sitagliptin/simvastatin (Juvisync)

Dosing and uses of Juvisync (sitagliptin-simvastatin)

• Adult
• Pediatric

 

Adult dosage forms and strengths

sitagliptin/simvastatin

tablet

• 50mg/10mg
• 50mg/20mg
• 50mg/40mg
• 100mg/10mg
• 100mg/20mg
• 100mg/40mg

 

Diabetes With Hyperlipidemic Complications

Discontinued by manufacturer (9/26/2013)

Indicated in patients for whom treatment with both sitagliptin and simvastatin is appropriate

Sitagliptin is a DPP-4 inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in type 2 DM patients

Simvastatin is a HMG-CoA reductase inhibitor indicated as an adjunctive therapy to diet for hyperlipidemia, heterozygous familial hypercholesteremia, and prevention of coronary events

After initiation or titration, lipid levels may be analyzed after 4 or more weeks and dosage adjusted if needed

Usual daily starting dose: 100 mg/40 mg PO qHs

Currently taking simvastatin: Initiate with 50 or 100 mg sitagliptin plus current simvastatin dose

 

Dosage modifications

Coadministration with dronedarone, verapamil, or diltiazem: Do not exceed simvastatin 10 mg/day

Coadministration with amiodarone, amlodipine or ranolazine: Do not exceed simvastatin 20 mg/day

Coadministration with grapefruit juice: Avoid large quantities of grapefruit juice (ie, >1 quart/day)

Patients with homozygous familial hypercholesterolemia: 100 mg/40 mg PO qDay in the evening (or 50 mg/40 mg with renal impairment); and should be used as an adjunct to other lipid lowering treatment

Chinese patients taking lipid-modifying doses of niacin (ie, ≥1 g/day): Increased risk of myopathy with simvastatin 40 mg/day; consider lower dose

Renal impairment

• Normal to mild (CrCl >50 mL/min): No dosage adjust required
• Moderate (CrCl 30-50 mL/min): Starting dose is 50 mg/40 mg qDay; if already taking simvastatin, initiate with sitagliptin 50 mg and current simvastatin dose
• Severe (CrCl <30 mL/min) or ESRD: Not recommended
• Do not use in patients with moderate or severe renal impairment who require sitagliptin 50 mg or 25 mg due to unavailability of these dosage strengths

Hepatic impairment

• Contraindicated in patients with active liver disease which may include unexplained persistent elevations in hepatic transaminase levels

 

Dosing Considerations

No studies in patients with a history of pancreatitis or Fredrickson types I and V dyslipidemias

 

Administration

Take as single dose in the evening

Swallow tablet whole, do not chew, crush, or split

 

Pediatric dosage forms and strengths

<18 years old: Safety and efficacy not established

 

Juvisync (sitagliptin-simvastatin) adverse (side) effects

1-10%

Upper respiratory tract infection

Headache

Constipation

Nausea

Nasopharyngitis

Diarrhea

Angioedema

Hypersensitivity reactions

Stevens-Johnson syndrome

Hypoglycemia

Peripheral edema

Abdominal pain

Transaminases increased (>3x ULN)

CPK elevation (>3x ULN)

Bronchitis

 

<1%

Myalgia

Myopathy

Rhabdomyolysis

 

Postmarketing Reports

Acute pancreatitis including fatal and nonfatal hemorrhagic and necrotizing pancreatitis; pancreatitis suspected, promptly discontinue

Acute renal failure, sometimes requiring dialysis, in patients treated with sitagliptin; assess renal function prior to initiation and periodically thereafter

Serious allergic/hypersensitivity reactions (anaphylaxis, angioedema, and exfoliative skin conditions including SJS) in patients treated with sitagliptin; stop therapy and assess for other potential causes, institute monitoring and treatment; select alternative treatment

Constipation, headache, vomiting

Hepatic enzyme elevations

Arthralgia, myalgia, pain in extremity, and back pain

Cognitive impairment (eg, memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use

 

Warnings

Hypersensitivity reactions (anaphylaxis or angioedema)

Do not use in patients with type 1 DM or diabetic ketoacidosis

Active liver disease or unexplained elevated hepatic transaminases

Women who are pregnant or may become pregnant

Nursing mothers

Coadministration with strong CYP3A4 inhibitors (itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone)

Concomitant administration of gemfibrozil, cyclosporine, or danazoL

 

Cautions

Persistent elevations in hepatic transaminase; monitor liver enzyme tests before initiating therapy and as clinically indicated thereafter

Increased risk of hypoglycemia when drug is added to an insulin secretagogue (eg, sulfonylurea) or insulin therapy; may lower dose of sulfonylurea or insulin to reduce risk

Increases in A1C and fasting serum glucose have been reported with simvastatin

Rare reports of immune-mediated necrotizing myopathy (IMNM), characterized by increased serum creatine kinase that persist despite discontinuing statin

Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis; if pancreatitis is suspected, promptly discontinue (postmarketing reports)

Acute renal failure, sometimes requiring dialysis, in patients treated with sitagliptin; assess renal function prior to initiation of and periodically thereafter (postmarketing reports)

Serious allergic/hypersensitivity reactions (anaphylaxis, angioedema, and exfoliative skin conditions including SJS) in patients treated with sitagliptin; promptly stop therapy and assess for other potential causes, institute monitoring and treatment; select alternative treatment (postmarketing reports)

Simvastatin and myopathy risk

• Predisposing factors include advanced age (≥65), female gender, uncontrolled hypothyroidism, and renal impairment
• Risk for myopathy increased when coadministered with other lipid-lowering drugs (other fibrates, ≥1 g/day of niacin, or, for patients with HoFH, lomitapide), colchicine, amiodarone, dronedarone, verapamil, diltiazem, amlodipine, or ranolazine
• Avoid simvastatin with strong CYP3A4 inhibitors (eg, itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone) and gemfibrozil, cyclosporine, and danazol
• See Contraindications for list of drugs contraindicated because of increased risk for myopathy when coadministered with simvastatin
• Increased risk for myopathy in Chinese patients coadministered niacin >1 g/day; use caution when treating with 100 mg/40 mg per day
• Risk of myopathy is greater in patients taking simvastatin 80 mg/day, especially in the 1st year of treatment
• Discontinue therapy immediately if myopathy is diagnosed or suspected
• See Adult Dosing for dose limitations

 

Pregnancy and lactation

Pregnancy category: X

Lactation: contraindicated; potentially unsafe

 

Pregnancy categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

 

Pharmacology of Juvisync (sitagliptin-simvastatin)

Mechanism of action

Sitagliptin: DPP-4 inhibitor, which may exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones; concentrations of active intact hormones are increased, thereby increasing and prolonging the action of these hormones

Simvastatin: Prodrug that is hydrolyzed to its active β-hydroxyacid form, simvastatin acid, after administration; inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes conversion of HMG-CoA to mevalonate, an early and rate limiting step in the biosynthetic pathway for cholesterol; reduces VLDL and TG and increases HDL-C

 

Pharmacokinetics

Absorption

• Bioavailability: 87% (sitagliptin); 5% (simvastatin)
• Peak Plasma Time: 1-4 hr (sitagliptin); 1.5 hr (simvastatin lactone); 4-6 hr (simvastatin acid)

Distribution

• Protein Bound: 38% (sitagliptin); 95% (simvastatin)
• Vd: 198 L (sitagliptin)

Metabolism

• Sitagliptin: Limited, minor metabolism by CYP3A4 and 2C8
• Simvastatin: Extensive first-pass extraction in liver via CYP3A4, availability of drug to general circulation is low (<5%); major active metabolites present in human plasma are β-hydroxyacid of simvastatin and its 6′-hydroxy, 6′-hydroxymethyl, and 6′-exomethylene derivatives

Elimination

• Half-life: 12.4 hr (sitagliptin)
• Renal clearance: 350 mL/min (sitagliptin)
• Urine: 87% (sitagliptin); 13% (simvastatin)
• Feces: 13% (sitagliptin); 60% (simvastatin)

 

Pharmacogenomics

SLCO1B1 (OATP1B1) CC genotype significantly increases AUCs of parent drug and metabolites compared with the CT or TT genotypes

This polymorphism is proposed to reduced transport into the liver, the main site of statin metabolism and elimination, resulting in elevated plasma concentrations

SLCO1B1 polymorphism is thought to have a lesser effect on the more hydrophilic statins (eg, rosuvastatin, fluvastatin) compared with more those that are more lipophilic (eg, atorvastatin, simvastatin)

Other genetic polymorphisms of elimination (eg, CYP450, P-glycoprotein) for each individual drug must also be considered to explain variability for statin clearance among patients that exhibit SCLO1B1 polymorphism

SLCO1B1 CC genotype is most common in Caucasians and Asians (15%)

Risk of myopathy is 2.6- to 4.3-fold higher if the C allele is present and 16.9-fold higher in CC homozygotes compared with TT homozygotes

Genetic testing laboratories

• Optivia Biotechnology, Inc (https://optiviabio.com/index.html)