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There have been postmarketing reports of acute pancreatitis in patients taking ONGLYZA. After initiation of ONGLYZA, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, ONGLYZA should promptly be discontinued and appropriate management should be initiated. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using ONGLYZA.
Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin
When ONGLYZA was used in combination with a sulfonylurea or with insulin, medications known to cause hypoglycemia, the incidence of confirmed hypoglycemia was increased over that of placebo used in combination with a sulfonylurea or with insulin. [See ADVERSE REACTIONS] Therefore, a lower dose of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia when used in combination with ONGLYZA. [See DOSAGE AND ADMINISTRATION.]
There have been postmarketing reports of serious hypersensitivity reactions in patients treated with ONGLYZA. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred within the first 3 months after initiation of treatment with ONGLYZA, with some reports occurring after the first dose. If a serious hypersensitivity reaction is suspected, discontinue ONGLYZA, assess for other potential causes for the event, and institute alternative treatment for diabetes. [See ADVERSE REACTIONS.]
Use caution in a patient with a history of angioedema to another dipeptidyl peptidase-4 (DPP4) inhibitor because it is unknown whether such patients will be predisposed to angioedema with ONGLYZA.
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with ONGLYZA or any other antidiabetic drug.
Patient Counseling Information
See FDA-approved patient labeling (Medication Guide).
Healthcare providers should instruct their patients to read the Medication Guide before starting ONGLYZA therapy and to reread it each time the prescription is renewed. Patients should be instructed to inform their healthcare provider if they develop any unusual symptom or if any existing symptom persists or worsens.
Patients should be informed of the potential risks and benefits of ONGLYZA and of alternative modes of therapy. Patients should also be informed about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and A1C testing, recognition and management of hypoglycemia and hyperglycemia, and assessment of diabetes complications. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be advised to seek medical advice promptly.
Patients should be informed that acute pancreatitis has been reported during postmarketing use of ONGLYZA. Before initiating ONGLYZA, patients should be questioned about other risk factors for pancreatitis, such as a history of pancreatitis, alcoholism, gallstones, or hypertriglyceridemia. Patients should also be informed that persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Patients should be instructed to promptly discontinue ONGLYZA and contact their healthcare provider if persistent severe abdominal pain occurs [see WARNINGS AND PRECAUTIONS].
Patients should be informed that serious allergic (hypersensitivity) reactions, such as angioedema, anaphylaxis, and exfoliative skin conditions, have been reported during postmarketing use of ONGLYZA. If symptoms of these allergic reactions (such as rash, skin flaking or peeling, urticaria, swelling of the skin, or swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing) occur, patients must stop taking ONGLYZA and seek medical advice promptly.
Patients should be informed that if they miss a dose of ONGLYZA they should take the next dose as prescribed, unless otherwise instructed by their healthcare provider. Patients should be instructed not to take an extra dose the next day.
Patients should be informed that ONGLYZA tablets must not be split or cut.
Patients should be informed that response to all diabetic therapies should be monitored by periodic measurements of blood glucose and A1C, with a goal of decreasing these levels toward the normal range. A1C is especially useful for evaluating long-term glycemic control. Patients should be informed of the potential need to adjust their dose based on changes in renal function tests over time.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Saxagliptin did not induce tumors in either mice (50, 250, and 600 mg/kg) or rats (25, 75, 150, and 300 mg/kg) at the highest doses evaluated. The highest doses evaluated in mice were equivalent to approximately 870 (males) and 1165 (females) times the human exposure at the MRHD of 5 mg/day. In rats, exposures were approximately 355 (males) and 2217 (females) times the MRHD.
Saxagliptin was not mutagenic or clastogenic with or without metabolic activation in an in vitro Ames bacterial assay, an in vitro cytogenetics assay in primary human lymphocytes, an in vivo oral micronucleus assay in rats, an in vivo oral DNA repair study in rats, and an oral in vivo/in vitro cytogenetics study in rat peripheral blood lymphocytes. The active metabolite was not mutagenic in an in vitro Ames bacterial assay.
Impairment of Fertility
In a rat fertility study, males were treated with oral gavage doses for 2 weeks prior to mating, during mating, and up to scheduled termination (approximately 4 weeks total) and females were treated with oral gavage doses for 2 weeks prior to mating through gestation day 7. No adverse effects on fertility were observed at exposures of approximately 603 (males) and 776 (females) times the MRHD. Higher doses that elicited maternal toxicity also increased fetal resorptions (approximately 2069 and 6138 times the MRHD). Additional effects on estrous cycling, fertility, ovulation, and implantation were observed at approximately 6138 times the MRHD.
Use In Specific Populations
Pregnancy Category B
There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, ONGLYZA, like other antidiabetic medications, should be used during pregnancy only if clearly needed.
Saxagliptin was not teratogenic at any dose tested when administered to pregnant rats and rabbits during periods of organogenesis. Incomplete ossification of the pelvis, a form of developmental delay, occurred in rats at a dose of 240 mg/kg, or approximately 1503 and 66 times human exposure to saxagliptin and the active metabolite, respectively, at the maximum recommended human dose (MRHD) of 5 mg. Maternal toxicity and reduced fetal body weights were observed at 7986 and 328 times the human exposure at the MRHD for saxagliptin and the active metabolite, respectively. Minor skeletal variations in rabbits occurred at a maternally toxic dose of 200 mg/kg, or approximately 1432 and 992 times the MRHD.
Coadministration of saxagliptin and metformin, to pregnant rats and rabbits during the period of organogenesis, was neither embryolethal nor teratogenic in either species when tested at doses yielding systemic exposures (AUC) up to 100 and 10 times the MRHD (saxagliptin 5 mg and metformin 2000 mg), respectively, in rats; and 249 and 1.1 times the MRHDs in rabbits. In rats, minor developmental toxicity was limited to an increased incidence of wavy ribs; associated maternal toxicity was limited to weight decrements of 11% to 17% over the course of the study, and related reductions in maternal food consumption. In rabbits, coadministration was poorly tolerated in a subset of mothers (12 of 30), resulting in death, moribundity, or abortion. However, among surviving mothers with evaluable litters, maternal toxicity was limited to marginal reductions in body weight over the course of gestation days 21 to 29; and associated developmental toxicity in these litters was limited to fetal body weight decrements of 7%, and a low incidence of delayed ossification of the fetal hyoid.
Saxagliptin administered to female rats from gestation day 6 to lactation day 20 resulted in decreased body weights in male and female offspring only at maternally toxic doses (exposures ≥ 1629 and 53 times saxagliptin and its active metabolite at the MRHD). No functional or behavioral toxicity was observed in offspring of rats administered saxagliptin at any dose.
Saxagliptin crosses the placenta into the fetus following dosing in pregnant rats.
Saxagliptin is secreted in the milk of lactating rats at approximately a 1:1 ratio with plasma drug concentrations. It is not known whether saxagliptin is secreted in human milk. Because many drugs are secreted in human milk, caution should be exercised when ONGLYZA is administered to a nursing woman.
Safety and effectiveness of ONGLYZA in pediatric patients under 18 years of age have not been established. Additionally, studies characterizing the pharmacokinetics of ONGLYZA in pediatric patients have not been performed.
In the six, double-blind, controlled clinical safety and efficacy trials of ONGLYZA, 634 (15.3%) of the 4148 randomized patients were 65 years and over, and 59 (1.4%) patients were 75 years and over. No overall differences in safety or effectiveness were observed between patients ≥ 65 years old and the younger patients. While this clinical experience has not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.
Saxagliptin and its active metabolite are eliminated in part by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in the elderly based on renal function. [See DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]
Last reviewed on RxList: 6/13/2013
This monograph has been modified to include the generic and brand name in many instances.
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