Source: FDA, National Drug Code (US) Revision Year: 2019
KOMBIGLYZE XR is contraindicated in patients with:
There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis.
Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.
If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of KOMBIGLYZE XR.
In KOMBIGLYZE XR-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable, with a clearance of up to 170 mL/minute under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.
Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue KOMBIGLYZE XR and report these symptoms to their healthcare provider.
For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:
Renal Impairment: The post-marketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient’s renal function include [see Clinical Pharmacology (12.3)]:
The concomitant use of KOMBIGLYZE XR with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation [see Drug Interactions (7)]. Therefore, consider more frequent monitoring of patients.
The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients [see Use in Specific Populations (8.5)].
Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop KOMBIGLYZE XR at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m²; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart KOMBIGLYZE XR if renal function is stable.
Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment. KOMBIGLYZE XR should be temporarily discontinued while patients have restricted food and fluid intake.
Several of the post-marketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue KOMBIGLYZE XR.
Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving KOMBIGLYZE XR.
Patients with hepatic impairment have developed with cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of KOMBIGLYZE XR in patients with clinical or laboratory evidence of hepatic disease.
There have been post-marketing reports of acute pancreatitis in patients taking saxagliptin. In a cardiovascular outcomes trial enrolling participants with established atherosclerotic cardiovascular disease (ASCVD) or multiple risk factors for ASCVD (SAVOR trial), cases of definite acute pancreatitis were confirmed in 17 of 8240 (0.2%) patients receiving saxagliptin compared to 9 of 8173 (0.1%) receiving placebo. Pre-existing risk factors for pancreatitis were identified in 88% (15/17) of those patients receiving saxagliptin and in 100% (9/9) of those patients receiving placebo.
After initiation of KOMBIGLYZE XR, observe patients for signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue KOMBIGLYZE XR and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using KOMBIGLYZE XR.
In a cardiovascular outcomes trial enrolling participants with established ASCVD or multiple risk factors for ASCVD (SAVOR trial), more patients randomized to saxagliptin (289/8280, 3.5%) were hospitalized for heart failure compared to patients randomized to placebo (228/8212, 2.8%). In a time-to-first-event analysis the risk of hospitalization for heart failure was higher in the saxagliptin group (estimated Hazard Ratio: 1.27; 95% CI: 1.07, 1.51). Subjects with a prior history of heart failure and subjects with renal impairment had a higher risk for hospitalization for heart failure, irrespective of treatment assignment.
Consider the risks and benefits of KOMBIGLYZE XR prior to initiating treatment in patients at a higher risk for heart failure. Observe patients for signs and symptoms of heart failure during therapy. Advise patients of the characteristic symptoms of heart failure, and to immediately report such symptoms. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of KOMBIGLYZE XR.
In controlled clinical trials of metformin of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. 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 Adverse Reactions (6.1)].
Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurements at 2- to 3-year intervals may be useful.
A patient with type 2 diabetes previously well-controlled on KOMBIGLYZE XR who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If acidosis of either form occurs, KOMBIGLYZE XR must be stopped immediately and other appropriate corrective measures initiated.
When saxagliptin 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 (6.1)]. Therefore, a lower dose of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia when used in combination with KOMBIGLYZE XR [see Dosage and Administration (2.3)].
Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol. Elderly, debilitated, or malnourished patients and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs.
There have been post-marketing reports of serious hypersensitivity reactions in patients treated with saxagliptin. These reactions include 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, assess for other potential causes for the event, and institute alternative treatment for diabetes [see Adverse Reactions (6.2)].
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 KOMBIGLYZE XR.
There have been post-marketing reports of severe and disabling arthralgia in patients taking DPP4 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 of the medication. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP4 inhibitor. Consider DPP4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate.
Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP‑4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP‑4 inhibitor. Tell patients to report development of blisters or erosions while receiving KOMBIGLYZE XR. If bullous pemphigoid is suspected, KOMBIGLYZE XR should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with KOMBIGLYZE XR.
The following serious adverse reactions are described below or elsewhere in the prescribing information:
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.
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.
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 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?footnote? 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%).
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 saxagliptin and placebo, except for confirmed hypoglycemia [see Adverse Reactions (6.1)].
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.
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 (5.6)].
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 saxagliptin-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 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/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.
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.
No clinically meaningful changes in vital signs have been observed in patients treated with saxagliptin alone or in combination with metformin.
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 treatment-naive 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.
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 (5.4)].
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:
Metformin hydrochloride:
Ketoconazole significantly increased saxagliptin exposure. Similar significant increases in plasma concentrations of saxagliptin are anticipated with other strong CYP3A4/5 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin). The dose of saxagliptin should be limited to 2.5 mg when coadministered with a strong CYP3A4/5 inhibitor [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].
Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently causes a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with KOMBIGLYZE XR may increase the risk for lactic acidosis.
Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis [see Clinical Pharmacology (12.3)]. Consider the benefits and risks of concomitant use.
Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving KOMBIGLYZE XR.
In the saxagliptin add-on to sulfonylurea, add-on to insulin, and add-on to metformin plus sulfonylurea trials, confirmed hypoglycemia was reported more commonly in patients treated with saxagliptin compared to placebo. When used with an insulin secretagogue (e.g., sulfonylurea) or insulin, a lower dose of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia.
Some medications can predispose to hyperglycemia and may lead to loss of glycemic control. These medications include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. When such drugs are administered to a patient receiving KOMBIGLYZE XR, the patient should be closely observed for loss of glycemic control. When such drugs are withdrawn from a patient receiving KOMBIGLYZE XR, the patient should be observed closely for hypoglycemia.
Limited available data with KOMBIGLYZE XR or saxagliptin in pregnant women are not sufficient to determine a 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 [see Data].
No adverse developmental effects independent of maternal toxicity were observed when saxagliptin and metformin were administered separately or in combination to pregnant rats and rabbits during the period of organogenesis [see Data].
The estimated background risk of major birth defects is 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.
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.
Saxagliptin:
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.
Metformin hydrochloride:
Metformin hydrochloride did not cause adverse developmental effect when administered to pregnant Sprague Dawley rats and rabbits up to 600 mg/kg/day during the period of organogenesis. This represents an exposure of about 2- and 6-times a 2000 mg clinical dose based on body surface area (mg/m²) for rats and rabbits, respectively.
Saxagliptin and Metformin:
Saxagliptin and metformin coadministered to pregnant rats and rabbits during the period of organogenesis did not result in adverse developmental effects considered clinically relevant in either species. Doses tested in rats provided exposure up to 100- and 10-times clinical exposure, and doses tested in rabbits provided exposure up to 249- and 1-times clinical exposure relative to the clinical dose of 5 mg saxagliptin and 2000 mg metformin. Minor skeletal abnormalities associated with maternal toxicity were observed in rats. 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, associated with fetal body weight decrements of 7%, and a low incidence of delayed ossification of the fetal hyoid bone.
There is no information regarding the presence of KOMBIGLYZE XR or saxagliptin in human milk, the effects on the breastfed infant, or the effects on milk production. Limited published studies report that metformin is present in human milk [see Data]. However, there is insufficient information on the effects of metformin on the breastfed infant and no available information on the effects of metformin 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 KOMBIGLYZE XR and any potential adverse effects on the breastfed child from KOMBIGLYZE XR or from the underlying maternal condition.
Published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11% to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants.
No studies in lactating animals have been conducted with the combined components of KOMBIGLYZE XR. In studies performed with the individual components, both saxagliptin and metformin are secreted in the milk of lactating rats. Saxagliptin is secreted in the milk of lactating rats at approximately a 1:1 ratio with plasma drug concentrations.
Safety and effectiveness of KOMBIGLYZE XR in pediatric patients under 18 years of age have not been established. Additionally, studies characterizing the pharmacokinetics of KOMBIGLYZE XR in pediatric patients have not been performed.
Elderly patients are more likely to have decreased renal function. Assess renal function more frequently in the elderly [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
In the seven, double-blind, controlled clinical safety and efficacy trials of saxagliptin, a total of 4751 (42.0%) of the 11301 patients randomized to saxagliptin 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.
Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and young patients. Metformin is known to be substantially excreted by the kidney. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients [see Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].
In a 12-week randomized placebo-controlled trial, saxagliptin 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 saxagliptin and placebo. The overall incidence of reported hypoglycemia was 20% among subjects treated with saxagliptin 2.5 mg and 22% among subjects treated with placebo. Four saxagliptin-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).
Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. KOMBIGLYZE XR is contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m² [see Dosage and Administration (2.3), Contraindications (4), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. KOMBIGLYZE XR is not recommended in patients with hepatic impairment [see Warnings and Precautions (5.1)].
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