FloLipid (simvastatin)

FloLipid Oral Suspension is a lipid-lowering agent that is derived synthetically from a fermentation product of Aspergillus terreus. After oral ingestion, simvastatin, which is an inactive lactone, is hydrolyzed to the corresponding β-hydroxyacid form.

This is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step in the biosynthesis of cholesterol.

FloLipid 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 IV hyperlipidemia).
• Reduce elevated TG and VLDL-C in patients with primary dysbetalipoproteinemia (Fredrickson type III 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.

Adolescent Patients With Heterozygous Familial Hypercholesterolemia (HeFH)

FloLipid is indicated as an adjunct to diet to reduce total-C, LDL-C, and Apo B levels in adolescent boys and girls who are at least one year post-menarche, 10 to 17 years of age, with HeFH, if after an adequate trial of diet therapy the following findings are present:

1. LDL cholesterol remains ≥190 mg/dL; or
2. LDL cholesterol remains ≥160 mg/dL and
   • There is a positive family history of premature cardiovascular disease (CVD) or
   • Two or more other CVD risk factors are present in the adolescent patient.

The minimum goal of treatment in pediatric and adolescent patients is to achieve a mean LDL-C <130 mg/dL. The optimal age at which to initiate lipid-lowering therapy to decrease the risk of symptomatic adulthood CAD has not been determined.

Limitations Of Use

FloLipid has not been studied in conditions where the major abnormality is elevation of chylomicrons (i.e., hyperlipidemia Fredrickson types I and V).

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

In the pre-marketing controlled clinical studies and their open extensions (2,423 patients with median duration of follow-up of approximately 18 months), 1.4% of patients were discontinued due to adverse reactions.

The most common adverse reactions that led to treatment discontinuation were:

• gastrointestinal disorders (0.5%),
• myalgia (0.1%), and
• arthralgia (0.1%).

The most commonly reported adverse reactions (incidence ≥5%) in simvastatin controlled clinical trials were:

• upper respiratory infections (9.0%),
• headache (7.4%),
• abdominal pain (7.3%),
• constipation (6.6%), and
• nausea (5.4%).

• The usual dosage range is 5 to 40 mg/day.
• FloLipid should be taken in the evening on an empty stomach.
• Shake bottle well for at least 20 seconds before using.
• In patients with CHD or at high risk of CHD, FloLipid can be started simultaneously with diet.
• The recommended usual starting dose is 10 or 20 mg once a day.
• For patients at high risk for a CHD event due to existing CHD, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease, the recommended starting dose is 40 mg/day.
• It is recommended to use FloLipid 40 mg/5 mL for dosages greater than or equal to 40 mg.
• Lipid determinations should be performed after 4 weeks of therapy and periodically thereafter.
• Patients should be advised to measure FloLipid with an accurate measuring device. A household teaspoon is not an accurate measuring device and could lead to overdosage.
• A pharmacist can recommend an appropriate measuring device and can provide instructions for measuring the correct dose.

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 increases the risk of myopathy and rhabdomyolysis, particularly with higher doses of simvastatin.
• Concomitant use of drugs labeled as having a strong inhibitory effect on CYP3A4 is contraindicated.
• If treatment with itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended during the course of treatment.
• 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.

Lipid-Lowering Drugs That Can Cause Myopathy When Given Alone

• Gemfibrozil: Contraindicated with simvastatin.
• Other fibrates: Caution should be used when prescribing with simvastatin.

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.

Niacin

• Cases of myopathy/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 simvastatin doses exceeding 20 mg/day coadministered with lipid-modifying doses of niacin-containing products.
• Because the risk for myopathy is dose-related, Chinese patients should not receive simvastatin 80 mg coadministered with lipid-modifying doses of niacin-containing products.

Digoxin

• In one study, concomitant administration of digoxin with simvastatin resulted in a slight elevation in digoxin concentrations in plasma. Patients taking digoxin should be monitored appropriately when simvastatin is initiated.

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 simvastatin 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 simvastatin is changed or 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 simvastatin with colchicine.