Drug Class Description
Antimycotics for systemic use-triazole derivatives
Generic Name
Posaconazole
Drug Description
Each ml of oral suspension contains 40 mg of posaconazole.
Presentation
Oral suspensionWhite suspension
Indications
Noxafil is indicated for use in the treatment of the following fungal infections in adults- Invasive aspergillosis in patients with disease that is refractory to amphotericin B or itraconazole or in patients who are intolerant of these medicinal products;- Fusariosis in patients with disease that is refractory to amphotericin B or in patients who are intolerant of amphotericin B;- Chromoblastomycosis and mycetoma in patients with disease that is refractory to itraconazole or in patients who are intolerant of itraconazole;- Coccidioidomycosis in patients with disease that is refractory to amphotericin B, itraconazole or fluconazole or in patients who are intolerant of these medicinal products;- Oropharyngeal candidiasis: as first-line therapy in patients who have severe disease or are immunocompromised, in whom response to topical therapy is expected to be poor.Refractoriness is defined as progression of infection or failure to improve after a minimum of 7 days of prior therapeutic doses of effective antifungal therapy.Noxafil is also indicated for prophylaxis of invasive fungal infections in the following patients:- Patients receiving remission-induction chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS) expected to result in prolonged neutropenia and who are at high risk of developing invasive fungal infections;- Hematopoietic stem cell transplant (HSCT) recipients who are undergoing high-dose immunosuppressive therapy for graft versus host disease and who are at high risk of developing invasive fungal infections.
Adult Dosage
Treatment should be initiated by a physician experienced in the management of fungal infections or in the supportive care in the high risk patients for which posaconazole is indicated as prophylaxis.Recommended dosage is shown in Table 1.Table 1. Recommended dose according to indication IndicationDose and duration of therapyRefractory Invasive Fungal Infections (IFI)/Intolerant patients with IFI400 mg (10 ml) twice a day. In patients who cannot tolerate a meal or a nutritional supplement, Noxafil should be administered at a dose of 200 mg (5 ml) four times a day. Duration of therapy should be based on the severity of the underlying disease, recovery from immunosuppression, and clinical response.Oropharyngeal CandidiasisLoading dose of 200 mg (5 ml) once a day on the first day, then 100 mg (2.5 ml) once a day for 13 days. Each dose of Noxafil should be administered with a meal, or with a nutritional supplement in patients who cannot tolerate food to enhance the oral absorption and to ensure adequate exposure.Prophylaxis of Invasive Fungal Infections200 mg (5 ml) three times a day. Each dose of Noxafil should be administered with a meal, or with a nutritional supplement in patients who cannot tolerate food to enhance the oral absorption and to ensure adequate exposure. The duration of therapy is based on recovery from neutropenia or immunosuppression. For patients with acute myelogenous leukemia or myelodysplastic syndromes, prophylaxis with Noxafil should start several days before the anticipated onset of neutropenia and continue for 7 days after the neutrophil count rises above 500 cells per mm3 .There are limited pharmacokinetic data in patients with severe gastrointestinal dysfunction (such as severe diarrhoea). Patients who have severe diarrhoea or vomiting should be monitored closely for breakthrough fungal infections.The oral suspension must be shaken well before use.Use in renal impairment: An effect of renal impairment on the pharmacokinetics of posaconazole is not expected and no dose adjustment is recommended.Use in hepatic impairment: There are limited pharmacokinetic data in patients with hepatic impairment; therefore, no recommendation for dose adjustment can be made. In the small number of subjects studied who had hepatic impairment, there was an increase in exposure and half-life with a decrease in hepatic function.Use in children: Safety and efficacy in children and adolescents below the age of 18 years have not been established. Therefore posaconazole is not recommended for use in patients below 18 years of age.
Child Dosage
Safety and efficacy in children and adolescents below the age of 18 years have not been established. Therefore posaconazole is not recommended for use in patients below 18 years of age.
Elderly Dosage
See Adult Dosage
Contra Indications
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.Co-administration with the HMG-CoA reductase inhibitors simvastatin, lovastatin and atorvastatin.
Special Precautions
Hypersensitivity: There is no information regarding cross-sensitivity between posaconazole and other azole antifungal agents. Caution should be used when prescribing Noxafil to patients with hypersensitivity to other azoles.Hepatic toxicity: Hepatic reactions (e.g. mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin and/or clinical hepatitis) have been reported during treatment with posaconazole. Elevated liver function tests were generally reversible on discontinuation of therapy and in some instances these tests normalised without interruption of therapy. Rarely, more severe hepatic reactions with fatal outcomes have been reported.Posaconazole should be used with caution in patients with severe hepatic impairment. In these patients, the prolonged elimination half-life may lead to increased exposure.Monitoring of hepatic function: Patients who develop abnormal liver function tests during Noxafil therapy must be routinely monitored for the development of more severe hepatic injury. Patient management should include laboratory eva luation of hepatic function (particularly liver function tests and bilirubin). Discontinuation of Noxafil should be considered if clinical signs and symptoms are consistent with development of liver disease.QTc prolongation: Some azoles have been associated with prolongation of the QTc interval. Noxafil must not be administered with medicinal products that are substrates for CYP3A4 and are known to prolong the QTc interval. Noxafil should be administered with caution to patients with pro-arrhythmic conditions such as:• Congenital or acquired QTc prolongation• Cardiomyopathy, especially in the presence of cardiac failure• Sinus bradycardia• Existing symptomatic arrhythmias• Concomitant use with medicinal products known to prolong the QTc interval.Electrolyte disturbances, especially those involving potassium, magnesium or calcium levels, should be monitored and corrected as necessary before and during posaconazole therapy.Posaconazole is an inhibitor of CYP3A4 and should only be used under specific circumstances during treatment with other medicinal products that are metabolised by CYP3A4.Rifabutin: Concomitant use with posaconazole should be avoided unless the benefit to the patient outweighs the risk.Rifamycin antibacterials (rifampicin, rifabutin), certain anticonvulsants (phenytoin, carbamazepine, phenobarbital, primidone), efavirenz and cimetidine: Posaconazole concentrations may be significantly lowered in combination; therefore, concomitant use with posaconazole should be avoided unless the benefit to the patient outweighs the risk.This medicinal product contains approximately 1.75 g of glucose per 5 ml of suspension. Patients with glucose-galactose malabsorption should not take this medicine.
Interactions
Effects of other medicinal products on posaconazole:Posaconazole is metabolised via UDP glucuronidation (phase 2 enzymes) and is a substrate for p-glycoprotein (P-gp) efflux in vitro. Therefore, inhibitors (e.g. verapamil, ciclosporin, quinidine, clarithromycin, erythromycin, etc.) or inducers (e.g. rifampicin, rifabutin, certain anticonvulsants, etc.) of these clearance pathways may increase or decrease posaconazole plasma concentrations, respectively.Rifabutin (300 mg once a day) decreased the Cmax (maximum plasma concentration) and AUC (area under the plasma concentration time curve) of posaconazole to 57 % and 51 %, respectively. Concomitant use of posaconazole and rifabutin and similar inducers (e.g. rifampicin) should be avoided unless the benefit to the patient outweighs the risk. See also below regarding the effect of posaconazole on rifabutin plasma levels.Efavirenz (400 mg once a day) decreased the Cmax and AUC of posaconazole by 45 % and 50 %, respectively. Concomitant use of posaconazole and efavirenz should be avoided unless the benefit to the patient outweighs the risk.Phenytoin (200 mg once a day) decreased the Cmax and AUC of posaconazole by 41 % and 50 %, respectively. Concomitant use of posaconazole and phenytoin and similar inducers (e.g. carbamazepine, phenobarbital, primidone) should be avoided unless the benefit to the patient outweighs the risk.H2 receptor antagonists and proton pump inhibitors: Posaconazole plasma concentrations (Cmax and AUC) were reduced by 39 % when posaconazole was administered with cimetidine (400 mg twice a day) due to reduced absorption possibly secondary to a decrease in gastric acid production. Concomitant use of posaconazole and cimetidine should be avoided unless the benefit to the patient outweighs the risk. The effect of other H2 receptor antagonists (e.g. famotidine, ranitidine) and proton pump inhibitors (e.g. omeprazole) that may suppress gastric acidity for several hours on plasma levels of posaconazole has not been studied but a reduction in bioavailability may occur so that co-administration should be avoided if possible.Effects of posaconazole on other medicinal products:Posaconazole is a potent inhibitor of CYP3A4. Co-administration of posaconazole with CYP3A4 substrates may result in large increases in exposure to CYP3A4 substrates as exemplified by the effects on tacrolimus, sirolimus, atazanavir and midazolam below. Caution is advised during co-administration of posaconazole with CYP3A4 substrates administered intravenously and the dose of the CYP3A4 substrate may need to be reduced. If posaconazole is used concomitantly with CYP3A4 substrates that are administered orally, and for which an increase in plasma concentrations may be associated with unacceptable adverse events, plasma concentrations of the CYP3A4 substrate and/or adverse events should be closely monitored and the dose adjusted as needed. Several of the interaction studies were conducted in healthy volunteers in whom a higher exposure to posaconazole occurs compared to patients administered the same dose. The effect of posaconazole on CYP3A4 substrates in patients might be somewhat lower than that observed in healthy volunteers, and is expected to be variable between patients due to the variable posaconazole exposure in patients. The effect of co-administration with posaconazole on plasma levels of CYP3A4 substrates may also be variable within a patient, unless posaconazole is administered in a strictly standardised way with food, given the large food effect on posaconazole exposure.Terfenadine, astemizole, cisapride, pimozide, halofantrine and quinidine (CYP3A4 substrates):Co-administration of posaconazole and terfenadine, astemizole, cisapride, pimozide, halofantrine or quinidine is contraindicated. Co-administration may result in increased plasma concentrations of these medicinal products, leading to QTc prolongation and rare occurrences of torsades de pointes.Ergot alkaloids: Posaconazole may increase the plasma concentration of ergot alkaloids (ergotamine and dihydroergotamine), which may lead to ergotism. Co-administration of posaconazole and ergot alkaloids is contraindicated.HMG-CoA reductase inhibitors metabolised through CYP3A4 (e.g. simvastatin, lovastatin, and atorvastatin): Posaconazole may substantially increase plasma levels of HMG-CoA reductase inhibitors that are metabolised by CYP3A4. Treatment with these HMG-CoA reductase inhibitors should be discontinued during treatment with posaconazole as increased levels have been associated with rhabdomyolysis.Vinca alkaloids: Posaconazole may increase the plasma concentration of vinca alkaloids (e.g. vincristine and vinblastine), which may lead to neurotoxicity. Therefore, concomitant use of posaconazole and vinca alkaloids should be avoided unless the benefit to the patient outweighs the risk. If co-administered, then it is recommended that dose adjustment of vinca alkaloids be considered.Rifabutin: Posaconazole increased the Cmax and AUC of rifabutin by 31 % and 72 %, respectively. Concomitant use of posaconazole and rifabutin should be avoided unless the benefit to the patient outweighs the risk (see also above regarding the effect of rifabutin on plasma levels of posaconazole). If these medicinal products are co-administered, careful monitoring of full blood counts and adverse events related to increased rifabutin levels (e.g. uveitis) is recommended.Ciclosporin: In heart transplant patients on stable doses of ciclosporin, posaconazole 200 mg once daily increased ciclosporin concentrations requiring dose reductions. Cases of elevated ciclosporin levels resulting in serious adverse events, including nephrotoxicity and one fatal case of leukoencephalopathy, were reported in clinical efficacy studies. When initiating treatment with posaconazole in patients already receiving ciclosporin, the dose of ciclosporin should be reduced (e.g. to about three quarters of the current dose). Thereafter blood levels of ciclosporin should be monitored carefully during co-administration, and upon discontinuation of posaconazole treatment, and the dose of ciclosporin should be adjusted as necessary.Tacrolimus: Posaconazole increased Cmax and AUC of tacrolimus (0.05 mg/kg body weight single dose) by 121 % and 358 %, respectively. Clinically significant interactions resulting in hospitalisation and/or posaconazole discontinuation were reported in clinical efficacy studies. When initiating posaconazole treatment in patients already receiving tacrolimus, the dose of tacrolimus should be reduced (e.g. to about one third of the current dose). Thereafter blood levels of tacrolimus should be monitored carefully during co-administration, and upon discontinuation of posaconazole, and the dose of tacrolimus should be adjusted as necessary.Sirolimus: Repeat dose administration of oral posaconazole (400 mg twice daily for 16 days) increased the Cmax and AUC of sirolimus (2 mg single dose) an average of 6.7-fold and 8.9-fold (range 3.1 to 17.5-fold), respectively, in healthy subjects. The effect of posaconazole on sirolimus in patients is unknown, but is expected to be variable due to the variable posaconazole exposure in patients. Co-administration of posaconazole with sirolimus is not recommended and should be avoided whenever possible. If it is considered that co-administration is unavoidable, then it is recommended that the dose of sirolimus should be greatly reduced at the time of initiation of posaconazole therapy and that there should be very frequent monitoring of trough concentrations of sirolimus in whole blood. Sirolimus concentrations should be measured upon initiation, during co-administration, and at discontinuation of posaconazole treatment, with sirolimus doses adjusted accordingly. It should be noted that the relationship between sirolimus trough concentration and AUC is changed during co-administration with posaconazole. As a result, sirolimus trough concentrations that fall within the usual therapeutic range may result in sub-therapeutic levels. Therefore trough concentrations that fall in the upper part of the usual therapeutic range should be targetted and careful attention should be paid to clinical signs and symptoms, laboratory parameters and tissue biopsies.HIV Protease Inhibitors: As HIV protease inhibitors are CYP3A4 substrates, it is expected that posaconazole will increase plasma levels of these antiretroviral agents. Following co-administration of oral posaconazole (400 mg twice daily) with atazanavir (300 mg once daily) for 7 days in healthy subjects Cmax and AUC of atazanavir increased by an average of 2.6-fold and 3.7-fold (range 1.2 to 26-fold), respectively. Following co-administration of oral posaconazole (400 mg twice daily) with atazanavir and ritonavir (300/100 mg once daily) for 7 days in healthy subjects Cmax and AUC of atazanavir increased by an average of 1.5-fold and 2.5-fold (range 0.9 to 4.1-fold), respectively. The addition of posaconazole to therapy with atazanavir or with atazanavir plus ritonavir was associated with increases in plasma bilirubin levels. Frequent monitoring for adverse events and toxicity related to antiretroviral agents that are substrates of CYP3A4 is recommended during co-administration with posaconazole.Midazolam and other benzodiazepines metabolised by CYP3A4: In a study in healthy volunteers posaconazole (200 mg once daily for 10 days) increased the exposure (AUC) of IV midazolam (0.05 mg/kg) by 83 %. In another study in healthy volunteers, repeat dose administration of oral posaconazole (200 mg twice daily for 7 days) increased the Cmax and AUC of IV midazolam (0.4 mg single dose) by an average of 1.3- and 4.6-fold (range 1.7 to 6.4-fold), respectively; Posaconazole 400 mg twice daily for 7 days increased the IV midazolam Cmax and AUC by 1.6 and 6.2-fold (range 1.6 to 7.6-fold), respectively. Both doses of posaconazole increased Cmax and AUC of oral midazolam (2 mg single oral dose) by 2.2 and 4.5-fold, respectively. In addition, oral posaconazole (200 mg or 400 mg) prolonged the mean terminal half-life of midazolam from approximately 3-4 hours to 8-10 hours during co-administration.Due to the risk of prolonged sedation it is recommended that dose adjustments should be considered when posaconazole is administered concomitantly with any benzodiazepine that is metabolised by CYP3A4 (e.g. midazolam, triazolam, alprazolam).Calcium channel blockers metabolised through CYP3A4 (e.g. diltiazem, verapamil, nifedipine, nisoldipine): Frequent monitoring for adverse events and toxicity related to calcium channel blockers is recommended during co-administration with posaconazole. Dose adjustment of calcium channel blockers may be required.Digoxin: Administration of other azoles has been associated with increases in digoxin levels. Therefore, posaconazole may increase plasma concentration of digoxin and digoxin levels need to be monitored when initiating or discontinuing posaconazole treatment.Sulfonylureas: Glucose concentrations decreased in some healthy volunteers when glipizide was co-administered with posaconazole. Monitoring of glucose concentrations is recommended in diabetic patients.
Adverse Reactions
The safety of posaconazole has been assessed in> 2,400 patients and healthy volunteers enrolled in clinical trials and from post-marketing experience. The most frequently reported serious related adverse reactions included nausea, vomiting, diarrhoea, pyrexia, and increased bilirubin. Within the organ system classes, adverse reactions are listed under headings of frequency using the following categories: very common (1/10); common (1/100 to <1/10); uncommon (1/1,000 to <1/100); rare ( 1/10,000 to <1/1,000); very rare (<1/10,000); not known.Table 2. Adverse reactions by body system and frequencyBlood and lymphatic system disordersCommon:Uncommon:Rare:neutropeniathrombocytopenia, leukopenia, anaemia, eosinophilia, lymphadenopathyhaemolytic uraemic syndrome, thrombotic thrombocytopenic purpura, pancytopenia, coagulopathy, haemorrhageImmune system disordersUncommon:Rare:allergic reactionhypersensitivity reactionEndocrine disordersRare:adrenal insufficiency, blood gonadotropin decreasedMetabolism and nutrition disordersCommon:Uncommon:electrolyte imbalance, anorexiahyperglycaemiaPsychiatric disordersRare:Not known:psychotic disorder, depressionconfusional stateNervous system disordersCommon:Uncommon:Rare:paresthesia, dizziness, somnolence, headacheconvulsions, neuropathy, hypoaesthesia, tremorcerebrovascular accident, encephalopathy, peripheral neuropathy, syncopeEye disordersUncommon:Rare:blurred visiondiplopia, scotomaEar and labyrinth disorderRare:hearing impairmentCardiac disordersUncommon:Rare:long QT syndrome, electrocardiogram abnormal, palpitationstorsade de pointes, sudden death, ventricular tachycardia, cardio-respiratory arrest, cardiac failure, myocardial infarctionVascular disordersUncommon:Rare:hypertension, hypotensionpulmonary embolism, deep vein thrombosisRespiratory, thoracic and mediastinal disordersRare:pulmonary hypertension, interstitial pneumonia, pneumonitisGastrointestinal disordersCommon:Uncommon:Rare:vomiting, nausea, abdominal pain, diarrhoea, dyspepsia, dry mouth, flatulencepancreatitisgastrointestinal haemorrhage, ileusHepatobiliary disordersCommon:Uncommon:Rare:liver function tests raised (ALT increased, AST increased, bilirubin increased, alkaline phosphatase increased, GGT increased)hepatocellular damage, hepatitis, jaundice, hepatomegalyhepatic failure, hepatitis cholestatic, cholestasis, hepatosplenomegaly, liver tenderness, asterixisSkin and subcutaneous tissue disordersCommon:Uncommon:Rare:rashmouth ulceration, alopeciaStevens Johnson syndrome, vesicular rashMusculoskeletal and connective tissue disordersUncommon:back painRenal and urinary disorders Uncommon:Rare:acute renal failure, renal failure, blood creatinine increasedrenal tubular acidosis, interstitial nephritisReproductive system and breast disordersUncommon:Rare:menstrual disorderbreast painGeneral disorders and administration site conditionsCommon:Uncommon:Rare:pyrexia (fever), asthenia, fatigueoedema, pain, chills, malaisetongue oedema, face oedemaInvestigationsUncommon:altered medicine levelsHepatobiliary disordersDuring post-marketing surveillance severe hepatic injury with fatal outcome has been reported
Manufacturer
Schering-Plough
Drug Availability
(POM)
Updated
05 November 2010
