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 (including myositis) [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 Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience in Adult Patients Because clinical studies on LESCOL/LESCOL XL are conducted in varying study populations and study designs, the frequency of adverse reactions observed in the clinical studies of LESCOL/LESCOL XL 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 LESCOL placebo-controlled clinical trials database of 2326 patients treated with LESCOL1 (age range 18-75 years, 44% women, 94% Caucasians, 4% Blacks, 2% other ethnicities) with a median treatment duration of 24 weeks, 3.4% of patients on LESCOL 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%). In the LESCOL XL database of controlled clinical trials of 912 patients treated with LESCOL XL (age range 21-87 years, 52% women, 91% Caucasians, 4% Blacks, 5% other ethnicities) with a median treatment duration of 24 weeks, 3.9% of patients on LESCOL XL discontinued due to adverse reactions regardless of causality. The most common adverse reactions that led to treatment discontinuation were abdominal pain (0.7%), diarrhea (0.5%), nausea (0.4%), dyspepsia (0.4%) and chest pain (0.3%). Clinically relevant adverse experiences occurring in the LESCOL and LESCOL XL controlled studies with a frequency >2%, regardless of causality, included the following: Table 1 Clinical adverse events reported in >2% in patients treated with LESCOL/LESCOL XL and at an incidence greater than placebo in placebo-controlled trials regardless of causality (% of patients) Pooled Dosages LESCOL1 N=2326 (%) Placebo1 N=960 (%) LESCOL XL2 N=912 (%) Musculoskeletal Myalgia 5.0 4.5 3.8 Arthritis 2.1 2.0 1.3 Arthropathy NA NA 3.2 Respiratory Sinusitis 2.6 1.9 3.5 Bronchitis 1.8 1.0 2.6 Gastrointestinal Dyspepsia 7.9 3.2 3.5 Diarrhea 4.9 4.2 3.3 Abdominal pain 4.9 3.8 3.7 Nausea 3.2 2.0 2.5 Flatulence 2.6 2.5 1.4 Tooth disorder 2.1 1.7 1.4 Psychiatric Insomnia 2.7 1.4 0.8 Genitourinary Urinary tract infection 1.6 1.1 2.7 Miscellaneous Headache 8.9 7.8 4.7 Influenza-like symptoms 5.1 5.7 7.1 Accidental Trauma 5.1 4.8 4.2 Fatigue 2.7 2.3 1.6 Allergy 2.3 2.2 1.0 1 Controlled trials with LESCOL Capsules (20 and 40 mg daily and 40 mg twice daily) compared to placebo 2 Controlled trials with LESCOL XL 80 mg Tablets as compared to LESCOL Capsules LESCOL Intervention Prevention Study In the LESCOL Intervention Prevention Study (LIPS), the effect of LESCOL 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 LESCOL 40 mg (n=844) or placebo (n=833) given twice daily for a median of 3.9 years [see Clinical Studies (14.3)]. Table 2 Clinical adverse events reported in ≥ 2% in patients treated with LESCOL/LESCOL XL and at an incidence greater than placebo in the LIPS Trial regardless of causality (% of patients) LESCOL 40 mg twice daily 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 (9-16 years of age, 80% Caucasian, 19% Other [ mixed ethnicity], 1% Asians) were treated with fluvastatin sodium administered as LESCOL capsules 20 mg-40 mg twice daily, or LESCOL XL 80 mg extended-release tablet [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 fluvastatin sodium therapy. Musculos keletal: 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.