Alogliptin and Pioglitazone (Page 5 of 11)

8.2 Lactation

Risk Summary

There is no information regarding the presence of pioglitazone or alogliptin in human milk, the effects on the breastfed infant, or the effects on milk production. Pioglitazone and alogliptin are present in rat milk; however, due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for alogliptin and pioglitazone tablets and any potential adverse effects on the breastfed infant from alogliptin and pioglitazone tablets or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

Discuss the potential for unintended pregnancy with premenopausal women as therapy with pioglitazone, like other thiazolidinediones, may result in ovulation in some anovulatory women.

8.4 Pediatric Use

Safety and effectiveness of alogliptin and pioglitazone tablets in pediatric patients have not been established.

Alogliptin and pioglitazone tablets are not recommended for use in pediatric patients based on adverse effects observed in adults, including fluid retention and congestive heart failure, fractures and urinary bladder tumors [see Warnings and Precautions (5.1, 5.5, 5.6, 5.7)].

8.5 Geriatric Use

Alogliptin and Pioglitazone

Of the total number of patients (N=1533) in clinical safety and efficacy studies treated with alogliptin and pioglitazone, 248 (16.2%) patients were 65 years and older and 15 (1%) patients were 75 years and older. No overall differences in safety or effectiveness were observed between these patients and younger patients. While this and other reported clinical experiences have not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be excluded.

Alogliptin

Of the total number of patients (N=9052) in clinical safety and efficacy studies treated with alogliptin, 2257 (24.9%) patients were ≥65 years old and 386 (4.3%) patients were ≥75 years old. No overall differences in safety or effectiveness were observed between patients ≥65 years old and younger patients.

Pioglitazone

A total of 92 patients (15.2%) treated with pioglitazone in the three pooled, 16 to 26 week, double-blind, placebo-controlled, monotherapy trials were ≥65 years old and two patients (0.3%) were ≥75 years old. In the two pooled 16 to 24 week add-on to sulfonylurea trials, 201 patients (18.7%) treated with pioglitazone were ≥65 years old and 19 (1.8%) were ≥75 years old. In the two pooled 16 to 24 week add-on to metformin trials, 155 patients (15.5%) treated with pioglitazone were ≥65 years old and 19 (1.9%) were ≥75 years old. In the two pooled 16 to 24 week add-on to insulin trials, 272 patients (25.4%) treated with pioglitazone were ≥65 years old and 22 (2.1%) were ≥75 years old.

In PROactive, 1068 patients (41%) treated with pioglitazone were ≥65 years old and 42 (1.6%) were ≥75 years old.

In pharmacokinetic studies with pioglitazone, no significant differences were observed in pharmacokinetic parameters between elderly and younger patients. These clinical experiences have not identified differences in effectiveness and safety between the elderly (≥65 years) and younger patients although small sample sizes for patients ≥75 years old limit conclusions [see Clinical Pharmacology (12.3)].

8.6 Renal Impairment

Alogliptin

A total of 602 patients with moderate renal impairment (eGFR ≥30 and <60 mL/min/1.73 m2) and four patients with severe renal impairment/end-stage renal disease (eGFR <30 mL/min/1.73 m2 or <15 mL/min/1.73 m2 , respectively) at baseline were treated with alogliptin in clinical trials in patients with type 2 diabetes. Reductions in HbA1c were generally similar in this subgroup of patients. The overall incidence of adverse reactions was generally balanced between alogliptin and placebo treatments in this subgroup of patients.

In the EXAMINE trial of high CV risk type 2 diabetes patients, 694 patients had moderate renal impairment and 78 patients had severe renal impairment or end-stage renal disease at baseline. The overall incidences of adverse reactions, serious adverse reactions and adverse reactions leading to study drug discontinuation were generally similar between the treatment groups.

8.7 Hepatic Impairment

Alogliptin

No dose adjustments are required in patients with mild to moderate hepatic impairment (Child-Pugh Grade A and B) based on insignificant change in systemic exposures (e.g., AUC) compared to subjects with normal hepatic function in a pharmacokinetic study. Alogliptin has not been studied in patients with severe hepatic impairment (Child-Pugh Grade C). Use caution when administering alogliptin to patients with liver disease [see Warnings and Precautions (5.4)].

Pioglitazone

No dose adjustments are required in patients with hepatic impairment (Child-Pugh Grade B and C) based on insignificant change in systemic exposures (e.g., AUC) compared to subjects with normal hepatic function in a pharmacokinetic study. However, use with caution in patients with liver disease [see Warnings and Precautions (5.4)].

10 OVERDOSAGE

Alogliptin

The highest doses of alogliptin administered in clinical trials were single doses of 800 mg to healthy subjects and doses of 400 mg once daily for 14 days to patients with type 2 diabetes (equivalent to 32 times and 16 times the maximum recommended clinical dose of 25 mg, respectively). No serious adverse reactions were observed at these doses.

In the event of an overdose, it is reasonable to institute the necessary clinical monitoring and supportive therapy as dictated by the patient’s clinical status. Per clinical judgment, it may be reasonable to initiate removal of unabsorbed material from the gastrointestinal tract.

Alogliptin is minimally dialyzable; over a three-hour hemodialysis session, approximately 7% of the drug was removed. Therefore, hemodialysis is unlikely to be beneficial in an overdose situation. It is not known if alogliptin is dialyzable by peritoneal dialysis.

Pioglitazone

During controlled clinical trials, one case of overdose with pioglitazone was reported. A male patient took 120 mg per day for four days, then 180 mg per day for seven days. The patient denied any clinical symptoms during this period.

In the event of overdosage, appropriate supportive treatment should be initiated according to patient’s clinical signs and symptoms.

11 DESCRIPTION

Alogliptin and pioglitazone tablets contain two oral antihyperglycemic drugs used in the management of type 2 diabetes: alogliptin and pioglitazone.

Alogliptin

Alogliptin is a selective, orally bioavailable inhibitor of the enzymatic activity of dipeptidyl peptidase-4 (DPP-4). Chemically, alogliptin is prepared as a benzoate salt, which is identified as 2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl}methyl)benzonitrile monobenzoate. It has a molecular formula of C18 H21 N5 O2 ∙C7 H6 O2 and a molecular weight of 461.51 daltons. The structural formula is:

Chemical Structure

Alogliptin benzoate is a white to off-white crystalline powder containing one asymmetric carbon in the aminopiperidine moiety. It is soluble in dimethylsulfoxide, sparingly soluble in water and methanol, slightly soluble in ethanol and very slightly soluble in octanol and isopropyl acetate.

Pioglitazone

Pioglitazone is an oral antihyperglycemic agent that acts primarily by decreasing insulin resistance. Chemically, pioglitazone is prepared as hydrochloride salt, which is identified as (±)-5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-thiazolidinedione monohydrochloride. It has a molecular formula of C19 H20 N2 O3 S∙HCl and a molecular weight of 392.90 daltons. The structural formula is:

Chemical Structure
(click image for full-size original)

Pioglitazone hydrochloride is an odorless white crystalline powder that contains one asymmetric carbon in the thiazolidinedione moiety. The synthetic compound is a racemate and the two enantiomers of pioglitazone interconvert in vivo. It is soluble in N,N dimethylformamide, slightly soluble in anhydrous ethanol, very slightly soluble in acetone and acetonitrile, practically insoluble in water and insoluble in ether.

Alogliptin and pioglitazone tablets are available as a fixed-dose combination tablet for oral administration containing 34 mg alogliptin benzoate equivalent to 25 mg alogliptin and any of the following strengths of pioglitazone hydrochloride:

  • 16.53 mg pioglitazone hydrochloride equivalent to 15 mg pioglitazone (25 mg/15 mg)
  • 33.06 mg pioglitazone hydrochloride equivalent to 30 mg pioglitazone (25 mg/30 mg)
  • 49.59 mg pioglitazone hydrochloride equivalent to 45 mg pioglitazone (25 mg/45 mg)

Alogliptin and pioglitazone tablets are also available as a fixed-dose combination tablet for oral administration containing 17 mg alogliptin benzoate equivalent to 12.5 mg alogliptin and any of the following strengths of pioglitazone hydrochloride:

  • 16.53 mg pioglitazone hydrochloride equivalent to 15 mg pioglitazone (12.5 mg/15 mg)
  • 33.06 mg pioglitazone hydrochloride equivalent to 30 mg pioglitazone (12.5 mg/30 mg)
  • 49.59 mg pioglitazone hydrochloride equivalent to 45 mg pioglitazone (12.5 mg/45 mg)

Alogliptin and pioglitazone tablets contain the following inactive ingredients: mannitol, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, magnesium stearate and lactose monohydrate; the tablets are film-coated with hypromellose, polyethylene glycol, titanium dioxide, talc and ferric oxide (yellow and/or red) and are marked with printing ink (Red A1 or Gray F1).

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