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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
KOMBIGLYZE XR (NDA-200678)
(METFORMIN HYDROCHLORIDE; SAXAGLIPTIN HYDROCHLORIDE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
10/11/2024 (SUPPL-28)
4 Contraindications
Additions and/or revisions underlined:
…
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)].
5 Warnings and Precautions
5.5 Hypoglycemia with Concomitant Use of Insulin or Insulin SecretagoguesAdditions and/or revisions underlined:
…
Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.
6 Adverse Reactions
Addition of the following to the bulleted line listing:
Lactic Acidosis [see Boxed Warning and Warnings and Precautions (5.1)]
Vitamin B12 Concentrations [see Warnings and Precautions (5.4)]
6.1 Clinical Trials Experience
Additions and/or revisions underlined:
…
Vitamin B12 Concentrations
Metformin HCl
In metformin clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of patients.
7 Drug Interactions
Underlined text added to the title:
7.6 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.
8 Use in Specific Populations
8.4 Pediatric UseAdditions and/or revisions underlined:
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.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions and/or revisions underlined:
…
Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues
Inform patients that hypoglycemia can occur, particularly when insulin or an insulin secretagogue is used in combination with KOMBIGLYZE XR. Educate patients about the risks, symptoms and appropriate management of hypoglycemia [see Warnings and Precautions (5.5)].
…
Missed Dose
If a dose is missed, advise patients to take KOMBIGLYZE XR as soon as they remember unless it is time for their next dose Instruct patients not to take two doses of KOMBLIGLYZE XR at the same time.
…
MEDICATION GUIDE
Extensive additions and/or revisions, please refer to label for complete information.
07/01/2019 (SUPPL-24)
6 Adverse Reactions
6.2 Postmarketing Experience
(additions underlined)
…
Rhabdomyolysis
02/27/2017 (SUPPL-18)
8 Use in Specific Populations
8.1 PregnancyPLLR conversion, as below:
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 studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk.
No adverse developmental effects independent of maternal toxicity were observed when saxagliptin and metformin were administered separately or in combination to pregnant rats and rabbits during the period of organogenesis.
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 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 mg metformin. Minor skeletal abnormalities associated with maternal toxicity and 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.
PLLR conversion, as below:
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.
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
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.
Animals
No studies is 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.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDEWhat is the most important information I should know about KOMBIGLYZE XR? Serious side effects can happen in people taking KOMBIGLYZE XR, including:
2. Inflammation of the pancreas (pancreatitis) which may be severe and lead to death
Before you start taking KOMBIGLYZE XR:
Stop taking KOMBIGLYZE XR and contact your healthcare provider right away if you have pain in your stomach area (abdomen) that is severe and will not go away. The pain may be felt going from your abdomen through to your back. The pain may happen with or without vomiting. These may be symptoms of pancreatitis.
3. Heart failure. Heart failure means your heart does not pump blood well enough.
Before you start taking KOMBIGLYZE XR:
Contact your healthcare provider right away if you have any of the following symptoms:
- swelling or fluid retention, especially in the feet, ankles or legs
- unusual tiredness
01/18/2017 (SUPPL-19)
Boxed Warning
(Additions and/or revisions are underlined)
WARNING: LACTIC ACIDOSIS
- 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 (greater than 5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally greater than 5 mcg/mL.
- 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
- If metformin-associated lactic acidosis is suspected, immediately discontinue KOMBIGLYZE XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.
4 Contraindications
(Additions and/or revisions are underlined)
KOMBIGLYZE XR is contraindicated in patients with:
Severe renal impairment (eGFR below 30 mL/min/1.73 m2).
5 Warnings and Precautions
5.1 Lactic Acidosis(Additions and/or revisions are underlined)
There have been post-marketing 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 (greater than 5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:pyruvate ratio; metformin plasma levels generally greater than 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:
- Before initiating KOMBIGLYZE XR, obtain an estimated glomerular filtration rate (eGFR).
- KOMBIGLYZE XR is contraindicated in patients with an eGFR less than 30 mL/minute/1.73 m(squared)
- Initiation of KOMBIGLYZE XR is not recommended in patients with eGFR between 30 and 45 mL/minute/1.73 m(squared)
- Obtain an eGFR at least annually in all patients taking KOMBIGLYZE XR. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.
- In patients taking KOMBIGLYZE XR whose eGFR later falls below 45 mL/minute/1.73 m(squared), assess the benefit and risk of continuing therapy.
Drug Interactions: 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. Therefore, consider more frequent monitoring of patients.
Age 65 or Greater: 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.
Radiological Studies with Contrast: 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 m(squared); 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.
Surgery and Other Procedures: 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.
Hypoxic States: 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.
Excessive Alcohol Intake: 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.
Hepatic Impairment: 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.
6 Adverse Reactions
(Additions and/or revisions are underlined)
- Severe and disabling arthralgia
(Additions and/or revisions are underlined)
Metformin hydrochloride
- Cholestatic, hepatocellular, and mixed hepatocellular liver injury
7 Drug Interactions
7.2 Carbonic Anhydrase Inhibitors(Newly added subsection)
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.
(Revised subsection title; additions and/or revisions are underlined)
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. Consider the benefits and risks of concomitant use.
(Newly added subsection)
Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving KOMBIGLYZE XR.
(Newly added subsection)
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.
8 Use in Specific Populations
8.5 Geriatric Use(Additions and/or revisions are underlined)
KOMBIGLYZE XR
…Assess renal function more frequently in the elderly.
Metformin hydrochloride
…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.
(Additions and/or revisions are underlined)
Metformin hydrochloride
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 m(squared).
(Newly added subsection)
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.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Additions and/or revisions are underlined)
Lactic Acidosis
Instruct patients to inform their doctor that they are taking KOMBIGLYZE XR prior to any surgical or radiological procedure, as temporary discontinuation of KOMBIGLYZE XR may be required until renal function has been confirmed to be normal.
(Additions and/or revisions are underlined)
What is the most important information I should know about KOMBIGLYZE XR? Serious side effects can happen in people taking KOMBIGLYZE XR, including:
Call your doctor right away if you have any of the following symptoms, which could be signs of lactic acidosis:
Most people who have had lactic acidosis with metformin have other things that, combined with the metformin, led to the lactic acidosis. Tell your doctor if you have any of the following, because you have a higher chance for getting lactic acidosis with KOMBIGLYZE XR if you:
have severe kidney problems or your kidneys are affected by certain x-ray tests that use injectable dye
drink alcohol very often, or drink a lot of alcohol…
The best way to keep from having a problem with lactic acidosis from metformin is to tell your doctor if you have any of the problems in the list above. Your doctor may decide to stop your KOMBIGLYZE XR for a while if you have any of these things. KOMBIGLYZE XR can have other serious side effects. See “What are the possible side effects of KOMBIGLYZE XR?
01/18/2017 (SUPPL-20)
5 Warnings and Precautions
5.9 Bullous Pemphigoid(Newly added subsection)
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.
6 Adverse Reactions
(Additions and/or revisions are underlined)
Bullous pemphigoid
(Additions and/or revisions are underlined)
Saxagliptin
- Bullous pemphigoid
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Additions and/or revisions are underlined)
Bullous Pemphigoid
Inform patients that bullous pemphigoid may occur with this class of drugs. Instruct patients to seek medical advice if blisters or erosions occur.
(Additions and/or revisions are underlined)
What are the possible side effects of KOMBIGLYZE XR? KOMBIGLYZE XR can cause serious side effects, including:
- Skin reaction. Some people who take medicines called DPP-4 inhibitors, one of the medicines in KOMBIGLYZE XR, may develop a skin reaction called bullous pemphigoid that can require treatment in a hospital. Tell your healthcare provider right away if you develop blisters or the breakdown of the outer layer of your skin (erosion). Your healthcare provider may tell you to stop taking KOMBIGLYZE XR.