Amlodipine And Atorvastatin

1 ). 1 ). To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. 1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Amlodipine and Atorvastatin Amlodipine and atorvastatin has been evaluated for safety in 1,092 patients in double-blind placebo-controlled studies treated for co-morbid hypertension and dyslipidemia. In general, treatment with amlodipine and atorvastatin was well tolerated.

For the most part, adverse reactions have been mild or moderate in severity. In clinical trials with amlodipine and atorvastatin, no adverse reactions peculiar to this combination have been observed. Adverse reactions are similar in terms of nature, severity, and frequency to those reported previously with amlodipine and atorvastatin.

The following information is based on the clinical experience with amlodipine and atorvastatin. S. and foreign clinical trials. In general, treatment with amlodipine was well tolerated at doses up to 10 mg daily. Most adverse reactions reported during therapy with amlodipine were of mild or moderate severity.

5% of patients and was not significantly different from placebo (about 1%). The most commonly reported side effects more frequent than placebo are dizziness and edema. 6 Edema, flushing, palpitations, and somnolence appear to be more common in women than in men.

1% of patients treated with amlodipine in controlled clinical trials or under conditions of open trials or marketing experience where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship: Cardiovascular : arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, peripheral ischemia, syncope, tachycardia, vasculitis.

Central and Peripheral Nervous System : hypoesthesia, neuropathy peripheral, paresthesia, tremor, vertigo. Gastrointestinal : anorexia, constipation, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia. General : allergic reaction, asthenia, 2 back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease.

Musculoskeletal System : arthralgia, arthrosis, muscle cramps, 2 myalgia. Psychiatric : sexual dysfunction (male 2 and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization. Respiratory System : dyspnea, 2 epistaxis.

Skin and Appendages : angioedema, erythema multiforme, pruritus, 2 rash, 2 rash erythematous, rash maculopapular. Special Senses : abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus. Urinary System : micturition frequency, micturition disorder, nocturia.

Autonomic Nervous System : dry mouth, sweating increased. Metabolic and Nutritional : hyperglycemia, thirst. Hemopoietic : leukopenia, purpura, thrombocytopenia. 2 These events occurred in less than 1% in placebo-controlled trials, but the incidence of these side effects was between 1% and 2% in all multiple dose studies.

Amlodipine therapy has not been associated with clinically significant changes in routine laboratory tests. No clinically relevant changes were noted in serum potassium, serum glucose, total TG, TC, HDL-C, uric acid, blood urea nitrogen, or creatinine.

Atorvastatin In the atorvastatin placebo-controlled clinical trial database of 16,066 patients (8,755 atorvastatin vs. 4%). Table 2 summarizes adverse reactions, reported in ≥ 2% and at a rate greater than placebo in patients treated with atorvastatin (n=8,755), from seventeen placebo-controlled trials.

Table 2. 3 Other adverse reactions reported in placebo-controlled trials include: Body as a Whole : malaise, pyrexia Digestive System : abdominal discomfort, eructation, flatulence, hepatitis, cholestasis Musculoskeletal System : musculoskeletal pain, muscle fatigue, neck pain, joint swelling Metabolic and Nutritional System : transaminases increase, liver function test abnormal, blood alkaline phosphatase increase, creatine phosphokinase increase, hyperglycemia Nervous System : nightmare Respiratory System : epistaxis Skin and Appendages : urticaria Special Senses : vision blurred, tinnitus Urogenital System : white blood cells urine positive.

7% of patients who received atorvastatin in clinical trials. 3% for 10, 20, 40, and 80 mg, respectively. One patient in clinical trials developed jaundice. Increases in liver enzyme tests in other patients were not associated with jaundice or other clinical signs or symptoms.

Upon dose reduction, drug interruption, or discontinuation, transaminase levels returned to or near pretreatment levels without sequelae. Eighteen of 30 patients with persistent liver enzyme elevations continued treatment with a reduced dose of atorvastatin.

6 )] 10,001 subjects (age range 29 to 78 years, 19% female; 94% White, 3% Black or African American, 1% Asian, 2% other) with clinically evident CHD were treated with atorvastatin 10 mg daily (n=5,006) or atorvastatin 80 mg daily (n=4,995).

9 years. 2% of individuals with atorvastatin 10 mg. 1%). 9 years. 1%). 0%). 8% of subjects in the placebo group. 2% vs. 3% vs. 4%) compared to placebo. The incidence of fatal hemorrhagic stroke was similar between groups (17 atorvastatin vs.

18 placebo). The incidence of non-fatal hemorrhagic strokes was significantly greater in the atorvastatin group (38 non-fatal hemorrhagic strokes) as compared to the placebo group (16 non-fatal hemorrhagic strokes). Patients who entered the trial with a hemorrhagic stroke appeared to be at increased risk for hemorrhagic stroke (16% atorvastatin vs.

4% placebo). 11 )]. 2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of amlodipine and atorvastatin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Amlodipine The following postmarketing event has been reported infrequently where a causal relationship is uncertain: gynecomastia. In postmarketing experience, jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported in association with use of amlodipine.

Postmarketing reporting has also revealed a possible association between extrapyramidal disorder and amlodipine. Amlodipine has been used safely in patients with chronic obstructive pulmonary disease, well-compensated congestive heart failure, coronary artery disease, peripheral vascular disease, diabetes mellitus, and abnormal lipid profiles.

Atorvastatin Gastrointestinal Disorders: pancreatitis General Disorders: fatigue Hepatobiliary Disorders: fatal and non-fatal hepatic failure Immune System Disorders: anaphylaxis Injury: tendon rupture Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis, myositis.

There have been rare reports of immune-mediated necrotizing myopathy associated with statin use. Nervous System Disorders : dizziness, peripheral neuropathy. , memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with the use of all statins.

Cognitive impairment was generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks). There have been rare reports of new-onset or exacerbation of myasthenia gravis, including ocular myasthenia, and reports of recurrence when the same or a different statin was administered.

Psychiatric Disorders: depression Respiratory Disorders: interstitial lung disease Skin and Subcutaneous Tissue Disorders: angioneurotic edema, bullous rashes (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis)

5 WARNINGS AND PRECAUTIONS Myopathy and Rhabdomyolysis: Risk factors include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use with certain other drugs, and higher Amlodipine and atorvastatin tablets dosage.

Discontinue amlodipine and atorvastatin tablets if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Temporarily discontinue amlodipine and atorvastatin tablets in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis.

Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing amlodipine and atorvastatin tablets dosage. 6).

Immune-Mediated Necrotizing Myopathy (IMNM):

Rare reports of IMNM, an autoimmune myopathy, have been reported with statin use. 2 ).

Hepatic Dysfunction:

Increases in serum transaminases have occurred, some persistent. Rare reports of fatal and non-fatal hepatic failure have occurred. Consider testing liver enzymes before initiating therapy and as clinically indicated thereafter. 3 ). 4) Symptomatic hypotension is possible, particularly in patients with severe aortic stenosis.

5 ). 1 Myopathy and Rhabdomyolysis Amlodipine and atorvastatin tablets may cause myopathy (muscle pain, tenderness, or weakness associated with elevated creatine kinase [CK]) and rhabdomyolysis. Acute kidney injury secondary to myoglobinuria and rare fatalities have occurred as a result of rhabdomyolysis in patients treated with statins, including Amlodipine and atorvastatin tablets.

6)]. , breast cancer resistant protein [BCRP], organic anion-transporting polypeptide [OATP1B1/OATP1B3] and P-glycoprotein [P-gp]), resulting in an increased risk of myopathy and rhabdomyolysis. Concomitant use of cyclosporine, gemfibrozil, tipranavir plus ritonavir or glecaprevir plus pibrentasvir with amlodipine and atorvastatin is not recommended.

Amlodipine and atorvastatin dosage modifications are recommended for patients taking certain anti-viral, azole antifungals, or macrolide antibiotic medications [see Dosage and Administration ( 2 )] . 1 )] . 3 )]. Discontinue amlodipine and atorvastatin tablets if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected.

Muscle symptoms and CK elevations may resolve if amlodipine and atorvastatin tablets are discontinued. , sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy).

Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the Amlodipine and atorvastatin dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.

2 Immune-Mediated Necrotizing Myopathy There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use, including reports of recurrence when the same or a different statin ws administered.

IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase that persists despite discontinuation of statin treatment; positive anti-HMG-CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents.

Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Discontinue amlodipine and atorvastatin tablets if IMNM is suspected. 1 )]. In most cases, these changes appeared soon after initiation, were transient, were not accompanied by symptoms, and resolved or improved on continued therapy or after a brief interruption in therapy.

7% of patients receiving atorvastatin in clinical trials. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including atorvastatin. 7 )]. Consider liver enzyme testing before atorvastatin initiation and when clinically indicated thereafter.

Atorvastatin is contraindicated in patients with acute liver failure or decompensated cirrhosis [see Contraindications ( 4 )]. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue atorvastatin.

4 Increased Angina and Myocardial Infarction Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of amlodipine, particularly in patients with severe obstructive coronary artery disease.

5 Hypotension Symptomatic hypotension is possible with use of amlodipine, particularly in patients with severe aortic stenosis. Because of the gradual onset of action, acute hypotension is unlikely. 6 Increases in HbA1c and Fasting Serum Glucose Levels Increases in HbA1c and fasting serum glucose levels have been reported with statins, including atorvastatin.

Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices. 3% atorvastatin vs. 0168). The incidence of fatal hemorrhagic stroke was similar across treatment groups (17 vs.

18 for the atorvastatin and placebo groups, respectively). 7%). 1 )]. Consider the risk/benefit of use of atorvastatin 80 mg in patients with recent hemorrhagic stroke.

3 )]. Hypersensitivity to amlodipine, atorvastatin or any excipients in amlodipine and atorvastatin tablets. 2 )]. Acute liver failure or decompensated cirrhosis (4). Hypersensitivity to amlodipine, atorvastatin or any excipient in amlodipine and atorvastatin tablets (4).