Lescol Xl Drug Information
Generic name: FLUVASTATIN SODIUM
Uses of Lescol Xl
- LESCOL XL is indicated:
- To reduce the risk of undergoing coronary revascularization procedures and slow the progression of coronary atherosclerosis in adults with clinically evident coronary heart disease.
- As an adjunct to diet to reduce low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia.
- As an adjunct to diet to reduce LDL-C in adults and pediatric patients 10 years of age and older with heterozygous familial hypercholesterolemia (HeFH) who require 80 mg of fluvastatin daily. LESCOL XL is indicated:
Dosage & Administration of Lescol Xl
Important Dosage Information • Take LESCOL
XL tablets orally once daily as a single dose, with or without food. • Do not break, crush, or chew LESCOL XL tablets. • LESCOL XL is only available as an 80 mg tablet. LESCOL XL cannot be titrated. • For patients that require a high-intensity statin or are unable to achieve their LDL-C goal receiving LESCOL XL 80 mg daily, prescribe alternative LDL-C-lowering treatment. • Assess LDL-C when clinically appropriate, as early as 4 weeks after initiating LESCOL XL.
Recommended Dosage in Adult Patients
The recommended dosage for LESCOL XL is 80 mg once daily.
Recommended Dosage in Pediatric Patients Aged 10 Years of Age and Older with HeFH LESCOL XL is not recommended for dosage initiation in pediatric patients because the recommended starting dosage cannot be achieved with the available strength of 80 mg. Recommend use of another fluvastatin product to initiate dosing in pediatric patients.
Side Effects of Lescol Xl
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse reactions occurring in the fluvastatin capsules and LESCOL XL controlled trials with a frequency ≥ 2% included the following: Table 1. Adverse Reactions Reported in ≥ 2% in Patients Treated with Fluvastatin Capsules/LESCOL XL and at an Incidence Greater Than Placebo in Placebo-Controlled Trials Pooled Dosages In the LESCOL Intervention Prevention Study (LIPS), the effect of LESCOL (fluvastatin capsules) 40 mg, administered twice daily on the risk of recurrent cardiac events was assessed in 1677 patients with coronary heart disease who had undergone a percutaneous coronary intervention.
Adverse Reactions Reported in ≥ 2% in Patients Treated with Fluvastatin Capsules/LESCOL XL and at an Incidence Greater Than Placebo in the LIPS Trial Elevations in Liver Enzyme Tests Approximately 1.1% of patients treated with fluvastatin capsules in clinical trials developed dose-related, persistent elevations of serum transaminase levels to more than 3 times the ULN. Fourteen of these patients (0.6%) were discontinued from therapy. The majority of patients with these abnormal biochemical findings were asymptomatic.
Ninety-one percent of the cases of persistent ALT/AST increased abnormalities (20 of 22 patients) occurred within 12 weeks of therapy and in all patients with persistent liver function test abnormalities there was an abnormal liver function test present at baseline or by Week 8. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Musculoskeletal: Muscle cramps, myopathy, rhabdomyolysis, arthralgias, muscle spasms, muscle weakness, myositis.
There have been rare reports of IMNM associated with statin use. Neurological: Dysfunction of certain cranial nerves (including alteration of taste, impairment of extra-ocular movement, facial paresis), tremor, vertigo, paresthesia, hypoesthesia, dysesthesia, peripheral neuropathy, peripheral nerve palsy. There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with the use of all statins.
The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks). There have been rare reports of new-onset or exacerbation of myasthenia gravis, including ocular myasthenia, and reports of recurrence when the same or a different statin was administered. Psychiatric: Anxiety, depression, psychic disturbances Respiratory: Interstitial lung disease Hypersensitivity reactions: An apparent hypersensitivity syndrome has been reported rarely which has included one or more of the following features: anaphylaxis, angioedema, lupus erythematosus-like syndrome, polymyalgia rheumatica, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR (erythrocyte sedimentation rate) increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity reaction, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome.
Gastrointestinal: Pancreatitis, hepatitis, including chronic active hepatitis, cholestatic jaundice, fatty change in liver, cirrhosis, fulminant hepatic necrosis, hepatoma, anorexia, vomiting, fatal and non-fatal hepatic failure. Skin: Rash, dermatitis, including bullous dermatitis, eczema, alopecia, pruritus, lichen planus, a variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails). Reproductive: Gynecomastia, loss of libido, erectile dysfunction.
Eye: Progression of cataracts (lens opacities), ophthalmoplegia. Laboratory abnormalities: elevated transaminases, alkaline phosphatase, gamma-glutamyl transpeptidase and bilirubin; thyroid function abnormalities.
| Adverse reaction | Placebo a N = 960 (%) | Fluvastatin capsules a N = 2326 (%) | LESCOL XL b N = 912 (%) |
| Influenza-like symptoms | 5.7 | 5.1 | 7.1 |
| Headache | 7.8 | 8.9 | 4.7 |
| Myalgia | 4.5 | 5.0 | 3.8 |
| Abdominal pain | 3.8 | 4.9 | 3.7 |
| Dyspepsia | 3.2 | 7.9 | 3.5 |
| Sinusitis | 1.9 | 2.6 | 3.5 |
| Diarrhea | 4.2 | 4.9 | 3.3 |
| Arthropathy | NA | NA | 3.2 |
| Urinary tract infection | 1.1 | 1.6 | 2.7 |
| Nausea | 2.0 | 3.2 | 2.5 |
| Bronchitis | 1.0 | 1.8 | 2.6 |
| Fatigue | 2.3 | 2.7 | 1.6 |
| Flatulence | 2.5 | 2.6 | 1.4 |
| Arthritis | 2.0 | 2.1 | 1.3 |
| Allergy | 2.2 | 2.3 | 1.0 |
| Insomnia | 1.4 | 2.7 | 0.8 |
| a Controlled trials with fluvastatin capsules (20 mg and 40 mg daily and 40 mg twice daily) compared to placebo. b Controlled trials with LESCOL XL 80 mg Tablets as compared to fluvastatin capsules. | |||
| Adverse reaction | Placebo N = 818 (%) | Fluvastatin Capsules 40 mg twice daily N = 822 (%) |
|---|---|---|
| Abdominal pain upper | 4.5 | 6.3 |
| Hypertension | 4.2 | 5.8 |
| Fatigue | 3.8 | 4.7 |
| Dyspepsia | 4.0 | 4.5 |
| Edema peripheral | 2.9 | 4.4 |
| Pain in extremity | 2.7 | 4.1 |
| Dizziness | 3.5 | 3.9 |
| Constipation | 2.1 | 3.3 |
| Nasopharyngitis | 2.1 | 2.8 |
| Dyspnea exertional | 2.4 | 2.8 |
| Gastric disorder | 2.1 | 2.7 |
| Nausea | 2.3 | 2.7 |
| Atrial fibrillation | 2.0 | 2.4 |
| Syncope | 2.2 | 2.4 |
| Bronchitis | 2.0 | 2.3 |
| Intermittent claudication | 2.1 | 2.3 |
| Myalgia | 1.6 | 2.2 |
| Arthralgia | 1.8 | 2.1 |
Warnings & Cautions for Lescol Xl
Myopathy and Rhabdomyolysis LESCOL XL may cause myopathy (muscle pain, tenderness, or weakness associated with elevated creatine kinase ) and rhabdomyolysis. Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis with statins, including LESCOL XL. Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in CK, values to greater than 10 times the upper limit of normal (ULN) was < 0.1% in fluvastatin clinical trials.
Risk Factors for Myopathy Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, and concomitant use with certain other drugs (including other lipid-lowering therapies). Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis Avoid concomitant use of LESCOL XL with gemfibrozil, cyclosporin, and fluconazole. When used concomitantly with LESCOL XL, lipid modifying doses (≥ 1 g/day) of niacin, fibrates, and colchicine may also increase the risk of myopathy and rhabdomyolysis.
Discontinue LESCOL XL if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK increases may resolve if LESCOL XL is discontinued. Temporarily discontinue LESCOL XL in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis, e.g., sepsis, shock, severe hypovolemia, major surgery, trauma, severe metabolic, endocrine, or electrolyte disorders, or uncontrolled epilepsy.
Inform patients of the risk of myopathy and rhabdomyolysis when starting LESCOL XL. Instruct patients to promptly report any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever.
Immune-Mediated Necrotizing Myopathy There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use, including reports of recurrence when the same or a different statin was administered. IMNM is characterized by proximal muscle weakness and elevated serum CK, which persist despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody, muscle biopsy showing necrotizing myopathy, and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary.
Treatment with immunosuppressive agents may be required. Discontinue LESCOL XL if IMNM is suspected.
Hepatic Dysfunction Increases in serum transaminases have been reported with use of LESCOL XL. In most cases, these changes appeared soon after initiation, were transient, were not accompanied by symptoms, and resolved or improved on continued therapy or after a brief interruption in therapy. Persistent increases to more than three times the ULN in serum transaminases have occurred in approximately 1.1% of patients receiving fluvastatin in clinical trials.
Marked persistent increases of hepatic transaminases have also occurred with fluvastatin. There have been rare post-marketing reports of fatal and non-fatal hepatic failure in patients taking statins, including LESCOL XL. Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury.
Consider liver enzyme testing before LESCOL XL initiation and thereafter, when clinically indicated. LESCOL XL is contraindicated in patients with acute liver failure or decompensated cirrhosis. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue LESCOL XL.
Increases in HbA1c and Fasting Serum Glucose Levels Increases in HbA1c and fasting serum glucose levels have been reported with statins, including LESCOL XL. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices.
Drug Interactions with Lescol Xl
Drug Interactions that Increase the Risk of Myopathy and Rhabdomyolysis with LESCOL XL Table 3 includes a list of drugs that increase the risk of myopathy and rhabdomyolysis when used concomitantly with fluvastatin and instructions for preventing or managing them. Table 3.
LESCOL XL Effects on Other Drugs Table 4 presents LESCOL
XL’s effect on other drugs and instructions for preventing or managing them. Table 4. LESCOL XL Effects on Other Drugs Concomitant administration of fluvastatin and glyburide increased glyburide exposures.
Intervention Monitor blood glucose levels when LESCOL XL is initiated. Phenytoin Clinical impact Concomitant administration of fluvastatin and phenytoin increased phenytoin exposures. Intervention Monitor plasma phenytoin levels when LESCOL XL is initiated.
| Gemfibrozil | |
| Clinical impact | There is an increased risk of myopathy/rhabdomyolysis when LESCOL XL is administered with gemfibrozil |
| Intervention | Avoid concomitant use of gemfibrozil with LESCOL XL. |
| Cyclosporine | |
| Clinical impact | Cyclosporine coadministration increases fluvastatin exposure. The risk of myopathy and rhabdomyolysis may be increased with concomitant use of cyclosporine with LESCOL XL. |
| Intervention | Avoid concomitant use of cyclosporine with LESCOL XL. |
| Fluconazole | |
| Clinical impact | Fluconazole coadministration increases fluvastatin exposure. The risk of myopathy and rhabdomyolysis may be increased with concomitant use of fluconazole with LESCOL XL. |
| Intervention | Avoid concomitant use of fluconazole with LESCOL XL |
| Niacin | |
| Clinical impact | Risk of myopathy and rhabdomyolysis may be enhanced with concomitant use with lipid-modifying doses (≥ 1 g/day) of niacin with LESCOL XL. |
| Intervention | Consider if the benefit of using lipid-modifying doses (≥ 1 g/day) of niacin concomitantly with LESCOL XL outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration. |
| Fibrates | |
| Clinical impact | Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis may be increased with concomitant use of fibrates with LESCOL XL. |
| Intervention | Consider if the benefit of using fibrates concomitantly with LESCOL XL outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration. |
| Colchicine | |
| Clinical impact | Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with fluvastatin. |
| Intervention | Consider if the benefit of using colchicine concomitantly with LESCOL XL outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dose titration. |
| Warfarin | |
| Clinical impact | There are postmarketing reports of clinically evident bleeding and/or increased INR in patients taking concomitant statins and warfarin. |
| Intervention | In patients taking warfarin, obtain an INR before starting LESCOL XL and frequently enough after initiation or discontinuation to ensure that no significant alteration in INR occurs. Once the INR is stable, monitor INR at regularly recommended intervals. |
| Glyburide | |
| Clinical impact | Concomitant administration of fluvastatin and glyburide increased glyburide exposures [see Clinical Pharmacology (12.3)]. |
| Intervention | Monitor blood glucose levels when LESCOL XL is initiated. |
| Phenytoin | |
| Clinical impact | Concomitant administration of fluvastatin and phenytoin increased phenytoin exposures [see Clinical Pharmacology (12.3)]. |
| Intervention | Monitor plasma phenytoin levels when LESCOL XL is initiated. |
Contraindications for Lescol Xl
- LESCOL XL is contraindicated in patients with:
- Acute liver failure or decompensated cirrhosis.
- Hypersensitivity to fluvastatin or any of the excipients in LESCOL XL. Hypersensitivity reactions, including anaphylaxis, angioedema, and Stevens-Johnson syndrome have been reported.
- Hypersensitivity to fluvastatin or any excipient in LESCOL XL
Overdosage Information for Lescol Xl
No specific antidotes for LESCOL XL are known. In the event of an overdose of LESCOL XL, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.
Clinical Studies of Lescol Xl
Secondary Prevention of Cardiovascular Disease In the LESCOL Intervention Prevention Study (LIPS), the effect of fluvastatin capsules 40 mg administered twice daily on the risk of recurrent cardiac events (time to first occurrence of cardiac death, nonfatal myocardial infarction, or revascularization) was assessed in 1677 adult patients with CHD who had undergone a percutaneous coronary intervention (PCI) procedure (mean time from PCI to randomization = 3 days). In this multicenter, randomized, double-blind, placebo-controlled trial, patients were treated with dietary/lifestyle counseling and either fluvastatin 40 mg (n = 844) or placebo (n = 833) given twice daily for a median of 3.9 years. Revascularization procedures comprised the majority of the initial recurrent cardiac events (143 revascularization procedures in the fluvastatin capsules group and 171 in the placebo group).
Consistent trends in risk reduction were observed in patients > 65 years of age. Figure 1. Primary Endpoint – Recurrent Cardiac Events (Cardiac Death, Nonfatal MI or Revascularization Procedure) (ITT Population) Outcome data for the LESCOL Intervention Prevention Study are shown in Figure 2.
After exclusion of revascularization procedures (CABG and repeat PCI) occurring within the first 6 months of the initial procedure involving the originally instrumental site, treatment with fluvastatin capsules was associated with a 32% (p = 0.002) reduction in risk of late revascularization procedures (CABG or PCI occurring at the original site > 6 months after the initial procedure, or at another site). Figure 2. LESCOL Intervention Prevention Study–- Primary and Secondary Endpoints In the Lipoprotein and Coronary Atherosclerosis Study (LCAS), the effect of fluvastatin capsule therapy on coronary atherosclerosis was assessed by quantitative coronary angiography (QCA) in patients with CAD and mild to moderate hypercholesterolemia (baseline LDL-C range 115 to 190 mg/dL).
In this randomized double-blind, placebo-controlled trial, 429 patients were treated with conventional measures (Step 1, AHA Diet) and either fluvastatin 40 mg/day or placebo. In order to provide treatment to patients receiving placebo with LDL-C levels ≥160 mg/dL at baseline, adjunctive therapy with cholestyramine was added after Week 12 to all patients in the study with baseline LDL-C values of ≥ 160 mg/dL, which were present in 25% of the study population. Quantitative coronary angiograms were evaluated at baseline and 2.5 years in 340 (79%) angiographic evaluable patients.
Compared to placebo, fluvastatin capsules significantly slowed the progression of coronary atherosclerosis as measured by within-patient per-lesion change in minimum lumen diameter (MLD), the primary endpoint (Figure 3 below), percent diameter stenosis (Figure 4), and the formation of new lesions (13% of all fluvastatin patients versus 22% of all placebo patients). A significant difference in favor of fluvastatin capsules was found between all fluvastatin and all placebo patients in the distribution among the three categories of definite progression, definite regression, and mixed or no change. Beneficial angiographic results (change in MLD) were independent of patients’ gender and consistent across a range of baseline LDL-C levels.
Figure 3. Change in Minimum Lumen Diameter (mm) Figure 4. Change in % Diameter Stenosis Primary Hyperlipidemia in Adults LESCOL XL has been studied in five controlled trials of adult patients with primary hyperlipidemia and mixed dyslipidemia.
LESCOL XL was administered to over 900 patients in trials from 4 to 26 weeks in duration. In the three largest of these trials, LESCOL XL given as a single daily dose of 80 mg significantly reduced Total-C, LDL-C, TG, and Apo B (Table 5). In patients with primary mixed dyslipidemia as defined by baseline plasma TG levels ≥ 200 mg/dL and < 400 mg/dL, treatment with LESCOL XL produced significant decreases in Total-C, LDL-C, TG, and Apo B (see Table 7).
Table 7. Median Percent Change in Lipid Levels in Adult Patients with Primary Hyperlipidemia and Mixed Dyslipidemia From Baseline to Week 24 Endpoint All Active Controlled Trials (LESCOL XL) HeFH in Pediatric Patients Aged 10 Years and Older Fluvastatin capsules were studied in two open-label, uncontrolled, dose-titration trials. The first trial enrolled 29 pre-pubertal males, 9 to12 years of age, who had an LDL-C level > 90 th percentile for age and one parent with primary hypercholesterolemia and either a family history of premature ischemic heart disease or tendon xanthomas.
The mean baseline LDL-C was 226 mg/dL (range, 137 to 354 mg/dL). Endpoint analyses were performed at Year 2. Fluvastatin decreased plasma levels of Total-C and LDL-C by 21% and 27%, respectively.
The mean achieved LDL-C was 161 mg/dL (range, 74 to 336 mg/dL). The mean baseline LDL-C was 225 mg/dL (range, 148 to 343 mg/dL). Endpoint analyses were performed at Week 114.
Fluvastatin decreased plasma levels of Total-C and LDL-C by 22% and 28%, respectively. The mean achieved LDL-C was 159 mg/dL (range, 90 to 295 mg/dL). The majority of patients in both trials (83% in the first trial and 89% in the second trial) were titrated to the maximum daily dose of 80 mg. lescol-03 lescol-04 lescol-05 lescol-06
| Total Chol | TG | LDL | Apo B | HDL | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Dose | N | %∆ | N | %∆ | N | %∆ | N | %∆ | N | %∆ |
| All Patients | ||||||||||
| LESCOL XL 80 mg a | 750 | -25 | 750 | -19 | 748 | -35 | 745 | -27 | 750 | +7 |
| Baseline TG ≥ 200 mg/dL | ||||||||||
| LESCOL XL 80 mg a | 239 | -25 | 239 | -25 | 237 | -33 | 235 | -27 | 239 | +11 |
| a Data for LESCOL XL 80 mg tablet from three 24- week controlled trials. | ||||||||||
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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