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Kombiglyze XR

  • Generic Name: saxagliptin and metformin hcl extended-release
  • Brand Name: Kombiglyze XR

Kombiglyze XR(Saxagliptin and Metformin HCl Extended-Release) side effects drug center

 

PROFESSIONAL

CONSUMER

SIDE EFFECTS

 

Kombiglyze XR Side Effects Center

What Is Kombiglyze XR?

Kombiglyze XR (saxagliptin and metformin hydrochloride) Extended-release Tablets is a combination drug indicated, along with diet and exercise, as a treatment for type 2 diabetes in adults. Kombiglyze XR is NOT indicated for use in type 1 diabetics or diabetic ketoacidosis. Kombiglyze XR is a combination of two prescription medications called saxagliptin and metformin hydrochloride that are available as generic drugs.

What Are Side Effects of Kombiglyze XR?

Common side effects of Kombiglyze XR include:

Tell your doctor if you have serious side effects of Kombiglyze XR including:

  • severe pain in your upper stomach spreading to your back,
  • nausea and vomiting,
  • fast heart rate,
  • pain or burning when you urinate, or
  • swelling or rapid weight gain.

Dosage for Kombiglyze XR

The dosage of Kombiglyze XR is individualized on the basis of the patient's current regimen, effectiveness, and tolerability.

What Drugs, Substances, or Supplements Interact with Kombiglyze XR?

Kombiglyze XR may interact with alcohol, antibiotics, antifungals, heart or blood pressure medications, HIV/AIDS medicines, diuretics (water pills), steroids, niacin, phenothiazines, thyroid medicines, birth control pills and other hormones, seizure medicines, diet pills, asthma medicines, medicines to treat colds or allergies, nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin or other salicylates, blood thinners, sulfa drugs, monoamine oxidase inhibitors (MAOIs), or insulin or other oral diabetes medications. Tell your doctor all medications and supplements you use.

Kombiglyze XR During Pregnancy or Breastfeeding

Tell your doctor if you are pregnant or plan to become pregnant during treatment with Kombiglyze XR; it is not expected to be harmful to a fetus. It is unknown if Kombiglyze XR passes into breast milk or if it could harm a nursing baby. Consult your doctor before breastfeeding.

Additional Information

Our Kombiglyze XR (saxagliptin and metformin hydrochloride) Extended-release Tablets Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

 

Kombiglyze XR Consumer Information

Get emergency medical help if you have signs of an allergic reaction: hives, itching, peeling skin; difficult breathing; swelling of your face, lips, tongue, or throat.

Stop taking this medicine 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.

Some people using metformin develop lactic acidosis, which can be fatal. Get emergency medical help if you have even mild symptoms such as:

  • unusual muscle pain;
  • feeling cold;
  • trouble breathing;
  • feeling dizzy, light-headed, tired, or very weak;
  • stomach pain, vomiting; or
  • irregular heart rate.

Call your doctor at once if you have any of these serious side effects:

  • severe autoimmune reaction--itching, blisters, breakdown of the outer layer of skin;
  • severe or ongoing pain in your joints;
  • pain or burning when you urinate; or
  • symptoms of heart failure--shortness of breath (even while lying down), swelling in your legs or feet, rapid weight gain.

Common side effects may include:

  • diarrhea, nausea;
  • headache; or
  • cold symptoms such as runny or stuffy nose, sneezing, sore throat.

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.

Read the entire detailed patient monograph for Kombiglyze XR (Saxagliptin and Metformin HCl Extended-Release)

 

Kombiglyze XR Professional Information

SIDE EFFECTS

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

  • Pancreatitis [see WARNINGS AND PRECAUTIONS]
  • Heart Failure [see WARNINGS AND PRECAUTIONS]
  • Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin [see WARNINGS AND PRECAUTIONS]
  • Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]
  • Severe and disabling arthralgia [see WARNINGS AND PRECAUTIONS]
  • Bullous pemphigoid [see WARNINGS AND PRECAUTIONS]

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.

Adverse Reactions In Efficacy Trials

Metformin Hydrochloride

In placebo-controlled monotherapy trials of metformin extended-release, diarrhea and nausea/vomiting were reported in >5% of metformin-treated patients and more commonly than in placebo-treated patients (9.6% versus 2.6% for diarrhea and 6.5% versus 1.5% for nausea/vomiting). Diarrhea led to discontinuation of study medication in 0.6% of the patients treated with metformin extended-release.

Saxagliptin

The data in Table 1 are derived from a pool of 5 placebo-controlled clinical trials [see Clinical Studies]. These data shown in the table reflect exposure of 882 patients to saxagliptin and a mean duration of exposure to saxagliptin 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 saxagliptin. These adverse reactions occurred more commonly on saxagliptin than on placebo and occurred in at least 5% of patients treated with saxagliptin.

Table 1: Adverse Reactions in Placebo-Controlled Trials* Reported in ≥5% of Patients Treated with Saxagliptin 5 mg and More Commonly than in Patients Treated with Placebo

  % of Patients
Saxagliptin 5 mg
N=882		 Placebo
N=799
Upper respiratory tract infection 7.7 7.6
Urinary tract infection 6.8 6.1
Headache 6.5 5.9
*The 5 placebo-controlled trials include two monotherapy trials and one add-on combination therapy trial with each of the following: metformin, thiazolidinedione, or glyburide. Table shows 24 -week data regardless of glycemic rescue.

In patients treated with saxagliptin 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 saxagliptin 5 mg versus placebo (8.1% and 4.3%, respectively). The incidence of peripheral edema for saxagliptin 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 saxagliptin 2.5 mg and saxagliptin 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 saxagliptin (pooled analysis of 2.5 mg, 5 mg, and 10 mg) and placebo. The 10 mg saxagliptin dosage is not an approved dosage. The incidence rate of fracture events in patients who received saxagliptin did not increase over time. Causality has not been established and nonclinical studies have not demonstrated adverse effects of saxagliptin 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 saxagliptin is not known.

Discontinuation of therapy due to adverse reactions occurred in 2.2%, 3.3%, and 1.8% of subjects receiving saxagliptin 2.5 mg, saxagliptin 5 mg, and placebo, respectively. The most common adverse reactions (reported in at least 2 subjects treated with saxagliptin 2.5 mg or at least 2 subjects treated with saxagliptin 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%).

Adverse Reactions With Concomitant Use With Insulin

In the add-on to insulin trial [see Clinical Studies], the incidence of adverse events, including serious adverse events and discontinuations due to adverse events, was similar between saxagliptin and placebo, except for confirmed hypoglycemia [see Clinical Trials Experience].

Adverse Reactions Associated With Saxagliptin Coadministered With Metformin Immediate-Release In Treatment-Naive Patients With Type 2 Diabetes

Table 2 shows the adverse reactions reported (regardless of investigator assessment of causality) in ≥5% of patients participating in an additional 24-week, active-controlled trial of coadministered saxagliptin and metformin in treatment-naive patients.

Table 2: Coadministration of Saxagliptin and Metformin Immediate-Release in Treatment-Naive Patients : Adverse Reactions Reported in ≥5% of Patients Treated with Combination Therapy of Saxagliptin 5 mg Plus Metformin Immediate-Release (and More Commonly than in Patients Treated with Metformin Immediate-Release Alone)

  Number (%) of Patients
Saxagliptin 5 mg + Metformin*
N=320		 Placebo + Metformin*
N=328
Headache 24 (7.5) 17 (5.2)
Nasopharyngitis 22 (6.9) 13 (4.0)
*Metformin immediate-release was initiated at a starting dose of 500 mg daily and titrated up to a maximum of 2000 mg daily.

In patients treated with the combination of saxagliptin and metformin immediate-release, either as saxagliptin add-on to metformin immediate-release therapy or as coadministration in treatment-naive patients, diarrhea was the only gastrointestinal-related event that occurred with an incidence ≥5% in any treatment group in both studies. In the saxagliptin add-on to metformin immediate-release trial, the incidence of diarrhea was 9.9%, 5.8%, and 11.2% in the saxagliptin 2.5 mg, 5 mg, and placebo groups, respectively. When saxagliptin and metformin immediate-release were coadministered in treatment-naive patients, the incidence of diarrhea was 6.9% in the saxagliptin 5 mg + metformin immediate-release group and 7.3% in the placebo + metformin immediate-release group.

Hypoglycemia

In the saxagliptin clinical trials, 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.

The incidence of reported hypoglycemia for saxagliptin 2.5 mg and saxagliptin 5 mg versus placebo given as monotherapy was 4% and 5.6% versus 4.1%, respectively. In the add-on to metformin immediate-release trial, the incidence of reported hypoglycemia was 7.8% with saxagliptin 2.5 mg, 5.8% with saxagliptin 5 mg, and 5% with placebo. When saxagliptin and metformin immediate-release were coadministered in treatment-naive patients, the incidence of reported hypoglycemia was 3.4% in patients given saxagliptin 5 mg + metformin immediate-release and 4% in patients given placebo + metformin immediate-release.

In the active-controlled trial comparing add-on therapy with saxagliptin 5 mg to glipizide in patients inadequately controlled on metformin alone, the incidence of reported hypoglycemia was 3% (19 events in 13 patients) with saxagliptin 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 saxagliptin-treated patients and in 35 glipizide-treated patients (8.1%) (p<0.0001).

In the saxagliptin add-on to insulin trial, the overall incidence of reported hypoglycemia was 18.4% for saxagliptin 5 mg and 19.9% for placebo. However, the incidence of confirmed symptomatic hypoglycemia (accompanying fingerstick blood glucose ≤50 mg/dL) was higher with saxagliptin 5 mg (5.3%) versus placebo (3.3%). Among the patients using insulin in combination with metformin, the incidence of confirmed symptomatic hypoglycemia was 4.8% with saxagliptin versus 1.9% with placebo.

In the saxagliptin add-on to metformin plus sulfonylurea trial, the overall incidence of reported hypoglycemia was 10.1% for saxagliptin 5 mg and 6.3% for placebo. Confirmed hypoglycemia was reported in 1.6% of the saxagliptin-treated patients and in none of the placebo-treated patients [see WARNINGS AND PRECAUTIONS].

Hypersensitivity Reactions

Saxagliptin

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 saxagliptin 2.5 mg, saxagliptin 5 mg, and placebo, respectively. None of these events in patients who received saxagliptin required hospitalization or were reported as life-threatening by the investigators. One saxagliptintreated patient in this pooled analysis discontinued due to generalized urticaria and facial edema.

Renal Impairment

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 saxagliptin-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 saxagliptin 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 saxagliptin-treated patients and a mean decrease of 2.4 mL/min/2 1.73m² for placebo treated patients. More subjects randomized to saxagliptin (421/5227, 8.1%) compared to subjects randomized to placebo (344/5073, 6.8%) had downward shifts in eGFR from >50 mL/min/1.73 m² (i.e., normal or mild renal impairment) to ≤50 mL/min/1.73 m² (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.

Infections

Saxagliptin

In the unblinded, controlled, clinical trial database for saxagliptin to date, there have been 6 (0.12%) reports of tuberculosis among the 4959 saxagliptin-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 saxagliptin 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 saxagliptin that remained stable throughout saxagliptin 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 saxagliptin use. Causality has not been established and there are too few cases to date to determine whether tuberculosis is related to saxagliptin use.

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

Vital Signs

Saxagliptin

No clinically meaningful changes in vital signs have been observed in patients treated with saxagliptin alone or in combination with metformin.

Laboratory Tests

Absolute Lymphocyte Counts

Saxagliptin

There was a dose-related mean decrease in absolute lymphocyte count observed with saxagliptin. From a baseline mean absolute lymphocyte count of approximately 2200 cells/microL, mean decreases of approximately 100 and 120 cells/microL with saxagliptin 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 saxagliptin 5 mg and metformin were coadministered in treatmentnaive patients compared to placebo and metformin. There was no difference observed for saxagliptin 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 saxagliptin 2.5 mg, 5 mg, 10 mg, and placebo groups, respectively. In most patients, recurrence was not observed with repeated exposure to saxagliptin although some patients had recurrent decreases upon rechallenge that led to discontinuation of saxagliptin. The decreases in lymphocyte count were not associated with clinically relevant adverse reactions. The 10 mg saxagliptin dosage is not an approved dosage.

In the SAVOR trial mean decreases of approximately 84 cells/microL with saxagliptin 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 saxagliptin 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 saxagliptin on lymphocyte counts in patients with lymphocyte abnormalities (e.g., human immunodeficiency virus) is unknown.

Vitamin B12 Concentrations

Metformin Hydrochloride

Metformin may lower serum vitamin B12 concentrations. Measurement of hematologic parameters on an annual basis is advised in patients on KOMBIGLYZE XR and any apparent abnormalities should be appropriately investigated and managed [see WARNINGS AND PRECAUTIONS].

Postmarketing Experience

Additional adverse reactions have been identified during post-approval use. 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.

Saxagliptin
  • Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions
  • Pancreatitis
  • Severe and disabling arthralgia
  • Bullous pemphigoid
  • Rhabdomyolysis
Metformin Hydrochloride
  • Cholestatic, hepatocellular, and mixed hepatocellular liver injury

Read the entire FDA prescribing information for Kombiglyze XR (Saxagliptin and Metformin HCl Extended-Release)

&Copy; Kombiglyze XR Patient Information is supplied by Cerner Multum, Inc. and Kombiglyze XR Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.