CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`202343Orig1s000
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`LABELING
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`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`JUVISYNC safely and effectively. See full prescribing information
`for JUVISYNC.
`
`JUVISYNC™ (sitagliptin and simvastatin) Tablets
`Initial U.S. Approval: 2011
`----------------------------INDICATIONS AND USAGE ----------------------------
`JUVISYNC (sitagliptin and simvastatin) is indicated in patients for
`whom treatment with both sitagliptin and simvastatin is appropriate. (1)
`Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor indicated as an
`adjunct to diet and exercise to improve glycemic control in adults with
`type 2 diabetes mellitus. (1.1)
`Simvastatin is an HMG-CoA reductase inhibitor (statin) indicated as an
`adjunctive therapy to diet to:
`• Reduce the risk of total mortality by reducing CHD deaths and
`reduce the risk of non-fatal myocardial infarction, stroke, and the
`need for revascularization procedures in patients at high risk of
`coronary events. (1.2)
`• Reduce elevated total-C, LDL-C, Apo B, TG and increase HDL-C in
`patients with primary hyperlipidemia (heterozygous familial and
`nonfamilial) and mixed dyslipidemia. (1.2)
`• Reduce elevated TG in patients with hypertriglyceridemia and
`reduce TG and VLDL-C
`in patients with primary dysbeta-
`lipoproteinemia. (1.2)
`• Reduce total-C and LDL-C in adult patients with homozygous
`familial hypercholesterolemia. (1.2)
`Important Limitations of Use:
`• JUVISYNC should not be used in patients with type 1 diabetes or for
`the treatment of diabetic ketoacidosis. (1.3)
`• JUVISYNC has not been studied in patients with a history of
`pancreatitis. (1.3, 5.1)
`• JUVISYNC has not been studied in Fredrickson types I and V
`dyslipidemias. (1.3)
`• Patients with moderate or severe renal impairment who require
`sitagliptin 50 or 25 mg should not use JUVISYNC due to the
`unavailability of these dosage strengths for JUVISYNC. (1.3)
`----------------------- DOSAGE AND ADMINISTRATION------------------------
`• Doses are 100 mg/10 mg, 100 mg/20 mg, and 100 mg/40 mg per
`day. (2.1)
`• Recommended usual starting dose is 100 mg/40 mg once a day in
`the evening. (2.1)
`• Patients already taking simvastatin (10, 20, or 40 mg) can initiate
`JUVISYNC at a dose of 100 mg sitagliptin and the dose of
`simvastatin already being taken. (2.1)
`--------------------- DOSAGE FORMS AND STRENGTHS ---------------------
`Tablets (sitagliptin/simvastatin): 100 mg/10 mg, 100 mg/20 mg, and
`100 mg/40 mg (3)
`-------------------------------CONTRAINDICATIONS -------------------------------
`• History of a serious hypersensitivity reaction, such as anaphylaxis or
`angioedema, to any component of this medication. (4, 5.6, 6.2)
`• Concomitant administration of strong CYP3A4 inhibitors. (4, 5.2)
`• Concomitant administration of gemfibrozil, cyclosporine, or danazol.
`(4, 5.2)
`• Active liver disease, which may include unexplained persistent
`elevations in hepatic transaminase levels. (4, 5.3)
`• Women who are pregnant or may become pregnant. (4, 8.1)
`• Nursing mothers. (4, 8.3)
`------------------------WARNINGS AND PRECAUTIONS------------------------
`• There have been postmarketing reports of acute pancreatitis,
`including fatal and non-fatal hemorrhagic or necrotizing pancreatitis.
`If pancreatitis is suspected, promptly discontinue JUVISYNC. (5.1)
`• Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): Risks
`increase with higher doses and concomitant use of certain
`medicines. Predisposing factors include advanced age (≥65),
`female gender, uncontrolled hypothyroidism, and renal impairment.
`(4, 5.2, 8.5)
`• Patients should be advised to report promptly any symptoms of
`myopathy. JUVISYNC therapy should be discontinued immediately
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`Reference ID: 3025884
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`6065500
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`if myopathy is diagnosed or suspected. See Drug Interaction table.
`(5.2)
`• Liver enzyme abnormalities: Persistent elevations
`in hepatic
`transaminase can occur. Check liver enzyme tests before initiating
`therapy and as clinically indicated thereafter. (5.3)
`• There have been postmarketing reports of acute renal failure,
`sometimes requiring dialysis, in patients treated with sitagliptin.
`Assessment of renal function is recommended prior to initiation of
`JUVISYNC and periodically thereafter. (5.4, 6.2)
`• There is an increased risk of hypoglycemia when JUVISYNC is
`added to an insulin secretagogue (e.g., sulfonylurea) or insulin
`therapy. Consider lowering the dose of the sulfonylurea or insulin to
`reduce the risk of hypoglycemia. (2.3, 5.5)
`• 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.
`In such cases, promptly stop
`JUVISYNC, assess for other potential causes, institute appropriate
`monitoring and treatment, and initiate alternative treatment. (5.6,
`6.2)
`------------------------------ ADVERSE REACTIONS-------------------------------
`Most common adverse reactions (incidence ≥5%) with simvastatin are:
`upper respiratory infection, headache, abdominal pain, constipation,
`and nausea. Adverse reactions reported in ≥5% of patients treated with
`sitagliptin and more commonly than in patients treated with placebo
`are: upper respiratory tract infection, nasopharyngitis and headache. In
`the add-on to sulfonylurea and add-on to insulin studies, hypoglycemia
`was also more commonly reported in patients treated with sitagliptin
`compared to placebo. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Merck
`Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877-
`888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`-------------------------------DRUG INTERACTIONS-------------------------------
`Drug Interactions Associated with Increased
`Risk of Myopathy/Rhabdomyolysis (2.4, 4, 5.2, 7.1, 7.2, 7.3,
`12.3)
`Prescribing Recommendations
`Contraindicated with JUVISYNC
`
`Interacting Agents
`Itraconazole, ketoconazole,
`posaconazole, erythromycin,
`clarithromycin, telithromycin,
`HIV protease inhibitors,
`nefazodone, gemfibrozil,
`cyclosporine, danazol
`Verapamil, diltiazem
`
`Amiodarone, amlodipine,
`ranolazine
`Grapefruit juice
`
`Do not exceed 100 mg/10 mg
`JUVISYNC daily
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`Do not exceed 100 mg/20 mg
`JUVISYNC daily
`Avoid large quantities of grapefruit
`juice (>1 quart daily)
`
`
`• Coumarin anticoagulants: Concomitant use with simvastatin
`prolongs INR. Achieve stable INR prior to starting JUVISYNC.
`Monitor INR frequently until stable upon initiation or alteration of
`JUVISYNC therapy. (7.6)
`• Other Lipid-lowering Medications: Use with other fibrate products or
`lipid-modifying doses (≥1 g/day) of niacin increases the risk of
`adverse skeletal muscle effects. Caution should be used when
`prescribing with JUVISYNC. (5.2, 7.2, 7.4).
`----------------------- USE IN SPECIFIC POPULATIONS -----------------------
`• Safety and effectiveness of JUVISYNC in children under 18 years
`have not been established. (8.4)
`• There are no adequate and well-controlled studies in pregnant
`women. (8.1)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved Medication Guide.
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`Revised: 10/2011
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`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`1.1 Sitagliptin
`1.2 Simvastatin
`1.3
`Important Limitations of Use
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosing
`2.2 Patients with Renal Impairment
`2.3 Concomitant Use with an Insulin Secretagogue (e.g.,
`Sulfonylurea) or with Insulin
`2.4 Coadministration with Other Drugs
`2.5 Patients with Homozygous Familial Hypercholesterolemia
`2.6 Chinese Patients Taking Lipid-Modifying Doses (≥1 g/day
`Niacin) of Niacin-Containing Products
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Pancreatitis
`5.2 Myopathy/Rhabdomyolysis
`5.3
`Liver Dysfunction
`5.4 Renal Impairment
`5.5 Use with Medications Known to Cause Hypoglycemia
`5.6 Hypersensitivity Reactions
`5.7 Endocrine Function
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postmarketing Experience
`7 DRUG INTERACTIONS
`7.1 Strong CYP3A4 Inhibitors, Cyclosporine, or Danazol
`7.2
`Lipid-Lowering Drugs That Can Cause Myopathy When
`Given Alone
`7.3 Amiodarone, Ranolazine, or Calcium Channel Blockers
`7.4 Niacin
`
`FULL PRESCRIBING INFORMATION
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`6065500
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`7.5 Digoxin
`7.6 Coumarin Anticoagulants
`7.7 Colchicine
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`8.7 Hepatic Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.2 Animal Toxicology and/or Pharmacology
`14 CLINICAL STUDIES
`14.1 Sitagliptin Clinical Studies
`14.2 Simvastatin Clinical Studies
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`17.1
`Instructions
`17.2 Laboratory Tests
`17.3 Muscle Pain
`17.4 Pregnancy
`17.5 Breastfeeding
`
`
`*Sections or subsections omitted from the full prescribing information
`are not listed.
`
`
`1
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`INDICATIONS AND USAGE
`JUVISYNC™ (sitagliptin and simvastatin) is indicated in patients for whom treatment with both
`sitagliptin and simvastatin is appropriate.
`1.1 Sitagliptin
`Sitagliptin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with
`type 2 diabetes mellitus. [See Clinical Studies (14.1).]
`1.2 Simvastatin
`Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in
`individuals at significantly
`increased
`risk
`for atherosclerotic
`vascular disease due
`to
`hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a diet
`restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been
`inadequate. In patients with coronary heart disease (CHD) or at high risk of CHD, simvastatin can be
`started simultaneously with diet.
`Reductions in Risk of CHD Mortality and Cardiovascular Events
`In patients at high risk of coronary events because of existing coronary heart disease, diabetes,
`peripheral vessel disease, history of stroke or other cerebrovascular disease, simvastatin is indicated to:
`• Reduce the risk of total mortality by reducing CHD deaths.
`• Reduce the risk of non-fatal myocardial infarction and stroke.
`• Reduce the need for coronary and non-coronary revascularization procedures.
`Hyperlipidemia
`Simvastatin is indicated to:
`• Reduce elevated
`lipoprotein cholesterol (LDL-C),
`low-density
`total cholesterol (total-C),
`apolipoprotein B (Apo B), and triglycerides (TG), and to increase high-density lipoprotein
`cholesterol (HDL-C) in patients with primary hyperlipidemia (Fredrickson type IIa, heterozygous
`familial and nonfamilial) or mixed dyslipidemia (Fredrickson type IIb).
`• Reduce elevated TG in patients with hypertriglyceridemia (Fredrickson type lV hyperlipidemia).
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`Reference ID: 3025884
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`JUVISYNC™
`(sitagliptin and simvastatin) Tablets
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`6065500
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`• Reduce elevated TG and VLDL-C in patients with primary dysbetalipoproteinemia (Fredrickson
`type lll hyperlipidemia).
`• Reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia as an
`adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are
`unavailable.
`Important Limitations of Use
`1.3
`JUVISYNC should not be used in patients with type 1 diabetes or for the treatment of diabetic
`ketoacidosis, as it would not be effective in these settings.
`JUVISYNC 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
`JUVISYNC. [See Warnings and Precautions (5.1).]
`JUVISYNC has not been studied in conditions where the major abnormality is elevation of
`chylomicrons (i.e., hyperlipidemia Fredrickson types I and V).
`Because doses of JUVISYNC appropriate for patients with moderate or severe renal impairment (CrCl
`<50 mL/min, approximately corresponding to serum creatinine levels of >1.7 mg/dL in men and
`>1.5 mg/dL in women) or end-stage renal disease (ESRD) are not available in this combination product,
`JUVISYNC is not recommended in patients with moderate or severe renal impairment or ESRD.
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`DOSAGE AND ADMINISTRATION
`2
`2.1 Recommended Dosing
`The dosages for therapy with JUVISYNC are 100 mg/10 mg, 100 mg/20 mg, and 100 mg/40 mg
`(sitagliptin/simvastatin) once daily. JUVISYNC should be taken as a single daily dose in the evening.
`JUVISYNC should be swallowed whole. The tablets must not be split, crushed, or chewed before
`swallowing.
`The recommended starting dose is 100 mg/40 mg per day. For patients already taking simvastatin
`(10, 20, or 40 mg daily) with or without sitagliptin 100 mg daily, JUVISYNC may be initiated at the dose of
`100 mg sitagliptin and the dose of simvastatin already being taken.
`After initiation or titration of JUVISYNC, lipid levels may be analyzed after 4 or more weeks and
`dosage adjusted, if needed.
`2.2 Patients with Renal Impairment
`JUVISYNC is not recommended in patients with moderate or severe renal impairment or ESRD.
`JUVISYNC can be used in patients with normal renal function or mild renal impairment (creatinine
`clearance [CrCl] ≥50 mL/min, approximately corresponding to serum creatinine levels of ≤1.7 mg/dL in
`men and ≤1.5 mg/dL in women). Because simvastatin does not undergo significant renal excretion,
`modification of the dose of the simvastatin component should not be necessary in patients with mild renal
`impairment.
`Assessment of renal function is recommended prior to initiation of JUVISYNC and periodically
`thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault
`formula. [See Warnings and Precautions (5.4); Clinical Pharmacology (12.3).] There have been
`postmarketing reports of worsening renal function in patients with renal impairment treated with sitagliptin,
`some of whom were prescribed inappropriate doses of sitagliptin.
`2.3 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin
`When JUVISYNC is used in combination with an insulin secretagogue (e.g., sulfonylurea) or with
`insulin, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of
`hypoglycemia. [See Warnings and Precautions (5.5).]
`2.4 Coadministration with Other Drugs
`Patients taking Verapamil, or Diltiazem
`• The dose of JUVISYNC should not exceed 100 mg/10 mg per day [see Warnings and Precautions
`(5.2); Drug Interactions (7.3); Clinical Pharmacology (12.3)].
`Patients taking Amiodarone, Amlodipine or Ranolazine
`• The dose of JUVISYNC should not exceed 100 mg/20 mg per day [see Warnings and Precautions
`(5.2); Drug Interactions (7.3); Clinical Pharmacology (12.3)].
`
`Reference ID: 3025884
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`3
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`6065500
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`JUVISYNC™
`(sitagliptin and simvastatin) Tablets
`
`2.5 Patients with Homozygous Familial Hypercholesterolemia
`The recommended dosage is 100 mg/40 mg per day in the evening. JUVISYNC should be used as an
`adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are
`unavailable.
`2.6 Chinese Patients Taking Lipid-Modifying Doses (≥1 g/day Niacin) of Niacin-Containing
`Products
`Because of an increased risk for myopathy in Chinese patients taking simvastatin 40 mg
`coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products, caution should
`be used when treating Chinese patients with JUVISYNC 100 mg/40 mg per day coadministered with lipid-
`modifying doses of niacin-containing products. The cause of the increased risk of myopathy is not known.
`It is also unknown if the risk for myopathy with coadministration of JUVISYNC with lipid-modifying doses
`of niacin-containing products observed in Chinese patients applies to other Asian patients. [See Warnings
`and Precautions (5.2).]
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`3
`•
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`•
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`•
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`DOSAGE FORMS AND STRENGTHS
`JUVISYNC 100 mg/10 mg tablets are pink-beige, bi-convex round, film-coated tablets, coded with the
`Merck logo and "753" on one side and plain on the other.
`JUVISYNC 100 mg/20 mg tablets are pink-beige, bi-convex modified capsule-shaped, film-coated
`tablets, coded with the Merck logo and "757" on one side and plain on the other.
`JUVISYNC 100 mg/40 mg tablets are orange-beige, bi-convex modified capsule-shaped, film-coated
`tablets, coded with the Merck logo and "773" on one side and plain on the other.
`
`CONTRAINDICATIONS
`4
`JUVISYNC is contraindicated in the following conditions:
`• History of a serious hypersensitivity reaction, such as anaphylaxis or angioedema, to any component
`of this medication. [See Warnings and Precautions (5.6); Adverse Reactions (6.2).]
`• Concomitant administration of strong CYP3A4
`inhibitors (e.g.,
`itraconazole, ketoconazole,
`posaconazole, HIV protease inhibitors, erythromycin, clarithromycin, telithromycin and nefazodone)
`[see Warnings and Precautions (5.2)].
`• Concomitant administration of gemfibrozil, cyclosporine, or danazol [see Warnings and Precautions
`(5.2)].
`• Active liver disease, which may include unexplained persistent elevations in hepatic transaminase
`levels [see Warnings and Precautions (5.3)].
`• Women who are pregnant or may become pregnant. Serum cholesterol and triglycerides increase
`during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal
`development. Because HMG-CoA reductase inhibitors (statins) decrease cholesterol synthesis and
`possibly the synthesis of other biologically active substances derived from cholesterol, simvastatin
`may cause fetal harm when administered to a pregnant woman. Atherosclerosis is a chronic process
`and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on the
`outcome of long-term therapy of primary hypercholesterolemia. There are no adequate and well-
`controlled studies of use with JUVISYNC during pregnancy; however, in rare reports congenital
`anomalies were observed following intrauterine exposure to statins. In rat and rabbit animal
`reproduction studies, simvastatin revealed no evidence of teratogenicity. JUVISYNC should be
`administered to women of childbearing age only when such patients are highly unlikely to
`conceive. If the patient becomes pregnant while taking this drug, JUVISYNC should be discontinued
`immediately and the patient should be apprised of the potential hazard to the fetus [see Use in
`Specific Populations (8.1)].
`• Nursing mothers. Because statins have the potential for serious adverse reactions in nursing infants,
`women who require treatment with JUVISYNC should not breastfeed their infants. A small amount of
`another drug in the statin class passes into breast milk. It is not known whether simvastatin is
`excreted into human milk [see Use in Specific Populations (8.3)].
`
`Reference ID: 3025884
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`4
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`6065500
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`
`
`JUVISYNC™
`(sitagliptin and simvastatin) Tablets
`
`5 WARNINGS AND PRECAUTIONS
`5.1 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 JUVISYNC,
`patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected,
`JUVISYNC 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 JUVISYNC. [See also Adverse Reactions (6.2).]
`5.2 Myopathy/Rhabdomyolysis
`Simvastatin occasionally causes myopathy manifested as muscle pain, tenderness or weakness with
`creatine kinase (CK) above ten times the upper limit of normal (ULN). Myopathy sometimes takes the
`form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and rare fatalities
`have occurred. The risk of myopathy is increased by high levels of statin activity in plasma. Predisposing
`factors for myopathy include advanced age (≥65 years), female gender, uncontrolled hypothyroidism, and
`renal impairment.
`The risk of myopathy, including rhabdomyolysis, is dose related. In a clinical trial database in
`which 41,413 patients were treated with simvastatin, 24,747 (approximately 60%) of whom were enrolled
`in studies with a median follow-up of at least 4 years, the incidence of myopathy was approximately
`0.03% and 0.08% at 20 and 40 mg/day, respectively. The incidence of myopathy with 80 mg (0.61%) was
`disproportionately higher than that observed at the lower doses. In these trials, patients were carefully
`monitored and some interacting medicinal products were excluded.
`In a clinical trial in which 12,064 patients with a history of myocardial infarction were treated with
`simvastatin (mean follow-up 6.7 years), the incidence of myopathy (defined as unexplained muscle
`weakness or pain with a serum creatine kinase [CK] >10 times upper limit of normal [ULN]) in patients on
`20 mg/day was approximately 0.02%; in patients treated with 80 mg/day, the incidence was 0.9%. The
`incidence of rhabdomyolysis (defined as myopathy with a CK >40 times ULN) in patients on 20 mg/day
`was 0%; in patients on 80 mg/day, the incidence was approximately 0.4%. The incidence of myopathy,
`including rhabdomyolysis, was highest during the first year and then notably decreased during the
`subsequent years of treatment. In this trial, patients were carefully monitored and some interacting
`medicinal products were excluded.
`All patients starting therapy with JUVISYNC, or whose dose of simvastatin is being increased,
`should be advised of the risk of myopathy, including rhabdomyolysis, and told to report promptly
`any unexplained muscle pain, tenderness or weakness. JUVISYNC therapy should be
`discontinued immediately if myopathy is diagnosed or suspected. In most cases, muscle symptoms
`and CK increases resolved when treatment was promptly discontinued. Periodic CK determinations may
`be considered in patients starting therapy with JUVISYNC or whose dose of simvastatin is being
`increased. There is no assurance that such monitoring will prevent myopathy.
`Many of the patients who have developed rhabdomyolysis on therapy with simvastatin have had
`complicated medical histories, including renal impairment usually as a consequence of long-standing
`diabetes mellitus. Such patients merit closer monitoring. JUVISYNC therapy should be discontinued if
`markedly elevated CPK levels occur or myopathy is diagnosed or suspected. JUVISYNC therapy should
`also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the
`development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery;
`trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.
`Drug Interactions
`The risk of myopathy and rhabdomyolysis is increased by high levels of statin activity in plasma.
`Simvastatin is metabolized by the cytochrome P450 isoform 3A4. Certain drugs which inhibit this
`metabolic pathway can raise the plasma levels of simvastatin and may increase the risk of myopathy.
`These include itraconazole, ketoconazole, and posaconazole, the macrolide antibiotics erythromycin and
`clarithromycin,
`the ketolide antibiotic
`telithromycin, HIV protease
`inhibitors,
`the antidepressant
`nefazodone, and large quantities of grapefruit juice (>1 quart daily). Combination of these drugs with
`JUVISYNC is contraindicated. If treatment with itraconazole, ketoconazole, posaconazole, erythromycin,
`
`Reference ID: 3025884
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`5
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`6065500
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`JUVISYNC™
`(sitagliptin and simvastatin) Tablets
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`clarithromycin or telithromycin is unavoidable, therapy with JUVISYNC must be suspended during the
`course of treatment. [See Contraindications (4); Drug Interactions (7.1).] In vitro studies have
`demonstrated a potential for voriconazole to inhibit the metabolism of simvastatin. Adjustment of the
`JUVISYNC dose may be needed to reduce the risk of myopathy, including rhabdomyolysis, if
`voriconazole must be used concomitantly with JUVISYNC. [See Drug Interactions (7.1).]
`The combined use of JUVISYNC with gemfibrozil, cyclosporine, or danazol is contraindicated [see
`Contraindications (4); Drug Interactions (7.1, 7.2)].
`Caution should be used when prescribing other fibrates with JUVISYNC, as these agents can cause
`myopathy when given alone and the risk is increased when they are coadministered [see Drug
`Interactions (7.2)].
`Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered
`with colchicine, and caution should be exercised when prescribing JUVISYNC with colchicine [see Drug
`Interactions (7.7)].
`The benefits of the combined use of JUVISYNC with the following drugs should be carefully weighed
`against the potential risks of combinations: amiodarone, verapamil, diltiazem, amlodipine, ranolazine and
`lipid-lowering drugs other than gemfibrozil (other fibrates or ≥1 g/day of niacin), [see Drug Interactions
`(7.2, 7.3, 7.4); Table 3 in Clinical Pharmacology (12.3)].
`Cases of myopathy, including rhabdomyolysis, have been observed with simvastatin coadministered
`with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products. In an ongoing, double-blind,
`randomized cardiovascular outcomes trial, an independent safety monitoring committee identified that the
`incidence of myopathy is higher in Chinese compared with non-Chinese patients taking simvastatin
`40 mg coadministered with lipid-modifying doses of a niacin-containing product. Caution should be used
`when treating Chinese patients with JUVISYNC 100 mg/40 mg per day coadministered with lipid-
`modifying doses of niacin-containing products. It is unknown if the risk for myopathy with coadministration
`of JUVISYNC with lipid-modifying doses of niacin-containing products observed in Chinese patients
`applies to other Asian patients [see Drug Interactions (7.4)].
`Prescribing recommendations for interacting agents are summarized in Table 1 [see also Dosage and
`Administration (2.4); Drug Interactions (7.1, 7.2, 7.3); Clinical Pharmacology (12.3)].
`
`Table 1
`Drug Interactions Associated with Increased
`Risk of Myopathy/Rhabdomyolysis
`Interacting Agents
`Prescribing Recommendations
`Itraconazole
`Contraindicated with JUVISYNC
`Ketoconazole
`Posaconazole
`Erythromycin
`Clarithromycin
`Telithromycin
`HIV protease inhibitors
`Nefazodone
`Gemfibrozil
`Cyclosporine
`Danazol
`Verapamil
`Diltiazem
`Amiodarone
`Amlodipine
`Ranolazine
`Grapefruit juice
`
`Do not exceed 100 mg/10 mg
`JUVISYNC daily
`Do not exceed 100 mg/20 mg
`JUVISYNC daily
`
`Avoid large quantities of grapefruit
`juice (>1 quart daily)
`
`
`
`
`
`
`
`Reference ID: 3025884
`
`6
`
`

`

`6065500
`
`
`
`JUVISYNC™
`(sitagliptin and simvastatin) Tablets
`
`
`Liver Dysfunction
`5.3
`Persistent increases (to more than 3X the ULN) in serum transaminases have occurred in
`approximately 1% of patients who received simvastatin in clinical studies. When drug treatment
`was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to
`pretreatment levels. The increases were not associated with jaundice or other clinical signs or symptoms.
`There was no evidence of hypersensitivity.
`In the Scandinavian Simvastatin Survival Study (4S) [see Clinical Studies (14.2)], the number of
`patients with more than one transaminase elevation to >3X ULN, over the course of the study, was not
`significantly different between the simvastatin and placebo groups (14 [0.7%] vs. 12 [0.6%]). Elevated
`transaminases resulted in the discontinuation of 8 patients from therapy in the simvastatin group
`(n=2221) and 5 in the placebo group (n=2223). Of the 1986 simvastatin treated patients in 4S with normal
`liver function tests (LFTs) at baseline, 8 (0.4%) developed consecutive LFT elevations to >3X ULN and/or
`were discontinued due to transaminase elevations during the 5.4 years (median follow-up) of the study.
`Among these 8 patients, 5 initially developed these abnormalities within the first year. All of the patients in
`this study received a starting dose of 20 mg of simvastatin; 37% were titrated to 40 mg.
`In 2 controlled clinical studies in 1105 patients, the 12-month incidence of persistent hepatic
`transaminase elevation without regard to drug relationship was 0.9% and 2.1% at the 40 and 80 mg dose,
`respectively. No patients developed persistent liver function abnormalities following the initial 6 months of
`treatment at a given dose.
`It is recommended that liver function tests be performed before the initiation of treatment, and
`thereafter when clinically indicated. There have been rare postmarketing reports of fatal and non-fatal
`hepatic failure in patients taking statins, including simvastatin. If serious liver injury with clinical symptoms
`and/or hyperbilirubinemia or jaundice occurs during treatment with JUVISYNC, promptly interrupt therapy.
`If an alternate etiology is not found do not restart JUVISYNC. Note that ALT may emanate from muscle,
`therefore ALT rising with CK may indicate myopathy [see Warnings and Precautions (5.2)].
`The drug should be used with caution in patients who consume substantial quantities of alcohol and/or
`have a past history of liver disease. Active liver diseases or unexplained transaminase elevations are
`contraindications to the use of JUVISYNC.
`As with other lipid-lowering agents, moderate (less than 3X ULN) elevations of serum transaminases
`have been reported following therapy with simvastatin. These changes appeared soon after initiation of
`therapy with simvastatin, were often transient, were not accompanied by any symptoms and did not
`require interruption of treatment. [See also Adverse Reactions (6.1).]
`5.4 Renal Impairment
`Assessment of renal function is recommended prior to initiating JUVISYNC and periodically
`thereafter. JUVISYNC is not recommended for use in patients with moderate or severe renal impairment
`or ESRD because doses of JUVISYNC appropriate for patients with moderate or severe renal impairment
`or ESRD are not available in this combination product. [See Dosage and Administration (2.2); Clinical
`Pharmacology (12.3).]
`There have been postmarketing reports of worsening renal function, including acute renal failure,
`sometimes requiring dialysis, in patients treated with sitagliptin. A subset of these reports involved
`patients with renal impairment, some of whom were prescribed inappropriate doses of sitagliptin. A return
`to baseline levels of renal impairment has been observed with supportive treatment and discontinuation
`of potentially causative agents.
`Sitagliptin has not been found to be nephrotoxic in preclinical studies at clinically relevant doses, or in
`clinical trials.
`5.5 Use with Medications Known to Cause Hypoglycemia
`When sitagliptin was used in combination with a sulfonylurea or with insulin, medications known to
`cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo used in
`combination with a sulfonylurea or with insulin. [See Adverse Reactions (6.1).] Therefore, a lower dose of
`sulfonylurea or insulin may be required to reduce the risk of hypoglycemia. [See Dosage and
`Administration (2.3).]
`
`Reference ID: 3025884
`
`7
`
`

`

`
`
`6065500
`
`JUVISYNC™
`(sitagliptin and simvastatin) Tablets
`
`5.6 Hypersensitivity Reactions
`[See also Adverse Reactions (6.2).]
`There have been postmarketing reports of serious hypersensitivity reactions in patients treated with
`sitagliptin. 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 JUVISYNC, assess for other potential causes
`for the event, and institute alternative treatment.
`Angioedema has also been reported with other dipeptidyl peptidase-4 (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 JUVISYNC.
`5.7 Endocrine Function
`Increases in A1C and fasting serum glucose lev