Onglyza Information
Onglyza (Saxagliptin hydrochloride) Indications And Usage
Onglyza (Saxagliptin hydrochloride) should not be used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis, as it would
not be effective in these settings.
Onglyza (Saxagliptin hydrochloride) has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at an increased risk for the development of pancreatitis while using Onglyza (Saxagliptin hydrochloride) . [See .]
Onglyza (Saxagliptin hydrochloride) Dosage And Administration
The recommended dose of Onglyza (Saxagliptin hydrochloride) is
2.5 mg or 5 mg once daily taken regardless of meals.
Onglyza (Saxagliptin hydrochloride) tablets must not be split or cut.
No dosage adjustment for Onglyza (Saxagliptin hydrochloride)
is recommended for patients with mild renal impairment (creatinine clearance
[CrCl] >50 mL/min).
The dose of Onglyza (Saxagliptin hydrochloride) is 2.5 mg once
daily for patients with moderate or severe renal impairment, or with end-stage
renal disease (ESRD) requiring hemodialysis (creatinine clearance [CrCl] ≤50 mL/min) [see and ].
Onglyza (Saxagliptin hydrochloride) should be administered following hemodialysis. Onglyza (Saxagliptin hydrochloride) has not been
studied in patients undergoing peritoneal dialysis.
Because
the dose of Onglyza (Saxagliptin hydrochloride) should be limited to 2.5 mg based upon renal function,
assessment of renal function is recommended prior to initiation of Onglyza (Saxagliptin hydrochloride)
and periodically thereafter. Renal function can be estimated from serum creatinine
using the Cockcroft-Gault formula or Modification of Diet in Renal Disease
formula. [See .]
When Onglyza (Saxagliptin hydrochloride) is used in combination with an insulin secretagogue (e.g., sulfonylurea) or with insulin, a lower dose of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia. [See .]
Onglyza (Saxagliptin hydrochloride) Contraindications
History of a serious hypersensitivity reaction to Onglyza (Saxagliptin hydrochloride) , such as anaphylaxis, angioedema, or exfoliative skin conditions. [See and .]
Onglyza (Saxagliptin hydrochloride) Warnings And Precautions
There have been postmarketing reports of acute pancreatitis in patients taking Onglyza (Saxagliptin hydrochloride) . After initiation of Onglyza (Saxagliptin hydrochloride) , patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, Onglyza (Saxagliptin hydrochloride) 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 (Saxagliptin hydrochloride) .
There have been postmarketing reports of serious hypersensitivity reactions in patients treated with Onglyza (Saxagliptin hydrochloride) . 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 (Saxagliptin hydrochloride) , with some reports occurring after the first dose. If a serious hypersensitivity reaction is suspected, discontinue Onglyza (Saxagliptin hydrochloride) , assess for other potential causes for the event, and institute alternative treatment for diabetes. [See .]
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 (Saxagliptin hydrochloride) .
Onglyza (Saxagliptin hydrochloride) Use In Specific Populations
In the six, double-blind, controlled
clinical safety and efficacy trials of Onglyza (Saxagliptin hydrochloride) , 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 and .]
Onglyza (Saxagliptin hydrochloride) Overdosage
In a controlled clinical trial, once-daily,
orally-administered Onglyza (Saxagliptin hydrochloride) in healthy subjects at doses up to 400 mg daily
for 2 weeks (80 times the MRHD) had no dose-related clinical adverse reactions
and no clinically meaningful effect on QTc interval or heart rate.
In
the event of an overdose, appropriate supportive treatment should be initiated
as dictated by the patient’s clinical status. Saxagliptin and its active metabolite
are removed by hemodialysis (23% of dose over 4 hours).
Onglyza (Saxagliptin hydrochloride) Description
Saxagliptin is an orally-active inhibitor
of the DPP4 enzyme.
Saxagliptin monohydrate is described
chemically as (1,3,5)-2-[(2)-2-Amino-2-(3-hydroxytricyclo[3.3.1.1]dec-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile,
monohydrate or (1,3,5)-2-[(2)-2-Amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrate. The empirical formula is CHNO•HO and the molecular weight
is 333.43. The structural formula is:
Saxagliptin monohydrate
is a white to light yellow or light brown, non-hygroscopic, crystalline powder.
It is sparingly soluble in water at 24°C ± 3°C, slightly soluble in ethyl
acetate, and soluble in methanol, ethanol, isopropyl alcohol, acetonitrile,
acetone, and polyethylene glycol 400 (PEG 400).
Each
film-coated tablet of Onglyza (Saxagliptin hydrochloride) for oral use contains either 2.79 mg saxagliptin
hydrochloride (anhydrous) equivalent to 2.5 mg saxagliptin or 5.58 mg saxagliptin
hydrochloride (anhydrous) equivalent to 5 mg saxagliptin and the following
inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose
sodium, and magnesium stearate. In addition, the film coating contains the
following inactive ingredients: polyvinyl alcohol, polyethylene glycol, titanium
dioxide, talc, and iron oxides.
Onglyza (Saxagliptin hydrochloride) Clinical Pharmacology
The pharmacokinetics of saxagliptin
and its active metabolite, 5-hydroxy saxagliptin were similar in healthy subjects
and in patients with type 2 diabetes mellitus. The Cand
AUC values of saxagliptin and its active metabolite increased proportionally
in the 2.5 to 400 mg dose range. Following a 5 mg single oral dose of saxagliptin
to healthy subjects, the mean plasma AUC values for saxagliptin and its active
metabolite were 78 ng•h/mL and 214 ng•h/mL, respectively. The corresponding
plasma C values were 24 ng/mL and 47 ng/mL, respectively.
The average variability (%CV) for AUC and C for
both saxagliptin and its active metabolite was less than 25%.
No
appreciable accumulation of either saxagliptin or its active metabolite was
observed with repeated once-daily dosing at any dose level. No dose- and time-dependence
were observed in the clearance of saxagliptin and its active metabolite over
14 days of once-daily dosing with saxagliptin at doses ranging from 2.5 to
400 mg.
Onglyza (Saxagliptin hydrochloride) Nonclinical Toxicology
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 Ames
bacterial assay, an cytogenetics assay in primary
human lymphocytes, an oral micronucleus assay in
rats, an oral DNA repair study in rats, and an oral / cytogenetics study in rat peripheral
blood lymphocytes. The active metabolite was not mutagenic in an Ames bacterial assay.
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.
Onglyza (Saxagliptin hydrochloride) Clinical Studies
Onglyza (Saxagliptin hydrochloride) has been studied as monotherapy
and in combination with metformin, glyburide, and thiazolidinedione (pioglitazone
and rosiglitazone) therapy.
A total of 4148 patients with type 2 diabetes
mellitus were randomized in six, double-blind, controlled clinical trials
conducted to evaluate the safety and glycemic efficacy of Onglyza (Saxagliptin hydrochloride) . A total
of 3021 patients in these trials were treated with Onglyza (Saxagliptin hydrochloride) . In these trials,
the mean age was 54 years, and 71% of patients were Caucasian, 16% were Asian,
4% were black, and 9% were of other racial groups. An additional 423 patients,
including 315 who received Onglyza (Saxagliptin hydrochloride) , participated in a placebo-controlled,
dose-ranging study of 6 to 12 weeks in duration.
In
these six, double-blind trials, Onglyza (Saxagliptin hydrochloride) was evaluated at doses of 2.5 mg and
5 mg once daily. Three of these trials also evaluated a saxagliptin dose of
10 mg daily. The 10 mg daily dose of saxagliptin did not provide greater efficacy
than the 5 mg daily dose. Treatment with Onglyza (Saxagliptin hydrochloride) at all doses produced clinically
relevant and statistically significant improvements in hemoglobin A1c (A1C),
fasting plasma glucose (FPG), and 2-hour postprandial glucose (PPG) following
a standard oral glucose tolerance test (OGTT), compared to control. Reductions
in A1C were seen across subgroups including gender, age, race, and baseline
BMI.
Onglyza (Saxagliptin hydrochloride) was not associated with significant changes
from baseline in body weight or fasting serum lipids compared to placebo.
Onglyza (Saxagliptin hydrochloride) has also been evaluated in three additional trials in patients with type 2 diabetes: an active-controlled trial comparing add-on therapy with Onglyza (Saxagliptin hydrochloride) to glipizide in 858 patients inadequately controlled on metformin alone, a trial comparing Onglyza (Saxagliptin hydrochloride) to placebo in 455 patients inadequately controlled on insulin alone or on insulin in combination with metformin, and a trial comparing Onglyza (Saxagliptin hydrochloride) to placebo in 170 patients with type 2 diabetes and moderate or severe renal impairment or ESRD.
Onglyza (Saxagliptin hydrochloride) Patient Counseling Information
See FDA-approved Medication Guide.
Patients should be informed of the
potential risks and benefits of Onglyza (Saxagliptin hydrochloride) 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 (Saxagliptin hydrochloride) . Before initiating Onglyza (Saxagliptin hydrochloride) , 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 (Saxagliptin hydrochloride) and contact their healthcare provider if persistent severe abdominal pain occurs [see ].
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 (Saxagliptin hydrochloride) . 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 (Saxagliptin hydrochloride) and seek medical advice promptly.
Patients should be informed that if they miss a dose of Onglyza (Saxagliptin hydrochloride) 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.
Healthcare providers should instruct their patients to read the Medication Guide before starting Onglyza (Saxagliptin hydrochloride) 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 that Onglyza (Saxagliptin hydrochloride) tablets must not be split or cut.
Onglyza (Saxagliptin hydrochloride)
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