Noxafil
Noxafil - General Information
Noxafil is a triazole antifungal drug that is used to treat invasive infections by Candida species and Aspergillus species in severely immunocompromised patients.
Pharmacology of Noxafil
Noxafil is a triazole antifungal drug that is used to treat invasive infections by Candida species and Aspergillus species in severely immunocompromised patients. There is also limited clinical evidence for its utility in treatment of invasive disease caused by Fusarium species (fusariosis). Two studies published in the January 25, 2007 issue of the New England Journal of Medicine suggest posaconazole may be superior to other triazoles, such as fluconazole or itraconazole, in the prevention of invasive fungal infections, although it may cause more serious side effects.
Noxafil for patients
NOXAFIL®
(posaconazole) Oral Suspension
Read the Patient Information that comes with NOXAFIL before you start taking it and each time you get a refill. There may be new information. This information does not replace talking with your doctor about your condition or treatment. Only your doctor can prescribe NOXAFIL and determine if it is right for you.
What is NOXAFIL?
- NOXAFIL® is a prescription medicine that is used to prevent invasive fungal infections (infections that can spread throughout the body) caused by Aspergillus or Candida in patients with weak immune systems because of medicines or diseases [such as stem cell transplantation with graft versus host disease or chemotherapy for hematologic malignancy (blood cancers)].
- NOXAFIL is also used to treat fungal infections in the mouth or throat area (known as “thrush”) caused by fungi called Candida. NOXAFIL can be used as initial treatment or as a treatment after itraconazole and/or fluconazole have failed.
NOXAFIL is for adults and children over 13 years of age.
What should I tell my doctor before taking NOXAFIL?
Tell your doctor about all your health conditions, including if you:
- are taking certain drugs that suppress your immune system like cyclosporine (Neoral ®), tacrolimus (Prograf®), or sirolimus (Rapamune®). Serious and rare fatal toxicity from cyclosporine has occurred when taken in combination with posaconazole and therefore reduction of the dose of drugs like cyclosporine, tacrolimus, or sirolimus and frequent monitoring of drug levels of these medicines is necessary when taking them in combination with posaconazole.
- have ever had an allergic reaction to other antifungal medicines such as ketoconazole, fluconazole, itraconazole, or voriconazole.
- are taking any other medicines, including prescription and non-prescription medicines, vitamins, and herbal supplements.
- have, or have had liver problems. Your doctor may do blood tests to make sure you should take NOXAFIL®.
- have, or have had an abnormal heart rate or rhythm.
- are, or think you are pregnant. Do not use NOXAFIL during pregnancy unless specifically advised by your doctor. You should use effective birth control while you are taking NOXAFIL if you are a woman who could become pregnant.
Contact your doctor immediately if you become pregnant while being treated with NOXAFIL.
Do not breast-feed while being treated with NOXAFIL, unless specifically advised by your doctor.
Who should not take NOXAFIL?
- Do NOT take NOXAFIL® if you are taking any of the medicines listed below. If any of these medicines are taken together with NOXAFIL, serious or life-threatening side effects from these medicines, or a decrease in the effect of NOXAFIL can occur. Tell your doctor right away if you are taking any of these medicines:
- ergot alkaloids [ergotamine, dihydroergotamine, methylsergide, methylergonovine, ergonovine or bromocriptine]
- terfenadine
- astemizole
- cisapride
- pimozide
- halofantrine
- quinidine
- rifabutin
- phenytoin
- cimetidine
- If you have questions or are uncertain about your medicines, talk with your doctor or pharmacist.
- Do not take NOXAFIL if you are allergic to anything in it. There is a list of what is in NOXAFIL at the end of this leaflet.
Can I take other medicines with NOXAFIL?
NOXAFIL® and many medicines can interact with each other and some must not be taken together. The dose of other medicines may need to be adjusted when taken with NOXAFIL [for example, cyclosporine (Neoral®), tacrolimus (Prograf®), or sirolimus (Rapamune®)]..
Knowing the medicines that you are taking is important. Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Keep a list of them with you to show your doctor or pharmacist. Do not take any new medicine without talking to your doctor.
What are possible side effects of NOXAFIL?
The most commonly reported side effects related to NOXAFIL® use were nausea, diarrhea, vomiting, headache, stomach pain, bloating, liver problems, low blood potassium, and decrease in neutrophils (certain type of white blood cells that fight infection).
Rarely, NOXAFIL may cause serious or life-threatening side effects. It may also cause severe drug interactions as discussed above. Call your doctor right away if you have any of the symptoms listed below.
Changes in heart rate or rhythm. People who have certain heart conditions or who take certain other medicines have a higher chance for this problem.
Rarely, very serious liver problems were reported in patients with serious underlying medical conditions. Your doctor may test your liver function while you are taking NOXAFIL. Call your doctor if you have any of these symptoms, as these may be signs of liver problems: you have itching, your eyes or skin turn yellow, you feel more tired than usual or feel like you have the flu, or you have nausea or vomiting.
Rarely, an increase in blood clots may occur in patients with blood cancers or post stem cell transplantation. These events may or may not be further increased in patients also on posaconazole and primarily occurred in patients also receiving cyclosporine or tacrolimus. If you notice swelling of one leg or shortness of breath, notify your doctor immediately.
These are not all the side effects associated with NOXAFIL. For more information, ask your doctor or pharmacist. If you experience any unusual effects while taking NOXAFIL, contact your doctor immediately.
How do I take NOXAFIL?
- NOXAFIL® comes in cherry-flavored liquid form. Shake NOXAFIL Oral Suspension well before use.
- Take NOXAFIL for as long as your doctor tells you. Take each dose of NOXAFIL with a full meal, or with a liquid nutritional supplement if you are unable to eat a full meal.
- Follow your doctor's instructions on when and how much of NOXAFIL you should take.
If you miss a dose of NOXAFIL, take it as soon as you remember.
- If you take too much NOXAFIL, call your doctor or poison control center immediately.
- Tell your doctor right away if you develop severe diarrhea or vomiting.
A measured dosing spoon is provided, marked for doses of 2.5 mL and 5 mL.
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It is recommended that the spoon is rinsed with water after each administration and before storage.
How do I store NOXAFIL?
- Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. DO NOT FREEZE. Keep all containers tightly closed.
- Keep NOXAFIL®, as well as other medicines, out of the reach of children.
General information about NOXAFIL
Doctors can prescribe medicines for conditions that are not in this leaflet. Use NOXAFIL® only as directed by your doctor. Do not give it to other people, even if they have the same symptoms as you. It may harm them.
This leaflet gives the most important information about NOXAFIL. For more information, talk to your doctor. You can ask your doctor or pharmacist for information about NOXAFIL that is written for health professionals.
What is in NOXAFIL?
Active ingredient: posaconazole
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.
Noxafil Interactions
A summary of significant drug interactions with posaconazole that have been studied clinically are provided in TABLES 8 and 9. Appropriate precautions for the co-administration of these drugs with posaconazole are provided.
TABLE 8. Summary of the Effect of Co-administered Drugs on Posaconazole
| Co-administered Drug | Recommendations |
| Cimetidine | Avoid concomitant use unless the benefit outweighs the risks. |
| Rifabutin | Avoid concomitant use unless the benefit outweighs the risks. |
| Phenytoin | Avoid concomitant use unless the benefit outweighs the risks. |
Co-administration of these drugs listed in TABLE 8 with posaconazole may result in lower plasma concentrations of posaconazole.
TABLE 9. Summary of the Effect of Posaconazole on Co-administered Drugs
| Co-administered Drug | Recommendations |
| Cyclosporine | Increased cyclosporine concentrations resulted in cyclosporine dose reductions in heart transplant patients co-administered posaconazole. At initiation of posaconazole treatment, reduce the cyclosporine dose to approximately three fourths of the original dose. Frequent monitoring of cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the cyclosporine dose adjusted accordingly. |
| Tacrolimus | Posaconazole has been shown to increase Cmax and AUC of tacrolimus significantly. At initiation of posaconazole treatment, reduce the tacrolimus dose to approximately one-third of the original dose. Frequent monitoring of tacrolimus whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus dose adjusted accordingly. |
| Rifabutin | Concomitant use of posaconazole and rifabutin should be avoided unless the benefit to the patient outweighs the risk. However, if concomitant administration is required frequent monitoring of full blood counts and adverse events due to increased rifabutin levels (eg, uveitis) is recommended. |
| Midazolam | Frequent monitoring of adverse effects of benzodiazepines metabolized by CYP3A4 should be performed and dose reduction of these benzodiazepines should be considered during co-administration with posaconazole. |
| Phenytoin | Frequent monitoring of phenytoin concentrations should be performed while co-administered with posaconazole and dose reduction of phenytoin should be considered. |
Although not studied in vitro or in vivo, posaconazole may affect the plasma concentrations of the drugs or drug classes described in TABLE 10. Appropriate precautions for the co-administration of these drugs with posaconazole are provided.
TABLE 10. Drugs Not Studied in vitro or in vivo but Likely to Result in Significant Drug Interactions
| Drug or Drug Class (CYP3A4 Substrates) |
Recommendations |
| Terfenadine, Astemizole, Pimozide, Cisapride, Quinidine | Increased plasma concentrations of these drugs can lead to QT prolongation with rare occurrences of torsade de pointes. Co-administration with posaconazole is contraindicated. |
| Ergot Alkaloids | Posaconazole may increase the plasma concentration of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism. Co-administration of posaconazole with ergot alkaloids is contraindicated. |
| Vinca Alkaloids | Posaconazole may increase the plasma concentrations of vinca alkaloids (eg, vincristine and vinblastine) which may lead to neurotoxicity. Therefore, it is recommended that the dose adjustment of the vinca alkaloid be considered. |
| Sirolimus | Frequent monitoring of sirolimus whole blood trough concentrations should be performed upon initiation, during co-administration, and at discontinuation of posaconazole treatment, with sirolimus doses reduced accordingly. |
| HMG-CoA reductase inhibitors (statins) metabolized through CYP3A4 | It is recommended that dose reduction of statins be considered during co-administration. Increased statin concentrations in plasma can be associated with rhabdomyolysis. |
| Calcium Channel Blockers metabolized through CYP3A4 | Frequent monitoring for adverse events and toxicity related to calcium channel blockers is recommended during co-administration. Dose reduction of calcium channel blockers may be needed. |
Noxafil Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Co-administration with ergot alkaloids.
Co-administration with the CYP3A4 substrates terfenadine, astemizole, cisapride, pimozide, halofantrine, or quinidine since this may result in increased plasma concentrations of these medicinal products, leading to QTc prolongation and rare occurrences of torsades de pointes.
Additional information about Noxafil
Noxafil Indication: For prophylaxis of invasive Aspergillus and Candida infections in patients, 13 years of age and older, who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy. Also for the treatment of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole.
Mechanism Of Action: As a triazole antifungal agent, posaconazole blocks the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of the enzyme lanosterol 14α-demethylase and accumulation of methylated sterol precursors.
Drug Interactions: Not Available
Food Interactions: Not Available
Generic Name: Posaconazole
Synonyms: Not Available
Drug Category: Antibiotics, Antifungal; Trypanocidal Agents
Drug Type: Small Molecule; Approved
Other Brand Names containing Posaconazole: Noxafil;
Absorption: Posaconazole is absorbed with a median Tmax of approximately 3 to 5 hours.
Toxicity (Overdose): During the clinical trials, some patients received posaconazole up to 1600 mg/day with no adverse events noted that were different from the lower doses. In addition, accidental overdose was noted in one patient who took 1200 mg BID for 3 days. No related adverse events were noted by the investigator.
Protein Binding: Posaconazole is highly protein bound (>98%), predominantly to albumin.
Biotransformation: Posaconazole primarily circulates as the parent compound in plasma. Of the circulating metabolites, the majority are glucuronide conjugates formed via UDP glucuronidation (phase 2 enzymes). Posaconazole does not have any major circulating oxidative (CYP450 mediated) metabolites. The excreted metabolites in urine and feces account for ~17% of the administered radiolabeled dose.
Half Life: Posaconazole is eliminated with a mean half-life (t½) of 35 hours (range 20 to 66 hours).
Dosage Forms of Noxafil: Suspension Oral
Chemical IUPAC Name: 4-[4-[4-[4-[[(5R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl)oxolan-3-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-2-[(2S,3S)-2-hydroxypentan-3-yl]-1,2,4-triazol-3-one
Chemical Formula: C37H42F2N8O4
Posaconazole on Wikipedia: https://en.wikipedia.org/wiki/Posaconazole
Organisms Affected: Aspergillis, Candida and other fungi