdominal pain
• diarrhea
• nausea
• vomiting

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Noxafil. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Noxafil may cause serious side effects, including:

• drug interactions with cyclosporine or tacrolimus. If you take Noxafil with cyclosporine or tacrolimus, your blood levels of cyclosporine or tacrolimus may increase. Serious side effects can happen in your kidney or brain if you have high levels of cyclosporine or tacrolimus in your blood. Your healthcare provider should do blood tests to check your levels of cyclosporine or tacrolimus if you are taking these medicines while taking Noxafil. Tell your healthcare provider right away if you have swelling in your arm or leg or shortness of breath.
• problems with the electrical system of your heart (arrhythmias and QTc prolongation). Certain medicines used to treat fungus called azoles, including Noxafil, the active ingredient in Noxafil, may cause heart rhythm problems. People who have certain heart problems or who take certain medicines have a higher chance for this problem. Tell your healthcare provider right away if your heartbeat becomes fast or irregular.
• liver problems. Some people who also have other serious medical problems may have severe liver problems that may lead to death, especially if you take certain doses of Noxafil. Your healthcare provider should do blood tests to check your liver while you are taking Noxafil. Call your healthcare provider right away if you have any of the following symptoms of liver problems:
  • itchy skin
  • nausea or vomiting
  • yellowing of your eyes
  • feeling very tired
  • flu-like symptoms
• increased amounts of midazolam in your blood. If you take Noxafil with midazolam, Noxafil increases the amount of midazolam in your blood. This can make your sleepiness last longer. Your healthcare provider should check you closely for side effects if you take midazolam with Noxafil.

Tell your doctor if you are pregnant or plan to become pregnant. The FDA categorizes medications based on safety for use during pregnancy.

Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy. 

Noxafil falls into category C. There are no well-controlled studies in pregnant women. Noxafil should be used during pregnancy only if the possible benefit outweighs the possible risk to the unborn baby

The liquid and tablet forms of posaconazole are not equivalent and may not have the same dose or schedule. Ask your pharmacist if you have any questions about the kind of posaconazole you receive at the pharmacy.

Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

Do not crush, chew, dissolve, or break a delayed-release tablet. Swallow it whole.

Shake the oral suspension (liquid) well just before you measure a dose. Measure the liquid with a special dose-measuring spoon or medicine cup. If you do not have a dose-measuring device, ask your pharmacist for one.

The posaconazole delayed-release tablet works best if you take it with food. Take the oral suspension within 20 minutes after a full meal. If you cannot eat a full meal, take the oral suspension with a nutritional supplement (such as BOOST) or with an acidic carbonated drink such as ginger ale.

Use this medicine for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared. Skipping doses may also increase your risk of further infection that is resistant to antifungal medicine. Posaconazole will not treat a viral infection such as the flu or a common cold.

Call your doctor if you have ongoing vomiting or diarrhea. Posaconazole may not work as well while during this time.

While using posaconazole, you may need frequent blood tests.

Store at room temperature away from moisture and heat. Do not freeze. Keep the bottle tightly closed when not in use.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Important Administration Instructions for Noxafil Injection, Noxafil Delayed-Release Tablets and Noxafil Oral Suspension

Noxafil delayed-release tablets and oral suspension are not to be used interchangeably due to the differences in the dosing of each formulation [see Dosage and Administration (2.3, 2.4, 2.5)].

Noxafil injection

• Administer via a central venous line, including a central venous catheter or peripherally inserted central catheter (PICC), by slow intravenous infusion over approximately 90 minutes [see Dosage and Administration (2.2)].
• If a central venous catheter is not available, Noxafil injection may be administered through a peripheral venous catheter by slow intravenous 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 intravenous treatment.
• When multiple dosing is required, the infusion should be done via a central venous line.
• Never administer Noxafil injection as an intravenous bolus injection.

Noxafil delayed-release tablets

• Swallow tablets whole. Do not divide, crush, or chew.
• Administer with food [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

Noxafil oral suspension

• Administer with a full meal or with a liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale) in patients who cannot eat a full meal [see Dosage and Administration (2.4)]
• Co-administration of drugs that can decrease the plasma concentrations of posaconazole should generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections [see Drug Interactions (7.6, 7.7, 7.8, 7.9, 7.13)]

Noxafil delayed-release tablets and Noxafil oral suspension

• Patients who have severe diarrhea or vomiting should be monitored closely for breakthrough fungal infections when receiving Noxafil delayed-release tablets or oral suspension.

Dosage, Preparation, Intravenous Line Compatibility and Administration of Noxafil Injection

Dosage:

Preparation:

• Equilibrate the refrigerated vial of Noxafil (posaconazole) injection to room temperature.
• To prepare the required dose, aseptically transfer one vial (16.7 mL) of Noxafil injection (containing 300 mg of posaconazole in solution) to an intravenous bag (or bottle) of a compatible admixture diluent (as described in Table 2), to achieve a final concentration of posaconazole that is between 1 mg/mL and 2 mg/mL. Use of other diluents is not recommended because they may result in particulate formation.
• Noxafil injection is a single dose sterile solution without preservatives. Once admixed, the product should be used immediately. If not used immediately, the solution can be stored up to 24 hours refrigerated 2-8°C (36-46°F). Noxafil injection is for single use only and any unused solution should be discarded.
• Parenteral drug products should be inspected visually for particulate matter prior to administration, whenever solution and container permit. Once admixed, the solution of Noxafil ranges from colorless to yellow. Variations of color within this range do not affect the quality of the product.

Intravenous Line Compatibility:

A study was conducted to evaluate physical compatibility of Noxafil injection with injectable drug products and commonly used intravenous diluents during simulated Y-site infusion. Compatibility was determined through visual observations, measurement of particulate matter and turbidity. Compatible diluents and drug products are listed in Tables 2 and 3 below. Any diluents or drug products not listed in the tables below should not be co-administered through the same intravenous line (or cannula).

• Noxafil injection can be infused at the same time through the same intravenous line (or cannula) with the following compatible diluents:

• Noxafil injection can be infused at the same time through the same intravenous line (or cannula) with the following drug products prepared in 5% dextrose in water or sodium chloride 0.9%. Co-administration of drug products prepared in other diluents may result in particulate formation.

Incompatible Diluents:

Noxafil injection must not be diluted with the following diluents:

Lactated Ringer's solution
5% dextrose with Lactated Ringer's solution
4.2% sodium bicarbonate

Administration:

• Noxafil injection must be administered through a 0.22 micron polyethersulfone (PES) or polyvinylidene difluoride (PVDF) filter.
• Administer via a central venous line, including a central venous catheter or PICC by slow infusion over approximately 90 minutes. Noxafil injection is not for bolus administration.
• If a central venous catheter is not available, Noxafil injection may be administered through a peripheral venous catheter 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 treatment.
• When multiple dosing is required, the infusion should be done via a central venous line. When administered through a peripheral venous catheter, the infusion should be administered over approximately 30 minutes. Note: In clinical trials, multiple peripheral infusions given through the same vein resulted in infusion site reactions [see Adverse Reactions (6.2)].

Dosage and Administration Instructions for Noxafil Delayed-Release Tablets

Dosage:

Administration Instructions for Noxafil Delayed-Release Tablets:

• Swallow tablets whole. Do not divide, crush, or chew.
• Administer Noxafil delayed-release tablets with food to enhance the oral absorption of posaconazole and optimize plasma concentrations [see Clinical Pharmacology (12.3)].
• Noxafil delayed-release tablets should be used only for the prophylaxis indication.
• Noxafil delayed-release tablets generally provide higher plasma drug exposures than Noxafil oral suspension under both fed and fasted conditions, and therefore is the preferred oral formulation for the prophylaxis indication.

Dosage and Administration Instructions for Noxafil Oral Suspension

Dosage:

Administration Instructions for Noxafil Oral Suspension:

• Shake Noxafil oral suspension well before use. Administer with measured dosing spoon (see Figure 1) provided.

Figure 1: A measured dosing spoon is provided, marked for doses of 2.5 mL and 5 mL.

• Rinse the spoon with water after each administration and before storage.
• Administer each dose of Noxafil oral suspension during or immediately (i.e., within 20 minutes) following a full meal to enhance the oral absorption of Noxafil and optimize plasma concentrations [see Clinical Pharmacology (12.3)].
• For patients who cannot eat a full meal, Noxafil delayed-release tablets should be used instead of Noxafil oral suspension. Noxafil delayed-release tablets should be used only for the prophylaxis indication. Noxafil delayed-release tablets provide higher plasma drug exposures than Noxafil oral suspension under fasted conditions [See Dosage and Administration (2.5)].
• In patients who cannot eat a full meal and for whom Noxafil delayed-release tablets or Noxafil injection are not options, administer each dose of Noxafil oral suspension with a liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale).
• For patients who cannot eat a full meal or tolerate an oral nutritional supplement or an acidic carbonated beverage and who do not have the option of taking Noxafil delayed-release tablets or Noxafil injection, an alternative antifungal therapy should be considered or patients should be monitored closely for breakthrough fungal infections.

Non-Interchangeability between Noxafil Delayed-Release Tablets and Noxafil Oral Suspension

Noxafil delayed-release tablets and oral suspension are not to be used interchangeably due to the differences in the dosing of each formulation. Therefore, follow the specific dosage recommendations for each of the formulations [see Dosage and Administration (2.3, 2.4)].

Dosage Adjustments in Patients with Renal Impairment

The pharmacokinetics of Noxafil oral suspension and delayed-release tablets are not significantly affected by renal impairment. Therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment.

• Noxafil injection should be avoided in patients with moderate or severe renal impairment (eGFR <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of Noxafil injection.
• In patients with moderate or severe renal impairment (estimated glomerular filtration rate (eGFR) <50 mL/min), receiving the Noxafil injection, accumulation of the intravenous vehicle, Betadex Sulfobutyl Ether Sodium (SBECD), is expected to occur. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral Noxafil therapy.

There is no experience with overdosage of posaconazole injection and delayed-release tablets.

During the clinical trials, some patients received posaconazole oral suspension up to 1600 mg/day with no adverse reactions noted that were different from the lower doses. In addition, accidental overdose was noted in one patient who took 1200 mg BID posaconazole oral suspension for 3 days. No related adverse reactions were noted by the investigator.

Posaconazole is not removed by hemodialysis.

Noxafil is an azole antifungal agent available as concentrated solution to be diluted before intravenous administration, delayed-release tablet, or suspension for oral administration.

Posaconazole is designated chemically as 4-[4-[4-[4-[[ (3R,5R)-5- (2,4-difluorophenyl)tetrahydro-5- (1H-1,2,4-triazol-1-ylmethyl)-3-furanyl]methoxy]phenyl]-1-piperazinyl]phenyl]-2-[(1S,2S)-1-ethyl-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one with an empirical formula of C37H42F2N8O4 and a molecular weight of 700.8. The chemical structure is:

Posaconazole is a white powder with a low aqueous solubility.

Noxafil injection is available as a clear colorless to yellow, sterile liquid essentially free of foreign matter. Each vial contains 300 mg of posaconazole and the following inactive ingredients: 6.68 g Betadex Sulfobutyl Ether Sodium (SBECD), 0.003 g edetate disodium, hydrochloric acid and sodium hydroxide to adjust the pH to 2.6, and water for injection.

Noxafil delayed-release tablet is a yellow, coated, oblong tablet containing 100 mg of posaconazole. Each delayed-release tablet contains the inactive ingredients: hypromellose acetate succinate, microcrystalline cellulose, hydroxypropylcellulose, silicon dioxide, croscarmellose sodium, magnesium stearate, and Opadry® II Yellow (consists of the following ingredients: polyvinyl alcohol partially hydrolyzed, Macrogol/PEG 3350, titanium dioxide, talc, and iron oxide yellow).

Noxafil oral suspension is a white, cherry-flavored immediate-release suspension containing 40 mg of posaconazole per mL and the following inactive ingredients: polysorbate 80, simethicone, sodium benzoate, sodium citrate dihydrate, citric acid monohydrate, glycerin, xanthan gum, liquid glucose, titanium dioxide, artificial cherry flavor, and purified water.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No drug-related neoplasms were recorded in rats or mice treated with posaconazole for 2 years at doses higher than the clinical dose. In a 2-year carcinogenicity study, rats were given posaconazole orally at doses up to 20 mg/kg (females), or 30 mg/kg (males). These doses are equivalent to 3.9- or 3.5-times the exposure achieved with a 400-mg BID oral suspension regimen, respectively, based on steady-state AUC in healthy volunteers administered a high-fat meal (400-mg BID oral suspension regimen). In the mouse study, mice were treated at oral doses up to 60 mg/kg/day or 4.8-times the exposure achieved with a 400-mg BID oral suspension regimen.

Posaconazole was not genotoxic or clastogenic when evaluated in bacterial mutagenicity (Ames), a chromosome aberration study in human peripheral blood lymphocytes, a Chinese hamster ovary cell mutagenicity study, and a mouse bone marrow micronucleus study.

Posaconazole had no effect on fertility of male rats at a dose up to 180 mg/kg (1.7 × the 400-mg BID oral suspension regimen based on steady-state plasma concentrations in healthy volunteers) or female rats at a dose up to 45 mg/kg (2.2 × the 400-mg BID oral suspension regimen).

Animal Toxicology and/or Pharmacology

In a nonclinical study using intravenous administration of posaconazole in very young dogs (dosed from 2 to 8 weeks of age), an increase in the incidence of brain ventricle enlargement was observed in treated animals as compared with concurrent control animals. No difference in the incidence of brain ventricle enlargement between control and treated animals was observed following the subsequent 5-month treatment-free period. There were no neurologic, behavioral or developmental abnormalities in the dogs with this finding, and a similar brain finding was not seen with oral posaconazole administration to juvenile dogs (4 days to 9 months of age).

The clinical significance of this finding is unknown; therefore, the use of posaconazole injection to patients under 18 years of age is not recommended.

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Administration

Noxafil Delayed-Release Tablets

Advise patients to take Noxafil delayed-release tablets with food.

Advise patients that Noxafil delayed-release tablets must be swallowed whole and not divided, crushed, or chewed.

Instruct patients that if they miss a dose, they should take it as soon as they remember. If they do not remember until it is within 12 hours of the next dose, they should be instructed to skip the missed dose and go back to the regular schedule. Patients should not double their next dose or take more than the prescribed dose.

Noxafil Oral Suspension

Advise patients to take each dose of Noxafil oral suspension during or immediately (i.e., within 20 minutes) following a full meal. In patients who cannot eat a full meal, each dose of Noxafil oral suspension should be administered with a liquid nutritional supplement or an acidic carbonated beverage (e.g., ginger ale) in order to enhance absorption.

Instruct patients that if they miss a dose, they should take it as soon as they remember. However, if it is almost time for the next dose, they should be instructed to skip the missed dose and go back to the regular schedule. Patients should not double their next dose or take more than the prescribed dose.

Drug Interactions

Advise patients to inform their physician immediately if they:

• develop severe diarrhea or vomiting.
• are currently taking drugs that are known to prolong the QTc interval and are metabolized through CYP3A4.
• are currently taking a cyclosporine or tacrolimus, or they notice swelling in an arm or leg or shortness of breath.
• are taking other drugs or before they begin taking other drugs as certain drugs can decrease or increase the plasma concentrations of posaconazole.

Serious and Potentially Serious Adverse Reactions

Advise patients to inform their physician immediately if they:

• notice a change in heart rate or heart rhythm, or have a heart condition or circulatory disease. Posaconazole can be administered with caution to patients with potentially proarrhythmic conditions.
• are pregnant, plan to become pregnant, or are nursing.
• have liver disease or develop itching, nausea or vomiting, their eyes or skin turn yellow, they feel more tired than usual or feel like they have the flu.
• have ever had an allergic reaction to other antifungal medicines such as ketoconazole, fluconazole, itraconazole, or voriconazole.

Manuf. for: Merck Sharp & Dohme Corp., a subsidiary of
MERCK & CO., INC., Whitehouse Station, NJ 08889, USA

Injection: Manuf. by: MSD International GmbH, Brinny, Innishannon, County Cork, Ireland

Delayed-Release Tablets: Manuf. by: N. V. Organon, Kloosterstraat 6, 5349 AB Oss, Netherlands

Oral Suspension: Manuf. by: Patheon Inc., Whitby, Ontario, Canada L1N 5Z5

For patent information: www.merck.com/product/patent/home.html

The trademarks referenced herein are owned by their respective companies.

Copyright © 2006-2017 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
All rights reserved.

uspi-mk5592-mf-1708r038

NDC 0085-4331-01

Noxafil®
(posaconazole)
Injection

300 mg/16.7 mL
(18 mg/mL)

For Intravenous Use Only

Requires further dilution prior to infusion.

Rx only
Single-Dose Vial

Take Noxafil exactly as prescribed by your doctor. Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

The liquid and tablet forms of posaconazole are not equivalent and may not have the same dose or schedule. Ask your pharmacist if you have any questions about the kind of Noxafil you receive at the pharmacy.

Do not crush, chew, dissolve, or break a delayed-release tablet. Swallow it whole.

Shake the oral suspension (liquid) well just before you measure a dose. Measure the liquid with a special dose-measuring spoon or medicine cup. If you do not have a dose-measuring device, ask your pharmacist for one.

Noxafil delayed-release tablets work best if you take it with food. Take the oral suspension within 20 minutes after a full meal. If you cannot eat a full meal, take the oral suspension with a nutritional supplement (such as BOOST) or with an acidic carbonated drink such as ginger ale.

Use this medicine for the full prescribed length of time. Your symptoms may improve before the infection is completely cleared. Skipping doses may also increase your risk of further infection that is resistant to antifungal medicine. Posaconazole will not treat a viral infection such as the flu or a common cold.

Call your doctor if you have ongoing vomiting or diarrhea. Noxafil may not work as well while during this time.

While using Noxafil, you may need frequent blood tests.

Store at room temperature away from moisture and heat. Do not freeze. Keep the bottle tightly closed when not in use.

Applies to posaconazole: intravenous solution, oral delayed release tablet, oral suspension

General

Thrombophlebitis was very common when multiple doses of the injection were administered via peripheral venous catheter, leading to administration via central venous catheter in later studies. The most common side effects reported with the IV injection were diarrhea, hypokalemia, pyrexia, and nausea.

The most common side effects reported with the delayed-release tablets were diarrhea, pyrexia, and nausea. The most common side effect leading to discontinuation of the delayed-release tablets was nausea (2%).

The most common side effects reported with the oral suspension in the prophylaxis clinical trials were fever, diarrhea, and nausea. The most common side effects leading to discontinuation of the oral suspension in these trials were associated with gastrointestinal disorders, including nausea (2%), vomiting (2%), and increased liver enzymes (2%).

The most common side effects reported with the oral suspension in the oropharyngeal candidiasis and refractory oropharyngeal candidiasis trials were fever, diarrhea, nausea, headache, vomiting, and coughing. The most common side effects leading to discontinuation of the oral suspension were respiratory impairment (1%) and pneumonia (1%) in patients with oropharyngeal candidiasis and AIDS (7%) and respiratory impairment (3%) in patients with refractory oropharyngeal candidiasis. Side effects occurred more often in patients with refractory oropharyngeal candidiasis. Serious side effects were reported in 55% of highly immunocompromised patients with advanced HIV disease. Fever (13%) and neutropenia (10%) were the serious side effects reported most often in these patients. Other serious side effects included altered drug levels (of other products), increased hepatic enzymes, nausea, rash, vomiting, bilirubinemia, and hepatocellular damage.[Ref]

Gastrointestinal

Very common (10% or more): Diarrhea (up to 42%), nausea (up to 38%), vomiting (up to 29%), abdominal pain (up to 27%), constipation (up to 21%), oral candidiasis (up to 12%), upper abdominal pain (up to 11%)
Common (1% to 10%): Dyspepsia, dry mouth, flatulence
Uncommon (0.1% to 1%): Mucositis, taste perversion, pancreatitis, mouth ulceration, loose stools, abdominal distension, dysphagia, ascites, eructation, gastritis, gastroesophageal reflux disease, esophagitis, tongue edema, tongue discoloration, tooth discoloration, mouth edema
Rare (less than 0.1%): Gastrointestinal hemorrhage, ileus, esophageal candidiasis, increased amylase, increased lipase, abdominal tenderness, cheilitis, hemorrhagic diarrhea, esophageal ulceration, hemorrhagic gastritis, odynophagia, increased pancreatic enzymes, proctalgia, retching, aphthous stomatitis, tenesmus, melena, gingivitis, glossitis, stomatitis[Ref]

Other

Very common (10% or more): Fever/pyrexia (up to 45%), rigors (up to 20%), fatigue (up to 17%), peripheral edema (16%), chills (up to 16%), leg edema (15%), mucosal inflammation (14%), asthenia (up to 13%), herpes simplex (up to 11%), pain (up to 11%)
Common (1% to 10%): Edema, weakness
Uncommon (0.1% to 1%): Altered drug levels, malaise, flushing, hot flushes, thirst, drug toxicity
Rare (less than 0.1%): Face edema, catheter-related infection, non-herpetic cold sores
Frequency not reported: Bacteremia, cytomegalovirus infection[Ref]

Metabolic

Very common (10% or more): Hypokalemia (up to 30%), anorexia (up to 19%), hypomagnesemia (up to 18%), decreased weight (up to 14%), decreased appetite (up to 12%), hyperglycemia (up to 11%), dehydration (up to 11%)
Common (1% to 10%): Hypocalcemia, electrolyte imbalance
Uncommon (0.1% to 1%): Hypertriglyceridemia, hyperuricemia, increased LDH
Rare (less than 0.1%): Hypercholesterolemia, hyperlipemia, hyperproteinemia, hypoalbuminemia, metabolic acidosis, vitamin K deficiency, increased weight[Ref]

Hematologic

Rare occurrences of hemolytic uremic syndrome and thrombotic thrombocytopenic purpura have been reported, generally in patients with concurrent cyclosporine or tacrolimus therapy for the prevention of transplant rejection or graft versus host disease.[Ref]

Very common (10% or more): Thrombocytopenia (up to 29%), anemia (up to 25%), neutropenia (up to 23%)
Common (1% to 10%): Hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, aggravated neutropenia
Uncommon (0.1% to 1%): Leukopenia, eosinophilia, lymphadenopathy
Rare (less than 0.1%): Pancytopenia, coagulopathy/coagulation disorder, hemorrhage, abnormal blood gases, neutrophilia, increased platelet count, decreased prothrombin, prolonged prothrombin time, purpura
Frequency not reported: Febrile neutropenia[Ref]

Nervous system

Very common (10% or more): Headache (up to 28%), dizziness (up to 11%)
Common (1% to 10%): Paresthesia, somnolence
Uncommon (0.1% to 1%): Tremor, convulsions, neuropathy, hypoesthesia, earache, vertigo, aphasia
Rare (less than 0.1%): Cerebrovascular accident, encephalopathy, peripheral neuropathy, syncope, hearing impairment, areflexia, ataxia, impaired cognition, dysphonia, dystonia, hemiparesis, hyperkinesia, hyperreflexia, hyporeflexia, hypotonia, impaired concentration, memory impairment, meningism, mononeuritis, restless leg syndrome, sciatica, tinnitus[Ref]

Respiratory

Very common (10% or more): Coughing (up to 25%), dyspnea (up to 20%), epistaxis (up to 17%), pharyngitis (up to 12%)
Common (1% to 10%): Pneumonia, pulmonary embolism
Uncommon (0.1% to 1%): Sinusitis, chest pain, nasal congestion, hiccups, pleuritic pain
Rare (less than 0.1%): Pulmonary hypertension, interstitial pneumonia, pneumonitis, upper respiratory tract infection, atelectasis, dry throat, nasal irritation, postnasal drip, pulmonary infiltration, rales, rhinitis, rhinorrhea[Ref]

Rare occurrences of pulmonary embolus have been reported, generally in patients with concurrent cyclosporine or tacrolimus therapy for the prevention of transplant rejection or graft versus host disease.[Ref]

Dermatologic

Very common (10% or more): Rash (up to 24%), pruritus (up to 11%), petechiae (up to 11%)
Common (1% to 10%): Increased sweating
Uncommon (0.1% to 1%): Alopecia, dry skin, maculopapular rash, urticaria, furunculosis, acne, pruritic rash
Rare (less than 0.1%): Stevens-Johnson syndrome, vesicular rash, dermatitis, erythema, erythematous rash, follicular rash, macular rash, night sweats, seborrhea, skin nodule, ecchymoses[Ref]

Cardiovascular

Very common (10% or more): Hypertension (up to 18%), hypotension (up to 14%), tachycardia (up to 12%)
Common (1% to 10%): Torsades de pointes
Uncommon (0.1% to 1%): Long QT syndrome, abnormal ECG, palpitations, bradycardia, QT/QTc prolongation, atrial fibrillation, atrial flutter, bundle branch block, extrasystoles, ventricular hypertrophy, supraventricular extrasystoles, vasculitis
Rare (less than 0.1%): Deep vein thrombosis, sudden death, ventricular tachycardia, cardiorespiratory arrest, cardiac failure, myocardial infarction, aortic valve sclerosis, cardiomegaly, decreased ejection fraction, mitral valve disease, supraventricular tachycardia, premature atrial contractions, premature ventricular contractions, atrioventricular block, atherosclerosis, ischemia, hematoma[Ref]

One patient taking posaconazole during a clinical trial developed torsades de pointes. This severely ill patient had a history of palpitations, recent cardiotoxic chemotherapy, hypokalemia, and hypomagnesemia; risk factors that may have contributed to or confounded the patient's condition.[Ref]

Hepatic

Very common (10% or more): Increased AST (up to 17%), changes in ALT (up to 17%), increased alkaline phosphatase (up to 13%), increased ALT (up to 11%)
Common (1% to 10%): Bilirubinemia, changes in bilirubin, increased total bilirubin, increased hepatic enzymes, abnormal hepatic function, hepatitis, hepatomegaly, jaundice, changes in AST, changes in alkaline phosphatase, increased gamma-glutamyl transpeptidase
Uncommon (0.1% to 1%): Hepatocellular damage
Rare (less than 0.1%): Hepatic failure, cholestatic hepatitis, cholestasis, hepatosplenomegaly, liver tenderness, asterixis, splenomegaly
Postmarketing reports: Severe hepatic injury with fatal outcome[Ref]

Clinically significant liver function test abnormalities during oropharyngeal candidiasis studies included increased AST, alkaline phosphatase, ALT, and total bilirubin. The majority of abnormal liver function tests in patients and healthy subjects were minor, transient, and did not lead to therapy discontinuation.

Changes in liver function tests from Grade 0, 1, or 2 at baseline to Grade 3 or 4 during prophylaxis studies included changes in ALT, bilirubin, AST, and alkaline phosphatase.

Total bilirubin greater than 1.5 times ULN (up to 22%), AST greater than 3 times ULN (up to 17%), alkaline phosphatase greater than 3 times ULN (up to 14%), and ALT greater than 3 times ULN (up to 11%) were reported.[Ref]

Psychiatric

Very common (10% or more): Insomnia (up to 17%)
Common (1% to 10%): Anxiety
Uncommon (0.1% to 1%): Altered mental status, confusion
Rare (less than 0.1%): Psychotic disorder, depression, amnesia, abnormal dreaming, emotional lability, decreased libido, paroniria, psychosis, delirium
Frequency not reported: Confusional state[Ref]

Musculoskeletal

Very common (10% or more): Musculoskeletal pain (up to 16%), arthralgia (up to 11%)
Common (1% to 10%): Back pain
Uncommon (0.1% to 1%): Myalgia, flank pain, muscle weakness, pain in extremity
Rare (less than 0.1%): Bone pain, chest wall pain, fasciitis, neck stiffness, cramps in the extremities, muscle cramps[Ref]

Genitourinary

Very common (10% or more): Vaginal hemorrhage (10%)
Uncommon (0.1% to 1%): Menstrual disorder, albuminuria, altered micturition frequency, dysuria, hematuria, nocturia
Rare (less than 0.1%): Breast pain, urinary tract infection, micturition disorder, urinary tract obstruction, leukorrhea[Ref]

Renal

Common (1% to 10%): Acute renal failure
Uncommon (0.1% to 1%): Increased blood creatinine, renal failure, renal insufficiency
Rare (less than 0.1%): Renal tubular acidosis, interstitial nephritis, increased BUN, renal calculus[Ref]

Endocrine

Common (1% to 10%): Adrenal insufficiency
Rare (less than 0.1%): Decreased blood gonadotropins[Ref]

Hypersensitivity

Common (1% to 10%): Allergic reaction
Rare (less than 0.1%): Hypersensitivity reactions[Ref]

Ocular

Uncommon (0.1% to 1%): Blurred vision, conjunctivitis
Rare (less than 0.1%): Diplopia, scotoma, eye pain, dry eyes, periorbital edema, photophobia[Ref]

Some side effects of Noxafil may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Animal studies have revealed evidence of embryotoxicity and teratogenicity. There are no controlled data in human pregnancy. AU TGA pregnancy category B3: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans. US FDA pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

This drug should not be used during pregnancy unless the benefit outweighs the risk to the fetus. AU TGA pregnancy category: B3 US FDA pregnancy category: C Comments: Effective contraception is recommended during therapy and for at least 2 weeks after the last dose; local protocol should be consulted regarding contraception timing.