Drug Safety-related Labeling Changes (SrLC)
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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.
AVANDAMET (NDA-021410)
(METFORMIN HYDROCHLORIDE; ROSIGLITAZONE MALEATE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
04/05/2017 (SUPPL-40)
Boxed Warning
(additions underlined)
WARNING: CONGESTIVE HEART FAILURE and LACTIC ACIDOSIS
Rosiglitazone maleate: CONGESTIVE HEART FAILURE
• Thiazolidinediones, including rosiglitazone, cause or exacerbate congestive heart failure in some patients. After initiation of AVANDAMET, and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of AVANDAMET must be considered.
• AVANDAMET is not recommended in patients with symptomatic heart failure. Initiation of AVANDAMET in patients with established NYHA Class III or IV heart failure is contraindicated.
Metformin hydrochloride: LACTIC ACIDOSIS
• Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin- associated lactic acidosis often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominalpain. Metformin- associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and increased lactate/pyruvate ratio; and metformin plasma levels generally >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 AVANDAMET and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.
4 Contraindications
(addition underlined)
• Initiation in patients with established New York Heart Association (NYHA) Class III or IV
heart failure [see Boxed Warning].
• Severe renal impairment (eGFR below 30 mL/minute/1.73 m2).
• Use in patients with acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.
• Use in patients with a history of a hypersensitivity reaction to rosiglitazone or any of the product’s ingredients.
5 Warnings and Precautions
5.1 Lactic Acidosis(subsection revised, additions 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 (>5 mmol/L), 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 AVANDAMET. In patients treated with AVANDAMET 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 to170 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 AVANDAMET 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 postmarketing 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 AVANDAMET, obtain an eGFR.
• AVANDAMET is contraindicated in patients with an eGFR less than 30 mL/minute/1.73 m2
• Initiation of AVANDAMET is not recommended in patients with eGFR between 30 –45 mL/minute/1.73 m2.
• Obtain an eGFR at least annually in all patients taking AVANDAMET. 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 AVANDAMET eGFR later falls below 45 mL/minute/1.73 m2, assess the benefit and risk of continuing therapy.
Drug Interactions: The concomitant use of AVANDAMET 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 AVANDAMET at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/minute/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 AVANDAMET 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. AVANDAMET should be temporarily discontinued while patients have restricted food and fluid intake.
Hypoxic States: Several of the postmarketing 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 AVANDAMET.
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 AVANDAMET.Hepatic Impairment: Patients with hepatic impairment have developed metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of AVANDAMET in patients with clinical or laboratory evidence of hepatic disease.
6 Adverse Reactions
6.3 Postmarketing Experience(additions underlined)
Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with postmarketing use of metformin.
7 Drug Interactions
7.2 Drugs that Reduce Metformin Clearance(subsection revised, additions 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.
(new subsection added)
Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide, or dichlorphenamide) frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with AVANDAMET may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients.
(new subsection added)
Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving AVANDAMET.
8 Use in Specific Populations
8.5 Geriatric Use(additions underlined)
Because reduced renal function is associated with increasing age, AVANDAMET should be used with caution in elderly patients. In general, dose selection for an elderly patient should 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.
(new subsection added)
Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. AVANDAMET is contraindicated in severe renal impairment, patients with an eGFR below 30 mL/minute/1.73 m2.
(new subsection added)
Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. AVANDAMET is not recommended in patients with hepatic impairment.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(additions underlined)
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
There are multiple medications available to treat type 2 diabetes. The benefits and risks of each available diabetes medication should be taken into account when choosing a particular diabetes medication for a given patient.
Patients should be informed of the following:
…
• Instruct patients to inform their doctor that they are taking AVANDAMET prior to any surgical or radiological procedure, as temporary discontinuation of AVANDAMET may be required until renal function has been confirmed to be normal.
…
(additions and revisions, please refer to label)