Alogliptin-Pioglitazone (alogliptin benzoate/pioglitazone HCl)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Alogliptin benzoate, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is an antidiabetic agent.
Pioglitazone, a thiazolidinedione (glitazone), is an antidiabetic agent.
Alogliptin inhibits dipeptidyl peptidase-4 (DPP-4), an enzyme that inactivates the incretin hormones: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Alogliptin selectively inhibits DPP-4 with no effect on DPP-8 or DPP-9 in vitro at concentrations approximating those from therapeutic exposures. Alogliptin increases circulating concentrations of GLP-1 and GIP in a glucose-dependent manner.
GLP-1 and GIP stimulate insulin secretion from pancreatic beta-cells in a glucose-dependent manner (i.e., when glucose concentrations are elevated). GLP-1 also decreases glucagon secretion from pancreatic alpha-cells, leading to reduced hepatic glucose production.
Alogliptin did not increase the QT interval corrected for rate (QTc) at daily dosages of 50 or 400 mg daily for 7 days in a randomized, placebo-controlled, active-comparator (moxifloxacin) study; the 400-mg dose produced plasma concentrations 19-fold higher than the maximum recommended clinical dose of 25 mg.
Following oral administration of a single dose of alogliptin (up to 800 mg) in healthy individuals, median time to peak plasma concentration was 1-2 hours; the drug has an absolute oral bioavailability of approximately 100%. Peak inhibition of DPP-4 occurs within 1--2 hours of administration with single and repeated dosing in patients with type 2 diabetes mellitus. Administration of alogliptin with food did not substantially alter total and peak exposure to the drug.
Alogliptin does not undergo extensive metabolism; 60-80% of the dose is excreted unchanged. Following administration of a radiolabeled dose of alogliptin, approximately 89% of administered radioactivity was excreted in urine (76%) and feces (13%). Terminal elimination half-life of alogliptin is approximately 21 hours following a single dose of 25 mg.
Age (range: 18--80 years), gender, and race do not have any clinically meaningful effect on the pharmacokinetics of alogliptin. Total and peak exposure to alogliptin are approximately 10% and 8% lower, respectively, in patients with moderate hepatic impairment (Child-Pugh class B); the effects of severe hepatic impairment (Child-Pugh class C) have not been studied. Exposure (as determined by plasma AUC) is increased 1.2-fold in patients with mild renal impairment (creatinine clearance >=60 to 90 mL/minute), 2-fold in patients with moderate renal impairment (creatinine clearance >=30 to <60 mL/minute), 3-fold in patients with severe renal impairment (creatinine clearance >=15 to <30 mL/minute), and 4-fold in patients with end-stage renal disease (creatinine clearance <15 mL/minute or requiring dialysis).
Pioglitazone is a thiazolidinedione (glitazone) antidiabetic agent that is structurally and pharmacologically related to troglitazone and rosiglitazone but unrelated to other antidiabetic agents, including sulfonylureas, biguanides, and alpha-glucosidase inhibitors.
Pioglitazone acts principally by increasing insulin sensitivity in target tissues, as well as decreasing hepatic gluconeogenesis. Pioglitazone is a peroxisome proliferator-activated receptorgamma (PPARgamma) agonist that increases transcription of insulin-responsive genes and increases insulin sensitivity. Pioglitazone ameliorates insulin resistance associated with type 2 diabetes mellitus without stimulating insulin release from pancreatic beta cells, thus avoiding the risk of hypoglycemia.
Because pioglitazone does not lower glucose concentrations below euglycemia, the drug is appropriately referred to as an antidiabetic agent rather than a hypoglycemic agent. Some evidence suggests that the glucoregulatory effects of thiazolidinediones are mediated in part via enhanced hepatic and peripheral glucose uptake and reduced systemic and tissue lipid availability.
Following oral administration of pioglitazone, peak plasma concentrations are achieved within 2 hours. Food delays time to peak concentrations to 3-4 hours but does not alter AUC. Pioglitazone is extensively (>99%) protein bound, principally to serum albumin.
Pioglitazone is extensively metabolized via hydroxylation and oxidation, principally via the cytochrome P-450 (CYP) 2C8 and CYP3A4 isoenzymes, with involvement of several other isoforms, including CYP1A1 (mainly an extrahepatic isoenzyme). The major circulating active metabolites of pioglitazone are M-III (keto derivative) and M-IV (hydroxyl derivative). Following oral administration, approximately 15% to 30% of the pioglitazone dose is recovered in the urine.
Renal elimination is negligible, and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and is eliminated in the feces. The mean serum half-life of pioglitazone and its metabolites (M-III and M-IV) range from 3 to 7 hours and 16 to 24 hours, respectively.
The serum elimination half-life of pioglitazone and metabolites remains unchanged in patients with moderate (creatinine clearance 30--50 mL/minute) and severe (creatinine clearance <30 mL/minute) renal impairment when compared to subjects with normal renal function. Compared with healthy controls, subjects with impaired hepatic function (Child-Pugh class B and C) have an approximate 45% reduction in pioglitazone and total pioglitazone (pioglitazone, M-III, M-IV) mean peak plasma concentration but no change in the mean AUC values. In healthy elderly subjects, mean peak plasma concentration was not significantly different, but AUC values were approximately 21% higher than those achieved in younger subjects; the mean half-life was also prolonged (10 hours) compared to younger subjects (7 hours).
These changes observed in elderly subjects is not considered clinically relevant. The mean peak plasma concentration and AUC values of pioglitazone were increased 20% to 60% in women compared to men.
Bioequivalence has been demonstrated between the fixed combination of pioglitazone and immediate-release metformin hydrochloride and each agent given concurrently as separate tablets at the currently approved dosage strengths (500 or 850 mg of metformin hydrochloride and 15 mg of pioglitazone). Bioequivalence also has been demonstrated between the fixed combination of pioglitazone and glimepiride and each agent given concurrently as separate tablets at the currently approved dosage strengths (2 or 4 mg of glimepiride and 30 mg of pioglitazone).
USES: This combination medication is used with a proper diet and exercise program to control high blood sugar in people with type 2 diabetes. Controlling high blood sugar helps prevent kidney damage, blindness, nerve problems, loss of limbs, and sexual function problems. Proper control of diabetes may also lessen your risk of a heart attack or stroke.
This product contains 2 medications: alogliptin and pioglitazone. Alogliptin works by increasing levels of natural substances called incretins. Incretins help to control blood sugar by increasing insulin release, especially after a meal.
They also decrease the amount of sugar your liver makes. Pioglitazone works by helping to restore your body's proper response to insulin.
Generic name: alogliptin benzoate/pioglitazone HCl
Pronunciation: (AL-oh-GLIP-tin/PYE-oh-GLI-ta-zone)
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Alogliptin-Pioglitazone
Indications
The following indications are listed for Alogliptin-Pioglitazone:
- Type 2 Diabetes Mellitus
Also known as: Adult Onset Diabetes, Adult Onset Diabetes Mellitus, Adult Onset Dm, Diabetes Mellitus Type 2, Diabetes Mellitus Type Ii, Ketosis-Resistant Diabetes Mellitus, Ketosis-Resistant Dm, Maturity Onset Diabetes, Maturity Onset Diabetes Mellitus, Non-Insulin Dependent Diabetes Mellitus, Non-Insulin-Dependent Diabetes Mellitus, Type Ii Diabetes Mellitus.
Dosing
Dosage of alogliptin benzoate is expressed in terms of alogliptin.
Dosage of pioglitazone hydrochloride is expressed in terms of pioglitazone.
When administered as a single-entity preparation, alogliptin may be administered orally once daily without regard to meals. Alogliptin tablets should be swallowed whole and should not be split.
When alogliptin is administered in fixed combination with metformin hydrochloride, the combination should be administered twice daily with food; dosage should be titrated gradually to minimize adverse GI effects of the metformin component. Fixed-combination tablets should be swallowed whole and should not be split before swallowing.
When alogliptin is administered in fixed combination with pioglitazone, the combination should be administered once daily without regard to meals. Fixed-combination tablets should be swallowed whole and should not be split before swallowing.
If a dose of alogliptin alone or in combination with metformin or pioglitazone is missed, the missed dose should be taken as soon as it is remembered followed by resumption of the regular schedule. If the missed dose is not remembered until the time of the next dose, the missed dose should be skipped and the regular schedule resumed; the dose should not be doubled to replace a missed dose.
Alogliptin and its metformin- or pioglitazone-containing combination products should be stored at 25degreesC (excursions permitted to 15-30degreesC). Keep alogliptin/metformin hydrochloride fixed-combination tablets in a tightly closed container. Keep alogliptin/pioglitazone fixed-combination tablets in a tightly closed container and protect from moisture and humidity.
Pioglitazone hydrochloride is administered orally once daily and can be taken without regard to meals. The fixed combination of pioglitazone and immediate-release metformin hydrochloride should be administered orally with meals to reduce the GI effects of the metformin component. The fixed combination of pioglitazone and glimepiride is administered once daily with the first main meal. See full prescribing for additional administration instructions for these fixed-combination products.
If a dose of pioglitazone is missed on one day, the dose should not be doubled the following day.
Store pioglitazone tablets at 25oC; excursions permitted to 15--30oC. Keep container closed and protect from light, moisture, and humidity.
No dosing information is available for this tab.
No dosing information is available for this tab.
Drug interactions
Alogliptin is principally renally excreted; cytochrome P-450 (CYP)-related metabolism is negligible.
Pioglitazone is metabolized principally by cytochrome P-450 (CYP) 2C8, and to a lesser degree, by CYP3A4, with additional contributions from a variety of isoforms including the mainly extrahepatic CYP1A1.
Pioglitazone is a weak inducer of CYP3A4.
There are no contraindication interactions for this drug.
There are no severe interactions for this drug.
There are no moderate interactions for this drug.
Contraindications
*Known serious hypersensitivity (e.g., anaphylaxis, angioedema, severe cutaneous adverse reactions) to alogliptin.
*Initiation in patients with established New York Heart Association (NYHA) class III or IV heart failure (HF).
*Known serious hypersensitivity reaction to pioglitazone or any ingredient in the formulation.
There are no contraindication contraindications for this drug.
There are no severe contraindications for this drug.
There are no moderate contraindications for this drug.
Adverse reactions
Most common adverse reactions (incidence >=4%) in patients receiving alogliptin monotherapy include nasopharyngitis, headache, and upper respiratory tract infection.
Most common adverse reactions (incidence >=4%) in patients receiving alogliptin in combination with metformin include upper respiratory tract infection, nasopharyngitis, diarrhea, hypertension, headache, back pain, and urinary tract infection.
Most common adverse reactions (incidence >=4%) in patients receiving alogliptin in combination with pioglitazone include nasopharyngitis, back pain, and upper respiratory tract infection.
The most common adverse effects of pioglitazone (>=5% of patients) reported in clinical trials were upper respiratory tract infection, headache, sinusitis, myalgia, and pharyngitis.
There are no severe adverse reactions for this drug.
There are no less severe adverse reactions for this drug.
Precautions
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Safety and efficacy of alogliptin alone, in fixed combination with metformin, or in fixed combination with pioglitazone have not been established in pediatric patients. Effectiveness of alogliptin monotherapy was not demonstrated in a 52-week, randomized, double-blind, placebo-controlled trial in 151 pediatric patients 10--17 years of age with inadequately controlled type 2 diabetes mellitus.
Safety and efficacy of pioglitazone have not been established in children or adolescents younger than 18 years of age; use in this age group currently is not recommended by the manufacturer because of adverse effects observed in adults (e.g., fluid retention and HF, fractures, urinary bladder tumors).
There is insufficient evidence with alogliptin in pregnant women to determine a drug-associated risk of major birth defects or miscarriage. No adverse developmental effects were observed when alogliptin was administered to pregnant rats and rabbits during organogenesis at exposures 180- and 149-times the 25 mg clinical dose, respectively, based on plasma drug exposure.
There is insufficient evidence with pioglitazone in pregnant women to evaluate a drug-associated risk for major birth defects or miscarriage. In reproduction studies in rats and rabbits, pioglitazone administered during organogenesis at exposures up to 5 and 35 times the maximum recommended human dose, respectively, was not associated with adverse developmental effects. However, delayed parturition and reduced embryofetal viability were observed with pioglitazone dosages at least 9 times the maximum recommended human dose. Offspring of pregnant rats who were administered pioglitazone at dosages at least 2 times the maximum recommended human dose during late gestation and lactation had delayed postnatal development attributed to decreased body weight.
Poorly controlled diabetes during pregnancy increases the risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, still birth, delivery complications, major birth defects, and macrosomia related morbidity.
There is no information regarding the presence of alogliptin in human milk, the effects on the breast-fed infant, or the effects on milk production. Alogliptin is distributed into milk in lactating rats. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for alogliptin and any potential adverse effects on the breast-fed infant from alogliptin or from the underlying maternal condition.
There are no data on the presence of pioglitazone in human milk, the effects on the breast-fed infant, or the effects on milk production. Pioglitazone is distributed into milk in rats. The benefits of breast-feeding should be weighed against the potential risk of adverse effects on the breast-fed infant from pioglitazone.
No dosage adjustment is necessary based on age.
Of 9052 patients in clinical trials of alogliptin, 24.9% were 65 years of age and older; 4.3% were 75 years of age and older. No substantial differences in safety and efficacy relative to younger adults were observed.
Pharmacokinetic, efficacy, and adverse effect profiles in geriatric patients are similar to those in younger adults, although small sample sizes in studies of patients 75 years or older limit conclusions. While pioglitazone AUC is about 21% higher in healthy geriatric individuals than in younger individuals and mean terminal half-life is also prolonged (10 versus 7 hours, respectively), these changes are not considered clinically relevant.
ICD codes
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Last reviewed · Source: First Databank (FDB) drug data
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