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    / Novartis


    Active Ingredient
    Pasireotide 0.3. 0.6, 0.9 mg/ml

    Status in Israel
    RX

    Presentation and Status in Health Basket

    Presentation Basket Yarpa Pharmasoft

    Ampoule

    60 X 0.3 mg/ml

    partial basket chart 48812 9688

    Ampoule

    60 X 0.6 mg/ml

    partial basket chart 48813 9689

    Ampoule

    60 X 0.9 mg/ml

    partial basket chart 48814 9690

    Dosage

    The recommended initial dose of Pasireotide is 0.6 mg by subcutaneous injection twice a day. Two months after the start of Pasireotide therapy, patients should be evaluated for clinical benefit. Patients who experience a significant reduction in urinary free cortisol [UFC] levels should continue to receive Pasireotide for as long as benefit is derived. A dose increase to 0.9 mg may be considered based on the response to the treatment, as long as the 0.6 mg dose is well tolerated by the patient. Patients who have not responded to Pasireotide after two months of treatment should be considered for discontinuation. Management of suspected adverse reactions at any time during the treatment may require temporary dose reduction of Pasireotide. Dose reduction by decrements of 0.3 mg twice a day is suggested.
    Paediatric population: The safety and efficacy of Pasireotide in children and adolescents aged 0 to 18 years have not been established. No data are available.
    Elderly patients (≥65 years): Data on the use of Pasireotide in patients older than 65 years are limited, but there is no evidence to suggest that dose adjustment is required in these patients.
    Renal impairment: No dose adjustment is required in patients with impaired renal function.
    Hepatic impairment: Dose adjustment is not required in patients with mildly impaired hepatic function (Child Pugh A). The recommended initial dose for patients with moderate hepatic impairment (Child Pugh B) is 0.3 mg twice a day. The maximum recommended dose for these patients is 0.6 mg twice a day. Pasireotide should not be used in patients with severe hepatic impairment (Child Pugh C).
    Method of administration: Pasireotide is to be administered subcutaneously by self injection. Patients should receive instructions from the physician or a healthcare professional on how to inject Pasireotide subcutaneously. Use of the same injection site for two consecutive injections is not recommended. Sites showing signs of inflammation or irritation should be avoided. Preferred injection sites for subcutaneous injections are the top of the thighs and the abdomen (excluding the navel or waistline). 


    Indications

    Treatment of adult patients with Cushing’s disease for whom surgery is not an option or for whom surgery has failed.


    Contra-Indications

    Hypersensitivity to the active substance or to any of the excipients. Severe hepatic impairment (Child Pugh C).


    Special Precautions

    Glucose metabolism: Alterations in blood glucose levels have been frequently reported in healthy volunteers and patients treated with pasireotide. Hyperglycaemia and, less frequently, hypoglycaemia, were observed in subjects participating in clinical studies with pasireotide. The degree of hyperglycaemia appeared to be higher in patients with pre-diabetic conditions or established diabetes mellitus. During the pivotal study, HbA1c levels increased significantly and stabilised but did not return to baseline values. More cases of discontinuation and a higher reporting rate of severe adverse events due to hyperglycaemia were reported in patients treated with the dose of 0.9 mg twice daily. The development of hyperglycaemia appears to be related to decreases in secretion of insulin (particularly in the post-dose period) and of incretin hormones (i.e. glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]). Glycaemic status (fasting plasma glucose/haemoglobin A1c [FPG/HbA1c]) should be assessed prior to starting treatment with pasireotide. FPG/HbA1c monitoring during treatment should follow establishedguidelines. Self monitoring of blood glucose and/or FPG assessments should be done weekly for the first two to three months and periodically thereafter, as clinically appropriate, as well as over the first two to four weeks after any dose increase. In addition, monitoring of FPG 4 weeks and HbA1c 3 months after the end of the treatment should be performed.
    Liver tests: Mild transient elevations in aminotransferases are commonly observed in patients treated with pasireotide. Rare cases of concurrent elevations in ALT (alanine aminotransferase) greater than 3 x ULN and bilirubin greater than 2 x ULN have also been observed. Monitoring of liver function is recommended prior to treatment with pasireotide and after one, two, four, eight and twelve weeks during treatment. Thereafter liver function should be monitored as clinically indicated. Patients who develop increased transaminase levels should be monitored with a second liver function evaluation to confirm the finding. If the finding is confirmed, the patient should be followed with frequent liver function monitoring until values return to pre-treatment levels. Therapy with pasireotide should be discontinued if the patient develops jaundice or other signs suggestive of clinically significant liver dysfunction, in the event of a sustained increase in AST (aspartate aminotransferase) or ALT of 5 x ULN or greater, or if ALT or AST elevations greater than 3 x ULN occur concurrently with bilirubin elevations greater than 2 x ULN. Following discontinuation of treatment with pasireotide, patients should be monitored until resolution. Treatment should not be restarted.
    Cardiovascular related events: Bradycardia has been reported with the use of pasireotide. Careful monitoring is recommended in patients with cardiac disease and/or risk factors for bradycardia, such as history of clinically significant bradycardia or acute myocardial infarction, high-grade heart block, congestive heart failure (NYHA Class III or IV), unstable angina, sustained ventricular tachycardia, ventricular fibrillation. Dose adjustment of medicinal products such as beta blockers, calcium channel blockers, or medicinal products to control electrolyte balance, may be necessary. Pasireotide has been shown to prolong the QT interval on the ECG in two dedicated healthy volunteer studies. The clinical significance of this prolongation is unknown. In clinical studies in Cushing’s disease patients, QTcF of >500 msec was observed in two out of 201 patients. These episodes were sporadic and of single occurrence with no clinical consequence observed. Episodes of torsade de pointes were not observed either in those studies or in clinical studies in other patient populations. Pasireotide should be used with caution and the benefit risk carefully weighed in patients who are at significant risk of developing prolongation of QT, such as those: with congenital long QT syndrome, with uncontrolled or significant cardiac disease, including recent myocardial infarction, congestive heart failure, unstable angina or clinically significant bradycardia, taking antiarrhythmic medicinal products or other substances that are known to lead to QT prolongation, with hypokalaemia and/or hypomagnesaemia. Monitoring for an effect on the QTc interval is advisable and ECG should be performed prior to the start of Pasireotide therapy, one week after the beginning of the treatment and as clinically indicated thereafter. Hypokalaemia and/or hypomagnesaemia must be corrected prior to administration of Pasireotide and should be monitored periodically during therapy.
    Hypocortisolism: Treatment with Pasireotide leads to rapid suppression of ACTH (adrenocorticotropic hormone) secretion in Cushing’s disease patients. Rapid, complete or near-complete suppression of ACTH may lead to a decrease in circulating levels of cortisol and potentially to transient hypocortisolism/hypoadrenalism. It is therefore necessary to monitor and instruct patients on the signs and symptoms associated with hypocortisolism (e.g. weakness, fatigue, anorexia, nausea, vomiting, hypotension, hyperkalaemia, hyponatraemia, hypoglycaemia). In the event of documented hypocortisolism, temporary exogenous steroid (glucocorticoid) replacement therapy and/or dose reduction or interruption of Pasireotide therapy may be necessary.
    Gallbladder and related events: Cholelithiasis is a recognised adverse reaction associated with long-term use of somatostatin analogues and has frequently been reported in clinical studies with pasireotide. Ultrasonic examination of the gallbladder before and at 6 to 12 month intervals during Pasireotide therapy is therefore recommended. The presence of gallstones in Pasireotide-treated patients is largely asymptomatic; symptomatic stones should be managed according to clinical practice.
    Pituitary hormones: As the pharmacological activity of pasireotide mimics that of somatostatin, inhibition of pituitary hormones other than ACTH cannot be ruled out. Monitoring of pituitary function (e.g. TSH/free T4, GH/IGF-1) before and periodically during Pasireotide therapy should therefore be considered, as clinically appropriate.
    Sodium content: The product contains less than 0.097 mg sodium.
    Effect on female fertility: The therapeutic benefits of a reduction or normalisation of serum cortisol levels in female patients with Cushing’s disease could potentially restore fertility. Female patients of childbearing potential should be advised to use adequate contraception during treatment with Pasireotide.
    Renal impairment: Due to the increase in unbound drug exposure, Pasireotide should be used with caution in patients with severe renal impairment or end stage renal disease.
    See prescribing information for full details.


    Side Effects

    Adrenal insufficiency, Hyperglycaemia, diabetes mellitus, Decreased appetite, type 2 diabetes mellitus, Headache, Sinus bradycardia, QT prolongation, Hypotension, Diarrhoea, abdominal pain, nausea, Vomiting, abdominal pain upper, Cholelithiasis, Alopecia, pruritus, Myalgia, arthralgia, Injection site reaction, fatigue, Glycosylated haemoglobin increased, Gamma-glutamyltransferase increased, alanine aminotransferase increased, lipase increased, blood glucose increased, blood amylase increased, prothrombin time prolonged.
    See prescribing information for full details.


    Drug interactions

    Anticipated pharmacokinetic interactions resulting in effects on pasireotide: The influence of the P-gp inhibitor verapamil on the pharmacokinetics of subcutaneous pasireotide was tested in a drug-drug interaction study in healthy volunteers. No change in the pharmacokinetics (rate or extent of exposure) of pasireotide was observed.
    Anticipated pharmacokinetic interactions resulting in effects on other medicinal products: Pasireotide may decrease the relative bioavailability of ciclosporin. Concomitant administration of pasireotide and ciclosporin may require adjustment of the ciclosporin dose to maintain therapeutic levels.
    Anticipated pharmacodynamic interactions
    Medicinal products that prolong the QT interval: Pasireotide should be used with caution in patients who are concomitantly receiving medicinal products that prolong the QT interval, such as class Ia antiarrhythmics (e.g. quinidine, procainamide, disopyramide), class III antiarrhythmics (e.g. amiodarone, dronedarone, sotalol, dofetilide, ibutilide), certain antibacterials (intravenous erythromycin, pentamidine injection, clarithromycin, moxifloxacin), certain antipsychotics (e.g. chlorpromazine, thioridazine, fluphenazine, pimozide, haloperidol, tiapride, amisulpride, sertindole, methadone), certain antihistamines (e.g. terfenadine, astemizole, mizolastine), antimalarials (e.g. chloroquine, halofantrine, lumefantrine), certain antifungals (ketoconazole, except in shampoo).
    Bradycardic medicinal products: Clinical monitoring of heart rate, notably at the beginning of treatment, is recommended in patientsnreceiving pasireotide concomitantly with bradycardic medicinal products, such as beta blockers (e.g. metoprolol, carteolol, propranolol, sotalol), acetylcholinesterase inhibitors (e.g. rivastigmine, physostigmine), certain calcium channel blockers (e.g. verapamil, diltiazem, bepridil), certain antiarrhythmics.
    Insulin and antidiabetic medicinal products: Dose adjustments (decrease or increase) of insulin and antidiabetic medicinal products (e.g. metformin, liraglutide, vildagliptin, nateglinide) may be required when administered concomitantly with pasireotide.


    Pregnancy and Lactation

    Pregnancy: There are no adequate data from the use of pasireotide in pregnant women. The potential risk for humans is unknown. Pasireotide should not be used during pregnancy unless clearly necessary.
    Lactation: It is unknown whether pasireotide is excreted in human milk.  Breast-feeding should be discontinued during treatment with Pasireotide.
    See prescribing information for full details.


    Overdose

    Doses up to 2.1 mg twice a day have been used in healthy volunteers, with the adverse reaction diarrhoea being observed at a high frequency. In the event of overdose, it is recommended that appropriate supportive treatment be initiated, as dictated by the patient’s clinical status, until resolution of the symptoms.


    Important notes

    Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
    Storage: Do not store above 25°C. Store in the original package in order to protect from light.


    Manufacturer
    Novartis Pharma Stein AG Switzerland
    Licence holder
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