Onglyza

Pregnancy

Limited available data in pregnant women are not sufficient to determine drug-associated risk for major birth defects and miscarriage; published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk

No adverse developmental effects independent of maternal toxicity observed when saxagliptin and metformin were administered separately or in combination to pregnant rats and rabbits during period of organogenesis

Poorly controlled diabetes in pregnancy increases maternal risk for diabetic ketoacidosis, pre- eclampsia, spontaneous abortions, preterm delivery, stillbirth and delivery complications. also increases fetal risk for major malformations and macrosomia related morbidity

Lactation

There is no information regarding presence of metformin or alogliptin in human milk, effects on breastfed infant, or effects on milk production; limited published studies report that metformin is present in human milk; however, there is insufficient information to determine effects of metformin on breastfed infant and no available information on effects of metformin on milk production; the developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on breastfed infant from therapy or from underlying maternal condition

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

Onglyza is a prescription medication used along with diet and exercise to treat type 2 diabetes. Onglyza belongs to a group of drugs called dipeptidyl peptidase-4 (DPP-4) inhibitors and works by increasing the amount of insulin made by the body after meals and by decreasing the amount of glucose produced by the liver.

This medication comes in tablet form and is taken by mouth. It is usually taken once daily, with or without food. Do not split or cut Onglyza tablets. Swallow the tablets whole.

Common side effects of Onglyza includes upper respiratory tract infection, urinary tract infection, and headache.

Appropriate studies have not been performed on the relationship of age to the effects of saxagliptin in the pediatric population. Safety and efficacy have not been established.

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  • For Type 2 diabetes:
    • Adults—2.5 or 5 milligrams (mg) once a day.
    • Children—Use and dose must be determined by your doctor.

Take the missed dose as soon as you remember (be sure to take the medicine with food if your doctor has instructed you to). Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Get emergency medical help if you have signs of an allergic reaction: hives, a purple or red skin rash that spreads and causes blistering and peeling; difficulty breathing; swelling of your face, lips, tongue, or throat.

Stop taking saxagliptin and call your doctor right away if you have symptoms of pancreatitis: severe pain in your upper stomach spreading to your back, nausea and vomiting, loss of appetite, or fast heartbeats.

Call your doctor at once if you have:

• severe or ongoing pain in your joints;

• pain or burning when you urinate; or

• heart problems--shortness of breath (even while lying down), feeling weak or tired, rapid weight gain, swelling (especially in your feet, legs, or midsection.

Common side effects may include:

• runny or stuffy nose, sore throat, cough; or

• headache.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Other drugs may increase or decrease the effects of saxagliptin on lowering your blood sugar. Tell your doctor about all medications you use. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

• Inhibits dipeptidyl peptidase-4 (DPP-4), an enzyme that inactivates incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).1 8 9 25 26

• More selective for inhibition of DPP-4 than for DPP-8 or DDP-9.14

• Increases circulating concentrations of GIP and GLP-1 in a glucose-dependent manner.1 8

• GIP and GLP-1 stimulate insulin synthesis and release from pancreatic β-cells in a glucose-dependent manner (i.e., when glucose concentrations are normal or elevated).1 8 9 25

• GLP-1 also decreases glucagon secretion from pancreatic α-cells in a glucose-dependent manner, leading to reduced hepatic glucose production.1 9 25

• Lowers fasting plasma glucose concentrations and reduces glucose excursions following glucose load or meal in patients with type 2 diabetes mellitus.1 25

• Saxagliptin usually not associated with hypoglycemia or substantial changes in body weight.2 3 4 10 25

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Anxiety
• bladder pain
• bloating or swelling of the face, arms, hands, lower legs, or feet
• bloody or cloudy urine
• blurred vision
• body aches or pain
• chills
• cold sweats
• confusion
• cool, pale skin
• cough
• depression
• difficult, burning, or painful urination
• difficulty with breathing
• dizziness
• ear congestion
• fast heartbeat
• fever
• frequent urge to urinate
• headache
• increased hunger
• loss of voice
• lower back or side pain
• nasal congestion
• nausea
• nightmares
• rapid weight gain
• runny nose
• seizures
• shakiness
• slurred speech
• sneezing
• sore throat
• tingling of the hands or feet
• unusual tiredness or weakness
• unusual weight gain or loss

• Chest pain
• constipation
• darkened urine
• decreased urine output
• difficulty with swallowing
• dilated neck veins
• extreme fatigue
• flaking or peeling of the skin
• hives or skin rash
• indigestion
• irregular breathing
• irregular heartbeat
• large, hard skin blisters
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• loss of appetite
• pains in the stomach, side, or abdomen, possibly radiating to the back
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• severe joint pain
• swelling of face, fingers, feet, or lower leg
• tightness in the chest
• troubled breathing
• vomiting
• weight gain
• yellow eyes or skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Diarrhea
• pain or tenderness around the eyes and cheekbones
• redness of the skin
• weakness
• welts

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take with or without food.
• Swallow whole. Do not chew, break, or crush.
• To gain the most benefit, do not miss doses.
• Keep taking Onglyza as you have been told by your doctor or other health care provider, even if you feel well.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of a urinary tract infection (UTI) like blood in the urine, burning or pain when passing urine, feeling the need to pass urine often or right away, fever, lower stomach pain, or pelvic pain.
• Trouble swallowing.
• Low blood sugar can happen. The chance of low blood sugar may be raised when this medicine is used with other drugs for high blood sugar (diabetes). Signs may be dizziness, headache, feeling sleepy, feeling weak, shaking, a fast heartbeat, confusion, hunger, or sweating. Call your doctor right away if you have any of these signs. Follow what you have been told to do if you get low blood sugar. This may include taking glucose tablets, liquid glucose, or some fruit juices.
• Very bad and sometimes deadly pancreas problems (pancreatitis) have happened with Onglyza. This could happen at any time during care. Signs of pancreatitis include very bad stomach pain, very bad back pain, or very upset stomach or throwing up. Call your doctor right away if you have any of these signs.
• Heart failure has happened in people taking this medicine. Tell your doctor if you have ever had heart failure or kidney problems. Call your doctor right away if you feel very tired or you have shortness of breath, a big weight gain, or swelling in the arms or legs.
• Drugs like this one may cause joint pain that can be very bad and disabling. Call your doctor right away if you have very bad joint pain or any joint pain that does not go away.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• This medicine comes with an extra patient fact sheet called a Medication Guide. Read it with care. Read it again each time Onglyza is refilled. If you have any questions about this medicine, please talk with the doctor, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take Onglyza or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to Onglyza (saxagliptin). This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

Monotherapy and Combination Therapy

Onglyza is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [see Clinical Studies (14)].

Limitation of Use

Onglyza is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis, as it would not be effective in these settings.

Recommended Dosage

The recommended dosage of Onglyza is 2.5 mg or 5 mg once daily taken regardless of meals. Onglyza tablets must not be split or cut.

Dosage in Patients with Renal Impairment

No dosage adjustment for Onglyza is recommended for patients with eGFR ≥45mL/min/1.73 m2.

The dosage of Onglyza is 2.5 mg once daily (regardless of meals) for patients with eGFR <45mL/min1.73 m2 (which includes a subset of moderate or severe renal impairment, or with end-stage renal disease (ESRD) requiring hemodialysis) [see Clinical Pharmacology (12.3) and Clinical Studies (14.2)]. Onglyza should be administered following hemodialysis. Onglyza has not been studied in patients undergoing peritoneal dialysis.

Because the dosage of Onglyza should be limited to 2.5 mg based upon renal function, assessment of renal function is recommended prior to initiation of Onglyza and periodically thereafter.

Dosage Adjustment with Concomitant Use of Strong CYP3A4/5 Inhibitors

The dosage of Onglyza is 2.5 mg once daily when coadministered with strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitors (e.g., ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin) [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin

When Onglyza 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 Warnings and Precautions (5.3)].

The following serious adverse reactions are described below or elsewhere in the prescribing information:

• Pancreatitis [see Warnings and Precautions (5.1)]

• Heart Failure [see Warnings and Precautions (5.2)]

• Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin [see Warnings and Precautions (5.3)]

• Hypersensitivity Reactions [see Warnings and Precautions (5.4)]

• Severe and disabling arthralgia [see Warnings and Precautions (5.5)]

• Bullous pemphigoid [see Warnings and Precautions (5.6)]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data in Table 1 are derived from a pool of 5 placebo-controlled clinical trials [see Clinical Studies (14)]. These data shown in the table reflect exposure of 882 patients to Onglyza and a mean duration of exposure to Onglyza of 21 weeks. The mean age of these patients was 55 years, 1.4 % were 75 years or older and 48.4% were male. The population was 67.5% White, 4.6% Black or African American, 17.4% Asian, Other 10.5% and 9.8% were of Hispanic or Latino ethnicity. At baseline the population had diabetes for an average of 5.2 years and a mean HbA1c of 8.2%. Baseline estimated renal function was normal or mildly impaired (eGFR≥60mL/min/1.73m2) in 91% of these patients.

Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use of Onglyza. These adverse reactions occurred more commonly on Onglyza than on placebo and occurred in at least 5% of patients treated with Onglyza.

In patients treated with Onglyza 2.5 mg, headache (6.5%) was the only adverse reaction reported at a rate ≥5% and more commonly than in patients treated with placebo.

In the add-on to TZD trial, the incidence of peripheral edema was higher for Onglyza 5 mg versus placebo (8.1% and 4.3%, respectively). The incidence of peripheral edema for Onglyza 2.5 mg was 3.1%. None of the reported adverse reactions of peripheral edema resulted in study drug discontinuation. Rates of peripheral edema for Onglyza 2.5 mg and Onglyza 5 mg versus placebo were 3.6% and 2% versus 3% given as monotherapy, 2.1% and 2.1% versus 2.2% given as add-on therapy to metformin, and 2.4% and 1.2% versus 2.2% given as add-on therapy to glyburide.

The incidence rate of fractures was 1.0 and 0.6 per 100 patient-years, respectively, for Onglyza (pooled analysis of 2.5 mg, 5 mg, and 10 mg) and placebo. The 10 mg dosage is not an approved dosage. The incidence rate of fracture events in patients who received Onglyza did not increase over time. Causality has not been established and nonclinical studies have not demonstrated adverse effects of Onglyza on bone.

An event of thrombocytopenia, consistent with a diagnosis of idiopathic thrombocytopenic purpura, was observed in the clinical program. The relationship of this event to Onglyza is not known.

Discontinuation of therapy due to adverse reactions occurred in 2.2%, 3.3%, and 1.8% of subjects receiving Onglyza 2.5 mg, Onglyza 5 mg, and placebo, respectively. The most common adverse reactions (reported in at least 2 subjects treated with Onglyza 2.5 mg or at least 2 subjects treated with Onglyza 5 mg) associated with premature discontinuation of therapy included lymphopenia (0.1% and 0.5% versus 0%, respectively), rash (0.2% and 0.3% versus 0.3%), blood creatinine increased (0.3% and 0% versus 0%), and blood creatine phosphokinase increased (0.1% and 0.2% versus 0%).

In the add-on to insulin trial [see Clinical Studies (14.1)], the incidence of adverse events, including serious adverse events and discontinuations due to adverse events, was similar between Onglyza and placebo, except for confirmed hypoglycemia [see Adverse Reactions (6.1)].

Adverse reactions of hypoglycemia were based on all reports of hypoglycemia. A concurrent glucose measurement was not required or was normal in some patients. Therefore, it is not possible to conclusively determine that all these reports reflect true hypoglycemia.

In the add-on to glyburide study, the overall incidence of reported hypoglycemia was higher for Onglyza 2.5 mg and Onglyza 5 mg (13.3% and 14.6%) versus placebo (10.1%). The incidence of confirmed hypoglycemia in this study, defined as symptoms of hypoglycemia accompanied by a fingerstick glucose value of ≤50 mg/dL, was 2.4% and 0.8% for Onglyza 2.5 mg and Onglyza 5 mg and 0.7% for placebo [see Warnings and Precautions (5.3)]. The incidence of reported hypoglycemia for Onglyza 2.5 mg and Onglyza 5 mg versus placebo given as monotherapy was 4% and 5.6% versus 4.1%, respectively, 7.8% and 5.8% versus 5% given as add-on therapy to metformin, and 4.1% and 2.7% versus 3.8% given as add-on therapy to TZD. The incidence of reported hypoglycemia was 3.4% in treatment-naive patients given Onglyza 5 mg plus metformin and 4% in patients given metformin alone.

In the active-controlled trial comparing add-on therapy with Onglyza 5 mg to glipizide in patients inadequately controlled on metformin alone, the incidence of reported hypoglycemia was 3% (19 events in 13 patients) with Onglyza 5 mg versus 36.3% (750 events in 156 patients) with glipizide. Confirmed symptomatic hypoglycemia (accompanying fingerstick blood glucose ≤50 mg/dL) was reported in none of the Onglyza-treated patients and in 35 glipizide-treated patients (8.1%) (p<0.0001).

In the add-on to insulin trial, the overall incidence of reported hypoglycemia was 18.4% for Onglyza 5 mg and 19.9% for placebo. However, the incidence of confirmed symptomatic hypoglycemia (accompanying fingerstick blood glucose ≤50 mg/dL) was higher with Onglyza 5 mg (5.3%) versus placebo (3.3%).

In the add-on to metformin plus sulfonylurea trial, the overall incidence of reported hypoglycemia was 10.1% for Onglyza 5 mg and 6.3% for placebo. Confirmed hypoglycemia was reported in 1.6% of the Onglyza-treated patients and in none of the placebo-treated patients [see Warnings and Precautions (5.3)].

Hypersensitivity-related events, such as urticaria and facial edema in the 5-study pooled analysis up to Week 24 were reported in 1.5%, 1.5%, and 0.4% of patients who received Onglyza 2.5 mg, Onglyza 5 mg, and placebo, respectively. None of these events in patients who received Onglyza required hospitalization or were reported as life-threatening by the investigators. One Onglyza-treated patient in this pooled analysis discontinued due to generalized urticaria and facial edema.

In the SAVOR trial, adverse reactions related to renal impairment, including laboratory changes (i.e., doubling of serum creatinine compared with baseline and serum creatinine >6 mg/dL), were reported in 5.8% (483/8280) of Onglyza-treated subjects and 5.1% (422/8212) of placebo-treated subjects. The most frequently reported adverse reactions included renal impairment (2.1% vs. 1.9%), acute renal failure (1.4% vs. 1.2%), and renal failure (0.8% vs. 0.9%), in the Onglyza versus placebo groups, respectively. From baseline to the end of treatment, there was a mean decrease in eGFR of 2.5 mL/min/1.73m2 for Onglyza-treated patients and a mean decrease of 2.4 mL/min/1.73m2 for placebo-treated patients. More subjects randomized to Onglyza (421/5227, 8.1%) compared to subjects randomized to placebo (344/5073, 6.8%) had downward shifts in eGFR from >50 mL/min/1.73m2 (i.e., normal or mild renal impairment) to ≤50 mL/min/1.73m2 (i.e., moderate or severe renal impairment). The proportions of subjects with renal adverse reactions increased with worsening baseline renal function and increased age, regardless of treatment assignment.

In the unblinded, controlled, clinical trial database for Onglyza to date, there have been 6 (0.12%) reports of tuberculosis among the 4959 Onglyza-treated patients (1.1 per 1000 patient-years) compared to no reports of tuberculosis among the 2868 comparator-treated patients. Two of these six cases were confirmed with laboratory testing. The remaining cases had limited information or had presumptive diagnoses of tuberculosis. None of the six cases occurred in the United States or in Western Europe. One case occurred in Canada in a patient originally from Indonesia who had recently visited Indonesia. The duration of treatment with Onglyza until report of tuberculosis ranged from 144 to 929 days. Post-treatment lymphocyte counts were consistently within the reference range for four cases. One patient had lymphopenia prior to initiation of Onglyza that remained stable throughout Onglyza treatment. The final patient had an isolated lymphocyte count below normal approximately four months prior to the report of tuberculosis. There have been no spontaneous reports of tuberculosis associated with Onglyza use. Causality has not been estimated and there are too few cases to date to determine whether tuberculosis is related to Onglyza use.

There has been one case of a potential opportunistic infection in the unblinded, controlled clinical trial database to date in an Onglyza-treated patient who developed suspected foodborne fatal salmonella sepsis after approximately 600 days of Onglyza therapy. There have been no spontaneous reports of opportunistic infections associated with Onglyza use.

No clinically meaningful changes in vital signs have been observed in patients treated with Onglyza.

Absolute Lymphocyte Counts

There was a dose-related mean decrease in absolute lymphocyte count observed with Onglyza. From a baseline mean absolute lymphocyte count of approximately 2200 cells/microL, mean decreases of approximately 100 and 120 cells/microL with Onglyza 5 mg and 10 mg, respectively, relative to placebo were observed at 24 weeks in a pooled analysis of five placebo-controlled clinical studies. Similar effects were observed when Onglyza 5 mg was given in initial combination with metformin compared to metformin alone. There was no difference observed for Onglyza 2.5 mg relative to placebo. The proportion of patients who were reported to have a lymphocyte count ≤750 cells/microL was 0.5%, 1.5%, 1.4%, and 0.4% in the Onglyza 2.5 mg, 5 mg, 10 mg, and placebo groups, respectively. In most patients, recurrence was not observed with repeated exposure to Onglyza although some patients had recurrent decreases upon rechallenge that led to discontinuation of Onglyza. The decreases in lymphocyte count were not associated with clinically relevant adverse reactions. The 10 mg dosage is not an approved dosage.

In the SAVOR trial mean decreases of approximately 84 cells/microL with Onglyza relative to placebo was observed. The proportion of patients who experienced a decrease in lymphocyte counts to a count of ≤750 cells/microL was 1.6% (136/8280) and 1.0% (78/8212) on Onglyza and placebo respectively.

The clinical significance of this decrease in lymphocyte count relative to placebo is not known. When clinically indicated, such as in settings of unusual or prolonged infection, lymphocyte count should be measured. The effect of Onglyza on lymphocyte counts in patients with lymphocyte abnormalities (e.g., human immunodeficiency virus) is unknown.

Postmarketing Experience

Additional adverse reactions have been identified during post-approval use of Onglyza. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Pregnancy

Limited data with Onglyza in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriages. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations].

No adverse developmental effects independent of maternal toxicity were observed when saxagliptin was administered to pregnant rats and rabbits during the period of organogenesis and in pregnant and lactating rats during the pre- and postnatal period [see Data].

The estimated background risk of major birth defects in 6 to 10% in women with pre-gestational diabetes with an HbA1c greater than 7 and has been reported to be as high as 20 to 25% in women with an HbA1c greater than 10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Disease-associated maternal and/or embryo/fetal risk

Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, still birth and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.

Animal Data

In embryo-fetal development studies, saxagliptin was administered to pregnant rats and rabbits during the period of organogenesis, corresponding to the first trimester of human pregnancy. No adverse developmental effects were observed

in either species at exposures 1503- and 152-times the 5 mg clinical dose in rats and rabbits, respectively, based on AUC. Saxagliptin crosses the placenta into the fetus following dosing in pregnant rats.

In a prenatal and postnatal development study, no adverse developmental effects were observed in maternal rats administered saxagliptin from gestation day 6 through lactation day 21 at exposures up to 470-times the 5 mg clinical dose, based on AUC.

Lactation

There is no information regarding the presence of Onglyza in human milk, the effects on the breastfed infant, or the effects on milk production.

Saxagliptin is present in the milk of lactating rats [see Data]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Onglyza and any potential adverse effects on the breastfed infant from Onglyza or from the underlying maternal condition.

Saxagliptin is secreted in the milk of lactating rats at approximately a 1:1 ratio with plasma drug concentrations.

Pediatric Use

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.

Geriatric Use

In the seven, double-blind, controlled clinical safety and efficacy trials of Onglyza, a total of 4751 (42.0%) of the 11301 patients randomized to Onglyza were 65 years and over, and 1210 (10.7%) were 75 years and over. No overall differences in safety or effectiveness were observed between subjects ≥65 years old and younger subjects. 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 (2.2) and Clinical Pharmacology (12.3)].

Renal Impairment

In a 12-week randomized placebo-controlled trial, Onglyza 2.5 mg was administered to 85 subjects with moderate (n=48) or severe (n=18) renal impairment or end-stage renal disease (ESRD) (n=19) [see Clinical Studies (14)]. The incidence of adverse events, including serious adverse events and discontinuations due to adverse events, was similar between Onglyza and placebo. The overall incidence of reported hypoglycemia was 20% among subjects treated with Onglyza 2.5 mg and 22% among subjects treated with placebo. Four Onglyza-treated subjects (4.7%) and three placebo-treated subjects (3.5%) reported at least one episode of confirmed symptomatic hypoglycemia (accompanying fingerstick glucose ≤50 mg/dL).

Summary of Use during Lactation

Because no information is available on the use of saxagliptin during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.

Drug Levels

Maternal Levels. Relevant published information was not found as of the revision date.

Infant Levels. Relevant published information was not found as of the revision date.

Effects in Breastfed Infants

Relevant published information was not found as of the revision date.

Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

Alternate Drugs to Consider

Acarbose, Chlorpropamide, Glyburide, Insulin, Metformin, Tolbutamide

References