Zituvimet Xr Drug Information

Generic name: SITAGLIPTIN AND METFORMIN HYDROCHLORIDE

Dipeptidyl Peptidase 4 Inhibitor [EPC]

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Uses of Zituvimet Xr

is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use ZITUVIMET XR is not recommended in patients with type 1 diabetes mellitus. ZITUVIMET XR has not been studied in patients with a history of pancreatitis.

It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using ZITUVIMET XR. ZITUVIMET XR is a combination of sitagliptin, 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. Limitations of Use: Not for the treatment of type 1 diabetes mellitus. Has not been studied in patients with a history of pancreatitis.

Dosage & Administration of Zituvimet Xr

Recommended Dosage and

Administration Take ZITUVIMET XR orally once daily with a meal. Patients taking two ZITUVIMET XR tablets should take the two tablets together once daily. Individualize the dosage of ZITUVIMET XR on the basis of the patient's current regimen, effectiveness, and tolerability.

The maximum recommended daily dose is 100 mg of sitagliptin and 2,000 mg of metformin hydrochloride (HCl) extended-release. The recommended starting dose in patients not currently treated with metformin is 100 mg sitagliptin and 1,000 mg metformin HCl extended-release once daily, with gradual dose escalation recommended to reduce gastrointestinal side effects associated with metformin. The starting dose in patients already treated with metformin should provide 100 mg sitagliptin and the previously prescribed dose of metformin.

For patients taking metformin HCl immediate-release 850 mg twice daily or 1,000 mg twice daily, the recommended starting dose of ZITUVIMET XR is two 50 mg sitagliptin and 1,000 mg metformin HCl extended-release tablets taken together once daily. Maintain the same total daily dose of sitagliptin and metformin when changing between sitagliptin and metformin HCl immediate-release or sitagliptin and metformin extended-release and ZITUVIMET XR. Do not split, crush or chew ZITUVIMET XR tablets.

Recommendations for Use in Renal Impairment Assess renal function prior to initiation

of ZITUVIMET XR and periodically thereafter. ZITUVIMET XR is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m 2 . Initiation of ZITUVIMET XR in patients with an eGFR between 30 and 45 mL/min/1.73 m 2 is not recommended. In patients taking ZITUVIMET XR whose eGFR later falls below 45 mL/min/1.73 m 2, assess the benefit risk of continuing therapy and limit dose of the sitagliptin component to 50 mg once daily.

Discontinuation for Iodinated Contrast Imaging Procedures Discontinue

ZITUVIMET 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 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 ZITUVIMET XR if renal function is stable .

Side Effects of Zituvimet Xr

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. Common Adverse Reactions Sitagliptin and Metformin Immediate-Release Coadministration in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Diet and Exercise Table 1 summarizes the most common (≥5% of patients) adverse reactions reported in a 24-week placebo-controlled factorial trial in which sitagliptin and metformin immediate-release were coadministered to patients with type 2 diabetes mellitus inadequately controlled on diet and exercise. Table 1: Sitagliptin and Metformin Immediate-Release Coadministered to Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Diet and Exercise: Adverse Reactions Reported in ≥5% of Patients Receiving Combination Therapy (and Greater than in Patients Receiving Placebo) Intent-to-treat population.

Number of Patients (%) Placebo Sitagliptin 100 mg once daily Metformin HCl Immediate-Release 500 mg or 1,000 mg twice daily Data pooled for the patients given the lower and higher doses of metformin. Sitagliptin 50 mg twice daily + Metformin HCl Immediate-Release 500 mg or 1,000 mg twice daily N = 176 N = 179 N = 364 N = 372 Diarrhea 7 5 28 28 Upper Respiratory Tract Infection 9 8 19 23 Headache 5 2 14 22 Sitagliptin Add-on Therapy in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Metformin Immediate-Release Alone In a 24-week placebo-controlled trial of sitagliptin 100 mg administered once daily added to a twice daily metformin immediate-release regimen, there were no adverse reactions reported in ≥5% of patients and more commonly than in patients given placebo. Discontinuation of therapy due to clinical adverse reactions was similar to the placebo treatment group (sitagliptin and metformin immediate-release, 1.9%; placebo and metformin immediate-release, 2.5%). Gastrointestinal Adverse Reactions The incidences of pre-selected gastrointestinal adverse experiences in patients treated with sitagliptin and metformin immediate-release were similar to those reported for patients treated with metformin immediate-release alone.

See Table 2. Table 2: Pre-selected Gastrointestinal Adverse Reactions Reported in Patients with Type 2 Diabetes Mellitus Receiving Sitagliptin and Metformin Immediate-Release Number of Patients (%) Trial of Sitagliptin and Metformin Immediate-Release in Patients Inadequately Controlled on Diet and Exercise Trial of Sitagliptin Add-on in Patients Inadequately Controlled on Metformin Immediate-Release Alone Placebo Sitagliptin 100 mg once daily Metformin HCl Immediate-Release 500 mg or 1,000 mg twice daily Data pooled for the patients given the lower and higher doses of metformin. Sitagliptin 50 mg twice daily + Metformin HCl Immediate-Release 500 mg or 1,000 mg twice daily Placebo and Metformin HCL Immediate- Release ≥1,500 mg daily Sitagliptin 100 mg once daily and Metformin HCl Immediate- Release ≥1,500 mg daily N = 176 N = 179 N = 364 N = 372 N = 237 N = 464 Diarrhea 7 5 28 28 6 11 Nausea 2 2 20 18 2 6 Vomiting 1 0 2 8 2 5 Abdominal Pain Abdominal discomfort was included in the analysis of abdominal pain in the trial of initial therapy. 4 6 14 11 9 10 Sitagliptin in Combination with Metformin Immediate-Release and Glimepiride In a 24-week placebo-controlled trial of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes mellitus inadequately controlled on metformin immediate-release and glimepiride (sitagliptin, N=116; placebo, N=113), the adverse reactions reported in ≥ 5% of patients treated with sitagliptin and more commonly than in patients treated with placebo were: hypoglycemia (Table 3) and headache (6.9%, 2.7%). Sitagliptin in Combination with Metformin Immediate-Release and Rosiglitazone In a placebo-controlled trial of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes mellitus inadequately controlled on metformin immediate-release and rosiglitazone (sitagliptin, N=181; placebo, N=97), the adverse reactions reported through Week 18 in ≥ 5% of patients treated with sitagliptin and more commonly than in patients treated with placebo were: upper respiratory tract infection (sitagliptin, 5.5%; placebo, 5.2%) and nasopharyngitis (6.1%, 4.1%). Through Week 54, the adverse reactions reported in ≥ 5% of patients treated with sitagliptin and more commonly than in patients treated with placebo were: upper respiratory tract infection (sitagliptin, 15.5%; placebo, 6.2%), nasopharyngitis (11%, 9.3%), peripheral edema (8.3%, 5.2%), and headache (5.5%, 4.1%). Sitagliptin in Combination with Metformin Immediate-Release and Insulin In a 24-week placebo-controlled trial of sitagliptin 100 mg as add-on therapy in patients with type 2 diabetes mellitus inadequately controlled on metformin immediate-release and insulin (sitagliptin, N=229; placebo, N=233), the only adverse reaction reported regardless of investigator assessment of causality in ≥ 5% of patients treated with sitagliptin and more commonly than in patients treated with placebo was hypoglycemia (Table 3). Hypoglycemia In the above trials (N=5), adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose measurement was not required although most (77%) reports of hypoglycemia were accompanied by a blood glucose measurement ≤70 mg/dL. When the combination of sitagliptin and metformin immediate-release was coadministered with a sulfonylurea or with insulin, the percentage of patients reporting at least one adverse reaction of hypoglycemia was higher than that observed with placebo and metformin immediate-release coadministered with a sulfonylurea or with insulin (Table 3). Table 3: Incidence and Rate of Hypoglycemia Adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose measurement was not required: Intent-to-treat population. in Placebo-Controlled Clinical Trials of Sitagliptin in Combination with Metformin Immediate-Release Coadministered with Glimepiride or Insulin Add-On to Glimepiride + Metformin Immediate-Release (24 weeks) Sitagliptin 100 mg + Metformin Immediate-Release + Glimepiride Placebo + Metformin Immediate-Release + Glimepiride N = 116 N = 113 Overall (%) 19 1 Rate (episodes/patient-year) Based on total number of events (i.e., a single patient may have had multiple events). 0.82 0.02 Severe (%) Severe events of hypoglycemia were defined as those events requiring medical assistance or exhibiting depressed level/loss of consciousness or seizure. 0 0 Add-On to Insulin + Metformin Immediate-Release (24 weeks) Sitagliptin 100 mg + Metformin Immediate-Release + Insulin Placebo + Metformin Immediate-Release + Insulin N = 229 N = 233 Overall (%) 35 19 Rate (episodes/patient-year) 0.98 0.61 Severe (%) 1 1 The overall incidence of reported adverse reactions of hypoglycemia in patients with type 2 diabetes mellitus inadequately controlled on diet and exercise was 0.6% in patients given placebo, 0.6% in patients given sitagliptin alone, 0.8% in patients given metformin immediate-release alone, and 1.6% in patients given sitagliptin in combination with metformin immediate-release. In patients with type 2 diabetes mellitus inadequately controlled on metformin immediate-release alone, the overall incidence of adverse reactions of hypoglycemia was 1.3% in patients given add-on sitagliptin and 2.1% in patients given add-on placebo.

In the trial of sitagliptin and add-on combination therapy with metformin immediate-release and rosiglitazone, the overall incidence of hypoglycemia was 2.2% in patients given add-on sitagliptin and 0% in patients given add-on placebo through Week 18. Through Week 54, the overall incidence of hypoglycemia was 3.9% in patients given add-on sitagliptin and 1% in patients given add-on placebo. In an additional 30-week placebo-controlled trial of patients with type 2 diabetes mellitus inadequately controlled with metformin comparing the maintenance of sitagliptin 100 mg versus withdrawal of sitagliptin when initiating basal insulin therapy, the event rate and incidence of documented symptomatic hypoglycemia (blood glucose measurement ≤70 mg/dL) did not differ between the sitagliptin and placebo groups. Vital Signs and Electrocardiograms With the combination of sitagliptin and metformin immediate-release, no clinically meaningful changes in vital signs or in electrocardiogram parameters (ECG) (including the QTc interval) were observed.

Pancreatitis In a pooled analysis of 19 double-blind clinical trials that included data from 10,246 patients randomized to receive sitagliptin 100 mg/day (N=5,429) or corresponding (active or placebo) control (N=4,817), the incidence of acute pancreatitis was 0.1 per 100 patient-years in each group (4 patients with an event in 4,708 patient-years for sitagliptin and 4 patients with an event in 3,942 patient-years for control). Sitagliptin The most common adverse experience in sitagliptin monotherapy reported in ≥5% of patients and more commonly than in patients given placebo was nasopharyngitis. Metformin Extended-Release In a 24-week clinical trial in which extended-release metformin or placebo was added to glyburide therapy, the most common (>5% and greater than placebo) adverse reactions in the combined treatment group were hypoglycemia (13.7% vs. 4.9%), diarrhea (12.5% vs. 5.6%), and nausea (6.7% vs. 4.2%). Laboratory Tests Sitagliptin The incidence of laboratory adverse reactions was similar in patients treated with sitagliptin and metformin immediate-release (7.6%) compared to patients treated with placebo and metformin (8.7%). In most but not all trials, a small increase in white blood cell count (approximately 200 cells/microL difference in WBC vs. placebo; mean baseline WBC approximately 6,600 cells/microL) was observed due to a small increase in neutrophils. This change in laboratory parameters is not considered to be clinically relevant.

Metformin In controlled clinical trials of metformin of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels, without clinical manifestations, was observed in approximately 7% of patients.

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

sitagliptin with metformin, sitagliptin, or metformin. 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. Skin and subcutaneous tissue disorders: hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, bullous pemphigoid, and exfoliative skin conditions including Stevens-Johnson syndrome Respiratory, thoracic and mediastinal disorders: upper respiratory tract infection Hepatobiliary disorders: hepatic enzyme elevations; cholestatic, hepatocellular, and mixed hepatocellular liver injury Gastrointestinal disorders: acute pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing pancreatitis, constipation, vomiting, mouth ulceration, stomatitis Renal and urinary disorders : worsening renal function, including acute renal failure (sometimes requiring dialysis) and tubulointerstitial nephritis Musculoskeletal and connective tissue disorders: severe and disabling arthralgia, myalgia, pain in extremity, back pain, pruritus, rhabdomyolysis Nervous system disorders: headache.

Warnings & Cautions for Zituvimet Xr

Lactic Acidosis

There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate/pyruvate ratio; metformin plasma levels were 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 ZITUVIMET XR. In ZITUVIMET 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 HCl is dialyzable, with a 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 ZITUVIMET XR and report these symptoms to their health care 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 ZITUVIMET XR, obtain an estimated glomerular filtration rate (eGFR). ZITUVIMET XR is contraindicated in patients with an eGFR below 30 mL/min/1.73 m 2 . Initiation of ZITUVIMET XR is not recommended in patients with an eGFR between 30 and less than 45 mL/min/1.73 m 2 In patients taking ZITUVIMET XR whose eGFR later falls below 45 mL/min/1.73 m 2, assess the benefit and risk of continuing therapy. Obtain an eGFR at least annually in all patients taking ZITUVIMET XR. In patients at increased risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently.

Drug Interactions The concomitant use of ZITUVIMET 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 ZITUVIMET 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 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 ZITUVIMET 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. ZITUVIMET XR 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 ZITUVIMET 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 ZITUVIMET 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 ZITUVIMET XR in patients with clinical or laboratory evidence of hepatic disease.

Pancreatitis

There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, in patients taking sitagliptin with or without metformin. After initiation of ZITUVIMET XR, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, ZITUVIMET XR should promptly be discontinued and appropriate management should be initiated.

It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using ZITUVIMET XR.

Heart Failure

An association between dipeptidyl peptidase-4 (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 ZITUVIMET XR 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 ZITUVIMET XR.

Acute Renal Failure

There have been postmarketing reports of worsening renal function in patients taking sitagliptin with or without metformin, including acute renal failure, sometimes requiring dialysis. Before initiation of therapy with ZITUVIMET XR and at least annually thereafter, renal function should be assessed. In patients in whom development of renal dysfunction is anticipated, particularly in elderly patients, renal function should be assessed more frequently and ZITUVIMET XR discontinued if evidence of renal impairment is present.

ZITUVIMET XR is contraindicated in patients with severe renal impairment .

Vitamin B 12 Deficiency

In controlled clinical trials of metformin of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of 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 measurements at 2- to 3-year intervals in patients on ZITUVIMET XR and manage any abnormalities .

Hypoglycemia with

Concomitant Use with Insulin or Insulin Secretagogues ZITUVIMET XR may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue (e.g., sulfonylurea). A lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with ZITUVIMET XR.

Hypersensitivity Reactions

There have been postmarketing reports of serious hypersensitivity reactions in patients treated with sitagliptin, one of the components of ZITUVIMET XR. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after initiation of treatment with sitagliptin, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue ZITUVIMET XR, assess for other potential causes for the event, and institute alternative treatment for diabetes.

Angioedema has also been reported with other 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 ZITUVIMET XR.

Severe and Disabling Arthralgia

There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of the medication.

A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate.

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 ZITUVIMET XR. If bullous pemphigoid is suspected, ZITUVIMET XR should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.

Drug Interactions with Zituvimet Xr

  • Table 4 presents clinically significant drug interactions with ZITUVIMET XR: Table 4: Clinically Significant Drug Interactions with ZITUVIMET XR Carbonic Anhydrase Inhibitors Clinical Impact: Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with ZITUVIMET XR may increase the risk for lactic acidosis.
  • Intervention: Consider more frequent monitoring of these patients.
  • Examples: Topiramate, zonisamide, acetazolamide or dichlorphenamide.
  • 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 / multidrug and toxin extrusion inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis .
  • Intervention: Consider the benefits and risks of concomitant use with ZITUVIMET XR.
  • Examples: Ranolazine, vandetanib, dolutegravir, and cimetidine.
  • Alcohol Clinical Impact: Alcohol is known to potentiate the effect of metformin on lactate metabolism.
  • Intervention: Warn patients against alcohol intake while receiving ZITUVIMET XR.
  • Insulin Secretagogues or Insulin Clinical Impact: Coadministration of ZITUVIMET XR with an insulin secretagogue (e.g., sulfonylurea) or insulin may increase the risk of hypoglycemia.
  • Intervention: Patients receiving an insulin secretagogue or insulin may require lower doses of the insulin secretagogue or insulin.
  • Drugs Affecting Glycemic Control Clinical Impact: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control.
  • Intervention: When such drugs are administered to a patient receiving ZITUVIMET XR, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving ZITUVIMET XR, observe the patient closely for hypoglycemia.
  • Examples: Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. Carbonic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring. Drugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine) may increase the accumulation of metformin. Consider the benefits and risks of concomitant use. Alcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake.

Contraindications for Zituvimet Xr

is contraindicated in patients with: Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) . Acute or chronic metabolic acidosis, including diabetic ketoacidosis. A history of a serious hypersensitivity reaction to sitagliptin, metformin, or any of the excipients in ZITUVIMET XR. Serious hypersensitivity reactions including anaphylaxis or angioedema have been reported. Severe renal impairment: eGFR below 30 mL/min/1.73 m 2. Metabolic acidosis, including diabetic ketoacidosis.

History of a serious hypersensitivity reaction to ZITUVIMET XR, sitagliptin, or metformin, such as. anaphylaxis or angioedema)

Overdosage Information for Zituvimet Xr

In the event of overdose with ZITUVIMET XR, consider contacting the Poison Help Line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. Employ supportive measures dictated by the patient's clinical status. Per clinical judgement, consider removal of unabsorbed material from the gastrointestinal tract, and clinical monitoring (including obtaining an ECG). Sitagliptin is modestly dialyzable.

In clinical studies, approximately 13.5% of the dose was removed over a 3- to 4-hour hemodialysis session. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.

Overdose of metformin has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases . Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions.

Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

Clinical Studies of Zituvimet Xr

Change from baseline (adjusted mean Least squares means adjusted for prior antihyperglycemic

therapy status and baseline value. ) 0.2 -0.7 -0.8 -1.1 -1.4 -

Difference from placebo (adjusted mean ) -0.8 p<0.001 compared to placebo. -1

-1.3 -1.6 -2.1 (95% CI) (-1.1, -0.6) (-1.2, -0.8) (-1.5, -1.1) (-1.8, -1.3) (-2.3, -1.8) Patients (%) achieving A1C <7% 15 (9%) 35 (20%) 41 (23%) 68 (38%) 79 (43%) 118 (66%) % Patients receiving rescue medication 32 21 17 12 8 2 FPG (mg/dL) N = 169 N = 178 N = 179 N = 179 N = 183 N = 180 Baseline (mean) 196 201 205 197 204 197 Change from baseline (adjusted mean ) 6 -17 -27 -29 -47 -64 Difference from placebo (adjusted mean ) -23 -33 -35 -53 -70 (95% CI) (-33, -14) (-43, -24) (-45, -26) (-62, -43) (-79, -60) 2-hour PPG (mg/dL) N = 129 N = 136 N = 141 N = 138 N = 147 N = 152 Baseline (mean) 277 285 293 283 292 287 Change from baseline (adjusted mean ) 0 -52 -53 -78 -93 -117 Difference from placebo (adjusted mean ) -52 -54 -78 -93 -117 (95% CI) (-67, -37) (-69, -39) (-93, -63) (-107, -78) (-131, -102) Figure 1: Mean Change from Baseline for A1C (%) over 24 Weeks with Sitagliptin and Metformin Immediate-Release, Alone and in Combination in Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Diet and Exercise * * All Patients Treated Population: least squares means adjusted for prior antihyperglycemic therapy and baseline value. Initial combination therapy or maintenance of combination therapy should be individualized and are left to the discretion of the health care provider. Sitagliptin Add-on Therapy in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Metformin Immediate-Release Alone A total of 701 patients with type 2 diabetes mellitus participated in a 24-week, randomized, double-blind, placebo-controlled trial designed to assess the efficacy of sitagliptin in combination with metformin immediate-release.

Patients already on metformin HCl immediate-release (N=431) at a dose of at least 1,500 mg per day were randomized after completing a 2-week, single-blind placebo run-in period. Patients on metformin immediate-release and another antihyperglycemic agent (N=229) and patients not on any antihyperglycemic agents (off therapy for at least 8 weeks, N=41) were randomized after a run-in period of approximately 10 weeks on metformin HCl immediate-release (at a dose of at least 1,500 mg per day) in monotherapy. Patients were randomized to the addition of either 100 mg of sitagliptin or placebo, administered once daily.

Patients who failed to meet specific glycemic goals during the trials were treated with pioglitazone rescue. In combination with metformin immediate-release, sitagliptin provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo with metformin immediate-release (Table 10). Rescue glycemic therapy was used in 5% of patients treated with sitagliptin 100 mg and 14% of patients treated with placebo. A similar decrease in body weight was observed for both treatment groups.

Table 10: Glycemic Parameters at Final Visit (24-Week Trial) of Sitagliptin as Add-on Combination Therapy with Metformin Immediate-Release Intent-to-treat population using last observation in the trial prior to pioglitazone rescue therapy. Sitagliptin 100 mg once daily + Metformin Immediate-Release Placebo + Metformin Immediate-Release A1C (%) N = 453 N = 224 Baseline (mean) 8 8 Change from baseline (adjusted mean Least squares means adjusted for prior antihyperglycemic therapy and baseline value. ) -0.7 -0 Difference from placebo + metformin immediate-release (adjusted mean ) (95% CI) -0.7 p<0.001 compared to placebo + metformin. (-0.8, -0.5) Patients (%) achieving A1C <7% 213 (47%) 41 (18%) FPG (mg/dL) N = 454 N = 226 Baseline (mean) 170 174 Change from baseline (adjusted mean ) -17 9 Difference from placebo + metformin immediate-release -25 (adjusted mean ) (95% CI) (-31, -20) 2-hour PPG (mg/dL) N = 387 N = 182 Baseline (mean) 275 272 Change from baseline (adjusted mean ) -62 -11 Difference from placebo + metformin immediate-release -51 (adjusted mean ) (95% CI) (-61, -41) Sitagliptin Add-on Therapy in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on the Combination of Metformin Immediate-Release and Glimepiride A total of 441 patients with type 2 diabetes mellitus participated in a 24-week, randomized, double-blind, placebo-controlled trial designed to assess the efficacy of sitagliptin in combination with glimepiride, with or without metformin immediate-release. Patients entered a run-in treatment period on glimepiride (≥4 mg per day) alone or glimepiride in combination with metformin HCl immediate-release (≥1,500 mg per day). After a dose-titration and dose-stable run-in period of up to 16 weeks and a 2-week placebo run-in period, patients with inadequate glycemic control (A1C 7.5% to 10.5%) were randomized to the addition of either 100 mg of sitagliptin or placebo, administered once daily.

Patients who failed to meet specific glycemic goals during the trials were treated with pioglitazone rescue. Patients receiving sitagliptin with metformin immediate-release and glimepiride had significant improvements in A1C and FPG compared to patients receiving placebo with metformin immediate-release and glimepiride (Table 11), with mean reductions from baseline relative to placebo in A1C of -0.9% and in FPG of -21 mg/dL. Rescue therapy was used in 8% of patients treated with add-on sitagliptin 100 mg and 29% of patients treated with add-on placebo. The patients treated with add-on sitagliptin had a mean increase in body weight of 1.1 kg vs. add-on placebo (+0.4 kg vs. -0.7 kg). In addition, add-on sitagliptin resulted in an increased rate of hypoglycemia compared to add-on placebo.

Table 11: Glycemic Parameters at Final Visit (24-Week Trial) for Sitagliptin in Combination with Metformin Immediate-Release and Glimepiride Intent-to-treat population using last observation in the trial prior to pioglitazone rescue therapy. Sitagliptin 100 mg + Metformin Immediate-Release and Glimepiride Placebo + Metformin Immediate-Release and Glimepiride A1C (%) N = 115 N = 105 Baseline (mean) 8.3

Change from baseline (adjusted mean Least squares means adjusted for prior antihyperglycemic

therapy status and baseline value. ) -0.6

Difference from placebo (adjusted mean ) (95% CI) -0.9 p<0.001 compared to

placebo. (-1.1, -0.7) Patients (%) achieving A1C <7% 26 (23%) 1 (1%) FPG (mg/dL) N = 115 N = 109 Baseline (mean) 179 179 Change from baseline (adjusted mean ) -8 13 Difference from placebo (adjusted mean ) (95% CI) -21 (-32, -10) Sitagliptin Add-on Therapy in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on the Combination of Metformin Immediate-Release and Rosiglitazone A total of 278 patients with type 2 diabetes mellitus participated in a 54-week, randomized, double-blind, placebo-controlled trial designed to assess the efficacy of sitagliptin in combination with metformin immediate-release and rosiglitazone. Patients on dual therapy with metformin HCl immediate-release ≥1,500 mg/day and rosiglitazone ≥4 mg/day or with metformin HCl immediate-release ≥1,500 mg/day and pioglitazone ≥30 mg/day (switched to rosiglitazone ≥4 mg/day) entered a dose-stable run-in period of 6 weeks. Patients on other dual therapy were switched to metformin HCl immediate-release ≥1,500 mg/day and rosiglitazone ≥4 mg/day in a dose titration/stabilization run-in period of up to 20 weeks in duration.

After the run-in period, patients with inadequate glycemic control (A1C 7.5% to 11%) were randomized 2:1 to the addition of either 100 mg of sitagliptin or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the trials were treated with glipizide (or other sulfonylurea) rescue. The primary time point for evaluation of glycemic parameters was Week 18. In combination with metformin immediate-release and rosiglitazone, sitagliptin provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo with metformin immediate-release and rosiglitazone (Table 12) at Week 18. At Week 54, mean reduction in A1C was -1% for patients treated with sitagliptin and -0.3% for patients treated with placebo in an analysis based on the intent-to-treat population.

Rescue therapy was used in 18% of patients treated with sitagliptin 100 mg and 40% of patients treated with placebo. There was no significant difference between sitagliptin and placebo in body weight change. Table 12: Glycemic Parameters at Week 18 for Sitagliptin in Add-on Combination Therapy with Metformin Immediate-Release and Rosiglitazone Intent-to-treat population using last observation in the trial prior to glipizide (or other sulfonylurea) rescue therapy.

Week 18 Sitagliptin 100 mg + Metformin Immediate- Release + Rosiglitazone Placebo + Metformin Immediate-Release + Rosiglitazone A1C (%) N = 176 N = 93 Baseline (mean) 8.8

Change from baseline (adjusted mean Least squares means adjusted for prior antihyperglycemic

therapy status and baseline value. ) -1 -

Difference from placebo + rosiglitazone + metformin immediate-release (adjusted mean ) (95%

CI) -0.7 p<0.001 compared to placebo + metformin + rosiglitazone. (-0.9, -0.4) Patients (%) achieving A1C <7% 39 (22%) 9 (10%) FPG (mg/dL) N = 179 N = 94 Baseline (mean) 181 182 Change from baseline (adjusted mean ) -30 -11 Difference from placebo + rosiglitazone + metformin immediate-release (adjusted mean ) (95% CI) -18 (-26, -10) 2-hour PPG (mg/dL) N = 152 N = 80 Baseline (mean) 256 248 Change from baseline (adjusted mean ) -59 -21 Difference from placebo + rosiglitazone + metformin immediate-release (adjusted mean ) (95% CI) -39 (-51, -26) Sitagliptin Add-on Therapy in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on the Combination of Metformin Immediate-Release and Insulin A total of 641 patients with type 2 diabetes mellitus participated in a 24-week, randomized, double-blind, placebo-controlled trial designed to assess the efficacy of sitagliptin as add-on to insulin therapy. Approximately 75% of patients were also taking metformin immediate-release. Patients entered a 2-week, single-blind run-in treatment period on pre-mixed, long-acting, or intermediate-acting insulin, with or without metformin HCl immediate-release (≥1,500 mg per day). Patients using short-acting insulins were excluded unless the short-acting insulin was administered as part of a pre-mixed insulin.

After the run-in period, patients with inadequate glycemic control (A1C 7.5% to 11%) were randomized to the addition of either 100 mg of sitagliptin (N=229) or placebo (N=233), administered once daily. Patients were on a stable dose of insulin prior to enrollment with no changes in insulin dose permitted during the run-in period. Patients who failed to meet specific glycemic goals during the double-blind treatment period were to have uptitration of the background insulin dose as rescue therapy.

Among patients also receiving metformin immediate-release, the median daily insulin (pre-mixed, intermediate or long acting) dose at baseline was 40 units in the sitagliptin-treated patients and 42 units in the placebo-treated patients. The median change from baseline in daily dose of insulin was zero for both groups at the end of the trial. Patients receiving sitagliptin with metformin immediate-release and insulin had significant improvements in A1C, FPG and 2-hour PPG compared to patients receiving placebo with metformin immediate-release and insulin (Table 13). The adjusted mean change from baseline in body weight was -0.3 kg in patients receiving sitagliptin with metformin immediate-release and insulin and -0.2 kg in patients receiving placebo with metformin immediate-release and insulin.

There was an increased rate of hypoglycemia in patients treated with sitagliptin. Table 13: Glycemic Parameters at Final Visit (24-Week Trial) for Sitagliptin as Add-on Combination Therapy with Metformin Immediate-Release and Insulin * * Intent-to-treat population using last observation in the trial prior to rescue therapy. † Least squares means adjusted for insulin use at the screening visit, type of insulin used at the screening visit (premixed vs. non pre-mixed ), and baseline value. ‡ Treatment by insulin stratum interaction was not significant (p>0.10). @ p<0.001 compared to placebo. Sitagliptin 100 mg + Metformin Immediate-Release + Insulin Placebo + Metformin Immediate-Release + Insulin A1C (%) N = 223 N = 229 Baseline (mean) 8.7

Change from baseline (adjusted mean †, ‡) -0.7 -0.1 Difference from placebo

(adjusted mean † ) (95% CI) -0.5 @ (-0.7, -0.4) Patients (%) achieving A1C <7% 32 (14%) 12 (5%) FPG (mg/dL) N = 225 N = 229 Baseline (mean) 173 176 Change from baseline (adjusted mean † ) -22 -4 Difference from placebo (adjusted mean † ) (95% CI) -18 @ (-28, -8.4) 2-hour PPG (mg/dL) N = 182 N = 189 Baseline (mean) 281 281 Change from baseline (adjusted mean † ) -39 1 Difference from placebo (adjusted mean † ) (95% CI) -40 @ (-53, -28) Maintenance of Sitagliptin During Initiation and Titration of Insulin Glargine A total of 746 patients with type 2 diabetes mellitus (mean baseline HbA1C 8.8%, disease duration 10.8 years) participated in a 30-week, randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of continuing sitagliptin during the initiation and up-titration of insulin glargine. Patients who were on a stable dose of metformin HCl (≥1,500 mg/day) in combination with a DPP-4 inhibitor and/or sulfonylurea but with inadequate glycemic control (A1C 7.5% to 11%) were enrolled in the trial. Those on metformin and sitagliptin (100 mg/day) directly entered the double-blind treatment period; those on another DPP-4 inhibitor and/or on a sulfonylurea entered a 4 to 8 week run-in period in which they were maintained on metformin and switched to sitagliptin (100 mg); other DPP-4 inhibitors and sulfonylureas were discontinued.

At randomization patients were randomized either to continue sitagliptin or to discontinue sitagliptin and switch to a matching placebo. On the day of randomization, insulin glargine was initiated at a dose of 10 units subcutaneously in the evening. Patients were instructed to up-titrate their insulin dose in the evening based on fasting blood glucose measurements to achieve a target of 72 to100 mg/dL. At 30 weeks, the mean reduction in A1C was greater in the sitagliptin group than in the placebo group (Table 14). At the end of the trial, 27.3% of patients in the sitagliptin group and 27.3% in the placebo group had a fasting plasma glucose (FPG) in the target range; there was no significant difference in insulin dose between arms.

Table 14: Change from Baseline in A1C and FPG at Week 30 in the Maintenance of Sitagliptin During Initiation and Titration of Insulin Glargine Trial Sitagliptin 100 mg + Metformin + Insulin Glargine Placebo + Metformin + Insulin Glargine A1C (%) N = 373 N is the number of randomized and treated patients. N = 370 Baseline (mean) 8.8

Week 30 (mean) 6.9 7.3 Change from baseline (adjusted mean) Analysis of

Covariance including all post-baseline data regardless of rescue or treatment discontinuation. Model estimates calculated using multiple imputation to model washout of the treatment effect using placebo data for all subjects having missing Week 30 data. -1.9 -

Difference from placebo (adjusted mean) (95% CI) -0.4 (-0.6, -0.3) p<0.001 compared

to placebo. Patients (%) with A1C <7% 202 (54.2%) 131 (35.4%) FPG (mg/dL) N = 373 N = 370 Baseline (mean) 199 201 Week 30 (mean) 118 123 Change from baseline (adjusted mean) -81 -76 Sitagliptin Add-on Therapy vs. Glipizide Add-on Therapy in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Metformin Immediate-Release The efficacy of sitagliptin was evaluated in a 52-week, double-blind, glipizide-controlled noninferiority trial in patients with type 2 diabetes mellitus.

Patients not on treatment or on other antihyperglycemic agents entered a run-in treatment period of up to 12 weeks duration with metformin HCl immediate-release monotherapy (dose of ≥1,500 mg per day) which included washout of medications other than metformin immediate-release, if applicable. After the run-in period, those with inadequate glycemic control (A1C 6.5% to 10%) were randomized 1:1 to the addition of sitagliptin 100 mg once daily or glipizide for 52 weeks. Patients receiving glipizide were given an initial dosage of 5 mg/day and then electively titrated over the next 18 weeks to a maximum dosage of 20 mg/day as needed to optimize glycemic control.

Thereafter, the glipizide dose was to be kept constant, except for down-titration to prevent hypoglycemia. The mean dose of glipizide after the titration period was 10 mg. After 52 weeks, sitagliptin and glipizide had similar mean reductions from baseline in A1C in the intent-to-treat analysis (Table 15). These results were consistent with the per protocol analysis (Figure 2). A conclusion in favor of the non-inferiority of sitagliptin to glipizide may be limited to patients with baseline A1C comparable to those included in the trial (over 70% of patients had baseline A1C less than 8% and over 90% had A1C less than 9%). Table 15: Glycemic Parameters in a 52-Week Trial Comparing Sitagliptin to Glipizide as Add-On Therapy in Patients Inadequately Controlled on Metformin Immediate-Release (Intent-to-Treat Population) * * The intent-to-treat analysis used the patients' last observation in the trial prior to discontinuation. † Least squares means adjusted for prior antihyperglycemic therapy status and baseline A1C value.

Sitagliptin 100 mg + Metformin Immediate-Release Glipizide + Metformin Immediate- Release A1C (%) N = 576 N = 559 Baseline (mean) 7.7

Change from baseline (adjusted mean † ) -0.5 -0.6

FPG (mg/dL) N = 583 N = 568 Baseline (mean) 166 164 Change from baseline (adjusted mean † ) -8 -8 Figure 2: Mean Change from Baseline for A1C (%) Over 52 Weeks in a Trial Comparing Sitagliptin to Glipizide as Add-On Therapy in Patients Inadequately Controlled on Metformin Immediate-Release (Per Protocol Population) * * The per protocol population (mean baseline A1C of 7.5%) included patients without major protocol violations who had observations at baseline and at Week 52. The incidence of hypoglycemia in the sitagliptin group (4.9%) was significantly (p<0.001) lower than that in the glipizide group (32%). Patients treated with sitagliptin exhibited a significant mean decrease from baseline in body weight compared to a significant weight gain in patients administered glipizide (-1.5 kg vs. + 1.1 kg). Image Image

Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.

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