Zituvimet Sitagliptin Metformin Hydrochloride User Manual
- June 17, 2024
- Zituvimet
Table of Contents
- Zituvimet Sitagliptin Metformin Hydrochloride
- INDICATIONS AND USAGE
- DOSAGE AND ADMINISTRATION
- WARNINGS AND PRECAUTIONS
- FULL PRESCRIBING INFORMATION
- INDICATIONS AND USAGE
- DOSAGE AND ADMINISTRATION
- DOSAGE FORMS AND STRENGTHS
- CONTRAINDICATIONS
- WARNINGS AND PRECAUTIONS
- ADVERSE REACTIONS
- DRUG INTERACTIONS
- USE IN SPECIFIC POPULATIONS
- OVERDOSAGE
- DESCRIPTION
- CLINICAL PHARMACOLOGY
- NONCLINICAL TOXICOLOGY
- CLINICAL STUDIES
- HOW SUPPLIED/STORAGE AND HANDLING
- PATIENT COUNSELING INFORMATION
- References
- Read User Manual Online (PDF format)
- Download This Manual (PDF format)
Zituvimet Sitagliptin Metformin Hydrochloride
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use ZITUVIMET
safely and effectively. See full prescribing information for ZITUVIMET.
ZITUVIMET (sitagliptin and metformin hydrochloride) tablets, for oral use
Initial U.S. Approval: 2007
WARNING: LACTIC ACIDOSIS
See full prescribing information for complete boxed warning.
- Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate ratio, and metformin plasma levels generally >5 mcg/mL. (5.1)
- Risk factors include renal impairment, concomitant use of certain drugs, age ≥65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, 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. (5.1)
- If lactic acidosis is suspected, discontinue ZITUVIMET and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended. (5.1)
INDICATIONS AND USAGE
ZITUVIMET 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. (1)
Limitations of Use
- ZITUVIMET is not recommended in patients with type 1 diabetes mellitus. (1)
- ZITUVIMET has not been studied in patients with a history of pancreatitis. (1)
DOSAGE AND ADMINISTRATION
- Take ZITUVIMET orally twice daily with meals. (2.1)
- Individualize the dosage of ZITUVIMET on the basis of the patient’s current regimen, effectiveness, and tolerability. (2.1)
- The maximum recommended daily dose is 100 mg of sitagliptin and 2,000 mg of metformin HCl. (2.1)
- The recommended starting dose in patients not currently treated with metformin is 50 mg sitagliptin and 500 mg metformin HCl twice daily, with gradual dose escalation recommended to reduce gastrointestinal side effects associated with metformin. (2.1)
- The starting dose in patients already treated with metformin should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and the dose of metformin already being taken. For patients taking metformin HCl 850 mg twice daily, the recommended starting dose of ZITUVIMET is 50 mg sitagliptin and 1,000 mg metformin HCl twice daily. (2.1)
- Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR) (2.2)
- Do not use in patients with eGFR below 30 mL/min/1.73 m2.
- ZITUVIMET is not recommended in patients with eGFR between 30 and less than 45 mL/min/1.73 m2.
- ZITUVIMET may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures. (2.3)
DOSAGE FORMS AND STRENGTHS
ZITUVIMET Tablets:
- sitagliptin 50 mg and metformin HCl 500 mg tablets
- sitagliptin 50 mg and metformin HCl 1,000 mg tablets (3)
CONTRAINDICATIONS
Severe renal impairment: (eGFR below 30 mL/min/1.73 m2) (4)
- Metabolic acidosis, including diabetic ketoacidosis. (4)
- History of a serious hypersensitivity reaction to ZITUVIMET, sitagliptin, or metformin, such as anaphylaxis or angioedema. (4)
WARNINGS AND PRECAUTIONS
- Lactic Acidosis: See boxed warning. (5.1)
- Pancreatitis: There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. If pancreatitis is suspected, promptly discontinue ZITUVIMET. (5.2)
- Heart Failure: Has been observed with two other members of the DPP-4 inhibitor class. Consider risks and benefits of ZITUVIMET in patients who have known risk factors for heart failure. Monitor patients for signs and symptoms. (5.3)
- Acute Renal Failure: Has been reported postmarketing, sometimes requiring dialysis. Before initiating ZITUVIMET and at least annually thereafter, assess renal function. (5.4)
- Vitamin B12 Deficiency: Metformin may lower vitamin B12 levels. Measure hematologic parameters annually and vitamin B12 at 2 to 3 year intervals and manage any abnormalities. (5.5)
- Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues: Increased risk of hypoglycemia when used in combination with insulin and/or an insulin secretagogue. A lower dose of insulin or insulin secretagogue may be required. (5.6)
- Hypersensitivity Reactions: There have been postmarketing reports of serious allergic and hypersensitivity reactions in patients treated with sitagliptin such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Promptly stop ZITUVIMET, assess for other potential causes, institute appropriate monitoring and treatment. (5.7)
- Severe and Disabling Arthralgia: Has been reported in patients taking DPP-4 inhibitors. Consider as a possible cause for severe joint pain and discontinue drug if appropriate. (5.8)
- Bullous Pemphigoid: There have been postmarketing reports requiring hospitalization in patients taking DPP-4 inhibitors. Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue ZITUVIMET. (5.9)
ADVERSE REACTIONS
- Most common adverse reactions (incidence ≥5%) of patients simultaneously started on sitagliptin and metformin and more commonly than in patients treated with placebo were diarrhea, upper respiratory tract infection, and headache. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
- Carbonic anhydrase inhibitors may increase risk of lactic acidosis. Consider more frequent monitoring. (7)
- 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. (7)
- Alcohol can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake. (7)
USE IN SPECIFIC POPULATIONS
- Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy. (8.3)
- Geriatric Use: Assess renal function more frequently. (8.5)
- Hepatic Impairment: Avoid use in patients with hepatic impairment. (8.7) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
FULL PRESCRIBING INFORMATION
WARNING: 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 is often subtle, accompanied only by
nonspecific symptoms such as malaise, myalgias, respiratory distress,
somnolence, and abdominal pain. Metformin-associated lactic acidosis was
characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap
acidosis (without evidence of ketonuria or ketonemia), an increased
lactate/pyruvate ratio, and metformin plasma levels generally >5 mcg/mL [see
Warnings and Precautions (5.1)]. Risk factors for metformin-associated lactic
acidosis include renal impairment, concomitant use of certain drugs (e.g.,
carbonic anhydrase inhibitors such as topiramate), age 65 years old or
greater, having a radiological study with contrast, surgery and other
procedures, hypoxic states (e.g., acute congestive heart failure), excessive
alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage
metformin-associated lactic acidosis in these high risk groups are provided in
the full prescribing information [see Dosage and Administration (2.2),
Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7),
and Use in Specific Populations (8.6, 8.7)]. If metformin-associated lactic
acidosis is suspected, immediately discontinue ZITUVIMET and institute general
supportive measures in a hospital setting. Prompt hemodialysis is recommended
[see Warnings and Precautions (5.1)].
INDICATIONS AND USAGE
ZITUVIMET is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use ZITUVIMET is not recommended in patients with type 1 diabetes mellitus. ZITUVIMET 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 [see Warnings and Precautions (5.2)].
DOSAGE AND ADMINISTRATION
Recommended Dosage
- Take ZITUVIMET orally twice daily with meals.
- Individualize the dosage of ZITUVIMET 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).
- Do not split or divide ZITUVIMET tablets.
- The recommended starting dose in patients not currently treated with metformin is 50 mg sitagliptin and 500 mg metformin HCl twice 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 sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and the dose of metformin already being taken. For patients taking metformin HCl 850 mg twice daily, the recommended starting dose of ZITUVIMET is 50 mg sitagliptin and 1,000 mg metformin HCl twice daily.
Recommendations for Use in Renal Impairment
- Assess renal function prior to initiation of ZITUVIMET and periodically thereafter.
- ZITUVIMET is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2 [see Contraindications (4) and Warnings and Precautions (5.1)].
- ZITUVIMET is not recommended in patients with an eGFR between 30 and less than 45 mL/min/1.73 m2 because these patients require a lower dosage of sitagliptin than what is available in the fixed combination ZITUVIMET product.
Discontinuation for Iodinated Contrast Imaging Procedures
Discontinue ZITUVIMET 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 m2;
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 if renal
function is stable [see Warnings and Precautions (5.1)].
DOSAGE FORMS AND STRENGTHS
Tablets
- sitagliptin 50 mg and metformin HCl 500 mg tablets are white to off-white, oval shaped, biconvex, film coated tablets debossed with “1786” on one side and plain on the other side.
- sitagliptin 50 mg and metformin HCl 1,000 mg tablets are reddish brown, oval shaped, biconvex, film coated tablets debossed with “1787” on one side and plain on the other side.
CONTRAINDICATIONS
ZITUVIMET is contraindicated in patients with:
- Severe renal impairment (eGFR below 30 mL/min/1.73 m2) [see Warnings and Precautions (5.1)].
- 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. Serious hypersensitivity reactions including anaphylaxis or angioedema have been reported [see Warnings and Precautions (5.7) and Adverse Reactions (6.2)].
WARNINGS AND PRECAUTIONS
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. In ZITUVIMET 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 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 [see Dosage and Administration (2.2) and Clinical Pharmacology
(12.3)]:
- Before initiating ZITUVIMET, obtain an estimated glomerular filtration rate (eGFR).
- ZITUVIMET is contraindicated in patients with an eGFR below 30 mL/min/1.73 m2 [see Contraindications (4)].
- ZITUVIMET is not recommended in patients with an eGFR between 30 and less than 45 mL/min/1.73 m2 because these patients require a lower dosage of sitagliptin than what is available in the fixed combination ZITUVIMET product.
- Obtain an eGFR at least annually in all patients taking ZITUVIMET. 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 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 ZITUVIMET 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 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 ZITUVIMET 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 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.
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.
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 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. After initiation of ZITUVIMET, patients should be observed
carefully for signs and symptoms of pancreatitis. If pancreatitis is
suspected, ZITUVIMET 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.
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
ZITUVIMET before 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.
Acute Renal Failure
There have been postmarketing reports of worsening renal function, including
acute renal failure, sometimes requiring dialysis. Before initiation of
therapy with ZITUVIMET and at least annually thereafter, renal function should
be assessed. In patients in whom the development of renal dysfunction is
anticipated, particularly in elderly patients, renal function should be
assessed more frequently and ZITUVIMET discontinued if evidence of renal
impairment is present. ZITUVIMET is contraindicated in patients with severe
renal impairment [see Contraindications (4) and Warnings and Precautions
(5.1)].
Vitamin B12 Deficiency
In controlled clinical trials of metformin of 29 weeks duration, a decrease to
subnormal levels of previously normal serum vitamin B12 levels was observed in
approximately 7% of patients. Such decrease, possibly due to interference with
B12 absorption from the B12-intrinsic factor complex, may be associated with
anemia but appears to be rapidly reversible with discontinuation of metformin
or vitamin B12 supplementation. Certain individuals (those with inadequate
vitamin B12 or calcium intake or absorption) appear to be predisposed to
developing subnormal vitamin B12 levels. Measure hematologic parameters on an
annual basis and vitamin B12 measurements at 2- to 3-year intervals in
patients on ZITUVIMET and manage any abnormalities [see Adverse Reactions
(6.1)].
Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues
ZITUVIMET may increase the risk of hypoglycemia when combined with insulin
and/or an insulin secretagogue (e.g., sulfonylurea) [see Adverse Reactions
(6)]. A lower dose of insulin or insulin secretagogue may be required to
minimize the risk of hypoglycemia when used in combination with ZITUVIMET [see
Drug Interactions (7)].
Hypersensitivity Reactions
There have been postmarketing reports of serious hypersensitivity reactions in
patients treated with sitagliptin, one of the components of ZITUVIMET. 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, assess for other potential causes for the
event, and institute alternative treatment for diabetes [see Adverse Reactions
(6.2)]. Angioedema has also been reported with other DPP-4 inhibitors. Use
caution in a patient with a history of angioedema with another DPP-4 inhibitor
because it is unknown whether such patients will be predisposed to angioedema
with ZITUVIMET.
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. If bullous pemphigoid is
suspected, ZITUVIMET should be discontinued and referral to a dermatologist
should be considered for diagnosis and appropriate treatment.
ADVERSE REACTIONS
The following adverse reactions are also discussed elsewhere in the prescribing information:
- Lactic Acidosis [see Warnings and Precautions (5.1)]
- Pancreatitis [see Warnings and Precautions (5.2)]
- Heart Failure [see Warnings and Precautions (5.3)]
- Acute Renal Failure [see Warnings and Precautions (5.4)]
- Vitamin B12 Deficiency [see Warnings and Precautions (5.5)]
- Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [see Warnings and Precautions (5.6)]
- Hypersensitivity Reactions [see Warnings and Precautions (5.7)]
- Severe and Disabling Arthralgia [see Warnings and Precautions (5.8)]
- Bullous Pemphigoid [see Warnings and Precautions (5.9)]
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 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 were coadministered to patients with type 2 diabetes mellitus
inadequately controlled on diet and exercise. Table 1: Sitagliptin and
Metformin 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)*
| Number of Patients (%) | |
|---|---|
| **** |
Placebo
| ****
Sitagliptin 100 mg once daily
| ****
Metformin HCl 500 mg/
Metformin HCl 1,000 mg twice daily †
| Sitagliptin
50 mg twice daily + Metformin HCl 500 mg/ Metformin HCl 1,000 mg
twice daily †
| N = 176| N = 179| N = 364 †| N = 372 †
Diarrhea| 7 (4)| 5 (2.8)| 28 (7.7)| 28 (7.5)
Upper Respiratory Tract
Infection
| 9 (5.1)| 8 (4.5)| 19 (5.2)| 23 (6.2)
Headache| 5 (2.8)| 2 (1.1)| 14 (3.8)| 22 (5.9)
- Intent-to-treat population.
- Data pooled for the patients given the lower and higher doses of metformin.
Sitagliptin Add-on Therapy in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Metformin Alone
In a 24-week placebo-controlled trial of sitagliptin 100 mg administered once
daily added to a
twice daily metformin regimen, there were no adverse reactions 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, 1.9%; placebo and metformin, 2.5%).
Gastrointestinal Adverse Reactions
The incidences of pre-selected gastrointestinal adverse experiences in
patients treated with sitagliptin and metformin were similar to those reported
for patients treated with metformin alone. See Table 2.
Table 2: Pre-selected Gastrointestinal Adverse Reactions Reported in Patients with Type 2 Diabetes Mellitus Receiving Sitagliptin and Metformin
| Number of Patients (%) |
|---|
Trial of Sitagliptin and Metformin in Patients Inadequately Controlled on Diet and Exercise| Trial of Sitagliptin Add-on in Patients Inadequately Controlled on Metformin Alone
Placebo
| ****
Sitagliptin 100 mg once daily
| ****
**Metformin HCl 500 mg/ Metformin HCl 1,000 mg twice daily ***
| **Sitagliptin 50 mg twice daily + Metformin HCl 500 mg/ Metformin HCl 1,000 mg twice daily *| **
Placebo and Metformin HCl
≥1,500 mg daily
| ****
Sitagliptin 100 mg once daily and Metformin HCl
≥1,500 mg daily
N = 176| N = 179| N = 364| N = 372| N = 237| N =
464
Diarrhea| 7 (4)| 5 (2.8)| 28 (7.7)| 28 (7.5)| 6 (2.5)| 11 (2.4)
Nausea| 2 (1.1)| 2 (1.1)| 20 (5.5)| 18 (4.8)| 2 (0.8)| 6 (1.3)
Vomiting| 1 (0.6)| 0 (0)| 2 (0.5)| 8 (2.2)| 2 (0.8)| 5 (1.1)
Abdominal Pain†| 4 (2.3)| 6 (3.4)| 14 (3.8)| 11 (3)| 9 (3.8)| 10 (2.2)
- Data pooled for the patients given the lower and higher doses of metformin.
- Abdominal discomfort was included in the analysis of abdominal pain in the trial of initial therapy.
Sitagliptin in Combination with Metformin 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
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 (see Table 3) and headache
(6.9%, 2.7%).
Sitagliptin in Combination with Metformin 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
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 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
and insulin (sitagliptin, N=229; placebo, N=233), the only adverse reaction
reported 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 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 coadministered with a
sulfonylurea or with insulin (Table 3).
*Table 3: Incidence and Rate of Hypoglycemia in Placebo-Controlled Clinical Trials of Sitagliptin in Combination with Metformin Coadministered with Glimepiride or Insulin**
Add-On to Glimepiride
+ Metformin (24 weeks)
| Sitagliptin 100 mg
+ Metformin
+ Glimepiride
| Placebo
+ Metformin
+ Glimepiride
---|---|---
| N = 116| N = 113
Overall (%)| 19 (16.4)| 1 (0.9)
Rate (episodes/patient-year)†| 0.82| 0.02
Severe (%)‡| 0 (0)| 0 (0)
Add-On to Insulin
+ Metformin (24 weeks)
| Sitagliptin 100 mg
+ Metformin
+ Insulin
| Placebo
+ Metformin
+ Insulin
| N = 229| N = 233
Overall (%)| 35 (15.3)| 19 (8.2)
Rate (episodes/patient-year)†| 0.98| 0.61
Severe (%)‡| 1 (0.4)| 1 (0.4)
- Adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose measurement was not required: Intent-to-treat population.
- Based on total number of events (i.e., a single patient may have had multiple events).
- Severe events of hypoglycemia were defined as those events requiring medical assistance or exhibiting depressed level/loss of consciousness or seizure.
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 alone, and 1.6% in patients given sitagliptin in combination with metformin. In patients with type 2 diabetes mellitus inadequately controlled on metformin 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 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, no clinically meaningful
changes in vital signs or in ECG (including in 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
The most common (>5%) established adverse reactions due to initiation of
metformin therapy are diarrhea, nausea/vomiting, flatulence, abdominal
discomfort, indigestion, asthenia, and headache.
Laboratory Tests Sitagliptin
The incidence of laboratory adverse reactions was similar in patients treated
with sitagliptin and metformin (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 weeks duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation.
Postmarketing Experience
Additional adverse reactions have been identified during postapproval use of ZITUVIMET, 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.
DRUG INTERACTIONS
Table 4 presents clinically significant drug interactions with ZITUVIMET:
Table 4: Clinically Significant Drug Interactions with ZITUVIMET
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 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 [OCT2] / multidrug and toxin extrusion
[MATE] inhibitors) 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 with
ZITUVIMET.
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.
Insulin Secretagogues or Insulin
Clinical Impact:| Coadministration of ZITUVIMET 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, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient
receiving ZITUVIMET, 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.
USE IN SPECIFIC POPULATIONS
Pregnancy
Risk Summary
Available data with ZITUVIMET and sitagliptin use in pregnant women are not
sufficient to inform a ZITUVIMET-associated or sitagliptin-associated risk for
major birth defects and miscarriage. Published studies with metformin use
during pregnancy have not reported a clear association with metformin and
major birth defects or miscarriage risk [see Data]. There are risks to the
mother and fetus associated with poorly controlled diabetes in pregnancy [see
Clinical Considerations]. No adverse developmental effects were observed when
sitagliptin was administered to pregnant rats and rabbits during organogenesis
at oral doses up to 30 times and 20 times, respectively, the 100 mg clinical
dose, based on AUC. No adverse developmental effects were observed when
metformin was administered to pregnant Sprague Dawley rats and rabbits during
organogenesis at doses up to 2 and 6 times, respectively, a 2,000 mg clinical
dose, based on body surface area [see Data]. The estimated background risk of
major birth defects is 6 to 10% in women with pre-gestational diabetes with a
hemoglobin A1c (A1C) >7% and has been reported to be as high as 20% to 25% in
women with a A1C >10%. In the U.S. general population, the estimated
background risk of major birth defects and miscarriage in clinically
recognized pregnancies is 2% to 4% and 15% to 20% respectively.
Clinical Considerations
Disease-Associated Maternal and/or Embryo/Fetal Risk Poorly controlled
diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis,
preeclampsia, spontaneous abortions, preterm delivery, and delivery
complications. Poorly controlled diabetes increases the fetal risk for major
birth defects, stillbirth, and macrosomia-related morbidity.
Data
Human Data
Published data from post-marketing studies do not report a clear association
with metformin and major birth defects, miscarriage, or adverse maternal or
fetal outcomes when metformin is used during pregnancy. However, these studies
cannot definitely establish the absence of any risk because of methodological
limitations, including small sample size and inconsistent comparator groups.
Animal Data Sitagliptin and Metformin
No animal reproduction studies were conducted with the coadministration of
sitagliptin and metformin.
Sitagliptin
In embryo-fetal development studies, sitagliptin administered to pregnant rats
and rabbits during organogenesis (gestation day 6 to 20) did not adversely
affect developmental outcomes at oral doses up to 250 mg/kg (30-times the 100
mg clinical dose) and 125 mg/kg (20-times the 100 mg clinical dose),
respectively, based on AUC. Higher doses in rats associated with maternal
toxicity increased the incidence of rib malformations in offspring at 1,000
mg/kg, or approximately 100times the clinical dose, based on AUC. Placental
transfer of sitagliptin was observed in pregnant rats and rabbits. Sitagliptin
administered to female rats from gestation day 6 to lactation day 21 caused no
functional or behavioral toxicity in offspring of rats at doses up to 1,000
mg/kg.
Metformin
Metformin did not cause adverse developmental effects when administered to
pregnant Sprague Dawley rats and rabbits up to 600 mg/kg/day during the period
of organogenesis. This represents an exposure of about 2-and 6-times a 2,000
mg clinical dose based on body surface area (mg/m2) for rats and rabbits,
respectively.
Lactation
Risk Summary There is no information regarding the presence of ZITUVIMET in
human milk, the effects on the breastfed infant, or the effects on milk
production. Limited published studies report that metformin is present in
human milk [see Data]. There are no reports of adverse effects on breastfed
infants exposed to metformin. There is no information on the effects of
metformin on milk production. Sitagliptin is present in rat milk and therefore
possibly present in human milk [see Data]. The developmental and health
benefits of breastfeeding should be considered along with the mother’s
clinical need for ZITUVIMET and any potential adverse effects on the breastfed
infant from ZITUVIMET or from the underlying maternal condition.
Data Sitagliptin
Sitagliptin is secreted in the milk of lactating rats at a milk-to-plasma
ratio of 4:1.
Metformin
Published clinical lactation studies report that metformin is present in human
milk, which resulted in infant doses of approximately 0.11% to 1% of the
maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13
and 1. However, the studies were not designed to establish the risk of use of
metformin during lactation because of the small sample size and limited
adverse event data collected in infants.
Females and Males of Reproductive Potential
Discuss the potential for unintended pregnancy with premenopausal women as
therapy with metformin may result in ovulation in some anovulatory women.
Pediatric Use
The safety and effectiveness of ZITUVIMET have not been established in
pediatric patients. Pediatric information describing clinical studies in
which efficacy was not demonstrated is approved for Merck Sharp and Dohme’s
JANUMET (sitagliptin and metformin hydrochloride) tablets. However, due to
Merck Sharp and Dohme’s marketing exclusivity rights, this drug product is not
labeled with that information.
Geriatric Use
ZITUVIMET
In general, dose selection for an elderly patient should be cautious, usually
starting at the low end of the dosing range, reflecting the greater frequency
of decreased hepatic, renal, or cardiac function, and of concomitant disease
or other drug therapy and the higher risk of lactic acidosis. Renal function
should be assessed more frequently in elderly patients [see Contraindications
(4); Warnings and Precautions (5.1, 5.4) and Clinical Pharmacology (12.3)].
Sitagliptin
Of the total number of subjects (N=3,884) in clinical studies of sitagliptin,
725 patients were 65 years and over, while 61 patients were 75 years and over.
No overall differences in safety or effectiveness of sitagliptin have been
observed between subjects 65 years and over and younger patients.
Metformin
Controlled clinical studies of metformin did not include sufficient numbers of
elderly patients to determine whether they respond differently from younger
patients, although other reported clinical experience has not identified
differences in responses between the elderly and young patients.
Renal Impairment
ZITUVIMET is not recommended in patients with an eGFR between 30 and less than
45 mL/min/1.73 m2 because these patients require a lower dosage of sitagliptin
than what is available in the fixed-dose combination ZITUVIMET product.
ZITUVIMET is contraindicated in severe renal impairment, patients with an eGFR
below 30 mL/min/1.73 m2 [see Dosage and Administration (2.2),
Contraindications (4), Warnings and Precautions (5.1) and Clinical
Pharmacology (12.3)].
Sitagliptin
Sitagliptin is excreted by the kidney, and sitagliptin exposure is increased
in patients with renal impairment [see Clinical Pharmacology (12.3)].
Metformin
Metformin is substantially excreted by the kidney, and the risk of metformin
accumulation and lactic acidosis increases with the degree of renal
impairment.
Hepatic Impairment
The use of metformin in patients with hepatic impairment has been associated
with some cases of lactic acidosis. ZITUVIMET is not recommended in patients
with hepatic impairment [see Warnings and Precautions (5.1)].
OVERDOSAGE
In the event of an overdose with ZITUVIMET, consider contacting the Poison Help Line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. Employ the usual supportive measures dictated by the patient’s clinical status. Per clinical judgment, consider the 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 [see Warnings and Precautions (5.1)]. Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for the removal of accumulated drug from patients in whom metformin overdosage is suspected.
DESCRIPTION
ZITUVIMET (sitagliptin and metformin HCl) tablets for oral use contain sitagliptin and metformin HCl.
Sitagliptin
Sitagliptin is an orally active inhibitor of the DPP-4 enzyme. Sitagliptin is
present in ZITUVIMET tablets in the form of a sitagliptin-free base.
Sitagliptin free base is described chemically as
7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine
with an empirical formula of C16H15F6N5O and a molecular weight of 407.31. The
structural formula is:
The sitagliptin-free base is a white to off-white, non-hygroscopic powder. It is soluble in methanol and slightly soluble in water.
Metformin HCl USP
Metformin HCl, USP (N, N-dimethyl limited carbon imidic diamide hydrochloride)
is not chemically or pharmacologically related to any other classes of oral
antihyperglycemic agents. Metformin HCl, USP is a white crystalline powder
with a molecular formula of C4H11N5•HCl and a molecular weight of 165.62.
Metformin HCl is freely soluble in water, slightly soluble in ethanol (95%),
and practically insoluble in acetone and in methylene chloride. The pKa of
metformin HCl is 12.4. The pH of a 1% aqueous solution of metformin HCl is
6.68.
The structural formula is as shown:
ZITUVIMET is available as film-coated tablets containing:
- 50 mg of sitagliptin and 389.93 mg of metformin equivalent to 500 mg metformin HCl (ZITUVIMET 50/500).
- 50 mg of sitagliptin and 779.86 mg of metformin equivalent to 1,000 mg metformin HCl (ZITUVIMET 50/1,000).
Each film-coated tablet of ZITUVIMET contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, low substituted hydroxypropyl cellulose, magnesium stearate, malic acid, microcrystalline cellulose, povidone, and sodium stearyl fumarate. In addition, the film coating contains the following inactive ingredients: polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. The film coating of 50 mg/1,000 mg also contains FD&C yellow #6 aluminum lake, iron oxide red, and iron oxide yellow.
CLINICAL PHARMACOLOGY
Mechanism of Action
ZITUVIMET combines two antihyperglycemic agents with complementary
mechanisms of action to improve glycemic control in patients with type 2
diabetes mellitus: sitagliptin, a DPP-4 inhibitor, and metformin HCl, a member
of the biguanide class.
Sitagliptin
Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in
patients with type 2 diabetes mellitus by slowing the inactivation of incretin
hormones. Concentrations of the active intact hormones are increased by
sitagliptin, thereby increasing and prolonging the action of these hormones.
Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-
dependent insulinotropic polypeptide (GIP), are released by the intestine
throughout the day, and levels are increased in response to a meal. These
hormones are rapidly inactivated by the enzyme DPP-4. The incretins are part
of an endogenous system involved in the physiologic regulation of glucose
homeostasis. When blood glucose concentrations are normal or elevated, GLP-1
and GIP increase insulin synthesis and release from pancreatic beta cells by
intracellular signaling pathways involving cyclic AMP. GLP-1 also lowers
glucagon secretion from pancreatic alpha cells, leading to reduced hepatic
glucose production. By increasing and prolonging active incretin levels,
sitagliptin increases insulin release and decreases glucagon levels in the
circulation in a glucose-dependent manner. Sitagliptin demonstrates
selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at
concentrations approximating those from therapeutic doses.
Metformin
Metformin is an antihyperglycemic agent that improves glucose tolerance in
patients with type 2 diabetes mellitus, lowering both basal and postprandial
plasma glucose. Metformin decreases hepatic glucose production, decreases
intestinal absorption of glucose, and improves insulin sensitivity by
increasing peripheral glucose uptake and utilization. With metformin therapy,
insulin secretion remains unchanged while fasting insulin levels and day-long
plasma insulin response may decrease.
Pharmacodynamics
Sitagliptin
In patients with type 2 diabetes mellitus, administration of sitagliptin led
to inhibition of DPP-4 enzyme activity for a 24-hour period. After an oral
glucose load or a meal, this DPP-4 inhibition resulted in a 2-to 3-fold
increase in circulating levels of active GLP-1 and GIP, decreased glucagon
concentrations, and increased responsiveness of insulin release to glucose,
resulting in higher C-peptide and insulin concentrations. The rise in insulin
with the decrease in glucagon was associated with lower fasting glucose
concentrations and reduced glucose excursion following an oral glucose load or
a meal. In studies with healthy subjects, sitagliptin did not lower blood
glucose or cause hypoglycemia.
Sitagliptin and Metformin Coadministration
In a two-day study in healthy subjects, sitagliptin alone increased active
GLP-1 concentrations, whereas metformin alone increased active and total GLP-1
concentrations to similar extents. Coadministration of sitagliptin and
metformin had an additive effect on active GLP-1 concentrations. Sitagliptin,
but not metformin, increased active GIP concentrations. It is unclear what
these findings mean for changes in glycemic control in patients with type 2
diabetes mellitus.
Cardiac Electrophysiology
In a randomized, placebo-controlled crossover study, 79 healthy subjects were
administered a single oral dose of sitagliptin 100 mg, sitagliptin 800 mg (8
times the recommended dose), and placebo. At the recommended dose of 100 mg,
there was no effect on the QTc interval obtained at the peak plasma
concentration, or at any other time during the study. Following the 800-mg
dose, the maximum increase in the placebo-corrected mean change in QTc from
baseline at 3 hours postdose was 8.0 msec. This increase is not considered to
be clinically significant. At the 800-mg dose, peak sitagliptin plasma
concentrations were approximately 11 times higher than the peak concentrations
following a 100-mg dose. In patients with type 2 diabetes mellitus
administered sitagliptin 100 mg (N=81) or sitagliptin 200 mg (N=63) daily,
there were no meaningful changes in QTc interval based on ECG data obtained at
the time of expected peak plasma concentration.
Pharmacokinetics
Sitagliptin
The pharmacokinetics of sitagliptin have been extensively characterized in
healthy subjects and patients with type 2 diabetes mellitus. Following a
single oral 100-mg dose to healthy volunteers, the mean plasma AUC of
sitagliptin was 8.52 μM•hr, Cmax was 950 nM, and apparent terminal half-life
(t1/2) was 12.4 hours. Plasma AUC of sitagliptin increased in a dose-
proportional manner and increased approximately 14% following 100 mg doses at
steady-state compared to the first dose. The intra-subject and inter-subject
coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The
pharmacokinetics of sitagliptin was generally similar in healthy subjects and
in patients with type 2 diabetes mellitus.
Absorption Sitagliptin
After oral administration of a 100 mg dose to healthy subjects, sitagliptin
was rapidly absorbed with peak plasma concentrations (median Tmax) occurring 1
to 4 hours post-dose. The absolute bioavailability of sitagliptin is
approximately 87%.
Effect of Food
Coadministration of a high-fat meal with sitagliptin did not affect the
pharmacokinetics of sitagliptin.
Metformin
The absolute bioavailability of a metformin HCl 500-mg tablet given under
fasting conditions is approximately 50% to 60%. Studies using single oral
doses of metformin HCl tablets 500 mg to 1,500 mg, and 850 mg to 2,550 mg
(approximately 1.3 times the maximum recommended daily dosage), indicate that
there is a lack of dose proportionality with increasing doses, which is due to
decreased absorption rather than an alteration in elimination.
Effect of Food
Food decreases the extent of and slightly delays the absorption of metformin,
as shown by approximately a 40% lower mean peak plasma concentration (Cmax), a
25% lower area under the plasma concentration versus time curve (AUC), and a
35-minute prolongation of time to peak plasma concentration (Tmax) following
administration of a single 850-mg tablet of metformin HCl with food, compared
to the same tablet strength administered fasting. The clinical relevance of
these decreases is unknown.
Distribution Sitagliptin
The mean volume of distribution at steady state following a single 100-mg
intravenous dose of sitagliptin to healthy subjects is approximately 198
liters. The fraction of sitagliptin reversibly bound to plasma proteins is low
(38%).
Metformin
The apparent volume of distribution (V/F) of metformin following single oral
doses of metformin HCl tablets 850 mg averaged 654 ± 358 L. Metformin is
negligibly bound to plasma proteins, in contrast to sulfonylureas, which are
more than 90% protein bound. Metformin partitions into erythrocytes, most
likely as a function of time. At usual clinical doses and dosing schedules of
metformin HCl tablets, steady-state plasma concentrations of metformin are
reached within 24 to 48 hours and are generally <1 mcg/mL.
Elimination Sitagliptin
Approximately 79% of sitagliptin is excreted unchanged in the urine with
metabolism being a minor pathway of elimination. The apparent terminal t1/2
following a 100 mg oral dose of sitagliptin was approximately 12.4 hours and
renal clearance was approximately 350 mL/min.
Metformin
Following oral administration, approximately 90% of the absorbed drug is
eliminated via the renal route within the first 24 hours, with a plasma
elimination half-life of approximately 6.2 hours. In blood, the elimination
half-life is approximately 17.6 hours, suggesting that the erythrocyte mass
may be a compartment of distribution.
Metabolism Sitagliptin
Following a [14C] sitagliptin oral dose, approximately 16% of the
radioactivity was excreted as metabolites of sitagliptin. Six metabolites were
detected at trace levels and are not expected to contribute to the plasma
DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the
primary enzyme responsible for the limited metabolism of sitagliptin was
CYP3A4, with contribution from CYP2C8.
Metformin
Intravenous single-dose studies in normal subjects demonstrate that metformin
is excreted unchanged in the urine and does not undergo hepatic metabolism (no
metabolites have been identified in humans) nor biliary excretion.
Excretion Sitagliptin
Following administration of an oral [14C] sitagliptin dose to healthy
subjects, approximately 100% of the administered radioactivity was eliminated
in feces (13%) or urine (87%) within one week of dosing.
Elimination of sitagliptin occurs primarily via renal excretion and involves
active tubular secretion. Sitagliptin is a substrate for human organic anion
transporter-3 (hOAT-3), which may be involved in the renal elimination of
sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not
been established. Sitagliptin is also a substrate of p-glycoprotein (P-gp),
which may also be involved in mediating the renal elimination of sitagliptin.
However, cyclosporine, a P-gp inhibitor, did not reduce the renal clearance of
sitagliptin.
Metformin
Elimination of metformin occurs primarily via renal excretion. Renal clearance
is approximately 3.5 times greater than creatinine clearance, which indicates
that tubular secretion is the major route of metformin elimination.
Specific Populations Patients with Renal Impairment
ZITUVIMET
Studies characterizing the pharmacokinetics of sitagliptin and metformin after
administration of ZITUVIMET in renally impaired patients have not been
performed [see Dosage and Administration (2.2)].
Sitagliptin
An approximately 2-fold increase in the plasma AUC of sitagliptin was observed
in patients with moderate renal impairment with eGFR of 30 to less than 45
mL/min/1.73 m2, and an approximately 4-fold increase was observed in patients
with severe renal impairment including patients with end-stage renal disease
(ESRD) on hemodialysis, as compared to normal healthy control subjects [see
Dosage and Administration (2.2)].
Metformin
In patients with decreased renal function, the plasma and blood half-life of
metformin is prolonged and the renal clearance is decreased [see
Contraindications (4) and Warnings and Precautions (5.1)]. Patients with
Hepatic Impairment
ZITUVIMET
Studies characterizing the pharmacokinetics of sitagliptin and metformin after
administration of ZITUVIMET in patients with hepatic impairment have not been
performed.
Sitagliptin
In patients with moderate hepatic impairment (Child-Pugh score 7 to 9), mean
AUC and Cmax of sitagliptin increased approximately 21% and 13%, respectively,
compared to healthy matched controls following administration of a single
100-mg dose of sitagliptin. These differences are not considered to be
clinically meaningful. There is no clinical experience in patients with severe
hepatic impairment (Child-Pugh score >9) [see Use in Specific Populations
(8.7)].
Metformin
No pharmacokinetic studies of metformin have been conducted in patients with
hepatic impairment. Effects of Age, Body Mass Index (BMI), Gender, and Race
Sitagliptin
Based on a population pharmacokinetic analysis or a composite analysis of
available pharmacokinetic data, BMI, gender, and race do not have a clinically
meaningful effect on the pharmacokinetics of sitagliptin. When the effects of
age on renal function are taken into account, age alone did not have a
clinically meaningful impact on the pharmacokinetics of sitagliptin based on a
population pharmacokinetic analysis. Elderly subjects (65 to 80 years) had
approximately 19% higher plasma concentrations of sitagliptin compared to
younger subjects.
Metformin
Limited data from controlled pharmacokinetic studies of metformin in healthy
elderly subjects suggest that total plasma clearance of metformin is
decreased, the half-life is prolonged, and Cmax is increased, compared to
healthy young subjects. From these data, it appears that the change in
metformin pharmacokinetics with aging is primarily accounted for by a change
in renal function. Metformin pharmacokinetic parameters did not differ
significantly between normal subjects and patients with type 2 diabetes
mellitus when analyzed according to gender. Similarly, in controlled clinical
studies in patients with type 2 diabetes mellitus, the antihyperglycemic
effect of metformin was comparable in males and females. No studies of
metformin pharmacokinetic parameters according to race have been performed. In
controlled clinical studies of metformin in patients with type 2 diabetes
mellitus, the antihyperglycemic effect was comparable in Whites (n=249),
Blacks or African Americans (n=51), and Hispanics (n=24).
Drug Interaction Studies ZITUVIMET
Coadministration of multiple doses of sitagliptin (50 mg) and metformin HCl
(1,000 mg) given twice daily did not meaningfully alter the pharmacokinetics
of either sitagliptin or metformin in patients with type 2 diabetes mellitus.
Pharmacokinetic drug interaction studies with ZITUVIMET have not been
performed; however, such studies have been conducted with the individual
components of ZITUVIMET (sitagliptin and metformin HCl).
Sitagliptin
In Vitro Assessment of Drug Interactions Sitagliptin is not an inhibitor of
CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19 or 2B6, and is not an inducer of
CYP3A4. Sitagliptin is a P-gp substrate but does not inhibit P-gp mediated
transport of digoxin. Based on these results, sitagliptin is considered
unlikely to cause interactions with other drugs that utilize these pathways.
Sitagliptin is not extensively bound to plasma proteins. Therefore, the
propensity of sitagliptin to be involved in clinically meaningful drug-drug
interactions mediated by plasma protein binding displacement is very low. In
Vivo Assessment of Drug Interactions
Effects of Sitagliptin on Other Drugs
In clinical studies, sitagliptin did not meaningfully alter the
pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, digoxin,
warfarin, or an oral contraception (ethinyl estradiol and norethindrone)
(Table 5), providing in vivo evidence of a low propensity for causing drug
interactions with substrates of CYP3A4, CYP2C8, CYP2C9, P-gp, and organic
cationic transporter (OCT).
Table 5: Effect of Sitagliptin on Systemic Exposure of Coadministered Drugs
Coadministered Drug
|
**Dose of Coadministered Drug ***
|
**Dose of Sitagliptin ***
| Geometric Mean Ratio (ratio with/without sitagliptin)
No Effect = 1
| AUC †| C max
Digoxin| 0.25 mg‡ once daily for
10 days
| 100 mg‡ once daily
for 10 days
| Digoxin| 1.11§| 1.18
Glyburide| 1.25 mg| 200 mg‡ once daily
for 6 days
| Glyburide| 1.09| 1.01
Simvastatin| 20 mg| 200 mg‡ once daily
for 5 days
| Simvastatin| 0.85¶| 0.8
Simvastatin Acid| 1.12¶| 1.06
Rosiglitazone| 4 mg| 200 mg‡ once daily
for 5 days
| Rosiglitazone| 0.98| 0.99
Warfarin| 30 mg single dose on
day 5
| 200 mg‡ once daily
for 11 days
| S(-) Warfarin| 0.95| 0.89
R(+) Warfarin| 0.99| 0.89
Ethinyl estradiol and norethindrone
| 21 days once daily of 35 µg ethinyl estradiol with norethindrone 0.5 mg x 7 days, 0.75 mg x 7
days, 1 mg x 7 days
|
200 mg‡ once daily for 21 days
| Ethinyl estradiol| 0.99| 0.97
Norethindrone
|
1.03
|
0.98
Metformin HCl| 1,000 mg‡ twice daily
for 14 days
| 50 mg‡ twice daily
for 7 days
| Metformin| 1.02#| 0.97
- All doses are administered as single dose unless otherwise specified.
- AUC is reported as AUC0-
- unless otherwise specified.
- Multiple doses. §AUC0-24hr.
- AUC0-last. #AUC0-12hr.
Effects of Other Drugs on Sitagliptin
Clinical data described below suggest that sitagliptin is not susceptible
to clinically meaningful interactions by coadministered medications (Table 6).
Table 6: Effect of Coadministered Drugs on Systemic Exposure of Sitagliptin
Coadministered Drug| Dose of Coadministered Drug | Dose of Sitagliptin | Geometric Mean Ratio (ratio with/without coadministered
drug) No Effect = 1
---|---|---|---
| AUC †| C max
Cyclosporine| 600 mg once daily| 100 mg once daily| Sitagliptin| 1.29| 1.68
Metformin HCl| 1,000 mg‡ twice daily for
14 days
| 50 mg‡ twice daily
for 7 days
| Sitagliptin| 1.02§| 1.05
- All doses are administered as single doses unless otherwise specified.
- AUC is reported as AUC0-∞ unless otherwise specified.
- Multiple doses. §AUC0-12hr.
Table 7: Effect of Metformin HCl on Systemic Exposure of Coadministered Drugs
Coadministered Drug| Dose of Coadministered Drug | Dose of Metformin HCl | Geometric Mean Ratio (ratio with/without metformin)
No Effect = 1
---|---|---|---
| AUC †| C max
Cimetidine| 400 mg| 850 mg| Cimetidine| 0.95‡| 1.01
Glyburide| 5 mg| 500 mg§| Glyburide| 0.78¶| 0.63¶
Furosemide| 40 mg| 850 mg| Furosemide| 0.87¶| 0.69¶
Nifedipine| 10 mg| 850 mg| Nifedipine| 1.10‡| 1.08
Propranolol| 40 mg| 850 mg| Propranolol| 1.01‡| 0.94
Ibuprofen| 400 mg| 850 mg| Ibuprofen| 0.97#| 1.01#
- All doses are administered as single doses unless otherwise specified.
- AUC is reported as AUC0
- unless otherwise specified.
- AUC0-24hr.
- GLUMETZA (metformin HCl extended-release tablets) 500 mg.
- Ratio of arithmetic means, a p-value of difference <0.05. #Ratio of arithmetic means.
Table 8: Effect of Coadministered Drugs on Systemic Exposure of Metformin HCl
Coadministered Drug| Dose of Coadministered Drug | Dose of Metformin HCl | Geometric Mean Ratio
(ratio with/without coadministered drug) No Effect = 1
---|---|---|---
| AUC †| C max
Glyburide| 5 mg| 500 mg‡| Metformin‡| 0.98§| 0.99§
Furosemide| 40 mg| 850 mg| Metformin| 1.09§| 1.22§
Nifedipine| 10 mg| 850 mg| Metformin| 1.16| 1.21
Propranolol| 40 mg| 850 mg| Metformin| 0.90| 0.94
Ibuprofen| 400 mg| 850 mg| Metformin| 1.05§| 1.07§
Drugs that are eliminated by renal tubular secretion may increase the
accumulation of metformin [see Warnings and Precautions (5.1) and Drug
Interactions (7)].
Cimetidine| 400 mg| 850 mg| Metformin| 1.40| 1.61
Carbonic anhydrase inhibitors may cause metabolic acidosis [see Warnings
and Precautions (5.1) and Drug Interactions (7)].
Topiramate| 100 mg¶| 500 mg¶| Metformin| 1.25¶| 1.17
- All doses are administered as single doses unless otherwise specified.
- AUC is reported as AUC0-∞ unless otherwise specified.
- GLUMETZA (metformin HCl extended-release tablets) 500 mg. §Ratio of arithmetic means. ¶Steady state 100 mg Topiramate every 12 hr + metformin HCl 500 mg every 12 hr AUC = AUC0-12hr.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
No animal studies have been conducted with the combined products in ZITUVIMET
to evaluate carcinogenesis, mutagenesis or impairment of fertility. The
following data are based on the findings in studies with sitagliptin and
metformin individually.A two-year carcinogenicity study was conducted in male
and female rats given oral doses of sitagliptin of 50, 150, and 500 mg/kg/day.
There was an increased incidence of combined liver adenoma/carcinoma in males
and females and of liver carcinoma in females at 500 mg/kg. This dose results
in exposures approximately 60 times the human exposure at the maximum
recommended daily adult human dose (MRHD) of 100 mg/day based on AUC
comparisons. Liver tumors were not observed at 150 mg/kg, approximately 20
times the human exposure at the MRHD. A two-year carcinogenicity study was
conducted in male and female mice given oral doses of sitagliptin of 50, 125,
250, and 500 mg/kg/day. There was no increase in the incidence of tumors in
any organ up to 500 mg/kg, approximately 70 times human exposure at the MRHD.
Sitagliptin was not mutagenic or clastogenic with or without metabolic
activation in the Ames bacterial mutagenicity assay, a Chinese hamster ovary
(CHO) chromosome aberration assay, an in vitro cytogenetics assay in CHO, an
in vitro rat hepatocyte DNA alkaline elution assay, and an in vivo
micronucleus assay.
In rat fertility studies with oral gavage doses of 125, 250, and 1,000 mg/kg, males were treated for 4 weeks prior to mating, during mating, up to scheduled termination (approximately 8 weeks total), and females were treated 2 weeks prior to mating through gestation day 7. No adverse effect on fertility was observed at 125 mg/kg (approximately 12 times human exposure at the MRHD of 100 mg/day based on AUC comparisons). At higher doses, non-dose-related increased resorptions in females were observed (approximately 25 and 100 times human exposure at the MRHD based on AUC comparison).
Metformin
Long-term carcinogenicity studies have been performed in rats (dosing duration
of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and
including 900 mg/kg/day and 1,500 mg/kg/day, respectively. These doses are
both approximately four times the maximum recommended human daily dose of
2,000 mg based on body surface area comparisons. No evidence of
carcinogenicity with metformin was found in either male or female mice.
Similarly, there was no tumorigenic potential observed with metformin in male
rats. There was, however, an increased incidence of benign stromal uterine
polyps in female rats treated with 900 mg/kg/day. There was no evidence of a
mutagenic potential of metformin in the following in vitro tests: Ames test
(S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal
aberrations test (human lymphocytes). Results in the in vivo mouse
micronucleus test were also negative. Fertility of male or female rats was
unaffected by metformin when administered at doses as high as 600 mg/kg/day,
which is approximately three times the maximum recommended human daily dose
based on body surface area comparisons.
CLINICAL STUDIES
The coadministration of sitagliptin and metformin has been evaluated in patients with type 2 diabetes mellitus inadequately controlled on diet and exercise and in combination with other antihyperglycemic agents.
Sitagliptin and Metformin Coadministration in Patients with Type 2 Diabetes
Mellitus Inadequately Controlled on Diet and Exercise
A total of 1,091 patients with type 2 diabetes mellitus and inadequate
glycemic control on diet and exercise participated in a 24-week, randomized,
double-blind, placebo-controlled factorial trial designed to assess the
efficacy of sitagliptin and metformin coadministration. Patients on an anti-
hyperglycemic agent (N=541) underwent a diet, exercise, and drug washout
period of up to 12 weeks duration. After the washout period, patients with
inadequate glycemic control (A1C 7.5% to 11%) were randomized after completing
a 2-week single-blind placebo run-in period. Patients not on anti-
hyperglycemic agents at trial entry (N=550) with inadequate glycemic control
(A1C 7.5% to 11%) immediately entered the 2-week single-blind placebo run-in
period and then were randomized. Approximately equal numbers of patients were
randomized to receive placebo, 100 mg of sitagliptin once daily, 500 mg or
1,000 mg of metformin HCl twice daily, or 50 mg of sitagliptin twice daily in
combination with 500 mg or 1,000 mg of metformin HCl twice daily. Patients who
failed to meet specific glycemic goals during the trial were treated with
glyburide (glibenclamide) rescue. Sitagliptin and metformin coadministration
provided significant improvements in A1C, FPG, and 2-hour PPG compared to
placebo, to metformin alone, and to sitagliptin alone (Table 9, Figure 1).
Mean reductions from baseline in A1C were generally greater for patients with
higher baseline A1C values. For patients not on an anti-hyperglycemic agent at
trial entry, mean reductions from baseline in A1C were: sitagliptin 100 mg
once daily, -1.1%; metformin HCl 500 mg bid, -1.1%; metformin HCl 1,000 mg
bid, -1.2%; sitagliptin 50 mg bid with metformin HCl 500 mg bid, -1.6%;
sitagliptin 50 mg bid with metformin HCl 1,000 mg bid, -1.9%; and for patients
receiving placebo, -0.2%. Lipid effects were generally neutral. The decrease
in body weight in the groups given sitagliptin in combination with metformin
was similar to that in the groups given metformin alone or placebo.
**Table 9: Glycemic Parameters at Final Visit (24-Week Trial) for Sitagliptin and Metformin, Alone and in Combination in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Diet and Exercise***
| Placebo| Sitagliptin 100 mg once daily| Metformin HCl
500 mg twice daily
| Metformin HCl
1,000 mg
twice daily
| Sitagliptin 50 mg twice daily
+ Metformin HCl
500 mg twice daily
| Sitagliptin 50 mg twice daily
+ Metformin HCl
1,000 mg twice daily
---|---|---|---|---|---|---
A1C (%)| N = 165| N = 175| N = 178| N = 177| N =
183| N = 178
Baseline (mean)| 8.7| 8.9| 8.9| 8.7| 8.8| 8.8
Change from baseline
(adjusted mean†)
| 0.2| -0.7| -0.8| -1.1| -1.4| -1.9
Difference from placebo (adjusted mean†)
(95% CI)
| | -0.8‡
(-1.1, -0.6)
| -1‡
(-1.2, -0.8)
| -1.3‡
(-1.5, -1.1)
| -1.6‡
(-1.8, -1.3)
| -2.1‡
(-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, 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 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. Patients already on
metformin (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
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
(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 studies were treated with pioglitazone rescue. In combination with
metformin, sitagliptin provided significant improvements in A1C, FPG, and
2-hour PPG compared to placebo with metformin (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
| Sitagliptin 100 mg once daily + Metformin | Placebo + Metformin | |
|---|---|---|
| A1C (%) | N = 453 | N = 224 |
| Baseline (mean) | 8 | 8 |
| Change from baseline (adjusted mean†) | -0.7 | -0 |
Difference from placebo + metformin (adjusted
mean†) (95% CI)
| -0.7‡
(-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 (adjusted
mean†) (95% CI)
| -25‡
(-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 (adjusted
mean†) (95% CI)
| -51‡
(-61, -41)
|
- Intent-to-treat population using last observation on trial prior to pioglitazone rescue therapy.
- Least squares mean adjusted for prior antihyperglycemic therapy and baseline value.
- p<0.001 compared to placebo + metformin.
Sitagliptin Add-on Therapy in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on the Combination of Metformin 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. Patients entered a run-in treatment period on glimepiride (≥4 mg per day) alone or glimepiride in combination with metformin HCl (≥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 studies were treated with pioglitazone rescue.
Patients receiving sitagliptin with metformin and glimepiride had significant improvements in A1C and FPG compared to patients receiving placebo with metformin 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 [see Warnings and Precautions (5.6) and Adverse Reactions (6.1)].
Table 11: Glycemic Parameters at Final Visit (24-Week Trial) for Sitagliptin in Combination with Metformin and Glimepiride
| Sitagliptin 100 mg
+ Metformin and Glimepiride
| Placebo
+ Metformin and Glimepiride
---|---|---
A1C (%)| N = 115| N = 105
Baseline (mean)| 8.3| 8.3
Change from baseline (adjusted mean†)| -0.6| 0.3
Difference from placebo (adjusted mean†) (95%| -0.9‡|
CI)| (-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%| -21‡|
CI)| (-32, -10)
- Intent-to-treat population using last observation on trial prior to pioglitazone rescue therapy.
- Least squares means adjusted for prior antihyperglycemic therapy status and baseline value.
- p<0.001 compared to placebo.
Sitagliptin Add-on Therapy in Patients with Type 2 Diabetes Mellitus
Inadequately Controlled on the Combination of Metformin 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 and rosiglitazone.
Patients on dual therapy with metformin HCl ≥1,500 mg/day and rosiglitazone ≥4
mg/day or with metformin HCl ≥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 ≥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 and rosiglitazone, sitagliptin provided significant improvements in
A1C, FPG, and 2-hour PPG compared to placebo with metformin 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 and Rosiglitazone***
| Week 18 | |
|---|---|
| Sitagliptin 100 mg + Metformin + Rosiglitazone |
-
Rosiglitazone
A1C (%)| N = 176| N = 93
Baseline (mean)| 8.8| 8.7
Change from baseline (adjusted mean†)| -1| -0.4
Difference from placebo + rosiglitazone + metformin| -0.7‡|
(adjusted mean†) (95% CI)| (-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| -18‡|
(adjusted mean†) (95% CI)| (-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| -39‡|
(adjusted mean†) (95% CI)| (-51, -26)- Intent-to-treat population using last observation in the trial prior to glipizide (or other sulfonylurea) rescue therapy.
- Least squares means adjusted for prior antihyperglycemic therapy status and baseline value.
- p<0.001 compared to placebo + metformin + rosiglitazone.
Sitagliptin Add-on Therapy in Patients with Type 2 Diabetes Mellitus
Inadequately Controlled on the Combination of Metformin 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. 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 (≥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
enrolment 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 up-titration of the background insulin dose as
rescue therapy.
Among patients also receiving metformin, 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 and insulin had significant improvements in A1C, FPG and 2-hour PPG compared to patients receiving placebo with metformin and insulin (Table 13). The adjusted mean change from baseline in body weight was -0.3 kg in patients receiving sitagliptin with metformin and insulin and -0.2 kg in patients receiving placebo with metformin and insulin. There was an increased rate of hypoglycemia in patients treated with sitagliptin [see Warnings and Precautions (5.6) and Adverse Reactions (6.1)].
**Table 13: Glycemic Parameters at Final Visit (24-Week Trial) for Sitagliptin as Add-on Combination Therapy with Metformin and Insulin ***
| Sitagliptin 100 mg
+ Metformin
+ Insulin
| Placebo
+ Metformin
+ Insulin
A1C (%)| N = 223| N = 229
Baseline (mean)| 8.7| 8.6
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)|
- Intent-to-treat population using last observation on trial prior to rescue therapy.
- Least squares means adjusted for insulin use at the screening visit, type of insulin used at the screening visit (pre-mixed vs. non pre-mixed [intermediate- or long-acting]), and baseline value.
- Treatment by insulin stratum interaction was not significant (p >0.10).
- p<0.001 compared to placebo.
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 (≥1500 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 to 100 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 = 370 †
Baseline (mean)| 8.8| 8.8
Week 30 (mean)| 6.9| 7.3
Change from baseline (adjusted mean)| -1.9| -1.4
Difference from placebo (adjusted mean) (95% CI)| -0.4 (-0.6, -0.3)‡|
Patients (%) with A1C| 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
- 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.
- N is the number of randomized and treated patients.
- p <0.001 compared to placebo.
Sitagliptin Add-on Therapy vs. Glipizide Add-on Therapy in Patients with
Type 2 Diabetes Mellitus Inadequately Controlled on Metformin
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
monotherapy (dose of ≥1,500 mg per day) which included washout of medications
other than metformin, 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 (Intent-to-Treat Population)
| Sitagliptin 100 mg | Glipizide | |
|---|---|---|
| + Metformin | + Metformin | |
| A1C (%) | N = 576 | N = 559 |
| Baseline (mean) | 7.7 | 7.6 |
| 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 |
- The intent-to-treat analysis used the patients’ last observation in the trial before discontinuation.
- Least squares means adjusted for prior antihyperglycemic therapy status and baseline A1C value.
**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 (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).
HOW SUPPLIED/STORAGE AND HANDLING
Tablets supplied as follows:
| Contents | Description | How Supplied | NDC |
|---|
50 mg sitagliptin and
500 mg metformin HCl
| White to off-white, oval shaped, biconvex, film coated tablets debossed with “1786” on one side and plain on the other side.| Bottles of 60 tablets with child-resistant closure.| NDC 70710-1786-
6
Bottles of 180 tablets with child-resistant closure.| NDC 70710-1786-
8
50 mg sitagliptin and| Reddish brown, oval| Bottles of 60 tablets with|
NDC 70710-1787-|
---|---|---|---|---
1,000 mg metformin| shaped, biconvex, film|
child-resistant closure.| 6|
HCl| coated tablets debossed with “1787” on one side and plain on the other
side
|
Bottles of 180 tablets with child-resistant closure.| NDC 70710-1787-
8
|
Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F and 86°F), [see USP Controlled Room Temperature]. Dispense in original container to protect from moisture. Once the bottle has been opened, the product must be used within 3 months
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Lactic Acidosis
Explain the risks of lactic acidosis, its symptoms, and conditions that
predispose to its development. Advise patients to discontinue ZITUVIMET
immediately and to promptly notify their healthcare provider if unexplained
hyperventilation, myalgias, malaise, unusual somnolence or other nonspecific
symptoms occur. Counsel patients against excessive alcohol intake and inform
patients about the importance of regular testing of renal function while
receiving ZITUVIMET. Instruct patients to inform their healthcare provider
that they are taking ZITUVIMET before any surgical or radiological procedure,
as temporary discontinuation may be required [see Warnings and Precautions
(5.1)].
Pancreatitis
Inform patients that acute pancreatitis has been reported during postmarketing
use of sitagliptin. Inform patients that persistent severe abdominal pain,
sometimes radiating to the back, which may or may not be accompanied by
vomiting, is the hallmark symptom of acute pancreatitis. Instruct patients to
promptly discontinue ZITUVIMET and contact their physician if persistent
severe abdominal pain occurs [see Warnings and Precautions (5.2)].
Heart Failure
Inform patients of the signs and symptoms of heart failure. Before initiating
ZITUVIMET, ask patients about a history of heart failure or other risk factors
for heart failure including moderate to severe renal impairment. Instruct
patients to contact their health care provider as soon as possible if they
experience symptoms of heart failure, including increasing shortness of
breath, rapid increase in weight or swelling of the feet [see Warnings and
Precautions (5.3)].
Vitamin B12 Deficiency
Inform patients about the importance of regular monitoring of hematological
parameters while receiving ZITUVIMET [see Warnings and Precautions (5.5)].
Hypoglycemia
Inform patients that the incidence of hypoglycemia is increased when ZITUVIMET
is added to an insulin secretagogue (e.g., sulfonylurea) or insulin therapy.
Explain to patients receiving ZITUVIMET in combination with these medications
the risks of hypoglycemia, its symptoms and treatment, and conditions that
predispose to its development [see Warnings and Precautions (5.6)].
Hypersensitivity Reactions
Inform patients that allergic reactions have been reported during
postmarketing use of sitagliptin, one of the components of ZITUVIMET. If
symptoms of allergic reactions (including rash, hives, and swelling of the
face, lips, tongue, and throat that may cause difficulty in breathing or
swallowing) occur, patients must stop taking ZITUVIMET and seek medical advice
promptly.
Severe and Disabling Arthralgia
Inform patients that severe and disabling joint pain may occur with this
class of drugs. The time to onset of symptoms can range from one day to years.
Instruct patients to seek medical advice if severe joint pain occurs [see
Warnings and Precautions (5.8)].
Bullous Pemphigoid
Inform patients that bullous pemphigoid may occur with this class of drugs.
Instruct patients to seek medical advice if blisters or erosions occur [see
Warnings and Precautions (5.9)].
Females of Reproductive Age: Inform females that treatment with ZITUVIMET may result in ovulation in some premenopausal anovulatory women which may lead to unintended pregnancy [see Use in Specific Populations (8.3)].
Administration Instructions
Inform patients that the tablets must never be split or divided before
swallowing. The trademarks depicted herein are owned by their respective
companies. Medication Guide available at
www.zydususa.com/medguides/ or call
1-877-993-8779
- Manufactured by: Zydus Lifesciences Ltd., Pharmez, Matoda, Ahmedabad, India.
- Distributed by: Zydus Pharmaceuticals (USA) Inc. Route 31 North, Pennington, NJ 08534
Medication Guide ZITUVIMET [zye too’ vi met] (sitagliptin and metformin hydrochloride) tablets, for oral use
Read this Medication Guide carefully before you start taking ZITUVIMET and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. If you have any questions about ZITUVIMET, ask your healthcare provider or pharmacist. What is the most important information I should know about ZITUVIMET? ZITUVIMET can cause serious side effects, including: 1. Lactic Acidosis. Metformin, one of the medicines in ZITUVIMET, can cause a rare but serious condition called lactic acidosis (a buildup of an acid in the blood) that can cause death. Lactic acidosis is a medical emergency and must be treated in the hospital. Stop taking ZITUVIMET and call your healthcare provider right away if you have any of the following symptoms, which could be signs of lactic acidosis:
- you feel cold in your hands or feet
- you feel dizzy or lightheaded
- you have a slow or irregular heartbeat
- you feel very weak or tired
- you have unusual (not normal) muscle pain
- you have trouble breathing
- you feel sleepy or drowsy
- you have stomach pains, nausea or vomiting
Most people who have had lactic acidosis with metformin have other things that, combined with the metformin, led to the lactic acidosis. Tell your healthcare provider if you have any of the following, because you have a higher chance for getting lactic acidosis with ZITUVIMET if you:
- have severe kidney problems or your kidneys are affected by certain x-ray tests that use injectable dye have liver problems
- drink alcohol very often, or drink a lot of alcohol in short-term “binge” drinking
- get dehydrated (lose a large amount of body fluids). This can happen if you are sick with a fever, vomiting, or diarrhea. Dehydration can also happen when you sweat a lot with activity or exercise and do not drink enough fluids.
- have surgery
- have a heart attack, severe infection, or stroke
- are 65 years of age or older
The best way to keep from having a problem with lactic acidosis from metformin is to tell your healthcare provider if you have any of the problems in the list above. Your healthcare provider may decide to stop your ZITUVIMET for a while if you have any of these things. ZITUVIMET can have other serious side effects. See “What are the possible side effects of ZITUVIMET?”
Inflammation of the pancreas (pancreatitis) which may be severe and lead to death. Certain medical problems make you more likely to get pancreatitis. Before you start taking ZITUVIMET, tell your healthcare provider if you have ever had:
- pancreatitis
- stones in your gallbladder (gallstones)
- high blood triglyceride levels
- a history of alcoholism
- kidney problems
Stop taking ZITUVIMET and call your healthcare provider right away if you have pain in your stomach area (abdomen) that is severe and will not go away. The pain may be felt going from your abdomen through to your back. The pain may happen with or without vomiting. These may be symptoms of pancreatitis.
Heart failure. Heart failure means that your heart does not pump blood well enough. Before you start taking ZITUVIMET, tell your healthcare provider if you have ever had heart failure or have problems with your kidneys. Contact your healthcare provider right away if you have any of the following symptoms:
- increasing shortness of breath or trouble breathing, especially when you lie down
- swelling or fluid retention, especially in the feet, ankles, or legs
- an unusually fast increase in weight
- unusual tiredness
- These may be symptoms of heart failure.
What is ZITUVIMET?
- ZITUVIMET is a prescription medicine that contains 2 prescription diabetes medicines, sitagliptin and metformin that is used along with diet and exercise to lower blood sugar in adults with type 2 diabetes.
- ZITUVIMET is not for people with type 1 diabetes.
- If you have had pancreatitis (inflammation of the pancreas) in the past, it is not known if you have a higher chance of getting pancreatitis while you take ZITUVIMET
- It is not known if ZITUVIMET is safe and effective in children.
Who should not take ZITUVIMET? Do not take ZITUVIMET if you:
- have severe kidney problems.
- have diabetic ketoacidosis.
- are allergic to any of the ingredients in ZITUVIMET. See the end of this Medication Guide for a complete list of ingredients in ZITUVIMET.
Symptoms of a serious allergic reaction to ZITUVIMET may include rash, raised red patches on your skin (hives) or swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing.
What should I tell my healthcare provider before taking ZITUVIMET?
Before you take ZITUVIMET, tell your healthcare provider about all of your
medical conditions, including if you:
- have or have had inflammation of your pancreas (pancreatitis).
- have kidney problems.
- have liver problems.
- have heart failure
- drink alcohol very often or drink a lot of alcohol in short-term “binge” drinking.
- are going to get an injection of dye or contrast agents for an x-ray procedure. ZITUVIMET may need to be stopped for a short time. Talk to your healthcare provider about when you should stop ZITUVIMET and when you should start ZITUVIMET again. See “What is the most important information I should know about ZITUVIMET?”.
- have low levels of vitamin B12 in your blood.
- are pregnant or plan to become pregnant. It is not known if ZITUVIMET will harm your unborn baby. If you are pregnant, talk with your healthcare provider about the best way to control your blood sugar while you are pregnant.
- are breastfeeding or plan to breastfeed. It is not known if ZITUVIMET will pass into your breast milk. Talk with your healthcare provider about the best way to feed your baby if you are taking ZITUVIMET.
- are a woman who has not gone through menopause (premenopausal) who does not have periods regularly or at all. ZITUVIMET can cause the release of an egg from an ovary in a woman (ovulation). This can increase your chance of getting pregnant. Tell your healthcare provider right away if you become pregnant while taking ZITUVIMET.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. ZITUVIMET may affect the way other medicines work and other medicines may affect how ZITUVIMET works. Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.
How should I take ZITUVIMET?
- Take ZITUVIMET 2 times a day by mouth. Your healthcare provider will tell you exactly how many ZITUVIMET tablets to take and when you should take them.
- Take ZITUVIMET with meals to help to lower your chance of having an upset stomach.
- Do not break or cut ZITUVIMET tablets before swallowing. If you cannot swallow ZITUVIMET tablets whole, tell your healthcare provider.
- Your healthcare provider may tell you to take ZITUVIMET along with certain other diabetes medicines. Low blood sugar (hypoglycemia) can happen more often when ZITUVIMET is taken with certain other diabetes medicines. See “What are the possible side effects of ZITUVIMET?”.
- When your body is under some types of stress, such as fever, trauma (such as a car accident), infection or surgery, the amount of diabetes medicine that you need may change. Tell your healthcare provider right away if you have any of these problems and follow your healthcare provider’s instructions.
- Your healthcare provider will do blood tests to check how well your kidneys are working before and during your treatment with ZITUVIMET.
- If you take too much ZITUVIMET, call your healthcare provider or Poison Help Line at 1-800-222-1222 or go to the nearest hospital emergency room right away.
What are the possible side effects of ZITUVIMET? ZITUVIMET may cause serious side effects, including:
- see “What is the most important information I should know about ZITUVIMET?”.
- kidney problems, sometimes requiring dialysis.
- low vitamin B12 (vitamin B12 deficiency). Using metformin for long periods of time may cause a decrease in the amount of vitamin B12 in your blood, especially if you have had low vitamin B12 blood levels before. Your healthcare provider may do blood tests to check your vitamin B12 levels.
- low blood sugar (hypoglycemia). If you take ZITUVIMET with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin, your risk of getting low blood sugar is higher. The dose of your sulfonylurea medicine or insulin may need to be lowered while you use ZITUVIMET. Signs and symptoms of low blood sugar may include:
- headache
- hunger
- sweating
- fast heart beat drowsiness
- dizziness
- feeling jittery
- irritability
- confusion
- weakness
Serious allergic reactions. If you have any symptoms of a serious allergic reaction, stop taking ZITUVIMET and call your healthcare provider right away or get emergency medical help. See “Who should not take ZITUVIMET?”. Your healthcare provider may give you a medicine for your allergic reaction and prescribe a different medicine for your diabetes.
- Joint pain. Some people who take medicines called DPP-4 inhibitors, one of the medicines in ZITUVIMET, may develop joint pain that can be severe. Call your healthcare provider if you have severe joint pain.
- Skin reaction. Some people who take medicines called DPP-4 inhibitors, one of the medicines in ZITUVIMET, may develop a skin reaction called bullous pemphigoid that can require treatment in a hospital. Tell your healthcare provider right away if you develop blisters or the breakdown of the outer layer of your skin (erosion). Your healthcare provider may tell you to stop taking ZITUVIMET.
The most common side effects of ZITUVIMET include:
- stuffy or runny nose and sore throat
- upper respiratory infection
- low blood sugar (hypoglycemia) when used in combination with certain medicines, such as a sulfonylurea or insulin
- gas, upset stomach, indigestion
- weakness
- nausea and vomiting
- headache
- diarrhea
Taking ZITUVIMET with meals can help lessen the common stomach side effects of metformin that usually happen at the beginning of treatment. If you have unusual or sudden stomach problems, talk with your healthcare provider. Stomach problems that start later during treatment may be a sign of something more serious. ZITUVIMET may have other side effects, including swelling of the hands or legs. Swelling of the hands and legs can happen if you take ZITUVIMET in combination with rosiglitazone (Avandia). Rosiglitazone is another type of diabetes medicine. Tell your healthcare provider if you have any side effect that bothers you, or does not go away. These are not all the possible side effects of ZITUVIMET. For more information, ask your healthcare provider or pharmacist. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store ZITUVIMET?
- Store ZITUVIMET in the original container at room temperature, between 68°F to 77°F (20°C to 25°C).
- Keep ZITUVIMET in the original container to protect it from moisture.
- Use ZITUVIMET within 3 months of opening the bottle.
Keep ZITUVIMET and all medicines out of the reach of children.
General information about the safe and effective use of ZITUVIMET.
Medicines are sometimes prescribed for purposes other than those listed in a
Medication Guide. Do not use ZITUVIMET for a condition for which it was not
prescribed. Do not give ZITUVIMET to other people, even if they have the same
symptoms you have. It may harm them.
- You can ask your healthcare provider or pharmacist for information about ZITUVIMET which is written for health professionals.
What are the ingredients in ZITUVIMET?
Active ingredients: sitagliptin and metformin hydrochloride Inactive
ingredients: colloidal silicon dioxide, croscarmellose sodium, low substituted
hydroxypropyl cellulose, magnesium stearate, malic acid, microcrystalline
cellulose, povidone, and sodium stearyl fumarate. In addition, the film
coating contains the following inactive ingredients: polyethylene glycol,
polyvinyl alcohol, talc, and titanium dioxide. The film coating of 50 mg/1,000
mg also contains: FD&C yellow #6 aluminum lake, iron oxide red, and iron oxide
yellow.
Manufactured by: Zydus Lifesciences Ltd., Pharmez, Matoda, Ahmedabad, India Distributed by: Zydus Pharmaceuticals (USA) Inc., Route 31 North, Pennington, NJ 08534 The trademarks depicted herein are owned by their respective companies. For more information, call 1-877-993-8779, email medicalaffairs@zydusua.com, or go to www.zyususa.com/medguides/
This Medication Guide has been approved by the U.S. Food and Drug Administration.
References
Read User Manual Online (PDF format)
Read User Manual Online (PDF format) >>