WARNINGS AND PRECAUTIONS
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.]
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.
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.
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, cobicistat-containing products, and grapefruit juice [see Clinical Pharmacology]. 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 Drug Interactions.]
The combined use of JUVISYNC with gemfibrozil, cyclosporine, or danazol is contraindicated [see Contraindications 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].
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].
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 Pharmacology] [also see Dosage and Administration, Patients with Homozygous Familial Hypercholesterolemia].
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 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].
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].
Table 1: Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis
Strong CYP3A4 Inhibitors, e.g.:
HIV protease inhibitors
|Contraindicated with JUVISYNC
|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) dailyFor 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.
|| Avoid grapefruit juice
Persistent increases (to more than 3× 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], the number of patients with more than one transaminase elevation to >3× 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 >3× 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].
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 3× 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.]
Assessment of renal function is recommended prior to initiating JUVISYNC and periodically thereafter. JUVISYNC is not recommended for use in patients with severe renal impairment or ESRD because doses of JUVISYNC appropriate for patients with severe renal impairment or ESRD are not available in this combination product. [See Dosage and Administration; Clinical Pharmacology.]
A dosage adjustment is recommended in patients with moderate renal impairment. [See Dosage and Administration; Clinical Pharmacology.] Caution should be used to ensure that the correct dose of JUVISYNC is prescribed for patients with moderate renal impairment (creatinine clearance ≥30 to <50 mL/min).
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.
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.] Therefore, a lower dose of sulfonylurea or insulin may be required to reduce the risk of hypoglycemia. [See Dosage and Administration.]
[See also Adverse Reactions.]
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.
Increases in A1C and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including simvastatin.
USE IN SPECIFIC POPULATIONS
Pregnancy Category X [See Contraindications (4).]
JUVISYNC is contraindicated in women who are or may become pregnant. Lipid-lowering drugs offer no benefit during pregnancy, because cholesterol and cholesterol derivatives are needed for normal fetal development. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy. There are no adequate and well-controlled studies of use of JUVISYNC during pregnancy; however, there are rare reports of congenital anomalies in infants exposed to statins in utero. Animal reproduction studies of simvastatin in rats and rabbits showed no evidence of teratogenicity. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are essential for fetal development. Because statins decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, JUVISYNC may cause fetal harm when administered to a pregnant woman. If JUVISYNC is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Women of childbearing potential, who require treatment with JUVISYNC for a lipid disorder, should be advised to use effective contraception. For women trying to conceive, discontinuation of JUVISYNC should be considered. If pregnancy occurs, JUVISYNC should be immediately discontinued.
Reproduction studies have been performed in rats and rabbits. Doses of sitagliptin up to 125 mg/kg (approximately 12 times the human exposure at the maximum recommended human dose) did not impair fertility or harm the fetus. There are, however, no adequate and well-controlled studies in pregnant women.
Sitagliptin administered to pregnant female rats and rabbits from gestation day 6 to 20 (organogenesis) was not teratogenic at oral doses up to 250 mg/kg (rats) and 125 mg/kg (rabbits), or approximately 30- and 20-times human exposure at the maximum recommended human dose (MRHD) of 100 mg/day based on AUC comparisons. Higher doses increased the incidence of rib malformations in offspring at 1000 mg/kg, or approximately 100 times human exposure at the MRHD.
Sitagliptin administered to female rats from gestation day 6 to lactation day 21 decreased body weight in male and female offspring at 1000 mg/kg. No functional or behavioral toxicity was observed in offspring of rats.
Placental transfer of sitagliptin administered to pregnant rats was approximately 45% at 2 hours and 80% at 24 hours postdose. Placental transfer of sitagliptin administered to pregnant rabbits was approximately 66% at 2 hours and 30% at 24 hours.
Simvastatin was not teratogenic in rats or rabbits at doses (25, 10 mg/kg/day, respectively) that resulted in 6 times the human exposure based on mg/m2 surface area. However, in studies with another structurally-related statin, skeletal malformations were observed in rats and mice.
There are rare reports of congenital anomalies following intrauterine exposure to statins. In a review of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or another structurally related statin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed those expected in the general population. However, the study was only able to exclude a 3- to 4-fold increased risk of congenital anomalies over the background rate. In 89% of these cases, drug treatment was initiated prior to pregnancy and was discontinued during the first trimester when pregnancy was identified.
It is not known whether simvastatin is excreted in human milk. Because a small amount of another drug in the same class as simvastatin is excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women taking JUVISYNC should not nurse their infants. A decision should be made whether to discontinue nursing or discontinue JUVISYNC, taking into account the importance of the drug to the mother [see Contraindications (4) ].
Sitagliptin is secreted in the milk of lactating rats at a milk to plasma ratio of 4:1. It is not known whether sitagliptin is excreted in human milk.
Safety and effectiveness of JUVISYNC in pediatric patients under 18 years of age have not been established.
Because advanced age (≥65 years) is a predisposing factor for myopathy, including rhabdomyolysis, JUVISYNC should be prescribed with caution in the elderly [see Clinical Pharmacology].
Sitagliptin is known to be substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, it may be useful to assess renal function in these patients prior to initiating dosing and periodically thereafter [see Dosage and Administration; Clinical Pharmacology].
Of the total number of subjects (N=3884) in pre-approval clinical safety and efficacy 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 were observed between subjects 65 years and over and younger subjects. While this and other reported clinical experience have not identified differences in responses between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.
Of the 2423 patients who received simvastatin in Phase III clinical studies and the 10,269 patients in the Heart Protection Study who received simvastatin, 363 (15%) and 5366 (52%), respectively were ≥65 years old. In HPS, 615 (6%) were ≥75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.
A pharmacokinetic study with simvastatin showed the mean plasma level of statin activity to be approximately 45% higher in elderly patients between 70-78 years of age compared with patients between 18-30 years of age. In 4S, 1021 (23%) of 4444 patients were 65 or older. Lipid-lowering efficacy was at least as great in elderly patients compared with younger patients, and simvastatin significantly reduced total mortality and CHD mortality in elderly patients with a history of CHD. In HPS, 52% of patients were elderly (4891 patients 65-69 years and 5806 patients 70 years or older). The relative risk reductions of CHD death, non-fatal MI, coronary and non-coronary revascularization procedures, and stroke were similar in older and younger patients [see Clinical Studies]. In HPS, among 32,145 patients entering the active run-in period, there were 2 cases of myopathy/rhabdomyolysis; these patients were aged 67 and 73. Of the 7 cases of myopathy/rhabdomyolysis among 10,269 patients allocated to simvastatin, 4 were aged 65 or more (at baseline), of whom one was over 75. There were no overall differences in safety between older and younger patients in either 4S or HPS.
Because advanced age (≥65 years) is a predisposing factor for myopathy, including rhabdomyolysis, simvastatin should be prescribed with caution in the elderly. In a clinical trial of patients treated with simvastatin 80 mg/day, patients ≥65 years of age had an increased risk of myopathy, including rhabdomyolysis, compared to patients <65 years of age. [See Warnings and Precautions; Clinical Pharmacology.]
JUVISYNC is not recommended for use in patients with severe renal impairment or ESRD [see Dosage and Administration].
JUVISYNC is contraindicated in patients with active liver disease which may include unexplained persistent elevations in hepatic transaminase levels [see Contraindications and Warnings and Precautions].