Instruction for use: Pasireotide (Pasireotidum)

Chemical name

[(3S, 6S, 9S, 12R, 15S, 18S, 20R) -9- (4-Aminobutyl) -3-benzyl-12- (1H-indol-3-ylmethyl) -2,5,8,11,14 , 17-hexaoxo-15-phenyl-6 - [(4-phenylmethoxyphenyl) methyl] -1,4,7,10,13,16-hexaazabicyclo [16.3.0] genicosan-20-yl] -N- (2- Aminoethyl) carbamate

Pharmacological group

Hormones of the hypothalamus, pituitary gland, gonadotropins and their antagonists

Nosological classification (ICD-10)

E24 Iscenko-Cushing's Syndrome

Disease of Itenko-Cushing, Cushing's Syndrome

Code CAS396091-73-9

Characteristics of Pasireotide

Synthetic analogue of somatostatin for injection, which is a cyclohexapeptide ..

Pharmacology

The pharmacological action is somatostatin-like.

Pharmacodynamics

Like the natural peptide hormones somatostatin-14 and somatostatin-28 (suppress the secretion of growth hormone), pasireotide has a pharmacological effect, binding to somatostatin receptors. Five different subtypes of the human somatostatin receptor (SSTR) are known: SSTR 1, 2, 3, 4 and 5. High affinity pasiretide binds to four of the five SSTR receptors.

Receptors to somatostatin are expressed in many tissues, especially in neuroendocrine tumors that secrete excess hormones, incl. ACTH, with the disease Itenko-Cushing. Due to its ability to bind firmly to somatostatin receptors, pasireotide can be used to treat diseases that are characterized by the expression of these receptors in target tissues.

In vitro studies have shown that cells of the ACTH-producing tumor of the pituitary gland removed from patients with Iscenko-Cushing's disease express a large amount of SSTR 5, while other receptor subtypes are either not expressed at all or are less expressed. Pasireotide binds to SSTR receptors of ACTH-producing adenoma pituitary cells, which leads to inhibition of ACTH secretion. The high affinity for 4 of the 5 somatostatin receptor subtypes, in particular SSTR 5, makes it possible to use pasireotide for the effective treatment of patients with Isenko-Cushing's disease.

In clinical studies, pasireotid after 1 month showed a decrease in the average daily concentration of cortisol in the urine, and this effect persisted with time. There was a decrease in SAD and DAD, BMI and concentration of total XC. In addition, against the background of treatment there was a decrease in clinical symptoms: face hyperemia, the amount of subclavian fat and fat in the back.

Metabolism of glucose

When paseriotide was used at a dose of 0.6 and 0.9 mg twice daily, healthy hyperlikemia with a significant decrease in the secretion of insulin and incretin hormones (eg, GLP-1 and HIP) was noted in healthy volunteers. Pasireotype 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 study participants who received pasireotide in monotherapy or in combination with hypoglycemic drugs (metformin, nateglinide, vildagliptin, or liraglutide, respectively, insulin preparations were not included in the study) 7 days. Hypoglycemic drugs from the group of GLP-1 receptor agonists and DPP-4 inhibitors were most effective for the treatment of hyperglycemia associated with the use of pasireotide.

Influence on the electrophysiology of the heart

The effect of pasireotide on the QT interval was evaluated in two open controlled cross-over studies. It was shown that pasireotide affects the QTc interval, with the maximum change in the mean length of this interval relative to the initial value (after subtracting the placebo effect) was observed 2 hours after the administration of the pasireotide. Against the background of pasireotid use, a decrease in heart rate was observed; In the case of pasireotide at a dose of 0.6 mg 2 times a day, the maximum difference in comparison with placebo was observed after 1 hour (-10.39 min-1), and in the case of pasireotide at a dose of 1.95 mg 2 times a day - After 0.5 hours (-14.91 min-1). There were no transient or prolonged episodes of pirouette tachycardia.

The prolongation of the QT interval with the use of paserotide is not mediated by the effect of the drug on the potassium channels of the human heart, encoded by the human ether-a-go-go-related gene. The effect of pasireotide on cardiac reconstruction was evaluated with 24-hour ECG monitoring to determine its ability to increase the risk of arrhythmia.

There was a significant improvement in the parameters of cardiac reconstruction with the use of pasireotide against the background of the existing elongation of the QT interval, which indicates that the prolongation of the QT interval caused by the use of pasireotide is not associated with the 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.

Pharmacokineticss

Suction

In healthy volunteers, the pacyreotide is rapidly absorbed after subcutaneous administration, and Tmax in the blood plasma is 0.25-0.5 h. Cmax and AUC approximately correspond to the dose after a single and multiple injection. Studies to assess the bioavailability of pasire-otide in humans have not been conducted.

Distribution

In healthy volunteers, the pacyreotide shows a large apparent volume of distribution (Vz / F> 100 L). The distribution between blood and plasma does not depend on concentration, pasireotide is predominantly distributed in plasma (91%). Pasireotide 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-gp. It is expected that the effect of P-gp on the absorption, distribution, metabolism and excretion of pasireotide is small. Pasireotype is not a substrate of BCRP, OCT1 (an organic cation 1 transporter) or OATP (organic polypeptides - anion transporters) 1B1, 1B3, 2B1.

Metabolism

Pasireotide is practically not metabolized in the liver and kidneys. In healthy volunteers, pasireotide is found in plasma, urine and feces mainly unchanged.

Excretion

Pasirethotide is excreted mainly through the intestine 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, incl. (48.3 ± 8.16)% - through the intestine and (7.63 ± 2.03)% - by the kidneys. The clearance (CL / F) of pasireotide in healthy volunteers and patients with Isenko-Cushing's disease is approximately 7.6 and 3.8 l / h, respectively.

With multiple SC administration, the pAC exhibits a linear dose-dependent Pharmacokineticss in the dose range from 0.05 to 0.6 mg once daily in healthy volunteers and 0.3-1.2 mg twice daily in patients with Isenko-Cushing's disease . The calculated effective 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 showed that sexual and racial affiliation does not affect the Pharmacokinetics parameters of pasireotide.

Special categories of patients

Patients aged <18 years. The efficacy and safety of pasireotide in patients <18 years of age is not established.

Patients> 65 years of age. Data from the analysis of the use of pasireotide in patients with Isenko-Cushing's disease> 65 years suggest that the safety and efficacy of its use in this population are not significantly different from those in younger patients.

Impaired renal function. In this group of patients, no separate clinical trials have been performed. However, since In the excretion of pasireotide in humans, renal clearance does not play a significant role, a significant effect of kidney function on the concentration of pasire-otide in the blood seems unlikely.

Violation of the function of the liver. According to the clinical study, Pharmacokinetics parameters were significantly higher in patients with impaired hepatic function (classes A, B and C according to Child-Pugh classification) when using pacyreotide than in patients with normal liver function: the AUCinf score was increased by 60 and 79% Cmax - by 67 and 69%, and CL / F decreased by 37 and 44% respectively.

Indications

Treatment of patients with Isenko-Cushing's disease if surgical treatment is impossible or ineffective.

Contraindications

Hypersensitivity to pasireotide; Severe liver dysfunction (Child-Pugh class C); Age to 18 years; The period of breastfeeding.

Restrictions for use

Impairment of glucose tolerance or diabetes mellitus; Heart disease and / or risk factors for bradycardia (clinically significant bradycardia or acute myocardial infarction in history, high-grade AV block, CHHA (grade III or IV according to NYHA classification), unstable angina, persistent ventricular tachycardia, ventricular fibrillation, congenital lengthening syndrome Interval QT); Simultaneous use of antiarrhythmic or other drugs leading to lengthening of the QT interval; Hypokalemia and / or hypomagnesemia; Impaired liver function; pregnancy.

pregnancy and lactation

The action category for fetus by FDA is C.

The use of pasireotide in pregnancy has not been studied. In animal studies, it has been shown that pasireotide can have a toxic effect on reproductive function. The potential risk to humans is unknown. Pasireotide should be used during pregnancy only in extreme cases, if the potential benefit exceeds the possible risk.

In studies of pasireotide in animals with its p / c introduction, it is shown that it penetrates into the milk of lactating animals.

It is not known whether pasireotide penetrates human breast milk. Since the risk for a child receiving pasireotid with breast milk can not be ruled out, during the period of breastfeeding, the use of pasireotide is contraindicated.

Side effects

In clinical studies of Phase II and III, pacreotide was given to 201 patients with Isenko-Cushing's disease. With the exception of cases of hypocorticism and a more severe degree of hyperglycemia, the safety profile of pasireotide is not significantly different from other somatostatin analogues.

Most of the adverse events of severity 3 and 4 were associated with hyperglycemia. The most frequent (frequency> 10%) were diarrhea, nausea, abdominal pain, cholelithiasis, hyperglycemia, diabetes mellitus, fatigue and increased concentrations of glycosylated hemoglobin (HbA1c). There were no lethal outcomes during the study.

The incidence of adverse events was estimated as follows: very often (≥1 / 10); Often (≥1 / 100, <1/10); Infrequently (≥1 / 1000, <1/100); Rarely (≥1 / 10000, <1/1000); Very rarely (<1/10000).

On the part of the blood and lymphatic system: infrequently - anemia.

From the endocrine system: often - adrenal insufficiency.

From the side of metabolism and eating disorders: very often - hyperglycemia, diabetes mellitus; Often - diabetes mellitus type 2, decreased appetite.

From the heart: often - sinus bradycardia, prolongation of the QT interval.

From the side of the vessels: often - arterial hypotension.

From the nervous system: often - a headache.

From the digestive system: very often - diarrhea, abdominal pain, nausea; Often - vomiting, pain in the upper abdomen.

From the liver and biliary tract: very often - cholelithiasis.

From the skin and subcutaneous tissues: often - alopecia, itching.

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

General disorders and disorders at the injection site: very often - reaction at the injection site, increased fatigue.

Laboratory and instrumental data: very often - an increase in HbA1c; Often - an increase in the concentration of glucose in the blood, increased activity of lipase, amylase, gamma-glutamyltransferase, ALT.

Description of individual undesirable phenomena

Disturbance of glucose metabolism. In the Phase III study in patients with Isenko-Cushing's disease, an increase in plasma glucose concentration was the most frequent laboratory disorder of severity 3 (23.2% of patients). In patients with normoglycemia at the time of enrollment, the mean HbA1c increased to a lesser extent than in patients with impaired glucose tolerance or diabetes mellitus.

During the first month of treatment, the average fasting plasma glucose concentration was usually increased, and in the following months it decreased and stabilized. Within 28 days after the abolition of pasireotide, fasting plasma glucose and HbA1c concentrations were usually reduced, but remained above the baseline values. No long-term follow-up data. In clinical trials due to the development of hyperglycemia, the drug was withdrawn in 3.1% of patients, due to the development of diabetes mellitus - in 2.5%.

Disorders from the digestive tract. As in the case of other somatostatin analogues, gastrointestinal disorders were often observed with the use of pacyreotide. Usually, such phenomena were characterized by a low degree of severity, did not require intervention and were resolved against the backdrop of ongoing treatment.

Reactions at the site of administration. In clinical studies, 13.6% of patients had reactions at the place of administration of pasireiform, among them: pain at the injection site, erythema, hematoma, hemorrhage and itching. These phenomena were resolved spontaneously and did not require intervention.

Activity of liver enzymes. Against the background of the use of pasireotide, as well as against the background of the use of other somatostatin analogues, 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 UGN) and bilirubin (2 times higher than UGN), which occurred within the first 10 days after the onset of pasireotide administration, were resolved while 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 of severity and resolved with the continuation of treatment. Nevertheless, the development of pancreatitis should be considered a possible side reaction of somatostatin analogues, because Cholelithiasis can be associated with the development of acute pancreatitis.

The following clinically relevant adverse reactions are mentioned in other sections of the description:

- hypokorticism (see "Precautions");

- Hyperglycemia and diabetes (see "Precautions");

- bradycardia and lengthening of the QT interval (see "Precautions");

- an increase in liver function tests (see "Precautions");

- cholelithiasis (see "Precautions");

- Insufficiency of pituitary hormones (see "Precautions").

Experience in clinical trials

Since clinical trials have been conducted with a different set of conditions, the frequency of occurrence of adverse reactions observed in these studies may not coincide with those obtained in other studies and observed in clinical practice.

A total of 162 patients with Isenko-Cushing's disease received pasireotide in Phase III clinical trials. At the beginning of the study, patients were randomized to two groups receiving pasireotide two times a day at a dose of 0.6 or 0.9 mg. The average age of the patients was approximately 40 years, the number of female patients prevailed (78%). The majority of patients had a persistent or recurrent form of Isenko-Cushing's disease (83%); Some patients (≤5%) in each of the study groups received a previous irradiation of the hypothalamic-hypophyseal system. The average exposure of pasireotide was 10.4 months, 68% of patients received pasireotide at least 6 months. In phase III clinical trials, adverse reactions were noted in 98% of patients. Most often (with a frequency of ≥20% in each group), diarrhea, nausea, hyperglycemia, cholelithiasis, headache, abdominal pain, fatigue and diabetes mellitus were noted. There were no deaths during this study. Serious adverse reactions were observed in 25% of patients. 17% of patients reported adverse reactions leading to discontinuation of the study.

The following are side effects observed with a total incidence of more than 5% in the randomized groups and in the study as a whole. Adverse reactions are ranked by the frequency of occurrence, the most frequently observed adverse reactions are listed first. Data are presented through the semicolon in the following order (number of cases (percentage of the number of participants,%): group receiving pasireotide at a dose of 0.6 mg twice a day (N = 82), a group receiving pasireotide at a dose of 0.9 mg 2 Once a day (N = 80), in general for both groups (N = 162).

Diarrhea - 48 (59%); 46 (58 per cent); 94 (58%).

Nausea - 38 (46%); 46 (58 per cent); 84 (52%).

Hyperglycemia - 31 (38%); 34 (43%); 65 (40%).

Chololithiasis is 25 (30%); 24 (30%); 49 (30%).

Headache - 23 (28%); 23 (29%); 46 (28%).

Abdominal pain - 19 (23%); 20 (25%); 39 (24%).

Increased fatigue - 12 (15%); 19 (24%); 31 (19%).

Diabetes mellitus - 13 (16%); 16 (20%); 29 (18%).

Reactions at the injection site - 14 (17%); 14 (18%); 28 (17%).

Nasopharyngitis - 10 (12%); 11 (14%); 21 (13%).

Alopecia - 10 (12%); 10 (13%); 20 (12%).

Asthenia - 13 (16%); 5 (6%); 18 (11%).

An increase in the level of HbA1c-10 (12%); 8 (10%); 18 (11%).

An increase in the level of ALT-11 (13%); 6 (8%); 17 (10%).

An increase in the level of gamma-glutamyl transferase - 10 (12%); 7 (20%); 17 (10%).

Peripheral edema - 9 (11%); 8 (10%); 17 (10%).

Pain in the upper abdomen - 10 (12%); 6 (8%); 16 (10%).

Decreased appetite - 7 (9%); 9 (11%); 16 (10%).

Hypercholesterolemia - 7 (9%); 9 (11%); 16 (10%).

Hypertension - 8 (10%); 8 (10%); 16 (10%).

Dizziness - 8 (10%); 7 (9%); 15 (9%).

Hypoglycemia - 12 (15%); 3 (4%); 15 (9%).

Diabetes mellitus type 2 - 10 (12%); 5 (6%); 15 (9%).

Anxiety is 5 (6%); 9 (11%); 14 (9%).

Influenza - 9 (11%); 5 (6%); 14 (9%).

Insomnia - 3 (4%); 11 (14%); 14 (9%).

Myalgia - 10 (12%); 4 (5%); 14 (9%).

Arthralgia - 5 (6%); 8 (10%); 13 (8%).

Itching - 6 (7%); 7 (9%); 13 (8%).

An increase in the level of lipase - 7 (9%); 5 (6%); 12 (7%).

Constipation - 7 (9%); 4 (5%); 11 (7%).

Hypotension - 5 (6%); 6 (8%); 11 (7%).

Vomiting - 3 (4%); 8 (10%); 11 (7%).

Back pain - 4 (5%); 6 (8%); 10 (6%).

Dry skin - 5 (6%); 5 (6%); 10 (6%).

Elongation of QT interval on ECG-5 (6%); 5 (6%); 10 (6%).

Hypokalemia - 6 (7%); 4 (5%); 10 (6%).

Pain in the extremities - 6 (7%); 4 (5%); 10 (6%).

Sinus bradycardia - 8 (10%); 2 (3%); 10 (6%).

Vertigo - 4 (5%); 6 (8%); 10 (6%).

Bloating - 4 (5%); 5 (6%); 9 (6%).

Adrenal insufficiency - 4 (5%); 5 (6%); 9 (6%).

Increase in the level of AST - 6 (7%); 3 (4%); 9 (6%).

An increase in blood glucose - 6 (7%); 3 (4%); 9 (6%).

Other significant adverse events that occurred with a frequency of less than 5% were anemia (4%), increased blood amylase (2%), and increased PV (2%).

Disorders from the digestive tract

In the Phase III study, GI disorders were reported, mainly in the form of diarrhea, nausea, abdominal pain and vomiting. Such adverse reactions began to develop mainly in the first month of treatment with pasireotide and did not require intervention.

Hyperglycemia and diabetes

In the phase III study, adverse reactions associated with hyperglycemia were often reported. For all patients, such reactions included hyperglycaemia (40%), diabetes mellitus (18%), an increase in HbA1c (11%), and type 2 diabetes (9%). In general, an increase in fasting blood plasma glucose and HbA1c was observed soon after the onset of pasireotide treatment and persisted during treatment. In the group of patients receiving pasiretotide 0.6 mg, the average fasting plasma glucose level increased from 98.6 mg / dl (baseline) to 125.1 mg / dl for the 6th month of treatment. In the group receiving pasiretotide at a dose of 0.9 mg, the increase from baseline in 97 mg / dL was up to 128 mg / dl for the 6th month. A similar increase in the level of HbA1c in these groups was from 5.8 to 7.2% and from 5.8 to 7.3%, respectively (see "Precautions").

One month after the withdrawal of pasireotide, the average fasting plasma glucose and HbA1c levels decreased, but remained above the baseline level. Data for longer follow-up are not available.

Increase in liver function tests

In the Phase III study, patients who received pasireotype received a transient increase in mean levels of aminotransferase. The mean values returned to the baseline by the 4th month of treatment. These increases were not associated with clinical symptoms of liver disease.

A parallel increase in the level of ALT> 3 × VGN and bilirubin> 2 × UGN, 1 patient with Isenko-Cushing's disease and 3 - healthy volunteers was observed in the program of clinical studies of pacyreotide in 4 patients (see "Precautions"). In all four cases, these increases were not seen in the first 10 days of treatment. In all these cases, increases in the level of total bilirubin were accompanied or preceded by an increase in the level of transaminase. A patient with Isenko-Cushing's disease developed jaundice. With the abolition of pasireotide, laboratory abnormalities were resolved in all four cases.

Hypocorticism

In the Phase III studies, cases of hypocorticism were noted in patients with Isenko-Cushing's disease (see "Side effects"). Most of these cases were resolved by a decrease in the dose of pasireotide and / or by the addition of short-term therapy of SCS in low doses (see "Precautions").

Reactions at the site of administration

Reactions at the site of administration were observed in 17% of patients who participated in the Phase III study on the use of pasireotide in Isenko-Cushing's disease. Such cases were most often noted as pain at the injection site, erythema, hematoma, hemorrhage and itching. These cases were resolved spontaneously and did not require intervention.

Thyroid function

In 7 patients who participated in the Phase III study of the use of pasireotide in Isenko-Cushing's disease, cases of hypothyroidism were noted. All 7 patients had a TSH level close to NGN or less at the beginning of the study, which excludes the possibility of establishing a convincing relationship between this side effect and the use of pasireotide.

Other laboratory abnormalities

In patients who received pasireotype in clinical studies, there was an asymptomatic and reversible increase in the level of lipase and amylase. Pancreatitis is a potential adverse reaction associated with the use of somatostatin analogues, due to the association between cholelithiasis and acute pancreatitis.

There was a slight increase in the level of Hb, which remained within the normal range. There was also an increase in the level of PV and partial thromboplastin time in comparison with baseline in 33 and 47% of patients, respectively. These increases were minimal.

These laboratory abnormalities are not of clinical significance.

Interaction

Pasireotide moderately binds to plasma proteins, only to a small extent is metabolized. Pacyreotide is a substrate of P-gp, but not an inhibitor or inducer of P-gp. There is no evidence to suggest that in therapeutic concentrations, pacyreotide is:

- substrate, inhibitor or inducer of cytochrome P450;

- substrate BCRP, OST1 or OATP1B1, 1B3, 2B1;

- an inhibitor of UDF-GT1A1, OAT1 or OAT3 carrier proteins, OATP1B1 or 1B3, OST1 or OST2, P-gp, BCRP, the carrier protein MRP2 or BSEP (exporting bile acid pump).

In a study of the effect of the P-gp inhibitor on the Pharmacokineticss of pasireotide, when it was administered concomitantly with verapamil, there was no change in the bioavailability of pasireotide in healthy volunteers.

Pharmacokinetics interactions that affect the effect of pasireotide. There is a risk of an increase in Cmax of pasireotide with simultaneous use with P-gp inhibitors (ketoconazole, cyclosporine, verapamil, clarithromycin), there is no clinical confirmation of this effect.

Pharmacokinetics interactions that affect the effect of concomitant drugs. A few published data suggest that somatostatin analogues indirectly (through the suppression of secretion of STH) 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. Pasireotid caution should be used in conjunction with drugs having a narrow therapeutic index and metabolized mainly involving isoenzyme CYP3A4 (quinidine, terfenadine).

In a study on dogs, it was shown that pasireotide reduces the concentration of cyclosporine in the blood by decreasing 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 correction of the dose of cyclosporin.

A few data for other somatostatin analogues suggest that in the case of using pasirethotide along with bromocriptine, the bioavailability of the latter increases.

Drugs affecting the QT interval. Pasireotide should be used with caution at the same time with antiarrhythmic and other drugs that can prolong the QT interval: antiarrhythmic drugs (quinidine, procainamide, disopyramide, amiodarone, dronedarone, sotalol, dofetilide, ibutilide), separate antibacterial drugs (erythromycin for IV application, clarithromycin, Moxifloxacin), individual antipsychotic drugs (chlorpromazine, thioridazine, fluphenazine, haloperidol, tiaprid, amisulpride, sertindole, methadone), some H1-histamine receptor blockers (terfenadine, astemizole, misolastine), ivomalyariynye drugs (chloroquine, halofantrine, Lumefantrine), some antifungal drugs (ketoconazole).

It is also recommended to monitor heart rate in patients taking pasireotid and drugs simultaneously, causing bradycardia: beta-adrenoblockers (metoprolol, propranolol, sotalol), m-cholinergic blockers (ipratropium bromide, oxybutynin), BCC (verapamil, diltiazem, bepridil) and antiarrhythmic drugs.

Insulin and oral hypoglycemic drugs. Patients receiving insulin or oral hypoglycemic drugs may require dosage adjustment (increase or decrease) PM data after treatment pasireotidom.

Influence of other drugs on pasireotide

LS prolonging the QT interval. The combined use of drugs prolonging the QT interval and pasireotide may have an additive effect on the prolongation of the QT interval. Caution should be exercised when combined use of pasireotide and drugs prolonging the QT interval (see "Precautions").

Influence of pasireotide on other drugs

Cyclosporine. The combined use of cyclosporin and may reduce pasireotida relative bioavailability of cyclosporin and therefore may require adjustment of the dose of cyclosporine to maintain its therapeutic level.

Bromocriptine. Joint use of analogues of somatostatin and bromocriptine may increase the level of bromocrithin in the blood. A dose reduction of bromocriptine may be required.

Overdose

Patients treated with pasire-otitis c / c had no cases of overdose. In healthy volunteers who received pasiretotide at doses up to 2.1 mg twice a day, diarrhea was often noted as an adverse event.

In case of an overdose of pasireotide, based on the patient's condition, start the appropriate symptomatic treatment and carry it out until the symptoms resolve.

Routes of administration

PC.

Precautions for the substance Pacireotide

Hypocorticism

Treatment with pasireotide leads to a rapid decrease in the secretion of ACTH in patients with Isenko-Cushing's disease. Rapid and complete or almost complete suppression of ACTH secretion can lead to a decrease in plasma cortisol concentrations and the development of transient hypocorticoidism. 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 2 months of treatment. In most cases, this condition was stopped by decreasing the dose of pasireotide and / or adding short-term therapy in small doses of GCS.

It is necessary to monitor the condition and instruct patients about the possible occurrence of symptoms of hypokorticism (eg, weakness, fatigue, nausea, vomiting, hypotension, hyponatremia or hypoglycemia). If confirmed hypocorticoidism may need a temporary replacement therapy of corticosteroids and / or dose reduction pasireotida, or a break in treatment.

Hypocorticism

Treatment with pasireotide leads to the suppression of ACTH secretion in the disease of Itenko-Cushing. Suppressing the secretion of ACTH can lead to a decrease in the level of circulating cortisol and potentially to hypocorticism.

The patient should be monitored and instructed about signs and symptoms associated with hypocorticism (eg, weakness, fatigue, anorexia, nausea, vomiting, hypotension, hyponatremia, or hypoglycaemia). When manifesting hypokorticism, a temporary dose reduction or a break in treatment with pasireotide should be considered, as well as temporary replacement therapy for GCS.

Metabolism of glucose

Patients receiving pasireotide may develop hyperglycemia (less often hypoglycemia).

The development of hyperglycemia appears to be associated with a decrease in insulin secretion (especially in the time interval after the administration of pacyreotide) and incretin hormones (eg, GLP-1 and HIP).

Hyperglycemia is more pronounced in patients who had a glucose tolerance disorder or diabetes mellitus before starting therapy. Prior to the use of pacyreotide, the fasting blood glucose concentration and HbA1c should be assessed. During the first 2-3 months of treatment, patients should independently monitor the concentration of glucose in the blood (fasting) at intervals of 1 week, as well as in the first 2-4 weeks after increasing the dose of pasireotide; Subsequently these indicators need to be monitored as clinical necessity.

If the patient is developing hyperglycemia while using pacyreotide, the use of hypoglycemic agents or correction of the scheme of their use is recommended.

In the treatment of hypoglycemic drugs, a decrease in the concentration of HbA1c <7% and fasting blood glucose <130 mg / dL (7.2 mmol / L) was observed in 43 and 72% of patients with Isenko-Cushing 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. In patients with Isenko-Cushing's disease and hyperglycemia, which is not amenable to correction (HbA1c> 8% when treated with hypoglycemic drugs), the risk of developing severe hyperglycemia and related complications (eg, ketoacidosis) is increased. In patients with hyperglycemia, which is poorly amenable to correction, before starting the use of pasireotid, the glycemic control should be strengthened and the therapy of diabetes mellitus should be adjusted.

Hyperglycemia and diabetes

In healthy volunteers and patients receiving pasireotide, there was an increase in blood glucose levels. In the Phase III study, development of pre-diabetes and diabetes was noted. In this study, almost all patients, including those who had a normal baseline glucose level, prediabetes and diabetes, developed hyperglycemia in the first 2 weeks of treatment. Patients with Iscenko-Cushing's disease and poorly controlled glycemia (defined by HbA1c> 8% against antidiabetic therapy) may be at a higher risk of developing severe hyperglycemia and related complications, such as ketoacidosis.

In connection with the predictability of this adverse reaction, before starting treatment with pasireotide, it is necessary to determine the glycemic status (fasting plasma glucose level or HbA1c). In patients with uncontrolled diabetes before starting treatment with pasireotid, intensive antidiabetic therapy should be initiated. Self-monitoring of blood glucose and / or fasting blood glucose in the blood plasma should be performed every week during the first 2-3 months of treatment and subsequently periodically, with clinical necessity. After withdrawal, glycemic monitoring (eg fasting blood plasma glucose or HbA1c) should be performed in accordance with established clinical practice. Patients who are prescribed antidiabetic therapy as a result of the use of pacyreotide may need more careful monitoring after discontinuation of treatment, especially if antidiabetic therapy is associated with a risk of hypoglycemia.

In patients with hyperglycemia, developed with pasireotid therapy, it is recommended to start or adjust antidiabetic therapy. The optimal treatment for controlling hyperglycemia caused by pasireotide is unknown. If, despite the appropriate treatment, hyperglycemia remains uncontrolled, you should reduce the dose of pasirethotide or stop taking it.

Violations by the CAS

On the background of the use of pasireotid, there were cases of bradycardia. Careful monitoring of patients with heart disease and / or risk factors for bradycardia is necessary (in particular, in patients who have a history of clinically significant bradycardia or acute myocardial infarction, high-grade AV blockade, CHF (NYHA class III or IV), Unstable angina, persistent ventricular tachycardia, ventricular fibrillation). It may be necessary to adjust the dose of drugs, such as beta-adrenoblockers, calcium antagonists.

Bradycardia and lengthening of the QT interval

Bradycardia. When pasireotid was used, cases of bradycardia were noted (see "Side effects"). Careful monitoring in patients with heart disease and / or risk factors for bradycardia, such as a clinically significant bradycardia in a history, high-grade AV blockade or concomitant use of drugs associated with bradycardia, should be carefully monitored. It may be necessary to adjust the dose of beta-blockers, CCB or correction of electrolyte disorders.

Elongation of the QT interval. The use of pasireotide is associated with the prolongation of the QT interval. The prolongation of the QT interval was observed in two studies using pasiretotide in therapeutic and super therapeutic doses. Caution should be exercised when using pacyreotide in patients with risk factors for developing QTc interval prolongation, such as:

- congenital prolonged elongation of the QT interval;

- uncontrolled or serious heart disease, including recent myocardial infarction, CHF, unstable angina, or clinically significant bradycardia;

- therapy with antiarrhythmic or other drugs, with the known ability to extend the QT interval;

Hypokalemia and / or hypomagnesemia.

Before starting the use of pasireotid, it is recommended to perform an ECG, and during treatment - to monitor the effect of pasireotide therapy on the QT interval. Before the appointment of pasireotide, it is necessary to correct hypokalemia and hypomagnesemia and periodically check the presence of these conditions during therapy.

Biochemical parameters of liver function

It is recommended to determine the biochemical parameters of liver function (bilirubin, activity of liver enzymes) prior to the initiation of pasireotid therapy, after 1-2 weeks of therapy, and then monthly for 3 months. The biochemical parameters of liver function are then examined according to clinical indications. Therapy with pasireotide should be discontinued in the following cases:

- the patient developed jaundice or other signs of pronounced impaired hepatic function on the background of pasireotide administration;

- the activity of ACT or ALT increased to 5 times the value of VGN or higher

- ALT and ACT activity reached a level 3 times higher than UGN and the bilirubin concentration reached values 2 times higher than UGN.

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

Increase in liver function tests

In a Phase III study, 5% of patients had ALT or AST levels> 3 × VLN. In general, 4 cases of concomitant increase in ALT level> 3 × VGN and bilirubin> 2 × VGN - in 1 patient with Isenko-Cushing's disease and 3 in healthy volunteers were noted in the course of the clinical program of pasireotide (see "Side effects"). In these cases, an increase in the level of total bilirubin appears to accompany or precede the elevation of the transaminase level.

It is necessary to check the parameters of liver tests 1-2 weeks after the start of treatment, then monthly for 3 months and thereafter every 6 months. If the baseline ALT level is normal and ALT increases to 3-5 × VGN during treatment, repeat the analysis within a week or for 48 hours if the excess is> 5 × VGN. If the baseline ALT value deviates from normal and ALT elevation during treatment is 3-5 × VGN from the baseline, the analysis should be repeated within a week or earlier if the excess is> 5 × VGN. Analyzes should be conducted in a laboratory that provides results on the same day. If the results of reanalysis confirm primary results or show their increase, it is necessary to suspend the use of pacyreotide and to investigate the possible cause of this phenomenon, which may or may not be related to the use of pasireotide. At any excess of the baseline level by 5 times, with a baseline different from normal and up to 5 × VGN at a normal baseline, serial measurements of ALT, AST, APF and total bilirubin should be performed weekly or more often. Treatment with pasireotide can be resumed with caution when returning indicators to normal or close to normal levels with careful observation and only if any other possible cause is found.

Chololithiasis

Chololithiasis is an established adverse side effect associated with long-term use of somatostatin analogues, incl. Pasireotide. It is recommended to carry out ultrasound of the gallbladder before using pasireotide and every 6-12 months of its use. The presence of gallstones in patients receiving pasireotide in most cases is not accompanied by clinical manifestations. Gallstone disease, accompanied by a characteristic clinical symptomatology, should be treated in accordance with accepted clinical practice.

Chololithiasis

In clinical studies of pasireotide, there were frequent cases of cholelithiasis (see "Side effects"). It is recommended to have an ultrasound of the gallbladder before starting the use of pasireotide and subsequently with an interval of 6-12 months during treatment.

Pituitary Hormones

Since the pharmacological activity of pasireotid resembles somatostatin, it can not be ruled out that, against its background, the synthesis of not only ACTH but also other pituitary hormones will be suppressed. In this regard, both before the beginning of treatment with pasireotid, and during treatment (according to clinical indications) it is necessary to monitor the function of the pituitary (including the determination of the concentration of TSH, growth hormone), as well as free thyroxine.

Monitoring of insufficiency of pituitary hormones

Since the pharmacological action of pasireotide is similar to that of somatostatin, it is possible to inhibit other than ACTH hormones in the pituitary gland. Prior to the appointment of pasirethotide and periodically during treatment for clinical need may need to monitor the function of the pituitary (eg, TSH / free thyroxine, growth hormone / IGF-1). Patients who undergo transsphenoidal surgery or pituitary irradiation are at an increased risk of developing pituitary hormone deficiency.

Impact on the ability to drive vehicles and / or work with machinery. Studies of the influence of pasireotide on the ability to drive vehicles and work with mechanisms have not been carried out. Given the possibility of developing some side effects (headache, fatigue), patients should be careful when driving vehicles and engaging in other potentially hazardous activities that require increased concentration.