Kombiglyze XR
(metformin hydrochloride)Dosage & Administration
Kombiglyze XR Prescribing Information
• Post-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (> 5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL [see Warnings and Precautions (5.1)].
• Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), 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 [see Dosage and Administration (2.2), Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7), and Use in Specific Populations (8.6, 8.7)].
• If metformin-associated lactic acidosis is suspected, immediately discontinue KOMBIGLYZE XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1)].
Limitations of Use
KOMBIGLYZE XR is not recommended for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.
Dosage Modifications with Concomitant Use of Strong CYP3A4/5 Inhibitors
The maximum recommended dosage of KOMBIGLYZE XR is 2.5 mg of saxagliptin and 1,000 mg of metformin HCl given orally once daily when used concomitantly with strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitors (e.g., ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin) [see Dosage and Administration (2.1), Drug Interactions (7.1), and Clinical Pharmacology (12.3)].
- Extended-Release Tablets:
- •
- 5 mg of saxagliptin and 500 mg of metformin HCl: light brown to brown, biconvex, capsule-shaped, film-coated tablets with “5/500” printed on one side and “4221” printed on the reverse side, in blue ink.
- •
- 5 mg of saxagliptin and 1,000 mg of metformin HCl: pink, biconvex, capsule-shaped, film-coated tablets with “5/1000” printed on one side and “4223” printed on the reverse side, in blue ink.
- •
- 2.5 mg of saxagliptin and 1,000 mg of metformin HCl: pale yellow to light yellow, biconvex, capsule-shaped, film-coated tablets with “2.5/1000” printed on one side and “4222” printed on the reverse side, in blue ink.
Pregnancy
Risk Summary
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 trials 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.
Clinical Considerations
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.
Data
Animal Data
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 HCI
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 2,000 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 2,000 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.
Lactation
Risk Summary
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.
Data
Human Data
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.
Animal Data
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.
Pediatric Use
The safety and effectiveness of KOMBIGLYZE XR as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus have not been established in pediatric patients.
Effectiveness of saxagliptin was not demonstrated in a 26-week, placebo-controlled, double-blind randomized clinical trial with a 26-week safety extension (NCT03199053) in 164 pediatric patients aged 10 to 17 years with inadequately controlled type 2 diabetes mellitus.
Geriatric Use
KOMBIGLYZE XR
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)].
Saxagliptin
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 patients 65 years of age and older and younger adult patients.
Metformin HCI
Controlled clinical trials of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently than younger patients. 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 Warnings and Precautions (5.1)].
Renal Impairment
Saxagliptin
In a 12-week randomized placebo-controlled trial, saxagliptin 2.5 mg was administered to 85 patients 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 patients treated with saxagliptin 2.5 mg and 22% among patients treated with placebo. Four saxagliptin-treated patients (4.7%) and three placebo-treated patients (3.5%) reported at least one episode of confirmed symptomatic hypoglycemia (accompanying fingerstick glucose ≤50 mg/dL).
Metformin HCI
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 (2.2), Contraindications (4), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
Hepatic Impairment
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)].
KOMBIGLYZE XR is contraindicated in patients with:
- •
- Severe renal impairment (eGFR below 30 mL/min/1.73 m2).
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- Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin.
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- A history of a serious hypersensitivity reaction to saxagliptin, metformin HCl, or any of the ingredients in KOMBLIGLYZE XR. Reactions such as anaphylaxis, angioedema, or exfoliative skin conditions have been reported [see Warnings and Precautions (5.6) and Adverse Reactions (6.2)].
Bullous Pemphigoid
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.
Postmarketing Experience
Additional adverse reactions have been identified during post-approval use of KOMBIGLYZE XR, saxagliptin, or metformin HCl. 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
- •
- Gastrointestinal Disorders: Pancreatitis
- •
- Immune System Disorders: Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions
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- Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis, Severe and disabling arthralgia
- •
- Skin and Subcutaneous Tissue Disorders: Bullous pemphigoid
Metformin HCl
- •
- Hepatobiliary Disorders: Cholestatic, hepatocellular, and mixed hepatocellular liver injury
Strong Inhibitors of CYP3A4/5 Enzymes
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 KOMBIGLYZE XR should be limited to 2.5 mg of saxagliptin when coadministered with a strong CYP3A4/5 inhibitor [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ].
Carbonic Anhydrase Inhibitors
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.
Drugs that Reduce Metformin Clearance
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
Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving KOMBIGLYZE XR.
Insulin or Insulin Secretagogues
Insulin and insulin secretagogues are known to cause hypoglycemia. Concomitant use of KOMBIGLYZE XR with insulin or an insulin secretagogue may require lower dosages of insulin or the insulin secretagogue to reduce the risk of hypoglycemia [see Warnings and Precautions (5.5)].
Drugs Affecting Glycemic Control
Certain drugs tend to produce 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 blocking drugs, and isoniazid. When such drugs are administered to a patient receiving KOMBIGLYZE XR, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving KOMBIGLYZE XR, observe the patient closely for hypoglycemia.
The biologically inert components of the tablet may occasionally remain intact during gastrointestinal transit and will be eliminated in the feces as a soft, hydrated mass.
Mechanism of Action
KOMBIGLYZE XR
KOMBIGLYZE XR contains two antihyperglycemic medications: saxagliptin, a dipeptidyl-peptidase-4 (DPP4) inhibitor, and metformin HCl, a biguanide.
Saxagliptin
Increased concentrations of the incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released into the bloodstream from the small intestine in response to meals. These hormones cause insulin release from the pancreatic beta cells in a glucose-dependent manner but are inactivated by the DPP4 enzyme within minutes. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, reducing hepatic glucose production. In patients with type 2 diabetes mellitus, concentrations of GLP-1 are reduced but the insulin response to GLP-1 is preserved. Saxagliptin is a competitive DPP4 inhibitor that slows the inactivation of the incretin hormones, thereby increasing their bloodstream concentrations and reducing fasting and postprandial glucose concentrations in a glucose-dependent manner in patients with type 2 diabetes mellitus.
Metformin HCl
Metformin improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in patients with type 2 diabetes mellitus or in healthy subjects except in unusual circumstances [see Warnings and Precautions (5.5)] and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.
Pharmacodynamics
Saxagliptin
In patients with type 2 diabetes mellitus, administration of saxagliptin inhibits DPP4 enzyme activity for a 24-hour period. After an oral glucose load or a meal, this DPP4 inhibition resulted in a 2- to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and increased glucose-dependent insulin secretion from pancreatic beta cells. The rise in insulin and decrease in glucagon were associated with lower fasting glucose concentrations and reduced glucose excursion following an oral glucose load or a meal.
Cardiac Electrophysiology
Saxagliptin
In a randomized, double-blind, placebo-controlled, 4-way crossover, active comparator trial using moxifloxacin in 40 healthy subjects, saxagliptin was not associated with clinically meaningful prolongation of the QTc interval or heart rate at daily doses up to 40 mg (8-times the MRHD).
Pharmacokinetics
KOMBIGLYZE XR
Bioequivalence and food effect of KOMBIGLYZE XR was characterized under low calorie diet. The low calorie diet consisted of 324 kcal with meal composition that contained 11.1% protein, 10.5% fat, and 78.4% carbohydrate. The results of bioequivalence studies in healthy subjects demonstrated that KOMBIGLYZE XR combination tablets are bioequivalent to coadministration of corresponding doses of saxagliptin (ONGLYZA) and metformin HCl extended-release as individual tablets under fed conditions.
Saxagliptin
The pharmacokinetics of saxagliptin and its active metabolite, 5-hydroxy saxagliptin were similar in healthy subjects and in patients with type 2 diabetes mellitus. The Cmax and AUC values of saxagliptin and its active metabolite increased proportionally in the 2.5 to 400 mg dose range. Following a 5 mg single oral dose of saxagliptin to healthy subjects, the mean plasma AUC values for saxagliptin and its active metabolite were 78 ng•h/mL and 214 ng•h/mL, respectively. The corresponding plasma Cmax values were 24 ng/mL and 47 ng/mL, respectively. The average variability (%CV) for AUC and Cmax for both saxagliptin and its active metabolite was less than 25%.
No appreciable accumulation of either saxagliptin or its active metabolite was observed with repeated once-daily dosing at any dose level. No dose- and time-dependence were observed in the clearance of saxagliptin and its active metabolite over 14 days of once-daily dosing with saxagliptin at doses ranging from 2.5 to 400 mg.
Metformin HCl
Metformin extended-release Cmax is achieved with a median value of 7 hours and a range of 4 to 8 hours. At steady state, the AUC and Cmax are less than dose proportional for metformin extended-release within the range of 500 to 2,000 mg. After repeated administration of metformin extended-release, metformin did not accumulate in plasma. Metformin is excreted unchanged in the urine and does not undergo hepatic metabolism. Peak plasma levels of metformin extended-release tablets are approximately 20% lower compared to the same dose of metformin immediate-release tablets, however, the extent of absorption (as measured by AUC) is similar between extended-release tablets and immediate-release tablets.
Absorption
Saxagliptin
The median time to maximum concentration (Tmax) following the 5 mg once daily dose was 2 hours for saxagliptin and 4 hours for its active metabolite.
Metformin HCl
Following a single oral dose of metformin extended-release, Cmax is achieved with a median value of 7 hours and a range of 4 to 8 hours.
Effect of Food
Saxagliptin
Administration with a high-fat meal resulted in an increase in Tmax of saxagliptin by approximately 20 minutes as compared to fasted conditions. There was a 27% increase in the AUC of saxagliptin when given with a meal as compared to fasted conditions. Food has no significant effect on the pharmacokinetics of saxagliptin when administered as KOMBIGLYZE XR combination tablets.
Metformin HCl
Although the extent of metformin absorption (as measured by AUC) from the metformin extended-release tablet increased by approximately 50% when given with food, there was no effect of food on Cmax and Tmax of metformin. Both high and low fat meals had the same effect on the pharmacokinetics of metformin extended-release. Food has no significant effect on the pharmacokinetics of metformin when administered as KOMBIGLYZE XR combination tablets.
Distribution
Saxagliptin
The in vitro protein binding of saxagliptin and its active metabolite in human serum is negligible. Therefore, changes in blood protein levels in various disease states (e.g., renal or hepatic impairment) are not expected to alter the disposition of saxagliptin.
Metformin HCl
Distribution studies with extended-release metformin have not been conducted; however, the apparent volume of distribution (V/F) of metformin following single oral doses of immediate-release metformin 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. Metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas, which are extensively bound to serum proteins.
Elimination
Metabolism
Saxagliptin
The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5). The major metabolite of saxagliptin is also a DPP4 inhibitor, which is one-half as potent as saxagliptin. Therefore, strong CYP3A4/5 inhibitors and inducers will alter the pharmacokinetics of saxagliptin and its active metabolite [see Drug Interactions (7.1)].
Metformin HCl
Intravenous single-dose studies in healthy subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion.
Metabolism studies with extended-release metformin tablets have not been conducted.
Excretion
Saxagliptin
Saxagliptin is eliminated by both renal and hepatic pathways. Following a single 50 mg dose of 14C-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its active metabolite, and total radioactivity, respectively. The average renal clearance of saxagliptin (~230 mL/min) was greater than the average estimated glomerular filtration rate (~120 mL/min), suggesting some active renal excretion. A total of 22% of the administered radioactivity was recovered in feces representing the fraction of the saxagliptin dose excreted in bile and/or unabsorbed drug from the gastrointestinal tract. Following a single oral dose of saxagliptin 5 mg to healthy subjects, the mean plasma terminal half-life (t1/2) for saxagliptin and its active metabolite was 2.5 and 3.1 hours, respectively.
Metformin HCl
Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.
Specific Populations
Geriatric Patients
Saxagliptin
No dosage adjustment is recommended based on age alone. Elderly subjects (65-80 years) had 23% and 59% higher geometric mean Cmax and geometric mean AUC values, respectively, for saxagliptin than young subjects (18-40 years). Differences in active metabolite pharmacokinetics between elderly and young subjects generally reflected the differences observed in saxagliptin pharmacokinetics. The difference between the pharmacokinetics of saxagliptin and the active metabolite in young and elderly subjects is likely due to multiple factors including declining renal function and metabolic capacity with increasing age. Age was not identified as a significant covariate on the apparent clearance of saxagliptin and its active metabolite in the population pharmacokinetic analysis.
Metformin HCl
Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function.
Male and Female Patients
Saxagliptin
No dosage adjustment is recommended based on gender. There were no differences observed in saxagliptin pharmacokinetics between males and females. Compared to males, females had approximately 25% higher exposure values for the active metabolite than males, but this difference is unlikely to be of clinical relevance. Gender was not identified as a significant covariate on the apparent clearance of saxagliptin and its active metabolite in the population pharmacokinetic analysis.
Metformin HCl
Metformin pharmacokinetic parameters did not differ significantly between healthy subjects and patients with type 2 diabetes mellitus when analyzed according to gender (males=19, females=16). Similarly, in controlled clinical studies in patients with type 2 diabetes mellitus, the antihyperglycemic effect of metformin was comparable in males and females.
Racial or Ethnic Groups
Saxagliptin
No dosage adjustment is recommended based on race. The population pharmacokinetic analysis compared the pharmacokinetics of saxagliptin and its active metabolite in 309 White subjects with 105 subjects of other races (consisting of six racial groups). No significant difference in the pharmacokinetics of saxagliptin and its active metabolite were detected between these two populations.
Metformin HCl
No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes mellitus, the antihyperglycemic effect was comparable in Whites (n=249), Black or African American (n=51), and Hispanic or Latino ethnicity (n=24).
Patients with Renal Impairment
Saxagliptin
A single-dose, open-label trial was conducted to evaluate the pharmacokinetics of saxagliptin (10 mg dose) in subjects with varying degrees of chronic renal impairment compared to subjects with normal renal function. The 10 mg dosage is not an approved dosage. The degree of renal impairment did not affect Cmax of saxagliptin or its metabolite. In subjects with moderate renal impairment with eGFR 30 to less than 45 mL/min/1.73 m2, severe renal impairment (eGFR 15 to less than 30 mL/min/1.73 m2) and ESRD patient on hemodialysis, the AUC values of saxagliptin or its active metabolite were >2 fold higher than AUC values in subjects with normal renal function.
Metformin HCl
In patients with decreased renal function, the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased [see Contraindications (4) and Warnings and Precautions (5.1)].
Patients with Hepatic Impairment
No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment.
Body Mass Index
Saxagliptin
No dosage adjustment is recommended based on body mass index (BMI) which was not identified as a significant covariate on the apparent clearance of saxagliptin or its active metabolite in the population pharmacokinetic analysis.
Drug Interaction Studies
Specific pharmacokinetic drug interaction studies with KOMBIGLYZE XR have not been performed, although such studies have been conducted with the individual saxagliptin and metformin components.
In Vitro Assessment of Drug Interactions
In in vitro studies, saxagliptin and its active metabolite did not inhibit CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4, or induce CYP1A2, 2B6, 2C9, or 3A4. Therefore, saxagliptin is not expected to alter the metabolic clearance of coadministered drugs that are metabolized by these enzymes. Saxagliptin is a P-glycoprotein (P-gp) substrate, but is not a significant inhibitor or inducer of P-gp.
In Vivo Assessment of Drug Interactions
| Coadministered Drug | Dosage of Coadministered Drug * | Dosage of Saxagliptin * | Geometric Mean Ratio (ratio with/without coadministered drug) No Effect = 1.00 | ||
|---|---|---|---|---|---|
| AUC † | Cmax | ||||
| |||||
No dosing adjustments required for the following: | |||||
Metformin | 1,000 mg | 100 mg | saxagliptin | 0.98 | 0.79 |
Glyburide | 5 mg | 10 mg | saxagliptin | 0.98 | 1.08 |
Pioglitazone ‡ | 45 mg QD for 10 days | 10 mg QD for 5 days | saxagliptin | 1.11 | 1.11 |
Digoxin | 0.25 mg q6h first day followed by q12h second day followed by QD for | 10 mg QD for 7 days | saxagliptin | 1.05 | 0.99 |
Dapagliflozin | 10 mg single dose | 5 mg single dose | saxagliptin 5-hydroxy saxagliptin | ↓1% ↑9% | ↓7% ↑6% |
Simvastatin | 40 mg QD for 8 days | 10 mg QD for 4 days | saxagliptin | 1.12 | 1.21 |
Diltiazem | 360 mg LA QD for 9 days | 10 mg | saxagliptin | 2.09 | 1.63 |
Rifampin § | 600 mg QD for 6 days | 5 mg | saxagliptin | 0.24 | 0.47 |
Omeprazole | 40 mg QD for 5 days | 10 mg | saxagliptin | 1.13 | 0.98 |
Aluminum hydroxide + magnesium hydroxide + simethicone | aluminum hydroxide: | 10 mg | saxagliptin | 0.97 | 0.74 |
Famotidine | 40 mg | 10 mg | saxagliptin | 1.03 | 1.14 |
Limit KOMBIGLYZE XR dose to 2.5 mg/1,000 mg once daily when coadministered with strong CYP3A4/5 inhibitors [see Drug Interactions (7.1) and Dosage and Administration (2.2)]: | |||||
Ketoconazole | 200 mg BID for 9 days | 100 mg | saxagliptin | 2.45 | 1.62 |
Ketoconazole | 200 mg BID for 7 days | 20 mg | saxagliptin | 3.67 | 2.44 |
ND=not determined; QD=once daily; q6h=every 6 hours; q12h=every 12 hours; BID=twice daily; LA=long acting.
| Coadministered Drug | Dosage of Coadministered Drug * | Dosage of Saxagliptin * | Geometric Mean Ratio (ratio with/without saxagliptin) No Effect = 1.00 | ||
|---|---|---|---|---|---|
| AUC † | Cmax | ||||
| |||||
No dosing adjustments required for the following: | |||||
Metformin | 1000 mg | 100 mg | metformin | 1.20 | 1.09 |
Glyburide | 5 mg | 10 mg | glyburide | 1.06 | 1.16 |
Pioglitazone ‡ | 45 mg QD for 10 days | 10 mg QD for 5 days | pioglitazone | 1.08 | 1.14 |
Digoxin | 0.25 mg q6h first day followed by q12h second day followed by QD for | 10 mg QD for 7 days | digoxin | 1.06 | 1.09 |
Simvastatin | 40 mg QD for 8 days | 10 mg QD for 4 days | simvastatin | 1.04 | 0.88 |
Diltiazem | 360 mg LA QD for 9 days | 10 mg | diltiazem | 1.10 | 1.16 |
Ketoconazole | 200 mg BID for 9 days | 100 mg | ketoconazole | 0.87 | 0.84 |
Ethinyl estradiol and norgestimate | ethinyl estradiol 0.035 mg and norgestimate 0.250 mg for 21 days | 5 mg QD for 21 days | ethinyl estradiol | 1.07 | 0.98 |
ND=not determined; QD=once daily; q6h=every 6 hours; q12h=every 12 hours; BID=twice daily; LA=long acting.
| Coadministered Drug | Dose of Coadministered Drug * | Dose of Metformin * | Geometric Mean Ratio (ratio with/without coadministered drug) No Effect = 1.00 | ||
|---|---|---|---|---|---|
| AUC † | Cmax | ||||
| |||||
No dosing adjustments required for the following: | |||||
Glyburide | 5 mg | 850 mg | metformin | 0.91 ‡ | 0.93 ‡ |
Furosemide | 40 mg | 850 mg | metformin | 1.09 ‡ | 1.22 ‡ |
Nifedipine | 10 mg | 850 mg | metformin | 1.16 | 1.21 |
Propranolol | 40 mg | 850 mg | metformin | 0.90 | 0.94 |
Ibuprofen | 400 mg | 850 mg | metformin | 1.05 ‡ | 1.07 ‡ |
Drugs that are eliminated by renal tubular secretion may increase the accumulation of metformin [see Drug Interactions (7.3)]. | |||||
Cimetidine | 400 mg | 850 mg | metformin | 1.40 | 1.61 |
| Coadministered Drug | Dose of Coadministered Drug * | Dose of Metformin * | Geometric Mean Ratio (ratio with/without metformin) No Effect = 1.00 | ||
|---|---|---|---|---|---|
| AUC † | Cmax | ||||
| |||||
No dosing adjustments required for the following: | |||||
Glyburide | 5 mg | 850 mg | glyburide | 0.78 ‡ | 0.63 ‡ |
Furosemide | 40 mg | 850 mg | furosemide | 0.87 ‡ | 0.69 ‡ |
Nifedipine | 10 mg | 850 mg | nifedipine | 1.10 § | 1.08 |
Propranolol | 40 mg | 850 mg | propranolol | 1.01 § | 1.02 |
Ibuprofen | 400 mg | 850 mg | ibuprofen | 0.97 ¶ | 1.01 ¶ |
Cimetidine | 400 mg | 850 mg | cimetidine | 0.95 § | 1.01 |
Carcinogenesis, Mutagenesis, Impairment of Fertility
KOMBIGLYZE XR
No animal studies have been conducted with the combined products in KOMBIGLYZE XR to evaluate carcinogenesis, mutagenesis, or impairment of fertility. The following data are based on studies with saxagliptin and metformin administered individually.
Saxagliptin
Carcinogenesis
Carcinogenicity was evaluated in 2-year studies conducted in CD-1 mice and Sprague-Dawley rats. Saxagliptin did not increase the incidence of tumors in mice dosed orally at 50, 250, and 600 mg/kg up to 870-times (males) and 1165-times (females) the 5 mg/day clinical dose, based on AUC. Saxagliptin did not increase the incidence of tumors in rats dosed orally at 25, 75, 150, and 300 mg/kg up to 355-times (males) and 2217-times (females) the 5 mg/day clinical dose, based on AUC.
Mutagenesis
Saxagliptin was not mutagenic or clastogenic in a battery of genotoxicity tests (Ames bacterial mutagenesis, human and rat lymphocyte cytogenetics, rat bone marrow micronucleus and DNA repair assays). The active metabolite of saxagliptin was not mutagenic in an Ames bacterial assay.
Impairment of Fertility
Saxagliptin administered to rats had no effect on fertility or the ability to maintain a litter at exposures up to 603-times and 776-times the 5 mg clinical dose in males and females, based on AUC.
Metformin HCI
Carcinogenesis
Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1,500 mg/kg/day, respectively. These doses are both approximately 4 times the maximum recommended human daily dose of 2,000 mg based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in either male or female mice. Similarly, there was no tumorigenic potential observed with metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/day.
Mutagenesis
There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.
Impairment of Fertility
Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately 3 times the maximum recommended human daily dose based on body surface area comparisons.
Animal Toxicology and/or Pharmacology
Saxagliptin
Saxagliptin produced adverse skin changes in the extremities of cynomolgus monkeys (scabs and/or ulceration of tail, digits, scrotum, and/or nose). Skin lesions were reversible within exposure approximately 20-times the 5 mg clinical dose, but in some cases were irreversible and necrotizing at higher exposures. Adverse skin changes were not observed at exposures similar to (1- to 3-times) the 5 mg clinical dose. Clinical correlates to skin lesions in monkeys have not been observed in human clinical trials of saxagliptin.
Saxagliptin Add-On Combination Therapy with Metformin HCI plus Sulfonylurea
A total of 257 patients with type 2 diabetes mellitus participated in this 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of saxagliptin in combination with metformin HCl plus a sulfonylurea in patients with inadequate glycemic control (A1C ≥7% and ≤10%). Patients were to be on a stable combined dose of metformin HCl extended-release or immediate-release (at maximum tolerated dose, with minimum dose for enrollment being 1,500 mg) and a sulfonylurea (at maximum tolerated dose, with minimum dose for enrollment being ≥50% of the maximum recommended dose) for 8 weeks prior to enrollment.
Patients who met eligibility criteria were entered in a 2-week enrollment period to allow assessment of inclusion/exclusion criteria. Following the 2-week enrollment period, eligible patients were randomized to either double-blind saxagliptin (5 mg once daily) or double-blind matching placebo for 24 weeks. During the 24-week double-blind treatment period, patients were to receive metformin HCl and a sulfonylurea at the same constant dose ascertained during enrollment. Sulfonylurea dose could be down titrated once in the case of a major hypoglycemic event or recurring minor hypoglycemic events. In the absence of hypoglycemia, titration (up or down) of trial medication during the treatment period was prohibited.
Saxagliptin in combination with metformin HCl plus a sulfonylurea provided significant improvements in A1C and PPG compared with placebo in combination with metformin HCl plus a sulfonylurea (Table 11). The percentage of patients who discontinued for lack of glycemic control was 6% in the saxagliptin group and 5% in the placebo group.
| Efficacy Parameter | Saxagliptin 5 mg + Metformin plus Sulfonylurea N=129 | Placebo + Metformin plus Sulfonylurea N=128 |
|---|---|---|
| ||
Hemoglobin A1C (%) | N=127 | N=127 |
Baseline (mean) | 8.4 | 8.2 |
Change from baseline (adjusted mean †) | −0.7 | −0.1 |
Difference from placebo (adjusted mean †) | −0.7 ‡ | |
95% Confidence Interval | (−0.9, −0.5) | |
2-hour Postprandial Glucose (mg/dL) | N=115 | N=113 |
Baseline (mean) | 268 | 262 |
Change from baseline (adjusted mean †) | −12 | 5 |
Difference from placebo (adjusted mean †) | −17 § | |
95% Confidence Interval | (−32, −2) | |
The change in fasting plasma glucose from baseline to Week 24 was also tested, but was not statistically significant. The percent of patients achieving an A1C <7% was 31% (39/127) with saxagliptin in combination with metformin HCI plus a sulfonylurea compared to 9% (12/127) with placebo. Significance was not tested.
Saxagliptin Add-on Combination Therapy with Metformin plus an SGLT2 Inhibitor
A total of 315 patients with type 2 diabetes mellitus participated in this 24 week randomized, double blind, placebo controlled trial to evaluate the efficacy and safety of saxagliptin added to dapagliflozin (an SGLT2 inhibitor) and metformin HCl in patients with a baseline of HbA1c ≥7% to ≤10.5%. The mean age of these patients was 54.6 years, 1.6% were 75 years or older and 52.7% were female. The population was 87.9% White, 6.3% Black or African American, 4.1% Asian, and 1.6% other races. At baseline the population had diabetes for an average of 7.7 years and a mean HbA1c of 7.9%. The mean eGFR at baseline was 93.4 mL/min/1.73 m2. Patients were required to be on a stable dose of metformin HCl (≥1,500 mg per day) for at least 8 weeks prior to enrollment. Eligible patients who completed the screening period entered the lead in treatment period, which included 16 weeks of open-label metformin HCl and 10 mg dapagliflozin treatment. Following the lead-in period, eligible patients were randomized to saxagliptin 5 mg (N=153) or placebo (N =162).
The group treated with add-on saxagliptin had statistically significant greater reductions in HbA1c from baseline versus the group treated with placebo (see Table 12).
| ||
Saxagliptin 5 mg (N=153) † | Placebo (N=162) † | |
In combination with Dapagliflozin and Metformin HCI | ||
Hemoglobin A1C (%) ‡ | ||
Baseline (mean) | 8.0 | 7.9 |
Change from baseline (adjusted mean §)
| −0.5 (−0.6, −0.4) | −0.2 (−0.3, −0.1) |
Difference from placebo (adjusted mean)
| −0.4 ¶ (−0.5, −0.2) | |
The known proportion of patients achieving HbA1c <7% at Week 24 was 35.3% in the saxagliptin-treated group compared to 23.1% in the placebo-treated group.
How Supplied
KOMBIGLYZE® XR (saxagliptin and metformin HCl extended-release) tablets have markings on both sides and are available in the strengths and packages listed in Table 15.
| Tablet Strength (saxagliptin and metformin HCl extended-release) | Film-Coated Tablet Color/Shape | Tablet Markings | Package Size | NDC Code |
|---|---|---|---|---|
5 mg/500 mg | light brown to brown, | “5/500” on one side and “4221” on the reverse, in blue ink | Bottles of 30 | 0310-6135-30 |
5 mg/1,000 mg | pink, | “5/1000” on one side and “4223” on the reverse, in blue ink | Bottles of 30 | 0310-6145-30 |
2.5 mg/1,000 mg | pale yellow to light yellow, | “2.5/1000” on one side and “4222” on the reverse, in blue ink | Bottles of 60 | 0310-6125-60 |
Storage and Handling
Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].
Metformin HCl
Metformin improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in patients with type 2 diabetes mellitus or in healthy subjects except in unusual circumstances [see Warnings and Precautions (5.5)] and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.
Kombiglyze XR Prior Authorization Resources
Most recent state uniform prior authorization forms
Reimbursement help (FRM)
Kombiglyze XR Financial Assistance Options
Copay savings program
Overview
- Reduce patient OOP costs for drug (and occasionally for drug administration/infusion costs or drug-related test costs)
Patient benefit
- A portion (or all) of patient OOP (deductible, copay), typically up to monthly and/or annual max
Patient eligibility
- Patient must enroll or activate (may permit HCPs to enroll on patient’s behalf for HCP-administered drugs)
- Generally, must have commercial insurance (rarely, may permit uninsured patients to use)
- May never be used with government insurance
How to sign up
- Cards may be downloadable digital cards or hard copies
- Some pharmacos offer debit cards with pre-loaded copay benefit
- Typically, available through multiple channels (e.g., rep to HCP to patient; pharmacy to patient; patient via website, Hub live agent, or copay vendor (live agent or IVR); patient and HCP via Hub enrollment form)
- Some HCP-administered product programs permit HCPs to enroll on a patient’s behalf through via Hub form