2013年11月26日，默沙东的Noxafil（posaconazole，泊沙康唑，100 mg）缓释片获FDA批准。Noxafil缓释片是一种新的配方，在治疗第一天的负荷剂量（loading dose）为300mg（即3片100mg缓释片），一天2次；从治疗的第二天开始，维持剂量（maintenance dose）为300mg（即3片100mg缓释片），一天1次。
同时，默沙东还销售Noxafil（40mg/mL）口服混悬液，剂量为每天给药3次。
Noxafil缓释片和口服混悬液，适应症为用于因免疫功能严重低下而具有高风险的侵袭性曲霉菌和念珠菌感染的13岁及以上患者，如患有移植物抗宿主病（GVHD）的造血干细胞移植（HSCT）受者，或那些因化疗导致长期的中性粒细胞减少（低白细胞计数）的恶性血液病患者。
Noxafil缓释片的获批，是基于一项药代动力学研究。该项研究是一项非对照、多中心临床研究，在已发生或预期将发生显著中性粒细胞减少（neutropenia）的急性髓性系白血病（AML）或骨髓增生异常综合症（MDS）患者、以及已接受造血干细胞移植（HSCT）同时正接受免疫抑制治疗以预防移植物抗宿主病（GVHD）的患者中开展中，评价了Noxafil缓释片的药代动力学、安全性和耐受性

Noxafil 100 mg gastro-resistant tablets
1. Name of the medicinal product
Noxafil 100 mg gastro-resistant tablets
2. Qualitative and quantitative composition
Each gastro-resistant tablet contains 100 mg of posaconazole.
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Gastro-resistant tablet (tablet)
Yellow-coated, capsule-shaped tablet of 17.5 mm length debossed with “100” on one side.
4. Clinical particulars

4.1 Therapeutic indications
Noxafil gastro-resistant tablets are 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.
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 gastro-resistant tablets are 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.
Noxafil tablets are not indicated for the treatment of oropharyngeal candidiasis. Please refer to the Summary of Product Characteristics of Noxafil oral suspension for use in oropharyngeal candidiasis.
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
Noxafil is also available as 40 mg/ml oral suspension. Noxafil tablets are the preferred formulation to optimize plasma concentrations and generally provide higher plasma drug exposures than Noxafil oral suspension. The tablet and oral suspension are not to be used interchangeably due to the differences in the dosing of each formulation.
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	Loading dose of 300 mg (three 100 mg tablets) twice a day on the first day, then 300 mg (three 100 mg tablets) once a day thereafter. Each dose may be taken without regard to food intake. Duration of therapy should be based on the severity of the underlying disease, recovery from immunosuppression, and clinical response.
Prophylaxis of invasive fungal infections	Loading dose of 300 mg (three 100 mg tablets) twice a day on the first day, then 300 mg (three 100 mg tablets) once a day thereafter. Each dose may be taken without regard to food intake. 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 and adolescents 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.
No data are available for the tablet formulation.
Method of administration
For oral use
Noxafil gastro-resistant tablets may be taken with or without food (see section 5.2). The tablets should be swallowed whole with water and should not be crushed, chewed, or broken.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
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 impairment 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
Liver function tests should be eva luated at the start of and during the course of posaconazole therapy. 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 (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), and efavirenz.
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).
Plasma exposure
Posaconazole plasma concentrations following administration of posaconazole tablets are generally higher than those obtained with posaconazole oral suspension. Posaconazole plasma concentrations following administration of posaconazole tablets may increase over time in some patients (see section 5.2). Safety data at higher exposure levels achieved with posaconazole tablets are at present limited.
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 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.
Fosamprenavir
Combining fosamprenavir with posaconazole may lead to decreased posaconazole plasma concentrations. If concomitant administration is required, close monitoring for breakthrough fungal infections is recommended. Repeat dose administration of fosamprenavir (700 mg BID x 10 days) decreased the Cmax and AUC of posaconazole oral suspension (200 mg QD on the 1st day, 200 mg BID on the 2nd day, then 400 mg BID x 8 Days) by 21 % and 23 %, respectively. The effect of posaconazole on fosamprenavir levels when fosamprenavir is given with ritonavir is unknown.
Phenytoin
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
No clinically relevant effects were observed when posaconazole tablets are concomitantly used with antacids, H2-receptor antagonists and proton pump inhibitors. No dosage adjustment of posaconazole tablets is required when posaconazole tablets are concomitantly used with antacids, H2-receptor antagonists and proton pump inhibitors.
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.
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 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 reactions related to increased rifabutin levels (e.g. uveitis) is recommended.
Sirolimus
Repeat dose administration of posaconazole oral suspension (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 targeted 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 oral suspension 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 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.
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 posaconazole oral suspension (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 posaconazole oral suspension (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 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 oral suspension (200 mg once daily for 10 days) increased the exposure (AUC) of intravenous midazolam (0.05 mg/kg) by 83 %. In another study in healthy volunteers, repeat dose administration of posaconazole oral suspension (200 mg twice daily for 7 days) increased the Cmax and AUC of intravenous 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 oral suspension 400 mg twice daily for 7 days increased the intravenous 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, posaconazole oral suspension (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.
Paediatric population
Interaction studies have only been performed in adults.
4.6 Fertility, 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 doses up to 180 mg/kg (3.4 times the 300-mg tablet based on steady-state plasma concentrations in patients) or female rats at a dose up to 45 mg/kg (2.6 times the 300-mg tablet based on steady-state plasma concentrations in patients). 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
Safety data mainly derive from studies with the oral suspension.
The tablet formulation was investigated in AML and MDS patients and those after HSCT with or at risk for Graft versus Host Disease (GvHD) only. Maximum duration of exposure to the tablet formulation was shorter than with the oral suspension. Plasma exposure resulting from the tablet formulation was higher than observed with the oral suspension. A higher incidence of adverse reactions cannot be ruled out.
Summary of the safety profile
Posaconazole tablets
The safety of posaconazole tablets has been assessed in 230 patients enrolled in the pivotal clinical study. Patients were enrolled in a non-comparative pharmacokinetic and safety trial of posaconazole tablets when given as antifungal prophylaxis. Patients were immunocompromised with underlying conditions including haematological malignancy, neutropenia post-chemotherapy, GVHD, and post HSCT. Posaconazole therapy was given for a median duration of 28 days. Twenty patients received 200 mg daily dose and 210 patients received 300 mg daily dose (following BID dosing on Day 1 in each cohort).
Posaconazole tablet and oral suspension safety
The safety of posaconazole oral suspension 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.
The safety of posaconazole tablet has been assessed in 336 patients and healthy volunteers enrolled in clinical trials. The safety profile of tablets was similar to that of the oral suspension.
Tabulated list of adverse reactions
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 frequency

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

See section 4.4.
Description of selected adverse reactions
Hepatobiliary disorders
During post-marketing surveillance of posaconazole oral suspension, severe hepatic injury with fatal outcome has been reported (see section 4.4).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, website www.mhra.gov.uk/yellowcard.
4.9 Overdose
There is no experience with overdosage of posaconazole tablets.
During clinical trials, patients who received posaconazole oral suspension 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 posaconazole oral suspension 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: J02AC04.
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.
Epidemiological Cut-off (ECOFF) Values for Aspergillus spp.
The ECOFF values for posaconazole, which distinguish the wild type population from isolates with acquired resistance have been determined by EUCAST methodology.
EUCAST ECOFF values:
•Aspergillus flavus: 0.5 mg/L
•Aspergillus fumigatus: 0.25 mg/L
•Aspergillus nidulans: 0.5 mg/L
•Aspergillus niger: 0.5 mg/L
•Aspergillus terreus: 0.25 mg/L
There are currently insufficient data to set clinical breakpoints for Aspergillus spp. ECOFF values do not equate to clinical breakpoints.
Breakpoints
EUCAST MIC breakpoints for posaconazole [susceptible (S); resistant (R)]:
•Candida albicans: S ≤0.06 mg/L, R >0.06 mg/L
•Candida tropicalis: S ≤0.06 mg/L, R >0.06 mg/L
•Candida parapsilosis: S ≤0.06 mg/L, R >0.06 mg/L
There are currently insufficient data to set clinical breakpoints for other Candida species.
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.
Clinical experience
Summary of posaconazole tablet bridging study
Study 5615 was a non-comparative multi-center study performed to eva luate the pharmacokinetic properties, safety, and tolerability of posaconazole tablet. Study 5615 was conducted in a similar patient population to that previously studied in the pivotal posaconazole oral suspension clinical program. The pharmacokinetics and safety data from Study 5615 were bridged to the existing data (including efficacy data) with the oral suspension.
The subject population included: 1) patients with AML or MDS who had recently received chemotherapy and had developed or were anticipated to develop significant neutropenia, or 2) patients who had undergone a HSCT and were receiving immunosuppressive therapy for prevention or treatment of GVHD. Two different dosing groups were eva luated: 200 mg BID on Day 1, followed by 200 mg QD thereafter (Part IA) and 300 mg BID on Day 1, followed by 300 mg QD thereafter (Part 1B and Part 2).
Serial PK samples were collected on Day 1 and at steady-state on Day 8 for all Part 1 subjects and a subset of Part 2 subjects. Moreover, sparse PK samples were collected at several days during steady state before the next dose (Cmin) for a larger subject population. Based on average Cmin concentrations, a predicted average concentration (Cav) could be calculated for 186 subjects dosed with 300 mg. PK analysis in patients of Cav found that 81 % of the subjects treated with the 300 mg QD dose attained steady state predicted Cav between 500-2,500 ng/mL. One subject (<1 %) had a predicted Cav below 500 ng/mL and 19 % of the subjects had a predicted Cav above 2,500 ng/mL. Subjects achieved a mean predicted Cav at steady state of 1,970 ng/mL.
In Table 3 a comparison is shown of exposure (Cav) after administration of posaconazole tablet and posaconazole oral suspension at therapeutic doses in patients depicted as quartile analysis. Exposures after tablet administration are generally higher than, but overlapping with, exposures after administration of posaconazole oral suspension.
Table 3. Cav quartile analyses of pivotal patient studies with posaconazole tablet and oral suspension

Posaconazole tablet	Posaconazole oral suspension
	Prophylaxis in AML and HSCT Study 5615	Prophylaxis in GVHD Study 316	Prophylaxis in Neutropenia Study 1899	Treatment - Invasive Aspergillosis Study 0041
	300 mg QD (Day 1 300 mg BID)*	200 mg TID	200 mg TID	200 mg QID (hospitalized) then 400 mg BID
Quartile	pCav Range (ng/mL)	Cav Range (ng/mL)	Cav Range (ng/mL)	Cav Range (ng/mL)
Q1	442 - 1,223	22 - 557	90 - 322	55 - 277
Q2	1,240 - 1,710	557 - 915	322 - 490	290 - 544
Q3	1,719 - 2,291	915 - 1,563	490 - 734	550 - 861
Q4	2,304 - 9,523	1,563 - 3,650	734 - 2,200	877 - 2,010
pCav: predicted Cav Cav = the average concentration when measured at steady state *20 patients received 200 mg QD (Day 1 200 mg BID)

Summary of posaconazole oral suspension studies
Invasive aspergillosis
Oral posaconazole suspension 800 mg/day in divided doses was eva luated 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 (Study 0041). 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 4, 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 4. Overall efficacy of posaconazole oral suspension at the end of treatment for invasive aspergillosis in comparison to an external control group

Posaconazole oral suspension		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 oral suspension 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 oral suspension 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 oral suspension 800 mg/day in divided doses for a median of 296 days and up to 460 days.
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, eva luator-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 leukaemia 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 leukaemia 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 oral suspension	Controla	P-Value
Proportion (%) of patients with proven/probable IFIs
On-treatment periodb
1899d	7/304 (2)	25/298 (8)	0.0009
316e	7/291 (2)	22/288 (8)	0.0038
Fixed-time periodc
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
Table 6. Results from clinical studies in prophylaxis of Invasive Fungal Infections

Study		Posaconazole oral suspension		Controla
Proportion (%) of patients with proven/probable Aspergillosis
On-treatment periodb
1899d	2/304 (1)		20/298 (7)
316e	3/291 (1)		17/288 (6)
Fixed-time periodc
1899d	4/304 (1)		26/298 (9)
316 d	7/301 (2)		21/299 (7)

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
In Study 1899, a significant decrease in all cause mortality in favour of posaconazole was observed [POS 49/304 (16 %) vs. FLU/ITZ 67/298 (22 %) p= 0.048]. Based on Kaplan-Meier estimates, the probability of survival up to day 100 after randomization, was significantly higher for posaconazole recipients; this survival benefit was demonstrated when the analysis considered all causes of death (P= 0.0354) as well as IFI-related deaths (P = 0.0209).
In Study 316, overall mortality was similar (POS, 25 %; FLU, 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).
Paediatric population
There is no paediatric experience for posaconazole tablets.
Sixteen patients 8-17 years of age were treated with posaconazole oral suspension 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 13-17 years of age received posaconazole oral suspension 600 mg/day for prophylaxis of invasive fungal infections (Studies 316 and 1899). The safety profile in these patients < 18 years of age appears similar to the safety profile observed in adults. Based on pharmacokinetic data in 10 of these paediatric patients, the pharmacokinetic 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 eva luation
Multiple, time-matched ECGs collected over a 12 hour period were obtained before and during administration of posaconazole oral suspension (400 mg twice daily with high fat meals) from 173 healthy male and female volunteers aged 18 to 85 years. No clinically relevant changes in the mean QTc (Fridericia) interval from baseline were observed.
[1] Includes other less common species or species unknown
5.2 Pharmacokinetic properties
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).
Absorption
Posaconazole tablets are absorbed with a median Tmax of 4 to 5 hours and exhibits dose proportional pharmacokinetics after single and multiple dosing up to 300 mg.
Following a single dose administration of 300 mg posaconazole tablets after a high fat meal to healthy volunteers, the AUC0-72 hours and Cmax were higher compared to administration under fasted condition (51 % and 16 % for AUC0-72 hours and Cmax respectively).
Posaconazole plasma concentrations following administration of posaconazole tablets may increase over time in some patients. The reason for this time-dependency is not completely understood.
Distribution
Posaconazole, after administration of the tablet, has a mean apparent volume of distribution of 394 L (42 %), ranging between 294-583 L among the studies in healthy volunteers.
Posaconazole is highly protein bound (> 98 %), predominantly to serum albumin.
Biotransformation
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.
Elimination
Posaconazole after administration of the tablets, is slowly eliminated with a mean half-life (t½) of 29 hours (range 26 to 31 hours) and a mean apparent clearance ranging from 7.5 to 11 L/hr. After administration of 14C-posaconazole, radioactivity was predominantly recovered in the faeces (77 % of the radiolabelled dose) with the major component being parent compound (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 plasma concentrations are attained by Day 6 at the 300 mg dose (QD after BID loading dose at Day 1).
Pharmacokinetics in special populations
Children (< 18 years)
There is no paediatric experience with posaconazole tablets.
The pharmacokinetics of posaconazole oral suspension have been eva luated in paediatric patients. Following administration of 800 mg per day of posaconazole oral suspension as a divided dose for treatment of invasive fungal infections, mean trough plasma concentrations from 12 patients 8 - 17 years of age (776 ng/ml) were similar to concentrations from 194 patients 18 - 64 years of age (817 ng/ml). No pharmacokinetic data are available from paediatric patients less than 8 years of age. Similarly, in the prophylaxis studies, the mean steady-state posaconazole average concentration (Cav) was comparable among ten adolescents (13-17 years of age) to Cav achieved in adults (≥ 18 years of age).
Gender
The pharmacokinetics of posaconazole tablets are comparable in men and women.
Elderly
The pharmacokinetics of posaconazole tablets are comparable in young and elderly subjects. No overall differences in safety were observed between the geriatric patients and younger patients; therefore, no dosage adjustment is recommended for geriatric patients.
Race
There is insufficient data among different races with posaconazole tablets.
There was a slight decrease (16 %) in the AUC and Cmax of posaconazole oral suspension in Black subjects relative to Caucasian subjects. However, the safety profile of posaconazole between the Black and Caucasian subjects was similar.
Weight
Pharmacokinetic modeling suggests that patients weighing greater than 120 kg may have lower posaconazole exposure. It is, therefore, suggested to closely monitor for breakthrough fungal infections in patients weighing more than 120 kg.
Patients, in particular those receiving posaconazole after HSCT, who have a low body weight (< 60 kg) are more likely to experience higher plasma concentrations of posaconazole and should be closely monitored for adverse events.
Renal impairment
Following single-dose administration of posaconazole oral suspension, 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 required. 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.
Similar recommendations apply to posaconazole tablets; however, a specific study has not been conducted with the posaconazole tablets.
Hepatic impairment
After a single oral dose of 400 mg posaconazole oral suspension to patients with mild (Child-Pugh Class A), moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic insufficiency (six per group), the mean AUC was 1.3 to 1.6-fold higher compared to that for matched control subjects with normal hepatic function. Unbound concentrations were not determined and it cannot be excluded that there is a larger increase in unbound posaconazole exposure than the observed 60 % increase in total AUC. The elimination half-life (t1/2) was prolonged from approximately 27 hours up to ~43 hours in respective groups. No dose adjustment is recommended for patients with mild to severe hepatic insufficiency but caution is advised due to the potential for higher plasma exposure.
Similar recommendations apply to posaconazole tablets; however, a specific study has not been conducted with the posaconazole tablets.
5.3 Preclinical safety data
As observed with other azole antifungal agents, effects related to inhibition of steroid hormone synthesis were seen in repeated-dose toxicity studies with posaconazole. Adrenal suppressive effects were observed in toxicity studies in rats and dogs at exposures equal to or greater than those obtained at therapeutic doses in humans.
Neuronal phospholipidosis occurred in dogs dosed for ≥ 3 months at lower systemic exposures than those obtained at therapeutic doses in humans. This finding was not seen in monkeys dosed for one year. In twelve-month neurotoxicity studies in dogs and monkeys, no functional effects were observed on the central or peripheral nervous systems at systemic exposures greater than those achieved 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 maximal plasma concentrations 8.5-fold greater than the concentrations 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 2.1-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 2.1-fold and 8.5-fold greater, respectively, than those achieved with the human therapeutic doses.
Reproduction, peri- and postnatal development studies were conducted in rats. At exposures lower than those obtained at therapeutic doses in humans, posaconazole caused skeletal variations and malformations, dystocia, increased length of gestation, reduced mean litter size and postnatal viability. In rabbits, posaconazole was embryotoxic at exposures greater than those obtained at therapeutic doses. As observed with other azole antifungal agents, these effects on reproduction were considered to be due to a treatment-related effect on steroidogenesis.
Posaconazole was not genotoxic in in vitro and in vivo studies. Carcinogenicity studies did not reveal special hazards for humans.
6. Pharmaceutical particulars
6.1 List of excipients
Tablet core
Hypromellose acetate succinate
Cellulose, microcrystalline
Hydroxypropylcellulose (E463)
Silica dental type
Croscarmellose sodium
Magnesium stearate
Tablet coat
polyvinyl alcohol
macrogol 3350
titanium dioxide (E171)
talc
iron oxide yellow (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Noxafil 100 mg gastro-resistant tablets are packaged in a PVC/ polychlorotrifluoroethylene laminate blister with push-through aluminium lidding.
Noxafil gastro-resistant tablets are packaged in a blister in cartons of 24 (2x12) or 96 (8x12) tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. Marketing authorisation holder
Merck Sharp & Dohme Ltd
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
8. Marketing authorisation number(s)
EU/1/05/320/002 24 tablets
EU/1/05/320/003 96 tablets
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 25 October 2005
Date of latest renewal: 25 October 2010
10. Date of revision of the text
23 April 2014
Detailed information on this medicininal product is available on the European Medicines Agency web site: http://www.ema.europa.eu.
© Merck Sharp & Dohme Limited 2014. All rights reserved.
SPC.NOX-TAB.100mg.14.UK.4071-X-028