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SITAGLIPTIN AND RELATED AGENTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Sitagliptin, linagliptin, saxagliptin and vildagliptin are dipeptidyl peptidase-4 (DPP-4) enzyme inhibitors, which are presumed to exert their actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones (ie, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). These agents increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner.

Specific Substances

    A) SITAGLIPTIN (SYNONYM)
    1) Fosfato de sitagliptina
    2) Stagliptin
    3) Sitaliptini Phosphas
    4) Sitagliptin phosphate
    5) CAS 654671-77-9
    6) Molecular Formula: C16-H15-F6-N5-O,H3-O4-P,H2O
    LINAGLIPTIN (SYNONYM)
    1) CAS 668270-12-0
    2) Molecular Formula: C25-H28-N8-O2
    SAXAGLIPTIN (SYNONYM)
    1) BMS-477118
    2) CAS 361442-04-8
    3) Molecular Formula: C18-H25-N3-02,H20
    VILDAGLIPTIN (SYNONYM)
    1) ATC: A10BH02
    2) CAS 274901-16-5
    3) Molecular Formula: C!7-H25-N3-O2

    1.2.1) MOLECULAR FORMULA
    1) ALOGLIPTIN BENZOATE: C18H21N5O2.C7H6O2
    2) LINAGLIPTIN: C25H28N8O2
    3) SAXAGLIPTIN MONOHYDRATE: C18H25N3O2.H2O
    4) SITAGLIPTIN PHOSPHATE MONOHYDRATE: C16H15F6N5O.H3PO4.H2O

Available Forms Sources

    A) FORMS
    1) SITAGLIPTIN is available in film-coated tablets in the following strengths (Prod Info JANUVIA(TM) oral tablets, 2006):
    1) 25 mg, pink, round, with "221" on one side in bottles of 30, 90 and blister packages of 100
    2) 50 mg, light beige, round with "112" on one side in bottles of 30, 90 and blister packages of 100
    3) 100 mg, beige, round with "277" on one side in bottles of 30, 90, blister packages of 100, 500 and 1000
    2) LINAGLIPTIN is available in 5 mg tablets (Prod Info TRADJENTA(TM) oral tablets, 2011).
    3) SAXAGLIPTIN is available in 2.5 or 5 mg tablets (Prod Info ONGLYZA(TM) oral tablets, 2009).
    B) USES
    1) SITAGLIPTIN can be used in patients with type 2 diabetes mellitus as a monotherapy, or as combination therapy along with metformin or a PPAR beta agonist (eg, thiazolidinediones) when a single agent does not adequately provide glycemic control (Prod Info JANUVIA(TM) oral tablets, 2006).
    2) LINAGLIPTIN is also used as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus; it is not indicated for use in patients with type 1 diabetes (Prod Info TRADJENTA(TM) oral tablets, 2011).
    3) SAXAGLIPTIN is also used as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (Prod Info ONGLYZA(TM) oral tablets, 2009).
    4) VILDAGLIPTIN is available in 2 different formulations: 50 mg of vildagliptin and 850 mg of metformin hydrochloride and 50 mg vildagliptin and 1000 mg of metformin hydrochloride as film coated-tablets to improve glycemic control in adults with type 2 diabetes mellitus (Prod Info Eucreas oral tablets, 2012).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: These agents (sitagliptin, vildagliptin, saxagliptin, linagliptin) are used to improve glycemic control in type 2 diabetes mellitus individuals either as a monotherapy or in combination with other hypoglycemic drugs.
    B) PHARMACOLOGY: Dipeptidyl peptidase (DPP)-4 inhibitors exert their activity in patients with type 2 diabetes mellitus by protecting the endogenous incretin hormones and enhancing their actions. Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are incretin hormones released in response to meal intake to maintain glucose homeostasis. Although these agents share the same mechanism of action, they may have slightly different pharmacokinetics.
    C) EPIDEMIOLOGY: Overdose is uncommon.
    D) TOXICOLOGY: Because DDP-4 inhibitors increase insulin release and suppress glucagon release in a glucose-dependent manner, they are not expected to cause significant hypoglycemia in normal subject unless coingested with other hypoglycemic agents.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EVENTS: Hypoglycemia, headache, nasopharyngitis, upper respiratory tract infection and urinary tract infection occurred infrequently during therapy with these agents. Gastrointestinal findings, which included abdominal pain, nausea, and diarrhea, were similar to the placebo group. Rates of hypoglycemia with other agents known to cause hypoglycemia (ie, metformin or pioglitazone) was similar to patients taking placebo. However, the potential to cause hypoglycemia when used with sulfonylureas or insulin has not been adequately studied.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Limited data. Clinical events may be similar to effects reported with therapeutic use.
    2) SEVERE TOXICITY: Has not been reported. One elderly woman ingested 1700 mg of sitagliptin and was treated with intravenous glucose and remained asymptomatic. Hypoglycemia can occur when combined with other hypoglycemic agents.
    0.2.20) REPRODUCTIVE
    A) Alogliptin, linagliptin, sitagliptin and saxagliptin are classified as FDA pregnancy category B. The combinations of alogliptin/metformin metformin/saxagliptin, and sitagliptin/metformin are classified as FDA pregnancy category B. The combinations of alogliptin/pioglitazone and empagliflozin/linagliptin are classified as FDA pregnancy category C, and the combination of simvastatin/sitagliptin phosphate is classified as FDA pregnancy category X. In animal studies, linagliptin demonstrated maternal toxicities, developmental delays, and embryofetal loss in rats and rabbits administered linagliptin doses up to 1000 and 1943 times the human clinical does, respectively, while sitagliptin did not harm the fetus and saxagliptin was not teratogenic in rats and rabbits. At the time of this review, there were no adequate and well-controlled reproductive studies in pregnant women.
    0.2.21) CARCINOGENICITY
    A) SITAGLIPTIN: In animal studies, liver adenoma/carcinoma were observed at doses of 500 mg/kg (60 times the human exposure) in male and female rats; no liver tumors were reported at doses of 150 mg/kg. No increased incidence in tumors in any organ were observed at doses of up to 500 mg/kg in mice. SAXAGLIPTIN: No tumors were induced in rats or mice at the highest doses tested. ALOGLIPTIN: Thyroid adenoma/carcinoma were observed at doses of 400 mg/kg or 800 mg/kg (308 times the human exposure) in male but not female rats. No tumors were induced in rats at 75 mg/kg (32 times the human exposure) or in mice at the highest doses tested.

Laboratory Monitoring

    A) If coingested with other hypoglycemic agents, monitor blood glucose frequently. Monitor for clinical evidence of hypoglycemia (diaphoresis, tachycardia, tremor, change in mental status) following exposure with these agents.
    B) Obtain an ECG after large overdose. Clinically insignificant QTc prolongation has been reported at *8 times the therapeutic dose with sitagliptin; it has not been reported with saxagliptin.
    C) Serum drug levels are not widely available or clinically indicated following exposure.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Although dipeptidyl peptidase-4 inhibitors produce very low rates of hypoglycemia with therapeutic use, hypoglycemia may develop after large overdose or if coingested with other hypoglycemic agents. Monitor serial blood glucose concentrations. Monitor for symptoms of hypoglycemia (diaphoresis, palpitations, tremor, change in mentation). Treat significant fluid loss with IV fluids; antidiarrheal agents as indicated.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Limited data. Treatment is symptomatic and supportive. DPP-4 inhibitors produce very low rates of hypoglycemia with therapeutic use. Following a significant exposure or coingested with other hypoglycemic agents, monitor serial blood glucose concentrations. Monitor for symptoms of hypoglycemia (diaphoresis, palpitations, tremor, change in mentation). Treat with dextrose as necessary. Monitor neurologic function in patients with evidence of hypoglycemia. A baseline ECG may be indicated following a significant ingestion; repeat as necessary.
    C) DECONTAMINATION
    1) PREHOSPITAL: Emesis is not indicated. Activated charcoal may be considered following a significant ingestion if the airway is protected.
    2) HOSPITAL: Activated charcoal may be considered following a significant ingestion if performed soon after exposure and the airway is protected.
    D) ANTIDOTE
    1) None.
    E) AIRWAY MANAGEMENT
    1) Airway management is unlikely to be necessary.
    F) ENHANCED ELIMINATION
    1) SITAGLIPTIN: It is modestly dialyzable. In clinical studies, 3 to 4 hours of hemodialysis removed 13.5% of a dose of sitagliptin .
    2) LINAGLIPTIN: Plasma protein binding is 82% to 99%. Extensively distributed in the tissues. Hemodialysis is not anticipated to be beneficial.
    3) SAXAGLIPTIN: It is not extensively bound to plasma proteins. Saxagliptin and its active metabolite can be removed by hemodialysis (23% of a dose over 4 hours).
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: An asymptomatic child with an inadvertent ingestion of a single dose can be monitored at home if a responsible adult is present. An asymptomatic adult or adolescent with an inadvertent ingestion of 1 to 2 tablets of sitagliptin, saxigliptin and linagliptin can likely be observed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate self-harm ingestion or coingestion of other hypoglycemic agents should be evaluated in a healthcare facility and monitored until symptoms resolve. Patients with hypoglycemia should be monitored until blood glucose is normal and symptoms have resolved. Patients may be discharged to home once symptoms have resolved and blood glucose or other laboratory studies are within normal limits and is cleared from a mental health standpoint.
    3) ADMISSION CRITERIA: Any adult who becomes hypoglycemic and all children with more than a minor ingestion should be admitted for observation. Patients with evidence of severe hypoglycemia or CNS effects should be admitted for further treatment.
    4) CONSULT CRITERIA: Contact a medical toxicologist or Poison Center for assistance in cases of severe poisonings or in whom the diagnosis is unclear. Patients with a deliberate self-harm ingestion should be evaluated by a mental health specialist.
    H) PHARMACOKINETICS
    1) SITAGLIPTIN: It is rapidly absorbed (greater than 87% absorbed) with peak plasma concentrations (median Tmax) occurring in 1 to 4 hours. Absolute bioavailability is approximately 87%. Mean volume of distribution at steady state is 198 L in healthy individual following a single 100 mg IV dose. Plasma protein binding is relatively low (38%). Terminal half-life following a 100 mg dose orally is 12.4 hours.
    2) SAXAGLIPTIN: Active metabolite 5-hydroxy saxagliptin. In vitro protein binding of saxagliptin and its active metabolite in human serum is negligible (less than 10%). Median time to maximum concentration (Tmax) is 2 hours for saxagliptin and 4 hours for its metabolite following a 5 mg dose. Absorption: Greater than 75%. Metabolism is primarily mediated by cytochrome P450 3A4/5. It is eliminated by both renal and hepatic pathways. Terminal half-life for saxagliptin (5 mg) and its active metabolite are 2.5 and 3.1 hours, respectively.
    3) LINAGLIPTIN: It has an absolute bioavailability of approximately 30%. Peak plasma concentrations of linagliptin occur at approximately 1.5 hours after a single 5 mg dose in healthy individuals. Extensively distributed into the tissues. Volume of distribution at steady state 368 to 918 L. Plasma protein binding is 82% to 99%. Half-life is approximately 12 hours. Elimination (80%) occurs via the enterohepatic system with a minor amount (5%) removed through the urine.
    4) VILDAGLIPTIN: Absorption: 85%; mean volume of distribution at steady state is 71 L; protein binding less than 10%. Inactive metabolites. Terminal half-life 2 to 3 hours.
    5) ALOGLIPTIN: Absorption: Greater than 75%; volume of distribution at steady state is 300 L; protein binding 20%. Inactive metabolite. Minimally metabolized. Terminal half-life is 21.4 hours for a single dose of 25 mg; 12.4 for a single dose of 800 mg.
    I) TOXICOKINETICS
    1) Because dipeptidyl peptidase 4 inhibitors increase insulin release and suppress glucagon release in a glucose-dependent manner, they are not expected to cause significant hypoglycemia in normal subject unless coingested with other hypoglycemic agents.
    J) PITFALLS
    1) Other agents or conditions that may also produce hypoglycemia. Early discharge with latent episode of hypoglycemia; agents within class have variable half-life.
    K) DIFFERENTIAL DIAGNOSIS
    1) Other agents or conditions that may also produce hypoglycemia or alterations in CNS function.

Range Of Toxicity

    A) TOXICITY: SITAGLIPTIN: Limited data. An elderly woman intentionally ingested 1700 mg of sitagliptin and was treated with intravenous glucose; hypoglycemia did not develop. Another elderly woman intentionally ingested 1800 mg and was given a regular diet; no symptoms developed. A dose of 800 mg did not cause toxic effects in healthy adults. Doses above 800 mg have not been studied. LINAGLIPTIN: Limited data. Single doses of up to 600 mg (120 times the recommended daily dose) administered to healthy subjects resulted in no adverse events. SAXAGLIPTIN: At doses of up to 400 mg daily (80 times the maximum recommended human dose) for 2 weeks, no significant adverse events occurred in healthy subjects.
    B) THERAPEUTIC DOSE: SITAGLIPTIN: 100 mg orally once daily as a monotherapy or in combination with metformin or PPAR(gamma) agonist (eg, thiazolidinediones). LINAGLIPTIN: Adult: 5 mg orally once daily. SAXAGLIPTIN: The recommended dose is 2.5 to 5 mg once daily. VILDAGLIPTIN/METFORMIN: The recommended daily dose is 100 mg vildagliptin and 2000 mg metformin.

Clinical Effects

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) SITAGLIPTIN: In two clinically-controlled trials of 806 patients, headache occurred in 5.1% (9/175) of patients treated with 100 mg sitagliptin alone, as compared to 3.9% (7/178) in the placebo group (Prod Info JANUVIA(TM) oral tablets, 2006). In a study of healthy male volunteers treated with sitagliptin, headache was one of the most frequently reported adverse event (Bergman et al, 2006).
    b) LINAGLIPTIN: Headache has been reported with linagliptin combination therapy (metformin and glimepiride) (Aletti & Cheng-Lai, 2012).
    c) SAXAGLIPTIN: In a clinical-controlled trial, headache was reported in 6.5% (57/882) of patients receiving 5 mg saxagliptin, as compared to 5.9% (47/799) in the placebo group (Prod Info ONGLYZA(TM) oral tablets, 2009).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Abdominal pain may occur with therapeutic use of these agents (Richard et al, 2011).
    b) In clinical controlled studies, overall incidence of abdominal pain was 2.3% for a 100 mg dose, which was similar to the place group (2.1%) (Prod Info JANUVIA(R) oral tablets, 2010; Raz et al, 2006). Similar rates of 2.3% and 1.7% were reported for patients receiving 2.5 and 5 mg of saxagliptin, respectively (Prod Info ONGLYZA(TM) oral tablets, 2009).
    B) NAUSEA
    1) WITH THERAPEUTIC USE
    a) Nausea was infrequently (1.4%) reported during therapeutic use (Prod Info JANUVIA(R) oral tablets, 2010; Raz et al, 2006).
    C) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) SITAGLIPTIN: In clinical controlled studies, the overall incidence of diarrhea for a 100 mg dose was 3.0%, which was similar to the placebo group (2.3%) (Prod Info JANUVIA(R) oral tablets, 2010; Raz et al, 2006).
    b) OTHER AGENTS: Diarrhea has been reported with therapeutic use of saxagliptin and vildagliptin (Richard et al, 2011).
    D) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Constipation has been reported with therapeutic use of vildagliptin or sitagliptin (Richard et al, 2011).
    E) ACUTE PANCREATITIS
    1) WITH THERAPEUTIC USE
    a) SITAGLIPTIN: In postmarketing surveillance, there have been rare reports of acute pancreatitis temporally associated with the initiation of sitagliptin therapy. However, preclinical studies in various species (ie, mice, rats, dogs and monkeys) and pooled data from clinical trials comprising 10246 patients with type 2 diabetes mellitus treated for up to 2 years with sitagliptin demonstrated no increased risk of pancreatitis. Similarly, no increased risk of pancreatitis was found in vildagliptin-treated patients (n=8000) (Baetta & Corsini, 2011).
    b) LINAGLIPTIN: Pancreatitis has been rarely reported with linagliptin therapy (Aletti & Cheng-Lai, 2012).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) INCREASED LIVER ENZYMES
    1) WITH THERAPEUTIC USE
    a) VILDAGLIPTIN: There have been rare reports of elevated liver enzymes with vildagliptin therapy. The patients remained asymptomatic and liver function returned to normal after the discontinuation of therapy (Baetta & Corsini, 2011).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) BACKACHE
    1) WITH THERAPEUTIC USE
    a) LINAGLIPTIN: Back pain and arthralgia have been reported infrequently with linagliptin combination therapy (ie, metformin and glimepiride) (Aletti & Cheng-Lai, 2012).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPOGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) Hypoglycemic events were similar in patients receiving either 100 mg sitagliptin (1.2%) or placebo (0.9%) (Prod Info JANUVIA(TM) oral tablets, 2006). Similar rates were reported for patients receiving saxagliptin compared to the placebo group (Prod Info ONGLYZA(TM) oral tablets, 2009). These agents when used as a monotherapy have overall very low rates of hypoglycemia compared to other antidiabetic agents (Baetta & Corsini, 2011).
    b) SITAGLIPTIN: In a placebo-controlled study of patients (n=13) with type 2 diabetes, coadministration of sitagliptin and metformin produced no clinical or laboratory evidence of hypoglycemia (Herman et al, 2006a).
    c) LINAGLIPTIN: In a safety and tolerability study of Japanese patients with type 2 diabetes mellitus, linagliptin doses of 0.5, 2.5 or 10 mg were randomly assigned to patients for 28 days. The various doses were well tolerated with no reports of hypoglycemia. Similar results were reported in a safety and tolerability study of 77 Caucasian patients receiving 2.5, 5 or 10 mg of linagliptin (Aletti & Cheng-Lai, 2012).
    1) INCIDENCE: The incidence of hypoglycemia is relatively low with linagliptin therapy (7.6% vs 4.1% with placebo). However, the incidence increased to 22.9% when linagliptin was combined with metformin and a sulfonylurea compared to 14% for those receiving the placebo combination (Aletti & Cheng-Lai, 2012). It is suggested that a lower dose of secretagogue is indicated when given in combination with linagliptin (Prod Info TRADJENTA(TM) oral tablets, 2011).
    2) WITH POISONING/EXPOSURE
    a) Because dipeptidyl peptidase 4 inhibitors increase insulin release and suppress glucagon release in a glucose-dependent manner, they are not expected to cause significant hypoglycemia in normal subjects unless coingested with other hypoglycemic agents.
    b) CASE REPORT/SITAGLIPTIN: An 86-year-old woman with type 2 diabetes mellitus intentionally ingested 1700 mg (34 50 mg tablets) of sitagliptin. Upon admission 4 hours after ingestion, she was alert with a blood glucose of 124 mg/dL and received a total of 52 g of glucose intravenously over 10 hours to prevent hypoglycemia. By the following day, the patient was started on an oral diet and resumed sitagliptin (50 mg) therapy. The plasma concentration peaked at 3793 nM (4.5 times higher the normal value) approximately 16 hours after exposure. After 3 days of monitoring, the patient remained stable and hypoglycemia was never observed throughout her hospitalization (Furukawa et al, 2012).
    c) SITAGLIPTIN: Hypoglycemia did NOT develop in healthy adult volunteers taking up to 800 mg sitagliptin (eight times the therapeutic dose) (Bergman et al, 2006; Herman et al, 2005). It was also not observed in healthy adults receiving up to 400 mg daily (80 times the maximum recommended human dose) of saxagliptin or in healthy volunteers given up to 600 mg (120 times the recommended daily dose) given linagliptin (Prod Info TRADJENTA(TM) oral tablets, 2011; Prod Info ONGLYZA(TM) oral tablets, 2009).
    d) CASE SERIES/SITAGLIPTIN: In a study of obese (BMI 30 to 40 kg/m(2)), nondiabetic men and women, no clinical or laboratory evidence of hypoglycemia was reported with the use of sitagliptin 200 mg twice daily for 28 days (Herman et al, 2006).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) LINAGLIPTIN: Hypersensitivity reactions (urticaria, angioedema, bronchospasm) have been reported rarely with linagliptin therapy (Aletti & Cheng-Lai, 2012).

Reproductive

    3.20.1) SUMMARY
    A) Alogliptin, linagliptin, sitagliptin and saxagliptin are classified as FDA pregnancy category B. The combinations of alogliptin/metformin metformin/saxagliptin, and sitagliptin/metformin are classified as FDA pregnancy category B. The combinations of alogliptin/pioglitazone and empagliflozin/linagliptin are classified as FDA pregnancy category C, and the combination of simvastatin/sitagliptin phosphate is classified as FDA pregnancy category X. In animal studies, linagliptin demonstrated maternal toxicities, developmental delays, and embryofetal loss in rats and rabbits administered linagliptin doses up to 1000 and 1943 times the human clinical does, respectively, while sitagliptin did not harm the fetus and saxagliptin was not teratogenic in rats and rabbits. At the time of this review, there were no adequate and well-controlled reproductive studies in pregnant women.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) ALOGLIPTIN
    a) At the time of this review, no data were available to assess the teratogenic potential of this agent (Prod Info NESINA oral tablets, 2013).
    2) LINAGLIPTIN
    a) At the time of this review, no data were available to assess the teratogenic potential of this agent (Prod Info TRADJENTA(TM) oral tablets, 2011).
    3) COMBINATION PRODUCTS
    a) LINAGLIPTIN/EMPAGLIFLOZIN
    1) At the time of this review, no data were available to assess the teratogenic potential of this combination product (Prod Info GLYXAMBI(R) oral tablets, 2015).
    B) ANIMAL STUDIES
    1) ALOGLIPTIN
    a) In animal studies, administration of alogliptin 200 and 500 mg/kg (approximately 149 and 180 times the clinical dose, respectively) in pregnant rats and rabbits during organogenesis did not result in teratogenicity. Alogliptin doses up to 250 mg/kg (approximately 95 times the clinical dose) did not result in embryonic or fetal harm in pregnant rats when administered from gestation day 6 to lactation day 20 (Prod Info NESINA oral tablets, 2013).
    2) LINAGLIPTIN
    a) Linagliptin has been shown to cross the placental barrier during studies with rats and rabbits. During animal reproduction studies with rats and rabbits administered doses of linagliptin up to 30 mg/kg and 150 mg/kg (approximately 49 and 1943 times the clinical human dose), respectively, during organogenesis, teratogenic effects were not observed. Evidence of maternal toxicity resulting in development delays in skeletal ossification was observed in rats and rabbits administered linagliptin at doses approximately 1000 and 1943 times the clinical human dose, respectively, as well as increased embryofetal loss in rats and visceral and skeletal variations and increased fetal resorptions in rabbits (Prod Info TRADJENTA(TM) oral tablets, 2011).
    3) SITAGLIPTIN
    a) No teratogenicity was observed in reproduction studies in rats and rabbits following oral sitagliptin doses that were approximately 30 and 20 times, respectively, the human exposure (AUC) at the maximum recommended human dose (MRHD) of 100 mg/day. However, an increased incidence of rib malformations occurred following higher sitagliptin doses that were approximately 100 times the human exposure at the MRHD. Placental transfer of sitagliptin in pregnant rats and rabbits was 45% and 66%, respectively, after 2 hours and was 80% and 30%, respectively, after 24 hours (Prod Info JUVISYNC(TM) oral tablets, 2011).
    b) In reproductive studies in rats and rabbits, doses of sitagliptin up to 125 mg/kg (12 times the human dose) did not harm the fetus (Prod Info JANUMET(TM) oral tablets, 2007).
    4) SAXAGLIPTIN
    a) No teratogenicity was observed during organogenesis in rats and rabbits at any dose. However, saxagliptin and its metabolite, when administered to pregnant rats, resulted in incomplete ossification of the pelvis at a dose of 240 mg/kg, or approximately 1503 and 66 times the maximum recommended human dose (MRHD; 5 mg), respectively. Maternal toxicity and decreased fetal weight were observed at 7986 and 328 times the human exposure at the MRHD of saxagliptin and its metabolite, respectively. Rabbits experienced minor fetal skeletal variations at 200 mg/kg, or approximately 1432 and 992 times the MRHD, respectively. Pregnant rats administered saxagliptin and its metabolite at maternally toxic doses (greater than or equal to 1629 and 53 times the MRHD, respectively) from gestation day 6 to lactation day 20 resulted in decreased weight in both male and female offspring (Prod Info ONGLYZA(TM) oral tablets, 2011).
    5) COMBINATION PRODUCTS
    a) ALOGLIPTIN/METFORMIN
    1) There was no evidence of fetal abnormalities following administration in pregnant rats of 100 mg/kg alogliptin concomitantly with 150 mg/kg metformin (approximately 28 times the clinical dose of 25 mg alogliptin and 2 times the clinical dose of 2000 mg metformin based on AUC) (Prod Info KAZANO oral tablets, 2013)
    b) ALOGLIPTIN/PIOGLITAZONE
    1) There was no evidence of fetal abnormalities following administration in pregnant rats of 100 mg/kg alogliptin plus 40 mg/kg pioglitazone combination during organogenesis. However, the pioglitazone-related effects of delayed development and reduced weights were slightly augmented in the rat fetuses (Prod Info OSENI oral tablets, 2013).
    c) LINAGLIPTIN/EMPAGLIFLOZIN
    1) Empagliflozin/linagliptin was not teratogenic in rats up to and including a combined dose of 700 mg/kg/day empagliflozin and 140 mg/kg/day linagliptin (253 and 353 times the clinical exposure) (Prod Info GLYXAMBI(R) oral tablets, 2015).
    d) LINAGLIPTIN/METFORMIN
    1) The coadministration of linagliptin and metformin at doses similar to the maximum recommended clinical dose to pregnant animals during organogenesis resulted in no adverse maternal or developmental outcomes. In animal studies with the individual components, linagliptin was not teratogenic in animals administered doses up to 1943 times the clinical human dose during organogenesis. In addition, the administration of linagliptin to pregnant animals during gestation day 6 through lactation day 21 resulted in no toxic effects in offspring exposed to 49 times the maximum recommended human dose. Metformin was not teratogenic in animals administered up to 3 times the clinical human dose. However, an increased incidence of fetal rib and scapula skeletal malformations was observed in animals administered metformin at higher maternally toxic doses (9 and 23 times the clinical exposure at recommended doses) (Prod Info JENTADUETO(R) XR extended-release oral tablets, 2016).
    e) SAXAGLIPTIN/METFORMIN
    1) No embryolethality or teratogenicity was noted in pregnant rats and rabbits administered a combination of metformin and saxagliptin at doses up to 100 times and 10 times the maximum recommended human doses (MRHD; saxagliptin 5 mg and metformin 2000 mg), respectively, in rats, and 249 times and 1.1 times the MRHD, respectively, in rabbits. Developmental toxicity included an increased incidence of wavy ribs in rats and fetal body decrements of 7% and a low incidence of fetal hyoid delayed ossification in rabbits (Prod Info KOMBIGLYZE(TM) XR extended-release oral tablets, 2010).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) ALOGLIPTIN
    a) At the time of this review, no data were available to assess the potential effects of exposure to alogliptin during pregnancy in humans (Prod Info NESINA oral tablets, 2013).
    2) LINAGLIPTIN
    a) At the time of this review, no data were available to assess the potential effects of exposure to linagliptin during pregnancy in humans (Prod Info TRADJENTA(TM) oral tablets, 2011).
    3) COMBINATION PRODUCTS
    a) LINAGLIPTIN/EMPAGLIFLOZIN
    1) At the time of this review, no data were available to assess the potential effects of exposure to the combined components of empagliflozin/linagliptin during pregnancy in humans (Prod Info GLYXAMBI(R) oral tablets, 2015).
    b) VILDAGLIPTIN/METFORMIN
    1) At the time of this review, there are no adequate data to assess the potential effect of exposure to vildagliptin/metformin in pregnant women (Prod Info Eucreas oral tablets, 2012).
    B) PREGNANCY CATEGORY
    1) The manufacturers have classified alogliptin, linagliptin, sitagliptin, saxagliptin, and combinations alogliptin/metformin, metformin/saxagliptin, and sitagliptin/metformin as FDA pregnancy category B (Prod Info KAZANO oral tablets, 2013; Prod Info NESINA oral tablets, 2013; Prod Info TRADJENTA(TM) oral tablets, 2011; Prod Info JANUMET(TM) oral tablets, 2007; Prod Info ONGLYZA(TM) oral tablets, 2011; Prod Info KOMBIGLYZE(TM) XR extended-release oral tablets, 2010).
    2) The combinations of alogliptin/pioglitazone and empagliflozin/linagliptin are classified as FDA pregnancy category C (Prod Info GLYXAMBI(R) oral tablets, 2015; Prod Info OSENI oral tablets, 2013).
    3) The combination of simvastatin/sitagliptin phosphate is classified as FDA pregnancy category X (Prod Info JUVISYNC(TM) oral tablets, 2011).
    4) LINAGLIPTIN/METFORMIN: There are no adequate or well-controlled studies of the linagliptin/metformin hydrochloride combination product or its individual components in pregnant women. Although the metformin component has been reported to cross the human placental barrier, some clinical data show that metformin administration during the first trimester was not associated with an increased risk for malformation nor increased perinatal complications. The use of metformin in premenopausal women may result in ovulation and unintended pregnancy in anovulatory women. Advise women that treatment with metformin may result in an unintended pregnancy in some premenopausal anovulatory females (Prod Info JENTADUETO(R) XR extended-release oral tablets, 2016). Administer the linagliptin/metformin combination product during pregnancy only if the benefit to the mother outweighs the potential risk to the fetus.
    C) ANIMAL STUDIES
    1) ALOGLIPTIN
    a) There are no adequate or well controlled studies of alogliptin use during human pregnancy. Alogliptin doses up to 250 mg/kg (approximately 95 times the clinical dose) did not result in embryonic or fetal harm in pregnant rats when administered from gestation day 6 to lactation day 20 (Prod Info NESINA oral tablets, 2013).
    2) LINAGLIPTIN
    a) Administration of linagliptin to pregnant rats during gestation days 6 through 21 resulted in decreased body weight and delayed development both physically and behaviorally in offspring at doses greater than 1000 times the human clinical dose. There was no evidence of toxicity in offspring exposed to 49 times the human clinical dose (Prod Info TRADJENTA(TM) oral tablets, 2011).
    3) COMBINATION PRODUCTS
    a) LINAGLIPTIN/EMPAGLIFLOZIN
    1) In rats, dose-related reduced body weight gain and reduced food consumption resulted from a combination of greater than or equal to 300 mg/kg/day empagliflozin and 60 mg/kg/day linagliptin (99 and 227 times the clinical exposure) (Prod Info GLYXAMBI(R) oral tablets, 2015).
    b) LINAGLIPTIN/METFORMIN
    1) The coadministration of linagliptin and metformin at doses similar to the maximum recommended clinical dose to pregnant animals during organogenesis resulted in no adverse maternal or developmental outcomes. In animal studies with the individual components, linagliptin was not teratogenic in animals administered doses up to 1943 times the clinical human dose during organogenesis. In addition, the administration of linagliptin to pregnant animals during gestation day 6 through lactation day 21 resulted in no toxic effects in offspring exposed to 49 times the maximum recommended human dose. Metformin was not teratogenic in animals administered up to 3 times the clinical human dose. However, an increased incidence of fetal rib and scapula skeletal malformations was observed in animals administered metformin at higher maternally toxic doses (9 and 23 times the clinical exposure at recommended doses) (Prod Info JENTADUETO(R) XR extended-release oral tablets, 2016).
    c) SAXAGLIPTIN/METFORMIN
    1) Developmental toxicity, including an increased incidence of wavy ribs in rats and fetal body decrements of 7% and a low incidence of fetal hyoid delayed ossification in rabbits, was reported following the administration of a combination of metformin and saxagliptin at doses up to 100 times and 10 times the maximum recommended human doses (MRHD; saxagliptin 5 mg and metformin 2000 mg), respectively, in rats, and 249 times and 1.1 times the MRHD, respectively, in rabbits. Maternal toxicity included weight decrements (11% to 17%) and related reductions in food consumption in rats, and marginal reductions in body weight in rabbits. In a subset analysis of rabbits, death, moribundity, or abortion were reported in 12 of 30 mothers (Prod Info KOMBIGLYZE(TM) XR extended-release oral tablets, 2010).
    d) VILDAGLIPTIN/METFORMIN
    1) For vildagliptin, reproductive toxicity has occurred in animals at high doses, while no reproductive effects have been observed for metformin. At the time of this review, no animal studies have been performed for this combination product (Prod Info Eucreas oral tablets, 2012).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) At the time of this review, no data were available to assess the potential effects of exposure to aligoliptin/pioglitazone, aligogliptin, linagliptin, empagliflozin/linagliptin, linagliptin/metformin, metformin/saxagliptin, metformin/sitagliptin, or saxagliptin during lactation in humans (Prod Info JENTADUETO(R) XR extended-release oral tablets, 2016; Prod Info GLYXAMBI(R) oral tablets, 2015; Prod Info OSENI oral tablets, 2013; Prod Info NESINA oral tablets, 2013; Prod Info TRADJENTA(TM) oral tablets, 2011; Prod Info KOMBIGLYZE(TM) XR extended-release oral tablets, 2010; Prod Info ONGLYZA(TM) oral tablets, 2011).
    B) ANIMAL STUDIES
    1) ALOGLIPTIN
    a) RATS: Animal studies have shown that alogliptin is excreted into the milk at a milk-to-plasma ratio of 2:1 (Prod Info NESINA oral tablets, 2013).
    2) LINAGLIPTIN
    a) Animal studies have shown that linagliptin is excreted into the milk at a milk-to-plasma ratio of 4:1 (Prod Info TRADJENTA(TM) oral tablets, 2011).
    3) SAXAGLIPTIN
    a) RATS: In lactating rats, saxagliptin is secreted into the milk at 1:1 ratio with plasma concentrations (Prod Info ONGLYZA(TM) oral tablets, 2011).
    4) SITAGLIPTIN
    a) RATS: Sitagliptin has been found in the milk of lactating rats at a milk-to-plasma ratio of 4:1 (Prod Info JUVISYNC(TM) oral tablets, 2011).
    5) COMBINATION DRUGS
    a) ALOGLIPTIN/METFORMIN
    1) At the time of this review, no data were available to assess the potential effects of exposure to linagliptin/metformin during lactation in humans. It is unknown whether linagliptin is excreted into human milk or has adverse effects on milk production or the breastfed infant. However, it has been shown to be excreted into rat milk. Limited data suggest that metformin is excreted into human milk, but there is insufficient information about whether it adversely effects milk production or the breastfed infant. Consider the mother's need for linagliptin/metformin hydrochloride against the developmental and health benefits of breastfeeding and the potential adverse effects of its exposure in the breastfed infant (Prod Info JENTADUETO(R) XR extended-release oral tablets, 2016).
    b) ALOGLIPTIN/PIOGLITAZONE
    1) Animal studies with the individual components of alogliptin and pioglitazone showed that they are both excreted into the milk of lactating rats (Prod Info OSENI oral tablets, 2013).
    c) LINAGLIPTIN/EMPAGLIFLOZIN
    1) Animal data have shown that empagliflozin and linagliptin are excreted into milk (Prod Info GLYXAMBI(R) oral tablets, 2015).
    d) SAXAGLIPTIN/METFORMIN
    1) Lactation studies of the metformin hydrochloride and saxagliptin hydrochloride combination have not been conducted in humans; therefore, it is unknown whether metformin or saxagliptin is excreted into human milk. Animal studies of the individual components of metformin hydrochloride and saxagliptin hydrochloride showed that both metformin and saxagliptin are excreted into the milk of lactating rats (Prod Info KOMBIGLYZE(TM) XR extended-release oral tablets, 2010).
    e) VILDAGLIPTIN/METFORMIN
    1) In animal studies, vildagliptin and metformin have both been found in excreted milk (Prod Info Eucreas oral tablets, 2012)
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) LINAGLIPTIN/EMPAGLIFLOZIN
    a) The effects of empagliflozin/linagliptin on fertility are unknown (Prod Info GLYXAMBI(R) oral tablets, 2015).
    B) UNINTENDED PREGNANCY
    1) The use of metformin in premenopausal women may result in ovulation and unintended pregnancy in anovulatory women (Prod Info JENTADUETO(R) XR extended-release oral tablets, 2016).
    C) ANIMAL STUDIES
    1) LINAGLIPTIN
    a) RATS: No impairment on fertility, early embryonic development, mating, or live births were observed in rats administered linagliptin doses up to 240 mg/kg (approximately 943 times the human clinical dose) (Prod Info TRADJENTA(TM) oral tablets, 2011).
    2) SAXAGLIPTIN
    a) RATS: No effects on fertility were seen in male rats that received oral gavage doses of saxagliptin for 2 weeks before, during, and up to termination of mating (4 weeks) or in female rats receiving oral gavage doses of saxagliptin for 2 weeks before mating through gestation day 7 at exposures of approximately 603 (male) and 776 (female) times the maximum recommended human dose (MRHD), respectively. Maternal toxicity and increased fetal resorptions were observed at higher doses (approximately 2068 and 6138 times the MRHD, respectively). Effects on estrous cycling, fertility, ovulation, and implantation were also observed at doses of 6138 times the MRHD (Prod Info ONGLYZA(TM) oral tablets, 2011).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) SITAGLIPTIN: In animal studies, liver adenoma/carcinoma were observed at doses of 500 mg/kg (60 times the human exposure) in male and female rats; no liver tumors were reported at doses of 150 mg/kg. No increased incidence in tumors in any organ were observed at doses of up to 500 mg/kg in mice. SAXAGLIPTIN: No tumors were induced in rats or mice at the highest doses tested. ALOGLIPTIN: Thyroid adenoma/carcinoma were observed at doses of 400 mg/kg or 800 mg/kg (308 times the human exposure) in male but not female rats. No tumors were induced in rats at 75 mg/kg (32 times the human exposure) or in mice at the highest doses tested.
    3.21.4) ANIMAL STUDIES
    A) LIVER CARCINOMA
    1) SITAGLIPTIN: In a two-year carcinogenicity study in male and female rats given oral doses of sitagliptin of 50, 150, and 500 mg/kg/day, resulted in an increased incidence of combined liver adenoma/carcinoma in males and females, and an increase of liver carcinoma in females at 500 mg/kg (60 times the human exposure). Liver tumors were not observed at 150 mg/kg. In mice studies, at doses of 50, 125, 250, and 500 mg/kg/day there was no increased incidence of tumors in any organ up to 500 mg/kg (Prod Info JANUVIA(TM) oral tablets, 2006).
    B) THYROID ADENOMA AND CARCINOMA
    1) ALOGLIPTIN: In a two-year carcinogenicity study in male and female rats given oral doses of alogliptin of 75, 400, and 800 mg/kg/day (approximately 308 times the human exposure at the maximum clinical dose of 25 mg), resulted in an increased incidence of combined thyroid C-cell adenomas and carcinomas in males but not females. Thyroid tumors were not observed at 75 mg/kg. In mice studies, at doses of 50, 150, and 300 mg/kg/day (up to approximately 51 times the human exposure at the maximum clinical dose of 25 mg) there was no increased incidence of tumors in any organ up to 300 mg/kg (Prod Info NESINA oral tablets, 2013).
    C) LACK OF EFFECT
    1) SAXAGLIPTIN: Tumors were not reported in either mice or rats at the highest doses tested. In mice, the dose was equivalent to approximately 870 (males) and 1165 (females) times the human exposure at the maximum recommended daily dose (MRHD) of 5 mg/day, while rats were exposed to 355 (males) and 2217 (females) times the MRHD (Prod Info ONGLYZA(TM) oral tablets, 2009).
    2) ALOGLIPTIN: Tumors were not reported in rats at a dose of 75 mg/kg (approximately 32 times the maximum recommended clinical dose of 25 mg based on AUC exposure) or in mice at doses of 50, 150, or 300 mg/kg (up to approximately 51 times the maximum recommended clinical dose based on AUC exposure) alogliptin for 2 years (Prod Info NESINA oral tablets, 2013).

Summary Of Exposure

    A) USES: These agents (sitagliptin, vildagliptin, saxagliptin, linagliptin) are used to improve glycemic control in type 2 diabetes mellitus individuals either as a monotherapy or in combination with other hypoglycemic drugs.
    B) PHARMACOLOGY: Dipeptidyl peptidase (DPP)-4 inhibitors exert their activity in patients with type 2 diabetes mellitus by protecting the endogenous incretin hormones and enhancing their actions. Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are incretin hormones released in response to meal intake to maintain glucose homeostasis. Although these agents share the same mechanism of action, they may have slightly different pharmacokinetics.
    C) EPIDEMIOLOGY: Overdose is uncommon.
    D) TOXICOLOGY: Because DDP-4 inhibitors increase insulin release and suppress glucagon release in a glucose-dependent manner, they are not expected to cause significant hypoglycemia in normal subject unless coingested with other hypoglycemic agents.
    E) WITH THERAPEUTIC USE
    1) ADVERSE EVENTS: Hypoglycemia, headache, nasopharyngitis, upper respiratory tract infection and urinary tract infection occurred infrequently during therapy with these agents. Gastrointestinal findings, which included abdominal pain, nausea, and diarrhea, were similar to the placebo group. Rates of hypoglycemia with other agents known to cause hypoglycemia (ie, metformin or pioglitazone) was similar to patients taking placebo. However, the potential to cause hypoglycemia when used with sulfonylureas or insulin has not been adequately studied.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Limited data. Clinical events may be similar to effects reported with therapeutic use.
    2) SEVERE TOXICITY: Has not been reported. One elderly woman ingested 1700 mg of sitagliptin and was treated with intravenous glucose and remained asymptomatic. Hypoglycemia can occur when combined with other hypoglycemic agents.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) PROLONGED QT INTERVAL
    1) WITH THERAPEUTIC USE
    a) LACK OF EFFECT
    1) SITAGLIPTIN: No significant change in vital signs or ECG, including QTc interval, have been observed in patients receiving sitagliptin therapy (Prod Info JANUVIA(TM) oral tablets, 2006; Herman et al, 2006a; Raz et al, 2006; Herman et al, 2005). It is not known what effect if any may occur in overdose.
    2) SAXAGLIPTIN: In a randomized, double-blind placebo-controlled study, saxagliptin therapy was not associated with clinically significant prolongation of QTc interval or heart rate at daily doses of 40 mg (8 times the maximum recommended human dose) (Prod Info ONGLYZA(TM) oral tablets, 2009).
    2) WITH POISONING/EXPOSURE
    a) SITAGLIPTIN
    1) LACK OF EFFECT: In a randomized placebo-controlled crossover study, 79 healthy volunteers were give a single oral dose of 100 mg, 800 mg sitagliptin and placebo. Doses of 800 mg produced a mean increase in QTc of 8.0 msec which was not considered clinically significant. Peak plasma concentrations were 11-fold higher at 800 mg, as compared to peak concentrations at 100 mg (Prod Info JANUVIA(TM) oral tablets, 2006).
    B) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) LINAGLIPTIN: Hypertension has been reported with linagliptin monotherapy (Aletti & Cheng-Lai, 2012).
    C) CARDIOVASCULAR FINDING
    1) WITH THERAPEUTIC USE
    a) BLOOD PRESSURE READING: In a pilot study of non-diabetic volunteers with mild to moderate hypertension, sitagliptin produced a small, but statistically significant reduction in systolic BP (2 to 3 mmHg). It was also found to reduce BP by approximately 5 mmHg in a group of type 2 diabetic patients that presented with elevated systolic BP (greater than or equal to 130 mmHg). Vildagliptin was also found to reduce systolic and diastolic BP, but the findings were not statistically significant (Baetta & Corsini, 2011).
    b) SAXAGLIPTIN: In a post hoc, pooled analysis using the phase IIb/III data from 8 randomized trials comprising 4607 saxagliptin patients, there was no increased cardiovascular risk with saxagliptin therapy (Frederich et al, 2010). Studies with other agents are currently underway (Baetta & Corsini, 2011).
    c) LINAGLIPTIN: Hypertriglyceridemia was observed more frequently (2.4% vs 0% placebo) when linagliptin was used concomitantly with a sulfonylurea (Aletti & Cheng-Lai, 2012).

Genotoxicity

    A) These agents have not be found to be mutagenic or clastogenic (Prod Info ONGLYZA(TM) oral tablets, 2009; Prod Info JANUVIA(TM) oral tablets, 2006; Prod Info NESINA oral tablets, 2013).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) NASOPHARYNGITIS
    1) WITH THERAPEUTIC USE
    a) Nasopharyngitis has been reported with therapeutic use of these agents (Prod Info TRADJENTA(TM) oral tablets, 2011; Prod Info ONGLYZA(TM) oral tablets, 2009; Prod Info JANUVIA(TM) oral tablets, 2006; Aletti & Cheng-Lai, 2012).
    b) In two clinically-controlled trials of 806 patients, nasopharyngitis occurred in 5.2% (23/443) of patients treated with 100 mg sitagliptin alone, as compared to 3.3% (12/363) in the placebo group (Prod Info JANUVIA(TM) oral tablets, 2006; Raz et al, 2006).
    B) UPPER RESPIRATORY INFECTION
    1) WITH THERAPEUTIC USE
    a) Upper respiratory tract infections have been reported with therapeutic use of these agents (Prod Info ONGLYZA(TM) oral tablets, 2009; Prod Info JANUVIA(TM) oral tablets, 2006).
    b) In two clinically-controlled trials of 806 patients, upper respiratory infection occurred in 6.3% (11/175) of patients treated with 100 mg sitagliptin in combination with pioglitazone as compared to 3.4% (6/178) in the placebo group (Prod Info JANUVIA(TM) oral tablets, 2006).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) If coingested with other hypoglycemic agents, monitor blood glucose frequently. Monitor for clinical evidence of hypoglycemia (diaphoresis, tachycardia, tremor, change in mental status) following exposure with these agents.
    B) Obtain an ECG after large overdose. Clinically insignificant QTc prolongation has been reported at *8 times the therapeutic dose with sitagliptin; it has not been reported with saxagliptin.
    C) Serum drug levels are not widely available or clinically indicated following exposure.
    4.1.2) SERUM/BLOOD
    A) If coingested with other hypoglycemic agents in overdose, monitor blood glucose following exposure with these agents (Prod Info JANUVIA(R) oral tablets, 2010; Prod Info ONGLYZA(TM) oral tablets, 2009).
    1) At therapeutic sitagliptin doses, rates of hypoglycemia with other agents known to cause hypoglycemia (ie, metformin or piogliazone) was similar to patients taking placebo. However, the potential to cause hypoglycemia when used with sulfonylureas or insulin has not been adequately studied (Prod Info JANUVIA(R) oral tablets, 2010).
    B) Serum drug levels are not clinically indicated following exposure with these agents.
    4.1.4) OTHER
    A) OTHER
    1) Obtain an ECG after a large overdose. Clinically insignificant QTc prolongation has been reported at 8 times the therapeutic dose with sitagliptin. It has not been observed with saxagliptin.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Any adult who becomes hypoglycemic and all children with more than a minor ingestion should be admitted for observation. Patients with evidence of severe hypoglycemia or CNS effects should be admitted to an intensive care setting.
    6.3.1.2) HOME CRITERIA/ORAL
    A) An asymptomatic child with an inadvertent ingestion of a single dose can be monitored at home if a responsible adult is present. An asymptomatic adult or adolescent with an inadvertent ingestion of 1 to 2 tablets of sitagliptin, saxigliptin and linagliptin can likely be observed at home.
    B) CASE SERIES: A retrospective, observational case series of children, adolescents and adults with both intentional and unintentional exposure to sitagliptin, saxagliptin, or linagliptin resulted in no serious toxicity at doses up to 18 times the therapeutic dose for adults. Of the 62 cases, 40 were adults with 3 intentional self-harm exposures, 3 were adolescents (ages 10 to 18 years) and 19 were children (ages 0 to 9 years). Hypoglycemia did not develop in any patient and most were managed at home. Only one child developed symptoms. A 2-year-old boy was found with an open bottle of sitagliptin and one (100 mg) tablet was missing; one episode of emesis developed. He was safely managed at home with no other symptoms. A 1.5 year-old girl ingested an estimated 5.5 mg/kg of sitagliptin and was taken to the ER. A single dose of activated charcoal was given. An initial blood sugar was 93 mg/dL that later decreased to 73 mg/dL. The child was allowed to eat and was monitored overnight with no other symptoms. Two young boys both age 4 years, ingested 6.6 and 13.3 mg/kg of sitagliptin and were monitored for 1 to 2 days, respectively. Both boys were allowed to eat with no glucose supplements administered; no symptoms developed. All 3 adolescent patients ingested sitagliptin (dose range, 100 to 200 mg) and remained asymptomatic. Of the 37 unintentional adult cases, most exposures were due to sitagliptin (mean dose 179.5 mg; dose range, 50 to 400 mg). The average amount ingested for the other agents by adults was 11.6 mg (range, 10 to 15 mg) for saxigliptin and 10 mg for linagliptin. All adults with unintentional exposures remained asymptomatic and were managed at home. Of the 3 patients with self-harm intent, all were admitted for evaluation. A 27-year-old woman ingested 700 mg of sitagliptin and developed abdominal pain that resolved over 6 hours. A 70 year-old woman ingested 1800 mg of sitagliptin and developed no symptoms and was discharged to psychiatric care (Darracq et al, 2014).
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Contact a medical toxicologist or Poison Center for assistance in cases of severe poisonings or in whom the diagnosis is unclear. Patients with a deliberate self-harm ingestion should be evaluated by a mental health specialist.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate self-harm ingestion or coingestion of other hypoglycemic agents should be evaluated in a healthcare facility and monitored until symptoms resolve. Patients with hypoglycemia should be monitored until blood glucose is normal and symptoms have resolved. Patients may be discharged to home once symptoms have resolved and blood glucose or other laboratory studies are within normal limits and is cleared from a mental health standpoint.

Monitoring

    A) If coingested with other hypoglycemic agents, monitor blood glucose frequently. Monitor for clinical evidence of hypoglycemia (diaphoresis, tachycardia, tremor, change in mental status) following exposure with these agents.
    B) Obtain an ECG after large overdose. Clinically insignificant QTc prolongation has been reported at *8 times the therapeutic dose with sitagliptin; it has not been reported with saxagliptin.
    C) Serum drug levels are not widely available or clinically indicated following exposure.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) EMESIS/NOT INDICATED
    1) Emesis is not indicated following exposure.
    B) ACTIVATED CHARCOAL
    1) Activated charcoal may be considered following a significant ingestion if performed soon after exposure and the airway is protected.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive.
    B) MONITORING OF PATIENT
    1) Monitor for signs and symptoms of hypoglycemia (diaphoresis, palpitations, tremor, change in mentation).
    2) Monitor serial blood glucose in symptomatic patients or those who have taken these agents with another hypoglycemic agent.
    3) Monitor vital signs and obtain an ECG following a significant ingestion; clinically insignificant QTc prolongation has been reported at 8 times the therapeutic dose with sitagliptin. It has not been observed with saxagliptin.
    C) HYPOGLYCEMIA
    1) THERAPEUTIC USE: Dipeptidyl peptidase-4 (DPP-4) inhibitors produce very low rates of hypoglycemia with therapeutic use due in part to their glucose-dependent manner of their insulinotropic effect (Baetta & Corsini, 2011).
    2) OVERDOSE: Minimal data. Because DDP-4 inhibitors increase insulin release and suppress glucagon release in a glucose-dependent manner, they are not expected to cause significant hypoglycemia in normal subject unless coingested with other hypoglycemic agents.
    a) CASE REPORT: An elderly woman ingested 1700 mg sitagliptin. Her blood glucose was normal (124 mg/dL) 4 hours after ingestion, but she was treated with intravenous glucose (total 52 g) for approximately 10 hours and did not develop hypoglycemia (Furukawa et al, 2012).
    1) Following a significant ingestion, serial blood glucose monitoring is indicated. Treat with dextrose as necessary.
    D) GASTROINTESTINAL TRACT FINDING
    1) Monitor fluid status in patients following a significant exposure; antidiarrheal agents may be indicated. Treat with IV fluids, if significant fluid loss occurs.

Enhanced Elimination

    A) HEMODIALYSIS
    1) SITAGLIPTIN is not extensively bound to plasma proteins (38%), but has a moderately large volume of distribution (198 L). A limited amount of drug may be dialyzable in overdose (Prod Info JANUVIA(R) oral tablets, 2013).
    a) In clinical studies, 3 to 4 hours of hemodialysis removed 13.5% of a dose of sitagliptin (Prod Info JANUVIA(R) oral tablets, 2013).
    2) LINAGLIPTIN: Plasma protein binding is concentration-dependent and can vary from 70% to 99%. Extensively distributed in the tissues (Prod Info TRADJENTA(R) oral tablets, 2013). Hemodialysis is not anticipated to be beneficial.
    3) SAXAGLIPTIN: It is not extensively bound to plasma proteins. Saxagliptin and its active metabolite can be removed by hemodialysis (23% of a dose over 4 hours) (Prod Info ONGLYZA oral tablets, 2013).

Range Of Toxicity

Summary

    A) TOXICITY: SITAGLIPTIN: Limited data. An elderly woman intentionally ingested 1700 mg of sitagliptin and was treated with intravenous glucose; hypoglycemia did not develop. Another elderly woman intentionally ingested 1800 mg and was given a regular diet; no symptoms developed. A dose of 800 mg did not cause toxic effects in healthy adults. Doses above 800 mg have not been studied. LINAGLIPTIN: Limited data. Single doses of up to 600 mg (120 times the recommended daily dose) administered to healthy subjects resulted in no adverse events. SAXAGLIPTIN: At doses of up to 400 mg daily (80 times the maximum recommended human dose) for 2 weeks, no significant adverse events occurred in healthy subjects.
    B) THERAPEUTIC DOSE: SITAGLIPTIN: 100 mg orally once daily as a monotherapy or in combination with metformin or PPAR(gamma) agonist (eg, thiazolidinediones). LINAGLIPTIN: Adult: 5 mg orally once daily. SAXAGLIPTIN: The recommended dose is 2.5 to 5 mg once daily. VILDAGLIPTIN/METFORMIN: The recommended daily dose is 100 mg vildagliptin and 2000 mg metformin.

Therapeutic Dose

    7.2.1) ADULT
    A) SITAGLIPTIN: 100 mg orally once daily as a monotherapy or in combination with metformin or PPAR(gamma) agonist (eg, thiazolidinediones) (Prod Info JANUVIA(TM) oral tablets, 2006).
    B) ALOGLIPTIN: 25 mg ORALLY once daily with or without food (Prod Info NESINA oral tablets, 2013).
    C) ALOGLIPTIN/METFORMIN: Initial dosage should be individualized based on patient's current regimen; to be taken orally twice daily with meals. MAXIMUM DOSE: Alogliptin 25 mg and metformin 2000 mg per day (Prod Info KAZANO oral tablets, 2013).
    D) ALOGLIPTIN BENZOATE/PIOGLITAZONE HYDROCHLORIDE: Initial dose, alogliptin 25 mg/pioglitazone 15 mg OR alogliptin 25 mg/pioglitazone 30 mg orally once daily; previously receiving pioglitazone; alogliptin 25 mg/pioglitazone 15 mg OR alogliptin 25 mg/pioglitazone 30 mg OR alogliptin 25 mg/pioglitazone 45 mg orally once daily with initial dose based on current therapy; maintenance dose, orally once daily based on glycemic response (HbA1c). MAXIMUM DOSE: Alogliptin 25 mg/pioglitazone 45 mg orally once daily (Prod Info OSENI oral tablets, 2013).
    E) EMPAGLIFLOZIN/LINAGLIPTIN: Initial dose: Empagliflozin 10 mg/linagliptin 5 mg ORALLY once daily in the morning; may be increased to empagliflozin 25 mg/linagliptin 5 mg ORALLY once daily (Prod Info GLYXAMBI(R) oral tablets, 2015).
    F) LINAGLIPTIN: 5 mg orally once daily (Prod Info TRADJENTA(TM) oral tablets, 2011).
    G) LINAGLIPTIN/METFORMIN: Initial dose: Linagliptin 2.5 mg/metformin 500 mg orally twice daily with meals; maintenance dose, individualize based on efficacy/tolerability; MAXIMUM DOSE: 2.5 mg linagliptin/1000 mg metformin twice daily (Prod Info JENTADUETO(TM) oral tablets, 2012).
    H) SAXAGLIPTIN: 2.5 to 5 mg orally once daily (Prod Info ONGLYZA(TM) oral tablets, 2009).
    I) VILDAGLIPTIN/METFORMIN: Initial dose: Vildagliptin 50 mg/metformin 850 mg or 50 mg/1000 mg orally twice daily with meals (morning and evenings). The recommended daily dose is 100 mg vildagliptin and 2000 mg metformin hydrochloride. MAXIMUM DOSE: Doses higher than 100 mg vildagliptin daily are not recommended (Prod Info Eucreas oral tablets, 2012).
    7.2.2) PEDIATRIC
    A) Safety and effectiveness have not been established in pediatric patients for these agents (Prod Info GLYXAMBI(R) oral tablets, 2015; Prod Info Eucreas oral tablets, 2012; Prod Info JENTADUETO(TM) oral tablets, 2012; Prod Info JANUVIA(TM) oral tablets, 2006; Prod Info TRADJENTA(TM) oral tablets, 2011; Prod Info ONGLYZA(TM) oral tablets, 2009).

Maximum Tolerated Exposure

    A) SUMMARY
    1) CASE SERIES: In a retrospective review of a state poison control system database, single-case exposures to immediate release sitagliptin, saxagliptin, and linagliptin from 2006 to 2012 were identified. Of the 197 cases, only 62 cases were included. Of the 62 cases, 40 were adults with 3 intentional self-harm exposures, 3 were adolescents (ages 10 to 18 years) and 19 were children (ages 0 to 9 years). Hypoglycemia did not develop in any patient and most were managed at home. Only one child developed symptoms. A 2-year-old boy was found with an open bottle of sitagliptin and one (100 mg) tablet was missing; one episode of emesis developed. He was safely managed at home with no other symptoms. A 1.5 year-old girl ingested an estimated 5.5 mg/kg of sitagliptin and was taken to the ER. A single dose of activated charcoal was given. An initial blood sugar was 93 mg/dL that later decreased to 73 mg/dL. The child was given a meal and monitored overnight with no other symptoms. Two young boys both age 4 years, ingested 6.6 and 13.3 mg/kg of sitagliptin and were monitored for 1 to 2 days, respectively. Both boys were allowed to eat with no glucose supplements administered; no symptoms developed. All 3 adolescent patients ingested sitagliptin (dose range, 100 to 200 mg) and remained asymptomatic. Of the 37 unintentional adult cases, most exposures were due to sitagliptin (dose range, 50 to 400 mg). The average amount ingested for the other agents by adults was 11.6 mg (range 10 to 15 mg) for saxigliptin and 10 mg for linagliptin. All adults with unintentional exposures remained asymptomatic and were managed at home. Of the 3 patients with self-harm intent, all were admitted for evaluation. A 27-year-old woman ingested 700 mg of sitagliptin and developed abdominal pain that resolved over 6 hours. A 70 year-old woman ingested 1800 mg of sitagliptin and developed no symptoms and was discharged to psychiatric care (Darracq et al, 2014).
    B) CASE REPORTS
    1) SITAGLIPTIN: Limited data. In one clinical-controlled trial in healthy subjects, doses of 800 mg produced mean increases in QTc of 8.0 msec which were not considered clinically significant. No toxic effects were observed at this dose. Doses of above 800 mg have not been studied (Prod Info JANUVIA(TM) oral tablets, 2006).
    a) CASE REPORT: An 86-year-old woman with type 2 diabetes mellitus intentionally ingested 1700 mg (34 50 mg tablets) of sitagliptin. Upon admission 4 hours after ingestion, she was alert with a blood glucose of 124 mg/dL and received a total of 52 g of glucose over 10 hours to prevent hypoglycemia. By the following day, the patient was started on an oral diet and resumed sitagliptin (50 mg) therapy. After 3 days of monitoring, the patient remained stable and hypoglycemia was not observed. The plasma concentration peaked at 3793 nM (4.5 times higher the normal value) (Furukawa et al, 2012).
    2) LINAGLIPTIN: Limited data. During clinical trials, healthy subjects received single doses of up to 600 mg (120 times the recommended daily dose) and developed no adverse events (Prod Info TRADJENTA(TM) oral tablets, 2011).
    3) SAXAGLIPTIN: At doses of up to 400 mg daily (80 times the maximum recommended human dose) for 2 weeks, no significant adverse events occurred in healthy subjects (Prod Info ONGLYZA(TM) oral tablets, 2009).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) LINAGLIPTIN: Following oral administration of a single linagliptin 5 mg dose, the mean Cmax in healthy subjects was 8.9 nanomole/L. The plasma steady-state Cmax (achieved by the 3rd dose) is approximately 1.3 times greater than the Cmax observed following the first dose (Prod Info TRADJENTA(TM) oral tablets, 2011).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) SUMMARY: These agents enhance glucose-dependent insulin secretion from beta cells and glucose-dependent suppression of glucagon release from pancreatic alpha cells, respectively. This is possible by mimicking the glucoregulatory effects of endogenous glucagon-like peptide-1 (GLP-1) (GLP-1 receptor agonists or incretin mimetics) or enhancing endogenous GLP-1 concentrations (DPP-4 inhibitors or incretin enhancers) (Baetta & Corsini, 2011).
    B) SITAGLIPTIN: Dipeptidyl peptidase IV (DDP4) inhibitors act by inhibiting the inactivation of incretins, particularly glucagon-like-peptide 1 (GLP-1). Incretins stimulate postprandial insulin secretion, but are rapidly inactivated by DDP4. Inhibition of DDP-4 prolongs the half life of GLP-1, and promotes glucose dependent synthesis and release of insulin (Herman et al, 2005). Saxagliptin is also a DPP4 inhibitor that slows the inactivation of the incretin hormones, which is capable of reducing fasting and postprandial glucose concentrations in patients with type 2 diabetes mellitus (Prod Info ONGLYZA(TM) oral tablets, 2009).
    C) LINAGLIPTIN: It is a dipeptidyl peptidase-4 (DPP-4) enzyme inhibitor, which exerts its activity in patients with type 2 diabetes mellitus by protecting the endogenous incretin hormones and enhancing their actions. Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are incretin hormones released throughout the day at a low basal level, and at increased levels in response to meal intake, to maintain glucose homeostasis. However, GLP and GLP-1 are metabolized rapidly by DPP-4 enzyme, resulting in loss of insulinotropic effects. Linagliptin inhibits the degradation of incretin hormones by DPP-4, thereby increasing insulin release in a glucose-dependent manner and decreasing the levels of circulating glucagon (Prod Info TRADJENTA(TM) oral tablets, 2011).

Toxicologic Mechanism

    A) Because dipeptidyl peptidase 4 inhibitors increase insulin release and suppress glucagon release in a glucose-dependent manner, they are not expected to cause significant hypoglycemia in normal subject unless coingested with other hypoglycemic agents.

Physicochemical

Physical Characteristics

    A) ALOGLIPTIN BENZOATE is a white to off-white crystalline powder that is soluble in dimethylsulfoxide; sparingly soluble in water and methanol; slightly soluble in ethanol; and very slightly soluble in isopropyl acetate and octanol (Prod Info NESINA oral tablets, 2013).
    B) LINAGLIPTIN is a white to yellowish, not or only slightly hygroscopic solid substance that is very slightly soluble in water (0.9 mg/mL), in acetone (approximately 1 mg/mL), and in isopropanol (less than 1 mg/mL); sparingly soluble in ethanol (approximately 10 mg/mL); and soluble in methanol (approximately 60 mg/mL) (Prod Info TRADJENTA(TM) oral tablets, 2011).
    C) SAXAGLIPTIN MONOHYDRATE is a white to light yellow or light brown, nonhygroscopic crystalline powder that is soluble in methanol, ethanol, isopropyl alcohol, acetonitrile, acetone, and polyethylene glycol 400 (PEG 400); slightly soluble in ethyl acetate; and sparingly soluble in water (at 21 to 27 degrees C) (Prod Info KOMBIGLYZE(TM) XR extended-release oral tablets, 2010).
    D) SITAGLIPTIN PHOSPHATE MONOHYDRATE is a white to off-white, crystalline, nonhygroscopic powder that is soluble in water and N,N-dimethyl formamide; slightly soluble in methanol; very slightly soluble in ethanol, acetone, and acetonitrile; and insoluble in isopropanol and isopropyl acetate (Prod Info JANUMET(R) oral tablets, 2010).

Molecular Weight

    A) ALOGLIPTIN BENZOATE: 461.51 daltons (Prod Info NESINA oral tablets, 2013)
    B) LINAGLIPTIN: 472.54 g/mol (Prod Info TRADJENTA(TM) oral tablets, 2011)
    C) SAXAGLIPTIN MONOHYDRATE: 333.43 (Prod Info KOMBIGLYZE(TM) XR extended-release oral tablets, 2010)
    D) SITAGLIPTIN PHOSPHATE MONOHYDRATE: 523.32 (Prod Info JANUMET(R) oral tablets, 2010)

References

General Bibliography

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    19) Product Information: Eucreas oral tablets, vildagliptin metformin HCl oral tablets. Novartis Europharm Limited (per EMA), Horsham, West Sussex, United Kingdom, 2012.
    20) Product Information: GLYXAMBI(R) oral tablets, empagliflozin linagliptin oral tablets. Boehringer Ingelheim Pharmaceuticals Inc. (per manufacturer), Ridgefield, CT, 2015.
    21) Product Information: JANUMET(R) oral tablets, sitagliptin/metformin HCl oral tablets. Merck Sharp & Dohme Corp, Whitehouse Station, NJ, 2010.
    22) Product Information: JANUMET(TM) oral tablets, sitagliptin, metformin hcl oral tablets. Merck & Co,Inc, Whitehouse Station, NJ, 2007.
    23) Product Information: JANUVIA(R) oral tablets, sitagliptin oral tablets. Merck & Co., Inc., Whitehouse Station, NJ, 2010.
    24) Product Information: JANUVIA(R) oral tablets, sitagliptin oral tablets. Merck Sharp & Dohme Corp. (per FDA), Whitehouse Station, NJ, 2013.
    25) Product Information: JANUVIA(R) oral tablets, sitagliptin oral tablets. Merck Sharp & Dohme Corp. (per FDA), Whitehouse, NJ, 2012.
    26) Product Information: JANUVIA(TM) oral tablets, sitagliptin phosphate oral tablets. Merck & Co,Inc, Whitehouse Station, NJ, 2006.
    27) Product Information: JENTADUETO(R) XR extended-release oral tablets, linagliptin and metformin hydrochloride extended-release oral tablets. Boehringer Ingelheim Pharmaceuticals (per manufactuer), Ridgefield, CT, 2016.
    28) Product Information: JENTADUETO(TM) oral tablets, linagliptin and metformin hydrochloride oral tablets. Boehringer Ingelheim Pharmaceuticals, Inc. (per manufacturer), Ridgefield, CT, 2012.
    29) Product Information: JUVISYNC(TM) oral tablets, sitagliptin simvastatin oral tablets. Merck Sharp & Dohme Corp. (per FDA), Whitehouse Station, NJ, 2011.
    30) Product Information: KAZANO oral tablets, alogliptin metformin HCl oral tablets. Takeda Pharmaceuticals America, Inc. (per manufacturer), Deerfield, IL, 2013.
    31) Product Information: KOMBIGLYZE(TM) XR extended-release oral tablets, saxagliptin and metformin hcl extended-release oral tablets. Bristol-Myers Squibb Company, Princeton, NJ, 2010.
    32) Product Information: NESINA oral tablets, alogliptin oral tablets. Takeda Pharmaceuticals America, Inc. (per manufacturer), Deerfield, IL, 2013.
    33) Product Information: ONGLYZA oral tablets, saxagliptin oral tablets. Bristol-Myers Squibb Company and AstraZeneca Pharmaceuticals LP (per manufacturer), Princeton, NJ, 2013.
    34) Product Information: ONGLYZA(TM) oral tablets, saxagliptin oral tablets. Bristol-Myers Squibb Company and AstraZeneca Pharmaceuticals LP, Princeton, NJ, 2011.
    35) Product Information: ONGLYZA(TM) oral tablets, saxagliptin oral tablets. Bristol-Myers Squibb, Princeton, NJ, 2009.
    36) Product Information: OSENI oral tablets, alogliptin pioglitazone oral tablets. Takeda Pharmaceuticals America, Inc. (per manufacturer), Deerfield, IL, 2013.
    37) Product Information: TRADJENTA(R) oral tablets, linagliptin oral tablets. Boehringer Ingelheim Pharmaceuticals, Inc. (per Manufacturer), Ridgefield, CT, 2013.
    38) Product Information: TRADJENTA(TM) oral tablets, linagliptin oral tablets. Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT, 2011.
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