Posaconazole Dr. Reddy's

Posaconazole.

Each modified release tablet contains: Posaconazole 100 mg.
Excipients/Inactive Ingredients: Tablet core: Hypromellose acetate succinate, Microcrystalline cellulose (pH 101 & pH 102), Hydroxypropylcellulose (Klucel EF & EXF), Colloidal Silicon Dioxide, Croscarmellose sodium, Magnesium stearate.
Tablet coat: Hypromellose 2910, Macrogol/polyethylene glycol 400, titanium dioxide, talc, iron oxide red.

Pharmacotherapeutic group: Antimycotics for systemic use, triazole derivatives. ATC code: J02AC04.
Pharmacology: Pharmacodynamics: Mechanism of action: Posaconazole inhibits the enzyme lanosterol 14α-demethylase (CYP51), which catalyses an essential step in ergosterol biosynthesis.
Pharmacokinetics: 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 Dosage & Administration and as follows 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 patients.
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 (once daily after twice daily 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 evaluated 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 data, the mean steady-state posaconazole average concentration (Cav) was comparable among 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 patients. No overall differences in safety were observed between 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 data with an oral tablet formulation 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 (Clcr ≥ 20 mL/min/1.73 m²) on posaconazole pharmacokinetics; therefore, no dose adjustment is required. In patients with severe renal impairment (Clcr < 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, there are no data with use of 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 impairment, 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 (t½) 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 impairment but caution is advised due to the potential for higher plasma exposure.
Similar recommendations apply to posaconazole tablets; however, there are no data with use of the posaconazole tablets.
Microbiology: Posaconazole has been shown 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.

POSACONAZOLE DR. REDDY'S Modified Release Tablets is indicated for use in the treatment of the following fungal infections in adults: Invasive aspergillosis in patients with disease that is refractory to amphotericin B or itraconazole or in patients who are intolerant of these medicinal products; Fusariosis, zygomycosis, coccidioidomycosis, chromoblastomycosis, and mycetoma in patients with disease that is refractory to other therapy or patients who are intolerant of other therapy.
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.
POSACONAZOLE DR. REDDY'S Modified Release Tablets is also indicated for prophylaxis of invasive fungal infections in the following adult patients: Patients receiving remission-induction chemotherapy for acute myelogenous leukaemia (AML) or myelodysplastic syndromes (MDS) expected to result in prolonged neutropenia and who are at high-risk of developing invasive fungal infections.
Haematopoietic 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.
POSACONAZOLE DR. REDDY'S Modified Release Tablets are not indicated for the treatment of oropharyngeal candidiasis. Refer to the package insert of Posaconazole oral suspension for use in oropharyngeal candidiasis.

Non-Interchangeability between POSACONAZOLE DR. REDDY'S Modified Release Tablets and Posaconazole Oral Suspension: POSACONAZOLE DR. REDDY'S Modified Release Tablets and oral suspension are not to be used interchangeably due to the differences in the dosing of each formulation. Therefore, follow the specific dosage recommendations for each of the formulations.
POSACONAZOLE DR. REDDY'S Modified Release Tablets may be taken without regard to food intake.
POSACONAZOLE DR. REDDY'S Modified Release Tablets are intended for oral administration only.
POSACONAZOLE DR. REDDY'S Modified Release Tablets should be swallowed whole, and not be divided, crushed, or chewed.
Important Administration Instructions for POSACONAZOLE DR. REDDY'S Modified Release Tablets and Posaconazole Oral Suspension: The prescriber should follow the specific dosing instructions for each formulation. The modified release tablet and oral suspension are not to be used interchangeably due to the differences in the dosing of each formulation.
Co-administration of drugs that can decrease the plasma concentrations of posaconazole should generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections (see Interactions).
Refractory Invasive Fungal Infections (IFI)/Intolerant Patients with IFI: 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. 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. Duration of therapy is based on recovery from neutropenia or immunosuppression. For patients with acute myelogenous leukemia or myelodysplastic syndromes, prophylaxis with POSACONAZOLE DR. REDDY'S 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.
Use in renal impairment: No dose adjustment is required for renal dysfunction and posaconazole is not significantly renally eliminated, an effect of severe renal insufficiency on the pharmacokinetics of posaconazole is not expected and no dose adjustment is recommended.
Due to variability in exposure, patients with severe renal impairment should be monitored closely for breakthrough fungal infections.
Use in hepatic impairment: There are limited pharmacokinetic data in patients with hepatic insufficiency; therefore, no recommendation for dose adjustment can be made. In the small number of subjects studied who had hepatic insufficiency, there was an increase in half-life with a decrease in hepatic function.
Use in pediatrics: 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.
Use in the Elderly: No dosage adjustment is recommended for elderly patients.

There is no experience with overdose of posaconazole tablets.
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 patient who took posaconazole oral suspension 1,200 mg twice a day for 3 days. No adverse reactions were noted.
Posaconazole is not removed by haemodialysis. There is no special treatment available in the case of overdose with posaconazole. Supportive care may be considered.

Hypersensitivity to the active substance or to any of the excipients listed in Description.
Co-administration with ergot alkaloids (see Interactions).
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 Precautions and Interactions).
Co-administration with the HMG-CoA reductase inhibitors simvastatin, lovastatin and atorvastatin (see Interactions).

Hypersensitivity: There is no information regarding cross-sensitivity between posaconazole and other azole antifungal agents. Caution should be used when prescribing POSACONAZOLE DR. REDDY'S 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 Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Monitoring of hepatic function: Liver function tests should be evaluated at the start of and during the course of posaconazole therapy. Patients who develop abnormal liver function tests during POSACONAZOLE DR. REDDY'S 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 DR. REDDY'S 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. POSACONAZOLE DR. REDDY'S must not be administered with medicinal products that are substrates for CYP3A4 and are known to prolong the QTc interval (see Contraindications and Interactions). POSACONAZOLE DR. REDDY'S 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 Contraindications).
Electrolyte disturbances, especially those involving potassium, magnesium or calcium levels, should be monitored and corrected as necessary before and during posaconazole therapy.
Drug Interactions: 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 Interactions).
Midazolam and other benzodiazepines: Due to the risk of prolonged sedation and possible respiratory depression co-administration of posaconazole with any benzodiazepines metabolised by CYP3A4 (e.g. midazolam, triazolam, alprazolam) should only be considered if clearly necessary. Dose adjustment of benzodiazepines metabolised by CYP3A4 should be considered (see Interactions).
Vincristine Toxicity: Concomitant administration of azole antifungals, including posaconazole, with vincristine has been associated with neurotoxicity and other serious adverse reactions, including seizures, peripheral neuropathy, syndrome of inappropriate antidiuretic hormone secretion, and paralytic ileus. Reserve azole antifungals, including posaconazole, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options (see Interactions).
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 Interactions).
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 Pharmacology: Pharmacokinetics under Actions). Safety data at higher exposure levels achieved with posaconazole tablets are at present limited.
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.
Sodium: This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.
Effects on ability to drive and use machines: 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.

Pregnancy: There is insufficient information on the use of posaconazole in pregnant women. Data in animals have shown reproductive toxicity. 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. 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 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.

Safety data mainly derive from data 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 tablet and oral suspension safety: The most frequently reported serious related adverse reactions included nausea, vomiting, diarrhoea, pyrexia, and increased bilirubin. 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; common; uncommon; rare; very rare; not known. (See table.)

Click on icon to see table/diagram/image

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 Precautions).

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. 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: Rifabutin (300 mg once a day) decreased the Cmax (maximum plasma concentration) and AUC (area under the plasma concentration time curve) of posaconazole. 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 as follows regarding the effect of posaconazole on rifabutin plasma levels.
Efavirenz: Efavirenz (400 mg once a day) decreased the Cmax and AUC of Posaconazole. 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 twice daily x 10 days) decreased the Cmax and AUC of posaconazole oral suspension (200 mg once daily on the 1st day, 200 mg twice daily on the 2nd day, then 400 mg twice daily x 8 Days). 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. 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 as follows. 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. The effect of posaconazole on CYP3A4 substrates in patients might be somewhat lower than that observed in healthy patients, 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 Contraindications).
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 Contraindications).
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 Contraindications).
Vinca alkaloids: Most of the vinca alkaloids (e.g. vincristine and vinblastine) are substrates of CYP3A4. Concomitant administration of azole antifungals, including posaconazole, with vincristine has been associated with serious adverse reactions (see Precautions). Posaconazole may increase the plasma concentrations of vinca alkaloids which may lead to neurotoxicity and other serious adverse reactions. Therefore, reserve azole antifungals, including posaconazole, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options.
Rifabutin: Posaconazole increased the Cmax and AUC of rifabutin. Concomitant use of posaconazole and rifabutin should be avoided unless the benefit to the patient outweighs the risk (see also previously mentioned 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). 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. 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). Clinically significant interactions resulting in hospitalisation and/or posaconazole discontinuation were reported. 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 patients, Cmax and AUC of atazanavir increased. 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 patients, Cmax and AUC of atazanavir increased. 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: Posaconazole oral suspension (200 mg once daily for 10 days) increased the exposure (AUC) of intravenous midazolam (0.05 mg/kg). 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); Posaconazole oral suspension 400 mg twice daily for 7 days increased the intravenous midazolam Cmax and AUC. Both doses of posaconazole increased Cmax and AUC of oral midazolam (2 mg single oral dose). In addition, posaconazole oral suspension (200 mg or 400 mg) prolonged the mean terminal half-life of midazolam 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) (see Precautions).
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 when glipizide was co-administered with posaconazole. Monitoring of glucose concentrations is recommended in diabetic patients.
All-trans retinoic acid (ATRA) or tretinoin: As ATRA is metabolised by the hepatic CYP450 enzymes, notably CYP3A4, concomitant administration with posaconazole, which is a strong inhibitor of CYP3A4, may lead to increased exposure to tretinoin resulting in an increased toxicity (especially hypercalcaemia). Serum calcium levels should be monitored and, if needed, appropriate dose adjustments of tretinoin should be considered during the treatment with posaconazole, and during the following days after treatment.
Paediatric population: Interaction data have only been performed in adults.

Incompatibilities: Not applicable.
Special precautions for disposal and other handling: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Store below 30°C.
Shelf life: 3 years.

Antifungals

J02AC04 - posaconazole ; Belongs to the class of triazole and tetrazole derivatives. Used in the systemic treatment of mycotic infections.

B