Posaconazole

Posaconazole is a potent inhibitor of CYP3A4. Co-administration of posaconazole with CYP3A4 substrates may result in large increases in exposure to CYP3A4 substrates as exemplified by the effects on tacrolimus, sirolimus, atazanavir and midazolam below. Caution is advised during co- administration of posaconazole with CYP3A4 substrates administered intravenously and the dose of the CYP3A4 substrate may need to be reduced. If posaconazole is used concomitantly with CYP3A4 substrates that are administered orally, and for which an increase in plasma concentrations may be associated with unacceptable adverse reactions, plasma concentrations of the CYP3A4 substrate and/or adverse reactions should be closely monitored and the dose adjusted as needed. Several of the interaction studies were conducted in healthy volunteers in whom a higher exposure to posaconazole occurs compared to patients administered the same dose. The effect of posaconazole on CYP3A4 substrates in patients might be somewhat lower than that observed in healthy volunteers, and is expected to be variable between patients due to the variable posaconazole exposure in patients. The effect of co-administration with posaconazole on plasma levels of CYP3A4 substrates may also be variable within a patient, unless posaconazole is administered in a strictly standardised way with food, given the large food effect on posaconazole exposure.

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.

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 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 should be considered if clinical signs and symptoms are consistent with development of liver disease.

Posaconazole plasma concentrations (C_max and AUC) were reduced by 39% when posaconazole was administered with cimetidine (400 mg twice a day) due to reduced absorption possibly secondary to a decrease in gastric acid production. Co-administration of posaconazole with H₂ receptor antagonists should be avoided if possible.

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

Glucose concentrations decreased in some healthy volunteers when glipizide was co-administered with posaconazole. Monitoring of glucose concentrations is recommended in diabetic patients.

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.

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 C_max and AUC of atazanavir increased by an average of 2.6-fold and 3.7-fold (range 1.2 to 26-fold), respectively. Following co-administration of posaconazole oral suspension (400 mg twice daily) with atazanavir and ritonavir (300/100 mg once daily) for 7 days in healthy subjects C_max and AUC of atazanavir increased by an average of 1.5-fold and 2.5-fold (range 0.9 to 4.1-fold), respectively. The addition of posaconazole to therapy with atazanavir or with atazanavir plus ritonavir was associated with increases in plasma bilirubin levels. Frequent monitoring for adverse reactions and toxicity related to antiretroviral agents that are substrates of CYP3A4 is recommended during co- administration with posaconazole.

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. 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.

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 C_max 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 C_max and AUC by 1.6 and 6.2-fold (range 1.6 to 7.6-fold), respectively. Both doses of posaconazole increased C_max and AUC of oral midazolam (2 mg single oral dose) by 2.2 and 4.5-fold, respectively. In addition, 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).

In heart transplant patients on stable doses of ciclosporin, posaconazole 200 mg once daily increased ciclosporin concentrations requiring dose reductions. Cases of elevated ciclosporin levels resulting in serious adverse reactions, including nephrotoxicity and one fatal case of leukoencephalopathy, were reported in clinical efficacy studies. When initiating treatment with posaconazole in patients already receiving ciclosporin, the dose of ciclosporin should be reduced (e.g. to about three quarters of the current dose). Thereafter blood levels of ciclosporin should be monitored carefully during co-administration, and upon discontinuation of posaconazole treatment, and the dose of ciclosporin should be adjusted as necessary.

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.

Efavirenz (400 mg once a day) decreased the C_max and AUC of posaconazole by 45% and 50%, respectively. Concomitant use of posaconazole and efavirenz should be avoided unless the benefit to the patient outweighs the risk.

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 C_max and AUC of posaconazole oral suspension (200 mg once daily on the 1 st day, 200 mg twice daily on the 2nd day, then 400 mg twice daily x 8 Days) by 21% and 23%, respectively. The effect of posaconazole on fosamprenavir levels when fosamprenavir is given with ritonavir is unknown.

Phenytoin (200 mg once a day) decreased the C_max and AUC of posaconazole by 41% and 50%, respectively. Concomitant use of posaconazole and phenytoin and similar inducers (e.g. carbamazepine, phenobarbital, primidone) should be avoided unless the benefit to the patient outweighs the risk.

Rifabutin (300 mg once a day) decreased the C_max (maximum plasma concentration) and AUC (area under the plasma concentration time curve) of posaconazole to 57% and 51%, respectively. Concomitant use of posaconazole and rifabutin and similar inducers (e.g. rifampicin) should be avoided unless the benefit to the patient outweighs the risk.

Posaconazole increased the C_max and AUC of rifabutin by 31% and 72%, respectively. Concomitant use of posaconazole and rifabutin should be avoided unless the benefit to the patient outweighs the risk. 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.

Repeat dose administration of posaconazole oral suspension (400 mg twice daily for 16 days) increased the C_max and AUC of sirolimus (2 mg single dose) an average of 6.7-fold and 8.9-fold (range 3.1 to 17.5-fold), respectively, in healthy subjects. The effect of posaconazole on sirolimus in patients is unknown, but is expected to be variable due to the variable posaconazole exposure in patients. Co-administration of posaconazole with sirolimus is not recommended and should be avoided whenever possible. If it is considered that co-administration is unavoidable, then it is recommended that the dose of sirolimus should be greatly reduced at the time of initiation of posaconazole therapy and that there should be very frequent monitoring of trough concentrations of sirolimus in whole blood. Sirolimus concentrations should be measured upon initiation, during co-administration, and at discontinuation of posaconazole treatment, with sirolimus doses adjusted accordingly. It should be noted that the relationship between sirolimus trough concentration and AUC is changed during co-administration with posaconazole. As a result, sirolimus trough concentrations that fall within the usual therapeutic range may result in sub-therapeutic levels. Therefore trough concentrations that fall in the upper part of the usual therapeutic range should be targeted and careful attention should be paid to clinical signs and symptoms, laboratory parameters and tissue biopsies.

Posaconazole increased C_max and AUC of tacrolimus (0.05 mg/kg body weight single dose) by 121% and 358%, respectively. Clinically significant interactions resulting in hospitalisation and/or posaconazole discontinuation were reported in clinical efficacy studies. When initiating posaconazole treatment in patients already receiving tacrolimus, the dose of tacrolimus should be reduced (e.g. to about one third of the current dose). Thereafter blood levels of tacrolimus should be monitored carefully during co-administration, and upon discontinuation of posaconazole, and the dose of tacrolimus should be adjusted as necessary.

Some azoles have been associated with prolongation of the QTc interval. Posaconazole must not be administered with medicinal products that are substrates for CYP3A4 and are known to prolong the QTc interval. Posaconazole should be administered with caution to patients with pro-arrhythmic conditions such as:

• Congenital or acquired QTc prolongation
• Cardiomyopathy, especially in the presence of cardiac failure
• Sinus bradycardia
• Existing symptomatic arrhythmias
• Concomitant use with medicinal products known to prolong the QTc interval.

Electrolyte disturbances, especially those involving potassium, magnesium or calcium levels, should be monitored and corrected as necessary before and during posaconazole therapy.

Pozaconazole is not removed by hemodialysis.

There is insufficient information on the use of posaconazole in pregnant women. Studies 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.

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

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.

Summary of the safety profile

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.

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 (cannot be estimated from the available data).

Adverse reactions by body system and frequency reported in clinical trials and/or post-marketing use*:

Blood and lymphatic system disorders

Common: neutropenia

Uncommon: thrombocytopenia, leukopenia, anaemia, eosinophilia, lymphadenopathy, splenic infarction

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

Not known: pseudoaldosteronism

Metabolism and nutrition disorders

Common: electrolyte imbalance, anorexia, decreased appetite, hypokalaemia, hypomagnesaemia

Uncommon: hyperglycaemia, hypoglycaemia

Psychiatric disorders

Uncommon: abnormal dreams, confusional state, sleep disorder

Rare: psychotic disorder, depression

Nervous system disorders

Common: paresthesia, dizziness, somnolence, headache, dysgeusia

Uncommon: convulsions, neuropathy, hypoaesthesia, tremor, aphasia, insomnia

Rare: cerebrovascular accident, encephalopathy, peripheral neuropathy, syncope

Eye disorders

Uncommon: blurred vision, photophobia, visual acuity reduced

Rare: diplopia, scotoma

Ear and labyrinth disorder

Rare: hearing impairment

Cardiac disorders

Uncommon: long QT syndrome, electrocardiogram abnormal, palpitations, bradycardia, supraventricular extrasystoles, tachycardia

Rare: torsade de pointes, sudden death, ventricular tachycardia, cardio-respiratory arrest, cardiac failure, myocardial infarction

Vascular disorders

Common: hypertension

Uncommon: hypotension, vasculitis

Rare: pulmonary embolism, deep vein thrombosis

Respiratory, thoracic and mediastinal disorders

Uncommon: cough, epistaxis, hiccups, nasal congestion, pleuritic pain, tachypnoea

Rare: pulmonary hypertension, interstitial pneumonia, pneumonitis

Gastrointestinal disorders

Very Common: nausea

Common: vomiting, abdominal pain, diarrhoea, dyspepsia, dry mouth, flatulence, constipation, anorectal discomfort

Uncommon: pancreatitis, abdominal distension, enteritis, epigastric discomfort, eructation, 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, cholestasis, hepatic toxicity, hepatic function abnormal

Rare: hepatic failure, hepatitis cholestatic, hepatosplenomegaly, liver tenderness, asterixis

Skin and subcutaneous tissue disorders

Common: rash, pruritis

Uncommon: mouth ulceration, alopecia, dermatitis, erythema, petechiae

Rare: Stevens Johnson syndrome, vesicular rash

Musculoskeletal and connective tissue disorders

Uncommon: back pain, neck pain, musculoskeletal 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, chest discomfort, drug intolerance, feeling jittery, mucosal inflammation

Rare: tongue oedema, face oedema

Investigations

Uncommon: altered medicine levels, blood phosphorus decreased, chest x-ray abnormal

* Based on adverse reactions observed with the oral suspension, gastro-resistant tablets, and concentrate for solution for infusion.

Description of selected adverse reactions

Hepatobiliary disorders

During post-marketing surveillance of posaconazole oral suspension, severe hepatic injury with fatal outcome has been reported.