David Leonardi, M.D. ABAAM, CNS

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Statin Side Effects

Overview  of Statin Side Effects
David Leonardi, M.D., ABAAM, CNS

All drugs produce some side effects and statins are no exception. Fortunately, side effects occur in only a small minority of people taking medications and they are most often minor and manageable. I recommend you use this article only as a reference and not dwell on it. It is very easy to get bogged down reading about possible side effects that are very unusual and likely don’t apply to you. Your time will be better spent on my articles that address specific side effects that you already feel you’re experiencing. Below are the most common side effects for all statins combined, and further below, a list for each statin and the frequency of occurrence.

  • Headache
  • Difficulty sleeping
  • Flushing of the skin
  • Muscle aches, tenderness, or weakness (myalgia or myopathy)
  • Drowsiness
  • Dizziness
  • Nausea and/or vomiting
  • Abdominal cramping and/or pain
  • Bloating and/or gas
  • Diarrhea
  • Constipation
  • Rash
  • A very unusual but far more serious side effect is rhabdomyolysis, or severe muscle damage. This is life threatening because muscle cells spill their contents into the blood. The release of myoglobin from muscle can cause acute renal failure and death if not treated promptly. That’s why you should report any new muscle pain to your doctor immediately if you’re taking a statin so he can examine you and perform a blood test for possible rhabdomyolysis.

Below are the most common reported adverse reactions on individual statins, accumulated from the Physician’s Desk Reference® , company official prescribing information and clinical trial data.

Lipitor® (atorvastatin)

The following table was adapted from the Lipitor clinical trial database table of adverse reactions as published by Pfizer® in the physician prescribing information. Included here are only those reactions that differed the most from placebo.

Reaction Drug % Placebo %
Diarrhea 6.8 6.3
Myalgia 3.5 3.1
Arthralgia 6.9 6.5
Dyspepsia 4.7 4.3
Nausea 4.0 3.5
Muscle spasm 3.6 3.0

Zocor® (simvastatin)

The following table was adapted from the Zocor 4S (Scandinavian Simvastatin Survival Study) clinical trial database table of adverse reactions as published by Merck® in the physician prescribing information. Included here are only those reactions that differed the most from placebo.

Reaction Drug % Placebo %
Edema or swelling 2.7 2.3
Atrial Fibrillation 5.7 5.1
Constipation 2.2 1.6
Gastritis 4.9 3.9
Diabetes 4.2 3.6
Myalgia 3.7 3.2
Headache 2.5 2.1
Vertigo 4.5 4.2
Insomnia 3.8 4.0
Bronchitis 6.6 6.3
Sinusitis 1.8 2.3
Eczema 4.5 3.0

Crestor® (rosuvastatin)

The following table was adapted from the Astra Zeneca premarketing  clinical trial table of adverse reactions as published by Astra Zeneca in the physician prescribing information. Included here are only those reactions that differed the most from placebo. This report is for all doses (5 mg to 40 mg combined).

Reaction Drug % Placebo %
Nausea 3.4 3.1
Myalgia 2.8 1.3
Headache 5.5 5.0

Crestor® (rosuvastatin)

The following table was adapted from the METEOR clinical trial table of adverse reactions as published by Astra Zeneca in the physician prescribing information. Included here are only those reactions that differed the most from placebo. This report is for only the highest dose of rosuvastatin (40 mg).

Reaction Drug % Placebo %
Arthralgia (joint pain) 10.1 7.1
Abdominal Pain 2.4 1.8
Myalgia 12.7 12.1
Headache 6.4 5.3
Increased CK (muscle enzyme) 2.6 0.7
Elevated ALT (liver enzyme) 2.2 0.7

Pravachol® (pravastatin)

The following table was adapted from the premarketing  clinical trial table of adverse reactions as published by Bristol-Myers Squibb® in the physician prescribing information. Included here are only those reactions that differed the most from placebo. This report is for all doses combined between 5 mg. and 40 mg.

Reaction Drug % Placebo %
Coronary chest pain 4.5 3.4
Rash 4.5 1.4
Nausea/vomiting 7.4 7.1
Diarrhea 6.7 5.6
Influenza 2.0 0.7
Myalgia 2.3 1.2
Headache 6.3 4.6
Cough 2.5 1.7
Increased CK (muscle enzyme) 4.1 3.6
Elevated ALT (liver enzyme) 2.9 1.2

Livalo® (pitavastatin)

The following is adapted from the Kiowa® Pharmaceuticals America, Inc. published prescribing information.Adverse reactions reported in 2%  or more of patients in controlled clinical studies and at a rate greater than or equal to placebo are shown in Table 1. These studies had treatment duration of up to 12 weeks.Table 1. Adverse Reactions* Reported by 2.0%  or more of Patients Treated with LIVALO and > Placebo in Short-Term Controlled Studies.

Reaction Placebo %
N=208
Livalo 1mg. (%) N=309 Livalo 2 mg. (%) N=951 Livalo 4 mg. (%) N=1540
Back Pain 2.9% 3.9% 1.8% 1.4%
Constipation 1.9% 3.6% 1.5% 2.2%
Diarrhea 1.9% 2.6% 1.5% 1.9%
Myalgia 1.4% 1.9% 2.8% 3.1%
Pain in extremity 1.9% 2.3% 0.6% 0.9%

* Adverse reactions by MedDRA preferred term.

Other adverse reactions reported from clinical studies were arthralgia, headache, influenza, and nasopharyngitis.The following laboratory abnormalities have also been reported: elevated creatine phosphokinase, transaminases, alkaline phosphatase, bilirubin, and glucose.
In controlled clinical studies and their open-label extensions, 3.9% (1 mg), 3.3% (2 mg), and 3.7% (4 mg) of pitavastatin-treated patients were discontinued due to adverse reactions. The most common adverse reactions that led to treatment discontinuation were:elevated creatine phosphokinase (0.6% on 4 mg) and myalgia (0.5% on 4 mg). Hypersensitivity reactions including rash, pruritus, and urticaria have been reported with LIVALO.

Mevacor® (lovastatin)

The following information on Mevacor was adapted from the Merck® prescribing information.

Expanded Clinical Evaluation of Lovastatin (EXCEL) Study

MEVACOR 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.

Placebo
(N = 1663)
%
MEVACOR
20 mg q.p.m.
(N = 1642)
%
MEVACOR
40 mg q.p.m.
(N = 1645)
%
MEVACOR
20 mg b.i.d.
(N = 1646)
%
MEVACOR
40 mg b.i.d.
(N = 1649)
%
Body As a Whole
Asthenia
1.4 1.7 1.4 1.5 1.2
Gastrointestinal
Abdominal pain
1.6 1.9 2.3 1.9 4.2
Constipation 2.5 2.0 2.0 2.6 1.3
Diarrhea 3.7 1.9 2.0 3.2 2.4
Dyspepsia 1.3 4.3 2.5 2.2 3.2
Flatulence 2.2 1.0 3.9 2.2 2.5
Nausea 3.5 2.6 1.6 4.5 2.2
Musculoskeletal
Muscle cramps
0.5 1.7 0.6 2.6 0.8
Myalgia 1.8 1.1 2.2 1.0 3.0
Nervous System/
Psychiatric
Dizziness
0.7 2.7 0.7 2.6 1.2
Headache 2.8 0.5 2.1 0.5 3.2
Skin
Rash
0.7 0.8 1.0 1.2 1.3
Special Senses
Blurred vision
0.8 1.1 0.9 0.9 1.2

 

Other clinical adverse experiences reported as possibly, probably or definitely drug-related in 0.5 to 1.0 percent 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 , 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 MEVACOR. The value for the placebo group was 2.5%.

Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)
In AFCAPS/TexCAPS involving 6,605 participants treated with 20-40 mg/day of MEVACOR (n=3,304) or placebo (n=3,301), the safety and tolerability profile of the group treated with MEVACOR 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.

Lescol® (fluvastatin)

The following information on Lescol® was adapted from the Novartis® prescribing information.

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%)

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
Arthritis
Arthropathy
5
2.1
NA
4.5
2.0
NA
3.8
1.3
3.2
Respiratory
Sinusitis
Bronchitis
2.6
1.8
1.9
1.0
3.5
2.6
Gastrointestinal
Dyspepsia
Diarrhea
Abdominal Pain
Nausea
Flatulence
Tooth Disorder
2.5
4.9
4.9
3.2
2.6
2.1
2.0
3.2
4.2
3.8
2.0
2.5
1.7
2.0
3.5
3.3
3.7
2.5
1.4
1.4
Psychiatric
Insomnia
2.7 1.4 0.8
Genitourinary
Urinary Tract Infection
1.6 1.1 2.7
Miscellaneous
Headache
Influenza-like symptoms
Accidental Trauma
Fatigue
8.95.15.1
2.7
7.85.74.8
1.3
4.77.14.2
1.6

1Controlled trials with LESCOL Capsules (20 and 40 mg daily and 40 mg twice daily) compared to placebo
2Controlled trials with LESCOL XL 80 mg Tablets as compared to LESCOL Capsules

 

© Copyright David Leonardi, M.D. All rights reserved. 2018