Noxafil 40mg / ml oral suspension

1. Name Of The Medicinal Product

Noxafil 40 mg/ml oral suspension

2. Qualitative And Quantitative Composition

Each ml of oral suspension contains 40 mg of posaconazole.

Excipients:

This medicinal product contains approximately 1.75 g of glucose per 5 ml of suspension.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Oral suspension

White suspension

4. Clinical Particulars

4.1 Therapeutic Indications

Noxafil is indicated for use in the treatment of the following fungal infections in adults (see section 5.1):

- 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.

4.2 Posology And Method Of Administration

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.

Posology

Recommended dose is shown in Table 1.

Table 1. Recommended dose according to indication

Indication	Dose and duration of therapy (See section 5.2)
Refractory Invasive Fungal Infections (IFI)/Patients with IFI intolerant to 1st line therapy	200 mg (5 ml) four times a day. Alternatively, patients who can tolerate food or a nutritional supplement may take 400 mg (10 ml) twice a day during or immediately following a meal or nutritional supplement. Duration of therapy should be based on the severity of the underlying disease, recovery from immunosuppression, and clinical response.
Oropharyngeal candidiasis	Loading 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 during or immediately after a meal, or a nutritional supplement in patients who cannot tolerate food to enhance the oral absorption and to ensure adequate exposure.
Prophylaxis of Invasive Fungal Infections	200 mg (5 ml) three times a day. Each dose of Noxafil should be administered during or immediately after a meal, or 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 .

Special populations

Renal impairment

An effect of renal impairment on the pharmacokinetics of posaconazole is not expected and no dose adjustment is recommended (see section 5.2).

Hepatic impairment

Limited data on the effect of hepatic impairment (including Child-Pugh C classification of chronic liver disease) on the pharmacokinetics of posaconazole demonstrate an increase in plasma exposure compared to subjects with normal hepatic function, but do not suggest that dose adjustment is necessary (see sections 4.4 and 5.2). It is recommended to exercise caution due to the potential for higher plasma exposure.

Paediatric population

The safety and efficacy of Noxafil in children aged below 18 years have not been established. Currently available data are described in sections 5.1 and 5.2, but no recommendation on a posology can be made.

Method of administration

For oral use

The oral suspension must be shaken well before use.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Co-administration with ergot alkaloids (see section 4.5).

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 (see sections 4.4 and 4.5).

Co-administration with the HMG-CoA reductase inhibitors simvastatin, lovastatin and atorvastatin (see section 4.5).

4.4 Special Warnings And Precautions For Use

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 hepatic insufficiency due to limited clinical experience and the possibility that posaconazole plasma levels may be higher in these patients (see sections 4.2 and 5.2).

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 evaluation 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 (see sections 4.3 and 4.5). 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 (other than those mentioned in section 4.3).

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 (see section 4.5).

Gastrointestinal dysfunction

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.

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 (see section 4.5).

Excipients

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.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

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 C_max (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 C_max 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 C_max 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 (C_max 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. Co-administration of posaconazole with H₂ receptor antagonists should be avoided if possible.

Similarly, administration of 400 mg posaconazole with esomeprazole (40 mg daily) decreased mean C_max and AUC by 46 % and 32 %, respectively, compared to dosing with 400 mg posaconazole alone. Co-administration of posaconazole with proton pump inhibitors should be avoided if possible.

Food: The absorption of posaconazole is significantly increased by food (see sections 4.2 and 5.2).

Alcohol: There are no data on interaction with posaconazole.

Herbal medicinal products: There are no data on interaction with posaconazole.

Smoking: There are no data on interaction with posaconazole.

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 reactions, plasma concentrations of the CYP3A4 substrate and/or adverse reactions 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 (see section 5.2).

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 (see section 4.3).

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 (see section 4.3).

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 (see section 4.3).

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 C_max 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 reactions related to increased rifabutin levels (e.g. uveitis) is recommended.

Sirolimus: Repeat dose administration of oral posaconazole (400 mg twice daily for 16 days) increased the C_max 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.

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 reactions, 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 C_max 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.

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 C_max 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 C_max 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 reactions 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 C_max 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 C_max and AUC by 1.6 and 6.2-fold (range 1.6 to 7.6-fold), respectively. Both doses of posaconazole increased C_max 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 reactions 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.

4.6 Pregnancy And Lactation

Pregnancy

There is insufficient information on the use of posaconazole in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Women of childbearing potential have to use effective contraception during treatment. Posaconazole must not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the foetus.

Breast-feeding

Posaconazole is excreted into the milk of lactating rats (see section 5.3). The excretion of posaconazole in human breast milk has not been investigated. Breast-feeding must be stopped on initiation of treatment with posaconazole.

Fertility

Posaconazole had no effect on fertility of male rats at a dose up to 180 mg/kg (1.7 times the 400-mg BID regimen based on steady-state plasma concentrations in healthy volunteers) or female rats at a dose up to 45 mg/kg (2.2 times the 400-mg BID regimen). There is no clinical experience assessing the impact of posaconazole on fertility in humans.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects of posaconazole on the ability to drive and use machines have been performed. Since certain adverse reactions (e.g. dizziness, somnolence, etc.) have been reported with posaconazole use, which potentially may affect driving/operating machinery, caution needs to be used.

4.8 Undesirable Effects

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 (

Table 2. Adverse reactions by body system and frequency
Blood and lymphatic system disorders Common: Uncommon: Rare:	neutropenia thrombocytopenia, leukopenia, anaemia, eosinophilia, lymphadenopathy haemolytic uraemic syndrome, thrombotic thrombocytopenic purpura, pancytopenia, coagulopathy, haemorrhage
Immune system disorders Uncommon: Rare:	allergic reaction hypersensitivity reaction
Endocrine disorders Rare:	adrenal insufficiency, blood gonadotropin decreased
Metabolism and nutrition disorders Common: Uncommon:	electrolyte imbalance, anorexia hyperglycaemia
Psychiatric disorders Rare: Not known:	psychotic disorder, depression confusional state
Nervous system disorders Common: Uncommon: Rare:	paresthesia, dizziness, somnolence, headache convulsions, neuropathy, hypoaesthesia, tremor cerebrovascular accident, encephalopathy, peripheral neuropathy, syncope
Eye disorders Uncommon: Rare:	blurred vision diplopia, scotoma
Ear and labyrinth disorder Rare:	hearing impairment
Cardiac disorders Uncommon: Rare:	long QT syndrome§, electrocardiogram abnormal§, palpitations torsade de pointes, sudden death, ventricular tachycardia, cardio-respiratory arrest, cardiac failure, myocardial infarction
Vascular disorders Uncommon: Rare:	hypertension, hypotension pulmonary embolism, deep vein thrombosis
Respiratory, thoracic and mediastinal disorders Rare:	pulmonary hypertension, interstitial pneumonia, pneumonitis
Gastrointestinal disorders Common: Uncommon: Rare:	vomiting, nausea, abdominal pain, diarrhoea, dyspepsia, dry mouth, flatulence pancreatitis gastrointestinal haemorrhage, ileus
Hepatobiliary disorders Common: Uncommon: Rare:	liver function tests raised (ALT increased, AST increased, bilirubin increased, alkaline phosphatase increased, GGT increased) hepatocellular damage, hepatitis, jaundice, hepatomegaly hepatic failure, hepatitis cholestatic, cholestasis, hepatosplenomegaly, liver tenderness, asterixis
Skin and subcutaneous tissue disorders Common: Uncommon: Rare:	rash mouth ulceration, alopecia Stevens Johnson syndrome, vesicular rash
Musculoskeletal and connective tissue disorders Uncommon:	back pain
Renal and urinary disorders Uncommon: Rare:	acute renal failure, renal failure, blood creatinine increased renal tubular acidosis, interstitial nephritis
Reproductive system and breast disorders Uncommon: Rare:	menstrual disorder breast pain
General disorders and administration site conditions Common: Uncommon: Rare:	pyrexia (fever), asthenia, fatigue oedema, pain, chills, malaise tongue oedema, face oedema
Investigations Uncommon:	altered medicine levels

^§ See section 4.4.

Hepatobiliary disorders

During post-marketing surveillance severe hepatic injury with fatal outcome has been reported (see section 4.4).

4.9 Overdose

During clinical trials, patients who received posaconazole doses up to 1,600 mg/day experienced no different adverse reactions from those reported with patients at the lower doses. Accidental overdose was noted in one patient who took 1,200 mg twice a day for 3 days. No adverse reactions were noted by the investigator.

Posaconazole is not removed by haemodialysis. There is no special treatment available in the case of overdose with posaconazole. Supportive care may be considered.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antimycotics for systemic use, triazole derivatives, ATC code: J02A C04.

Mechanism of action

Posaconazole inhibits the enzyme lanosterol 14α-demethylase (CYP51), which catalyses an essential step in ergosterol biosynthesis.

Microbiology

Posaconazole has been shown in vitro to be active against the following microorganisms: Aspergillus species (Aspergillus fumigatus, A. flavus, A. terreus, A. nidulans, A. niger, A. ustus), Candida species (Candida albicans, C. glabrata, C. krusei, C. parapsilosis, C. tropicalis, C. dubliniensis, C. famata, C. inconspicua, C. lipolytica, C. norvegensis, C. pseudotropicalis), Coccidioides immitis, Fonsecaea pedrosoi, and species of Fusarium, Rhizomucor, Mucor, and Rhizopus. The microbiological data suggest that posaconazole is active against Rhizomucor, Mucor, and Rhizopus, however the clinical data are currently too limited to assess the efficacy of posaconazole against these causative agents.

Resistance

Clinical isolates with decreased susceptibility to posaconazole have been identified. The principle mechanism of resistance is the acquisition of substitutions in the target protein, CYP51.

Combination with other antifungal agents

The use of combination antifungal therapies should not decrease the efficacy of either posaconazole or the other therapies; however, there is currently no clinical evidence that combination therapy will provide an added benefit.

Pharmacokinetic / Pharmacodynamic relationships

A correlation between total medicinal product exposure divided by MIC (AUC/MIC) and clinical outcome was observed. The critical ratio for subjects with Aspergillus infections was ~200. It is particularly important to try to ensure that maximal plasma levels are achieved in patients infected with Aspergillus (see sections 4.2 and 5.2 on recommended dose regimens and the effects of food on absorption).

Clinical experience

Invasive aspergillosis

Oral posaconazole 800 mg/day in divided doses was evaluated for the treatment of invasive aspergillosis in patients with disease refractory to amphotericin B (including liposomal formulations) or itraconazole or in patients who were intolerant of these medicinal products in a non-comparative salvage therapy trial. Clinical outcomes were compared with those in an external control group derived from a retrospective review of medical records. The external control group included 86 patients treated with available therapy (as above) mostly at the same time and at the same sites as the patients treated with posaconazole. Most of the cases of aspergillosis were considered to be refractory to prior therapy in both the posaconazole group (88 %) and in the external control group (79 %).

As shown in Table 3, a successful response (complete or partial resolution) at the end of treatment was seen in 42 % of posaconazole-treated patients compared to 26 % of the external group. However, this was not a prospective, randomised controlled study and so all comparisons with the external control group should be viewed with caution.

Table 3. Overall efficacy of posaconazole at the end of treatment for invasive aspergillosis in comparison to an external control group

	Posaconazole	External control group
Overall Response	45/107 (42 %)	22/86 (26 %)
Success by Species
All mycologically confirmed Aspergillus spp.1	34/76	(45 %)	19/74	(26 %)
A. fumigatus	12/29	(41 %)	12/34	(35 %)
A. flavus	10/19	(53 %)	3/16	(19 %)
A. terreus	4/14	(29 %)	2/13	(15 %)
A. niger	3/5	(60 %)	2/7	(29 %)

Fusarium spp.

11 of 24 patients who had proven or probable fusariosis were successfully treated with posaconazole 800 mg/day in divided doses for a median of 124 days and up to 212 days. Among eighteen patients who were intolerant or had infections refractory to amphotericin B or itraconazole, seven patients were classed as responders.

Chromoblastomycosis/Mycetoma

9 of 11 patients were successfully treated with posaconazole 800 mg/day in divided doses for a median of 268 days and up to 377 days. Five of these patients had chromoblastomycosis due to Fonsecaea pedrosoi and 4 had mycetoma, mostly due to Madurella species.

Coccidioidomycosis

11 of 16 patients were successfully treated (at the end of treatment complete or partial resolution of signs and symptoms present at baseline) with posaconazole 800 mg/day in divided doses for a median of 296 days and up to 460 days.

Treatment of azole-susceptible Oropharyngeal Candidiasis (OPC)

A randomised, evaluator-blind, controlled study was completed in HIV-infected patients with azole-susceptible oropharyngeal candidiasis (most patients studied had C. albicans isolated at baseline). The primary efficacy variable was the clinical success rate (defined as cure or improvement) after 14 days of treatment. Patients were treated with posaconazole or fluconazole oral suspension (both posaconazole and fluconazole were given as follows: 100 mg twice a day for 1 day followed by 100 mg once a day for 13 days).

The clinical response rates from the above study are shown in the Table 4 below.

Posaconazole was shown to be non-inferior to fluconazole for clinical success rates at Day 14 as well as 4 weeks after the end of treatment.

Table 4. Clinical success rates in Oropharyngeal Candidiasis

Endpoint	Posaconazole	Fluconazole
Clinical success rate at Day 14	91.7 % (155/169)	92.5 % (148/160)
Clinical success rate 4 weeks after end of treatment	68.5 % (98/143)	61.8 % (84/136)

Clinical success rate was defined as the number of cases assessed as having a clinical response (cure or improvement) divided by the total number of cases eligible for analysis.

Prophylaxis of Invasive Fungal Infections (IFIs) (Studies 316 and 1899)

Two randomised, controlled prophylaxis studies were conducted among patients at high risk for developing invasive fungal infections.

Study 316 was a randomised, double-blind trial of posaconazole oral suspension (200 mg three times a day) versus fluconazole capsules (400 mg once daily) in allogeneic hematopoietic stem cell transplant recipients with graft-versus-host disease (GVHD). The primary efficacy endpoint was the incidence of proven/probable IFIs at 16 weeks post-randomization as determined by an independent, blinded external expert panel. A key secondary endpoint was the incidence of proven/probable IFIs during the on-treatment period (first dose to last dose of study medicinal product + 7 days). The majority (377/600, [63 %]) of patients included had Acute Grade 2 or 3 or chronic extensive (195/600, [32.5 %]) GVHD at study start. The mean duration of therapy was 80 days for posaconazole and 77 days for fluconazole.

Study 1899 was a randomised, evaluator-blinded study of posaconazole oral suspension (200 mg three times a day) versus fluconazole suspension (400 mg once daily) or itraconazole oral solution (200 mg twice a day) in neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukemia or myelodysplastic syndromes. The primary efficacy endpoint was the incidence of proven/probable IFIs as determined by an independent, blinded external expert panel during the on-treatment period. A key secondary endpoint was the incidence of proven/probable IFIs at 100 days post-randomization. New diagnosis of acute myelogenous leukemia was the most common underlying condition (435/602, [72 %]). The mean duration of therapy was 29 days for posaconazole and 25 days for fluconazole/itraconazole.

In both prophylaxis studies, aspergillosis was the most common breakthrough infection. See Table 5 and 6 for results from both studies. There were fewer breakthrough Aspergillus infections in patients receiving posaconazole prophylaxis when compared to control patients.

Table 5. Results from clinical studies in prophylaxis of Invasive Fungal Infections.

Study	Posaconazole	Controla	P-Value
Proportion (%) of patients with proven/pr