WARNING FOR KOMBIGLYZE XR: LACTIC ACIDOSIS
US Full Prescribing Information including Boxed WARNING about lactic acidosis, and Medication Guide
Lactic acidosis is a rare, but serious, complication that can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic impairment, renal impairment, and acute congestive heart failure.
The onset of lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress.
Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate.
If acidosis is suspected, KOMBIGLYZE™ XR (saxagliptin and metformin HCl extended-release) should be discontinued and the patient hospitalized immediately. [See Warnings and Precautions]
Click here for Important Safety Information including complete Boxed WARNING about lactic acidosis
A TREATMENT FOR ADULTS WITH TYPE 2 DIABETES MELLITUS, IN ADDITION TO DIET AND EXERCISE
SAFETY PROFILE
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ANALYSIS OF ADVERSE REACTIONS
Established tolerability profile in a 24-week study of treatment-naïve patients
Most commonly reported adverse reactions (≥5% and more commonly than with placebo)1,a
PERCENTAGE OF PATIENTS
| IN TREATMENT-NAÏVE STUDYa,b | Saxagliptin 5 mg + metformin IR | Placebo + metformin IR |
|---|---|---|
| Headache | 7.5% | 5.2% |
| Nasopharyngitis | 6.9% | 4.0% |
| (n=320) | (n=328) |
aMetformin IR was initiated at a starting dose of 500 mg and titrated up to a maximum of 2000 mg daily.
bIn this study, saxagliptin 5 mg and metformin IR were administered as separate tablets.
- There was a dose-related mean decrease in absolute lymphocyte count observed with saxagliptin1
- Incidence of diarrhea was 6.9% with saxagliptin 5 mg + metformin IR vs 7.3% with placebo + metformin IR over 24 weeks1,2
- A total of 2.5% in the saxagliptin 5 mg + metformin IR group and 3.4% in the placebo + metformin IR group discontinued due to adverse events over 24 weeks2
Adverse reactions in placebo-controlled monotherapy trials of metformin XR occurring in >5% of metformin XR-treated patients and more commonly than in placebo-treated patients1
PERCENTAGE OF PATIENTS
| Metformin XR | Placebo | |
|---|---|---|
| Diarrhea | 9.6% | 2.6% |
| Nausea/Vomiting | 6.5% | 1.5% |
- Diarrhea led to discontinuation of study medication in 0.6% of the patients treated with metformin extended-release1
Pooled analysis of adverse reactions occurring in ≥5% of patients treated with saxagliptin 5 mg and more commonly than in patients treated with placebo1,c
Overall incidence of adverse events with saxagliptin in monotherapy and add-on therapy studies was similar to placebo, 72% vs 71%, respectively.1
PERCENTAGE OF PATIENTS
| IN MONOTHERAPY AND ADD-ON THERAPY STUDIESc | Saxagliptin 5 mg | Placebo |
|---|---|---|
| Upper Respiratory Tract Infection | 7.7% | 7.6% |
| Urinary Tract Infection | 6.8% | 6.1% |
| Headache | 6.5% | 5.9% |
| (n=882) | (n=799) |
- In patients treated with saxagliptin 2.5 mg, headache (6.5%) was the only adverse reaction occurring in ≥5% of patients and more commonly than placebo1
- Adverse reactions reported in ≥2% of patients treated with saxagliptin 5 mg or saxagliptin 2.5 mg and ≥1% more frequently compared with placebo, respectively, included:
- Sinusitis: 2.6%, 2.9% vs 1.6%
- Abdominal pain: 1.7%, 2.4% vs 0.5%
- Gastroenteritis: 2.3%, 1.9% vs 0.9%
- Vomiting: 2.3%, 2.2% vs 1.3%
- Hypersensitivity-related events (eg, urticaria, facial edema) were reported in 1.5%, 1.5%, and 0.4% of patients who received saxagliptin 5 mg, 2.5 mg, and placebo, respectively1
- There was a dose-related mean decrease in absolute lymphocyte count observed with saxagliptin1
cPrespecified pooled analysis of 2 monotherapy studies, the add-on to metformin study, the add-on to glyburide study, and the add-on to a TZD study; 24-week data regardless of glycemic rescue.
Most common adverse events associated with discontinuation of therapy over 6 months1,d
Discontinuation of therapy due to adverse events occurred in 3.3%, 2.2%, and 1.8% of patients receiving saxagliptin 5 mg, 2.5 mg, and placebo, respectively.1
PERCENTAGE OF PATIENTS
| Saxagliptin 5 mg | Saxagliptin 2.5 mg | Placebo | |
|---|---|---|---|
| Lymphopenia | 0.5% | 0.1% | 0.0% |
| Rash | 0.3% | 0.2% | 0.3% |
| Blood Creatinine Increase | 0.0% | 0.3% | 0.0% |
| Blood Creatine Phosphokinase Increase | 0.2% | 0.1% | 0.0% |
| (n=882) | (n=882) | (n=799) |
dReported in at least 2 patients treated with saxagliptin.
In the clinical trial database for saxagliptin to date, there have been 6 reports (0.12%) of tuberculosis among the patients treated with saxagliptin compared with no reports among the patients treated with comparator. Causality has not been established. In addition, 1 patient treated with saxagliptin developed suspected foodborne fatal salmonella sepsis. There have been no spontaneous reports of tuberculosis or opportunistic infections associated with saxagliptin use.
INCIDENCE OF HYPOGLYCEMIC EVENTS
LOWER RATES OF REPORTED HYPOGLYCEMIA OVER 24 WEEKS1,2,e
Saxagliptin 5 mg + metformin IR (n=320)
Placebo + metformin IR (n=328)
eReported hypoglycemic events were a combination of reports of either signs or symptoms consistent with hypoglycemia with or without documented glucose levels or reported low glucose levels without symptoms. 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 a pool of 5 placebo-controlled trials, the most common adverse reactions reported in ≥5% of patients treated with saxagliptin 5 mg vs placebo were upper respiratory tract infection (7.7%, 7.6%), urinary tract infection (6.8%, 6.1%), and headache (6.5%, 5.9%)1
- In other pivotal clinical trials of pooled data, in patients treated with ONGLYZA 2.5 mg, headache (6.5%) was the only adverse reaction occurring in ≥5% of patients and more commonly than in patients treated with placebo1
Saxagliptin 5 mg add-on therapy to metformin + sulfonylurea
Incidence of hypoglycemic events at Week 241,4
fAdverse reactions of hypoglycemia were based on all reports of hypoglycemia.
gDefined as symptoms of hypoglycemia accompanied by a fingerstick glucose ≤50 mg/dL.
GI EVENTS
Incidence of diarrhea over 24 weeks2,3,h
PERCENTAGE OF PATIENTS
| Saxagliptin 5 mg + metformin IR | Saxagliptin 2.5 mg + metformin IR | Placebo + metformin IR | |
|---|---|---|---|
| Uncontrolled on Metformin Monotherapy | 5.8% | 9.9% | 11.2% |
| (n=191) | (n=192) | (n=179) | |
| Treatment-Naïvei | 6.9% | -- | 7.3% |
| (n=320) | (n=328) |
hIn these studies, saxagliptin and metformin IR were administered as separate tablets.
iMetformin IR was initiated at a starting dose of 500 mg and titrated up to a maximum of 2000 mg daily.
- In both studies, mean decrease in body weight from baseline to Week 24 with KOMBIGLYZE XR was similar to that of metformin IR alone1,2
Important Safety Information for KOMBIGLYZE XR
Risk factors include renal impairment, concomitant use of certain drugs, age >65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the Full Prescribing Information.
If lactic acidosis is suspected, discontinue KOMBIGLYZE XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.
Contraindications
- Severe renal impairment (eGFR below 30 mL/min/1.73 m2)
- Prior serious hypersensitivity reaction to saxagliptin or hypersensitivity to metformin hydrochloride
- Metabolic acidosis, including diabetic ketoacidosis
Warnings and Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Indication and Limitations of Use
Warnings and Precautions
Pancreatitis: There have been post-marketing reports of acute pancreatitis in patients taking saxagliptin, and in the SAVOR cardiovascular outcomes trial. Observe for pancreatitis. If pancreatitis is suspected, discontinue KOMBIGLYZE XR.
Heart Failure: In the SAVOR cardiovascular outcomes trial, more patients treated with saxagliptin were hospitalized for heart failure compared to placebo. Patients with a prior history of heart failure or renal impairment had a higher risk for hospitalization for heart failure. Consider the risks and benefits of KOMBIGLYZE XR in patients who have known risk factors for heart failure. Monitor for signs and symptoms. If heart failure develops, consider discontinuation of KOMBIGLYZE XR.
Vitamin B12 Deficiency: Metformin may lower vitamin B12 levels. Measure hematological parameters annually.
Hypoglycemia: When saxagliptin was used in combination with a sulfonylurea or with insulin, the incidence of confirmed hypoglycemia was increased over that of placebo. Consider lowering the dose of these agents when coadministered with KOMBIGLYZE XR.
Hypoglycemia could occur when caloric intake is deficient, strenuous exercise is not compensated by caloric supplementation, or when KOMBIGLYZE XR is used with other glucose-lowering agents or ethanol.
Hypersensitivity: Serious reactions have been reported in patients treated with saxagliptin, including anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred within the first 3 months after initiation of treatment with saxagliptin, with some reports occurring after the first dose. If a serious hypersensitivity reaction is suspected, discontinue KOMBIGLYZE XR. Use caution in patients with a history of angioedema to another DPP-4 inhibitor.
Severe and Disabling Arthralgia has been reported in patients taking DPP-4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider discontinuing drug if appropriate.
Bullous Pemphigoid: There have been postmarketing reports of bullous pemphigoid requiring hospitalization in patients taking DPP-4 inhibitors. Tell patients to report development of blisters or erosions. If suspected, discontinue KOMBIGLYZE XR.
Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with KOMBIGLYZE XR.
Adverse Reactions
Most common adverse reactions reported in ≥5% of patients treated with saxagliptin and more commonly than in patients treated with placebo were upper respiratory tract infection (7.7%, 7.6%), urinary tract infection (6.8%, 6.1%), and headache (6.5%, 5.9%).
Adverse reactions reported in >5% of patients treated with metformin XR and more commonly than in patients treated with placebo were diarrhea (9.6% vs 2.6%) and nausea/vomiting (6.5% vs 1.5%).
Adverse reactions reported in ≥5% of treatment-naive patients treated with coadministered saxagliptin and metformin IR and more commonly than in patients treated with metformin IR alone were headache (7.5% vs 5.2%) and nasopharyngitis (6.9% vs 4.0%).
Drug Interactions
Strong CYP3A4/5 inhibitors (eg, ketoconazole): Coadministration with KOMBIGLYZE XR significantly increases saxagliptin concentrations. Recommend limiting saxagliptin dosage to 2.5 mg once daily.
Use in Specific Populations
Assess renal function prior to initiation of KOMBIGLYZE XR and periodically thereafter. If eGFR falls below 45 mL/minute/1.73 m2, assess the benefit risk of continuing therapy and limit dose of the saxagliptin component to 2.5 mg once daily. Discontinue KOMBIGLYZE XR if eGFR falls below 30 mL/minute/1.73 m2.
Indication and Limitations of Use
- KOMBIGLYZE XR is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both saxagliptin and metformin is appropriate
- KOMBIGLYZE XR is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis
Please see US Full Prescribing Information for KOMBIGLYZE XR (5/500•5/1000•2.5/1000 mg tablets), including Boxed WARNING about lactic acidosis, and Medication Guide.
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KOMBIGLYZE XR is a registered trademark of the AstraZeneca group of companies.
KOMBIGLYZE XR is a registered trademark of the AstraZeneca group of companies.
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©2018 AstraZeneca. All rights reserved. US-24045 Last Updated 11/18
Indication and Limitations of Use for KOMBIGLYZE® XR (saxagliptin and metformin HCl extended-release) tablets
KOMBIGLYZE XR is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both saxagliptin and metformin is appropriate.
KOMBIGLYZE XR is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.
