ALTOCOR™ (lovastatin extended-release tablets)
ALTOCOR™ (lovastatin extended-release tablets) Clinical Studies
In clinical studies with ALTOCOR™ (lovastatin extended-release tablets) , adverse reactions have generally been mild and transient. In controlled studies with 467 patients who received ALTOCOR™ (lovastatin extended-release tablets) , < 3% of patients were discontinued due to adverse experiences attributable to ALTOCOR (lovastatin extended-release tablets) ™ . This was similar to the discontinuation rate in the placebo and lovastatin immediate-release treatment groups. Pooled results from clinical studies with ALTOCOR™ (lovastatin extended-release tablets) show that the most frequently reported adverse reactions in the ALTOCOR™ (lovastatin extended-release tablets) group were infection, headache and accidental injury. Similar incidences of these adverse reactions were seen in the lovastatin and placebo groups. The most frequent adverse events thought to be related to ALTOCOR™ (lovastatin extended-release tablets) were nausea, abdominal pain, insomnia, dyspepsia, headache, asthenia, and myalgia. In controlled trials (e.g., vs. placebo and vs. lovastatin immediate-release), clinical adverse experiences reported as ≥ 5% in any treatment group are shown in Table VII below.
Table VII: Pooled Controlled Studies TESS by Body System and COSTART Term, Most Common ( ≥ 5% in Any Group)
|n =||Placebo 34||ALTOCOR™ 467||MEVACOR™ 329|
|Body System||COSTART Term|
|Body as a Whole||Infection||3 (9)||52 (11)||52 (16)|
|Accidental Injury||3 (9)||26 (6)||12 (4)|
|Asthenia||2 (6)||12 (3)||6 (2)|
|Headache||2 (6)||34 (7)||26 (8)|
|Back Pain||1 (3)||23 (5)||18 (5)|
|Flu Syndrome||1 (3)||24 (5)||18 (5)|
|Pain||0||14 (3)||17 (5)|
|Digestive||Diarrhea||2 (6)||15 (3)||8 (2)|
|Musculoskeletal||Arthralgia||2 (6)||24 (5)||20 (6)|
|Myalgia||5 (15)||14 (3)||11 (3)|
|Nervous||Dizziness||2 (6)||10 (2)||5 (2)|
|Respiratory||Sinusitis||1 (3)||17 (4)||20 (6)|
|Urogenital||Urinary Tract Infection||2 (6)||8 (2)||9 (3)|
Lovastatin Immediate-Release Phase III Clinical Studies
In Phase III controlled clinical studies involving 613 patients treated with lovastatin immediate-release, the adverse experience profile was similar to that shown below for the 8,245-patient EXCEL study [see Expanded Clinical Evaluation of Lovastatin (EXCEL) Study]. Persistent increases of serum transaminases have been noted (see WARNINGS, Liver Dysfunction). About 11% of patients had elevations of CK levels of at least twice the normal value on one or more occasions. The corresponding values for the control agent cholestyramine was 9 %. This was attributable to the noncardiac fraction of CK. Large increases in CK have sometimes been reported (see WARNINGS, Myopathy/Rhabdomyolysis).
Expanded Clinical Evaluation of Lovastatin (EXCEL) Study
Lovastatin immediate-release was compared to placebo in 8,245 patients with hypercholesterolemia [Total-C 240-300 mg/dL (6.2-7.8 mmol/L)] in the randomized, double-blind, parallel, 48-week EXCEL study. Clinical adverse experiences reported as possibly, probably or definitely drug-related in ≥ 1% in any treatment group are shown in the table below. For no event was the incidence on drug and placebo statistically different.
Table VIII: Clinical Adverse Events Reported as Possibly, Probably or Definitely Drug-Related in ≥ 1% in Any Treatment Group in the EXCEL Study
| Lovastatin IR
20 mg q.p.m.
| Lovastatin IR
40 mg q.p.m.
| Lovastatin IR
20 mg b.i.d.
| Lovastatin IR
40 mg b.i.d.
|Body As a Whole|
Other clinical adverse experiences reported as possibly, probably or definitely drug-related in 0.5% to 1.0% of patients in any drug-treated group are listed below. In all these cases the incidence on drug and placebo was not statistically different. Body as a Whole: chest pain; Gastrointestinal: acid regurgitation, dry mouth, vomiting; Musculoskeletal: leg pain, shoulder pain, arthralgia; Nervous System/Psychiatric: insomnia, paresthesia; Skin: alopecia, pruritus; Special Senses: eye irritation.
In the EXCEL study (see CLINICAL PHARMACOLOGY, Clinical Studies), 4.6% of the patients treated up to 48 weeks were discontinued due to clinical or laboratory adverse experiences which were rated by the investigator as possibly, probably or definitely related to therapy with lovastatin immediate-release. The value for the placebo group was 2.5%.
Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)
In AFCAPS/TexCAPS (see CLINICAL PHARMACOLOGY, Clinical Studies) involving 6,605 participants treated with 20-40 mg/day of lovastatin immediate-release (n=3,304) or placebo (n=3,301), the safety and tolerability profile of the group treated with lovastatin immediate-release was comparable to that of the group treated with placebo during a median of 5.1 years of follow-up. The adverse experiences reported in
AFCAPS/TexCAPS were similar to those reported in EXCEL [see ADVERSE REACTIONS, Expanded Clinical Evaluation of Lovastatin (EXCEL) Study].
In controlled clinical studies in which lovastatin immediate-release was administered concomitantly with cholestyramine, no adverse reactions peculiar to this concomitant treatment were observed. The adverse reactions that occurred were limited to those reported previously with lovastatin or cholestyramine. Other lipid-lowering agents were not administered concomitantly with lovastatin during controlled clinical studies. Preliminary data suggests that the addition of gemfibrozil to therapy with lovastatin is not associated with greater reduction in LDL-C than that achieved with lovastatin alone. In uncontrolled clinical studies, most of the patients who have developed myopathy were receiving concomitant therapy with cyclosporine, gemfibrozil or niacin (nicotinic acid) (see WARNINGS, Myopathy/Rhabdomyolysis)
The following effects have been reported with drugs in this class. Not all the effects listed below have necessarily been associated with lovastatin therapy.
Skeletal: muscle cramps, myalgia, myopathy, rhabdomyolysis, arthralgias.
Neurological: dysfunction of certain cranial nerves (including alteration of taste, impairment of extra-ocular movement, facial paresis), tremor, dizziness, vertigo, memory loss, paresthesia, peripheral neuropathy, peripheral nerve palsy, psychic disturbances, anxiety, insomnia, depression.
Hypersensitivity Reactions: An apparent hypersensitivity syndrome has been reported rarely which has included one or more of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, 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; and rarely, cirrhosis, fulminant hepatic necrosis, and hepatoma; anorexia, vomiting.
Skin: alopecia, pruritus. A variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails) have been reported.
Reproductive: gynecomastia, loss of libido, erectile dysfunction.
Eye: progression of cataracts (lens opacities), ophthalmoplegia.
Laboratory Abnormalities: elevated transaminases, alkaline phosphatase, y-glutamyl transpeptidase, and bilirubin; thyroid function abnormalities.