Spiceel® (Sprycel® )

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceDasatinibDasatinib
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  • Dasatinib-native
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    NATIVA, LLC     Russia
  • Spiceel®
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    Bristol-Myers Squibb Company     Italy
  • Spiceel®
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    Bristol-Myers Squibb Company     USA
  • Spiceel®
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    Bristol-Myers Squibb     France
    • Dosage form: & nbsp

    film-coated tablets

    Composition:

    Each tablet, coated with a shell, contains: Active substance: dasatinib 20 mg, 50 mg or 70 mg.

    Excipients: lactose monohydrate 27.0 / 67.5 / 94.5 mg, microcrystalline cellulose 27.0 / 67.5 / 94.5 mg, giprolose 2.4 / 6.0 / 8.4 mg, croscarmellose sodium 3.2 / 8.0 / 11.2 mg, magnesium stearate 0.4 / 1.0 / 1.4 mg, opadrai white YS-1-18177-A (titanium dioxide (31.2% - 1.0 / 2.2 / 2.6 mg), hypromellose-bsR (59.8% - 1.9 / 4.2 / 5.0 mg), macrogol-400 ( 9.0% -0.3 / 0.6 / 0.8 mg) 3.2 / 7.0 / 8.4 mg.

    Description:Tablets of 20 mg: round biconvex tablets, covered with a film coating of white or almost white color, marked "BMS"on one side and" 527 "on the other.50 mg tablets: oval biconvex tablets coated with a white or almost white film shell marked"BMS"on one side and" 528 "on the other.Tables 70 mg: round biconvex tablets coated with a white or almost white film shell, marked"BMS"on one side and" 524 "on the other.
    Pharmacotherapeutic group:antitumor agent - protein tyrosine kinase inhibitor.
    ATX: & nbsp

    L.01.X.E.06   Dasatinib

    Pharmacodynamics:

    Dasatinib inhibits tyrosine kinase BCR-ABL and family tyrosine kinase SRC, as well as many other oncogenic kinases, including c-KIT, Ephrine kinase (EPN) receptor and PDGFβ-receptor. Dasatinib binds to the active and inactive forms of the enzyme BCR-ABL and at subnanomolar concentrations (0.6-0.8 nM) inhibits it.

    Mechanism of action
    In conditions in vitro dasatinib shows activity on cellular models of leukemia, both in relation to sensitive and resistant to imatinib cells. Dasatinib overcomes the resistance to imatinib associated with overexpression BCR-ABL, domain mutations BCR-ABL kinase activation of alternative mechanisms inducing family kinases SRC (LYN, HSC), as well as overexpression of the multiple drug resistance gene. When investigating domain mutations BCR-ABL in clinical trials in patients with newly diagnosed chronic myelogenous leukemia in the chronic phase who stopped taking the preparation of Spricel, mutations of TZ151, F317I/L and V299L. Based on experiments in vitro dasatinib does not appear to be active with respect to the mutation of TK 151.

    Pharmacokinetics:

    Suction

    Absorption is fast.The maximum concentration of dasatinib is observed 0.5-3 hours after ingestion.

    The area under the concentration-time curve (AUC) and excretion are dose-dependent in the dose range from 25 to 120 mg 2 times a day. The average total terminal half-life of dasatinib in patients is 5-6 hours. When taking a single dose of 100 mg of dasatinib 30 minutes after a meal with a high fat content, an increase in the mean AUC on 14%; after a meal with a low fat content - by 21%. Eating does not have a significant effect on absorption.

    Distribution

    The apparent volume of distribution of dasatinib in patients is 2505 liters, which indicates a significant distribution in the extravascular space. At concentrations used in clinical practice, the binding of dasatinib to plasma proteins is 96%.

    Metabolism

    CYP3A4 is the main enzyme responsible for the metabolism of dasatinib. After oral administration of 100 mg [14C] -dazatinib by healthy volunteers, 29% of the radioactivity in plasma was accounted for by the unchanged dasatinib. Judging by the concentration in the plasma and activity in vitro it can be assumed that metabolites do not play a big role in the pharmacological action of dasatinib.

    Excretion

    The drug is excreted mainly by the intestines, mainly in the form of metabolites. After a single oral intake of [14C] -dazatinib 4% and 85% of radioactivity is excreted by the kidneys and intestines, respectively, for 10 days. Unchanged dasatinib is 0.1% and 19% of the dose excreted by the kidneys and intestines, respectively, the rest of the dose is represented by metabolites.

    The pharmacokinetics of dasatinib was studied in 8 patients with moderate impairment of liver function after a single dose of 50 mg and in 5 patients with severe impaired liver function after a single dose of 20 mg in comparison with pharmacokinetics in healthy volunteers after taking the drug at a dose of 70 mg . The values ​​of the maximum concentration (CmOh) and AUC for dasatinib were lower by 47% and 8%, respectively, with moderate damage to the liver, compared with the values ​​in healthy volunteers. In patients with severe disturbance of the liver function, the decrease in CmOh and AUC for dasatinib reached 43% and 28%, respectively.In patients with impaired renal function, the pharmacokinetics of dasatinib does not change.

    Indications:

    - The first detected chronic myelogenous leukemia in the chronic phase;

    - Chronic myelogenous leukemia in the chronic phase, the phase of acceleration or phase of the myeloid or lymphoid blast crisis with resistance or intolerance to previous therapy, including imatinib;

    - Acute lymphoblastic leukemia with a positive Philadelphia chromosome (Ph+ ALL) with resistance or intolerance to previous therapy.

    Contraindications:

    Hypersensitivity to dasatinib or other components of the drug. Pregnancy and lactation.

    Age to 18 years (efficiency and safety not established)
    Carefully:

    Liver failure; simultaneous reception of anticoagulants and drugs that affect the function of platelets; interval lengthening Q-T or the risk of lengthening (hypokalemia, hypomagnesemia, congenital syndrome of elongated Q-T interval, therapy with antiarrhythmic and other drugs that can lengthen Q-T interval, prior therapy with high doses of anthracyclines); hereditary lactose intolerance,deficiency of lactase or impaired absorption of glucose and galactose (the preparation contains lactose 135 mg or 189 mg, respectively, a daily dose of the preparation of Sprice © in 100 mg or 140 mg), simultaneous use with isoenzyme substrates CYP3A4 with a narrow therapeutic range.

    Pregnancy and lactation:

    Patients during treatment and at least 3 months afterwards must use reliable contraceptive methods. If the pregnancy occurred during treatment with the drug Spriceil®, and if it became known that the drug was used during pregnancy, the patient should immediately be informed of the possible risk to the fetus. According to the results of postmarketing studies, it is established that the use of the Spricel® drug during pregnancy can lead to spontaneous abortion, as well as cause fetal and neonatal anomalies. It is not known whether the dasatinib in breast milk. For the duration of treatment with the preparation Spricel®, breast-feeding should be discontinued.

    Dosing and Administration:

    Tablets should be taken whole inside, regardless of food intake.

    Recommended initial doses of the Spricel® preparation:

    - 100 mg once a day (morning or evening) in the chronic phase of chronic myelogenous leukemia;

    - 140 mg once a day (morning or evening) in the remaining cases.

    A dose change is possible in view of the clinical response and tolerability of the drug by the patient.

    Increase in dose

    In the absence of a hematologic or cytogenetic response at the recommended initial dose, it is possible to increase the dose of Sprice © to:

    - 140 mg once a day for the chronic phase of chronic myelogenous leukemia;

    - 180 mg once a day with advanced phases of chronic myelogenous leukemia (acceleration or blast crisis phase) or acute limboflastnom leukemia with a positive Philadelphia chromosome (Ph+ ALL).

    Acceptance of the drug is discontinued if there are signs of progression of the disease or when the patient is intolerant of the drug.

    Correction of dose due to side effects

    Myelosuppression
    When myelosuppression should reduce the dose, interrupt therapy or cancel it. If necessary, transfusions of platelet or erythrocyte mass should be performed. With stable myelosuppression, it is possible to use hematopoietic growth factors.

    Correction of dose for neutropenia and thrombocytopenin
    Chronic phase of chronic myelogenous leukemia (initial dose of 100 mg once a day) With an absolute number of neutrophils <0.5 x 109/ l or the number of platelets <50 x 109/ l:

    1. To take a break in the treatment with the preparation of Spriceil® until the absolute number of neutrophils is reached> 1.0 x 109/ l and the number of platelets> 50 x 109/ l;

    2. Resume the therapy in the same dose;

    3. When the number of platelets is less than 25 x 109/ l or an absolute number of neutrophils less than 0.5 x 10%, observed more than 7 days - to take a break in treatment, and after reaching the baseline, the therapy to resume at a reduced dose of 80 mg once a day (second episode). For patients with newly diagnosed chronic myelogenous leukemia in the chronic phase, the third episode of thrombocyto / neutropenia reduces the dose to 50 mg once a day. At the onset of the third episode of thrombocyto / neutropenia in patients with other phases of myeloid leukemia and the presence of resistance to previous therapy with other drugs (including imatinib) or her intolerance stop treatment with the drug Spriceil®.

    Chronic myelogenous leukemia (in the phase of acceleration or blast crisis) and acute lymphoblastic leukemia with a positive Philadelphia chromosome (Ph+ ALL) (initial dose of 140 mg once a day)

    With an absolute number of neutrophils <0.5 x 109/ l or the number of platelets <10 x 109/ l:

    1. Determine whether leukemia is caused by cytopenia (aspiration or bone marrow biopsy);

    2. If cytopenia is not associated with leukemia, treatment should be discontinued until an absolute number of neutrophils is achieved> 1.0 x 109/ l and the number of platelets> 20 x 109/ l and resume therapy at the previous dose;

    3. In case of recurrence of cytopenia, the nature of cytopenia should be re-verified and the therapy resumed at a reduced dose of 100 mg once a day (second episode) or 80 mg once a day (third episode);

    4. If the resulting cytopenia is associated with leukemia, consider increasing the dose to 180 mg once a day.

    With the development of severe non-hematologic side effects, treatment is suspended until the symptom of the side effect disappears or until the patient's condition improves. Treatment can be resumed in a reduced dose.

    Application for renal dysfunction
    The renal clearance of dasatinib and its metabolites is <4%, so dose adjustment for impaired renal function is not required.

    Application for violations of liver function
    Dasatinib is metabolized mainly by the liver, so the drug should be used with caution in patients with moderate and severe liver dysfunction.

    Use in elderly patients
    Clinically significant differences in pharmacokinetics in elderly patients have not been identified, so dose adjustment is not required.

    Side effects:

    In most patients, adverse events were transient, treatment with Spiceil® was discontinued due to adverse reactions in 12% of patients with a newly diagnosed chronic phase of chronic myelogenous leukemia, as well as 15% of patients in the chronic phase of chronic myelogenous leukemia with resistance to imatinib or its intolerance, 16% in the phase of acceleration of chronic myelogenous leukemia, 15% in the phase of myeloid blast crisis of chronic myelogenous leukemia, as well as in 8% of patients with acute lymphoblastic leukemia with positive Philadelphia chromosome. The frequency of side effects is shown in accordance with the scale: very often (> 1/10), often (> 1/100, <1/10), infrequently (> 1/1000, <1/100), rarely (> 1 / 10000, <1/1000).

    Infections and infestations:

    Often: infection (including bacterial, viral, fungal).

    Often: pneumonia (including bacterial, viral and fungal), upper respiratory tract infections, herpetic infections, enterocolitis, sepsis (including infrequently with fatal outcome).

    From the hematopoietic system:

    Often: febrile neutropenia, pancytopenia.

    Rarely: erythroblastopenia.

    From the immune system:

    Infrequently: hypersensitivity reactions (including erythema nodosum).

    Metabolic disorders:

    Often: anorexia, anorexia, hyperuricemia.

    Infrequently: hypoalbuminemia.

    From the nervous system:

    Often: headache.

    Often: insomnia, depression, neuropathy (including peripheral neuropathy), dizziness, perversion of taste, drowsiness.

    Infrequently: anxiety, emotional lability, psychosis, decreased libido, hemorrhages (such as intracerebral hematoma, intracerebral haemorrhage, epidural hematoma, intracranial hemorrhage, hemorrhagic stroke, subarachnoid hemorrhage, subdural hematoma, subdural hemorrhage), tremor, fainting, amnesia.

    Rarely: convulsions, cerebrovascular accident (stroke), transient ischemic attack, inflammation of the optic nerve, paralysis of the VII pair of cranial nerves (facial nerve).

    From the side of the organ of vision:

    Often: visual disorders (blurred vision, blurred vision, decreased visual acuity), dry eyes, bleeding in the sclera of the eye,conjunctival hemorrhages.

    Infrequently: conjunctivitis.

    Rarely: visual impairment.

    From the side of the organ of hearing and balance:

    Often: noise in ears.

    Infrequently: Vertigo.

    From the cardiovascular system:

    Often: bleeding (such as nasal bleeding, bleeding gums, bruises, petechia, purpura).

    Often: "tidal", increased blood pressure, pericardial effusion, arrhythmia (including tachycardia), cardiac dysfunction (including ventricular dysfunction, heart failure, congestive heart failure, cardiomyopathy, congestive cardiomyopathy, diastolic dysfunction, ejection fraction reduction, ventricular failure), heart palpitations .

    Infrequently: interval lengthening Q-T on ECG, angina pectoris, cardiomegaly, lowering of arterial pressure, thrombophlebitis, pericarditis, ventricular arrhythmia (including ventricular tachycardia), myocardial infarction (including fatal outcome).

    Rarely: "pulmonary heart," myocarditis, acute coronary syndrome, "marbling of the skin."

    From the respiratory system:

    Often: pleural effusion, shortness of breath, cough.

    Often: pulmonary infiltrates, pulmonary edema, pneumonitis, pulmonary hypertension.

    Infrequently: bronchial asthma, bronchospasm.

    Rarely: acute respiratory distress syndrome.

    From the digestive system:

    Often: diarrhea, nausea, vomiting, abdominal pain.

    Often: inflammation of the mucous membranes (including mucositis / stomatitis), gastrointestinal bleeding, dyspepsia, bloating, constipation, gastritis, soft tissue damage to the oral cavity (including dry mouth, cheilitis, vesicular rash on the lips, dry lips, ulcers on the lips, erosion mucous membrane of the oral cavity), colitis (including neutropenic colitis).

    Infrequently: dysphagia, ascites, anal fissures, ulceration of the upper gastrointestinal tract, pancreatitis, esophagitis.

    Rarely: gastrointestinal enteropathy with loss of protein, intestinal obstruction.

    From the liver and bile ducts:

    Infrequently: cholestasis, cholecystitis, hepatitis.

    From the skin and subcutaneous tissue:

    Often: skin rash.

    Often: itching, acne, alopecia, dry skin, hyperhidrosis, urticaria, dermatitis (including eczema).

    Infrequently: skin ulcers, bullous dermatosis, disorders of pigmentation, nail lesions,photosensitization, acute febrile neutrophilic dermatosis, panniculitis, palmar-plantar erythrodysesthesia syndrome.

    From the side of the musculoskeletal system and connective tissue:

    Often: musculoskeletal pain.

    Often: arthralgia, muscle weakness, myalgia, musculoskeletal stiffness, muscle spasms.

    Infrequently: an increase in the activity of creatine phosphokinase in the blood, rhabdomyolysis of myositis, tendonitis.

    From the urinary system:

    Infrequently: renal failure, frequent urination, proteinuria, hematuria.

    On the part of the reproductive system:

    Infrequently: gynecomastia, menstrual irregularities, vaginal bleeding, uterine bleeding.

    Other:

    Often: fluid retention, localized swelling of subcutaneous tissue of various locations, edema of the tongue, edema of the lips, edema of the conjunctiva, increased fatigue, increased body temperature.

    Often: generalized edema, asthenia, pain, chest pain, chills, decreased or increased body weight, confusion

    Infrequently: malaise, intolerance of high and low temperatures, tumor lysis syndrome.

    In addition, when using the drug, information is received on the following phenomena, the frequency of which is not established, and their relationship with the use of the drug is not proved:

    From the cardiovascular system:

    Atrial fibrillation / atrial flutter; thrombosis / embolism (including pulmonary embolism, deep vein thrombosis).

    From the respiratory system:

    interstitial lung diseases, pulmonary arterial hypertension.

    From the digestive system:

    gastrointestinal bleeding with fatal outcome.

    Changes in laboratory indicators:

    - Thrombocytopenia, anemia and neutropenia of grade 3 or 4, especially in patients with advanced phases of chronic myelogenous leukemia or acute lymphoblastic leukemia with a positive Philadelphia chromosome;

    - Hypokalemia, hypocalcemia, hypophosphatemia,

    - Increased activity of hepatic transaminases (alanine aminotransferase (ALT), aspartate aminotransferase (ACT)),

    - Increased serum bilirubin and / or serum creatinine concentrations.

    The most common side effects with the use of the Spricel® preparation in patients with newly diagnosed chronic myelogenous leukemia in the chronic phase are the delayfluids and diarrhea; in patients with imatinib resistance or intolerance, fluid retention and diarrhea, headache, dyspnea, rash, fatigue, nausea, haemorrhages (such as gastrointestinal bleeding and others).

    Overdose:

    Overdose of the drug Spriceil® was recorded in two patients who took 280 mg of drug per day during 1 week, which resulted in a significant decrease in the number of platelets. In case of an overdose, careful monitoring of patients is required to control the degree of myelosuppression; if necessary, symptomatic therapy.

    Interaction:

    Drugs that can increase the concentration of dasatinib in the blood plasma
    Inhibitor inhibitors     CYP3A    4:
    dasatinib is a substrate of isoenzyme CYP3A4. Isoenzyme inhibitors CYP3A4 (e.g., ketoconazole, itraconazole, erythromycin, clarithromycin, ritonavir, atazanavir, indinavir, nelfinavir, saquinavir, telithromycin, grapefruit juice) can increase the concentration of dasatinib in the blood plasma, therefore, their combined use with dasatinib should be avoided. Patients who can not avoid the systemic intake of a potent inhibitor of isoenzyme CYP3A4, should be carefully monitored for the timely detection of signs of toxicity.

    Drugs that can reduce the concentration of dasatinib in the blood plasma
    Inductors of isoenzyme     CYP3A4:
    inducers of isoenzyme CYP3A4 can reduce the concentration of dasatinib in plasma. The joint use of powerful isoenzyme inducers should be avoided CYP3A4 with dasatinib. Patients taking isoenzyme inducers CYP3A4 (e.g., dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital or preparations of St. John's wort perfumed (Hypericum perforatum), instead of these drugs should be prescribed drugs that do not possess (or have a minimal degree) ability to induce this isoenzyme.

    Antacids (preparations containing aluminum hydroxide / magnesium hydroxide):
    If antacids are needed, it is recommended that they be taken at least 2 hours before or 2 hours after dasatinib intake.

    H2-histamine receptor blockers and proton pump inhibitors:
    Long-term suppression of gastric acid secretion with H2-histamine receptor blockers and proton pump inhibitors (eg, famotidine and omeprazole) can lead to a decrease in dasatinib concentration. The combined use of these drugs and dasatinib is not recommended. AT As an alternative, antacids can be used (2 hours before or 2 hours after taking Spricel®).

    Effect of dasatinib on other drugs
    Substrates of the isoenzyme CYP3A4:
    Dasatinib is an isoenzyme inhibitor CYP3A4, therefore its combined use with isoenzyme substrates CYP3A4 can enhance the action of this substrate. Substrates of the isoenzyme CYP3A4 with a narrow therapeutic range, such as alfentanil, astemizole, terfenadine, cisapride, ciclosporin, fentanyl, pimozide, quinidine, sirolimus, tacrolimus and ergot alkaloids (ergotamine, dihydroergotamine) should be used with caution in patients receiving dasatinib.

    Special instructions:

    When treated with Spricel®, severe (grade 3 and 4) can occur due to the general toxicity criteria of the National Cancer Institute of the United StatesNCI CTC) thrombocytopenia, anemia and neutropenia. More often they are registered in patients with advanced phases of chronic myelogenous leukemia or acute lymphoblastic leukemia with a positive Philadelphia chromosome than in patients with a chronic phase of chronic myelogenous leukemia.

    A complete clinical blood test should be performed weekly for the first 2 months of treatment, and then monthly or more often, according to clinical indications. The oppression of the bone marrow is usually reversible and occurs with the temporary cancellation or reduction of the dose of the preparation of Spricele®. In patients with newly diagnosed chronic myelogenous leukemia, myelosuppression was less frequent than in patients in the chronic phase of myeloid leukemia with resistance to imatinib or its intolerance. Severe hemorrhages in the brain, including fatal ones, have been reported in less than 1% of patients with imatinib resistance or intolerance who have received Spricecel®. Severe gastrointestinal bleeding was noted in 4% of patients with resistance to imatinib or its intolerance; they usually required a temporary discontinuation of the drug and blood transfusions. Other severe bleeding was reported in 2% of patients with imatinib resistance or intolerance. Most cases of bleeding in these patients were associated with severe thrombocytopenia.

    When taking Spricel®, fluid retention may occur.Among patients with newly diagnosed chronic myeloid leukemia, severe fluid retention was observed in 3% of patients.

    In patients with imatinib resistance or intolerance, severe fluid retention (3 and 4) was reported in 11%, including pronounced pleural and pericardial effusion in 7% and 2% of patients, respectively. Pronounced ascites and generalized edema developed in less than 1% of patients with imatinib resistance. 1% of patients with imatinib resistance have severe pulmonary edema. When there is shortness of breath or a dry cough, an X-ray examination of the chest organs is necessary. Fluid retention is usually stopped with maintenance therapy with the inclusion of diuretics or a short course of glucocorticosteroids. When expressed pleural effusion, oxygen therapy and thoracocentesis were required. Fluid retention was observed more often in patients taking the drug twice a day. It should be noted that fluid retention and dyspnea are more common in patients over 65 years of age, therefore careful monitoring of patients of this age group should be ensured.

    Elongation Q-T interval was observed in less than 1% of patients with newly diagnosed chronic myeloid leukemia in the chronic phase who received the Spricele® preparation, with an average length of 3.0 ms. Elongation Q-T interval in the treatment with the drug Spriceil® was observed in more than 1% of patients with resistance or intolerance to imatinib therapy. Dasatinib should be used with caution in patients with an elongated Q-T interval or with the risk of its lengthening (hypokalemia, hypomagnesemia, congenital syndrome of elongated Q-T interval, therapy with antiarrhythmic and other drugs that can lengthen Q-T interval, prior therapy with high doses of anthracyclines). Before the appointment of the preparation Spricel®, correction of hypokalemia and hypomagnesemia should be performed. Most patients who had cardiac side effects were at risk or had a history of heart disease. Therefore, during therapy with Spiceil®, you must carefully monitor the parameters of the heart and monitor patients at risk or having a history of heart disease in order to identify and, if necessary, correct possible adverse reactions from the cardiovascular system.In patients, laboratory blood abnormalities were noted: hypocalcemia, hypokalemia, increased transaminase activity, and / or bilirubin concentration. With the development of hypocalcemia, the condition is corrected by ingestion of calcium preparations. If the activity of transaminases or the concentration of bilirubin increases, the dose of the drug should be reduced or suspended.

    With the use of the Spricele® drug, cases of pulmonary arterial hypertension (PAH) confirmed by right heart catheterization have been reported. PAH was noted both during treatment with the drug Spricel®, and after a year or more after its termination. Often in cases of development of PAH in the treatment with the drug Spriceol®, the patients had concomitant diseases or during the treatment they simultaneously took Spricel® and other medications. Before starting treatment with the drug Spriceil®, a patient should be examined to identify possible signs and symptoms of heart and lung disease. If a patient has shortness of breath or fatigue during treatment with Spriceol®, the most typical etiology should be excluded, including pleural effusion, pulmonary edema, anemia and the presence of pulmonary infiltrate.In this case, it is necessary to take into account the recommendations given in the section "Method of administration and dose" for cases of development of non-hematological adverse reactions: with the development of severe non-hematologic side effects, treatment is suspended until the symptom of the side effect disappears or until the patient's condition improves. If a different diagnosis was not made during the examination of the patient, the diagnosis of PAH should be taken into consideration. In case of confirmation of PAH in a patient, treatment with Spriceol® is discontinued without subsequent resumption, ensuring subsequent monitoring of the patient's condition in accordance with standard recommendations. After discontinuation of the drug in patients with PAH, there was an improvement in their hemodynamic and clinical parameters. Patients (both men and women) during treatment and at least 3 months afterwards should use reliable contraceptive methods. If pregnancy occurred during the treatment with the Spricele® drug, or if it became known that the drug was used during pregnancy, the patient should immediately be informed of the possible risk to the fetus.

    Lactose content
    The preparation Spricel® contains lactose: in a daily dose of 100 mg - 135 mg of lactose and in a daily dose of 140 mg - 189 mg of lactose.

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

    Studies on the effect of the drug on the ability to drive and control technology was not conducted. If the patient observes treatment-related symptoms, such as dizziness and visual disturbances affecting his ability to concentrate and respond quickly, it is recommended that you stop driving and performing potentially dangerous activities that require increased attention and speed of psychomotor reactions.

    Form release / dosage:

    Tablets, film-coated 20 mg, 50 mg, 70 mg.

    Packaging:

    For 60 tablets in a bottle of high-density polyethylene with a lid that can not be opened by children.

    Inside the vial, a container with a desiccant (silica gel) is placed on which a warning mark is placed.

    The neck of the bottle is covered with a cotton swab and sealed with aluminum foil. 1 bottle with instructions for use in cardboard pack

    ATTENTION: A container with a desiccant is placed in the package of the preparation, on which there is a picture and a warning inscription - "Do not eat. Contents: Silica Gel." - "Do not eat. Contents: Silica gel. "The desiccant is designed to protect the preparation from moisture. Do not open the container with the desiccant, do not take the contents of the container inside!

    Storage conditions:

    At a temperature of 15 to 30 ° C.

    KEEP OUT OF THE REACH OF CHILDREN!

    Shelf life:3 years. Do not use the product after the expiry date printed on the package.
    Terms of leave from pharmacies:On prescription
    Registration number:LSR-000256/08
    Date of registration:29.01.2008
    The owner of the registration certificate:Bristol-Myers Squibb CompanyBristol-Myers Squibb Company USA
    Manufacturer: & nbsp
    Representation: & nbspBRISTOL-Majers SKVIBB, LLCBRISTOL-Majers SKVIBB, LLCRussia
    Information update date: & nbsp14.01.2014
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