Signifor - instructions for use, doses, side effects, contraindications

Active substancePasyreotidePasyreotide

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solution PC

Dosage form: & nbsphypodermic solution

Composition:

1 ampoule contains: active substance: pasyreotide diazpartate (corresponding to the pacyreotide base) - 0.3762 mg (0.3 mg), 0.7524 mg (0.6 mg), 1.1286 mg (0.9 mg); Excipients: Mannitol - 49.50 mg, 49.50 mg, 49.50 mg; tartaric acid 1.501 mg, 1.501 mg, 1.501 mg; sodium hydroxide - to pH 4.2, to pH 4.2, to pH 4.2; water for injection - up to 1 ml, up to 1 ml, up to 1 ml.

Description:A clear, colorless solution.

Pharmacotherapeutic group:synthetic somatostatin analogue

ATX: & nbsp

H.01.C.B Hormones that slow growth

H.01.C.B.05 Pasyreotide

Pharmacodynamics:Pasireotide is a new analog of somatostatin for injection, which is a cyclohexapeptide. Like the natural peptide hormones somatostatin-14 and somatostatin-28 (which suppress the secretion of growth hormone), as well as other somatostatin analogues, pasyreotide has a pharmacological effect, binding to somatostatin receptors. There are five different subtypes of the human receptor for somatostatin (SSTR - human somatostatin receptor): SSTR 1, 2, 3, 4 and 5. Somatostatin analogues bind to SSTR-receptors with different affinities (Table 1). Pasyreotide with a high affinity binds to four out of five SSTRreceptors.

Table 1. Affinity linking somatostatin (SRIF-14), pasyreotide, octreotide and lantreotide with five different subtypes human receptor SSTR (SSTR 1-5)

Substance	SSTR 1	SSTR 2	SSTR3	SSTR4	SSTR 5
Somatostatin	0,93+0,12	0,15+0,02	0,56+0,17	1,5+0,4	0,29+0,04
(SRIF-14)
Pasyreotide	9,3±0,1	1,0+0,1	1,5+0,3	> 100	0,16+0,01
Octreotide	280+80	0,38+0,08	7,1+1,4	> 1000	6,3+1,0
Lantreotide	180+20	0,54+0,08	14+9	230+40	17+5

The average values of the half-maximal inhibition concentration (IC50) taking into account the standard error of the mean value (+ SOS), expressed in nmol / l (nM).

Receptors to somatostatin are expressed in many tissues, especially in neuroendocrine tumors that secrete excess hormones, including adrenocorticotropic hormone (ACTH) in the case of Itenko-Cushing's disease. Due to its ability to bind firmly to somatostatin receptors, pasyreotide can be used to treat diseases that are characterized by the expression of these receptors in target tissues.

Research in vitro showed that the cells of the ACTH-producing tumor of the pituitary gland removed from patients with Isenko-Cushing's disease express a large number SSTR 5, while others receptor subtypes are either not expressed at all, or are expressed in lesser amounts. Pasyreotide communicates with SSTR- receptors of cells of ACTH-producing adenomas of the pituitary, which leads to inhibition of ACTH secretion.High affinity for 4 out of 5 subtypes of somatostatin receptors, in particular to SSTR5, makes it possible to use pasireotide for the effective treatment of patients with Isenko-Cushing's disease.

In clinical trials pasyreotide already after 1 month showed a rapid decrease in the average daily concentration of cortisol in the urine, and this effect persisted with time. There was a decrease in systolic and diastolic blood pressure, body mass index (BMI) and total cholesterol concentration. In addition, against the background of treatment there was a decrease in clinical symptoms: facial hyperemia, the amount of subclavian fat and fat in the back.

Metabolism of glucose

With the use of pasertiotide in a dose of 0.6 and 0.9 mg twice daily for healthy volunteers, development of hyperglycemia with a significant decrease in insulin secretion and incretin hormones (eg, glucagon-like peptide type 1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GUI]). Pasyreotide did not affect the sensitivity of tissues to insulin. In another study in healthy volunteers, the effect of pasireotide on blood glucose concentration was studied by comparing the groups of study participants who received pasyreotide in monotherapy or in combination with a hypoglycemic drug (metformin, nateglinide, vildagliptin or lyraglutide, respectively; insulin preparations were not included in the study) for 7 days. Hypoglycemic drugs from the GLP-1 receptor agonist group and the dipetidyl peptidase-4 inhibitors were most effective in treating the hyperglycaemia associated with the use of pasyreotide.
Influence on the electrophysiology of the heart The effect of pasyreotide on the length of the interval QT were evaluated in two open, controlled cross-over studies. It was shown that pasyreotide affects the interval QTc, the maximum change in the average length of this interval relative to the initial value (after subtracting the placebo effect) was observed 2 hours after the administration of the drug. Against the background of the use of pasyreotide, there was a decrease in the heart rate; in the case of pasireotide in a dose 0.6 mg 2 times a day, the maximum difference in comparison with placebo was observed after 1 h (-10.39 min^-1), and in the case of pasireotide in a dose 1.95 mg 2 times a day - after 0.5 hours (-14.91 minutes^-1).There were no transient or prolonged episodes of pirouette tachycardia.

Interval lengthening QT when using paserotide is not mediated by the effect of the drug on the potassium channels of the human heart, encoded by the gene hERG (human ether-a-go-go-related gene). The effect of pasertiotide on cardiac reconstruction was evaluated with 24-hour electrocardiographic monitoring to determine the ability of the drug to increase the risk of arrhythmia.

There was a significant improvement in the parameters of cardiac reconstruction with the use of pasyreotide against the background of the existing lengthening of the interval QT, which indicates that due to the use of pasyreotide interval lengthening QT is not associated with a risk of arrhythmia. Quantitative analysis of the morphological parameters of the T-wave revealed no changes indicating a violation of the spatial homogeneity of the cardiac repolarization process.

Pharmacokinetics:

Suction

In healthy volunteers pasyreotide is rapidly absorbed after subcutaneous administration, and the time to reach the maximum concentration in the blood plasma (T_max) is 0.25 - 0.5 h. The maximum concentration (C_max) and the area under the pharmacokinetic curve "concentration-time" (AUC) approximately correspond to the dose after a single and multiple administration. Studies in assessing the bioavailability of pasire-otide in humans have not been conducted. Data on the bioavailability of preclinical studies in rats and monkeys show that the absolute bioavailability of pasyreotide in human injections is complete.

Distribution

In healthy volunteers pasyreotide showed a large apparent volume of distribution (Vz / F> 100 l). Distribution between blood and plasma does not depend on concentration, pasyreotide mainly distributed in plasma (91%). The drug moderately binds to plasma proteins (88%), with binding independent of concentration.

Pasirethotide has a low passive penetrating ability, and is most likely a substrate of P-glycoprotein. It is expected that the effect of P-glycoprotein on the absorption, distribution, metabolism and excretion of pasyreotide is small. Pasyreotide is not a substrate BCRP (breast cancer resistance protein), OST1 (organic cation transportator 1) or OATP (organic polypeptides - anion transporters)1B1, 1B3, 2B1.

Metabolism

Pasyreotide is practically not metabolized in the liver and kidneys. In healthy volunteers pasyreotide is found in plasma, urine and feces, mostly in unchanged form.

Excretion

Pacireotide is excreted mainly through the intestines, and in small amounts by the kidneys. It was shown that 55.9 ± 6.63% of the radioactive dose is excreted in the first 10 days after administration, including 48.3 ± 8.16% through the intestine and 7.63 ± 2.03% by the kidneys.

Clearance (CL / F) pasireotide in healthy volunteers and patients with the disease Itenko-Cushing's is ~ 7.6 l / h and ~ 3.8 l / h, respectively.

With multiple injections pasyreotide demonstrates a linear and dose-dependent pharmacokinetics in the dose range from 0.05 to 0.6 mg once a day in healthy volunteers, and 0.3 mg to 1.2 mg twice daily in patients with Isenko-Cushing's disease. The calculated effective half-life (T1 /₂) in healthy volunteers is about 12 hours (an average of 10 to 13 hours for doses of 0.05, 0.2 and 0.6 mg per day).

Population analysis of the pharmacokinetics (PK) of pasyreotide showed that sexual and racial affiliation does not affect the parameters of PK.

Special categories of patients Patients aged < 18 years The efficacy and safety of Signlif® in patients under the age of 18 years is not established.

Patients> 65 years of age

The data of the analysis of the use of the drug in patients with Isenko-Cushing's disease over the age of 65 give grounds to believe that the safety and effectiveness of the drug at This population does not differ significantly from the use in patients younger age.

Patients with impaired renal function In this group of patients no clinical studies have been conducted.

However, since the excretion of pasyreotide in human renal clearance essential role does not play, significant influence renal function for concentration pasirethotide in the blood unlikely.

Patients with impaired hepatic function

According to the clinical study, patients with impaired liver function (class A, B and C according to the Child-Pugh), with the use of pasyreotide pharmacokinetic parameters were significantly higher than in patients with normal liver function: measure AUCinf increased by 60% and 79%, FROM_maxincreased on 67% and 69%, a CL/F declined by 37% and 44%, respectively.

Indications:

Treatment of patients with illness Itenko-Cushing, if it is impossible to conduct or ineffectiveness of the surgical treatment.

Contraindications:

- Hypersensitivity to pasireotid or any other component of the drug.

- Severe function impairment liver (class C according to Child-Pugh).

- Children under 18 years old

- The period of breastfeeding.

Carefully:

In patients with impaired tolerance to glucose or diabetes mellitus; from heart diseases and / or factors risk of bradycardia (clinically significant bradycardia or acute myocardial infarction in anamnesis, atrioventricular block degree, chronic heart failure (grade III or IV according to classification NYHA), unstable angina, persistent ventricular tachycardia, ventricular fibrillation, congenital syndrome of interval lengthening QT); in patients taking antiarrhythmic drugs or other drugs that lead to lengthening interval QT; in patients with hypokalemia and / or hypomagnesemia; in patients with impaired liver function; during pregnancy.

Pregnancy and lactation:

The use of pasireotid in pregnancy not studied. In animal studies It is shown that the drug can provide toxic effect on reproductive function.A potential risk to a person is not known. Signifor should be used during pregnancy only in extreme cases, if the potential The benefits exceed the possible risk.

In studies of pasyreotide in animals with its subcutaneous injection, it is shown that the drug penetrates into the milk of lactating animals.

It is not known whether the pasyreotide at breast milk rights. Because the risk

for a child receiving a drug with breast milk, can not be excluded, in breastfeeding period drug is contraindicated.

Dosing and Administration:

The recommended initial dose of the drug Signifor is 0.9 mg subcutaneously (SC) 2 times a day. In patients with impaired glucose tolerance or diabetes mellitus recommended application of of the drug in a dose of 0.6 mg 2 times in a day. Increase the dose of the drug, based on clinical efficacy and tolerability in a particular patient. If necessary, an increase in the initial dose from 0.6 mg 2 times a day to 0.9 mg 2 times a day is possible with good tolerability of the initial dose. Individual dose reduction is possible by the decision of the attending physician in patients with stabletherapeutic response.

A effectiveness of treatment, which is is manifested in a significant decrease concentration of free cortisol in daily urine and / or in decreasing symptoms of the disease), wherein it is recommended that pasireotide therapy, while free cortisol in the urine is observed two months after the initiation of therapy. If the patient does not respond to the therapy, consider stopping it. In the event of undesirable events, it may be necessary to temporarily reduce the dose of pasyreotide to 0.3 mg 2 times a day.

Method of administration

A drug Signifor® is intended for self-percutaneous administration. Patients should be trained by a doctor or other health care provider to administer the drug.

Entering the drug twice in a row in the same place is not recommended. The drug should not be administered to places where there are signs of inflammation or irritation.

Preferably, subcutaneous injections are made to the skin of the upper third of the thighs and abdomen (except for the navel and waist region).

Use in patients with impaired renal function

Correction of the dose is not required.

Use in patients with impaired liver function

The recommended initial dose for patients with impaired liver function of moderate severity (class B by Child-Pugh) is 0.3 mg twice a day.

The maximum recommended dose for patients with moderate impaired liver function (Child-Pugh class B) is 0.6 mg twice a day.

In patients with lungs impaired hepatic function (class A on Child-Pugh) to adjust the dose of the drug is not required.

Use in patients> 65 years of age

Correction of the dose is not required.

Use in patients <18 years of age

In children and adolescents with a disease Itenko- Cushing's drug administration Signifor contraindicated, since the efficacy and safety of Signlophor in patients under the age of 18 years is not established.

Side effects:

In clinical research II and Phase III Signignor ® received 201 patients with illness of Itenko-Cushing. Behind except for cases of development hypokorticism and a more severe degree hyperglycemia, safety profile Signifor significantly differs from other analogues somatostatin.

Most adverse events (AEs) 3 and 4 severity levels were associated with hyperglycaemia. The most frequent AEs (frequency> 10%) were diarrhea, nausea, pain in the abdomen, cholelithiasis, hyperglycemia, diabetes mellitus, fatigue and increase in concentration glycosylated hemoglobin (HbAlc).

Lethal outcomes during the study were not It was.

Frequency of development of undesirable phenomena was estimated as follows:

arising "very often" (> 1/10), "often" (> 1/100; <1/10), "infrequently" (> 1/1000; <1/100), "rarely" (> 1/10000; <1/1000), "very rarely" (<1/10000).

Violations from the blood and lymphatic system: infrequently, anemia.

Disorders from the endocrine system: often adrenal failure.

Disorders from the metabolism and nutrition: very often hyperglycemia, diabetes mellitus; often - type 2 diabetes, a decrease in appetite.

Heart Disease: often - sinus bradycardia, lengthening interval QT.

Vascular disorders: often - arterial hypotension.

Impaired nervous system: often a headache.

Disorders from the digestive system system: very often - diarrhea, pain in the abdomen, nausea; often - vomiting, pain in upper abdomen.

Disorders from the liver and bile ducts: Often - cholelithiasis.

Disturbances from the skin and subcutaneous fabrics: often - alopecia, itching.

Disturbances from the musculoskeletal and connective tissue: often - myalgia, arthralgia.

General disorders and disorders in place introduction: very often - reaction in place introduction, fatigue.

Laboratory and instrumental data: very often - increase HbAlc; often - an increase in the concentration of glucose in blood, increased lipase activity, amylase, gamma-glutamyltransferase, alanine aminotransferase (ALT), increased prothrombin time.

Description of individual undesirable phenomena

Disturbance of glucose metabolism

In the Phase III study in patients with Isenko-Cushing's disease increase glucose concentrations plasma blood was most frequent laboratory violation of grade 3 (23.2% of patients). Have patients with normoglycemia at the time of the average index HbAlc increased by less degree than in patients with impaired tolerance to glucose or sugar diabetes.

During the first month of treatment, the mean indicators concentrations glucose plasma of fasting blood usually increased, and in the following months declined and stabilized. Within 28 days after abolition of pacyreotide indicators concentrations plasma glucose blood fasting and HbAlc, as a rule, decreased, but remained above the original values.

Long-term follow-up are absent. In the course of clinical research for development reasons hyperglycemia drug was abolished in 3.1% of patients, due to development of diabetes mellitus - in 2,5%.

Disorders from the gastro-intestinal tract

As in the case of other analogs somatostatin, against the background of pasireiformes were often noted in the gastro-intestinal disorders. Usually similar phenomena were characterized by a low degree did not require intervention and were resolved against the backdrop of continuing treatment.

Reactions at the site of administration

In clinical trials, 13.6% patients had reactions in place Signifor®, among them: pain at the injection site, erythema, hematoma, bleeding and itching. These phenomena were resolved spontaneously and did not require intervention.

Activity of liver enzymes Against the background of the use of pasyreotide, as well as against the background of the use of other somatostatin analogs, there was a transient increase in the activity of liver enzymes. In most cases, these phenomena were not accompanied by clinical symptoms, characterized by a low degree of severity and resolved, despite the continuation of treatment. Several cases of increased ALT activity (3 times higher than the upper limit of the norm) and bilirubin (2 times higher than the upper limit of the norm), which occurred within the first 10 days after the start of the Signphor drug, were resolved and the treatment was discontinued. There were no cases of drug-induced hepatitis.

Activity of pancreatic enzymes

In clinical studies on the background of pasireotide, there was an increase in lipase and amylase activity, not accompanied by clinical symptoms. These phenomena were characterized by a low degree and were resolved against the background of continuation of treatment. Nevertheless, the development of pancreatitis should be considered a possible adverse reaction of somatostatin analogues, since cholelithiasis can be associated with the development of acute pancreatitis.

Overdose:

In patients who received a drug Signifor®, cases of overdose was not noted. In healthy volunteers who received pasyreotide at doses up to 2.1 mg twice a day, as a side effect was often noted diarrhea.

In case of an overdose, based on the patient's condition, start the appropriate symptomatic treatment and it before the resolution of symptoms.

Interaction:

Pasireiform at a moderate level binds to plasma proteins, only in a small degree is exposed metabolism. Pasyreotide is an substrate of P-glycoprotein (P-GP), but not inhibitor or inductor P-GP. No data, allowing suggest that in therapeutic concentrations pasyreotide is an:

- substrate, inhibitor or inducer of cytochrome P450;

- substrate BCRP (breast cancer resistance protein), OST1 (organic cation 1 transporter) or OATP (organic polypeptides - anion transporters) 1B1, 1B3, 2B1;

- an inhibitor UGT1A1 (uridine-diphosphateglucoronyl-transferase, isoform 1A1), OAT1 or OATZ carrier proteins, OATP 1B1 or 1B3, OST1 or OST2, R-GP, BCRP, carrier protein (MRP2) or in SEP (exporting bile acids pump).

In a study of the effect of the P-HPP inhibitor on the pharmacokinetics of pasyreotide, when administered subcutaneously with verapamil, healthy volunteers did not change the bioavailability of pasyreotide.

Pharmacokinetic interactions affecting the effect of pasyreotide Exist risk increase concentration (C_max) of pasyreotide, with simultaneous applying it with other inhibitors of P-GP (ketoconazole, ciclosporin, verapamil, clarithromycin), there is no clinical confirmation of this effect. Pharmacokinetic interactions that affect the effect of concomitant medicines A few published data indicate that somatostatin analogues are mediated suppression secretion of growth hormone) can reduce the clearance of substances metabolized with the participation of cytochrome P450 isoenzymes. The available data do not allow to exclude a similar effect in pasireotide. Pasyreotide should be used with caution at the same time with drugs that have a narrow therapeutic index and metabolized predominantly with the participation of isoenzyme CYP3A4 (quinidine, terfenadine).

In a study on dogs, it was shown that pasyreotide reduces the concentration of cyclosporine in the blood by reducing the absorption of the latter in the intestine. Whether this interaction takes place in humans is not known. In this connection, in the case of using pasirethotide simultaneously with cyclosporine, there may be a need for dose adjustment cyclosporine.

A few data for others analogs of somatostatin allow suggest that in the case of pasireotide simultaneously with bromocriptine bioavailability the latter increases.

Medicines affecting interval QT

Pasyreotide should be taken with caution apply simultaneously with antiarrhythmic and other drugs that can lengthen interval QT: antiarrhythmic drugs (quinidine, procainamide, disopyramide, amiodarone, dronedaron, sotalol, dofetilide, ibutilide), individual antibacterial preparations (erythromycin for intravenous application, clarithromycin, moxifloxacin) are separate antipsychotics (chlorpromazine, thioridazine, fluphenazine, haloperidol, tiapride, amisulpride, sertindole, methadone), some blockers of H1-histamine receptors (terfenadine, astemizole, misolastine), antimalarials (chloroquine, halofantrine, lumefantrine), some antifungal agents (ketoconazole).

It is also recommended to monitor heart rate (heart rate) in patients, accepting at the same time pasyreotide and drugs, causing bradycardia: beta-blockers (metoprolol, propranolol, sotalol), m-holinoblokatory (ipratropium bromide, oxybutynin), blockers of "slow" calcium channels (verapamil, diltiazem, beprideal) and antiarrhythmic preparations.

Insulin and oral hypoglycemic drugs

Patients receiving insulin or oral hypoglycemic drugs, dosage adjustment (increase or decrease) of these drugs after the onset of pasyreotide treatment may be required.

Special instructions:

Hypocorticism

Treatment with pasireotid leads to a rapid decrease in secretion of ACTH in patients with Isenko-Cushing's disease. Fast and complete or almost complete suppression of ACTH secretion can lead to a decrease in the concentration of cortisol plasma blood and the development of transient hypokorticism.Cases of hypocorticism have been described in patients with Isenko-Cushing's disease in Phase III studies; Hypocorticism developed, as a rule, in the first two months of treatment. In most cases, this condition was stopped by decreasing the dose of pasyreotide and / or adding short-term therapy to small doses glucocorticosteroids (GCS).

It is necessary to monitor the condition and instruct patients about the possible occurrence of symptoms of hypokorticism (eg, weakness, fatigue, nausea, vomiting, arterial hypotension, hyponatremia, or hypoglycemia). In the case of a confirmed hypokorticism may be required temporary replacement therapy for SCS and / or a decrease in the dose of pasyreotide, or break in treatment.

Metabolism of glucose

In patients receiving pasyreotide, may develop hyperglycemia (less often hypoglycemia). The development of hyperglycemia, apparently, is associated with a decrease in insulin secretion (especially in the period after introduction of the drug) and incretinovyh hormones (eg, GLP-1 and HIP).

Hyperglycemia is more pronounced in patients who had prior therapy impaired glucose tolerance or diabetes. Before use pacyreotide should be evaluated fasting blood glucose HbAlc. During the first 2-3 months of treatment patients must independently control blood glucose concentration (fasting) with intervals of one week, as well as in the first 2-4 weeks after increasing the dose preparation; subsequently, these indicators should be controlled as clinical necessity.

If the patient is developing hyperglycemia when using Signignor®, the use of hypoglycemic agents or correction of the scheme of their use is recommended.

In the treatment of hypoglycemic decreased concentrations HbAlc <7% and glucose fasting blood <130 mg / dL (7.2 mmol / L) in 43 and 72% of patients with Isenko-Cushing's disease, respectively. With persistent hyperglycemia, poorly amenable to correction with adequate hypoglycemic therapy, a decrease in the dose of pasirethotide or its withdrawal is required.

Have patients with Isenko-Cushing's disease and hyperglycemia, poorly susceptible correction (HbAlc > 8% on therapy hypoglycemic drugs), increased risk of severe hyperglycemia and related complications (eg, ketoacidosis). Have patients with hyperglycemia, poor subject to correction, before use of pasyreotide should be strengthened glycemic control and adjust therapy of diabetes.

Disorders from the cardiovascular system

Against the background of the use of pasyreotide there were cases of bradycardia. Careful monitoring of the patients with heart disease and / or risk factors for bradycardia (in particularly in patients with a history of there is a clinically significant bradycardia or acute myocardial infarction, atrioventricular block degree, chronic cardiac Insufficiency (grade III or IV classification of NYHA), unstable stenocardia, persistent ventricular tachycardia, ventricular fibrillation).

It may be necessary to adjust the dose of such drugs, like beta-blockers, calcium antagonists, etc.

Pasyreotide should be taken with caution apply in patients who have an interval QT either already elongated, or maybe is elongated with high probability, in particular in patients:

- with congenital lengthening syndrome interval QT;

- with uncontrolled or serious heart disease, including, recently, suffered myocardial infarction, chronic heart failure, unstable angina or clinically significant bradycardia; taking antiarrhythmic medications or other medications leading to lengthening of the interval QT;

- with hypokalemia and / or hypomagnesemia. It is recommended to control the length of the interval QTc on the background of the use of pasireotid: electrocardiography is recommended to be performed before the beginning of treatment, and then according to clinical indications. Before the beginning of pasireotide therapy in patients with hypokalemia and hypomagnesemia, it is necessary to normalize the content of potassium and magnesium in the blood plasma; on the background of further treatment should periodically monitor their concentration. Biochemical parameters of liver function It is recommended to determine the biochemical parameters of liver function (bilirubin, activity of "liver" enzymes) before the beginning of pasireotide therapy, after 1-2 weeks of therapy, and then monthly for three months. The biochemical parameters of liver function are then examined according to clinical indications.Therapy with Signignor® should be discontinued, if:

the patient developed jaundice or other symptoms during the treatment with Signnif® signs of severe impairment of function liver;

activity of aspartate aminotransferase (ACT) or ALT rose to a value of 5 times above the upper limit of the norm or higher;

- ALT activity and ACT has reached 3 times above the upper limit of the norm, and the concentration of bilirubin reached values are 2 times higher than the upper limit norms.

If the biochemical indicators of liver function is presumably associated with use of the drug, further resumption of therapy Signlifor is not recommended.

Chololithiasis

Chololithiasis - established adverse side effect, prolonged analogues of somatostatin, including, pasireotide. It is recommended that ultrasound examination of gallstones bladder before the use of pasyreotide and every 6-12 months of its use.

Presence of stones in the gallbladder patients receiving pasyreotide, at most cases are not accompanied by clinical manifestations.

Gallstone disease, accompanied by a characteristic clinical symptomatology, should be treated in accordance with accepted clinical practice.

Pituitary Hormones

Because of its pharmacological activity pasyreotide like somatostatin, we can not exclude that, against the background of its use, the synthesis of not only ACTH but also other pituitary hormones will be suppressed. In this regard, both before the start of treatment with pasireotide, and during treatment (according to clinical indications), it is necessary to monitor the function of the pituitary (determining the concentration of thyroid-stimulating hormone, growth hormone, etc.), as well as free thyroxine.

Effect on the ability to drive transp. cf. and fur:

Studies of the effect of the drug on Ability manage transport means and mechanisms were conducted. Given the possibility development of some side effects on the background of taking Signignor(headache, fatigue) to patients Care should be taken when management of vehicles and other potentially dangerous activities requiring increased concentration of attention.

Form release / dosage:

Solution for subcutaneous administration 0.3 mg / ml, 0.6 mg / ml and 0.9 mg / ml.

1 ml each in ampoules from colorless glass, the ampoule has a broken point. 6

ampoules are placed into the paper with instructions for use in

cardboard tutu.

Multi-pack. 3, 5 or 10 packs of 6 ampoules.

Packaging:ampoules (6) - packs cardboard
ampoules (6) - packs cardboard-packs cardboard

Storage conditions:

Keep in a dark place at temperature not higher than 30 ° С.

Keep out of the reach of children.

Shelf life:

2 years

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002254

Date of registration:26.09.2013

The owner of the registration certificate:Novartis Pharma AGNovartis Pharma AG Switzerland

Manufacturer: & nbsp

NOVARTIS PHARMA STEIN, AG Switzerland

Representation: & nbspNOVARTIS PHARMA LLCNOVARTIS PHARMA LLC

Information update date: & nbsp21.08.2015

Illustrated instructions

Instructions

Signifor® (Signifor®)