LINAGLIPTIN: 7,762 Adverse Event Reports & Safety Profile

Linagliptin and metformin hydrochloride tablets for oral use contain: linagliptin and metformin hydrochloride.

Linagliptin

Linagliptin is an inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme. The chemical name of linagliptin is 1H-Purine-2,6-dione, 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]- The molecular formula is C 25 H 28 N 8 O 2 and the molecular weight is 472.54 g/mol. The structural formula is: Linagliptin is a white to yellowish, not or only slightly hygroscopic solid substance. It is very slightly soluble in water (0.9 mg/mL). Linagliptin is soluble in methanol (ca. 60 mg/mL), sparingly soluble in ethanol (ca. 10 mg/mL), very slightly soluble in isopropanol (<1 mg/mL), and very slightly soluble in acetone (ca.1 mg/mL).

Metformin Hydrochloride

Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is a biguanide. Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of C 4 H 11 N 5

• HCl and a molecular weight of 165.63 g/mol. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. The structural formula is: Linagliptin and Metformin Hydrochloride Tablets Linagliptin and metformin hydrochloride tablets are available for oral administration as tablets containing:
• 2.5 mg linagliptin and 500 mg metformin hydrochloride (equivalent to 389.93 mg of metformin)
• 2.5 mg linagliptin and 850 mg metformin hydrochloride (equivalent 662.88 mg of metformin)
• 2.5 mg linagliptin and 1,000 mg metformin hydrochloride (equivalent to 779.86 mg of metformin) Each film-coated tablet of linagliptin and metformin hydrochloride tablets contains the following inactive ingredients: colloidal silicon dioxide, copovidone, corn starch, hypromellose, magnesium stearate, meglumine, povidone, propylene glycol, titanium dioxide, talc, yellow iron oxide (2.5 mg/500 mg; 2.5 mg/850 mg) and/or red iron oxide (2.5 mg/850 mg; 2.5 mg/1,000 mg). lina-met-tabs-structure1 lina-met-tabs-structure2

AND USAGE Linagliptin and metformin hydrochloride tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use Linagliptin and metformin hydrochloride tablets are not recommended in patients with type 1 diabetes mellitus. Linagliptin and metformin hydrochloride tablets have not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at an increased risk for the development of pancreatitis while using linagliptin and metformin hydrochloride tablets [see Warnings and Precautions (5.2 )]. Linagliptin and metformin hydrochloride tablets are a combination of linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor and metformin hydrochloride (HCl), a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus ( 1 ) Limitations of Use

• Not recommended in patients with type 1 diabetes mellitus ( 1 )
• Has not been studied in patients with a history of pancreatitis ( 1 )

AND ADMINISTRATION

• Individualize the starting dosage of linagliptin and metformin hydrochloride tablets based on the patient's current regimen ( 2.1 )
• The maximum recommended dosage is 2.5 mg linagliptin/1,000 mg metformin HCl twice daily ( 2.1 )
• Take orally twice daily with meals, with gradual dosage escalation to reduce the gastrointestinal effects due to metformin ( 2.1 )
• Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR) ( 2.2 ) o Do not use in patients with eGFR below 30 mL/min/1.73 m 2 o Initiation is not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m 2 o Assess risk/benefit of continuing if eGFR falls below 45 mL/min/1.73 m 2 o Discontinue if eGFR falls below 30 mL/min/1.73 m 2
• Linagliptin and metformin hydrochloride tablets may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures ( 2.3 )

2.1 Recommended Dosage and Administration The dosage of linagliptin and metformin hydrochloride tablets should be individualized on the basis of both effectiveness and tolerability, while not exceeding the maximum recommended dosage of 2.5 mg linagliptin/1,000 mg metformin hydrochloride (HCl), taken orally twice daily. Linagliptin and metformin hydrochloride tablets should be given twice daily with meals. Dosage escalation should be gradual to reduce the gastrointestinal (GI) side effects associated with metformin use. Recommended starting dosage:

• In patients currently not treated with metformin HCl, initiate treatment with 2.5 mg linagliptin/500 mg metformin HCl twice daily.
• In patients already treated with metformin HCl, start with 2.5 mg linagliptin and the current dosage of metformin HCl taken at each of the two daily meals (e.g., a patient on metformin HCl 1,000 mg twice daily would be started on 2.5 mg linagliptin/1,000 mg metformin HCl twice daily with meals).
• Patients already treated with linagliptin and metformin HCl individual components may be switched to linagliptin and metformin hydrochloride tablets containing the same dosages of each component.

2.2 Recommended Dosing in Renal Impairment Assess renal function prior to initiation of linagliptin and metformin hydrochloride tablets and periodically thereafter. Linagliptin and metformin hydrochloride tablets are contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m 2 . Initiation of linagliptin and metformin hydrochloride tablets in patients with an eGFR between 30 to 45 mL/min/1.73 m 2 is not recommended. In patients taking linagliptin and metformin hydrochloride tablets whose eGFR later falls below 45 mL/min/1.73 m 2 , assess benefit /risk of continuing therapy. Discontinue linagliptin and metformin hydrochloride tablets if the patient&apos;s eGFR later falls below 30 mL/min/1.73 m 2 [ see Contraindications (4) and Warnings and Precautions (5.1)] .

2.3 Discontinuation for Iodinated Contrast Imaging Procedures Discontinue linagliptin and metformin hydrochloride tablets 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 2 ; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart linagliptin and metformin hydrochloride tablets if renal function is stable [ see Warnings and Precautions (5.1 ) ].

Linagliptin and metformin hydrochloride are contraindicated in patients with:

• severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) [see Warnings and Precautions (5.1 )] .
• acute or chronic metabolic acidosis, including diabetic ketoacidosis [see Warnings and Precautions (5.1 )].
• hypersensitivity to linagliptin, metformin, or any of the excipients in linagliptin and metformin hydrochloride, reactions such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity have occurred with linagliptin [see Warnings and Precautions (5.4 ) and Adverse Reactions (6.1 )] . Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) ( 4 ) Metabolic acidosis, including diabetic ketoacidosis ( 4 ) Hypersensitivity to linagliptin, metformin, or any of the excipients in linagliptin and metformin hydrochloride ( 4 )

REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information:

• Pancreatitis [see Warnings and Precautions (5.1) ]
• Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions (5.2) ]
• Hypersensitivity Reactions [see Warnings and Precautions (5.3) ]
• Severe and Disabling Arthralgia [see Warnings and Precautions (5.4) ]
• Bullous Pemphigoid [see Warnings and Precautions (5.5) ]
• Heart Failure [see Warnings and Precautions (5.6) ] Most common adverse reaction (incidence ≥5% and more often than placebo) was nasopharyngitis ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience 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. The safety evaluation of TRADJENTA 5 mg once daily in patients with type 2 diabetes mellitus is based on 14 placebo-controlled trials, 1 active-controlled trial, and one trial in patients with severe renal impairment. In the 14 placebo-controlled studies, a total of 3,625 patients were randomized and treated with TRADJENTA 5 mg daily and 2,176 with placebo. The mean exposure in patients treated with TRADJENTA across studies was 29.6 weeks. The maximum follow-up was 78 weeks. TRADJENTA 5 mg once daily was studied as monotherapy in three placebo-controlled trials of 18 and 24 weeks&apos; duration and in five additional placebo-controlled studies lasting ≤18 weeks. The use of TRADJENTA in combination with other antihyperglycemic agents was studied in six placebo-controlled trials: two with metformin (12 and 24 weeks&apos; treatment duration); one with a sulfonylurea (18 weeks&apos; treatment duration); one with metformin and sulfonylurea (24 weeks&apos; treatment duration); one with pioglitazone (24 weeks&apos; treatment duration); and one with insulin (primary endpoint at 24 weeks). In a pooled dataset of 14 placebo-controlled clinical trials, adverse reactions that occurred in ≥2% of patients receiving TRADJENTA (n = 3,625) and more commonly than in patients given placebo (n = 2,176), are shown in Table 1.

Table

1 Adverse Reactions Reported in ≥2% of Patients Treated with TRADJENTA and Greater than Placebo in Placebo-Controlled Clinical Studies of TRADJENTA Monotherapy or Combination Therapy Adverse Reactions TRADJENTA 5 mg (%) n = 3,625 Placebo (%) n = 2,176 Nasopharyngitis 7.0

6.1 Diarrhea 3.3

3.0 Cough 2.1

1.4 Rates for other adverse reactions for TRADJENTA 5 mg vs placebo when TRADJENTA was used in combination with specific antidiabetic agents were: urinary tract infection (3.1% vs 0%) and hypertriglyceridemia (2.4% vs 0%) when TRADJENTA was used as add-on to sulfonylurea; hyperlipidemia (2.7% vs 0.8%) and weight increased (2.3% vs 0.8%) when TRADJENTA was used as add-on to pioglitazone; and constipation (2.1% vs 1%) when TRADJENTA was used as add-on to basal insulin therapy. Other adverse reactions reported in clinical studies with treatment of TRADJENTA were hypersensitivity (e.g., urticaria, angioedema, localized skin exfoliation, or bronchial hyperreactivity) and myalgia.

Following

104 weeks' treatment in a controlled trial comparing TRADJENTA with glimepiride in which all patients were also receiving metformin, adverse reactions reported in ≥5% of patients treated with TRADJENTA (n = 776) and more frequently than in patients treated with a sulfonylurea (n = 775) were back pain (9.1% vs 8.4%), arthralgia (8.1% vs 6.1%), upper respiratory tract infection (8.0% vs 7.6%), headache (6.4% vs 5.2%), cough (6.1% vs 4.9%), and pain in extremity (5.3% vs 3.9%). In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient year exposure while being treated with TRADJENTA compared with 3.7 cases per 10,000 patient year exposure while being treated with comparator (placebo and active comparator, sulfonylurea). Three additional cases of pancreatitis were reported following the last administered dose of linagliptin.

Other Adverse Reactions Hypoglycemia Table

2 summarizes the incidence of hypoglycemia in placebo-controlled studies of TRADJENTA. The incidence of hypoglycemia increased when TRADJENTA was administered with sulfonylurea or insulin.

Table

2 Incidence (%) of Hypoglycemia in Placebo-Controlled Clinical Studies of TRADJENTA in Patients with Type 2 Diabetes Mellitus *Hypoglycemia requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Add-on to Sulfonylurea (18 Weeks) Placebo (N=84) TRADJENTA (N=161) Hypoglycemia with plasma glucose <54 mg/dL (%) 1.2

1.9 Severe* hypoglycemia (%) 0 0 Add-on to Metformin and Sulfonylurea (24 Weeks) Placebo (N=263) TRADJENTA (N=792) Hypoglycemia with plasma glucose &lt;54 mg/dL (%) 5.3

8.1 Severe* hypoglycemia (%) 0.8

0.6 Add-on to Basal Insulin (52 Weeks) Placebo (N=630) TRADJENTA (N=631) Hypoglycemia with plasma glucose &lt;54 mg/dL (%) 21.6

19.8 Severe* hypoglycemia (%) 1.1

1.7 In an active-controlled (glimepiride) cardiovascular safety trial with TRADJENTA (CAROLINA) with median time on treatment of 5.9 years, the incidence of severe hypoglycemia was 0.3% in the TRADJENTA group (N=3,014) and 2.2% in glimepiride group (N=3,000). Use in Renal Impairment TRADJENTA was compared to placebo as add-on to pre-existing antidiabetic therapy over 52 weeks in 133 patients with severe renal impairment (estimated GFR &lt;30 mL/min). For the initial 12 weeks of the trial, background antidiabetic therapy was kept stable and included insulin, sulfonylurea, glinides, and pioglitazone. For the remainder of the trial, dosage adjustments in antidiabetic background therapy were allowed. In general, the incidence of adverse events including severe hypoglycemia was similar to those reported in other TRADJENTA trials. The observed incidence of hypoglycemia was higher (TRADJENTA, 63% compared to placebo, 49%) due to an increase in asymptomatic hypoglycemic events especially during the first 12 weeks when background glycemic therapies were kept stable. Ten TRADJENTA-treated patients (15%) and 11 placebo-treated patients (17%) reported at least one episode of confirmed symptomatic hypoglycemia (accompanying finger stick glucose ≤54 mg/dL). During the same time period, severe hypoglycemic events, defined as an event requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions, were reported in 3 (4.4%) TRADJENTA-treated patients and 3 (4.6%) placebo-treated patients. Events that were considered life-threatening or required hospitalization were reported in 2 (2.9%) patients on TRADJENTA and 1 (1.5%) patient on placebo. Renal function as measured by mean eGFR and creatinine clearance did not change over 52 weeks&apos; treatment compared to placebo.

Laboratory Test

Abnormalities in Clinical Trials Changes in laboratory findings were similar in patients treated with TRADJENTA 5 mg compared to patients treated with placebo. Increase in Uric Acid: Changes in laboratory values that occurred more frequently in the TRADJENTA group and ≥1% more than in the placebo group were increases in uric acid (1.3% in the placebo group, 2.7% in the TRADJENTA group). Increase in Lipase: In a placebo-controlled clinical trial with TRADJENTA in type 2 diabetes mellitus patients with micro- or macroalbuminuria, a mean increase of 30% in lipase concentrations from baseline to 24 weeks was observed in the TRADJENTA arm compared to a mean decrease of 2% in the placebo arm. Lipase levels above 3 times upper limit of normal were seen in 8.2% compared to 1.7% patients in the TRADJENTA and placebo arms, respectively. Increase in Amylase: In a cardiovascular safety trial comparing TRADJENTA versus glimepiride in patients with type 2 diabetes mellitus, amylase levels above 3 times upper limit of normal were seen in 1.0% compared to 0.5% of patients in the TRADJENTA and glimepiride arms, respectively. The clinical significance of elevations in lipase and amylase with TRADJENTA is unknown in the absence of potential signs and symptoms of pancreatitis [see Warnings and Precautions (5.1) ].

Vital

Signs No clinically meaningful changes in vital signs were observed in patients treated with TRADJENTA.

6.2 Postmarketing Experience Additional adverse reactions have been identified during postapproval use of TRADJENTA. 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.

• Gastrointestinal Disorders: Acute pancreatitis, including fatal pancreatitis [see Indications and Usage (1) ], mouth ulceration, stomatitis
• Immune System Disorders: Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions
• Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis, severe and disabling arthralgia
• Skin and Subcutaneous Tissue Disorders: Bullous pemphigoid, rash

AND PRECAUTIONS Lactic acidosis: See boxed warning ( 5.1 ) Pancreatitis: There have been reports of acute pancreatitis, including fatal pancreatitis. If pancreatitis is suspected, promptly discontinue linagliptin and metformin hydrochloride. ( 5.2 ) Hypoglycemia: Consider lowering the dosage of insulin secretagogue or insulin to reduce the risk of hypoglycemia when initiating linagliptin and metformin hydrochloride ( 5.3 ) Hypersensitivity reactions: Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema, and exfoliative skin conditions) have occurred with linagliptin and metformin hydrochloride. If hypersensitivity reactions occur discontinue linagliptin and metformin hydrochloride, treat promptly, and monitor until signs and symptoms resolve. ( 5.4 ) Vitamin B 12 deficiency: Metformin may lower vitamin B 12 levels. Measure hematologic parameters annually and vitamin B 12 at 2 to 3 year intervals and manage any abnormalities. ( 5.5 ) Arthralgia: Severe and disabling arthralgia has been reported in patients taking linagliptin. Consider as a possible cause for severe joint pain and discontinue drug if appropriate. ( 5.6 ) Bullous pemphigoid : There have been reports of bullous pemphigoid requiring hospitalization. Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue linagliptin and metformin hydrochloride. ( 5.7 ) Heart failure: Heart failure has been observed with two other members of the DPP-4 inhibitor class. Consider risks and benefits of linagliptin and metformin hydrochloride in patients who have known risk factors for heart failure. Monitor for signs and symptoms. ( 5.8 )

5.1 Lactic Acidosis Metformin 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 (&gt;5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio; metformin plasma levels generally &gt;5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase 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 linagliptin and metformin hydrochloride. In linagliptin and metformin hydrochloride-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin is dialyzable, with clearance of up to 170 mL/min 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 linagliptin and metformin hydrochloride 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.2 ) and Clinical Pharmacology (12.3 )]</span> :

• Before initiating linagliptin and metformin hydrochloride, obtain an estimated glomerular filtration rate (eGFR).
• Linagliptin and metformin hydrochloride is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m 2 [see Contraindications (4) ].
• Initiation of linagliptin and metformin hydrochloride is not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m 2 .
• Obtain an eGFR at least annually in all patients taking linagliptin and metformin hydrochloride. 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 linagliptin and metformin hydrochloride whose eGFR later falls below 45 mL/min/1.73 m 2 , assess the benefit and risk of continuing therapy.

Drug

Interactions: The concomitant use of linagliptin and metformin hydrochloride 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.

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 [see Use in Specific Populations (8.5 )].

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 linagliptin and metformin hydrochloride 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 2 ; 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 linagliptin and metformin hydrochloride 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. Linagliptin and metformin hydrochloride 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 linagliptin and metformin hydrochloride.

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 linagliptin and metformin hydrochloride.

Hepatic

Impairment: Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of linagliptin and metformin hydrochloride in patients with clinical or laboratory evidence of hepatic disease.

5.2 Pancreatitis Acute pancreatitis, including fatal pancreatitis, has been reported in patients treated with linagliptin. In the CARMELINA trial <span class="opacity-50 text-xs">[see Clinical Studies (14.2 )]</span>, acute pancreatitis was reported in 9 (0.3%) patients treated with linagliptin and in 5 (0.1%) patients treated with placebo. Two patients treated with linagliptin in the CARMELINA trial had acute pancreatitis with a fatal outcome. There have been postmarketing reports of acute pancreatitis, including fatal pancreatitis, in patients treated with linagliptin. Take careful notice of potential signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue linagliptin and metformin hydrochloride 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 linagliptin and metformin hydrochloride.

5.3 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues Insulin secretagogues and insulin are known to cause hypoglycemia. The risk of hypoglycemia is increased when linagliptin and metformin hydrochloride is used in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin <span class="opacity-50 text-xs">[see Adverse Reactions (6.1 )]</span> . Therefore, a lower dosage of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with linagliptin and metformin hydrochloride.

5.4 Hypersensitivity Reactions There have been postmarketing reports of serious hypersensitivity reactions in patients treated with linagliptin. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred predominantly within the first 3 months after initiation of treatment with linagliptin, with some reports occurring after the first dose. If a serious hypersensitivity reaction is suspected, discontinue linagliptin and metformin hydrochloride, assess for other potential causes for the event, and institute alternative treatment for diabetes mellitus. Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution in a patient with a history of angioedema to another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with linagliptin and metformin hydrochloride.

5.5 Vitamin B 12 Deficiency In metformin clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of metformin-treated patients. Such decrease, possibly due to interference with B 12 absorption from the B 12 -intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B 12 supplementation. Certain individuals (those with inadequate vitamin B 12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B 12 levels. Measure hematologic parameters on an annual basis and vitamin B 12 at 2 to 3 year intervals in patients on linagliptin and metformin hydrochloride and manage any abnormalities <span class="opacity-50 text-xs">[see Adverse Reactions (6.1 )]</span> .

5.6 Severe and Disabling Arthralgia There have been postmarketing reports of severe and disabling arthralgia in patients taking linagliptin. 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 DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate.

5.7 Bullous Pemphigoid Bullous pemphigoid was reported in 7 (0.2%) patients treated with linagliptin compared to none in patients treated with placebo in the CARMELINA trial <span class="opacity-50 text-xs">[see Clinical Studies (14.2 )]</span> , and 3 of these patients were hospitalized due to 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 linagliptin and metformin hydrochloride. If bullous pemphigoid is suspected, linagliptin and metformin hydrochloride should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

5.8 Heart Failure An association between DPP-4 inhibitor treatment and heart failure has been observed in cardiovascular outcomes trials for two other members of the DPP-4 inhibitor class. These trials evaluated patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease. Consider the risks and benefits of linagliptin and metformin hydrochloride prior to initiating treatment in patients at risk for heart failure, such as those with a prior history of heart failure and a history of renal impairment, and observe these 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 linagliptin and metformin hydrochloride.

INTERACTIONS Table 2 describes clinically relevant interactions with linagliptin and metformin hydrochloride.

Table

2 Clinically Relevant Interactions with linagliptin and metformin hydrochloride Carbonic Anhydrase Inhibitors Clinical Impact 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 linagliptin and metformin hydrochloride may increase the risk of lactic acidosis.

Intervention

Consider more frequent monitoring of these patients. Drugs that Reduce Metformin Clearance Clinical Impact 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 )].

Intervention

Consider the benefits and risks of concomitant use.

Alcohol Clinical Impact

Alcohol is known to potentiate the effect of metformin on lactate metabolism.

Intervention

Warn patients against excessive alcohol intake while receiving linagliptin and metformin hydrochloride. Insulin or Insulin Secretagogues Clinical Impact The risk of hypoglycemia is increased when linagliptin and metformin hydrochloride is used in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin.

Intervention

Coadministration of linagliptin and metformin hydrochloride with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower dosages of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.

Drugs Affecting Glycemic Control Clinical

Impact Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid.

Intervention

When such drugs are administered to a patient receiving linagliptin and metformin hydrochloride, the patient should be closely observed to maintain adequate glycemic control. When such drugs are withdrawn from a patient receiving linagliptin and metformin hydrochloride, the patient should be observed closely for hypoglycemia. Inducers of P-glycoprotein or CYP3A4 Enzymes Clinical Impact Rifampin decreased linagliptin exposure, suggesting that the efficacy of linagliptin may be reduced when administered in combination with a strong P-gp or CYP3A4 inducer.

Intervention

Use of alternative treatments is strongly recommended when linagliptin is to be administered with a strong P-gp or CYP3A4 inducer.

Carbonic Anhydrase

Inhibitors: May increase risk of lactic acidosis. Consider more frequent monitoring. ( 7 ) Drugs that Reduce Metformin Clearance: May increase risk of lactic acidosis. Consider benefits and risks of concomitant use. (7 ) Alcohol: Can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake. ( 7 ) Strong P-glycoprotein/CYP3A4 Inducer: Efficacy may be reduced when administered in combination (e.g., rifampin). Use of alternative treatments is strongly recommended. ( 7 )