Summary of medicine characteristics - Posaconazole SP
1. NAME OF THE MEDICINAL PRODUCT
Posaconazole SP 40 mg/ml oral suspension
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml of oral suspension contains 40 mg of posaconazole.
For a full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Oral suspension
White suspension
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Posaconazole SP 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 immunocompromised, in
Refractoriness is defined as p
ine therapy in patients who have severe disease or are onse to topical therapy is expected to be poor.
of prior therapeutic doses of effective antifungal therapy.
ion of infection or failure to improve after a minimum of 7 days
Posaconazole SP is also i patients:
ted for prophylaxis of invasive fungal infections in the following
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.
sology and method of administration
ent should be initiated by a physician experienced in the management of fungal infections or in 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
| Indication | Dose and duration of therapy | |
| Refractory Invasive Fungal Infections (IFI)/Intolerant patients with IFI | 400 mg (10 ml) twice a day. In patients who cannot tolerate a meal or a nutritional supplement, Posaconazole SP 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. | À) |
| 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 Posaconazole SP 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. J | |
| Prophylaxis of Invasive Fungal Infections | 200 mg (5 ml) three times a day. Each dose of Posaconazole SP 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 Posaconazole SP 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 (see section 5.2).
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 (see sections 4.4 and 5.2).
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 (see sections 5.1 and 5.2).
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 Posaconazole SP 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 w posaconazole. Elevated liver function tests were generally reversible on discontinuation of 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
uring
Posaconazole SP 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 Posaconazole SP should be considered if clinical signs and symptoms are consistent with development of liver disease.
QTc prolongation: Some azoles have been associated with prolon the QTc interval. Posaconazole SP must not be administered with medicinal products that are substrates for CYP3A4 and are known to prolong the QTc interval (see sections 4. 4.5). Posaconazole SP should be
administered with caution to patients with pro-arrhythmic ions such as:
- • Congenital or acquired QTc prolongation
Cardiomyopathy, especially in the presence Sinus bradycardia
Existing symptomatic arrhythmias Concomitant use with medicinal products k mentioned in section 4.3).
diac failure
own to prolong the QTc interval (other than those
ing potassium, magnesium or calcium levels, should efore and during posaconazole therapy.
Posaconazole is an inhibitor of treatment with other medicinal
Electrolyte disturbances, especially tho be monitored and corrected as necess
nd should only be used under specific circumstances during s that are metabolised by CYP3A4 (see section 4.5).
Rifabutin: Concomitant use with posaconazole should be avoided unless the benefit to the patient outweighs the risk (see section 4.5).
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).
This medi glucose-ga
oduct contains approximately 1.75 g of glucose per 5 ml of suspension. Patients with malabsorption should not take this medicine.
action 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 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 be the patient outweighs the risk.
0.
Phenytoin (200 mg once a day) decreased the Cmax and AUC of posaconazole by 41 respectively. Concomitant use of posaconazole and phenytoin and similar inducers carbamazepine, phenobarbital, primidone) should be avoided unless the benefit to the patient outweighs the risk.
H 2 receptor antagonists and proton pump inhibitors : Posaconazole plasma AUC) were reduced by 39 % when posaconazole was administered with c day) due to reduced absorption possibly secondary to a decrease in gastric Concomitant use of posaconazole and cimetidine should be avoided unles outweighs the risk. The effect of other H2 receptor antagonists (e.g. famoti
pump inhibitors (e.g. omeprazole) that may suppress gastric aci of posaconazole has not been studied but a reduction in bioavai administration should be avoided if possible.
a concentrations (Cmax and imetidine (400 mg twice a acid production.
s the benefit to the patient idine, ranitidine) and proton veral hours on plasma levels
Effects of posaconazole on other medicinal products: Posaconazole is a potent inhibitor of CYP3A4. Co-
bility may occur so that co-
substrates may result in large increases in exposur effects on tacrolimus, sirolimus, atazanavir and administration of posaconazole with CYP3A4
the CYP3A4 substrate may need to be re substrates that are administered orally, an associated with unacceptable adverse eve adverse events should be closely monitor
ed. If
inistration of posaconazole with CYP3A4 CYP3A4 substrates as exemplified by the am below. Caution is advised during co-
trates administered intravenously and the dose of osaconazole is used concomitantly with CYP3A4
in patients might be somewh variable between patients d administration with posaco a patient, unless posaconaz food effect on posaconazol
studies were conducted in healt compared to patients administer
to
d for which an increase in plasma concentrations may be ts, plasma concentrations of the CYP3A4 substrate and/or d and the dose adjusted as needed. Several of the interaction ers in whom a higher exposure to posaconazole occurs
same dose. The effect of posaconazole on CYP3A4 substrates an that observed in healthy volunteers, and is expected to be e variable posaconazole exposure in patients. The effect of coon plasma levels of CYP3A4 substrates may also be variable within
le is administered in a strictly standardised way with food, given the large 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).
aloids : Posaconazole may increase the plasma concentration of ergot alkaloids (ergotamine droergotamine), which may lead to ergotism. Co-administration of posaconazole and ergot
ds 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 risk. If co-administered, then it is recommended that dose adjustment of vinca alkaloids be con
Rifabutin : Posaconazole increased the Cmax and AUC of rifabutin by 31 % and 72 %, respec Concomitant use of posaconazole and rifabutin should be avoided unless the benefit to the p 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, posaconaz 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 tacr dose) by 121 % and 358 %, respectively. Clinically signifi and/or posaconazole discontinuation were reported in clin
posaconazole treatment in patients already receivin reduced (e.g. to about one third of the current dose monitored carefully during co-administration, a of tacrolimus should be adjusted as necessary.
.05 mg/kg body weight single teractions resulting in hospitalisation efficacy studies. When initiating
rolimus, the dose of tacrolimus should be Thereafter blood levels of tacrolimus should be
discontinuation of posaconazole, and the dose
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 administration of posaconazole possible. If it is considered that of sirolimus should be greatly r
should be very frequent concentrations should be posaconazole treatment, relationship between siro
variable due to the variable posaconazole exposure in patients. Co-with sirolimus is not recommended and should be avoided whenever co-administration is unavoidable, then it is recommended that the dose duced at the time of initiation of posaconazole therapy and that there ing of trough concentrations of sirolimus in whole blood. Sirolimus
with posaconazo range may res of the usual th and sympt
asured upon initiation, during co-administration, and at discontinuation of h sirolimus doses adjusted accordingly. It should be noted that the us trough concentration and AUC is changed during co-administration ult, sirolimus trough concentrations that fall within the usual therapeutic
sub-therapeutic levels. Therefore trough concentrations that fall in the upper part eutic range should be targetted and careful attention should be paid to clinical signs oratory 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 aconazole (400 mg twice daily) with atazanavir (300 mg once daily) for 7 days in healthy
s Cmax and AUC of atazanavir increased by an average of 2.6-fold and 3.7-fold (range 1.2 to 26, 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 azanavir 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 single dose) by an average of 1.3– and 4.6-fold (range 1.7 to 6.4-fold), respectively; Posaconazol 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 810 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).
verapamil, nifedipine, to calcium channel blockers stment of calcium channel
Calcium channel blockers metabolised through CYP3A4 (e.g. diltiazem nisoldipine): Frequent monitoring for adverse events and toxicity relate is recommended during co-administration with posaconazole. Dose adju blockers may be required.
Digoxin : Administration of other azoles has been associated Therefore, posaconazole may increase plasma concentration monitored when initiating or discontinuing posaconazole tre
increases in digoxin levels.
igoxin and digoxin levels need to be nt.
Sulfonylureas : Glucose concentrations decreased in some healthy volunteers when glipizide was coadministered with posaconazole. Monitoring of glucose concentrations is recommended in diabetic patients.
-
4.6 Pregnancy and lactation
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.
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.
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.
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 events included nausea, vomiting, diarrhoea, pyrexia, and increased bilirubin. ____________
-
Table 2. Treatment-related adverse events (TRAE) by body system and frequency Common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000)
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:
11 t
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:
psychotic disorder, depression
Nervous system disorders
Common:
Uncommon:
Rare:
paresthesia, dizziness, somnolence, headache convulsion, neuropathy, hypoaesthesia, tremor cerebrovascular accident, encephalopathy, peripheral neuropathy, syncope
Eye disorders
Uncommon:
Rare:
blurred vision diplopia, scotoma
Ear and labyrinth disorder
Rare:
hearing impaired
Cardiac disorders
Uncommon:
Rare:
ry
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:
medicine level changed
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 clinica 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. mechanism of resistance is the acquisition of substitutions in the target protein, CYP
e
Combination with other antifungal agents
The use of combination antifungal therapies should not decrease the effi the other therapies; however, there is currently no clinical evidence that provide an added benefit.
Pharmacokinetic / Pharmacodynamic relationships:
A correlation between total medicinal product exposure divided by outcome was observed. The critical ratio for subjects with Asperg
particularly important to try to ensure that maximal plasma lev with Aspergillus (see sections 4.2 and 5.2 on recommended do absorption).
r posaconazole or therapy will
C/MIC) and clinical ctions was ~200. It is eved in patients infected
egimens and the effects of food on
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 bo osaconazole 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. Overal cy 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 A. fumigatus | 12/29 | (41 %) | 12/34 | (35 %) |
| AfaVA. flavus | 10/19 | (53 %) | 3/16 | (19 %) |
| A. te A. terreus | 4/14 | (29 %) | 2/13 | (15 %) |
| A. niger | 3/5 | (60 %) | 2/7 | (29 %) |
1 Includes other less common species or species unknown
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 VJ | 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 | Control a | P-Value |
| Proportion (%) of patients with proven/probable IFIs | |||
| On-treatment period b . | |||
| 1899d | 7/304 (2) | 25/298 (8) | K 0.0009 |
| 316e | 7/291 (2) | 22/288 (8) | – 0.0038 |
| Fixed-time period c | |||
| 1899d | 14/304 (5) | 33/298 (11) | 0.0031 |
| 316 d | 16/301 (5) | 27/299 (9) | 0.0740 |
FLU = fluconazole; ITZ = itraconazole; POS = posaconazole.
a: FLU/ITZ (1899); FLU (316).
b: In 1899 this was the period from randomization to last dose of study medicinal product plus 7 days; in 316 it was the
period from first dose to last dose of study medicinal product plus 7 days.
-
c: In 1899, this was the period from randomization to 100 days post-randomization; in 316 it was the period from the baseline day to 111 days post-baseline.
-
d: All randomized
-
e: All treated
16 it was the
period from the
Table 6. Results from clinical studies in prophylaxis of Invasive Fungal Infections.
Study
Posaconazole
Control a
Proportion (%) of patients with proven/probable Aspergillosis
On-treatment period b ft
1899d
2/304 (1)
20/298 (7)
♦ sz
316e
3/291 (1)
17/288 (6)
Fixed-time periodc
Cv
1899d
4/304 (1)
26/298 (9)
316 d
7/301 (2)
21/299 (7)
FLU = fluconazole; ITZ = itraconazole; POS = posaconazole.
a:
b:
FLU/ITZ (1899); FLU (316).
In 1899 this was the period from randomization to last dose of study medicinal product plus 7 period from first dose to last dose of study medicinal product plus 7 days.
In 1899, this was the period from randomization to 100 days post-randomization; in 316 it wa baseline day to 111 days post-baseline.
All randomized
All treated
c:
d:
e:
In Study 1899, a significant decrease in all cause mortality in favo [POS 49/304 (16 %) vs. FLU/ITZ 67/298 (22 %) p= 0.048]. Base
probability of survival up to day 100 after randomization, was recipients; this survival benefit was demonstrated when the a (P= 0.0354) as well as IFI-related deaths (P = 0.0209).
conazole was observed lan-Meier estimates, the y higher for posaconazole
sis considered all causes of death
In Study 316, overall mortality was similar (POS, 25 %;
, 28 %); however, the proportion of IFI-
related deaths was significantly lower in the POS group (4/301) compared with the FLU group (12/299; P= 0.0413).
Use in paediatric patients
Sixteen patients 8–17 years of age were treated with 800 mg/day in a study for invasive fungal infections. Based on the available data in 16 of these paediatric patients, the safety profile appears to be similar to patients > 18 years of age.
Additionally, twelve patients 1 fungal infections (Studies 316 a similar to the safety profile obse paediatric patients, the pha
f age received 600 mg/day for prophylaxis of invasive
. The safety profile in these patients < 18 years of age appears n adults. Based on pharmacokinetic data in 10 of these inetic profile appears to be similar to patients > 18 years of age.
Safety and efficacy in paediatric patients below the age of 18 years have not been established.
Electrocardiogram evaluation
Multiple, time-matched ECGs collected over a 12 hour period were obtained before and during administra aconazole (400 mg twice daily with high fat meals) from 173 healthy male and
female vo ed 18 to 85 years. No clinically relevant changes in the mean QTc (Fridericia)
interval fr e were observed.
5.2
osa
acokinetic properties
nazole is absorbed with a median tmax of 3 hours (fed patients). The pharmacokinetics of onazole are linear following single and multiple dose administration of up to 800 mg when taken ith a high fat meal. No further increases in exposure were observed when doses above 800 mg daily were administered to patients and healthy volunteers. In the fasting state, AUC increased less than in proportion to dose above 200 mg. In healthy volunteers under fasting conditions, dividing the total
daily dose (800 mg) into 200 mg four times daily compared to 400 mg twice daily, was shown to increase posaconazole exposure by 58 % over 48 hours.
ution
Effect of food on oral absorption in healthy volunteers
The AUC of posaconazole is about 2.6 times greater when administered with a non-fat meal or nutritional supplement (14 grams fat) and 4 times greater when administered with a high-fat mea (~ 50 grams fat) relative to the fasted state. Posaconazole should be administered with food or a nutritional supplement (see section 4.2).
Distribution
Posaconazole is slowly absorbed and slowly eliminated with a large apparent volume (1,774 litres) and is highly protein bound (> 98 %), predominantly to serum albumin.
Metabolism
Posaconazole does not have any major circulating metabolites and its concentrations are unlikely to be altered by inhibitors of CYP450 enzymes. Of the circulating metabolites, the majority are glucuronide conjugates of posaconazole with only minor amounts of oxidative (CYP450 mediated) metabolites observed. The excreted metabolites in urine and faeces account for approximately 17 % of the administered radiolabelled dose.
ange 20 to 66 hours). After
Excretion
Posaconazole is slowly eliminated with a mean half-life (t^) of administration of 14C-posaconazole, radioactivity was predo recovered in the faeces (77 % of the radiolabelled dose) with the major component being par pound (66 % of the radiolabelled dose). Renal clearance is a minor elimination pathway, with 14 % of the radiolabelled dose excreted in urine (< 0.2 % of the radiolabelled dose is parent compound). Steady-state is attained following 7 to 10 days of multiple-dose administration.
Pharmacokinetics in special populations Children (< 18 years)
Following administration of 800 mg per invasive fungal infections, mean trough (776 ng/ml) were similar to concentrati pharmacokinetic data are available fr prophylaxis studies, the mean st among ten adolescents (13–17 y
of posaconazole as a divided dose for treatment of oncentrations from 12 patients 8 – 17 years of age s from 194 patients 18 – 64 years of age (817 ng/ml). No iatric patients less than 8 years of age. Similarly, in the osaconazole average concentration (Cav) was comparable e) to Cav achieved in adults (> 18 years of age).
Gender
The pharmacokinetics of
zole are comparable in men and women.
Elderly ( > 65 years)
An increase in : (26 %) and AUC (29 %) was observed in elderly subjects (24 subjects > 65 years of age) relative to unger subjects (24 subjects 18 – 45 years of age). However, in clinical efficacy trials, the safeile of posaconazole between the young and elderly patients was similar.
Race
There was a slight decrease (16 %) in the AUC and Cmax of posaconazole in Black subjects relative to Caucasian subjects. However, the safety profile of posaconazole between the Black and Caucasian subjects was similar.
mpairment
ing single-dose administration, there was no effect of mild and moderate renal impairment (n=18, Cl cr > 20 ml/min/1.73 m2) on posaconazole pharmacokinetics; therefore, no dose adjustment is equired. In subjects with severe renal impairment (n=6, Cl cr < 20 ml/min/1.73 m2), the AUC of posaconazole was highly variable [> 96 % CV (coefficient of variance)] compared to other renal groups [< 40 % CV]. However, as posaconazole is not significantly renally eliminated, an effect of
severe renal impairment on the pharmacokinetics of posaconazole is not expected and no dose adjustment is recommended. Posaconazole is not removed by haemodialysis.
Hepatic impairment
In a study with small number of subjects (n=12) who had hepatic impairment, there was an increase i exposure associated with prolongation of half-life in hepatic impaired patients (26.6, 35.3, and 46.1 hours for the mild, moderate and severe groups, respectively compared to 22.1 hours in su normal hepatic function). An approximately 2-fold increase in steady-state AUC is estimated i with severe hepatic impairment. Due to the limited pharmacokinetic data in patients with hepati impairment, posaconazole should be used with caution in patients with severe hepatic i since the prolonged half-life that may occur will lead to increased exposure.
ts
5.3 Preclinical safety data
As observed with other azole antifungal agents, effects related to inhibition of synthesis were seen in repeated-dose toxicity studies with posaconazole. Adre
hormone
pressive effects
were observed in toxicity studies in rats and dogs at exposures equal to or greater than those obtained at therapeutic doses in humans.
systemic exposures than in monkeys dosed for one tional effects were observed eater than those achieved
Neuronal phospholipidosis occurred in dogs dosed for > 3 months those obtained at therapeutic doses in humans. This finding was n year. In twelve-month neurotoxicity studies in dogs and monkeys on the central or peripheral nervous systems at systemic exposure therapeutically.
Pulmonary phospholipidosis resulting in dilatation and obstruction of the alveoli was observed in the 2-year study in rats. These findings are not necessarily indicative of a potential for functional changes in humans.
No effects on electrocardiograms, including QT and QTc intervals, were seen in a repeat dose safety pharmacology study in monkeys at systemic exposures 4.6-fold greater than the exposures obtained at therapeutic doses in humans. Echocardiography revealed no indication of cardiac decompensation in a repeat dose safety pharmacology study in rats at a systemic exposure 1.4-fold greater than that achieved therapeutically. Increased systolic and arterial blood pressures (up to 29 mm-Hg) were seen in rats and monkeys at systemic exposures 1.4-fold and 4.6-fold greater, respectively, than those achieved with therapeutic doses.
Reproduction, peri- and p than those obtained at the malformations, dystocia, i In rabbits, posaconazole w
natal development studies were conducted in rats. At exposures lower eutic doses in humans, posaconazole caused skeletal variations and eased length of gestation, reduced mean litter size and postnatal viability. embryotoxic at exposures greater than those obtained at therapeutic r azole antifungal agents, these effects on reproduction were considered
with
doses. As obser to be due to a tr
-related effect on steroidogenesis.
Posaconazole ot genotoxic in in vitro and in vivo studies. Carcinogenicity studies did not reveal special hazards for humans.
RMACEUTICAL PARTICULARS
ist of excipients
lysorbate 80
Simeticone
Sodium benzoate (E211) Sodium citrate dihydrate
Citric acid monohydrate
Glycerol
Xanthan gum
Liquid glucose
Titanium dioxide (E171)
Artificial cherry flavour containing benzyl alcohol and propylene glycol Purified water
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
Unopened container: 2 years
After first opening the container: 4 weeks.
6.4 Special precautions for storage
Do not freeze.
closed with a plastic child-resistant
6.5 Nature and contents of container
105 ml of oral suspension in a 123 ml bottle (glass am cap (polypropylene) and a measuring spoon (polystyrene) with 2 graduations: 2.5 ml and 5 ml.6.6 Special precautions for disposal
No special requirements
7. MARKETING AUTHORISATION HOLDER
8. MARKETING AUTHORISATION NUMBER(S)
FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
25 October 2005