Norvasc

• Pfizer Laboratories

Medicines can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Norvasc there are no specific foods that you must exclude from your diet when receiving Norvasc.

Tell your doctor about any prescription and non-prescription medicines you are taking, including natural or herbal remedies. Tell your doctor if you:

• ever had heart disease
• ever had liver problems
• are pregnant, or plan to become pregnant. Your doctor will decide if Norvasc is the best treatment for you.
• are breastfeeding. Do not breast feed while taking Norvasc. You can stop breastfeeding or take a different medicine.

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

Hypertension

Management of hypertension (alone or in combination with other classes of antihypertensive agents);1 2 3 4 5 6 21 113 128 129 130 131 132 133 134 500 may be used in fixed combination with aliskiren, aliskiren and hydrochlorothiazide, benazepril, olmesartan, olmesartan and hydrochlorothiazide, perindopril, telmisartan, valsartan, or valsartan and hydrochlorothiazide when such combined therapy is indicated.21 113 128 129 130 131 132 133 134

Calcium-channel blockers are recommended as one of several preferred agents for the initial management of hypertension; other options include ACE inhibitors, angiotensin II receptor antagonists, and thiazide diuretics.501 502 503 504 While there may be individual differences with respect to specific outcomes, these antihypertensive drug classes all produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes.501 502 503 504 Individualize choice of therapy; consider patient characteristics (e.g., age, ethnicity/race, comorbidities, cardiovascular risk) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, cost).500 501 502 503 504 515

Calcium-channel blockers may be preferred in hypertensive patients with certain coexisting conditions (e.g., ischemic heart disease)523 and in geriatric patients, including those with isolated systolic hypertension.502 510

Black hypertensive patients generally tend to respond better to monotherapy with calcium-channel blockers or thiazide diuretics than to other antihypertensive drug classes (e.g., ACE inhibitors, angiotensin II receptor antagonists).69 70 95 108 109 500 501 504 However, diminished response to these other drug classes is largely eliminated when administered concomitantly with a calcium-channel blocker or thiazide diuretic.500 504

The optimum BP threshold for initiating antihypertensive drug therapy is controversial.501 504 505 506 507 508 515 523 530 Further study needed to determine optimum BP thresholds/goals; individualize treatment decisions.501 503 507 515 526 530

JNC 7 recommends initiation of drug therapy in all patients with uncomplicated hypertension and BP ≥140/90 mm Hg;500 JNC 8 panel recommends SBP threshold of 150 mm Hg for patients ≥60 years of age.501 Although many experts agree that SBP goal of <150 mm Hg may be appropriate for patients ≥80 years of age,502 504 505 530 application of this goal to those ≥60 years of age is controversial, especially for those at higher cardiovascular risk.501 502 505 506 508 511 515

In the past, initial antihypertensive drug therapy was recommended for patients with diabetes mellitus or chronic kidney disease who had BP ≥130/80 mm Hg;500 503 current hypertension management guidelines generally recommend a BP threshold of 140/90 mm Hg for these individuals (same as for the general population of patients without these conditions), although a goal of <130/80 mm Hg may still be considered.501 502 503 504 520 530 535 536 541

Amlodipine should not be used for acute management of hypertensive crises.1 500

Addition of an ACE inhibitor or angiotensin II receptor antagonist may reduce incidence of amlodipine-associated edema.21 134 504

May use amlodipine/atorvastatin fixed-combination preparation when treatment with both amlodipine (for hypertension) and atorvastatin (for dyslipidemias and prevention of cardiovascular events) is appropriate.107

CAD

Amlodipine is used for management of Prinzmetal variant angina and chronic stable angina pectoris;1 2 3 4 9 has been used alone or in combination with other antianginal agents.1 2 3 4 9 Calcium-channel blockers are considered the drugs of choice in management of Prinzmetal variant angina.b

Amlodipine is used in patients with recently documented CAD (by angiography) and without heart failure or an ejection fraction <40% to reduce the risk of coronary revascularization procedure and hospitalization due to angina.1

May use amlodipine/atorvastatin fixed-combination preparation when treatment with both amlodipine (for CAD) and atorvastatin (for dyslipidemias and prevention of cardiovascular events) is appropriate.107

The following information addresses potential interactions with amlodipine. When amlodipine is used in fixed combination with other drugs, consider interactions associated with the concomitant agent(s).21 107 113 128 129 130 131 132 133 134

Drugs Affecting Hepatic Microsomal Enzymes

Moderate or potent CYP3A inhibitors: Increased amlodipine exposure.1 Amlodipine dosage reduction may be necessary.1 Monitor patients for symptoms of hypotension or edema.1

CYP3A inducers: Data lacking; closely monitor BP.1

Specific Drugs and Food

Storage

Oral

Amlodipine: Tight, light-resistant containers at 15–30°C.1

Amlodipine/aliskiren and amlodipine/aliskiren/hydrochlorothiazide fixed combinations: Original container at 25ºC (may be exposed to 15–30ºC); protect from heat and moisture.128 131

Amlodipine/perindopril, amlodipine/valsartan, and amlodipine/valsartan/hydrochlorothiazide fixed combinations: 25ºC (may be exposed to 15–30ºC); protect from moisture.113 130 133

Amlodipine/atorvastatin, amlodipine/olmesartan, and amlodipine/olmesartan/hydrochlorothiazide fixed combinations: 25°C (may be exposed to 15–30°C).107 132 134

Amlodipine/telmisartan fixed combination: Original blister packs at 25ºC (may be exposed to 15–30ºC); protect from light and moisture.129 Do not remove from blister pack until immediately before administration.129

Amlodipine/benazepril fixed combination: Tight container at 25ºC (may be exposed to 15–30ºC).21

• When amlodipine is used in fixed combination with other drugs, importance of informing patients of important cautionary information about the concomitant agent(s).21 107 113 128 129 130 131 132 133 134

• Importance of taking amlodipine/aliskiren or amlodipine/aliskiren/hydrochlorothiazide fixed-combination tablets in a consistent manner relative to meals.128 131

• Importance of storing amlodipine/aliskiren or amlodipine/aliskiren/hydrochlorothiazide fixed-combination tablets in original container.128 131

• Importance of not removing amlodipine/telmisartan fixed-combination tablets from blister pack until immediately before administration.129

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

• Importance of advising patients of other important precautionary information.1 (See Cautions.)

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of liver problems like dark urine, feeling tired, not hungry, upset stomach or stomach pain, light-colored stools, throwing up, or yellow skin or eyes.
• Very bad dizziness or passing out.
• Chest pain that is new or worse.
• A fast heartbeat.
• A heartbeat that does not feel normal.
• Shortness of breath, a big weight gain, or swelling in the arms or legs.
• Stiff muscles, shakiness, or muscle movements that are not normal.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

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 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 [see Clinical Studies (14.4)], 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.

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 [see Clinical Pharmacology (12.3)].

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 [see Clinical Pharmacology (12.2)].

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 [see Clinical Pharmacology (12.3)].

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 [see Clinical Pharmacology (12.3)].

Norvasc is the besylate salt of amlodipine, a long-acting calcium channel blocker.

Amlodipine besylate is chemically described as 3-Ethyl-5-methyl (±)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, monobenzenesulphonate. Its empirical formula is C20H25CIN2O5•C6H6O3S, and its structural formula is:

Amlodipine besylate is a white crystalline powder with a molecular weight of 567.1. It is slightly soluble in water and sparingly soluble in ethanol. Norvasc (amlodipine besylate) Tablets are formulated as white tablets equivalent to 2.5, 5, and 10 mg of amlodipine for oral administration. In addition to the active ingredient, amlodipine besylate, each tablet contains the following inactive ingredients: microcrystalline cellulose, dibasic calcium phosphate anhydrous, sodium starch glycolate, and magnesium stearate.

Take Norvasc exactly as prescribed by your doctor. Follow all directions on your prescription label. Your doctor may occasionally change your dose. Do not use this medicine in larger or smaller amounts or for longer than recommended.

You may take Norvasc with or without food. Take the medicine at the same time each day.

Your blood pressure will need to be checked often.

Your chest pain may become worse when you first start taking Norvasc or when your dose is increased. Call your doctor if your chest pain is severe or ongoing.

If you are being treated for high blood pressure, keep using Norvasc even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medicine for the rest of your life.

Your hypertension or heart condition may be treated with a combination of drugs. Use all medications as directed by your doctor. Read the medication guide or patient instructions provided with each medication. Do not change your doses or stop taking any of your medications without your doctor's advice. This is especially important if you also take nitroglycerin.

Norvasc is only part of a complete program of treatment that may also include diet, exercise, weight control, and other medications. Follow your diet, medication, and exercise routines very closely.

Store at room temperature away from moisture, heat, and light.

Take the missed dose as soon as you remember. If you are more than 12 hours late, skip the missed dose. Do not take extra medicine to make up the missed dose.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include rapid heartbeats, redness or warmth in your arms or legs, or fainting.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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