Side Effects of Norvasc (amlodipine besylate)

Norvasc (amlodipine) is a calcium channel blocker (CCB) used to treat and prevent angina resulting from coronary spasm as well as from exertion. Norvasc is also used to treat high blood pressure (hypertension). 

Chest pain or heart pain (angina) occurs because of insufficient oxygen delivered to the heart muscles. Insufficient oxygen may be a result of coronary artery blockage or spasm, or because of exertion which increases the need of the heart for oxygen in patients with coronary artery narrowing (coronary artery disease or atherosclerosis). 

Common side effects of Norvasc include:

• headache,
• swelling of the lower extremities,
• dizziness,
• flushing,
• fatigue,
• nausea, and
• palpitations.

Serious side effects of Norvasc include:

• increased frequency and severity of angina,
• heart attacks, and
• congestive heart failure.

Drug interactions of Norvasc include sildenafil and similar drugs used to treat erectile dysfunction, which when combined may lead to excessive lowering of blood pressure with complications. 

Use of Norvasc significantly increases blood levels of simvastatin. 

The following, combined with Norvasc, results in excessive blood pressure reduction:

• ketoconazole,
• itraconazole, and
• ritonavir. 

Generally, Norvasc is avoided in pregnancy, and by nursing mothers and children although there are no adequate studies of Norvasc use during pregnancy. It is unknown if Norvasc is excreted in breast milk. 

Side effects of amlodipine are generally mild and reversible. The two most common side effects are:

• headache and
• edema (swelling) of the lower extremities.

Other side effects include:

• dizziness,
• flushing,
• fatigue,
• nausea, and
• palpitations.

More serious side effects include:

• increase in the frequency and severity of angina,
• heart attacks, and
• congestive heart failure.

Increase in the frequency and severity of angina or heart attack due to amlodipine happens on rare occasions in patients with severe coronary artery disease when first starting amlodipine, or at the time of an increase in dosage.

Excessive lowering of blood pressure during initiation of amlodipine treatment can occur, especially in patients already taking other medications that lower blood pressure.

In rare instances, congestive heart failure has been associated with amlodipine, particularly in patients already taking a beta blocker.

Clinical Trials Experience

• Because clinical trials are conducted under widely varying conditions, 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.
• Norvasc has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials.
• In general, treatment with Norvasc was well-tolerated at doses up to 10 mg daily. Most adverse reactions reported during therapy with Norvasc were of mild or moderate severity.
• In controlled reactions reported during therapy with Norvasc were of mild or moderate severity.
• In controlled clinical trials directly comparing Norvasc (N=1730) at doses up to 10 mg to placebo (N=1250), discontinuation of Norvasc because of adverse reactions was required in only about 1.5% of patients and was not significantly different from placebo (about 1%).
• The most commonly reported side effects more frequent than placebo are reflected in the table below. The incidence (%) of side effects that occurred in a dose related manner are as follows:

Other adverse reactions that were not clearly dose related but were reported with an incidence greater than 1.0% in placebo-controlled clinical trials include the following:

For several adverse experiences that appear to be drug and dose related, there was a greater incidence in women than men associated with amlodipine treatment as shown in the following table:

The following events occurred in <1% but >0.1% of patients 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,¹ back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease.

Musculoskeletal System: arthralgia, arthrosis, muscle cramps,¹ myalgia.

Psychiatric: sexual dysfunction (male¹ and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization.

Respiratory System: dyspnea,¹ epistaxis.

Skin and Appendages : angioedema, erythema multiforme, pruritus,¹ rash,¹ 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.

Norvasc 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 triglycerides,
• total cholesterol,
• HDL cholesterol,
• uric acid,
• blood urea nitrogen, or
• creatinine.

In the CAMELOT and PREVENT studies, the adverse event profile was similar to that reported previously (see above), with the most common adverse event being peripheral edema.

Postmarketing Experience

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.

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.

Norvasc 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.

¹ 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.

Impact Of Other Drugs On Amlodipine

CYP3A Inhibitors

Co-administration with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to amlodipine and may require dose reduction. Monitor for symptoms of hypotension and edema when amlodipine is co-administered with CYP3A inhibitors to determine the need for dose adjustment.

CYP3A Inducers

No information is available on the quantitative effects of CYP3A inducers on amlodipine. Blood pressure should be closely monitored when amlodipine is co-administered with CYP3A inducers.

Sildenafil

Monitor for hypotension when sildenafil is co-administered with amlodipine.

Impact Of Amlodipine On Other Drugs

Simvastatin

Co-administration of simvastatin with amlodipine increases the systemic exposure of simvastatin. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily.

Immunosuppressants

Amlodipine may increase the systemic exposure of cyclosporine or tacrolimus when co-administered. Frequent monitoring of trough blood levels of cyclosporine and tacrolimus is recommended and adjust the dose when appropriate.