Vipidia (Vipidia)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceAlogliptinAlogliptin
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  • Vipidia
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    Takeda Pharmaceuticals USA, Inc.     USA
    • Dosage form: & nbspfilm-coated tablets
    Composition:

    1 tablet of 12.5 mg contains

    Active substance: alogliptin benzoate - 17 mg (in terms of alogliptin - 12.5 mg).

    Excipients:

    Core: mannitol 96.7 mg, microcrystalline cellulose 22.5 mg, giprolose 4.5 mg, croscarmellose sodium 7.5 mg, magnesium stearate 1.8 mg.

    Film Sheath: hypromellose 2910 5.34 mg, titanium dioxide 0.6 mg, iron dye oxide yellow 0.06 mg, macrogol-8000 trace amounts, gray ink F1 traces1.

    1 Inks gray F1 contain: shellac 26%, iron dye oxide black 10%, ethanol 26%, butanol 38 %.

    1 tablet of 25 mg contains

    Active substance: alogliptin benzoate - 34 mg (in terms of alogliptin - 25 mg).

    Excipients:

    Core: mannitol 79.7 mg, cellulose microcrystalline 22.5 mg, giprolose 4,5 mg, croscarmellose sodium 7.5 mg, magnesium stearate 1.8 mg.

    Film Sheath: hypromellose 2910 5.34 mg, titanium dioxide 0.6 mg, iron oxide red oxide 0.06 mg, macro-8000 trace amounts, gray ink F1 trace amounts.

    1 Inks gray F1 contain: shellac 26%, iron dye oxide black 10%, ethanol 26%, butanol 38 %.

    Description:

    Dosage 12.5 mg

    Oval biconvex tablets, covered with a film coating of yellow color, with the inscriptions "TAK" and "ALG-12.5" on one side.

    Dosage of 25 mg

    Oval biconvex tablets, covered with a film coating of light red color, with the inscriptions "TAK" and "ALG-25" on one side.

    Pharmacotherapeutic group:Hypoglycemic agent - dipeptidyl peptidase-4 inhibitor (DPP-4)
    ATX: & nbsp

    A.10.B.X   Other hypoglycemic drugs

    A.10.B.H.04   Alogliptin

    Pharmacodynamics:

    Alogliptin is a potent and highly selective inhibitor of DPP-4. Its selectivity for DPP-4 is more than 10,000 times greater than its effect on other related enzymes, including DPP-8 and DPP-9. DPP-4 is the main enzyme involved in the rapid destruction of the hormones of the incretin family: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (HIP). Hormones of the family of incretins are secreted in the intestine, their concentration rises in response to food intake. GLP-1 and HIP increase the synthesis of insulin and its secretion by beta cells of the pancreas. GLP-1 also inhibits the secretion of glucagon and reduces the production of glucose by the liver. Therefore, increasing the concentration of incretins, alogliptin increases the glucose-dependent secretion of insulin and decreases the secretion of glucagon at an increased concentration of glucose in the blood. In patients with type 2 diabetes mellitus with hyperglycemia, these changes in the secretion of insulin and glucagon lead to a decrease in the concentration of glycosylated hemoglobin HbA1c and a decrease in the concentration of glucose in blood plasma as an empty stomach, and postprandial glucose.

    Pharmacokinetics:

    The pharmacokinetics of alogliptin is similar in healthy individuals and in patients with type 2 diabetes mellitus.

    Suction

    The absolute bioavailability of alogliptin is approximately 100%. Simultaneous reception with food with a high fat content did not affect the area under the curve "concentration-time" (AUC) alogliptin, so it can be taken regardless of food intake.

    In healthy individuals, after a single oral intake of up to 800 mg of alogliptin, fast absorption of the drug is noted with the achievement of average maximum concentration (mean TCmOh) in the interval from 1 to 2 hours from the moment of reception.

    Neither healthy volunteers nor patients with type 2 diabetes had a clinically significant cumulation of alogliptin after repeated administration.

    AUC Alogliptin proportionally increases with a single admission in the therapeutic range of doses from 6.25 mg to 100 mg. Coefficient of variability AUC Alogliptin among patients is small (17%).

    AUC (0-inf) Alogliptin after a single dose was similar to AUC (0-24) after taking the same dose once a day for 6 days. This indicates the absence of time dependence in the kinetics of alogliptin after repeated administration.

    Distribution

    After a single intravenous injection of alogliptin at a dose of 12.5 mg in healthy volunteers, the volume of distribution in the terminal phase was 417 liters, indicating that alogliptin well distributed in tissues. The connection with plasma proteins is approximately 20-30%.

    Metabolism

    Alogliptin is not subjected to intensive metabolism, from 60 to 70% of alogliptin is excreted unchanged by the kidneys.

    After the introduction 14C-labeled alogliptin inside, two major metabolites were identified: N-demethylated alogliptin, M-I (<1% of the starting material), and N-acetylated alogliptin, M-II (<6% of the starting material). M-I is an active metabolite and a highly selective inhibitor of DPP-4, similar in action to the alglyptine itself; M-II does not show an inhibitory activity against DPP-4 or other DPP enzymes.

    In studies in vitro it was revealed that CYP2D6 and CYP3A4 participate in the limited metabolism of alogliptin.

    Also research in vitro show that alogliptin does not induce CYP1A2, CYP2C9, CYP2B6 and does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4 in concentrations reached at the recommended dose of 25 mg of alogliptin. In conditions in vitro Alogliptin can induce to a small extent CYP3A4, but in in vivo alogliptin does not induce CYP3A4.

    Alogliptin does not inhibit kidney transporter of organic human anions (OAT1), third (OATZ) types and kidney transporter of organic cations of the second (OCT2) type.

    Alogliptin exists mainly in the form of (R) -enantiomer (> 99%) and under conditions in vivo or in small amounts, or not at all subjected to a chiral transformation in (S) -enantiomer. (S) -enantiomer is not detected when taking alogliptin in therapeutic doses.

    Excretion

    After oral administration 14C-labeled alogliptin 76% of the total radioactivity was excreted by the kidneys and 13% by the intestine.

    The average renal clearance of alogliptin (170 ml / min) is greater than the average glomerular filtration rate (about 120 ml / min), suggesting that alogliptin partially excreted by active renal excretion. The mean terminal half-life of alogliptin (T1/2) is approximately 21 hours.

    Pharmacokinetics in selected patient groups

    Patients with renal insufficiency

    A study of alogliptin at a dose of 50 mg per day was performed in patients with varying degrees of severity of chronic renal failure. Patients included in the study were divided into 4 groups according to the Cockcroft-Gault formula: patients with mild (creatinine clearance from 50 to 80 ml / min), moderate (creatinine clearance from 30 to 50 ml / min) and severe renal failure (creatinine clearance less than 30 ml / min), as well as patients with terminal stage of chronic renal failure who need hemodialysis.

    AUC Alogliptin in patients with mild renal insufficiency increased approximately 1.7 times in comparison with the control group. Nevertheless, this increase AUC was within the permissible deviation for the control group, so dose adjustment in such patients is not required (see Dosage and Administration). Increase AUC Alogliptin approximately twice as compared with the control group was observed in patients with moderate renal insufficiency. Approximately fourfold increase AUC was noted in patients with severe renal insufficiency, as well as in patients with terminal stage of chronic renal failure compared with the control group. (Patients with terminal stage of renal failure underwent hemodialysis immediately after taking alogliptin. % doses were removed from the body during a 3-hour dialysis session.)

    Thus, in order to achieve a therapeutic concentration of alogliptin in blood plasma similar to that in patients with normal renal function, dose adjustment is necessary in patients with moderate renal insufficiency (see Dosage and Administration). Alogliptin It is not recommended for patients with severe renal failure, as well as with terminal stage of renal failure requiring hemodialysis.

    Patients with hepatic insufficiency

    In patients with moderate hepatic impairment AUC and CmOh alogliptin decrease by approximately 10% and 8%, respectively, compared with patients with normal liver function. These values ​​are clinically insignificant. Thus, the correction of the dose for mild to moderate severity of liver failure (5 to 9 points on the Child-Pugh) is not required. No clinical data are alogliptina in patients with severe liver failure (more than 9 points on the Child-Pugh, cm. Dosing and dose).

    Other patient groups

    Age (65-81 years), gender, race, body weight of patients no clinically significant effects on pharmacokinetic parameters alogliptina. Correction of the dose of the drug is not required (see Dosage and Administration).

    Pharmacokinetics in children under 18 years of age have not been studied.

    Indications:

    Diabetes mellitus type 2 for improvement of glycemic control with ineffectiveness of diet and exercise: in adults as monotherapy, in combination with other oral hypoglycemic agents or with insulin.

    Contraindications:

    - increased sensitivity to alogliptin or to any auxiliary substance,or severe hypersensitivity reactions to any DPP-4 inhibitor in history, including anaphylactic reactions, anaphylactic shock and angioedema;

    - type 1 diabetes mellitus;

    - diabetic ketoacidosis;

    - chronic heart failure (functional class III-IV on the functional classification of chronic heart failure of the New York Heart Association);

    - severe hepatic insufficiency (more than 9 on the Child-Pugh scale) due to the lack of clinical data on the use;

    - severe renal insufficiency;

    - pregnancy, the period of breastfeeding - due to the lack of clinical data on use;

    - children under 18 years of age - due to the lack of clinical data for use.

    Carefully:

    Acute pancreatitis in the anamnesis (see Special instructions).

    In patients with moderate renal insufficiency (see Special instructions).

    In combination with a sulfonylurea compound or insulin (see Specific guidance).

    Admission of a three-component combination of the preparation Vipidia with metformin and thiazolidinedione (see Special instructions).

    Pregnancy and lactation:

    There have been no studies of the use of alogliptin in pregnant women. Studies in animals have not shown a direct or indirect adverse effect of alogliptin on the reproductive system. However, for the sake of precaution, the use of the drug Vipidia during pregnancy is contraindicated.

    There are no data on the penetration of alogliptin into human milk in human milk. Studies in animals have shown that alogliptin penetrates into breast milk, therefore, the risk of side effects in infants can not be ruled out. In this regard, the use of the drug during breastfeeding is contraindicated.

    Dosing and Administration:

    The drug is taken orally.

    The recommended dose of Vipidia is 25 mg once a day as a monotherapy or in addition to metformin, thiazolidinedione, sulfonylurea or insulin, or as a three-component combination with metformin, thiazolidinedione or insulin. The drug Vipidia can be taken regardless of food intake. Tablets should be swallowed whole, not liquid, squeezed with water.

    In the event that the patient missed taking the drug Vipidia, he should take the missed dose as soon as possible. It is unacceptable to take a double dose of the drug Vipidia on the same day.

    In the appointment of the drug Vipidia in addition to metformin or thiazolidinedione, the dose of the last drugs should be left unchanged.

    When combining the drug Vipidia with a derivative of sulfonylureas or insulin, the dose of the latter is expediently reduced to reduce the risk of developing hypoglycemia.

    In connection with the risk of hypoglycemia, caution should be exercised in appointing a three-component combination of the preparation Vipidia with metformin and thiazolidinedione. In the case of hypoglycemia, it is possible to consider a reduction in the dose of metformin or thiazolidinedione. The effectiveness and safety of alogliptin when administered in a triple combination with metformin and a sulfonylurea derivative have not been investigated.

    Patients with renal insufficiency

    Patients with mild renal insufficiency (creatinine clearance from> 50 to ≤80 ml / min) are not required to correct the dose of Vipidia.

    In patients with moderate renal insufficiency (creatinine clearance from ≥30 to ≤50 ml / min), the dose of Vipidia is 12.5 mg once daily.

    Alogliptin should not be used in patients with severe renal insufficiency and patients with end-stage renal failure who need hemodialysis (creatinine clearance <30 mL / min).

    Patients with renal insufficiency are recommended to assess the function of the kidneys before treatment with Vipidia and periodically during treatment.

    Patients with hepatic insufficiency

    It is not necessary to correct the dose of the drug Vipidia in patients with mild to moderate hepatic insufficiency (from 5 to 9 on the Child-Pugh scale). The drug was not studied in patients with severe hepatic insufficiency (more than 9 on the Child-Pugh scale), so it should not be used in this group of patients.

    Patients over 65 years of age

    It is not necessary to correct the dose of the drug Vipidia in patients older than 65 years. Nevertheless, the dose of alogliptin should be selected with particular care in connection with the potential for reducing the kidney function in this group of patients.

    Side effects:

    The frequency of side effects of the drug is assessed as follows:

    Very Frequent: ≥ 1/10

    Frequent: ≥ 1/100, <1/10

    Infrequent: ≥ 1/1000, <1/100

    Rare: ≥ 1/10 000, <1/1000

    Very rare: <1/10 000

    The frequency is not established (data from post-marketing observations)

    Disturbances from the nervous system:

    Often: headache.

    Disorders from the gastrointestinal tract:

    Often: pain in the epigastric region, gastroesophageal reflux disease.

    Frequency not established: acute pancreatitis.

    Disturbances from the liver and bile ducts:

    The frequency is not established: a violation of the liver, including liver failure.

    Disturbances from the skin and subcutaneous tissues:

    Often: itching, rash.

    The frequency is not established: exfoliative skin diseases, including Stevens-Johnson syndrome, angioedema, urticaria.

    Infectious or parasitic diseases

    Often: infections of the upper respiratory tract, nasopharyngitis.

    Immune system disorders

    Frequency not established: hypersensitivity reactions, including anaphylactic reaction.

    Overdose:

    The maximum dose of alogliptin in clinical trials was 800 mg / day in healthy volunteers and 400 mg / day in patients with type 2 diabetes for 14 days.This is 32 and 16 times, respectively, exceeds the recommended daily dose of 25 mg of alogliptin.

    Any serious adverse events with the drug in these doses were absent.

    In case of overdosage, gastric lavage and symptomatic treatment may be recommended.

    Alogliptin is poorly dialyzed. In clinical studies, only 7% of the dose was removed from the body during a 3-hour dialysis session. There is no data on the effectiveness of peritoneal dialysis of alogliptin.

    Interaction:

    Effect of other drugs on alogliptin

    Alogliptin is mostly excreted unchanged kidneys, and is slightly metabolized by the enzyme cytochrome system (CYP) P450.

    In studies on the interaction with other drugs on the pharmacokinetics of alogliptin, the following drugs did not have a clinically significant effect: gemfibrozil (an inhibitor CYP2C8/9), fluconazole (inhibitor CYP2C9), ketoconazole (inhibitor CYP3A4), cyclosporine (p-glycoprotein inhibitor), α-glycosidase inhibitor, digoxin, metformin, cimetidine, pioglitazone or atorvastatin.

    Effect of alogliptin on other drugs

    In studies in vitro shown, that alogliptin Does not inhibit and does not induce isoforms CYP 450 in concentrations achieved with the intake of alogliptin in the recommended dose of 25 mg. Interactions with isoforms CYP 450 is not expected, and it was not revealed.

    In studies in vitro revealed that alogliptin is neither a substrate nor an inhibitor of OAT1, OAT3 and OST2. In addition, clinical trial data do not indicate interaction with inhibitors or substrates of p-glycoprotein.

    In clinical studies on interaction with other drugs alogliptin did not have a clinically significant effect on the pharmacokinetics of the following drugs: caffeine, (R)- and (S)- warfarin, pioglitazone, glibenclamide, tolbutamide, dextromethorphan, atorvastatin, midazolam, oral contraceptives (norethindrone and ethinyl estradiol), digoxin, fexofenadine, metformin or cimetidine. Based on these data, alogliptin Does not inhibit cytochrome system isoenzymes CYP1A2, CYP3A4, CYP2D6, CYP2C9, p-glycoprotein and OST2.

    Alogliptin had no effect on the prothrombin index or the International Normalized Ratio (INR) in healthy volunteers with concurrent admission with warfarin.

    The use of alogliptin in combination with metformin, or pioglitazone (thiazolidinedione), or an inhibitor of α-glycosidase, or glibenclamide (sulfonylurea derivative) did not show clinically significant pharmacokinetic interactions.

    Special instructions:

    Use with other hypoglycemic drugs

    FROM To reduce the risk of hypoglycemia, it is recommended to reduce the dose of sulfonylurea, insulin or a combination of pioglitazone (thiazolidinedione) with metformin while using with the drug Vipidia (see Dosage and Administration).

    Unexplained combinations

    The efficacy and safety of the use of the preparation Vipidia in combination with inhibitors of sodium-dependent glucose-2 cotransporter or analogs of the glucagon-like peptide and in the triple combination with metformin and sulfonylurea derivatives have not been studied.

    Renal insufficiency

    Because patients with moderate renal insufficiency are required to correct the dose of the drug Vipidia, it is recommended to assess the function of the kidneys before and periodically during treatment (see Dosage and Administration).

    The drug Vipidia should not be used in patients with severe renal failure, as well as in patients with terminal stage of chronic renal failure requiring hemodialysis (see Dosage and Administration).

    Acute pancreatitis

    The use of DPP-4 inhibitors is associated with a potential risk of acute pancreatitis. In a generalized analysis of 13 clinical studies of the use of alogliptin 25 mg / day, 12.5 mg / day, comparator and placebo, the incidence of acute pancreatitis was 3, 1, 1 or 0 cases per 1000 patient years in each group, respectively. Patients should be informed of the characteristic symptoms of acute pancreatitis: persistent severe pain in the abdomen, which can radiate into the back. If you suspect a development of acute pancreatitis, taking Vipidia is stopped; when the acute pancreatitis is confirmed, the drug is not renewed. There is no evidence as to whether there is an increased risk of developing pancreatitis while taking the drug Vipidia in patients with pancreatitis in the anamnesis. Therefore, patients with pancreatitis in history should be careful.

    Liver failure

    Post-marketing reports were received on liver function abnormalities, including hepatic failure with alogliptin. Their relationship with the use of the drug has not been established. However, patients should be carefully examined for possible abnormalities in liver function. If there are abnormalities in liver function and an alternative etiology of their occurrence is not established, consideration should be given to the possibility of discontinuing drug treatment.

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

    The drug Vipidia has little or no effect on the ability to drive vehicles and mechanisms. Nevertheless, it is necessary to take into account the risk of developing hypoglycemia when using the drug in combination with other hypoglycemic drugs (sulfonylureas, insulin or combination therapy with pioglitazone and metformin) and to use caution in the management of vehicles and mechanisms.

    Form release / dosage:Tablets coated with a film coating of 12.5 mg and 25 mg.
    Packaging:

    For 7 tablets in Al / Al blister, 4 blisters together with instructions for use are placed in a cardboard box.

    Storage conditions:

    Store at a temperature not exceeding 25 ° C. Keep out of the reach of children.

    Shelf life:

    3 years.

    Do not use after the expiration date.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-002644
    Date of registration:08.10.2014
    Expiration Date:08.10.2019
    The owner of the registration certificate:Takeda Pharmaceuticals USA, Inc.Takeda Pharmaceuticals USA, Inc. USA
    Manufacturer: & nbsp
    Representation: & nbspTakeda Pharmaceuticals Ltd.Takeda Pharmaceuticals Ltd.
    Information update date: & nbsp19.02.2017
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