Summary Of Exposure |
A) USES: HMG-CoA reductase inhibitors are used in the treatment of hypercholesterolemia. The following agents are available in the United States: atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin. Atorvastatin, lovastatin, pravastatin, and simvastatin are also available in combination with other agents (atorvastatin/amlodipine; lovastatin/niacin; pravastatin/aspirin; simvastatin/ezetimibe; simvastatin/niacin; simvastatin/sitagliptin).
B) PHARMACOLOGY: HMG-CoA reductase inhibitors competitively inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase, preventing conversion of HMG-CoA to mevalonate, the rate determining enzyme for cholesterol synthesis.
C) EPIDEMIOLOGY: Exposure is common but overdose is rare.
D) WITH THERAPEUTIC USE
1) Nausea, flatulence, diarrhea, abdominal pain, myopathy, myalgias, rhabdomyolysis, elevated liver enzymes, hepatitis, dermatitis, diplopia, blepharoptosis (ptosis), ophthalmoplegia, tendinitis, and tendon rupture have been reported in patients receiving statins. Other reported adverse effects (rare) include hyperkalemia (lovastatin), photosensitivity (simvastatin), dermatomyositis (simvastatin and pravastatin), limb compartment syndrome (simvastatin and atorvastatin), acute renal failure (lovastatin), pancreatitis (pravastatin and lovastatin/gemfibrozil), chest pain (pravastatin), atrial fibrillation (simvastatin), vasculitis (atorvastatin), hemolytic anemia (lovastatin), thrombocytopenic purpura (atorvastatin), thrombotic thrombocytopenic purpura (simvastatin), akathisia (lovastatin), extrapyramidal effects (lovastatin), nasopharyngitis (atorvastatin), upper respiratory infection (pravastatin), cough (pravastatin), lung fibrosis (simvastatin), peripheral neuropathy (lovastatin and simvastatin).
E) WITH POISONING/EXPOSURE
1) MILD TO MODERATE TOXICITY: Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses. Ingestion of up to 6 grams of lovastatin has been reported without specific effects or sequelae.
2) SEVERE TOXICITY: Severe toxicity is not expected, unless a coingestant is present.
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Heent |
3.4.3) EYES
A) The formation of lens opacities has been postulated (Cenedella, 1987) as a result of blocking cholesterol biosynthesis in the lens. Lens opacities have been detected in clinical trials when baseline slit-lamp examinations are used for comparison. 1) In those patients with observed opacities, no loss of visual acuity has been reported. When the patients treated with lovastatin are compared as a group, there was no increase over baseline in opacity occurrence.
2) Slit-lamp examinations are recommended to monitor for this effect in patients receiving lovastatin on a chronic basis (Hunninghake et al, 1987).
B) The role of lovastatin in causing cataract formation is unclear; there is insufficient evidence to implicate the drug as a cause of lenticular opacities in humans (Hunninghake et al, 1988; Newell, 1989). 1) However, the manufacturer recommends slit-lamp examination as a precaution, before or shortly after starting treatment with lovastatin, and annually thereafter.
2) Part of the reason for this concern arises from the fact that triparanol, an unrelated late-stage cholesterol synthesis inhibitor, was withdrawn from the market in 1962 because of significant cataract formation (Fraunfelder, 1988; Kirby, 1967).
C) Spontaneous adverse event reports obtained from the databases of National Registry of Drug-Induced Ocular Side Effects, the World Health Organization (WHO), and the Food and Drug Administration (FDA) associated 256 case reports of diplopia, blepharoptosis (ptosis), and ophthalmoplegia with the use of statins from the time of the first statin (lovastatin) approval at the end of 1987 to the time of this report in 2008. During the 20 year period, there were 39 reports associated with lovastatin, 46 with pravastatin (year approved, 1991), 73 with simvastatin (year approved, 1991), 8 with fluvastatin (year approved, 1993), 68 with atorvastatin (year approved, 1996), 17 with cerivastatin (year approved, 1997; year withdrawn, 2001) and 5 with rosuvastatin (year approved, 2003). Simvastatin and atorvastatin have more adverse event reports because they were more frequently prescribed than fluvastatin or the now-discontinued cerivastatin. The median age was 69 years (range, 34 years to 89 years), which included 143 men, 91 women, and 22 gender not specified. The average dose was within the range recommended in the package insert for each different statin. A total of 108 patients were taking no other medications except the statin; the other 148 patients were taking concurrent medications that included high blood pressure medications such as beta-blockers, diuretics and calcium-channel blockers. Seven of these patients were taking a second statin and 5 were taking gemfibrozil. Women frequently were taking estrogen replacement therapy, and many patients took an aspirin daily. Nine patients had diabetes mellitus and 91 patients had hypertension. The median time from the start of statin therapy to the appearance of the adverse events was 3.5 months (range from 1 day to 84 months) according to the 113 cases where the duration of therapy was reported. There were 62 positive dechallenge and 14 positive rechallenge case reports. The authors concluded from the 62 positive dechallenge case reports that it appeared the statin-associated ocular side effects of diplopia, ptosis and ophthalmoplegia were completely reversible after the statin drug was discontinued (Fraunfelder & Richards, 2008). D) A 60-year-old woman complained of painless horizontal diplopia, vertigo, blurry vision, and paresthesias of both upper extremities 2.5 months after starting atorvastatin 10 milligrams per day. Neurological abnormalities included generalized hyperreflexia, finger-nose ataxia, and gait ataxia; anti- acetylcholine receptor (anti-AchR) antibodies were 10 times the upper limit of normal range. Patient's neurological condition improved within 2 days after the discontinuation of atorvastatin, and had complete resolution of gait instability, paresthesias, ptosis, and diplopia in primary gaze at 10 weeks. Extraocular motility was also improved and anti-AchR antibody level returned to normal. Atorvastatin was suspected to cause the external ophthalmoplegia after all other illnesses known to be associated with a false-positive anti-AchR level and ophthalmoplegia had been ruled out (Negvesky et al, 2000). E) Unilateral, upper eyelid swelling and ptosis developed in 43-year-old man after 2 years of atorvastatin 10 mg/day for hypercholesterolemia. Ocular and neurologic examinations were normal. Other medications included aspirin and folic acid. Myositis was suggested on an orbital MRI. Blepharoptosis completely resolved within 4 days of stopping atorvastatin. At a 10-month follow-up, blepharoptosis did not recur (Ertas et al, 2006). |
Cardiovascular |
3.5.2) CLINICAL EFFECTS
A) VASCULITIS 1) WITH THERAPEUTIC USE a) ATORVASTATIN: A 45-year-old man with a history of hypercholesterolemia developed antineutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis after previous (2 months prior to presentation) treatment with atorvastatin 10 mg daily for 6 months. The patient presented to the hospital with a 6-week history of pain and stiffness involving his bilateral legs, which later progressed to involve his forearms. Tenderness was noted in both calves, and the patient was unable to bear weight. The patient also reported numbness in the left toe which later spread to involve his arms, and tinnitus and hearing loss in his left ear. No respiratory, gastrointestinal, or urinary symptoms were noted. Laboratory tests revealed elevated inflammatory markers with a C-reactive protein (CRP) of 198 mg/mL and a positive ANCA titer of 1:160. Viral serology as well as antinuclear antibody and rheumatoid factor testing were negative. Myopathic features in the anterior and posterior compartments of both legs, without myopathic features in the upper limbs, were noted on electromyography. The patient was diagnosed with drug-induced ANCA-associated vasculitis (based on the findings of mononeuritis multiplex, sensorineural hearing loss, and markedly elevated anti-myeloperoxidase (MPO) ANCA levels) and statin-induced distal myopathy. Corticosteroids (three 500 mg doses of methylprednisolone, followed by tapering dose of oral corticosteroids from 30 mg once daily) along with azathioprine 2.5 mg/kg were initiated. The patient responded well with improvement in myalgia, hearing loss, and sensory symptoms, and later went into complete remission. Within 6 weeks, his inflammatory markers had returned to normal and MPO-ANCA normalized within 3 months of initiating immunosuppressive therapy. At follow-up, the patient was being maintained on a tapering regimen of corticosteroids (7 mg daily) and azathioprine (Haroon & Devlin, 2008).
B) CHEST PAIN 1) WITH THERAPEUTIC USE a) PRAVASTATIN 1) Pooled adverse events data from 7 long-term, placebo-controlled clinical trials reported chest pain in 10% of patients receiving pravastatin 40 mg daily (n=10,764) compared with 9.8% of patients receiving placebo (n=10,719) (Prod Info PRAVACHOL(R) oral tablets, 2011).
2) In short-term, placebo-controlled clinical trials of up to 8 months duration, chest pain occurred in 4%, 1.3%, 3.3%, and 1.2% of patients receiving pravastatin 5 (n=100), 10 (n=153), 20 (n=478), or 40 mg (n=171), respectively, compared with 1.9% of patients receiving placebo (n=411) (Prod Info PRAVACHOL(R) oral tablets, 2011).
C) ATRIAL FIBRILLATION 1) WITH THERAPEUTIC USE a) SIMVASTATIN 1) During a randomized, double-blind, controlled clinical trial involving 4444 patients with CHD (age range 35 to 71 years), atrial fibrillation was reported regardless of causality in 5.7% of patients receiving simvastatin 20 to 40 mg/day (n=2221) compared with 5.1% of patients receiving placebo (n=2223) over a median of 5.4 years (Prod Info ZOCOR(R) oral tablets, 2010).
2) Based on a temporal relationship, simvastatin was suspected of causing atrial fibrillation in a 61-year-old man with a history of hypertension and hyperlipidemia. The patient was taking amlodipine 5 mg and lisinopril 5 mg, both once daily. An ECG made prior to initiation of simvastatin showed no abnormalities, with the exception of left atrial overloading with the diphasic P wave showing a wide negative component in the V1 lead. Heart rate was regular at 83 beats/min. Simvastatin 5 mg once daily was started. Two weeks later, the patient experienced palpitations (not related to exertion), which persisted over the next 2 days. An ECG showed paroxysmal atrial fibrillation/flutter; it continued even after administration of verapamil 5 mg intravenously. Simvastatin was withdrawn while amlodipine and lisinopril were continued. Three days later, the patient converted to sinus rhythm. Over 19 months of follow-up, sinus rhythm was maintained, with no complaints of palpitations (Akahane et al, 2003).
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Respiratory |
3.6.2) CLINICAL EFFECTS
A) FIBROSIS OF LUNG 1) WITH THERAPEUTIC USE a) SIMVASTATIN 1) CASE REPORT: A 76-year-old woman died 12 weeks after presenting with an erythematous rash, proximal limb weakness, and dyspnea on exertion. The patient had been receiving simvastatin, 10 mg daily, for 18 months. An autopsy revealed interstitial pulmonary fibrosis with smaller areas consistent with aspiration pneumonia and bronchiolitis obliterans-organizing pneumonia (Hill et al, 1995).
2) CASE REPORT: A 61-year-old male presented with dyspnea at rest and a respiratory rate of over 40 breaths/minute. Subsequent x-ray examination showed an interstitial lung disease and pleural effusion. Six months earlier, he had simvastatin started, 10 mg/day, and was already taking isosorbide dinitrate, phenprocoumon and diltiazem for several years. Several days after stopping simvastatin, biopsies of lung tissues revealed diffuse fibrosis of the alveolar septa. His condition improved significantly within a few days of starting prednisone therapy (de Groot et al, 1996).
B) NASOPHARYNGITIS 1) WITH THERAPEUTIC USE a) ATORVASTATIN: In a clinical database consisting of 17 placebo controlled trials with a median atorvastatin treatment duration of 53 weeks and patients ranging in age from 10 to 93 years, the incidence of nasopharyngitis was reported as 8.3% with any atorvastatin dose (n=8755). Specifically, incidences for nasopharyngitis were reported as 12.9% with the 10 mg/day dose, 5.3% at 20 mg/day, 7% at 40 mg/day, and 4.2% at 80 mg/day compared with 8.2% for placebo (n=7311) (Prod Info LIPITOR(R) oral tablets, 2009).
C) BILATERAL PLEURAL EFFUSION 1) WITH THERAPEUTIC USE a) PRAVASTATIN: In a case report, a nonsmoking 60-year-old man presented with bilateral pleural effusions following approximately 1 year of treatment with pravastatin 40 mg/day. The patient had no history of allergy or any deleterious exposure to the respiratory tract. His symptoms of several day's duration included persistent bilateral pleuritic chest pain and mild dyspnea, but no systemic symptoms or extrathoracic abnormalities. Small bilateral pleural effusions were discovered via radiography and a subsequent CT scan elucidated effusions and bilateral pleural thickening, but no intravascular clot. The only significant blood finding was an elevated C-reactive protein of 13.6 mg/L (upper limit less than 6 mg/L). Fibrotic and nonspecific inflammatory changes of the thickened pleura was demonstrated by a fine needle biopsy. Approximately one month following presentation, when pleural effusions persisted, pravastatin therapy was discontinued. Three months following discontinuation of therapy the patient had resolution of symptoms, normative C-reactive protein levels, no evidence of pleural effusion and some residual pleural thickening. Six months later the patient was still asymptomatic with no reaccumulation of the pleural effusion (Kalomenidis et al, 2007).
D) UPPER RESPIRATORY INFECTION 1) WITH THERAPEUTIC USE a) PRAVASTATIN 1) In short-term, placebo-controlled clinical trials of up to 8 months duration, upper respiratory infection occurred in 6%, 9.8%, 5.2%, and 4.1% of patients receiving pravastatin 5 (n=100), 10 (n=153), 20 (n=478), or 40 mg (n=171), respectively, compared with 5.8% of patients receiving placebo (n=411) (Prod Info PRAVACHOL(R) oral tablets, 2011).
2) Pooled adverse events data from 7 long-term, placebo-controlled clinical trials reported upper respiratory tract infection in 21.2% of patients receiving pravastatin 40 mg daily (n=10,764) compared with 20.2% of patients receiving placebo (n=10,719) (Prod Info PRAVACHOL(R) oral tablets, 2011).
E) COUGH 1) WITH THERAPEUTIC USE a) PRAVASTATIN 1) In short-term, placebo-controlled clinical trials of up to 8 months duration, cough occurred in 4%, 1.3%, 3.1%, and 1.2% of patients receiving pravastatin 5 (n=100), 10 (n=153), 20 (n=478), or 40 mg (n=171), respectively, compared with 1.7% of patients receiving placebo (n=411) (Prod Info PRAVACHOL(R) oral tablets, 2011).
2) Pooled adverse events data from 7 long-term, placebo-controlled clinical trials reported cough in 8.2% of patients receiving pravastatin 40 mg daily (n=10,764) compared with 7.4% of patients receiving placebo (n=10,719) (Prod Info PRAVACHOL(R) oral tablets, 2011).
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Neurologic |
3.7.2) CLINICAL EFFECTS
A) SECONDARY PERIPHERAL NEUROPATHY 1) WITH THERAPEUTIC USE a) LOVASTATIN: A 47-year-old woman began lovastatin therapy, 20 mg daily, and 12 months later reported stocking and glove paresthesias. The symptoms resolved 8 weeks after lovastatin was discontinued. The patient then began pravastatin therapy, 20 mg daily, and 2 weeks later developed paresthesia involving her upper extremities to the elbows and lower extremities to the knees. Pravastatin was stopped and the paresthesias diminished over the next 4 weeks (Jacobs, 1994).
b) LOVASTATIN: A case series reported two cases of patients who were taking lovastatin for several months before developing numbness, tingling, and painful paresthesias of the arms and legs. Symptoms slowly resolved, in both patients, 6 weeks after discontinuing lovastatin treatment (Ahmad, 1995).
c) Peripheral neuropathy was reported in a single case by the manufacturer. Thirty other patients tested by visually evoked response, nerve conduction measurements, and electromyography showed no evidence of neurotoxic effects. A cause and effect relationship could not be established (Prod Info MEVACOR(R) oral tablets, 2009).
d) SIMVASTATIN: Four cases of peripheral neuropathy have been reported following therapy with simvastatin. Onset occurred soon after initiation of therapy in 2 patients and after 2 years in the other 2 patients. A mixed sensorimotor neuropathy was demonstrated by electrophysiological studies in all patients. Symptoms improved over several months following discontinuation of therapy (Phan et al, 1995).
B) AKATHISIA 1) WITH THERAPEUTIC USE a) LOVASTATIN 1) CASE SERIES: A case series reported that two patients experienced insomnia, increased anxiety, and irritability several weeks after beginning lovastatin therapy. All symptoms resolved 48 hours after discontinuation of the medication. It is likely that the increased anxiety and irritability were due to the insomnia associated with lovastatin use (Rosenson & Goranson, 1993).
2) CASE SERIES: Two children reported experiencing sleep disturbances after beginning lovastatin therapy. One child also experienced appetite loss. Symptoms resolved upon discontinuation of the medication (Sinzinger et al, 1994).
C) EXTRAPYRAMIDAL DISEASE 1) WITH THERAPEUTIC USE a) LOVASTATIN: The development of parkinsonism was induced in two patients following chronic lovastatin therapy (Muller et al, 1995). 1) CASE REPORT: The first patient, a 67-year-old man, developed abnormal gait, postural hypokinesia, and limb rigidity three months after initiating lovastatin therapy, 20 mg daily. The extrapyramidal effects completely disappeared 12 months after discontinuing the lovastatin.
2) CASE REPORT: The second patient, a 63-year-old woman, developed hypomania, hypophonia, bradykinesia, resting and postural tremors, and cervical rigidity two years after beginning lovastatin therapy, 20 mg daily. The Parkinson symptoms gradually disappeared after withdrawal of the medication.
D) HEADACHE 1) WITH THERAPEUTIC USE a) PITAVASTATIN: Headache has been reported in clinical studies of pitavastatin (Prod Info LIVALO oral film coated tablet, 2009; Saito et al, 2002).
b) FLUVASTATIN: Headache occurred in 8.9% of patients using fluvastatin 20 to 80 mg daily (n=2326) for an average of 16 months during placebo-controlled clinical trials, compared with 7.8% of placebo patients (n=960) and 4.7% of patients taking fluvastatin extended-release 80 mg daily (n=912) (Prod Info LESCOL(R) oral capsules, extended release tablets, 2006; Prod Info LESCOL(R) oral capsules, 2006).
3.7.3) ANIMAL EFFECTS
A) ANIMAL STUDIES 1) CNS EFFECTS a) DOGS: Focal hemorrhage and perivascular edema were observed in different regions of the central nervous system in dogs given lethal dosage levels of lovastatin (LDL concentrations were not detectable). 1) Degeneration of the optic tract in the central nervous system was also observed in dogs. This was not necessarily associated with regions of vascular damage (Prod Info MEVACOR(R) oral tablets, 2009). CNS vascular lesions, characterized by perivascular hemorrhage and edema and mononuclear cell infiltration of perivascular spaces, were seen in dogs treated with pravastatin (Prod Info PRAVACHOL(R) oral tablets, 2007).
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Gastrointestinal |
3.8.2) CLINICAL EFFECTS
A) GASTROINTESTINAL TRACT FINDING 1) WITH THERAPEUTIC USE a) The most common adverse effects reported were gastrointestinal, including nausea, flatulence and diarrhea (The Lovastatin Study Group II, 1986; Cilla et al, 1993; Bakker-Arkema et al, 1996).
b) In clinical trials, abdominal pain, constipation, and diarrhea were reported occasionally, usually less than 5% of patients (Prod Info LIVALO oral film coated tablet, 2009; Saito et al, 2002a; Saito et al, 2002; Noji et al, 2002).
B) DIARRHEA 1) WITH THERAPEUTIC USE a) ATORVASTATIN: In a clinical database consisting of 17 placebo controlled trials with a median atorvastatin treatment duration of 53 weeks and patients ranging in age from 10 to 93 years, the incidence of diarrhea was reported as 6.8% with any dose of atorvastatin (n=8755). Specifically, incidences for diarrhea were reported as 7.3% with the 10 mg/day dose, 6.4% at 20 mg/day, 14.1% at 40 mg/day, and 5.2% at 80 mg/day compared with 6.3% for placebo (n=7311) (Prod Info LIPITOR(R) oral tablets, 2009).
b) FLUVASTATIN: Diarrhea occurred in 4.9% of patients using fluvastatin 20 to 80 mg daily (n=2326) for an average of 16 months during placebo-controlled clinical trials, compared with 4.2% of placebo patients (n=960) and 3.3% of patients taking fluvastatin extended-release 80 mg daily (n=912) (Prod Info LESCOL(R) oral capsules, extended release tablets, 2006; Prod Info LESCOL(R) oral capsules, 2006).
c) PRAVASTATIN: In short-term, placebo-controlled clinical trials of up to 8 months duration, diarrhea occurred in 8%, 8.5%, 6.5%, and 4.7% of patients receiving pravastatin 5 (n=100), 10 (n=153), 20 (n=478), or 40 mg (n=171), respectively, compared with 5.6% of patients receiving placebo (n=411) (Prod Info PRAVACHOL(R) oral tablets, 2011).
C) NAUSEA 1) WITH THERAPEUTIC USE a) ATORVASTATIN: In a clinical database consisting of 17 placebo controlled trials with a median atorvastatin treatment duration of 53 weeks and patients ranging in age from 10 to 93 years, the incidence of nausea was reported as 4% with any atorvastatin dose (n=8755). Specifically, incidences for nausea were reported as 3.7% with the 10 mg/day dose, 3.7% at 20 mg/day, 7.1% at 40 mg/day, and 3.8% at 80 mg/day compared with 3.5% for placebo (n=7311) (Prod Info LIPITOR(R) oral tablets, 2009).
b) FLUVASTATIN: Nausea occurred in 3.2% of patients using fluvastatin 20 to 80 mg daily (n=2326) for an average of 16 months during placebo-controlled clinical trials, compared with 2% of placebo patients (n=960) and 2.5% of patients taking fluvastatin extended-release 80 mg daily (n=912) (Prod Info LESCOL(R) oral capsules, extended release tablets, 2006; Prod Info LESCOL(R) oral capsules, 2006).
c) PRAVASTATIN: In short-term, placebo-controlled clinical trials of up to 8 months duration, nausea/vomiting occurred in 4%, 5.9%, 10.5%, and 2.3% of patients receiving pravastatin 5 (n=100), 10 (n=153), 20 (n=478), or 40 mg (n=171), respectively, compared with 7.1% of patients receiving placebo (n=411) (Prod Info PRAVACHOL(R) oral tablets, 2011).
D) INDIGESTION 1) WITH THERAPEUTIC USE a) FLUVASTATIN: Dyspepsia occurred in 7.9% of patients using fluvastatin 20 to 80 mg daily (n=2326) for an average of 16 months during placebo-controlled clinical trials, compared with 3.2% of placebo patients (n=960) and 3.5% of patients taking fluvastatin extended-release 80 mg daily (n=912) (Prod Info LESCOL(R) oral capsules, extended release tablets, 2006; Prod Info LESCOL(R) oral capsules, 2006).
E) PANCREATITIS 1) WITH THERAPEUTIC USE a) GEMFIBROZIL-LOVASTATIN COMBINATION: Pancreatitis was reported in a 55-year-old woman who was receiving gemfibrozil-lovastatin combination therapy to treat hyperlipidemia. Eleven days after discontinuing the medications, the patient's pancreatic enzyme levels returned to normal (Abdul-Ghaffar & El-Sonbaty, 1995). b) PRAVASTATIN 1) Pancreatitis has been reported during postmarketing surveillance of pravastatin (Prod Info PRAVACHOL(R) oral tablets, 2011).
2) A 50-year-old woman developed pancreatitis 3 days after being started on pravastatin 10 mg daily for hypercholesterolemia. Concurrent medications included enalapril, hydrochlorothiazide, olanzapine, a combination of metformin and rosiglitazone, and a combination of acetaminophen and tramadol (as needed basis), all of which were discontinued upon hospitalization. Presenting symptoms were right upper quadrant abdominal pain, nausea, and vomiting for 1 day. Laboratory values and an abdominal CT scan confirmed pancreatitis. Other possible causes were eliminated using an abdominal ultrasound and MRI cholangiopancreatography. The patient developed respiratory distress while in the hospital, which resolved with supportive care, and was discharged 14 days after admission. All previous medications were restarted without incident during hospitalization, with the exception of pravastatin and hydrochlorothiazide. Rechallenge of the pravastatin was not attempted, but due to the strong association between onset of symptoms and start of therapy, and the resolution of symptoms upon discontinuation, pravastatin was considered the most likely cause for the pancreatitis (Tsigrelis & Pitchumoni, 2006).
3) A 56-year-old man developed acute pancreatitis after taking pravastatin 20 mg orally once daily for 6 months to treat hypercholesterolemia. The patient presented with a 2-day history of epigastric pain radiating to the back, nausea, and vomiting. Physical examination revealed diffuse abdominal tenderness and a distended abdomen with hypoactive bowel sounds. Serum amylase was elevated at 1,615 Units/L, but all other laboratory values were normal. The head of the pancreas was edematous and hypoechoic as shown by ultrasound. The patient was not taking any other medications, did not have a history of alcohol ingestion, and no abnormal findings were evident on magnetic resonance cholangiopancreatography. Pravastatin was discontinued and the patient was treated symptomatically. Serum amylase returned to normal after 3 days and the patient was discharged after 5 days. Five months later, the patient self-initiated pravastatin 40 mg daily and developed radiating epigastric pain within 3 days. Serum amylase was elevated at 2,334 units/L. Pravastatin was again discontinued, and he was discharged 6 days later (Anagnostopoulos et al, 2003).
3.8.3) ANIMAL EFFECTS
A) ANIMAL STUDIES 1) SKIN HYPERTROPHY a) In RODENTS, hyperplasia of the squamous epithelium of the nonglandular mucosa of the stomach (forestomach) was noted at high dosage levels of lovastatin. 1) Coadministration of mevalonate ameliorates this change in the stomach. This anatomical structure is unique to rodents. No similar effects were observed in other animal species (Prod Info MEVACOR(R) oral tablets, 2009).
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Hepatic |
3.9.2) CLINICAL EFFECTS
A) LIVER ENZYMES ABNORMAL 1) WITH THERAPEUTIC USE a) Elevated liver enzymes have been reported in several cases (de Groot et al, 1996; Yoshida & Levin, 1993).
b) LOVASTATIN: Alanine aminotransferase was noted to rise during lovastatin treatment. The highest reported value was 82 Units/liter (The Lovastatin Study Group II, 1986; The Lovastatin Study Group II, 1986).
c) LOVASTATIN: A 43-year-old man developed cholestasis, consisting of nausea and vomiting, right upper quadrant abdominal pain, and pale stools after 2 months of lovastatin therapy. The patient's aspartate aminotransferase and alkaline phosphatase levels increased to 184 and 190 Units/liter, respectively. Two weeks after discontinuing lovastatin therapy, the patient's alkaline phosphatase level decreased to 91 Units/liter (Yoshida & Levin, 1993).
d) ATORVASTATIN: Minor and sporadic elevations of liver enzymes developed during clinical trials with atorvastatin (Bakker-Arkema et al, 1996).
e) SIMVASTATIN: Aminotransaminases were severely elevated within 6 months of starting simvastatin in a 61-year-old male. Significant improvement of his liver function tests occurred a few days later following discontinuation of the drug (de Groot et al, 1996).
f) Elevated serum transaminases have been reported with pitavastatin use. In most cases, the elevations were transient and resolution or improvement was reported after continued therapy or after therapy was temporarily withheld . These changes were not dose-related (Prod Info LIVALO oral film coated tablet, 2009; Noji et al, 2002; Kajinami et al, 2000a; Saito et al, 2002a; Saito et al, 2002).
B) TOXIC HEPATITIS 1) WITH THERAPEUTIC USE a) LOVASTATIN: A 64-year-old man developed jaundice, increased serum bilirubin levels, and increased liver enzyme levels approximately 2 months after beginning lovastatin therapy, 40 mg daily. A liver biopsy showed mild fibrosis, edema, and centrilobular necrosis. Two months after withdrawal of lovastatin therapy, liver enzyme levels returned to normal (Grimbert et al, 1994).
b) LOVASTATIN: Hepatitis developed in a 50-year-old woman 7 months after initiation of lovastatin therapy. Serum liver enzyme levels were elevated and a physical examination of the patient showed slight enlargement of the liver with diffuse tenderness. Signs and symptoms gradually resolved after discontinuation of the lovastatin (Raveh et al, 1992).
c) ATORVASTATIN: Twelve weeks after switching to atorvastatin 30 mg/day from fenofibrate and simvastatin, a 70-year-old woman with primary hypercholesterolemia developed acute hepatitis. Her liver enzyme levels were elevated: aspartate aminotransferase 151 international units/L, alanine aminotransferase 230 international units/L, alkaline phosphatase 591 international units/L, and gamma-glutamyltransferase 650 international units/L. Percutaneous liver biopsy indicated chronic inflammation infiltrate of portal tracts with some eosinophils and piecemeal necrosis. Atorvastatin therapy was discontinued and 2 months later her liver enzyme levels returned to normal. She was then placed on simvastatin 20 mg daily and her liver enzyme levels remained normal at 5 months follow-up. Since there was not a cross-toxicity between the 2 drugs, the authors suggested that liver toxicity might not be a class drug effect (Nakad et al, 1999).
d) SIMVASTATIN OR ATORVASTATIN: Three patients (one woman and two men, 47 to 57 years of age) developed autoimmune hepatitis (AIH) after taking statins (simvastatin or atorvastatin) for 4 to 5 months. Positive titers of antinuclear antibodies, anti-smooth muscle antibodies (1/40 to 1/160) and hypergammaglobulinemia were observed in all 3 patients. Patients had features that met the criteria for AIH, according to the International Autoimmune Hepatitis Group scoring system. Liver biopsies revealed different stages of fibrosis and moderate-to-severe lobular hepatitis with prominent plasma cell infiltration, consistent with AIH. Initially, the woman developed hepatitis after taking fluvastatin for 12 weeks. The liver enzymes remained elevated for 4 months after discontinuation of fluvastatin. Approximately 3 years later, she developed elevated liver enzymes again after using simvastatin 20 milligrams (mg) for 4 months. The other two patients developed AIH after receiving atorvastatin 20 and 40 mg/day for 4 to 5 months. AIH persisted despite the discontinuation of atorvastatin. All 3 patients recovered after 3 months to 1 year of treatment with prednisone and azathioprine or mycophenolate. Three other cases of AIH were reported in patients after receiving atorvastatin or rosuvastatin. These patients also recovered following treatment with prednisone, prednisolone, mycophenolate or tacrolimus (Alla et al, 2006).
C) ACUTE HEPATIC FAILURE 1) WITH THERAPEUTIC USE a) ATORVASTATIN: A case of fatal hepatic failure was reported in an 83-year-old man who experienced loss of appetite, fatigue, discolored stools, and progressive, painless jaundice beginning 2 weeks after initiation of atorvastatin. The patient had a history of coronary artery disease, renal impairment, and chronic obstructive pulmonary disease; his medications included isosorbide dinitrate, acetylsalicylic acid, beclomethasone, formoterol, and oxazepam. After an endarterectomy, he started atorvastatin 20 mg once daily. Four weeks after the addition of atorvastatin, he was hospitalized. On admission, his liver enzymes were extremely elevated (alanine aminotransferase (ALT) 1401 units/L; aspartate aminotransferase (AST) 1312 units/L); atorvastatin was withdrawn. Liver biopsy revealed a florid cholestatic hepatitis with periportal inflammation and mixed cellular infiltration. The patient developed progressive encephalopathy, hepatorenal syndrome, and died 4 weeks after hospitalization (Perger et al, 2003).
3.9.3) ANIMAL EFFECTS
A) ANIMAL STUDIES 1) HEPATIC ENZYMES INCREASED a) In dogs, elevation of ALT was observed without signs of clinical disease or morphologic liver damage. Rabbits were uniquely sensitive to development of centrilobular necrosis leading to death at doses as low as 100 mg/kg/day.
2) HEPATIC FUNCTION ABNORMAL a) Studies in RATS demonstrated 2 distinct changes: profound induction of HMG-CoA reductase (especially in the liver) and eosinophilic or basophilic foci occurred (Prod Info MEVACOR(R) oral tablets, 2009).
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Genitourinary |
3.10.2) CLINICAL EFFECTS
A) ACUTE RENAL FAILURE SYNDROME 1) WITH THERAPEUTIC USE a) LOVASTATIN: Acute renal failure secondary to rhabdomyolysis has been reported in several patients taking lovastatin (Prod Info MEVACOR(R) oral tablets, 2009; East et al, 1988; Norman et al, 1988; Corpier et al, 1988; Ayanian et al, 1988; Fernandez Zatarain et al, 1994).
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Musculoskeletal |
3.15.2) CLINICAL EFFECTS
A) DRUG-INDUCED MYOPATHY 1) WITH THERAPEUTIC USE a) A few case reports include myositis, including of the eye (blepharoptosis and skin) (Walker et al, 2008; Ertas et al, 2006; Folzenlogen, 2001; Noel et al, 2001).
b) CASE REPORT: A case of severe myopathy and rhabdomyolysis was reported in a 52-year-old female taking concomitant simvastatin (40 mg/day) and gemfibrozil (1,200 mg/day). Her presenting CK level was 13,580 International Units/L and serum aldolase level was elevated at 45 Units/L. Seven days after stopping the 2 drugs, and given supportive care, the patient recovered and was discharged (Tal et al, 1997).
c) CASE REPORT - Unilateral, upper eyelid swelling and ptosis developed in 43-year-old man after 2 years of atorvastatin 10 mg/day for hypercholesterolemia. Ocular and neurologic examinations were normal. Myositis was suggested on an orbital MRI. Blepharoptosis completely resolved within 4 days of stopping atorvastatin. At a 10-month follow-up, blepharoptosis did not recur (Ertas et al, 2006).
d) CASE REPORT: Inflammatory myositis and polymyositis were diagnosed in a 76-year-old man receiving atorvastatin 20 mg/day (length of therapy not specified) for hypercholesterolemia. Other medications included 1 baby aspirin/day, atenolol 25 mg/day, vitamin E, and folic acid. His symptoms included decreased forearm and hand strength and diminished proximal muscle strength of the lower extremities. Laboratory findings included elevated creatine kinase (CK) and abnormally high hepatic transaminases; his anti-nuclear antibody test was positive. Biopsy of the quadriceps revealed areas of dense endomysial mononuclear infiltrate, muscle cell necrosis, and variation in fiber size. Atorvastatin was discontinued. Four weeks later, CK remained elevated. He began prednisone 60 mg/day and weekly oral methotrexate, which brought some normalization. Atorvastatin was re-introduced; however, muscle weakness (including dysphagia) re-appeared, and CK levels increased. Atorvastatin was stopped. With re-initiation of prednisone/methotrexate therapy, symptom resolution followed. Attempts to completely withdraw the immunosuppressants were unsuccessful, and, after 9 months, the patient was being maintained on prednisone 5 to 10 mg/day and weekly methotrexate 15 mg (Folzenlogen, 2001).
e) CASE REPORT: Atorvastatin induced dermatomyositis in a 44-year-old man under treatment for familial hypercholesterolemia. The patient had taken atorvastatin 10 mg/day for a year. He was hospitalized with progressive dysphagia, dysphonia, and severe asthenia. His symptoms included severe proximal muscle paresis, a facial heliotrope rash, necrotic skin lesions of the left ear, elevated serum creatine kinase, and a positive titer for antinuclear antibodies. Muscle biopsy revealed severe necrosis of segmental muscle fibers. Atorvastatin was withdrawn, and the clinical course improved rapidly and spontaneously. However, 9 months later, antinuclear antibodies remained elevated (Noel et al, 2001).
B) MUSCLE WEAKNESS 1) WITH THERAPEUTIC USE a) Severe proximal muscle weakness in upper and lower extremities has been described in patients given HMG-CoA reductase inhibitor therapy. The creatine phosphokinase was elevated in all cases. Histologic examinations of the skeletal muscle showed myopathic changes, such as atrophy and muscle fiber necrosis (Chucrallah et al, 1992; Schalke et al, 1992; Hill et al, 1995).
C) MUSCLE PAIN 1) WITH THERAPEUTIC USE a) ATORVASTATIN: In a clinical database consisting of 17 placebo controlled trials with a median atorvastatin treatment duration of 53 weeks and patients ranging in age from 10 to 93 years, the incidence of myalgia was reported as 3.5% with any atorvastatin dose (n=8755). Specifically, incidences for myalgia were reported as 3.6% with the 10 mg/day dose, 5.9% at 20 mg/day, 8.4% at 40 mg/day, 2.7% at 80 mg/day compared with 3.1% for placebo (n=7311) (Prod Info LIPITOR(R) oral tablets, 2009).
b) LOVASTATIN: A patient receiving 50 mg of lovastatin for 2 days developed mild muscle cramps of the calf and neck. Creatine phosphokinase was reported NOT to rise. The cramps persisted throughout the study period (Tobert et al, 1982).
c) Elevated creatine phosphokinase has been associated with myalgias (Prod Info MEVACOR(R) oral tablets, 2009).
d) CASE SERIES: A case series found no difference in peak creatine kinase rise or time until peak was reached, in a double-blind crossover study of 10 healthy subjects who took lovastatin 40 mg once daily for 30 days or placebo for 30 days. Each subject walked 3 km/hr downhill at a 14 degree incline for 1 hour to simulate excessive muscle exertion (Curry & Reust, 1989).
e) CASE SERIES: Rosenson (1993) reported that 3 of 4 patients, receiving combined gemfibrozil-lovastatin therapy, developed myalgias. Two of the patients experienced muscle aches and tenderness after the second agent was added. The symptoms resolved upon withdrawal of the medications (Rosenson, 1993).
f) PITAVASTATIN: In clinical trials, myalgia has been reported in patients receiving pitavastatin (Prod Info LIVALO oral film coated tablet, 2009).
D) BACKACHE 1) WITH THERAPEUTIC USE a) PITAVASTATIN: In clinical trials, back pain has been reported in patients receiving pitavastatin (Prod Info LIVALO oral film coated tablet, 2009).
E) JOINT PAIN 1) WITH THERAPEUTIC USE a) PITAVASTATIN: Arthralgia has been reported in clinical studies of pitavastatin (Prod Info LIVALO oral film coated tablet, 2009).
b) ATORVASTATIN: In a clinical database consisting of 17 placebo controlled trials with a median atorvastatin treatment duration of 53 weeks and patients ranging in age from 10 to 93 years, the incidence of arthralgia was reported as 6.9% with any atorvastatin dose (n=8755). Specifically, incidences for arthralgia were reported as 8.9% with the 10 mg/day dose, 11.7% at 20 mg/day, 10.6% at 40 mg/day, and 4.3% at 80 mg/day compared to 6.5% for placebo (n=7311) (Prod Info LIPITOR(R) oral tablets, 2009).
F) RHABDOMYOLYSIS 1) WITH THERAPEUTIC USE a) Myopathy and rhabdomyolysis were rare side effect of HMG-CoA reductase inhibitor monotherapy and appeared to be dose-related. The risk of development of rhabdomyolysis is considerably increased with concurrent administration of all CYP3A inhibitors, such as cyclosporine with simvastatin or lovastatin, or cerivastatin with gemfibrozil, or pravastatin with fibrates, or simvastatin with clarithromycin (Lee & Maddix, 2001; Hong & Sequeira, 2000; Bermingham et al, 2000; Wenisch et al, 2000; Prod Info PRAVACHOL(R) oral tablets, 2007) . b) Rhabdomyolysis, and subsequent development of acute renal failure, were reported in cardiac transplant patients and in hypertensive patients (Prod Info MEVACOR(R) oral tablets, 2009; East et al, 1988; Norman et al, 1988; Corpier et al, 1988; Goldman et al, 1989; Wallace & Mueller, 1992)(Zatarain, et al, 1994). Organ transplant patients taking cyclosporine and HMG-CoA reductase inhibitors appear to be more susceptible to the development of rhabdomyolysis. Time of onset of this reaction is usually about 2 months after initiation of therapy (Maltz et al, 1999). 1) Hepatic impairment due to concomitant cyclosporine therapy was thought to have predisposed some patients to elevated HMG-CoA reductase inhibitor levels (Corpier et al, 1988).
c) In August, 2001, Bayer Pharmaceutical Division announced a voluntary withdrawal of cerivastatin (Baycol(R)) from the market due to 31 reports of fatal rhabdomyolysis following cerivastatin therapy. Twelve of these reports involved concomitant use of gemfibrozil ((Anon, 2001)). d) Rhabdomyolysis, with subsequent renal impairment, has occurred in patients taking HMG-CoA enzyme inhibitors in combination with gemfibrozil, cholestyramine, niacin, cyclosporine, macrolide antibiotics and/or itraconazole (Grunden & Fisher, 1997; Tal et al, 1997) Abdul-Ghaffer & El-Sonbaty, 1995; (Lees & Lees, 1995; Chrysanthopoulos & Kounis, 1992; Kogan & Orenstein, 1990). e) CASE REPORT: Rhabdomyolysis occurred in a patient on low dose lovastatin. The patient was 79-years-old, non-immunocompromised, and receiving gemfibrozil. Renal and respiratory failure also developed (Kogan & Orenstein, 1990). f) CASE REPORT: A 68-year-old with multiple illnesses was given 40 mg of lovastatin per day. Rhabdomyolysis occurred after a 10-day course of erythromycin (Spach et al, 1991). g) CASE REPORT: A case of severe myopathy and rhabdomyolysis was reported in a 52-year-old female taking concomitant simvastatin (40 mg/day) and gemfibrozil (1,200 mg/day). Her presenting creatine kinase level was 13,580 International Units/L and serum aldolase level was elevated at 45 International Units/L. Seven days after stopping the 2 drugs, and given supportive care, the patient recovered and was discharged (Tal et al, 1997). h) CASE REPORT: Fatal (non-traumatic) rhabdomyolysis associated with simvastatin therapy in a 55-year-old renal transplant patient who was also receiving concurrent cyclosporine has been reported. The patient had been receiving 20 mg/day of simvastatin for 3 months prior to presenting symptoms. Creatine phosphokinase levels had peaked to a level of 10,157 International Units/L (Weise & Possidente, 2000). i) CASE REPORT: Rhabdomyolysis was reported in a 64-year-old woman receiving the combination of cerivastatin and gemfibrozil for 3 weeks. On admission her serum creatine kinase concentration was >16,000 International Units/L, CPK-MB isoenzyme concentration was 248.2 ng/mL and myoglobin concentration was >1000 ng/mL. The patient recovered following vigorous rehydration and urine alkalinization (Bermingham et al, 2000). j) Rhabdomyolysis and myopathy with acute renal failure secondary to myoglobinuria has been reported with pitavastatin use. Although rhabdomyolysis may occur at any dose level, risk increases in a dose-dependent manner (Prod Info LIVALO oral film coated tablet, 2009). G) COMPARTMENT SYNDROME 1) WITH THERAPEUTIC USE a) SIMVASTATIN: A 56-year-old man presented with sudden onset of left lower leg pain with an inflamed patch over his left shin and firm anterior, lateral, and posterior compartments. Three weeks earlier he had his daily dose of simvastatin doubled to 40 milligrams. On admission, creatine kinase was 4500 International Units/L. Over the next 24 hours, the patient's pain increased, and a compartment monitor was inserted into the anterior compartment with a pressure reading of 50 mm Hg. He was taken to surgery, where a four-compartment fasciotomy was performed. Necrotic muscle in the anterior and lateral compartments was found, with no evidence of pus or hematoma. With these findings and the clinical presentation, the authors speculated that statin-induced myositis was the source of this patient's compartment syndrome (Walker et al, 2008).
b) ATORVASTATIN: Based upon a single case report, left lower limb compartment syndrome developed in a 46 year-old man maintained on atorvastatin for 3 years. With a history of renal failure, he was also receiving ramipril 2.5 mg/day and acetylsalicylic acid 100 mg/day. An invasive fasciotomy of the anterolateral and posterolateral compartments was performed. Follow-up after a year showed a decrease in range of motion in the patient's ankle, weakness, and hypotrophy of the leg (Flamini et al, 2008).
H) RUPTURE OF TENDON 1) WITH THERAPEUTIC USE a) Although the causality relationship was unclear, there was a total of 247 case reports of tendon rupture associated with statin use as of March 2006 according to the Food and Drug Administration database; of which 124 cases were related to atorvastatin therapy. The majority (81%) of the reported cases involving atorvastatin were male, aged 57 +/- 10 years; and 53% of the cases led to hospitalization (Pullatt et al, 2007).
b) Tendinitis and tendon rupture were observed in 96 patients (median age 56 years old) who were treated with statins during the period 1990 through 2005, according to a retrospective analysis of data collected through 31 French Pharmacovigilance Centers. The median time to onset of symptoms was 243 days (range, 0 to 5659 days), with 59% of the cases appearing in the first year after the statin was initiated. All patients were receiving dosages within the standard range. The specific drugs involved were atorvastatin (37% of patients), simvastatin (31% of patients), pravastatin (22%), fluvastatin (5%), and rosuvastatin (5%). Tendinitis was reported in 63 patients, tendinitis followed by tendon rupture occurred in 12, and de novo tendon rupture was reported in 21, with Achilles tendon disorders being the most common (52.1% of cases). Statin treatment was reinitiated in 7 of the patients, resulting in a 100% recurrence of tendon complications. Predisposing factors included hyperuricemia in 5 patients, sport practice in 15 patients, diabetes in 11, and history of tendinopathy in 11. Regression of symptoms occurred a median of 23 days after discontinuing the statin (Marie et al, 2008).
I) MYASTHENIA GRAVIS 1) WITH THERAPEUTIC USE a) A case series described development of myasthenia gravis in 4 individuals within 2 weeks of starting treatment with a statin. The patients, ranging from 55 to 71 years of age (3 men, 1 woman), were being treated with either rosuvastatin, simvastatin, or pravastatin. Myasthenic symptoms in 3 of the 4 patients included fluctuating ptosis or vertical diplopia, with development of weakness with chewing in 1 patient. The fourth patient, who had a prior occurrence of myasthenia but was currently asymptomatic, developed mild weakness of the legs and neck 1 week after starting pravastatin. Acetylcholine receptor (AChR) binding antibodies were elevated in 3 of the 4 cases (0.06 to 17.5 nanomoles/liter) and single fiber electromyogram in 2 patients displayed increased jitter. Discontinuation of the statin and/or treatment with pyridostigmine resulted in partial to substantial recovery in 3 cases. For the 1 patient in whom recovery was not seen, additional treatment with prednisone resulted in slow but complete recovery over 1 year. In one of the patients, who was on simvastatin, a rechallenge with pravastatin caused a recurrence of myasthenic symptoms. While the exact mechanism for this adverse effect has not been elucidated, it is proposed that statin-induced myotoxicity may exacerbate weakness in patients with underlying myasthenia gravis or alternatively, statins may induce de novo formation of antibodies that are directed at the neuromuscular junction (Purvin et al, 2006).
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Endocrine |
3.16.2) CLINICAL EFFECTS
A) HYPERGLYCEMIA 1) WITH THERAPEUTIC USE a) PRAVASTATIN: A 63-year-old woman presented with polyuria, polydipsia, and hyperglycemia three weeks after beginning pravastatin. The patient was immediately started on insulin therapy. After pravastatin was discontinued, the patient's blood glucose levels returned to normal and the insulin was gradually withdrawn (Jonville-Bera et al, 1994).
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Immunologic |
3.19.2) CLINICAL EFFECTS
A) DRUG-INDUCED LUPUS ERYTHEMATOSUS 1) WITH THERAPEUTIC USE a) CASE SERIES: A case series reported that two patients, on lovastatin therapy, developed a lupus-like syndrome, characterized by musculoskeletal pain, fever, malaise, and cough. The diagnosis was confirmed by the positive antinuclear antibody assays. The lupus was completely reversible upon withdrawal of the lovastatin (Ahmad, 1991). b) CASE REPORT: A case of fatal lupus-like syndrome with ARDS, induced by fluvastatin, is reported in a 67-year-old female. Within one week of starting fluvastatin (20 mg/day), a rash followed by swelling and pain in one knee and joints of her hands developed. She discontinued fluvastatin after 10 weeks, then presented to the hospital one month later. 1) Symptoms improved with non-steroidal anti-inflammatory agents, but her respiratory status deteriorated progressively, despite assisted ventilation and immunosuppressive therapy, and she died. Adult respiratory distress syndrome was evident at necropsy (Sridhar & Abdulla, 1998).
B) HYPERSENSITIVITY REACTION 1) WITH THERAPEUTIC USE a) Hypersensitivity reactions including rash, pruritus, and urticaria have been observed following pitavastatin therapy (Prod Info LIVALO oral film coated tablet, 2009).
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Reproductive |
3.20.1) SUMMARY
A) Atorvastatin, fluvastatin, lovastatin, pitavastatin, rosuvastatin, simvastatin, simvastatin/sitagliptin phosphate, and niacin/simvastatin are classified as FDA pregnancy category X. Pravastatin is also contraindicated during pregnancy. Studies of several structurally-related HMG-CoA reductase inhibitors have shown congenital abnormalities in infants and skeletal malformations in rats and mice. It is not known whether lovastatin, simvastatin, or rosuvastatin is excreted into human breast milk. Pravastatin is known to be excreted into human breast milk. Because of the potential for serious adverse effects in the infant, pravastatin is contraindicated in nursing mothers.
3.20.2) TERATOGENICITY
A) CONGENITAL ANOMALY 1) No statistically significant difference in major birth defects was seen in the offspring of women treated with simvastatin (n=124), atorvastatin (n=67), pravastatin (n=32), rosuvastatin (n=18), fluvastatin (n=7), or cerivastatin (n=1) during the first trimester of pregnancy (median duration, 6 weeks; interquartile [IQR] range, 4 to 7 weeks) compared with unexposed controls (n=249) in a multicenter prospective observational controlled study (p=0.43). Statin-exposed infants showed no particular pattern of birth defects, and none exhibited CNS anomalies. Major birth defects, limited to malformations that caused severe structural impairment or required surgical correction, included one case each among atorvastatin-exposed infants of a missing middle phalanx, dilated left renal pelvis, and cutaneous angioma; one case each among pravastatin-exposed infants of sacrococcygeal teratoma with hip joint deformity and fetal death associated with urethral obstruction; and one case each with rosuvastatin exposure of trisomy 21 (electively terminated), fetal death associated with cardiomegaly and severe fetal arrhythmia, and hemangioma on the neck and temple. No major birth defects were reported with simvastatin, fluvastatin, or cerivastatin use (Winterfeld et al, 2013).
2) Intrauterine exposure to statins during pregnancy has resulted in rare reports of congenital anomalies; however, in a prospective review of approximately 100 pregnancies in which women were exposed to simvastatin or lovastatin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed the rate expected in the general population. Notably, in 89% of these pregnancies, drug therapy was started prior to pregnancy and was discontinued during the first trimester when pregnancy was identified. Rare reports of congenital anomalies have been documented following intrauterine exposure to HMG-CoA reductase inhibitors (Prod Info PRAVACHOL(R) oral tablets, 2016; Prod Info LIVALO oral film coated tablet, 2009).
3) The incidence of major birth defects and neonatal health problems did not differ significantly between 64 pregnant women exposed to a statin (atorvastatin [n=46], simvastatin [n=9], pravastatin [n=6], and rosuvastatin [n=3]) and 64 pregnant women not exposed to any known teratogens during the first trimester in a prospective cohort study. Major birth defects were reported in 2.2% and 1.9% of the statin and control groups, respectively. The incidence of neonatal health problems was 15.2% in the statin group and 9.6% in the control group, respectively (Taguchi et al, 2008).
4) In a prospective review of approximately 100 pregnancies in which women were exposed to simvastatin or another structurally-related HMG-CoA reductase inhibitor, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed that which would be expected in the general population. The frequency of cases is adequate only to exclude a 3- to 4-fold increase in congenital anomalies over the background incidence. In 89% of the pregnancies, drug therapy was started prior to pregnancy and was discontinued during the first trimester when pregnancy was identified. Rare reports of congenital anomalies have been documented following intrauterine exposure to HMG-CoA reductase inhibitors (Prod Info SIMCOR(R) extended-release oral tablets, 2008).
5) Teratogenetic effects appear to be associated with lipophilic but not hydrophilic statins according to a review of cases of first-trimester exposure to statins reported to the US Food and Drug Administration (n=178). Of the 178 reported cases, 126 could not be evaluated for teratogenic effects due to the following: pregnancy aborted, elective or spontaneous (n=88); pregnancy loss due to maternal illness (n=15); fetal genetic disorders (n=3); transient neonatal disorders (n=5); and loss to follow-up (n=15). Of the remaining 52 evaluatable cases, 7 were associated with atorvastatin, 1 with cerivastatin, 1 with fluvastatin, 15 with lovastatin, 3 with pravastatin, and 25 with simvastatin. Among the 52 evaluatable cases, there were 20 reports of malformations. Severe defects of the CNS occurred in 5 cases, including 2 of holoprosencephaly. Unilateral limb deficiencies, such as long-bone shortening and aplasia or hypoplasia of the foot, were reported in 5 cases, including 1 of an infant who also had a CNS defect. All cases of adverse outcomes at birth were associated with the use of statins, which are lipophilic (atorvastatin, cerivastatin, lovastatin, and simvastatin). No malformations were reported in the 14 infants exposed to pravastatin, which is hydrophilic. Fluvastatin is hydrophilic as well (no malformation occurred in the 1 evaluatable case). One mother with type 1 diabetes who was exposed to atorvastatin bore an infant with spina bifida and a right-arm abnormality; this mother was the only one with diabetes among the 20 malformation cases. Two infants (1 exposed to lovastatin, the other to simvastatin) had rare forms of the VACTERL teratogenicity (3 or more defects related to vertebral, anal, cardiac, tracheal, esophageal, renal, or limb areas) (Edison & Muenke, 2004).
6) Although the safety of atorvastatin use during pregnancy has not been established, one case report described VACTERL teratogenicity in a baby born to a woman who took lovastatin, another HMG-CoA reductase inhibitor, with dextroamphetamine sulfate during the first trimester of pregnancy (Prod Info LIPITOR(R) oral tablets, 2009a; Ghidini et al, 1992).
B) ANIMAL STUDIES 1) ATORVASTATIN a) RATS, RABBITS: There was no evidence of teratogenicity when rats and rabbits were given atorvastatin doses up to 30 times the human exposure based on surface area and up to 20 times the human exposure, respectively (Prod Info LIPITOR(R) oral tablets, 2009a).
2) LOVASTATIN a) RATS: Skeletal abnormalities were observed in female rats administered lovastatin 800 mg/kg/day during gestation. Abnormalities reported were limited to the ribs and vertebra. Teratogenicity was blocked when mevalonic acid was supplemented in the diet. Cholesterol supplemented in the diet had no effect (Minsker et al, 1983).
3) PITAVASTATIN a) RATS: There are no adequate and well-controlled studies of pitavastatin in pregnant women. Pitavastatin crosses the placenta in rats and was found in fetal tissue following a single dose of 1 mg/kg/day during gestation. Teratogenicity was not evident in rats at doses 22 times human exposure based on AUC. Doses of pitavastatin 0.1 to 30 mg/kg/day administered to pregnant rats from organogenesis through weaning contributed to maternal mortality at 0.3 mg/kg/day or greater and impaired lactation and decreased neonate survival rates in all dose groups (0.1 mg/kg/day, is approximately 1 time human exposure at 4 mg/kg/day based on AUC). Reduced body weight and abortion was noted at all doses in pregnant rabbits administered pitavastatin 0.1 mg/kg/day, 0.3 mg/kg/day, and 1 mg/kg/day (4 times human exposure at 4 mg/kg/day based on AUC) during fetal organogenesis (Prod Info LIVALO oral film coated tablet, 2009).
4) PRAVASTATIN a) RATS: Pravastatin is known to cross the placental barrier. On gestational day 18, pravastatin was found in the fetal tissue at 30% of the maternal plasma levels in pregnant rats administered pravastatin 20 mg/kg (Prod Info PRAVACHOL(R) oral tablets, 2016).
5) ROSUVASTATIN a) RATS, RABBITS: Teratogenicity was not evident in rats or rabbits at systemic exposures equivalent to those achieved with the human therapeutic dose of 40 mg/day. In rats, oral rosuvastatin doses of up to 12 times the maximum recommended human dose given before mating and continued through day 7 postcoitus led to decreased fetal body weights and delayed ossification. The administration of the same doses from day 7 of pregnancy to day 21 of lactation resulted in lower pup survival rates. Teratogenicity was not evident in rats at systemic exposures equivalent to those achieved with the human therapeutic dose of 40 mg/day (Prod Info CRESTOR(R) oral tablets, 2007).
6) SIMVASTATIN a) RATS, RABBITS, MICE: In animal reproductive studies in which rats and rabbits were administered simvastatin at 3 times the human exposure based on body surface area, simvastatin was not teratogenetic. However, skeletal malformations were observed in rats and mice in studies with another structurally-related HMG-CoA reductase inhibitor. There have been no animal reproductive studies conducted with the niacin/simvastatin combination (Prod Info SIMCOR(R) extended-release oral tablets, 2008).
3.20.3) EFFECTS IN PREGNANCY
A) PREGNANCY CATEGORY 1) ATORVASTATIN a) Atorvastatin is classified as FDA pregnancy category X (Prod Info LIPITOR(R) oral tablets, 2009a).
2) FLUVASTATIN a) Fluvastatin is classified as FDA pregnancy category X (Prod Info LESCOL(R) XL oral extended-release tablets, 2006).
3) LOVASTATIN a) Lovastatin is classified as FDA pregnancy category X (Prod Info MEVACOR(R) oral tablets, 2007).
4) PRAVASTATIN a) Pravastatin is contraindicated during pregnancy and should not be administered to women likely to become pregnant during pravastatin therapy. In the event a woman conceives while taking pravastatin, the medication should be discontinued and the patient counseled regarding the potential hazards to the fetus (Prod Info PRAVACHOL(R) oral tablets, 2016).
5) PITAVASTATIN a) Pitavastatin is classified as FDA pregnancy category X (Prod Info LIVALO oral film coated tablet, 2009)
6) ROSUVASTATIN a) Rosuvastatin is classified as FDA pregnancy category X (Prod Info CRESTOR(R) oral tablets, 2007).
7) SIMVASTATIN a) Simvastatin/sitagliptin phosphate is classified as FDA pregnancy category X (Prod Info JUVISYNC(TM) oral tablets, 2011).
b) Niacin/simvastatin is classified as FDA pregnancy category X (Prod Info SIMCOR(R) extended-release oral tablets, 2008).
B) PREGNANCY OUTCOMES 1) No statistically significant difference in major birth defects was seen in the offspring of women treated with simvastatin (n=124), atorvastatin (n=67), pravastatin (n=32), rosuvastatin (n=18), fluvastatin (n=7), or cerivastatin (n=1) during the first trimester of pregnancy (median duration, 6 weeks; interquartile (IQR) range, 4 to 7 weeks) compared with unexposed controls (n=249) in a multicenter prospective observational controlled study (p=0.43). While prematurity was more prevalent among statin-treated patients than controls (16.1% versus 8.5%, respectively; odds ratio [OR], 2.1), there was no significant difference between statin-treated patients and controls in median gestational age at birth (39 weeks; IQR, 37 to 40 weeks versus 39 weeks; IQR, 38 to 40 weeks, respectively) or birth weight (3280 g, IQR 2835 to 3590 g versus 3250 g, IQR 2880 to 3630 g, respectively; p=0.95). In addition, adjusted analyses showed no higher risk of miscarriage (adjusted hazard ratio, 1.36) among statin-treated patients (Winterfeld et al, 2013).
2) The incidence of pregnancy outcomes did not differ significantly compared to all of the other outcomes between 64 pregnant women exposed to a statin (atorvastatin [n=46], simvastatin [n=9], pravastatin [n=6], and rosuvastatin [n=3]) and 64 pregnant women not exposed to any known teratogens during the first trimester in a prospective, cohort study. There were no significant differences between the statin and control groups in rate of live birth (71.9% vs 81.2%), stillbirth (1.5% vs 1.6%), spontaneous abortion (21.9% vs 17.2%), or therapeutic abortion (4.7% vs 0%) (Taguchi et al, 2008).
C) GESTATIONAL AGE AT BIRTH 1) No statistically significant difference in major birth defects was seen in the offspring of women treated with simvastatin (n=124), atorvastatin (n=67), pravastatin (n=32), rosuvastatin (n=18), fluvastatin (n=7), or cerivastatin (n=1) during the first trimester of pregnancy (median duration, 6 weeks; interquartile [IQR] range, 4 to 7 weeks) compared with unexposed controls (n=249) in a multicenter prospective observational controlled study. While prematurity was more prevalent among statin-treated patients than controls (16.1% versus 8.5%, respectively; odds ratio, 2.1), there was no significant difference between statin-treated patients and controls in median gestational age at birth (39 weeks; IQR, 37 to 40 weeks versus 39 weeks; IQR, 38 to 40 weeks, respectively or birth weight (3280 g, IQR 2835 to 3590 g versus 3250 g, IQR, 2880 to 3630 g, respectively). In addition, adjusted analyses showed no higher risk of miscarriage (adjusted hazard ratio, 1.36) among statin-treated patients (Winterfeld et al, 2013).
2) Mean gestational age at birth differed significantly between 64 pregnant women exposed to a statin (atorvastatin (n=46), simvastatin (n=9), pravastatin (n=6), and rosuvastatin (n=3)) and 64 pregnant women not exposed to any known teratogens during the first trimester in a prospective, cohort study. Mean gestational age at birth was 38.4 and 39.3 weeks in the statin and the control groups, respectively (Taguchi et al, 2008).
D) BIRTHWEIGHT 1) No statistically significant difference in major birth defects was seen in the offspring of women treated with simvastatin (n=124), atorvastatin (n=67), pravastatin (n=32), rosuvastatin (n=18), fluvastatin (n=7), or cerivastatin (n=1) during the first trimester of pregnancy (median duration, 6 weeks; interquartile [IQR] range, 4 to 7 weeks) compared with unexposed controls (n=249) in a multicenter prospective observational controlled study (p=0.43). While prematurity was more prevalent among statin-treated patients than controls (16.1% versus 8.5%, respectively; odds ratio, 2.1), there was no significant difference in median gestational age at birth between statin-treated patients and controls (39 weeks; IQR, 37 to 40 weeks versus 39 weeks; IQR 38 to 40 weeks, respectively) or birth weight (3280 g; IQR, 2835 to 3590 g versus 3250 g; IQR, 2880 to 3630 g, respectively). In addition, adjusted analyses showed no higher risk of miscarriage (adjusted hazard ratio, 1.36) among statin-treated patients (Winterfeld et al, 2013).
2) Birthweight differed significantly between 64 pregnant women exposed to a statin (atorvastatin [n=46], simvastatin [n=9], pravastatin [n=6], and rosuvastatin [n=3]) and 64 pregnant women not exposed to any known teratogens during the first trimester in a prospective, cohort study. Mean birthweights were 3.14 and 3.45 kg in the statin and control groups, respectively (Taguchi et al, 2008).
E) LACK OF EFFECT 1) PRAVASTATIN a) A 39-year-old woman inadvertently received pravastatin 80 mg/day for the first 24 weeks of her pregnancy without apparent adverse effects. The patient was being treated for diabetes and dyslipidemia. Her initial therapy for high cholesterol (total cholesterol, 411 mg/dL) was atorvastatin. However, the atorvastatin was discontinued when her hepatic enzymes became significantly elevated (ALT 238 mg/dL; AST 298 mg/dL). With improvement of liver enzymes, she was started on pravastatin 40 mg/day, which was subsequently titrated to 80 mg/day; her other medications were metformin 1 g twice daily and nateglinide 120 mg three times daily. She presented to her gynecologist with a 24-week period of amenorrhea, at which time a single live intrauterine pregnancy was confirmed. All medications were withdrawn and she began a twice-daily insulin regimen. A male infant weighing 2.4 kg was delivered by elective cesarean section at 39 weeks. The 1- and 5-min Apgar scores were 8 and 9, respectively. The perinatal and neonatal periods were uncomplicated and early developmental milestones were achieved on schedule (Teelucksingh et al, 2004).
F) ANIMAL STUDIES 1) ATORVASTATIN a) RATS: There was decreased pup survival at birth, neonate, weaning, and maturity in pups of rats dosed with 225 mg/kg/day (22 times the human AUC at 80 mg/day) from gestation day 7 through to lactation day 21 (weaning). Body weight was decreased on days 4 and 21 in pups of rats dosed at 100 mg/kg/day (6 times the human AUC at 80 mg/day); pup body weight was decreased at birth and at days 4, 21, and 91 at 225 mg/kg/day. Pup development was delayed at 100 mg/kg/day (rotorod performance) and 225 mg/kg/day (acoustic startle, pinnae detachment, and eye opening). Additionally, atorvastatin has been shown to cross the rat placenta and reach a level in fetal liver equivalent to that of maternal plasma.(Prod Info LIPITOR(R) oral tablets, 2009a).
2) ROSUVASTATIN a) RABBITS: In rabbits, oral rosuvastatin doses of up to 3 mg/kg/day (equivalent to maximum recommended human dose) from day 6 of gestation to day 18 of lactation led to lower fetal viability and increased maternal mortality (Prod Info CRESTOR(R) oral tablets, 2007).
3.20.4) EFFECTS DURING BREAST-FEEDING
A) LOVASTATIN 1) It is unknown if lovastatin is excreted in human breast milk (Prod Info MEVACOR(R) oral tablets, 2007).
B) PITAVASTATIN 1) No reports describing the use of pitavastatin during human lactation or measuring the amount, if any, of the drug excreted into milk have been located. Because of the potential for adverse events in nursing infants, pitavastatin use is contraindicated during lactation (Prod Info LIVALO oral film coated tablet, 2009).
C) PRAVASTATIN 1) Pravastatin is known to be excreted into human breast milk. Because of the potential for serious adverse effects in the infant, pravastatin is contraindicated in nursing mothers (Prod Info PRAVACHOL(R) oral tablets, 2016).
D) ROSUVASTATIN 1) Rosuvastatin was detected in the milk of a 31-year-old lactating woman following treatment for familial hypercholesterolemia. Treatment with rosuvastatin 40 mg/day was initiated 33 days postpartum and samples were collected over a 3-day period. The samples were primarily hind milk samples and any differences between fore- and hind milk statin concentration was unknown. Following the use of rosuvastatin, its concentration increased rapidly between hour 1 and hour 7 and peaked at 10 hours. Breast milk concentrations were 21.9 to 22.8 ng/mL over the 3-day test period. Serum rosuvastatin concentrations were lower than overall breast milk concentrations 23 hours after rosuvastatin administration (18 ng/mL) (Schutte et al, 2013).
2) Rosuvastatin is contraindicated in nursing women (Prod Info CRESTOR(R) oral tablets, 2009). Rosuvastatin was detected in the milk of a 31-year-old lactating woman (Schutte et al, 2013). In animal studies, rosuvastatin concentrations were 3 times higher in breast milk than in plasma. Advise patients who require rosuvastatin treatment to avoid breastfeeding due to the potential for serious adverse reactions in nursing infants (Prod Info CRESTOR(R) oral tablets, 2009).
E) SIMVASTATIN 1) Lactation studies with the combination product of niacin and simvastatin have not been conducted in humans. It is unknown whether simvastatin is excreted in human milk; however, a small amount of another drug in this class is excreted in human milk (Prod Info SIMCOR(R) extended-release oral tablets, 2008).
F) ANIMAL STUDIES 1) ATORVASTATIN a) RATS: In animal studies, nursing rat pups had plasma and liver drug levels of 50% and 40%, respectively, of that in the mother’s milk (Prod Info LIPITOR(R) oral tablets, 2009a).
2) PRAVASTATIN a) Lactation studies have not been conducted in humans, but it has been reported that a small amount of pravastatin is excreted into human breast milk. In animal studies, pravastatin was excreted in the milk of lactating rats at levels 0.2 to 6.5 times those of maternal plasma exposure at exposures 2 times the maximum recommended human dose (Prod Info PRAVACHOL(R) oral tablets, 2016).
3) ROSUVASTATIN a) RATS: In rat studies, rosuvastatin levels were 3 times higher in breast milk than in plasma (Prod Info CRESTOR(R) oral tablets, 2007).
3.20.5) FERTILITY
A) ANIMAL STUDIES 1) ATORVASTATIN a) RATS: No changes in fertility were observed in studies in rats performed at doses up to 15 times the human exposure. There was aplasia and aspermia in the epididymis of 2 of 10 rats treated with atorvastatin at doses 16 times the human AUC for 3 months. Testicular weights were significantly lower at 30 and 100 mg/kg and epididymal weight was lower at 100 mg/kg. Decreased sperm motility, spermatid head concentration, and increased abnormal sperm were observed when male rats were given 100 mg/kg/day for 11 weeks prior to mating. In dogs given doses of 10, 40, or 120 mg/kg for 2 years, atorvastatin caused no adverse effects on semen parameters or reproductive organ histopathology (Prod Info LIPITOR(R) oral tablets, 2009a).
2) PITAVASTATIN a) RATS, RABBITS: No changes in fertility were observed in male or female rats at pitavastatin doses of 10 mg/kg/day and 30 mg/kg/day, respectively, at systemic exposures 56 and 354 times the clinical exposure at 4 mg/kg/day based on AUC. Male and female rabbits administered pitavastatin doses of 1 mg/kg/day and higher (30 times clinical exposure 4 mg/kg/day based on AUC) resulted in mortality; however, the cause of death was not determined but signs of renal toxicity indicative of possible ischemia was observed. Lower doses of pitavastatin (15 times the human exposure) showed no signs of toxicity in male and female rabbits; however, decreased implantations, increased resorptions, and decreased fetal viability were noted (Prod Info LIVALO oral film coated tablet, 2009).
3) PRAVASTATIN a) RATS: No adverse effects on fertility or general reproduction were observed during fertility studies performed on adult rats administered pravastatin at doses up to 23 times the human dose based on area under the curve(Prod Info PRAVACHOL(R) oral tablets, 2016).
4) ROSUVASTATIN a) RATS, DOGS, MONKEYS: No changes in fertility were observed in studies in rats given doses of rosuvastatin up to 10 times the human exposure. Spermatidic giant cells were observed in dogs and monkeys exposed to 20 and 10 times the human exposure, respectively, for 1 and 6 months, respectively. Similar findings have been reported with other HMG-CoA reductase inhibitors (Prod Info CRESTOR(R) oral tablets, 2007).
5) SIMVASTATIN a) Decreased fertility was seen in male rats given doses of 25 mg/kg body weight of simvastatin for 34 weeks. However, this effect was not seen in a subsequent fertility study in which simvastatin was administered at the same dose level for 11 weeks (the entire cycle of spermatogenesis including epididymal maturation). No microscopic changes were observed in the testes. In rats given doses 44 times higher than those in humans taking 40 mg/day based on body surface area, seminiferous tubule degeneration (necrosis and loss of spermatogenic epithelium) was observed. In studies in dogs, drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration, and giant cell formation were reported with simvastatin doses at approximately 4 times the human exposure based on AUC (Prod Info JUVISYNC(TM) oral tablets, 2011).
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Carcinogenicity |
3.21.2) SUMMARY/HUMAN
A) At the time of this review, no evidence of carcinogenicity of statin medications has been determined.
3.21.4) ANIMAL STUDIES
A) CARCINOMA 1) ATORVASTATIN a) A marked increase in liver adenomas was seen in male mice given doses up to 400 mg/kg/day (6 times the mean human plasma drug exposure after 80 mg oral dose) for 2 years and liver carcinomas in female mice given high doses. Rare muscle tumors occurred in rats given doses up to 100 mg/kg/day (6 times the human plasma drug exposure after an 80 mg oral dose)(Prod Info LIPITOR(R) oral tablets, 2009).
2) FLUVASTATIN a) A low incidence of forestomach squamous papillomas and carcinoma of the forestomach was reported in rat and mouse studies with doses up to 30 mg/kg/day (7 times the mean human plasma drug concentration after a 40 mg dose). Additionally, an increased incidence of thyroid follicular cell adenomas and carcinomas was found in male rats treated with fluvastatin (Prod Info LESCOL(R) XL oral extended-release tablets, 2006).
3) LOVASTATIN a) A 21-month study in mice showed an increased incidence of carcinomas and adenomas at lovastatin doses of 500 mg/kg/day (approximately 4 times the highest recommended human dose) (Prod Info MEVACOR(R) oral tablets, 2009) .
b) Papilloma of the nonglandular mucosa of the stomach was reported in mice receiving 100 to 500 mg/kg/day. No tumors were observed at 20 mg/kg/day. Human stomachs have no equivalent to the nonglandular mucosa (Prod Info MEVACOR(R) oral tablets, 2009).
c) A positive dose response relationship for hepatocellular carcinogenicity was observed in male rats at drug exposures doses up to 180 mg/kg/day (between 2 to 7 times the human exposure of 80 mg/day) (Prod Info MEVACOR(R) oral tablets, 2009).
4) PRAVASTATIN a) An increased incidence of hepatocellular carcinomas was seen in male rats at the highest dose of pravastatin. An increased incidence of malignant lymphomas was seen in female mice at the higher doses (Prod Info PRAVACHOL(R) oral tablets, 2007).
5) SIMVASTATIN a) Increased incidences of liver adenomas, liver carcinomas, and lung adenomas was seen in mice at doses of 100 mg/kg and 400 mg/kg (approximately 4 to 8 times higher than the mean human plasma exposure after an 80 mg dose). Also, a higher incidence of Harderian gland adenomas was observed in the 400 mg/kg group(Prod Info ZOCOR(R) oral tablets, 2010) .
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Hematologic |
3.13.2) CLINICAL EFFECTS
A) HEMOLYTIC ANEMIA 1) WITH THERAPEUTIC USE a) LOVASTATIN: Hemolytic anemia was reported in a 57-year-old woman 3 weeks after beginning lovastatin therapy, 20 mg daily. The anemia resolved after discontinuing the lovastatin. Simvastatin therapy was started without any signs of the hemolytic anemia recurring, indicating that the anemia was due to an idiosyncratic reaction to the lovastatin molecule or one of its metabolites, and not due to HMG- CoA reductase inhibition (Robbins et al, 1995).
B) THROMBOCYTOPENIC DISORDER 1) WITH THERAPEUTIC USE a) ATORVASTATIN: A 46-year-old man was admitted to the hospital with thrombocytopenic purpura. Two months prior to admission, he had started atorvastatin therapy. Concomitant medications included allopurinol, colchicine, atenolol, and acenocoumarol. Platelet count at admission was reported to be 3 x 10(9)/L. Atorvastatin and colchicine were discontinued. Following therapy with packed platelets, steroids, and gamma-globulin, his platelet count improved and he was discharged. The patient reinstituted his atorvastatin and colchicine the next day, and consequently was readmitted to the hospital 4 days later with widespread petechiae and decreased platelet count (5 x 10(9)/L). Following therapy, he improved and has remained off of the atorvastatin, but was restarted on colchicine, with no further occurrence of thrombocytopenia (Gonzalez-Ponte et al, 1998).
C) THROMBOTIC THROMBOCYTOPENIC PURPURA 1) WITH THERAPEUTIC USE a) SIMVASTATIN: Thrombotic thrombocytopenic purpura (TTP) is reported in a 43- year-old man after his second dose of simvastatin (10 mg twice daily). The only other concomitant medication was lisinopril, which he had been taking for 2 years. He experienced severe headache, fever, malaise, and petechiae within 24 hours of initiating simvastatin. Platelet count on admission was less than 10 x 10(9)/L, LDH was 2700 U/L, hemoglobin 9.2 grams/deciliter and absolute reticulocyte count was 350 x 10(9)/L. The patient recovered after 10 daily plasma exchanges and discontinuation of simvastatin (McCarthy et al, 1998).
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Dermatologic |
3.14.2) CLINICAL EFFECTS
A) DERMATITIS 1) WITH THERAPEUTIC USE a) LOVASTATIN: A patient receiving 15 mg of lovastatin for 2 days developed an erythematous rash which resolved by the end of the study period despite continued drug administration. It was postulated that this may have been a reaction associated with a food allergy (Tobert et al, 1982).
b) SIMVASTATIN: Three patients developed dermatitis, consisting of pruritic eczematous skin rashes, one to six months after initiating simvastatin and/or pravastatin therapy. The dermatitis resolved following treatment with corticosteroids and after withdrawal of the simvastatin and pravastatin (Krasovec et al, 1993).
c) CASE REPORT: A 59-year-old man, taking atenolol, aspirin, cholestyramine, pravastatin, and gemfibrozil, developed dermatitis. The dermatitis resolved upon withdrawal of the pravastatin. A patch test was performed, revealing a positive reaction to pravastatin (De Boer & Bruynzeel, 1994).
B) PHOTOSENSITIVITY 1) WITH THERAPEUTIC USE a) SIMVASTATIN: A 50-year-old man developed erythema and vesicles on sun-exposed areas 3 weeks after beginning simvastatin therapy. A screening phototest, performed while the patient was on simvastatin therapy, produced erythema and reddish papules 6 days after irradiation. A screening phototest, performed 4 weeks after discontinuation of the simvastatin, showed no erythema or papules, indicating that the photosensitivity was induced by simvastatin (Morimoto et al, 1995).
C) DERMATOMYOSITIS 1) WITH THERAPEUTIC USE a) SIMVASTATIN: Dermatomyositis with lung involvement, consisting of an erythematous rash, proximal limb weakness, and dyspnea on exertion, developed in a 76-year-old woman 18 months after beginning simvastatin therapy. The patient died two weeks later due to deteriorating lung function (Hill et al, 1995).
b) PRAVASTATIN: One study reported a case of dermatomyositis, without lung involvement, in a 66-year-old woman treated for 5 months with pravastatin. The patient experienced severe proximal muscle weakness in the upper limbs and erythematous skin lesions on the upper body. The symptoms gradually resolved after the discontinuation of pravastatin (Schalke et al, 1992).
D) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE 1) WITH THERAPEUTIC USE a) ATORVASTATIN: Rarely, the HMG-CoA enzyme inhibitors may cause toxic epidermal necrolysis (TEN) a few days after onset of therapy. There is one reported case of a 73-year-old woman who developed TEN 4 days after atorvastatin (10 mg/day) was added to her therapy regimen. The patient was hospitalized for 2 weeks and atorvastatin was discontinued. Complete resolution of TEN symptoms occurred over 4 months (Pfeiffer, 1998).
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Genotoxicity |
A) ATORVASTATIN : No evidence of mutagenicity or clastogenicity was observed in in vitro tests, with or without metabolic activation(Prod Info LIPITOR(R) oral tablets, 2009) .
B) ATORVASTATIN/EZETIMIBE: No evidence of mutagenicity or clastogenicity was observed with in vitro Ames test with Salmonella typhimurium and Escherichia coli with or without metabolic activation or in vitro chromosomal aberration assay with human peripheral blood lymphocytes with or without activation (Prod Info LIPTRUZET(R) oral tablets, 2013).
C) FLUVASTATIN : No evidence of mutagenicity was observed in in vitro studies with or without metabolic activation. No evidence of mutagenicity was seen in in vivo rat or mouse micronucleus tests (Prod Info LESCOL(R) XL oral extended-release tablets, 2006).
D) LOVASTATIN and SIMVASTATIN : No evidence of mutagenicity was noted by a microbial mutagen test using mutant strains of Salmonella typhimurium with or without rat or mouse liver metabolic activation. No evidence of mutagenicity was seen in an in vitro chromosomal aberration assay in mouse bone marrow (Prod Info MEVACOR(R) oral tablets, 2009; Prod Info ZOCOR(R) oral tablets, 2010).
E) PRAVASTATIN : No evidence of mutagenicity was noted in in vitro tests with or without liver metabolic activation(Prod Info PRAVACHOL(R) oral tablets, 2007) .
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