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LESCOL XL (NDA-021192)

(FLUVASTATIN SODIUM)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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11/28/2023 (SUPPL-29)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

LESCOL XL is contraindicated in patients with:

  • Acute liver failure or decompensated cirrhosis [see Warnings and Precautions (5.3)].

  • Hypersensitivity to fluvastatin or any of the excipients in LESCOL XL. Hypersensitivity reactions, including anaphylaxis, angioedema, and Stevens-Johnson syndrome have been reported [see Adverse Reactions (6.2)].

5 Warnings and Precautions

5.1 Myopathy and Rhabdomyolysis

Subsection title revised

Additions and/or revisions underlined:

LESCOL XL may cause myopathy (muscle pain, tenderness, or weakness associated with elevated creatine kinase [CK]) 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 [see Adverse Reactions (6.1)].

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) [see Drug Interactions (7.1)].

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 [see Drug Interactions (7.1)].

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.

5.2 Immune-Mediated Necrotizing Myopathy

Additions and/or revisions underlined:

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.

5.3 Hepatic Dysfunction

Subsection title revised

Additions and/or revisions underlined:

Increases in serum transaminases have been reported with use of LESCOL XL [see Adverse Reactions (6.1)]. 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 [see Contraindications (4)]. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue LESCOL XL.

5.4 Increases in HbA1c and Fasting Serum Glucose Levels

Subsection title revised

Additions and/or revisions underlined:

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.

6 Adverse Reactions

Additions and/or revisions underlined:

The following serious adverse reactions are discussed in greater detail in other sections of the label:

  • Myopathy and Rhabdomyolysis [see Warnings and Precautions (5.1)]

  • Immune-Mediated Necrotizing Myopathy [see Warnings and Precautions (5.2)]

  • Hepatic Dysfunction [see Warnings and Precautions (5.3)]

  • Increases in HbA1c and Fasting Serum Glucose Levels [see Warnings and Precautions (5.4)]

6.1 Clinical Trials Experience

Extensive changes; please refer to label for complete information

6.2 Postmarketing Experience

Additions and/or revisions underlined:

The following adverse reactions have been identified during postapproval use of fluvastatin. 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 [see Warnings and Precautions (5.2)].

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.

7 Drug Interactions

Subsection title revised

Extensive changes; please refer to label for complete information

8 Use in Specific Populations

8.1 Pregnancy

Pregnancy and Lactation Labeling Rule (PLLR) conversion; please refer to label for complete information

8.2 Lactation

Newly added subsection:

Risk Summary

There is no information about the presence of fluvastatin in human milk, the effects of the drug on the breastfed infant or the effects of the drug on milk production. However, it has been shown that another drug in this class passes into human milk. Studies in rats have shown that fluvastatin and/or its metabolites are present in the milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk (see Data). Statins, including LESCOL XL, decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol and may cause harm to the breastfed infant.

Because of the potential for serious adverse reactions in a breastfed infant, based on the mechanism of action, advise patients that breastfeeding is not recommended during treatment with LESCOL XL [see Use in Specific Populations (8.1), Clinical Pharmacology (12.1)].

Data

Following a single oral administration of 1 mg/kg of radioactive fluvastatin to lactating rats, the concentration of total radioactivity was determined. Fluvastatin and/or its metabolites were measured in the breast milk at a 2:1 ratio (milk:plasma).

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of LESCOL XL as an adjunct to diet to reduce LDL-C have been established in pediatric patients 10 years of age and older with HeFH. Use of LESCOL XL for this indication is based on open-label, uncontrolled clinical trials in 114 pediatric patients 9 years of age and older with HeFH. In these limited uncontrolled studies, there was no significant effect on growth or sexual maturation in the males or females, or on menstrual cycle length in females.

The safety and effectiveness of LESCOL XL have not been established in pediatric patients younger than 10 years of age with HeFH or in pediatric patients with other types of hyperlipidemia (other than HeFH).

8.5 Geriatric Use

Additions and/or revisions underlined:

Fluvastatin exposures were not significantly different between the nonelderly and elderly populations (age ? 65 years)[see Clinical Pharmacology (12.3)].

Advanced age (? 65 years) is a risk factor for LESCOL XL-associated myopathy and rhabdomyolysis. Dose selection for an elderly patient should be cautious, recognizing the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of myopathy. Monitor geriatric patients receiving LESCOL XL for the increased risk of myopathy [see Warnings and Precautions (5.1)].

8.6 Renal Impairment

Additions and/or revisions underlined:

Renal impairment is a risk factor for myopathy and rhabdomyolysis.
Dose adjustments for mild to moderate renal impairment are not necessary. Fluvastatin has not been studied at doses greater than 40 mg in patients with severe renal impairment; therefore, use LESCOL XL with caution in patients with severe renal impairment. Monitor all patients with renal impairment for development of myopathy [see Warnings and Precautions (5.1), Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

Additions and/or revisions underlined:

LESCOL XL is contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications (4), Warnings and Precautions (5.3)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Myopathy and Rhabdomyolysis

Advise patients that LESCOL XL may cause myopathy and rhabdomyolysis. Instruct patients to promptly report any unexplained muscle pain, tenderness, or weakness particularly if accompanied by malaise or fever [see Warnings and Precautions (5.1), Drug Interactions (7.1)].

Hepatic Dysfunction

nform patients that LESCOL XL may cause liver enzyme elevations and possibly liver failure. Advise patients to promptly report fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice [see Warnings and Precautions (5.3)].

Increases in HbA1c and Fasting Serum Glucose Levels

Inform patients that increases in HbA1c and fasting serum glucose levels may occur with LESCOL XL. Encourage patients to optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices [see Warnings and Precautions (5.4)].

Pregnancy

Advise pregnant patients and patients who can become pregnant of the potential risk to a fetus. Advise patients to inform their healthcare provider of a known or suspected pregnancy to discuss if LESCOL XL should be discontinued [see Use in Specific Populations (8.1)].

Lactation

Advise patients that breastfeeding is not recommended during treatment with LESCOL XL [see Use in Specific Populations (8.2)].

PATIENT INFORMATION

Extensive changes; please refer to label for complete information

09/25/2020 (SUPPL-31)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Immune-Mediated Necrotizing Myopathy

(New subsection added)

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; 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. Consider risk of IMNM carefully prior to initiation of a different statin. If therapy is initiated with a different statin, monitor for signs and symptoms of IMNM.

08/04/2017 (SUPPL-26)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Addition of the following:

Respiratory: interstitial lung disease