DRUGS & SUPPLEMENTS

Lymetel

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Lymetel uses


1 INDICATIONS AND USAGE

Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other non-pharmacologic measures alone has been inadequate.

Lymetel capsules are an HMG-CoA reductase inhibitor indicated as an adjunctive therapy to diet to:

  • Reduce elevated TC, LDL-C, Apo B, and TG, and to increase HDL-C in adult patients with primary hypercholesterolemia and mixed dyslipidemia (1.1)
  • Reduce elevated TC, LDL-C, and Apo B levels in boys and post-menarchal girls, 10 to 16 years of age, with heterozygous familial hypercholesterolemia after failing an adequate trial of diet therapy (1.1 )
  • Reduce the risk of undergoing revascularization procedures in patients with clinically evident CHD (1.2)
  • Slow the progression of atherosclerosis in patients with CHD (1.2)

Limitations of Use:

  • Lymetel capsules have not been studied in conditions where the major abnormality is elevation of chylomicrons, VLDL, or IDL (i.e., hyperlipoproteinemia Types I, III, IV, or V). (1.3)

1.1 Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia

Lymetel capsules are indicated

  • as an adjunct to diet to reduce elevated total cholesterol (Total-C), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG) and apolipoprotein B (Apo B) levels, and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hypercholesterolemia and mixed dyslipidemia (Fredrickson Type IIa and IIb).
  • as an adjunct to diet to reduce Total-C, LDL-C, and Apo B levels in adolescent boys and adolescent girls who are at least one year post-menarche, 10 to 16 years of age, with heterozygous familial hypercholesterolemia and the following findings are present:
    • LDL-C remains ≥ 190 mg/dL or
    • LDL-C remains ≥ 160 mg/dL and:
      • - there is a positive family history of premature cardiovascular disease or
      • - two or more other cardiovascular disease risk factors are present

The NCEP classification of cholesterol levels in pediatric patients with a familial history of hypercholesterolemia or premature CVD is summarized below.


Category


Total-C (mg/dL)


LDL-C (mg/dL)


Acceptable


< 170


< 110


Borderline


170 to 199


110 to 129


High


≥ 200


≥ 130


Children treated with Lymetel in adolescence should be re-evaluated in adulthood and appropriate changes made to their cholesterol-lowering regimen to achieve adult treatment goals.

1.2 Secondary Prevention of Cardiovascular Disease

In patients with clinically evident CHD, Lymetel capsules are indicated to:

  • reduce the risk of undergoing coronary revascularization procedures
  • slow the progression of coronary atherosclerosis

1.3 Limitations of Use

Lymetel capsules have not been studied in conditions where the major abnormality is elevation of chylomicrons, VLDL, or IDL (i.e., hyperlipoproteinemia Types I, III, IV, or V).

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2 DOSAGE AND ADMINISTRATION

  • Dose range: 20 mg to 80 mg/day
  • Lymetel capsules can be taken with or without food. (2.1)
  • Do not open Lymetel capsules prior to administration (2.1)
  • Adults: the recommended starting dose is 40 mg to 80 mg (administered as one Lymetel capsule, 40 mg twice daily) (2.2)
  • Do not take two Lymetel capsules, 40 mg at one time
  • Children with heterozygous familial hypercholesterolemia (ages 10 to 16, inclusive): the recommended starting dose is Lymetel capsule, 20 mg once daily (2.3)

2.1 General Dosing Information

Dose range: 20 mg to 80 mg/day.

Lymetel capsules can be administered orally as a single dose, with or without food.

Do not open Lymetel capsules prior to administration.

Do not take two Lymetel capsules, 40 mg at one time.

Since the maximal effect of a given dose is seen within 4 weeks, periodic lipid determinations should be performed at this time and dosage adjusted according to the patient’s response to therapy and established treatment guidelines.

For patients requiring LDL-C reduction to a goal of ≥ 25%, the recommended starting dose is 40 mg as one capsule in the evening, or 80 mg in divided doses of the 40 mg capsule given twice daily. For patients requiring LDL-C reduction to a goal of < 25% a starting dose of 20 mg may be used.

2.2 Adult Patients With Hypercholesterolemia and Mixed Dyslipidemia

Adult patients can be started on Lymetel capsules. The recommended starting dose for Lymetel capsules is one 40 mg capsule in the evening, or one Lymetel capsule, 40 mg twice daily. Do not take two Lymetel capsules, 40 mg at one time.

2.3 Pediatric Patients With Heterozygous Familial Hypercholesterolemia

The recommended starting dose is one Lymetel capsule, 20 mg. Dose adjustments, up to a maximum daily dose administered as Lymetel capsules, 40 mg twice daily should be made at 6 week intervals. Doses should be individualized according to the goal of therapy [see NCEP Pediatric Panel Guidelines and CLINICAL STUDIES (14)]1.

1 National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics. 89(3):495-501. 1992.

2.4 Use With Cyclosporine

Do not exceed a dose of 20 mg b.i.d. Lymetel capsules in patients taking cyclosporine [see Drug Interactions ].

2.5 Use With Fluconazole

Do not exceed a dose of 20 mg b.i.d. Lymetel capsules in patients taking fluconazole [see Drug Interactions (7.2)].

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3 DOSAGE FORMS AND STRENGTHS

  • 20 mg are hard gelatin capsules with ivory opaque body and pink opaque cap, filled with an off-white to yellowish powder with small agglomerates. Cap imprinted with “TEVA” and body imprinted with “7442”.
  • 40 mg are hard gelatin capsules with yellow opaque body and pink opaque cap, filled with an off-white to yellowish powder with small agglomerates. Cap imprinted with “TEVA” and body imprinted with “7443”.

Lymetel capsules: 20 mg, 40 mg (3)

4 CONTRAINDICATIONS

  • Hypersensitivity to any component of this medication
  • Active liver disease or unexplained, persistent elevations in serum transaminases (4, 5.2)
  • Women who are pregnant or may become pregnant (4, 8.1)
  • Nursing mothers (4, 8.3)

4.1 Hypersensitivity to any Component of This Medication

Lymetel capsules are contraindicated in patients with hypersensitivity to any component of this medication.

4.2 Active Liver Disease

Lymetel capsules are contraindicated in patients with active liver disease or unexplained, persistent elevations in serum transaminases [see Warnings and Precautions ].

4.3 Pregnancy

Lymetel capsules are contraindicated in 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. Lymetel capsules may cause fetal harm when administered to pregnant women. 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.

Lymetel capsules should be administered to women of childbearing age only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If the patient becomes pregnant while taking this drug, Lymetel capsules should be discontinued and the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].

4.4 Nursing Mothers

Lymetel is secreted into the breast milk of animals and because HMG-CoA reductase inhibitors have the potential to cause serious adverse reactions in nursing infants, women who require treatment with Lymetel capsules should be advised not to breastfeed their infants [see Use in Specific Populations (8.3)].

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5 WARNINGS AND PRECAUTIONS

  • Skeletal muscle effects : Risks increase with advanced age (≥ 65), uncontrolled hypothyroidism, renal impairment, and combination use with cyclosporine,or gemfibrozil. Advise patients to promptly report to their physician unexplained and/or persistent muscle pain, tenderness, or weakness and discontinue Lymetel if myopathy is diagnosed or suspected. (5.1, 8.5, 8.7)
  • Patients should be advised to report promptly any symptoms of myopathy. Lymetel capsules therapy should be discontinued if myopathy is diagnosed or suspected (5.1)
  • Liver enzyme abnormalities: Persistent elevations in hepatic transaminases can occur. Check liver enzyme tests before initiating therapy and as clinically indicated thereafter (5.2)

5.1 Skeletal Muscle

Rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with Lymetel capsules and other drugs in this class.

Lymetel capsules should be prescribed with caution in patients with predisposing factors for myopathy. These factors include advanced age (> 65 years), renal impairment, and inadequately treated hypothyroidism.

The risk of myopathy and/or rhabdomyolysis with statins is increased with concurrent therapy with cyclosporine, erythromycin, fibrates or niacin. Myopathy was not observed in a clinical trial in 74 patients involving patients who were treated with Lymetel sodium together with niacin. Isolated cases of myopathy have been reported during postmarketing experience with concomitant administration of Lymetel sodium and colchicine. No information is available on the pharmacokinetic interaction between Lymetel sodium and colchicine.

Uncomplicated myalgia has also been reported in Lymetel sodium-treated patients [see Adverse Reactions (6)]. In clinical trials, uncomplicated myalgia has been observed infrequently in patients treated with Lymetel sodium at rates indistinguishable from placebo. Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in CPK values to greater than 10 times the upper limit of normal, was < 0.1% in Lymetel clinical trials. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK.

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; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.

All patients should be advised to promptly report to their physician unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing Lymetel.

Lymetel sodium therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Lymetel sodium therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.

5.2 Liver Enzymes

Increases in serum transaminases have been reported with HMG-CoA reductase inhibitors, including Lymetel sodium. In most cases, the elevations were transient and resolved or improved on continued therapy or after a brief interruption in therapy.

Approximately 1.1% of patients treated with Lymetel capsules in worldwide trials developed dose-related, persistent elevations of serum transaminase levels to more than 3 times the upper limit of normal. Fourteen of these patients (0.6%) were discontinued from therapy. In all clinical trials, a total of 33/2969 patients (1.1%) had persistent transaminase elevations with an average Lymetel sodium exposure of approximately 71.2 weeks; 19 of these patients (0.6%) were discontinued. The majority of patients with these abnormal biochemical findings were asymptomatic.

In a pooled analysis of all placebo-controlled studies in which Lymetel capsules were used, persistent transaminase elevations (> 3 times the upper limit of normal [ULN] on two consecutive weekly measurements) occurred in 0.2%, 1.5%, and 2.7% of patients treated with daily doses of 20, 40, and 80 mg (titrated to 40 mg twice daily) Lymetel capsules, respectively. Ninety-one percent of the cases of persistent liver function test 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.

In the pooled analysis of the 24 week controlled trials, persistent transaminase elevation occurred in 1.8% and 4.9% of patients treated with Lymetel capsules, 40 mg and Lymetel capsules, 40 mg twice daily, respectively.

It is recommended that liver enzyme tests be performed prior to the initiation of Lymetel sodium, and if signs or symptoms of liver injury occur.

There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including Lymetel. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with Lymetel sodium, promptly interrupt therapy. If an alternate etiology is not found do not restart Lymetel sodium.

In very rare cases, possibly drug-related hepatitis was observed that resolved upon discontinuation of treatment.1 Active liver disease or unexplained serum transaminase elevations are contraindications to the use of Lymetel sodium [see Contraindications (4) and Warnings and Precautions (5.2)]. Caution should be exercised when Lymetel sodium is administered to patients with a history of liver disease or heavy alcohol ingestion [see Clinical Pharmacology (12.3)]. Such patients should be closely monitored.

5.3 Endocrine Effects

Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including Lymetel sodium.

Statins interfere with cholesterol synthesis and lower circulating cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone production.

Lymetel sodium exhibited no effect upon non-stimulated cortisol levels and demonstrated no effect upon thyroid metabolism as assessed by measurement of thyroid stimulating hormone (TSH). Small declines in total serum testosterone have been noted in treated groups, but no commensurate elevation in LH occurred, suggesting that the observation was not due to a direct effect upon testosterone production. No effect upon FSH in males was noted. Due to the limited number of premenopausal females studied to date, no conclusions regarding the effect of Lymetel sodium upon female sex hormones may be made.

Two clinical studies in patients receiving Lymetel at doses up to 80 mg daily for periods of 24 to 28 weeks demonstrated no effect of treatment upon the adrenal response to ACTH stimulation. A clinical study evaluated the effect of Lymetel at doses up to 80 mg daily for 28 weeks upon the gonadal response to HCG stimulation. Although the mean total testosterone response was significantly reduced (p < 0.05) relative to baseline in the 80 mg group, it was not significant in comparison to the changes noted in groups receiving either 40 mg of Lymetel or placebo.

Patients treated with Lymetel sodium who develop clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should be exercised if a statin or other agent used to lower cholesterol levels is administered to patients receiving other drugs (e.g., ketoconazole, spironolactone, cimetidine) that may decrease the levels of endogenous steroid hormones.

5.4 CNS Toxicity

CNS effects, as evidenced by decreased activity, ataxia, loss of righting reflex, and ptosis were seen in the following animal studies: the 18 month mouse carcinogenicity study at 50 mg/kg/day, the 6 month dog study at 36 mg/kg/day, the 6 month hamster study at 40 mg/kg/day, and in acute, high-dose studies in rats and hamsters (50 mg/kg), rabbits (300 mg/kg) and mice (1500 mg/kg). CNS toxicity in the acute high-dose studies was characterized (in mice) by conspicuous vacuolation in the ventral white columns of the spinal cord at a dose of 5000 mg/kg and (in rats) by edema with separation of myelinated fibers of the ventral spinal tracts and sciatic nerve at a dose of 1500 mg/kg. CNS toxicity, characterized by periaxonal vacuolation, was observed in the medulla of dogs that died after treatment for 5 weeks with 48 mg/kg/day; this finding was not observed in the remaining dogs when the dose level was lowered to 36 mg/kg/day. CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with other members of this drug class. No CNS lesions have been observed after chronic treatment for up to 2 years with Lymetel in the mouse (at doses up to 350 mg/kg/day), rat (up to 24 mg/kg/day), or dog (up to 16 mg/kg/day).

Prominent bilateral posterior Y suture lines in the ocular lens were seen in dogs after treatment with 1, 8, and 16 mg/kg/day for 2 years.

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6 ADVERSE REACTIONS

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

  • Rhabdomyolysis with myoglobinuria and acute renal failure and myopathy [see Warnings and Precautions (5.1)].
  • Liver Enzyme Abnormalities [see Warnings and Precautions (5.2)].

Most frequent adverse reactions (rate ≥ 2% and > placebo) are: headache, dyspepsia, myalgia, abdominal pain and nausea (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact TEVA USA, PHARMACOVIGILANCE at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Studies Experience in Adult Patients

Because clinical studies on Lymetel capsules are conducted in varying study populations and study designs, the frequency of adverse reactions observed in the clinical studies of Lymetel capsules cannot be directly compared with that in the clinical studies of other statins and may not reflect the frequency of adverse reactions observed in clinical practice.

In the Lymetel capsules placebo-controlled clinical trials database of 2326 patients treated with Lymetel capsules1 (age range 18 to 75 years, 44% women, 94% Caucasians, 4% Blacks, 2% other ethnicities) with a median treatment duration of 24 weeks, 3.4% of patients on Lymetel capsules and 2.3% patients on placebo discontinued due to adverse reactions regardless of causality. The most common adverse reactions that led to treatment discontinuation and occurred at an incidence greater than placebo were: transaminase increased (0.8%), upper abdominal pain (0.3%), dyspepsia (0.3%), fatigue (0.2%) and diarrhea (0.2%).

Clinically relevant adverse experiences occurring in the Lymetel capsules controlled studies with a frequency ≥ 2%, regardless of causality, included the following:


Lymetel CapsulesControlled trials with Lymetel capsules (20 and 40 mg daily and 40 mg twice daily) compared to placebo

N = 2326

(%)


Placebo

N = 960

(%)


Musculoskeletal


Myalgia


5.0


4.5


Arthritis


2.1


2.0


Arthropathy


NA


NA


Respiratory


Sinusitis


2.6


1.9


Bronchitis


1.8


1.0


Gastrointestinal


Dyspepsia


7.9


3.2


Diarrhea


4.9


4.2


Abdominal pain


4.9


3.8


Nausea


3.2


2.0


Flatulence


2.6


2.5


Tooth disorder


2.1


1.7


Psychiatric


Insomnia


2.7


1.4


Genitourinary


Urinary tract infection


1.6


1.1


Miscellaneous


Headache


8.9


7.8


Influenza-like symptoms


5.1


5.7


Accidental Trauma


5.1


4.8


Fatigue


2.7


2.3


Allergy


2.3


2.2


Lymetel Capsules Intervention Prevention Study

In the Lymetel Capsules Intervention Prevention Study, the effect of Lymetel capsules, 40 mg, administered twice daily on the risk of recurrent cardiac events was assessed in 1677 patients with CHD who had undergone a percutaneous coronary intervention (PCI) procedure. This was a multicenter, randomized, double-blind, placebo-controlled study, patients were treated with dietary/lifestyle counseling and either Lymetel capsules, 40 mg (n = 844) or placebo (n = 833) given twice daily for a median of 3.9 years [see Clinical Studies (14.3)].


Lymetel Capsules,

40 mg b.i.d.

N = 822

(%)


Placebo

N = 818

(%)


Cardiac disorders


Atrial fibrillation


2.4


2.0


Gastrointestinal disorders


Abdominal pain upper


6.3


4.5


Constipation


3.3


2.1


Dyspepsia


4.5


4.0


Gastric disorder


2.7


2.1


Nausea


2.7


2.3


General disorders


Fatigue


4.7


3.8


Edema peripheral


4.4


2.9


Infections and infestations


Bronchitis


2.3


2.0


Nasopharyngitis


2.8


2.1


Musculoskeletal and connective tissue disorders


Arthralgia


2.1


1.8


Myalgia


2.2


1.6


Pain in extremity


4.1


2.7


Nervous system disorders


Dizziness


3.9


3.5


Syncope


2.4


2.2


Respiratory disorders


Dyspnea exertional


2.8


2.4


Vascular disorders


Hypertension


5.8


4.2


Intermittent claudication


2.3


2.1

6.2 Clinical Studies Experience in Pediatric Patients

In patients aged < 18 years, efficacy and safety have not been studied for treatment periods longer than two years.

In two open-label, uncontrolled studies, 66 boys and 48 girls with heterozygous familial hypercholesterolemia were treated with Lymetel sodium administered as Lymetel capsules, 20 mg to 40 mg twice daily, or Lymetel sodium extended-release tablets, 80 mg [see Clinical Studies (14.2) and Use in Specific Populations (8.4)].

6.3 Postmarketing Experience

Because adverse reactions from spontaneous reports are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following effects have been reported with drugs in this class. Not all the effects listed below have necessarily been associated with Lymetel sodium therapy.

Musculoskeletal: muscle cramps, myalgia, myopathy, rhabdomyolysis, arthralgias, muscle spasms, muscle weakness, myositis.

There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [see Warnings and Precautions (5.1)].

Neurological: dysfunction of certain cranial nerves (including alteration of taste, impairment of extra-ocular movement, facial paresis), tremor, dizziness, 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 statin use. These cognitive issues have been reported for 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).

Psychiatric: anxiety, insomnia, 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, 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

  • Cyclosporine: Combination increases Lymetel exposure. Limit Lymetel dose to 20 mg
  • Fluconazole: Combination increases Lymetel exposure. Limit Lymetel dose to 20 mg (2.5, 7.2)
  • Concomitant lipid-lowering therapies: Use with fibrates or lipid-modifying doses (≥ 1 g/day) of niacin increases the risk of adverse skeletal muscle effects. Caution should be used when prescribing with Lymetel (5.1, 7.3, 7.4)
  • Glyburide: Monitor blood glucose levels when Lymetel dose is changed (7)
  • Phenytoin: Monitor plasma phenytoin levels when Lymetel treatment is initiated or when the dosage is changed (7)
  • Warfarin and coumarin derivates: Monitor prothrombin times when Lymetel coadministration is initiated, discontinued, or the dosage changed (7)

7.1 Cyclosporine

Cyclosporine coadministration increases Lymetel exposure. Therefore, in patients taking cyclosporine, therapy should be limited to Lymetel 20 mg twice daily [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

7.2 Fluconazole

Administration of Lymetel 40 mg single dose to healthy volunteers pre-treated with fluconazole for 4 days results in an increase of Lymetel exposure. Therefore, in patients taking fluconazole, therapy should be limited to Lymetel 20 mg twice daily [see Clinical Pharmacology ].

7.3 Gemfibrozil

Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are coadministered with gemfibrozil, concomitant administration of Lymetel sodium with gemfibrozil should be avoided.

7.4 Other Fibrates

Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of other fibrates, Lymetel sodium should be administered with caution when used concomitantly with other fibrates [see Warnings and Precautions and Clinical Pharmacology (12.3)].

7.5 Niacin

The risk of skeletal muscle effects may be enhanced when Lymetel sodium is used in combination with lipid-modifying doses (≥ 1 g/day) of niacin; a reduction in Lymetel sodium dosage should be considered in this setting [see Warnings and Precautions (5.1)].

7.6 Glyburide

Concomitant administration of Lymetel and glyburide increased glyburide exposures. Patients on concomitant therapy of glyburide and Lymetel should continue to be monitored appropriately [see Clinical Pharmacology ].

7.7 Phenytoin

Concomitant administration of Lymetel and phenytoin increased phenytoin exposures. Patients should continue to be monitored appropriately when Lymetel therapy is initiated or when Lymetel dose is changed [see Clinical Pharmacology (12.3)].

7.8 Warfarin

Bleeding and/or increased prothrombin times have been reported in patients taking coumarin anticoagulants concomitantly with other HMG-CoA reductase inhibitors. Therefore, patients receiving warfarin-type anticoagulants should have their prothrombin times closely monitored when Lymetel sodium is initiated or the dosage of Lymetel sodium is changed.

7.9 Colchicine

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

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category X

Lymetel sodium is contraindicated in women who are or may become pregnant [see Contraindications ].

Lipid lowering drugs are contraindicated during pregnancy, because cholesterol and cholesterol derivatives are needed for normal fetal development. Serum cholesterol and triglycerides increase during normal pregnancy. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy.

There are no adequate and well-controlled studies of use with Lymetel sodium during pregnancy. Rare reports of congenital anomalies have been received following intrauterine exposure to other statins. In a review2 of about 100 prospectively followed pregnancies in women exposed to other statins, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed the rate expected in the general population. The number of cases is adequate only to exclude a 3 to 4 fold increase in congenital anomalies over background incidence. In 89% of prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified.

Teratology studies with Lymetel in rats and rabbits showed maternal toxicity at high dose levels, but there was no evidence of embryotoxic or teratogenic potential [see Nonclinical Toxicology (13)].

Lymetel sodium should be administered to women of child-bearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If a woman becomes pregnant while taking Lymetel sodium, the drug should be discontinued and the patient advised again as to the potential hazards to the fetus.

8.3 Nursing Mothers

Based on animal data, Lymetel is present in breast milk in a 2:1 ratio (milk:plasma). Because of the potential for serious adverse reactions in nursing infants, nursing women should not take Lymetel sodium [see Contraindications (4)].

8.4 Pediatric Use

The safety and efficacy of Lymetel sodium in children and adolescent patients 9 to 16 years of age with heterozygous familial hypercholesterolemia have been evaluated in open-label, uncontrolled clinical trials for a duration of two years. The most common adverse events observed were influenza and infections. In these limited uncontrolled studies, there was no detectable effect on growth or sexual maturation in the adolescent boys or on menstrual cycle length in girls [see Clinical Studies, Adverse Reactions (6.3), and Dosage and Administration (2.2)]. Adolescent females should be counseled on appropriate contraceptive methods while on Lymetel sodium therapy [see Contraindications (4)].

8.5 Geriatric Use

Lymetel exposures were not significantly different between the nonelderly and elderly populations (age ≥ 65 years) [see Clinical Pharmacology (12.3)]. Since advanced age (≥ 65 years) is a predisposing factor for myopathy, Lymetel sodium should be prescribed with caution in the elderly.

8.6 Hepatic Impairment

Lymetel sodium is contraindicated in patients with active liver disease or unexplained, persistent elevations in serum transaminases [see Clinical Pharmacology ].

8.7 Renal Impairment

Dose adjustments for mild to moderate renal impairment are not necessary. Lymetel has not been studied at doses greater than 40 mg in patients with severe renal impairment; therefore caution should be exercised when treating such patients at higher doses [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE

To date, there has been limited experience with overdosage of Lymetel. If an overdose occurs, it should be treated symptomatically with laboratory monitoring and supportive measures should be instituted as required. The dialyzability of Lymetel sodium and of its metabolites in humans is not known at present [seeWarnings and Precautions (5)].

In the pediatric population, there have been reports of overdosage with Lymetel sodium in children including a 2-year-old and the other 3 years of age, either of whom may have possibly ingested Lymetel sodium. The maximum amount of Lymetel sodium that could have been ingested was 80 mg (4 x 20 mg capsules). Vomiting was induced by ipecac in both children and no capsules were noted in their emesis. Neither child experienced any adverse symptoms and both recovered from the incident without problems.

In the postmarketing experience there have been reports of accidental ingestion of Lymetel tablets in infants up to 3 years of age. In one case, increased serum CPK values were noted. There have been reports of intentional overdose in adolescents with the development of hepatic enzyme elevations, convulsions and gastroenteritis/vomiting/diarrhea.

11 DESCRIPTION

Lymetel sodium is a water-soluble cholesterol lowering agent which acts through the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase.

Lymetel sodium is [R*,S*-(E)]-(±)-7-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoic acid, monosodium salt. Its structural formula is:

Outcome data for the Lymetel Capsules 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 Lymetel 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).

In the Lipoprotein and Coronary Atherosclerosis Study (LCAS), the effect of Lymetel 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 Lymetel capsules, 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, fluvasatin 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 Lymetel patients versus 22% of all placebo patients). A significant difference in favor of Lymetel capsules was found between all Lymetel 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 1. Primary Endpoint - Recurrent Cardiac Events (Cardiac Death, Nonfatal MI or Revascularization Procedure) (ITT Population) Figure 2. Lymetel Capsules INtervention Prevention Study - Primary and SEcondary Endpoints Figure 3. Change in Minimum Lumen Diameter (mm) Figure 4. Change in % Diameter Stenosis

15 REFERENCES

  • National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics. 89(3):495-501.1992.
  • Manson, J.M., Freyssinges, C., Ducrocq, M.B., Stephenson, W.P., Postmarketing Surveillance of Lovastatin and Simvastatin Exposure During Pregnancy, Reproductive Toxicology, 10(6): 439-446, 1996.

16 HOW SUPPLIED/STORAGE AND HANDLING

Lymetel capsules USP are available as follows:

20 mg - hard gelatin capsules with ivory opaque body and pink opaque cap, filled with an off-white to yellowish powder with small agglomerates, cap imprinted with “TEVA” and body imprinted with “7442”, in bottles of 30 (NDC 0093-7442-56) and 100 (NDC 0093-7442-01).

40 mg - hard gelatin capsules with yellow opaque body and pink opaque cap, filled with an off-white to yellowish powder with small agglomerates, cap imprinted with “TEVA” and body imprinted with “7443”, in bottles of 30 (NDC 0093-7443-56) and 100 (NDC 0093-7443-01).

Store and Dispense

Store at 20° to 25°C (68° to 77°F).

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). Protect from light.

17 PATIENT COUNSELING INFORMATION

Information for Patients

Patients taking Lymetel capsules should be advised that high cholesterol is a chronic condition and they should adhere to their medication along with their National Cholesterol Education Program -recommended diet, a regular exercise program, and periodic testing of a fasting lipid panel to determine goal attainment.

Patients should be advised about substances they should not take concomitantly with Lymetel capsules [see Warnings and Precautions (5.1)]. Patients should also be advised to inform other healthcare professionals prescribing a new medication that they are taking Lymetel capsules.

17.1 Muscle Pain

Patients starting therapy with Lymetel capsules should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing Lymetel.

17.2 Liver Enzymes

It is recommended that liver enzyme tests be performed before the initiation of Lymetel capsules and if signs or symptoms of liver injury occur. All patients treated with Lymetel capsules should be advised to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice.

17.3 Pregnancy

Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using Lymetel capsules. Discuss future pregnancy plans with your patients, and discuss when to stop taking Lymetel capsules if they are trying to conceive. Patients should be advised that if they become pregnant they should stop taking Lymetel capsules and call their healthcare professional.

17.4 Breastfeeding

Women who are breastfeeding should not use Lymetel capsules. Patients who have a lipid disorder and are breastfeeding should be advised to discuss the options with their healthcare professional.

Manufactured In Israel By:

Teva Pharmaceutical Ind. Ltd.

Jerusalem, 9777402, Israel

Manufactured For:

Teva Pharmaceuticals USA, Inc.

North Wales, PA 19454

Rev. E 8/2017

FDA-Approved Patient Labeling

Lymetel (floo'' va stat' in) Capsules USP

20 mg, 40 mg

You must read and follow all instructions before using Lymetel capsules.

Read the Patient Information every time you or a family member gets Lymetel capsules. There may be new information. This Patient Information does not take the place of talking with your doctor about your medical condition or treatment. If you have any questions about Lymetel capsules, ask your doctor or pharmacist.

What are Lymetel capsules?

Lymetel capsules are a prescription medicine called "statins" that lower cholesterol in your blood. They lower the "bad" cholesterol and triglycerides in your blood. They can raise your "good" cholesterol as well.

Lymetel capsules are for people whose cholesterol does not come down enough with exercise and a low-fat diet alone.

Lymetel capsules may be used in patients with heart disease (coronary artery disease) to:

  • lower the chances of heart problems which would require procedures to help restore blood flow to the heart.
  • slow the buildup of too much cholesterol in the arteries of the heart.

Treatment with Lymetel capsules has not been shown to prevent heart attacks or stroke.

Lymetel capsules are taken one or two times a day.

Who should not take Lymetel capsules?

Do not take Lymetel capsules if you:

  • are pregnant or think you may be pregnant, or are planning to become pregnant. Lymetel capsules may harm your unborn baby. If you get pregnant, stop taking Lymetel capsules and call your doctor right away.
  • are breast-feeding. Lymetel sodium can pass into your breast milk and may harm your baby
  • have liver problems
  • are allergic to Lymetel capsules or any of their ingredients. The active ingredient in Lymetel capsules is Lymetel. See the end of this leaflet for a complete list of ingredients in Lymetel capsules.

Lymetel capsules have not been studied in children under 9 years of age.

Before taking Lymetel capsules, tell your doctor if you:

  • have muscle aches or weakness
  • drink more than 2 glasses of alcohol daily
  • have diabetes
  • have a thyroid problem
  • have kidney problems

Some medicines should not be taken with Lymetel capsules. Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Lymetel capsules and certain other medicines can interact causing serious side effects. Especially tell your doctor if you take medicines for:

  • your immune system
  • cholesterol
  • infections
  • heart failure
  • seizures
  • diabetes
  • heartburn or stomach ulcers

Know all the medicines you take. Keep a list of all the medicines you take with you to show your doctor and pharmacist.

How should I take Lymetel capsules?

  • Your doctor will prescribe the medicine that is right for you. Take Lymetel capsules exactly as prescribed. Do not change your dose or stop Lymetel capsules without talking to your doctor. Your doctor may do blood tests to check your cholesterol levels during treatment with Lymetel capsules. Your dose of Lymetel capsules may be changed based on these blood test results.
  • Take Lymetel capsules at the same time every evening. When Lymetel capsules are taken twice daily, the capsules may be taken once in the morning and once in the evening. Lymetel capsules can be taken with or without food.
  • Do not open Lymetel capsules.
  • Your doctor should start you on a low-fat and low-cholesterol diet before giving you Lymetel capsules. Stay on this low-fat and low-cholesterol diet while taking Lymetel capsules.
  • If you miss a dose of Lymetel capsules, take it as soon as you remember. Do not take Lymetel capsules if it has been more than 12 hours since your last dose. Wait and take the next dose at your regular time. Do not take 2 doses of Lymetel capsules at the same time.
  • If you take too many Lymetel capsules or overdose, call your doctor or Poison Control Center right away. Or, go to the nearest emergency room.

What should I avoid while taking Lymetel capsules?

  • Talk to your doctor before you start any new medicines. This includes prescription and nonprescription medicines, vitamins and herbal supplements. Lymetel capsules and certain other medicines can interact causing serious side effects.
  • Do not get pregnant. If you get pregnant, stop taking Lymetel capsules right away and call your doctor.

What are the possible side effects of Lymetel capsules?

When taking Lymetel capsules, some patients may develop serious side effects, including:

muscle problems. Call your health care professional right away if you experience unexplained muscle pain, tenderness, or weakness especially with fever. This may be an early sign of a rare muscle problem that could lead to serious kidney problems.

The risk of muscle problems is greater in people who are 65 years of age or older, or who already have thyroid or kidney problems. The chance of muscle problems may be increased if you are taking certain other medicines with Lymetel capsules.

If you have muscle problems that do not go away even after your health care professional has advised you to stop taking Lymetel capsules, notify your health care professional. Your health care professional may do further tests to diagnose the cause of your muscle problems.

liver problems. Your doctor should do blood tests to check your liver before you start taking Lymetel capsules, and if you have symptoms of liver problems while you take Lymetel capsules. Call your doctor right away if you have the following symptoms of liver problems:

  • feel tired or weak
  • loss of appetite
  • upper belly pain
  • dark amber colored urine
  • yellowing of your skin or the whites of your eyes

The most common side effects of Lymetel capsules are headache, upset stomach and stomach pain, diarrhea, flu-like symptoms, muscle pain, sinus infection, tiredness, or trouble sleeping. These side effects are usually mild and may go away. The following additional side effects have been reported with Lymetel capsules: memory loss, and confusion.

Talk to your doctor or pharmacist if you have side effects that bother you or that will not go away.

These are not all the side effects of Lymetel capsules. Ask your doctor or pharmacist for a complete list.

How should I store Lymetel capsules?

  • Store Lymetel capsules at room temperature, 20° to 25°C (68° to 77°F). Protect from light.
  • Do not keep medicine that is out of date or that you no longer need.
  • Keep Lymetel capsules out of the reach of children. Be sure that if you throw medicines away, they are out of the reach of children.

General information about Lymetel capsules

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use Lymetel capsules for a condition for which they were not prescribed. Do not give Lymetel capsules to other people, even if they have the same problem you have; they may harm them.

For more information, call 1-888-838-2872, MEDICAL AFFAIRS.

What are the ingredients in Lymetel capsules USP?

Active Ingredient: Lymetel sodium (hydrated form)

Inactive Ingredients: black iron oxide, colloidal silicon dioxide, crospovidone, gelatin, lactose monohydrate, magnesium stearate, propylene glycol, red iron oxide, shellac, titanium dioxide, and yellow iron oxide. The imprinting ink may contain potassium hydroxide.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Manufactured In Israel By:

TEVA PHARMACEUTICAL IND. LTD.

Jerusalem, 9777402, Israel

Manufactured For:

TEVA PHARMACEUTICALS USA, INC.

North Wales, PA 19454

Rev. D 12/2015

NDC 0093-7442-01

Lymetel

Capsules USP

20 mg

PHARMACIST: PLEASE DISPENSE WITH

ATTACHED PATIENT INFORMATION

LEAFLET

Rx only

100 CAPSULES

TEVA

NDC 0093-7443-01

Lymetel

Capsules USP

40 mg

PHARMACIST: PLEASE DISPENSE

WITH ATTACHED PATIENT

INFORMATION LEAFLET

Rx only


100 CAPSULES

TEVA

Lymetel pharmaceutical active ingredients containing related brand and generic drugs:

infoActive ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Lymetel available forms, composition, doses:

infoForm of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Lymetel destination | category:

infoDestination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Lymetel Anatomical Therapeutic Chemical codes:

infoA medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Lymetel pharmaceutical companies:

infoPharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."LESCOL (FLUVASTATIN SODIUM) CAPSULE [PHYSICIANS TOTAL CARE, INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. "fluvastatin". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).
  3. "fluvastatin". http://www.drugbank.ca/drugs/DB0109... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Lymetel?

Depending on the reaction of the Lymetel after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Lymetel not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Lymetel addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sDrugs.com conducted a study on Lymetel, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Lymetel consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Arunabha Ray, MD Pharmacology

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