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Juvisync (Sitagliptin Phosphate / Simvastatin) - Drug Interactions, Contraindications, Overdosage, etc

 
 



DRUG INTERACTIONS

[See Clinical Pharmacology.]

Strong CYP3A4 Inhibitors, Cyclosporine, or Danazol

Strong CYP3A4 inhibitors: Simvastatin, like several other inhibitors of HMG-CoA reductase, is a substrate of CYP3A4. Simvastatin is metabolized by CYP3A4 but has no CYP3A4 inhibitory activity; therefore it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A4.

Elevated plasma levels of HMG-CoA reductase inhibitory activity increase the risk of myopathy and rhabdomyolysis, particularly with higher doses of simvastatin. [See Warnings and Precautions; Clinical Pharmacology.] Concomitant use of drugs labeled as having a strong inhibitory effect on CYP3A4 is contraindicated [see Contraindications (4) ]. If treatment with itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with JUVISYNC must be suspended during the course of treatment. If JUVISYNC is suspended during treatment with any of these agents, consideration should be given to the use of sitagliptin to maintain glycemic control until JUVISYNC can be reinstated.

Cyclosporine or Danazol: The risk of myopathy, including rhabdomyolysis, is increased by concomitant administration of cyclosporine or danazol. Therefore, concomitant use of these drugs is contraindicated [see Contraindications Warnings and Precautions; Clinical Pharmacology].

Lipid-Lowering Drugs That Can Cause Myopathy When Given Alone

Gemfibrozil: Contraindicated with JUVISYNC [see Contraindications Warnings and Precautions] .

Other fibrates: Caution should be used when prescribing with JUVISYNC [see Warnings and Precautions].

Amiodarone, Dronedarone, Ranolazine, or Calcium Channel Blockers

The risk of myopathy, including rhabdomyolysis, is increased by concomitant administration of amiodarone, dronedarone, ranolazine, or calcium channel blockers such as verapamil, diltiazem, or amlodipine [see Dosage and Administration; Warnings and Precautions; Table 6 in Clinical Pharmacology].

Niacin

Cases of myopathy, including rhabdomyolysis, have been observed with simvastatin coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products. In particular, caution should be used when treating Chinese patients with JUVISYNC 100 mg/40 mg or 50 mg/40 mg coadministered with lipid-modifying doses of niacin-containing products. [See Warnings and Precautions; Clinical Pharmacology.]

Digoxin

No dosage adjustment of digoxin or JUVISYNC is recommended. Patients receiving digoxin should be monitored.

Coumarin Anticoagulants

In two clinical studies, one in normal volunteers and the other in hypercholesterolemic patients, simvastatin 20-40 mg/day modestly potentiated the effect of coumarin anticoagulants: the prothrombin time, reported as International Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in the volunteer and patient studies, respectively. With other statins, clinically evident bleeding and/or increased prothrombin time has been reported in a few patients taking coumarin anticoagulants concomitantly. In such patients, prothrombin time should be determined before starting JUVISYNC and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of JUVISYNC is changed or JUVISYNC is discontinued, the same procedure should be repeated. Simvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.

Colchicine

Cases of myopathy, including rhabdomyolysis, have been reported with simvastatin coadministered with colchicine, and caution should be exercised when prescribing JUVISYNC with colchicine.

OVERDOSAGE

Sitagliptin

During controlled clinical trials in healthy subjects, single doses of up to 800 mg sitagliptin were administered. Maximal mean increases in QTc of 8.0 msec were observed in one study at a dose of 800 mg sitagliptin, a mean effect that is not considered clinically important [see Clinical Pharmacology]. There is no experience with doses above 800 mg in humans. In Phase I multiple-dose studies, there were no dose-related clinical adverse reactions observed with sitagliptin with doses of up to 600 mg per day for periods of up to 10 days and 400 mg per day for up to 28 days.

In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy as dictated by the patient's clinical status.

Sitagliptin is modestly dialyzable. In clinical studies, approximately 13.5% of the dose was removed over a 3- to 4-hour hemodialysis session. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.

Simvastatin

Significant lethality was observed in mice after a single oral dose of 9 g/m2. No evidence of lethality was observed in rats or dogs treated with doses of 30 and 100 g/m2, respectively. No specific diagnostic signs were observed in rodents. At these doses the only signs seen in dogs were emesis and mucoid stools.

A few cases of overdosage with simvastatin have been reported; the maximum dose taken was 3.6 g. All patients recovered without sequelae. Supportive measures should be taken in the event of an overdose. The dialyzability of simvastatin and its metabolites in man is not known at present.

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; Adverse Reactions.]
  • Concomitant administration of strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and cobicistat-containing products) [see Warnings and Precautions].
  • Concomitant administration of gemfibrozil, cyclosporine, or danazol [see Warnings and Precautions].
  • Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels [see Warnings and Precautions].
  • 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].
  • 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].

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