`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
` ---------------------------RECENT MAJOR CHANGES ---------------------------
`Dosage and Administration
`02/2013
`Recommended Dosing (2.1)
`10/2012
`Coadministration with Other Drugs (2.4)
`Patients with Homozygous Familial Hypercholesterolemia (2.5)
`10/2013
`Contraindications (4)
`10/2012
`Warnings and Precautions
`
`Myopathy/Rhabdomyolysis (5.2)
`10/2013
`--------------------------- 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
`
`in patients with primary dysbeta­
`reduce TG and VLDL-C
`
`
`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 severe renal impairment who require sitagliptin 25 mg
`
`should not use JUVISYNC due to the unavailability of this dosage
`strength for JUVISYNC. (1.3)
`-----------------------DOSAGE AND ADMINISTRATION -----------------------
`
`
` Doses
`are
`100 mg/10 mg,
`100 mg/20 mg,
`100 mg/40 mg,
`
`50 mg/10 mg, 50 mg/20 mg, and 50 mg/40 mg per day. (2.1)
` Recommended usual starting dose for patients with normal or mildly
`
`
`impaired renal function is 100 mg/40 mg once a day in the evening.
`
`(2.1)
` Adjustment of the starting dose to 50 mg/40 mg once a day is
`
`
`recommended for patients with moderate renal impairment (CrCl
`greater than or equal to 30 to less than 50 mL/min, equivalent to
`serum Cr levels greater than 1.7 to less than or equal to 3.0 mg/dL
`for men and greater than 1.5 to less than or equal to 2.5 mg/dL for
`women). (2.2)
` Patients already taking simvastatin (10, 20, or 40 mg) can initiate
`
`JUVISYNC at a dose of 100 or 50 mg sitagliptin and the dose of
`simvastatin already being taken. (2.1)
`
`
`Reference ID: 3394865
`
`--------------------- DOSAGE FORMS AND STRENGTHS --------------------
`
`
`Tablets
`(sitagliptin/simvastatin):
`100 mg/10 mg,
`100 mg/20 mg,
`100 mg/40 mg, 50 mg/10 mg, 50 mg/20 mg, and 50 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 unexplained
`
`and/or persistent muscle pain, tenderness, or weakness. JUVISYNC
`therapy should be discontinued
`immediately
`if myopathy
`is
`diagnosed or suspected. See Drug Interaction table. (5.2)
`in hepatic
` Liver enzyme abnormalities: Persistent elevations
`
`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
`In such cases, promptly stop
`Stevens-Johnson syndrome.
`
`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, 2.5, 4, 5.2, 7.1, 7.2, 7.3, 12.3)
`Interacting Agents
`Prescribing Recommendations
`Strong CYP3A4 inhibitors
`Contraindicated with JUVISYNC
`(e.g., itraconazole,
`ketoconazole, posaconazole,
`voriconazole, erythromycin,
`clarithromycin, telithromycin,
`HIV protease inhibitors,
`boceprevir, telaprevir,
`nefazodone), gemfibrozil,
`cyclosporine, danazol
`
`
`
`

`

`Verapamil, diltiazem,
`dronedarone
`
`Amiodarone, amlodipine,
`ranolazine
`
`Lomitapide
`
`
`
`Do not exceed 10 mg simvastatin
`(100 mg/10 mg or 50 mg/10 mg
`JUVISYNC) daily
`Do not exceed 20 mg simvastatin
`(100 mg/20 mg or 50 mg/20 mg
`JUVISYNC) daily
`For patients with HoFH, do not
`exceed 20 mg simvastatin
`(100 mg/20 mg or 50 mg/20 mg
`JUVISYNC) daily*
`Avoid grapefruit juice
`Grapefruit juice
`* For patients with HoFH who have been taking 80 mg simvastatin
`chronically (e.g., for 12 months or more) without evidence of muscle
`toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
`
` 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.
`
`Revised: 10/2013
`
`
`
`
`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 (greater than
`or equal to 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
` Hypersensitivity Reactions
`5.6
`
` Endocrine Function
`5.7
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2
` Postmarketing Experience
`7 DRUG INTERACTIONS
`7.1 Strong CYP3A4 Inhibitors, Cyclosporine, or Danazol
`Lipid-Lowering Drugs That Can Cause Myopathy When
`7.2
`Given Alone
`7.3 Amiodarone, Dronedarone, Ranolazine, or Calcium Channel
`Blockers
`
` Niacin
` Digoxin
` Coumarin Anticoagulants
` Colchicine
`
`7.4
`7.5
`7.6
`7.7
`
`FULL PRESCRIBING INFORMATION
`
`8 USE IN SPECIFIC POPULATIONS
` Pregnancy
`8.1
`
` Nursing Mothers
`8.3
`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
`
`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
`individuals at significantly
`increased
`risk
`for atherosclerotic vascular disease due
`to
`in
`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
`2
`
`Reference ID: 3394865
`
`
`
`

`

`
`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 total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-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).
`
`
` 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 (HoFH)
`as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or if such treatments are
`unavailable.
`Important Limitations of Use
`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 severe renal impairment (CrCl
`<30 mL/min, approximately corresponding to serum creatinine levels of >3.0 mg/dL in men and
`>2.5 mg/dL in women) or end-stage renal disease (ESRD) are not available in this combination product,
`JUVISYNC is not recommended in patients with severe renal impairment or ESRD.
`
`1.3
`
`DOSAGE AND ADMINISTRATION
`2
`2.1 Recommended Dosing
`The dosages for therapy with JUVISYNC are 100 mg/10 mg, 100 mg/20 mg, 100 mg/40 mg,
`50 mg/10 mg, 50 mg/20 mg, and 50 mg/40 mg (sitagliptin/simvastatin) once daily. JUVISYNC should be
`taken as a single daily dose in the evening. JUVISYNC must not be split or divided 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 severe renal impairment or ESRD. JUVISYNC can
`be used in patients with normal renal function or mild renal impairment (creatinine clearance [CrCl] greater
`than or equal to 50 mL/min, approximately corresponding to serum creatinine levels of less than or equal
`to 1.7 mg/dL in men and less than or equal to 1.5 mg/dL in women), without adjustment of the sitagliptin
`dose. 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.
`For patients with moderate renal impairment (CrCl greater than or equal to 30 to less than
`50 mL/min, approximately corresponding to serum creatinine levels of greater than 1.7 to less than or
`equal to 3.0 mg/dL in men and greater than 1.5 to less than or equal to 2.5 mg/dL in women), the
`recommended starting dose of JUVISYNC is 50 mg/40 mg once daily. For patients with moderate renal
`
`Reference ID: 3394865
`
`3
`
`
`
`

`

`
`impairment who are already taking simvastatin (10, 20, or 40 mg daily) with or without sitagliptin 50 mg
`
`daily, JUVISYNC may be initiated at the dose of 50 mg sitagliptin and the dose of simvastatin already
`being taken.
`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, Diltiazem, or Dronedarone
`
` The dose of simvastatin should not exceed 10 mg per day (100 mg/10 mg or 50 mg/10 mg per
`day of JUVISYNC) [see Warnings and Precautions (5.2); Drug Interactions (7.3); Clinical
`
`Pharmacology (12.3)].
`Patients taking Amiodarone, Amlodipine or Ranolazine
`
` The dose of simvastatin should not exceed 20 mg per day (100 mg/20 mg or 50 mg/20 mg per
`day of JUVISYNC) [see Warnings and Precautions (5.2); Drug Interactions (7.3); Clinical
`
`Pharmacology (12.3)].
`2.5 Patients with Homozygous Familial Hypercholesterolemia
`
`The recommended dosage is 100 mg/40 mg (for patients with normal or mildly impaired renal
`function) or 50 mg/40 mg (for patients with moderately impaired renal function) 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.
`Simvastatin exposure is approximately doubled with concomitant use of lomitapide; therefore, the
`dose of simvastatin should be reduced by 50% if initiating lomitapide. For patients with normal or mildly
`impaired renal function, JUVISYNC dosage should not exceed 100 mg/20 mg daily (or 100 mg/40 mg
`daily for patients who have previously taken simvastatin 80 mg daily chronically, e.g., for 12 months or
`more, without evidence of muscle toxicity) while taking lomitapide. For patients with moderately impaired
`renal function, JUVISYNC dosage should not exceed 50 mg/20 mg daily (or 50 mg/40 mg daily for
`patients who have previously taken simvastatin 80 mg daily chronically, e.g., for 12 months or more,
`without evidence of muscle toxicity) while taking lomitapide.
`2.6 Chinese Patients Taking Lipid-Modifying Doses (greater than or equal to 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 (greater than or equal to 1 g/day niacin) of niacin-containing
`products, caution should be used when treating Chinese patients with JUVISYNC 100 mg/40 mg or
`50 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).]
`
`3
`
`
`
`
`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.
`JUVISYNC 50 mg/10 mg tablets are red, bi-convex modified capsule-shaped, film-coated
`tablets, coded with the Merck logo and "533" on one side and plain on the other.
`
`
`
`
`
`
`
`Reference ID: 3394865
`
`4
`
`
`
`

`

`
`
`4
`
`
`
`
`
`
`
`JUVISYNC 50 mg/20 mg tablets are orange-beige, bi-convex modified capsule-shaped, film-
`coated tablets, coded with the Merck logo and "535" on one side and plain on the other.
`JUVISYNC 50 mg/40 mg tablets are red, bi-convex modified capsule-shaped, film-coated
`tablets, coded with the Merck logo and "537" on one side and plain on the other.
`
`CONTRAINDICATIONS
`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, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, 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)].
`
`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
`
`Reference ID: 3394865
`
`5
`
`
`
`

`

`
`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.
`There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune
`myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated
`serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing
`necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.
`All patients starting therapy with JUVISYNC, or whose dose of JUVISYNC 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 particularly if accompanied by malaise or
`
`fever or if muscle signs and symptoms persist after discontinuing JUVISYNC. 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 is being
`increased, but 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, posaconazole, and voriconazole, the macrolide antibiotics
`erythromycin and clarithromycin, the ketolide antibiotic telithromycin, HIV protease inhibitors, boceprevir,
`
`telaprevir, the antidepressant nefazodone, and grapefruit juice [see Clinical Pharmacology (12.3)].
`Combination of these drugs with JUVISYNC is contraindicated. If short-term treatment with strong
`
`CYP3A4 inhibitors is unavoidable, therapy with JUVISYNC must be suspended during the course of
`
`treatment. [See Contraindications (4); 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, dronedarone, verapamil, diltiazem,
`amlodipine, ranolazine and lipid-lowering drugs other than gemfibrozil (other fibrates, 1 g/day of niacin,
`or, for patients with HoFH, lomitapide), [see Drug Interactions (7.2, 7.3, 7.4); Table 6 in Clinical
`
`Reference ID: 3394865
`
`6
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`

`
`Pharmacology (12.3)] [also see Dosage and Administration, Patients with Homozygous Familial
`Hypercholesterolemia (2.5)].
`rhabdomyolysis, have been observed with simvastatin
`including
`Cases of myopathy,
`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 or 50 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, 2.5); Drug Interactions (7.1, 7.2, 7.3); Clinical Pharmacology (12.3)].
`
`
` Table 1: Drug Interactions Associated with Increased
`
` Risk of Myopathy/Rhabdomyolysis
`Prescribing Recommendations
`Interacting Agents
`Contraindicated with JUVISYNC
`Strong CYP3A4 Inhibitors, e.g.:
`Itraconazole
`Ketoconazole
`Posaconazole
`Voriconazole
`Erythromycin
`Clarithromycin
`Telithromycin
`HIV protease inhibitors
`Boceprevir
`Telaprevir
`Nefazodone
`Gemfibrozil
`Cyclosporine
`Danazol
`Verapamil
`Diltiazem
`Dronedarone
`Amiodarone
`Amlodipine
`Ranolazine
`Lomitapide
`
`Do not exceed 10 mg simvastatin
`(100 mg/10 mg or 50 mg/10 mg
`JUVISYNC) daily
`
`Do not exceed 20 mg simvastatin
`(100 mg/20 mg or 50 mg/20 mg
`JUVISYNC) daily
`
`For patients with HoFH, do not
`exceed
`20 mg
`simvastatin
`(100 mg/20 mg or 50 mg/20 mg
`JUVISYNC) daily*
`Avoid grapefruit juice
`Grapefruit juice
`* For patients with HoFH who have been taking 80 mg simvastatin chronically
`
`(e.g., for 12 months or more) without evidence of muscle toxicity, do not
`exceed 40 mg simvastatin when taking lomitapide.
`
`5.3 Liver Dysfunction
`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
`
`
`
`Reference ID: 3394865
`
`7
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`discontinued