Category: Articles

A handy nutritional-needs chart to clip and save

Youngsters may be the ones urged to eat their vegetables and drink their milk, but experts say someone ought to be offering similar advice to adults. That’s because nutritional requirements change with age.

Older people may need more of vitamins such as B12 and folic acid, for example, because the ability to absorb these nutrients decreases over the years. And since aging reduces the skin’s capacity to synthesize vitamin D from sunlight, it’s essential that mature adults get enough.

It’s best to get all the necessary vitamins and minerals by eating well-balanced meals. But that can be difficult. If you’re unsure that you’re getting your share of nutrients, you may want to consider a daily multivitamin supplement, especially if your variety of foods is limited, you drink a lot of alcohol, or you have an impaired immune system. (Most experts hesitate to recommend individual vitamin supplements unless there’s a demonstrated need, because some vitamins are toxic in large doses.)

The chart on this page will tell you what the daily nutritional needs of mature adults are, and the role each nutrient plays.

Nutrient Needs
Vitamins		  RDA*
Vitamin A   	Women 800 IU 	Men 1,000 IU
Role: Aids new cell development; boosts the immune system; maintains bones, teeth, skin, eyes, mucous membranes. 
Selected sources: liver, carrots, sweet potatoes, fish, dairy products.

Thiamin (B1)	Women 1.1 mg  	Men 1.5 mg 
Role: Plays an important role in converting blood sugar into energy.
Selected sources: brewer's yeast, kidney beans, peas, lean meats.

Riboflavin (B2)	Women 1.3 mg 	Men 1.7 mg 
Role: Helps the body obtain energy from carbohydrates and proteins. Selected sources: milk, cheese, eggs, fish.

Niacin (B3)	Women 15 mg 	Men 19 mg
Role: Helps convert food into energy, synthesize DNA, and process fat. 
Selected sources: cottage cheese, lean meats.

Vitamin B6  	Women 1.6 mg	Men 2.0 mg
Role: Helps the body resist stress; may reduce symptoms of premenstrual syndrome. 
Selected sources: liver, whole-grain breads, potatoes.

Folic acid (B9) 	Women 180 mcg 	Men 200 mcg
(400 mcg for women of childbearing age) 
Role: Essential for production of red blood cells and proper nervous system development.
Selected sources: spinach, brewer's yeast, soybeans, orange juice.

Vitamin B12  	Women 2 mg	Men 2 mg
Role: Necessary for the nervous system to function; aids in red blood cell development.
Selected sources: fish, dairy foods, eggs.

Vitamin C 	Women 60 mg	Men 60 mg
Role: Maintains gums, teeth, bones, and connective tissue; helps the body absorb iron. 
Selected sources: orange juice, broccoli, green peppers, potatoes, strawberries.

Vitamin D  	Women 5 to10 mcg	Men 5 to10 mcg
Role: Maintains strong bones and teeth.
Selected sources: sunlight, fortified milk.

Vitamin E  	Women 8 mg	Men 10 mg
Role: Helps the body form red blood cells and use vitamin K; protects tissues from damage. 
Selected sources: vegetable oils, nuts, wheat germ. 

Vitamin K  	Women 65 mcg 	Men 65 to 80 mcg 
Role: Essential for blood clotting.
Selected sources: brussels sprouts, cabbage, liver. 

Major Minerals

Calcium 	Women  800 mg  	Men 800 to 1,200 mg 
Role: Essential for strong bones; enables muscles to relax and contract.
Selected sources: yogurt, cheese, tofu, broccoli.

Iodine:    	Women 150 mcg 	Men 120 to 150 mcg 
Role: Needed for proper thyroid function.
Selected sources: iodized salt, seafood, milk.

Iron   	Women 10 to 15 mg 	Men 10 to 12 mg 
Role: Delivers oxygen to cells via the blood. 
Selected sources: prune juice, chickpeas, spinach, cheddar cheese.

Magnesium  	Women 280 mg	Men 350 mg 
Role: Helps bones and teeth remain strong; keeps body's metabolism in balance.
Selected sources: soybeans, avocados.

Phosphorus  	Women 800 mg	Men 800 to 1,200 mg
Role: Participates in chemical reactions; aids growth, maintenance, and repair of tissues. 
Selected sources: red meat, fish, cheese, eggs.  

Zinc   	Women 12 mg  	Men 12 to 15 mg 
Role: Works with red blood cells to transport waste from tissues. 
Selected sources: meat, milk, wheat bran, yeast.

*RDA = recommended dietary allowance, which represents the daily amount the U.S. government believes is necessary to prevent deficiency. RDAs for pregnant and lactating women may be different.

Abbreviations: IU = international units; mcg = micrograms; mg = milligrams

(terfenadine)
60 mg Tablets

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WARNING BOX
DESCRIPTION
CLINICAL PHARMACOLOGY
INDICATIONS AND USAGE
CONTRAINDICATIONS
WARNINGS
PRECAUTIONS
ADVERSE REACTIONS
OVERDOSAGE
DOSAGE AND ADMINISTRATION
HOW SUPPLIED

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WARNING BOX

QT INTERVAL
PROLONGATION/VENTRICULAR
ARRHYTHMIA

RARE CASES OF SERIOUS CARDIOVASCULAR ADVERSE EVENTS, INCLUDING DEATH,
CARDIAC ARREST, TORSADES DE POINTES, AND OTHER VENTRICULAR ARRHYTHMIAS,
HAVE BEEN OBSERVED IN THE FOLLOWING CLINICAL SETTINGS, FREQUENTLY IN
ASSOCIATION WITH INCREASED TERFENADINE LEVELS WHICH LEAD TO
ELECTROCARDIOGRAPHIC QT PROLONGATION:

1. CONCOMITANT ADMINISTRATION OF KETOCONAZOLE (NIZORAL) OR
ITRACONAZOLE (SPORANOX)

2. OVERDOSE, INCLUDING SINGLE DOSES AS LOW AS 360 MG

3. CONCOMITANT ADMINISTRATION OF CLARITHROMLYCIN, ERYTHROMYCIN OR
TROLEANDOMYCIN

4. SIGNIFICANT HEPATIC SYSFUNCTION

TERFENADINE IS CONTRAINDICATED IN PATIENTS TAKING KETOCONAZOLE,
ITRACONAZOLE, ERYTHROMYCIN, CLARITHROMYCIN, OR TROLEANDOMYCIN, AND IN
PATIENTS WITH SIGNIFICANT HEPATIC DYSFUNCTION.

DO NOT EXCEED RECOMMENDED DOSE.

IN SOME CASES, SEVERE ARRHYTHMIAS HAVE BEEN PRECEDED BY EPISODES OF
SYNCOPE. SYNCOPE IN PATIENTS RECEIVING TERFENADINE SHOULD LEAD TO
DISCONTINUATION OF TREATMENT AND FULL EVALUATION OF POTENTIAL
ARRHYTHMIAS.

(See CONTRAINDICATIONS, WARNINGS, CLINICAL PHARMACOLOGY, AND
PRECAUTIONS:
DRUG INTERACTIONS.)

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DESCRIPTION

SELDANE (terfenadine) is available as tablets for oral administration. Each tablet contains 60
mg terfenadine. Tablets also contain, as inactive ingredients: corn starch, gelatin, lactose,
magnesium sterate, and sodium bicarbonate.

Terfenadine is a histamine H₁-receptor antagonist with the chemical name alpha-[4-(1,1-Dimethylethyl) phenyl]-4-(hydroxydiphenylmethyl)-1-piperidinebutanol(+/-). The molecular weight is
471.68. The molecular formula is C₃₂H₄₁NO₂.

It has the following chemical structure:

Terfenadine occurs as a white to off-white crystalline
powder. It is freely soluble in chloroform, soluble in ethanol, and very slightly soluble in water.

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CLINICAL PHARMACOLOGY

Terfenadine is chemically distinct from other antihistamines.

Histamine skin wheal studies have shown that SELDANE in single and repeated doses of 60 mg
in 64 subjects has an antihistaminic effect beginning at 1-2 hours, reaching its maximum at 3-4
hours, and lasting in excess of 12 hours. The correlation between response on skin wheal testing
and clinical efficacy is unclear. The four best controlled and largest clinical trials each lasted 7
days and involved about 1,000 total patients in comparisons of SELDANE (60 mg b.i.d.) with an
active drug (chlorpheniramine, 4 mg t.i.d.; dexchlorpheniramine, 2 mg t.i.d. or clemastine 1 mg
b.i.d. About 50-70% of SELDANE or other antihistamine recipients had moderate to complete
relief of symptoms, compared with 30-50% of placebo recipients. The frequency of drowsiness with SELDANE was
similar to the frequency with placebo and less than with other antihistamines. None of these
studies showed a difference between SELDANE and other anithistamines in the frequency of
anticholinergic effects. In studies which included 52 subjects in whom EEG assessments were
made, no depressant effects have been observed.

Animal studies have demonstrated that terfenadine is a histamine H₁-receptor antagonist. In
these animal studies, no sedative or anticholinergic effects were observed at effective
antihistaminic doses. Radioactive disposition and autoradiographic studies in rats and
radioligand binding studies with guinea pig brain H₁-receptors indicate that, at effective
antihistamine doses, neither terfenadine nor its metabolites penetrate the blood brain barrier
well.

On the basis of a mass balance study using ¹⁴C labeled terfenadine the oral absorption of
terfenadine was estimated to be at least 70%. Terfenadine itself undergoes extensive (99%) first
pass metabolism to two primary metabolites, an active acid metabolite and an inactive
dealkylated metabolite. Therefore, systemic availability of terfenadine is low under normal
conditions, and parent terfenadine is not normally detectable in plasma at levels > 10 ng/mL.
Although in rare cases there was measurable plasma terfenadine in apparently normal
individuals without identifiable risk factors, implications of the finding with respect to the
variability of terfenadine metabolism in the normal population cannot be assessed without
further study. Further studies of terfenadine metabolism in the general population are pending.
From information gained in the ¹⁴C study it appears that approximately forty percent of the total
dose is eliminated renally (40% as acid metabolite, 30% dealkyl metabolite, and 30% minor
unidentified metabolites). Sixty percent of the dose is eliminated in the feces (50% as the acid
metabolite, 2% unchanged terfenadine, and the remainder as minor unidentified metabolites).
Studies investigating the effect of hepatic and renal insufficiency on the metabolism and
excretion of terfenadine are incomplete. Preliminary information indicated that in cases of
hepatic impairment, significant concentrations of unchanged terfendadine can be detected with
the rate of acid metabolite formation being decreased. A single-dose study in patients with
hepatic impairment revealed increased parent terfenadine and impaired metabolism, suggestion
that additional drug accumulation may occur after repetitive dosing in such patients.
Terfenadine is contraindicated for use in patients with significant hepatic dysfunction. (See
CONTRAINDICATIONS and WARNINGS.) In subjects with normal hepatic function, unchanged
terfenadine plasma concentrations have not been detected. Elevated levels of parent
terfenadine, whether due to significant hepatic dysfunction, concomitant medications, or
overdose, have been associated with QT interval prolongation and serious cardiac adverse
events.(See CONTRAINDICATIONS and WARNINGS.) In controlled clinical trials in otherwise normal patients with rhinitis, small increases in QT interval were observed at doses of 60
mg b.i.d. In studies at 300 mg b.i.d. a mean increase in QTc of 10% (range -4% to +30%) (mean increase of 46 msec) was
observed.

Data have been reported demonstrating that compared to young subjects, elderly subjects
experience a 25% reduction in clearance of the acid metabolite after single-dose oral
administration of 120 mg. Further studies are necessary to fully characterize pharmacokinetics
in the elderly.

In vitro studies demonstrate that terfenadine is extensively (97%) bound to human serum protein
while the acid metabolite is approximately 70% bound to human serum protein. Based on data
gathered from in vitro models of antihistaminic activity, the acid metabolite of terfenadine has
approximately 30% of the H₁ blocking activity of terfenadine. The relative contribution of
terfenadine and the acid metabolite to the pharmacodynamic effects have not been clearly
defined. Since unchanged terfenadine is usually not detected in plasma, and active acid
metabolite concentrations are relatively high, the acid metabolite may be the entity responsible
for the majority of efficacy after oral administration of terfenadine.

In a study involving the administration of a single 60 mg SELDANE tablet to 24 subjects, mean
peak plasma levels of the acid metabolite were 263 ng/mL (range 133-423 ng/mL) and occurred
approximately 2.5 hours after dosing. Plasma concentrations of unchanged terfenadine were not
detected. The elimination profile of the acid metabolite was biphasic in nature with an initial
mean plasma half-life of 3.5 hours followed by a mean plasma half-life of 6 hours. Ninety
percent of the plasma level time curve was associated with these half-lives. Although the
elimination profile is somewhat complex, the effective pharmacokinetic half-life can be estimated
at approximately 8.5 hours. However, receptor binding and pharmacologic effects, both
therapeutic and adverse, may persist well beyond that time.

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INDICATIONS AND USAGE

SELDANE is indicated for the relief of symptoms associated with seasonal allergic rhinitis such
as sneezing, rhinorrhea, pruritus, and lacrimation.

Clinical studies conducted to date have not demonstrated effectiveness of terfenadine in the
common cold.

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CONTRAINDICATIONS

CONCOMITANT ADMINISTRATION OF TERFENADINE WITH KETOCONAZOLE (NIZORAL)
OR ITRACONAZOLE (SPORANOX) IS CONTRAINDICATED. TERFENADINE IS ALSO
CONTRAINDICATED IN PATIENTS WITH DISEASE STATES OR OTHER CONCOMITANT
MEDICATIONS KNOWN TO IMPAIR ITS METABOLISM, INCLUDING SIGNIFICANT HEPATIC
DYSFUNCTION, AND CONCURRENT USE OF CLARITHROMYCIN, ERYTHROMYCIN, OR
TROLEANDOMYCIN. QT PROLONGATION HAS BEEN DEMONSTRATED IN SOME
PATIENTS TAKING TERFENADINE IN THESE SETTINGS, AND RARE CASES OF SERIOUS
CARDIOVASCULAR EVENTS, INCLUDING DEATH, CARDIAC ARREST, AND TORSADES DE
POINTES, HAVE BEEN REPORTED IN THESE PATIENT POPULATIONS. (See WARNINGS
and PRECAUTIONS:
Drug Interactions.)

SELDANE is contraindicated in patients with a known hypersensitivity to terfenadine or any of its
ingredients.

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WARNINGS

Terfenadine undergoes extensive metabolism in the liver by a specific cytochrome P-450
isoenzyme. This metabolic pathway may be impaired in patients with hepatic dysfunction
(alcoholic cirrhosis, hepatitis) or who are taking drugs such as ketoconazole, itraconazole, or
clarithromycin, erythromycin, or troleandomycin (macrolide antibiotics), or other potent inhibitors
of this isoenzyme. Interference with this metabolism can lead to elevated terfenadine plasma
levels associated with QT prolongation and increased risk of ventricular tachyarrhythmias (such
as torsades de pointes, ventricular tachycardia and ventricular fibrillation) at the recommended
dose. SELADANE is contraindicated for use by patients with these conditions (see WARNING
BOX, CONTRAINDICATIONS, and PRECAUTIONS: Drug Interactions).

Other patients who may be at risk for these adverse cardiovascular events include patients who
may experience new or increased QT prolongation while receiving certain drugs or having
conditions which lead to QT prolongations. These include patients taking certain
antiarrhythmics, bepridil, certain psychotropics, probucol, or astemizole; patients with electrolyte
abnormalities such as hypokalemia or hypomagnesemia, or taking diuretics with potential for
inducing electrolyte abnormalities; and patients with congenital QT syndrome. SELDANE is not
recommended for use by patients with these conditions.

The relationship of underlying cardiac disease to the development of ventricular
tachyarrhythmias while on SELDANE therapy is unclear; nonetheless, SELDANE should also be
used with caution in these patients.

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PRECAUTIONS

Information for Patients
Patients taking SELDANE should receive the following information and instructions.
Antihistamines are prescribed to reduce allergic symptoms. Patients should be advised to take
SELDANE only as needed and NOT TO EXCEED THE PRESCRIBED DOSE. Patients should
be questioned about use of any other prescription or over-the-counter medication, and should
be cautioned regarding the potential for life-threatening arrhythmias with concurrent use of
ketoconazole, itraconazole, clarithromycin, erythromycin, or troleandomycin. Patients should be
advised to consult the physician before concurrent use of other medications with terfenadine.
Patients should be questioned about pregnancy or lactation before starting SELDANE therapy,
since the drug should be used in pregnancy or lactation only if the potential benefit justifies the
potential risk to fetus or baby. Patients should also be instructed to store this medication in a
tightly closed container in a cool, dry place, away from heat or direct sunlight, and away from
children.

Drug Interactions
Ketoconazole

Spontaneious adverse reaction reports of patients taking concomitant ketoconazole with
recommended doses of terfenadine demonstrate QT interval prolongation and rare serious
cardiac events, e.g. death, cardiac arrest, and ventricular arrhythemia including torsades de
pointes. Pharmacokinetic data indicate that ketoconazole markedly inhibits the metabolism of
terfenadine, resulting in elevated plasma terfenadine levels. Presence of unchanged terfenadine
is associated with statistically significant prolongation of the QT and Qtc intervals.
Concomitant administration of ketoconazole and terfenadine is contraindicated (see
CONTRAINDICATIONS, WARNINGS, and ADVERSE REACTIONS).

Itraconazole
Torsades de pointes and elevated parent terfenadine levels have been reported during
concomitant use of terenadine and itraconazole in clinical trials of itraconazole and from foreign
post-marketing sources. One death has also been reported from foreign post-marketing sources.
Concomitant administration of itraconazole and terfenadin is contraindicated (see
CONTRAINDICATIONS, WARNINGS, and ADVERSE REACTIONS.)

Due to the chemical similarity of other azole-type antifungal agents (including fluconazole,
metronidazole, and miconazole) to ketoconazole and itraconazole, concomitant use of these
products with terfenadine is not recommended pending full examination of potential interactions.

Macrolides
Clinical drug interaction studies indicate that erythromycin and clarithromycin can exert an effect
on terfenadine metabolism by a mechanism which may be similar to that of ketoconazole, but to a
lesser extent. Although erythromycin measurably decreases the clearance of the terfenadine
acid metabolite, its influence on terfenadin plasma levels is still under investigation. A few
spontaneous accounts of QT interval prolongation with ventricular arrhythmia, including torsades
de pointes, have been reported in patients receiving erythromycin or troleandomycin.

Concomitant administration of terfenadine with clarithromycin, erythromycin, or troleandomycin
is contraindicated (see CONTRAINDICATIONS, WARNINGS, ADVERSE REACTIONS).
Pending full characterization of potential interactions, concomitant administration of terfenadine
with other macrolide antibiotics, including azithromycin, is not recommended. Studies to
evaluate the potential interaction of terfenadine with azithromycin are in progress.

Carcinogenesis, Mutagenesis, Impairment of Fertility
Oral doses of terfenadine, corresponding to 63 times the recommended human daily dose, in
mice for 18 months or in rats for 24 months, revealed no evidence of tumorigenicity. Microbial
and micronucleus test assays with terfenadine have revealed no evidence of mutagenesis.

Reproduction and fertility studies in rats showed no effects on male or female fertility at oral
doses of up to 21 times the human daily dose. At 63
times the human daily dose there was a small but significant reduction in implants and at 125
times the human daily dose reduced implants and increased post-implantation losses were
observed, which were judged to be secondary to maternal toxicity.

Pregnancy Category C
There was no evidence of animal teratogencity. Reproduction studies have been performed in
rats at doses 63 times and 125 times the human daily dose and have revealed decreased pup
weight gain and survival when terfenadine was administered throughout pregnancy and
lactation. There are no adequate and well-controlled studies in pregnant women. SELDANE
should be used during pregnancy only if the potential benefit justifies the potential risk to the
fetus.

Nonteratogenic Effects
SELDANE is not recommended for nursing women. The drug has caused decreased pup weight
gain and survival in rats given doses 63 times and 125 times the human daily dose throughout
pregnancy and lactation. Effects on pups exposed to SELDANE only during lactation are not
known, and there are no adequate and well controlled studies in women during lactation.

Pediatric Use
Safety and effectiveness of SELDANE in pediatric patients below the age of 12 years have not
been established.

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ADVERSE REACTIONS

Cardiovascular Adverse Events
Rare reports of severe cardiovascular adverse effects have been received which include
ventriuclar tachyarrhythmias (torsades de pointes, ventricular tachycardia, ventricular fibrillation,
and cardiac arrest), hypotension, palpitations, syncope, and dizziness. Rare reports of deaths
resulting from ventriuclar tachyarrhythmias have been received (see CONTRAINDICATIONS,
WARNINGS and PRECAUTIONS: Drug Interactions).
Hypotension, palpitations, syncope, and dizziness could reflect undetected ventriucular arrhythmia.
IN SOME PATIENTS, DEATH, CARDIAC ARREST OR TORSADES DE POINTES HAVE
BEEN PRECEDED BY EPISODES OF SYNCOPE.(see WARNING BOX).
Rare reports of serious cardiovascular adverse events have been received, some involving QT
prolongation and torsades de pointes, in apparently normal individuals without identifiable risk
factors; there is not conclusive evidence of a causal relationship of these events with
terfenadine. Although in rare cases there was measurable plasma terfenadine, the implications
of this finding with respect to the variability of terfenadine metabolism in the normal population
cannot be assessed without further study. In controlled clinical trials in otherwise normal patients
with rhinitis, small increases in QTc interval were observed at doses of 60 mg b.i.d. in studies at
300 mg b.i.d. a mean increase in QTc of 10% (range -4% to +30%)(mean increase of 46 msec)
was observed.

General Adverse Events
Experience from clinical studies, including both controlled and uncontrolled studies involving
more than 2,400 patients who received SELDANE, provides information on adverse experience
incidence for periods of a few days up to six months. The usual dose in these studies was 60
mg twice daily, but in a small number of patients the dose was as low as 20 mg twice a day, or
as high as 600 mg daily.

In controlled clinical studies using the recommended dose of 60 mg b.i.d., the incidence of
reported adverse effects in patients receiving SELDANE was similar to that reported in patients
receiving placebo.(See Table below)

Adverse Events Reported in Clinical Trials

                          Percent of Patients Reporting
                          Controlled Studies*   All Clinical Studies**
                         SELDANE   Placebo     Control   SELDANE   Placebo
Adverse Event             n=781     n=665       n=626***  n=2462    n=1478

Central Nervous System
  Drowsiness                9.0       8.1         18.1      8.5       8.2
  Headache                  6.3       7.4          3.8     15.8      11.2
  Fatigue                   2.9       0.9          5.8      4.5       3.0
  Dizziness                 1.4       1.1          1.0      1.5       1.2
  Nervousness               0.9       0.2          0.6      1.7       1.0
  Weakness                  0.9       0.6          0.2      0.6       0.5
  Appetite Increase         0.6       0.0          0.0      0.5       0.0
Gastrointestinal System
  Gastrointestinal Distress
  (Abdominal distress,
  Nausea, Vomiting,
  Change in bowel habits)   4.6       3.0          2.7      7.6       5.4
Eye, Ear, Nose, and Throat		
  Dry Mouth/Nose/Throat     2.3       1.8          3.5      4.8       3.1	
  Cough                     0.9       0.2          0.5      2.5       1.7
  Sore Throat               0.5       0.3          0.5      3.2       1.6
  Epistaxis                 0.0       0.8          0.2      0.7       0.4
Skin
  Eruption (including rash
  and urticaria) or itching 1.0       1.7          1.4      1.6       2.0

*   Duration of treatment in "CONTROLLED STUDIES" was usually 7-14 days.
**  Duration of treatment in "ALL CLINICAL STUDIES" was up to 6 months.
*** CONTROL DRUGS: Chlorpheniramine (291 patients), d-Chlorpheniramine (189
patients), Clemastine (146 patients)

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In addition to the more frequent side efects reported in clinical trials (see Table), adverse effects have been reported at a lower incidence in clinical trials and/or spontaneously during marketing of SELDANE that warrant listing as possibly associated with drug administration.
These include: alopecia (hair loss or thinning), anaphylaxis, angioedema, bronchospasm,
confusion, depression, galactorrhea, insomnia, menstrual disorders (including dymenorrhea),
musculoskeletal symptoms, nightmares, paresthesia, photosensitivity, rapid flare of psoriasis,
seizures, sinus tachycardia, sweating, thrombocytopenia, tumor, urinary frequency and visual
disturbances.

In clinical trials, several instances of mild, or in one case, moderate transaminase elevations
were seen in patients receiving SELDANE. Mild elevations were also seen in placebo treated
patients. Marketing experiences include isolated reports of jaundice, cholestatic hepatitis, and
hepatitis. In most cases available information is incomplete.

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OVERDOSAGE

Signs and symptoms of overdosage may be absent or mild (e.g headache, nausea, confusion);
but adverse cardiac events including cardiac arrest, ventricular arrhythmias including torsades
de pointes and QT prolongation have been reported at overdoses of 360 mg or more and
occur more frequently at doses in excess of 600 mg and QTc prolongations of up to 30% have
been observed at a dose of 300 mg b.i.d Seizures and syncope have also been reported. USE
OF DOSES IN EXCESS OF 60 MG B.I.D IS NOT RECOMMENDED. (SEE WARNING BOX,
CLINICAL PHARMACOLOGY, and ADVERSE REACTIONS.)

In overdose cases where ventricular arrhythmias are associated with significant QTc prolongation,
treatment with antiarrhythmics known to prolong QT intervals is not recommended.

Therefore, in cases of overdosage, cardiac monitoring for at least 24 hours is recomendedand
for as long as QTc is prolonged, along with standard measures to remove any unabsorbed drug.
Limited experience with the use of hemoperfusion (n=1) or hemodialysis (n=3) was not successful
in completely removing the acid metabolite of terfenadine from the blood.

Treatment of the signs and symptoms of overdosage should be symptomatic and supportive after
the acute stage.

Oral LD₅₀ values for terfenadine were greater than 5000 mg/kg in mature mice and rats. The oral
LD₅₀ was 438 mg/kg in newborn rats.

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DOSAGE AND ADMINISTRATION

One tablet (60 mg) twice daily for adults and pediatric patients 12 years and older.

USE OF DOSES IN EXCESS OF 60 MG B.I.D IS NOT RECOMMENDED BECAUSE OF THE
INCREASED POTENTIAL FOR QT INTERVAL PROLONGATION AND ADVERSE CARDIAC
EVENTS.(See WARNING BOX.) USE OF TERFENADINE IN PATIENTS WITH SIGNIFICANT
HEPATIC DYSFUNCTION AND IN PATIENTS TAKING KETOCONAZOLE, ITRACONAZOLE,
CLARITHROMYCIN, ERYTHROMYCIN, OR TROLEANDOMYCIN IS CONTRAINDICATED. (See
CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions.)

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HOW SUPPLIED

NDC 0068-0723-61

60 mg tablets in bottles of 100

NDC 0068-0723-65

60 mg tablets in bottles of 500

Tablets are round, white, and debossed “SELDANE”. Store tablets at controlled room temperature (59-86^oF) (15-30^oC). PRotect form exposure to temperatures above 104^oF (40^oC) and moisture.

Prescribing Information as of January 1995

Merrell Dow Pharmaceuticals Inc.
Subsidiary of Marion Merrell Dow Inc.
Kansas City, MO 64114

U.S. Patent 4,254,129.
Other patent applications pending.

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(amlodipine besylate)
Tablets

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DESCRIPTION
CLINICAL PHARMACOLOGY
INDICATIONS AND USAGE
CONTRAINDICATIONS
WARNINGS
PRECAUTIONS
ADVERSE REACTIONS
OVERDOSAGE
DOSAGE AND ADMINISTRATION
HOW SUPPLIED

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DESCRIPTION

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

NORVASC® is chemically described as (R.S.) 3-ethyl-5-methyl-2- (2-aminoethoxymethyl)-4-(2-chlorophenyl) 1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate benzenesulphonate. Its empirical formula is C₂0H₂₅CIN₂0₅·C₆H₆0₃S, 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 arnlodipine 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.

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CLINICAL PHARMACOLOGY

Mechanism of Action: NORVASC is a dihydropyridine calcium antagonist (calcium ion antagonist or slow
channel blocker) that inhibits the transmenibrane influx of calcium ions into vascular smooth muscle and cardiac
muscle. Experimental data suggest that NORVASC binds to both dihydropyridine and nondihydropyridine
binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the
movement of extracellular calcium ions into these cells through specific ion channels. NORVASC inhibits
calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than
on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by NORVASC. Within the
physiologic pH range, NORVASC is an ionized compound (pKa=8.6), and its kinetic interaction with the
calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor
binding site, resulting in a gradual onset of effect.

NORVASC is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction
in peripheral vascular resistance and reduction in blood pressure.

The precise mechanisms by which NORVASC relieves angina have not been fully delineated, but are thought to
include the following:

Exertional Angina: In patients with exertional angina, NORVASC reduces the total peripheral resistance (after-
load) against which the heart works and reduces the rate pressure product, and thus myocardial oxygen demand,
at any given level of exercise.

Vasospastic Angina: NORVASC has been demonstrated to block constriction and restore blood flow in coronary
arteries and arterioles in response to calcium, potassium epinephrine, serotonin, and thromboxane A₂ analog in
experimental animal models and in human coronary vessels in vitro. This inhibition of coronary spasm is
responsible for the effectiveness of NORVASC in vasospastic (Prinzmetal’s or variant) angina.

Pharmacokinetics and Metabolism: After oral administration of therapeutic doses of NORVASC, absorption
produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability has been estimated to be
between 64 and 90%. The bioavailability of NORVASC is not altered by the presence of food.

NORVASC is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the
parent compound and 60% of the metabolites excreted in the urine. Ex vivo studies have shown that
approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients. Elimination
from the plasma is biphasic with a terminal elimination half-life of about 30-50 hours. Steady-state plasma levels
of NORVASC are reached after 7 to 8 days of consecutive daily dosing.

The pharmacokinetics of NORVASC are not significantly influenced by renal impairment. Patients with renal
failure may therefore receive the usual initial dose.

Elderly patients and patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting
increase in AUC of approximately 40-60%, and a lower initial dose may be required.

Pharmacodynamics: Hemodynamics Following administration of therapeutic doses to patients with
hypertension, NORVASC produces vasodilation resulting in a reduction of supine and standing blood pressures.
These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma
catecholamine levels with chronic dosing. Although the acute intravenous administration of amlodipine
decreases arterial blood pressure and increases heart rate in hemodynamic studies of patients with chronic stable
angina, chronic administration of oral amlodipine in clinical trials did not lead to clinically significant changes in
heart rate or blood pressures in normotensive patients with angina.

With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours.
Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in
blood pressure with NORVASC is also correlated with the height of pretreatment elevation; thus, individuals
with moderate hypertension (diastolic pressure 105-114 mmHg) had about a 50% greater response than patients
with mild hypertension (diastolic pressure 90-104 mmHg). Normotensive subjects experienced no clinically
significant change in blood pressures (+1/ -2 mmHg).

As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during
exercise (or pacing) in patients with normal ventricular function treated with NORVASC have generally
demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end
diastolic pressure or volume. In hemodynamic studies, NORVASC has not been associated with a negative
inotropic effect when administered in the therapeutic dose range to intact animals and man, even when
coadministered with beta-blockers to man. Similar findings, however, have been observed in normals or well
compensated patients with heart failure with agents possessing significant negative inotropic effects.

In a double-blind, placebo-controlled clinical trial involving 118 patients with well compensated heart failure
(NYHA Class II and Class III), treatment with NORVASC did not lead to worsened heart failure, based on
measures of exercise tolerance, left ventricular ejection fraction and clinical symptomatology. Studies in patients
with NYHA Class IV heart failure have not been performed and, in general, all calcium channel blockers should
be used with caution in any patient with heart failure.

In hypertensive patients with normal renal function, therapeutic doses of NORVASC resulted in a decrease in
renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without
change in filtration fraction or proteinuria.

Electrophysiologic Effects: NORVASC does not change sinoatrial nodal function or atrioventricular conduction
in intact animals or man. In patients with chronic stable angina, intravenous administration of 10 mg did not
significantly alter A-H and H-V conduction and sinus node recovery time after pacing. Similar results were
obtained in patients receiving NORVASC and concomitant beta blockers. In clinical studies in which
NORVASC was administered in combination with beta-blockers to patients with either hypertension or angina,
no adverse effects on electrocardiographic parameters were observed. In clinical trials with angina patients
alone, NORVASC therapy did not alter electrocardiographic intervals or produce higher degrees of AV blocks.

Effects in Hypertension: The antihypertensive efficacy of NORVASC has been demonstrated in a total of 15
double-blind, placebo-controlled, randomized studies involving 800 patients on NORVASC and 538 on placebo.
Once daily administration produced statistically significant placebo-corrected reductions in supine and standing
blood pressures at 24 hours postdose, averaging about 12/6 mmHg in the standing position and 13/7 mmHg in
the supine position in patients with mild to moderate hypertension. Maintenance of the blood pressure effect
over the 24 hour dosing interval was observed, with little difference in peak and trough effect. Tolerance was
not demonstrated in patients studied for up to 1 year. The 3 parallel, fixed dose, dose response studies showed
that the reduction in supine and standing blood pressures was dose-related within the recommended dosing
range. Effects on diastolic pressure were similar in young and older patients. The effect on systolic pressure was
greater in older patients, perhaps because of greater baseline systolic pressure. Effects were similar in black and
white patients.

Effects in Chronic Stable Angina: The effectiveness of 5-10 mg/day of NORVASC in exercise-induced angina has been evaluated in 8 placebo-controlled, double-blind clinical trials of up to 6 weeks duration involving 1038
patients (684 NORVASC, 354 placebo) with chronic stable angina. In 5 of the 8 studies significant increases in exercise time (bicycle or treadmill) were seen with the 10 mg dose. Increases in symptom-limited exercise time averaged 12.8% (63 sec) for NORVASC 10 mg, and averaged 7.9% (38 sec) for NORVASC 5 mg. NORVASC 10 mg also increased time to 1 mm ST segment deviation in several studies and decreased angina attack rate.
The sustained efficacy of NORVASC in angina patients has been demonstrated over long-term dosing. In
patients with angina there were no clinically significant reductions in blood pressures (4/1 mmHg) or changes in
heart rate (+0.3 bpm).

Effects in Vasospastic Angina: In a double-blind, placebo-controlled clinical trial of 4 weeks duration in 50
patients, NORVASC therapy decreased attacks by approximately 4/week compared with a placebo decrease of
approximately 1/week (p<0.01). Two of 23 NORVASC and 7 of 27 placebo patients discontinued from the
study due to lack of clinical improvement.

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INDICATIONS AND USAGE
1. Hypertension
NORVASC is indicated for the treatment of hypertension. It may be used alone or in combination with other
antihypertensive agents.

2. Chronic Stable Angina
NORVASC is indicated for the treatment of chronic stable angina. NORVASC may be used alone or in
combination with other antianginal agents.

3. Vasospastic Angina (Prinzmetal’s or Variant Angina) NORVASC is indicated for the treatment of confirmed
or suspected vasospastic angina. NORVASC may be used as monotherapy or in combination with other
antianginal drugs.

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CONTRAINDICATIONS
NORVASC is contraindicated in patients with known sensitivity to amlodipine.
WARNINGS

Increased Angina and/or Myocardial Infarction: Rarely, patients, particularly those with severe obstructive
coronary artery disease, have developed documented increased frequency, duration and/or severity of angina or
acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase. The
mechanism of this effect has not been elucidated.

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PRECAUTIONS

General: Since the vasodilation induced by NORVASC is gradual in onset, acute hypotension has rarely been
reported after oral administration of NORVASC. Nonetheless, caution should be exercised when administering
NORVASC as with any other peripheral vasodilator particularly in patients with severe aortic stenosis.

Use in Patients with Congestive Heart Failure: Although hemodynamic studies and a controlled trial in
NYHA Class II-III heart failure patients have shown that NORVASC did not lead to clinical deterioration as
measured by exercise tolerance, left ventricular ejection fraction, and clinical symptomatology, studies have not
been performed in patients with NYHA Class IV heart failure. In general, all calcium channel blockers should be
used with caution in patients with heart failure.

Beta-Blocker Withdrawal: NORVASC is not a beta-blocker and therefore gives no protection against the
dangers of abrupt beta-blocker withdrawal; any such withdrawal should be by gradual reduction of the dose of
beta-blocker

Patients with Hepatic Failure: Since NORVASC is extensively metabolized by the liver and the plasma
elimination half-life (t 1/2) is 56 hours in patients with impaired hepatic function, caution should be exercised
when administering NORVASC to patients with severe hepatic impairment.

Drug Interactions: In vitro data in human plasma indicate that NORVASC has no effect on the protein binding
of drugs tested (digoxin, phenytoin, warfarin, and indomethacin). Special studies have indicated that the co-
administration of NORVASC with digoxin did not change serum digoxin levels or digoxin renal clearance in
normal volunteers; that co-administration with cimetidine did not alter the pharmacokinetics of amlodipine; and
that co-administration with warfarin did not change the warfarin prothrombin response time.

In clinical trials, NORVASC has been safely administered with thiazide diuretics, beta-blockers, angiotensin
converting enzyme inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, non-steroidal anti-
inflammatory drugs, antibiotics, and oral hypoglycemic drugs.

Drug/Laboratory Test Interactions: None known.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Rats and mice treated with amlodipine in the diet for two years, at concentrations calculated to provide daily dosage levels of 0.5,11.25, and 2.5 mg/kg/day showed
no evidence of carcinogenicity The highest dose (for mice, similar to, and for rats twice^* the maximum
recommended clinical -dose of 10 mg on a Mg/M² basis), was close to the maximum tolerated dose for mice but
not for rats.

Mutagenicity studies revealed no drug related effects at either the gene or chromosome levels.
There was no effect on the fertility of rats treated with amloclipine (males for 64 days and females 14 days prior
to mating) at doses up to 10 mg/kg/day (8 times^* the maximum recommended human dose of 10 mg on a
Mg/M² basis).

Pregnancy Category C: No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats or rabbits were treated orally with up to 10 mg/kg amlodipine (respectively 8 times^* and 23 times^* the
maximum recommended human dose of 10 mg on a Mg/M² basis) during their respective periods of major
organogenesis. However, litter size was significantly decreased (by about 50%) and the number of intrauterine
deaths was significantly increased (about 5-fold) in rats administered 10 mg/kg amloclipine for 14 days before
mating and throughout mating and gestation. Amlodipine has been shown to prolong both the gestation period
and the duration of labor in rats at this dose. There are no adequate and well-controlled studies in pregnant
women. Amlodipine should be used during pregnancy only if the potential benefit justifies the potential risk to
the fetus.

Nursing Mothers: It is not known whether amloclipine is excreted in human milk. In the absence of this
information, it is recommended that nursing be discontinued while NORVASC is administered.

Pediatric Use: Safety and effectiveness of NORVASC in children have not been established.

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ADVERSE REACTIONS

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) in doses up to 10 mg to placebo (N=1250), discontinuation of NORVASC due
to adverse reactions was required in only about 1.5% of patients and was not significantly different from placebo
(about 1%). The most common side effects are headache and edema. The incidence (%) of side effects which
occurred in a dose related manner are as follows:

	Adverse      	2.5mg   5.0mg  10.0mg  Placebo
	Event		N=275	N=296	N=268	N=520

	Edema	 	1.8	3.0	10.8	0.6
	Dizziness	1.1	3.4	3.4	1.5
	Flushing	0.7	1.4	2.6	0.0
	Palpitation	0.7	1.4	4.5	0.6

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

			Placebo Controlled Studies
				NORVASC (%) 	PLACEBO (%)
		  		(N=1730)	(N=1250)

	Headache		  7.3		  7.8
	Fatigue			  4.5		  2.8
	Nausea			  2.9		  1.9
	Abdominal Pain		  1.6		  0.3
	Somnolence		  1.4		  0.6

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:

			NORVASC                  PLACEBO
	ADR	  	M=%	 F=%	  	 M=%	  F=%
		     (N=1218)  (N=512)  	(N=914)  (N=336)

	Edema		5.6	14.6		 1.4	  5.1
	Flushing	1.5	4.5		 0.3	  0.9
	Palpitations	1.4	3.3		 0.9	  0.9
	Somnolence	1.3	1.6		 0.8	  0.3

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, hypotension, peripheral ischemia, syncope, tachycardia, postural dizziness, postural hypotension.

Central and Peripheral Nervous System: hypoesthesia, paresthesia, tremor, vertigo.

Gastrointestinal: anorexia, constipation, dyspepsia” dysphagia. diarrhea, flatteries vomiting. gingival
hyperplasia.
General: asthenia,^** back pain, hot flushes, malaise, pain, rigors, weight gain.

Musculo-skeletal System: arthralgia, arthrosis, muscle cramps,^** myalgia.

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

Respiratory System: dyspnea,^**epistaxis.

Skin and Appendages: pruritus,^** rash,^** rash erythematous, rash maculopapular.

^*Based on patient weight of 50 kg.

^**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.

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: thirst.

Hemopoietic: purpura.

The following events occurred in <= 0.1% of patients:
cardiac failure, pulse irregularity, extrasystoles, skin
discoloration, urticaria, skin dryness, alopecia, dermatitis, muscle weakness, twitching, ataxia, hypertonia,
migraine, cold and clammy skin, apathy, agitation, amnesia, gastritis, increased appetite, loose stools, coughing,
rhinitis, dysuria, polyuria, parosmia, taste perversion, abnormal visual accommodation, and xerophthalmia.
Other reactions occurred sporadically and cannot be distinguished from medications or concurrent disease states
such as myocardial infarction and angina.

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 postmarketing experience, jaundice and hepatic enzyme elevations (mostly consistent with cholestasis) in some
cases severe enough to require hospitalization have been reported in association with use of amlodipine.

NORVASC has been used safely in patients with chronic obstructive pulmonary disease, well compensated
congestive heart failure, peripheral vascular disease, diabetes mellitus, and abnormal lipid profiles.

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OVERDOSAGE

Single oral doses of 40 mg/kg and 100 mg/kg in mice and rats, respectively, caused deaths. A single oral dose of
4 mg/kg or higher in dogs caused a marked peripheral vasodilation and hypotension.

Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly
a reflex tachycardia. In humans, experience with intentional overdosage of NORVASC is limited. Reports of
intentional overdosage include a patient who ingested 250 mg and was asymptomatic and was not hospitalized;
another (120 mg) was hospitalized, underwent gastric lavage and remained normotensive; the third (105 mg) was
hospitalized and had hypotension (90/50 mmHg) which normalized following plasma expansion. A patient who
took 70 mg amlodipine and an unknown quantity of benzodiazepine in a suicide attempt, developed shock which
was refractory to treatment and died the following day with abnormally high benzodiazepine plasma
concentration. A case of accidental drug overdose has been documented in a 19 month old male who ingested
30 mg amlodipine (about 2 mg/kg). During the emergency room presentation, vital signs were stable with no
evidence of hypotension, but a heart rate of 180 bpm. Ipecac was administered 3.5 hours after ingestion and on
subsequent observation (overnight) no sequelae were noted.

If massive overdose should occur, active cardiac and respiratory monitoring should be instituted. Frequent blood
pressure measurements are essential. Should hypotension occur, cardiovascular support including elevation of
the extremities and the judicious administration of fluids should be initiated. If hypotension remains unresponsive
to these conservative measures, administration of vasopressors (such as phenylephrine), should be considered
with attention to circulating volume and urine output. Intravenous calcium gluconate may help to reverse the
effects of calcium entry blockade. As NORVASC is highly protein bound, hemodialysis is not likely to be of
benefit.

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DOSAGE AND ADMINISTRATION

The usual initial antihypertensive oral dose of NORVASC is 5 mg once daily with a maximum dose of 10 mg
once daily. Small, fragile, or elderly individuals, or patients with hepatic insufficiency may be started on 2.5 mg
once daily and this dose may be used when adding NORVASC to other antihypertensive therapy.

Dosage should be adjusted according to each patient’s need. In general, Nitration should proceed over 7 to 14
days so that the physician can fully assess the patient’s response to each dose level. Titration may proceed more
rapidly, however, if clinically warranted, provided the patient is assessed frequently.

The recommended dose for chronic stable or vasospastic angina is 5-10 mg, with the lower dose suggested in the
elderly and in patients with hepatic insufficiency. Most patients will require 10 mg for adequate effect. See
ADVERSE REACTIONS section for information related to dosage and side effects.

Co-administration with Other Antihypertensive and/or Antianginal Drugs: NORVASC has been safely
administered with thiazides, ACE inhibitors, beta-blockers, long-acting nitrates, and/or sublingual nitroglycerin.

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HOW SUPPLIED

NORVASC® -2.5 mg Tablets (arnlodipine besylate equivalent to 2.5 mg of amlodipine per tablet) are supplied
as white, diamond, flat-faced, beveled edged engraved with “NORVASC” oil one side and “2.5” on the other side
and supplied as follows:

NDC 0069-1520-66 Bottle of 100

NORVASC®-5 mg Tablets (amlodipine besylate equivalent to 5 mg of amlodipine per tablet) are white, elongated octagon, flat-faced, beveled edged engraved with both “NORVASC” and “5” on one side and plain on the other side and supplied as follows:

NDC 0069-1530-66 Bottle of 100
NDC 0069-1530-41 Unit Dose package of 100
NDC 0069-1530-72 Bottle of 300

NORVASC®-10 mg Tablets (amlodipine besylate equivalent to 10 mg of amlodipine per tablet) are white, round, flat-faced, beveled edged engraved with both “NORVASC” and “10” on one side and plain on the other side and supplied as follows:

NDC 0069-1540-66 Bottle of 100
NDC 0069-1540-41 Unit Dose package of 100

Store bottles at controlled room temperature, 59º to 86ºF (15ºC to 30ºC) and dispense in tight, light-resistant
containers (USP).

©1995 PFIZER INC

(verapamil HCl)
Sustained Release Oral Tablets

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DESCRIPTION
CLINICAL PHARMACOLOGY
INDICATIONS AND USAGE
CONTRAINDICATIONS
WARNINGS
PRECAUTIONS
ADVERSE REACTIONS
OVERDOSAGE
DOSAGE AND ADMINISTRATION
HOW SUPPLIED

---

DESCRIPTION

ISOPTIN SR (verapamil hydrochloride) is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist).
ISOPTIN SR is available for oral administration as light green, capsule shaped, scored, film-coated tablets containing
240 mg verapamil hydrochloride, as light pink, oval shaped, scored, film-coated tablets containing 180 mg verapamil
hydrochloride, and as light violet, oval shaped, film-coated tablets containing 120 mg verapamil hydrochloride. The
tablets are designed for sustained release of the drug in the gastrointestinal tract; sustained release characteristics are
not altered when the tablet is divided in half.
The structural formula of verapamil HCI is given below:

Verapamil HCl is an almost white, crystalline powder, practically free of odor, with a bitter taste. It is soluble in water,
chloroform and methanol. Verapamil HCI is not chemically related to other cardioactive drugs.
In addition to verapamil HCI, the ISOPTIN SR tablet contains the following ingredients: alginate, hydroxypropyl
methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, talc, and
titanium dioxide. The following are the color additives per tablet strength:

	
	Strength (mg)		Color Additive(s)
	120			Iron Oxide
	180			Iron Oxide
	240			D&C; yellow #1 0 Lake dye,
				and FD&C; blue #2 Lake dye

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CLINICAL PHARMACOLOGY

ISOPTIN is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist) which exerts its
pharmacologic effects by modulating the influx of ionic calcium across the cell membrane of the arterial smooth muscle
as well as in conductile and contractile myocardial cells.

Mechanism of Action
Essential Hypertension
ISOPTIN exerts antihypertensive effects, by decreasing systemic vascular resistance, usually without orthostatic
decreases in blood pressure or reflex tachycardia; bradycardia (rate less than 50 beats/min) is uncommon (1.4%). During
isometric or dynamic exercise ISOPTIN does not alter systolic cardiac function in patients with normal ventricular
function. ISOPTIN does not alter total serum calcium levels. However, one report suggested that calcium levels above
the normal range may alter the therapeutic effect of ISOPTIN.

Other Pharmacological Actions of ISOPTIN Include the Following
ISOPTIN (verapamil HCl) dilates the main coronary arteries and coronary arterioles. both in normal and ischemic
regions, and is a potent inhibitor of coronary artery spasm, whether spontaneous or ergonovine-induced. This property
increases myocardial oxygen delivery in patients with coronary artery spasm, and is responsible for the effectiveness of
ISOPTIN in vasospastic (Prinzmetal’s or variant) as well as unstable angina at rest. Whether this effect plays any role in
classical effort angina is not clear, but studies of exercise tolerance have not shown an increase in the maximum
exercise rate pressure product, a widely accepted measure of oxygen utilization. This suggests that, in general, relief of
spasm of dilation of coronary arteries is not an important factor in classical angina.
ISOPTIN regularly reduces the total systemic resistance (afterload) against which the heart works both at rest and at a
given level of exercise by dilating peripheral arterioles.
Electrical activity through the AV node depends, to a significant degree, upon calcium influx through the slow channel.
By decreasing the influx of calcium, ISOPTIN prolongs the effective refractory period within the AV node and slows AV
conduction in a rate-related manner.
Normal sinus rhythm is usually not affected, but in patients with sick sinus syndrome, ISOPTIN may interfere with sinus
node impulse generation and may induce sinus arrest or sinoatrial block. Atrioventricular block can occur in patients
without preexisting conduction defects (see WARNINGS).
ISOPTIN does not alter the normal atrial action potential or intraventricular conduction time, but depresses amplitude,
velocity of depolarization and conduction in depressed atrial fibers. ISOPTIN may shorten the antegrade effective
refractory period of accessory bypass tracts. Acceleration of ventricular rate and/or ventricular fibrillation has been
reported in patients with atrial flutter or atrial fibrillation and a coexisting accessory AV pathway following administration
of verapamil (see WARNINGS).
ISOPTIN has a local anesthetic action that is 1.6 times that of procaine on an equimolar basis. It is not known whether
this action is important at the doses used in man.

Pharmacokinetics and Metabolism: With the immediate release formulation, more than 90% of the orally
administered dose of ISOPTIN is absorbed. Because of rapid biotransformation of verapamil during its first pass through
the portal circulation, bioavailability ranges from 20% to 35%. Peak plasma concentrations are reached between 1 and 2
hours after oral administration. Chronic oral administration of 120 mg of ISOPTIN every 6 hours resulted in plasma
levels of verapamil ranging from 125 to 400 mg/mL with higher values reported occasionally, A nonlinear correlation
between the verapamil dose administered and verapamil plasma levels does exist. No relationship has been established
between the plasma concentration of verapamil and a reduction in blood pressure.

In early dose titration with verapamil a relationship exists between verapamil plasma concentrations and the
prolongation of the PR interval. However, during chronic administration this relationship may disappear. The mean
elimination half-life in single dose studies ranged from 2.8 to 7.4 hours. In these same studies, after repetitive dosing,
the half-life increased to a range from 4.5 to 12.0 hours (after less than 10 consecutive doses given 6 hours apart). Half-
life of verapamil may increase during titration.

Aging may affect the pharmacokinetics of verapamil, Elimination half-life may be prolonged in the elderly.
In multiple dose studies under fasting conditions the bioavailability measured by AUC of ISOPTIN SR was similar to
ISOPTIN immediate release; rates of absorption were, of course, different. In a randomized, single-dose, crossover
study using healthy volunteers, administration of 240 mg ISOPTIN SR with food produced peak plasma verapamil
concentrations of 79 ng/mL, time to peak plasma verapamil concentration of 7.71 hours, and AUC (0-24 hr) of 841 ng-hr/
mL. When ISOPTIN SR was administered to fasting subjects, peak plasma verapamil concentration was 164 ng/mL; time
to peak plasma verapamil concentration was 5.21 hours; and AUC (0-24 hr) was 1,478 ng-hr/mL. Similar results were
demonstrated for plasma norverapamil. Food thus produces decreased bioavailability (AUC) but a narrower peak to
trough ratio. Good correlation of dose and response is not available, but controlled studies of ISOPTIN SR have shown
effectiveness of doses similar to the effective doses of ISOPTIN (immediate release).
In healthy man, orally administered ISOPTIN undergoes extensive metabolism in the liver. Twelve metabolites have
been identified in plasma; all except norverapamil are present in trace amounts only. Norverapamil can reach steady-
state plasma concentrations approximately equal to those of verapamil itself. The cardiovascular activity of
norverapamil appears to be approximately 20% that of verapamil. Approximately 70% of an administered dose is
excreted as metabolites in the urine and 16% or more in the feces within 5 days. About 3% to 4% is excreted in the urine
as unchanged drug. Approximately 90% is bound to plasma proteins. In patients with hepatic insufficiency, metabolism
of immediate release verapamil is delayed and elimination half-life prolonged up to 14 to 16 hours (see PRECAUTIONS);
the volume of distribution is increased and plasma clearance reduced to about 30% of normal. Verapamil clearance
values suggest that patients with liver dysfunction may attain therapeutic verapamil plasma concentrations with one-third
of the oral daily dose required for patients with normal liver function.

After four weeks of oral dosing (120 mg q.i.d.), verapamil and norverapamil levels were noted in the cerebrospinal fluid
with estimated partition coefficient of 0.06 for verapamil and 0.04 for norverapamil.

Hemodynamics and Myocardial Metabolism: ISOPTIN reduces afterload and myocardial contractility. Improved left
ventricular diastolic function in patients with IHSS and those with coronary heart disease has also been observed with
ISOPTIN therapy. In most patients, including those with organic cardiac disease, the negative inotropic action of
ISOPTIN is countered by reduction of afterload and cardiac index is usually not reduced. In patients with severe left
ventricular dysfunction however, (e.g., pulmonary wedge pressure above 20 mmHg or ejection fraction lower than 30%),
or in patients on beta-adrenergic blocking agents or other cardiodepressant drugs, deterioration of ventricular function
may occur (see DRUG INTERACTIONS).

Pulmonary Function: ISOPTIN does not induce bronchoconstriction and hence, does not impair ventilatory function.

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INDICATIONS AND USAGE

ISOPTIN SR (verapamil HCI) is indicated for the management of essential hypertension.

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CONTRAINDICATIONS

Verapamil HCI is contraindicated in:

1. Severe left ventricular dysfunction (see WARNINGS)
2. Hypotension (less than 90 mmHg systolic pressure) or cardiogenic shock
3. Sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker)
4. Second- or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker).
5. Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g., Wolff-Parkinson-White, Lown-Ganong-Levine syndromes). (see WARNINGS)
6. Patients with known hypersensitivity to verapamil hydrochloride.

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WARNINGS

Heart Failure: Verapamil has a negative inotropic effect which, in most patients, is compensated by its afterload
reduction (decreased systemic vascular resistance) properties without a net impairment of ventricular performance. In
clinical experience with 4,954 patients, 87 (1.8%) developed congestive heart failure or pulmonary edema. Verapamil
should be avoided in patients with severe left ventricular dysfunction (e.g., ejection fraction less than 30%, pulmonary
wedge pressure above 20mm Hg, or severe symptoms of cardiac failure) and in patients with any degree of ventricular
dysfunction if they are receiving a beta adrenergic blocker (see DRUG INTERACTIONS). Patients with milder ventricular
dysfunction should, it possible, be controlled with optimum doses of digitalis and/ or diuretics before verapamil treatment
(Note interactions with digoxin under: PRECAUTIONS).

Hypotension: Occasionally, the pharmacologic action of verapamil may produce a decrease in blood pressure below
normal levels which may result in dizziness or symptomatic hypotension. The incidence of hypotension observed in
4,954 patients enrolled in clinical trials was 2.5%. In hypertensive patients, decreases in blood pressure below normal are
unusual. Tilt table testing (60 degrees) was not able to induce orthostatic hypotension.

Elevated Liver Enzymes: Elevations of transaminases with and without concomitant elevations in alkaline phosphatase
and bilirubin have been reported. Such elevations have sometimes been transient and may disappear even in the face
of continued verapamil treatment. Several cases of hepatocellular injury related to verapamil have been proven by
rechallenge; half of these had clinical symptoms (malaise, fever, and/or right upper quadrant pain) in addition to
elevations of SGOT, SGPT and alkaline phosphatase. Periodic monitoring of liver function in patients receiving
verapamil is therefore prudent.

Accessory Bypass Tract (Wolff-Parkinson-White or Lown-Ganong-Levine): Some patients with paroxysmal and/ or
chronic atrial fibrillation or atrial flutter and a coexisting accessory AV pathway have developed increased antegrade
conduction across the accessory pathway bypassing the AV node, producing a very rapid ventricular response or
ventricular fibrillation after receiving intravenous verapamil (or digitalis). Although a risk of this occurring with oral
verapamil has not been established, such patients receiving oral verapamil may be at risk and its use in these patients is
contraindicated (see CONTRAINDICATIONS).

Treatment is usually DC-cardioversion. Cardioversion has been used safely and effectively after oral ISOPTIN.
Atrioventricular Block: The effect of verapamil on AV conduction and the SA node may lead to asymptomtic first-
degree AV block and transient bradycardia, sometimes accompanied by nodal escape rhythms. PR interval prolongation
is correlated with verapamil plasma concentrations, especially the early titration phases of therapy. Higher degrees of AV
block, however, were infrequently (0.8%) observed. Marked first degree block or progressive development to
second- or third-degree AV block requires a reduction in dosage or, in rare instances. discontinuation of verapamil HCI
and institution of appropriate therapy depending upon the clinical situation.

Patients with Hypertrophic Cardiomyopathy (IHSS): In 120 patients with hypertrophic cardiomyopathy (most of them
refractory or intolerant to propranolol) who received therapy with verapamil at doses up to 720 mg/day, a variety of
serious adverse effects were seen, Three patients died in pulmonary edema; all had severe left ventricular outflow
obstruction and a past history of left ventricular dysfunction. Eight other patients had pulmonary edema and/or severe
hypotension; abnormally high (over 20 mmHg) capillary wedge pressure and a marked left ventricular outflow obstruction
were present in most of these patients. Concomitant administration of quinidine (see DRUG INTERACTIONS) preceded
the severe hypotension in 3 of the 8 patients (2 of whom developed pulmonary edema). Sinus bradycardia occurred in
11 % of the patients, second-degree AV block in 4% and sinus arrest in 2%. It must be appreciated that this group of
patients had a serious disease with a high mortality rate. Most adverse effects responded well to dose reduction and only
rarely did verapamil have to be discontinued.

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PRECAUTIONS

General
Use In Patients with Impaired Hepatic Functions: Since verapamil is highly metabolized by the liver, it should be
administered cautiously to patients with impaired hepatic function. Severe liver dysfunction prolongs the elimination half-
life of immediate release verapamil to about 14 to 16 hours, hence, approximately 30% of the dose given to patients with
normal liver function should be administered to these patients. Careful monitoring for abnormal prolongation of the PR
interval or other signs of excessive pharmacologic effects (see OVERDOSAGE) should be carried out.

Use In Patients with Attenuated (Decreased) Neuromuscular Transmission: It has been reported that verapamil
decreases neuromuscular transmission in patients with Duchenne’s muscular dystrophy, and that verapamil prolongs
recovery from the neuromuscular blocking agent vecuronium. It may be necessary to decrease the dosage of verapamil
when it is administered to patients with attenuated neuromuscular transmission.

Use In Patients with Impaired Renal Function: About 70% of an administered dose of verapamil is excreted as
metabolites in the urine. Verapamil is not removed by hemodialysis, Until further data are available, verapamil should be
administered cautiously to patients with impaired renal function. These patients should be carefully monitored for
abnormal prolongation of the PR interval or other signs of overdosage (see OVERDOSAGE).

Drug Interactions
Beta Blockers: Concomitant therapy with beta-adrenergic blockers and verapamil may result in additive negative effects
on heart rate, atrioventricular conduction, and/or cardiac contractility, The combination of sustained-release verapamil
and beta-adrenergic blocking agents has not been studied. However, there have been reports of excessive bradycardia
and AV block, including complete heart block, when the combination has been used for the treatment of hypertension,
For hypertensive patients, the risks of combined therapy may outweigh the potential benefits. The combination should
be used only with caution and close monitoring.

Asymptomatic bradycardia (36 beats/min) with a wandering atrial pacemaker has been observed in a patient receiving
concomitant timolol (a beta -adrenergic blocker) eyed drops and oral verapamil.

A decrease in metoprolol and propranolol clearance has been observed when either drug is administered concomitantly
with verapamil. A variable effect has been seen when verapamil and atenolol were given together.

Digitalis: Clinical use of verapamil in digitalized patients has shown the combination to be well tolerated if digoxin doses
are properly adjusted. Chronic verapamil treatment can increase serum digoxin levels by 50 to 75% during the first week
of therapy, and this can result in digitalis toxicity, In patients with hepatic cirrhosis the influence of verapamil on digoxin
kinetics is magnified. Verapamil may reduce total body clearance and extrarenal clearance of digitoxin by 27% and 29%,
respectively. Maintenance digitalis doses should be reduced when verapamil is administered, and the patient should be
carefully monitored to avoid over-or underdigitalization. Whenever overdigitalization is suspected, the daily dose of
digitalis should be reduced or temporarily discontinued. Upon discontinuation of ISOPTIN (verapamil HCI), the patient
should be reassessed to avoid underdigitalization.

Antihypertensive Agents: Verapamil administered concomitantly with oral antihypertensive agents (e.g., vasodilators,
angiotensin-converting enzyme inhibitors, diuretics, beta blockers) will usually have an additive effect on lowering blood
pressure. Patients receiving these combinations should be appropriately monitored. Concomitant use of agents that
attenuate alpha-adrenergic function with verapamil may result in a reduction in blood pressure that is excessive in some
patients. Such an effect was observed in one study following the concomitant administration of verapamil and prazosin.

Antiarrhythmic Agents
Disopyramide: Until data on possible interactions between verapamil and disopyramide phosphate are obtained,
disopyramide should not be administered within 48 hours before or 24 hours after verapamil administration.

Flecainide: A study of healthy volunteers showed that the concomitant administration of flecainide and verapamil may
have additive effects on myocardial contractility, AV conduction, and repolarization. Concomitant therapy with flecainide
and verapamil may result in additive negative inotropic effect and prolongation of atrioventricular conduction.

Quinidine: In a small number of patients with hypertrophic cardiomyopathy (IHSS), concomitant use of verapamil and
quinidine resulted in significant hypotension. Until further data are obtained, combined therapy of verapamil and
quinidine in patients with hypertrophic cardiomyopathy should probably be avoided.
The electrophysiological effects of quinidine and verapamil on AV conduction were studied in 8 patients. Verapamil
significantly counteracted the effects of quinidine on AV conduction were studied in 8 patients Verapamil significantly
counteracted the effects of quinidine on AV conduction. There has been a report of increased quinidine levels during
verapamil therapy.

Nitrates: Verapamil has been given concomitantly with short and long-acting nitrates without any undesirable drug
interactions. The pharmacologic profile of both drugs and the clinical experience suggest beneficial interactions.

Other
Cimetidine: The interaction between cimetidine and chronically administered verapamil has not been studied. Variable
results on clearance have been obtained in acute studies of healthy volunteers; clearance of verapamil was either
reduced or unchanged.

Lithium: Increased sensitivity to the effects of lithium (neurotoxicity) has been reported during concomitant verapamil
lithium therapy with either no change or an increase in serum lithium levels. However, the addition of verapamil has also
resulted in the lowering of serum lithium levels in patients receiving chronic stable oral lithium. Patients receiving both
drugs must be monitored carefully.

Carbamazepine: Verapamil therapy may increase carbamazepine concentrations during combined therapy. This may
produce carbamazepine side effects such as diplopia, headache, ataxia, or dizziness.

Rifampin: Therapy with rifampin may markedly reduce oral verapamil bioavailability.

Phenobarbital: Phenobarbital therapy may increase verapamil clearance.

Cyclosporin: Verapamil therapy may increase serum levels of cyclosporin.

Theophylline: Verapamil may inhibit the clearance and increase the plasma levels of theophylline.

Inhalation Anesthetics: Animal experiments have shown that inhalation anesthetics depress cardiovascular activity by
decreasing the inward movement of calcium ions. When used concomitantly, inhalation anesthetics and calcium
antagonists, such as verapamil, should be titrated carefully to avoid excessive cardiovascular depression.

Neuromuscular Blocking Agents: Clinical data and animal studies suggest that verapamil may potentiate the activity
of neuromuscular blocking agents (curare-like and depolarizing). It may be necessary to decrease the dose of verapamil
and/or the dose of the neuromuscular blocking agent when the drugs are used concomitantly.

Carcinogenesis, Mutagenesis, Impairment of Fertility: An 18-month toxicity study in rats. at a low multiple (6 fold) of
the maximum recommended human dose, and not the maximum tolerated dose. did not suggest a tumorigenic potential,
There was no evidence of a carcinogenic potential of verapamil administered in the diet of rats for two years at doses of
10, 35, and 120 mg/kg per day or approximately 1x, 3.5x, and 12x, respectively, the maximum recommended human
daily dose (480 mg per day or 9.6 mg/kg/day).
Verapamil was not mutagenic in the Ames test in 5 test strains at 3 mg per plate, with or without metabolic activation.
Studies in female rats at daily dietary doses up to 5.5 times (55 mg/kg/day) the maximum recommended human dose did
not show impaired fertility. Effects on male fertility have not been determined.

Pregnancy: Pregnancy Category C. Reproduction studies have been performed in rabbits and rats at oral doses up to
1.5 (15 mg/kg/day) and 6 (60 mg/kg/day) times the human oral daily dose, respectively, and have revealed no evidence
of teratogenicity. In the rat, however, this multiple of the human dose was embryocidal and retarded fetal growth and
development, probably because of adverse maternal effects reflected in the reduced weight gains of the dams. This oral
dose has also been shown to cause hypotension in rats, There are no adequate and well-controlled studies in pregnant
women, Because animal reproduction studies are not always predictive of human response, this drug should be used
during pregnancy only it clearly needed. ISOPTIN (verapamil HCI) crosses the placental barrier and can be detected in
umbilical vein blood at delivery.

Labor and Delivery: It is not known whether the use of verapamil during labor or delivery has immediate or delayed
adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or
other obstetric intervention. Such adverse experiences have not been reported in the literature, despite a long history of
use of ISOPTIN in Europe in the treatment of cardiac side effects of beta-adrenergic agonist agents used to treat
premature labor.

Nursing Mothers: ISOPTIN is excreted in human milk. Because of the potential for adverse reactions in nursing infants
from verapamil, nursing should be discontinued while verapamil is administered.

Pediatric Use: Safety and efficacy of ISOPTIN in children below the age of 18 years have not been established.

Animal Pharmacology and/or Animal Toxicology: In chronic animal toxicology studies verapamil caused lenticular
and/or suture line changes at 30 mg/kg/day or greater and frank cataracts at 62.5 mg/kg/day or greater in the beagle dog
but not the rat. Development of cataracts due to verapamil has not been reported in man.

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ADVERSE REACTIONS

Serious adverse reactions are uncommon when ISOPTIN (verapamil HCl) therapy is initiated with upward dose titration
within the recommended single and total daily dose. See WARNINGS for discussion of heart failure, hypotension,
elevated liver enzymes, AV block, and rapid ventricular response. Reversible (upon discontinuation of verapamil)
nonobstructive, paralytic, ileus has been infrequently reported in association with the use of verapamil. The following
reactions to orally administered ISOPTIN occurred at rates greater than 1.0% or occurred at lower rates but appeared
clearly drug related in clinical trials in 4,954 patients.

Constipation			7.3%	Fatigue				1.7%
Dizziness			3.3%	Dyspnea				1.4%
Nausea				2.7%	Bradycardia (HR <50/min)	1.4%
Hypotension			2.5%	AV Block-total 1º, 2º, 3º	1.2%
Headache			2.2%	2º and 3º			0.8%
Edema				1.9%	Rash				1.2%
CHF/Pulmonary Edema 		1.8%    Flushing                        0.6%

		Elevated Liver Enzymes (see WARNING)

In clinical trials related to the control of ventricular response in digitalized patients who had atrial fibrillation or atrial
flutter, ventricular rates below 50/min at rest occurred in 15% of patients and asymptomatic hypotension occurred in 5%
of patients.

The following reactions, reported in 1.0% or less of patients, occurred under conditions (open trials, marketing
experience) where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship.

Cardiovascular:

• angina pectoris, atrioventricular dissociation, chest pain, claudication, myocardial infarction,

 

• palpitations, purpura (vasculitis), syncope.

Digestive System:

• diarrhea, dry mouth, gastrointestinal distress, gingival hyperplasia.

Hemic and Lymphatic:

• ecchymosis or bruising.

Nervous System:

• cerebrovascular accident, confusion, equilibrium disorders, insomnia, muscle cramps, parathesia,

 

• psychotic symptoms, shakiness, somnolence.

 

• Skin: arthralgia and rash, exanthema, hair loss, hyperkeratosis, maculae, sweating, urticaria, Stevens-Johnson

 

• syndrome, erythema multiforme.

Special Senses:

• blurred vision.

Urogenital:

gynecomastia, impotence, galactorrhea/ hyperprolactinemia, increased urination, spotty menstruation.

Treatment of Acute Cardiovascular Adverse Reactions: The frequency of cardiovascular adverse reactions which
require therapy is rare, hence, experience with their treatment is limited. Whenever severe hypotension or complete AV
block occur following oral administration of verapamil the appropriate emergency measures should be applied
immediately, e.g., intravenously administered isoproterenol HCI, levarterenol bitartrate, atropine (all in the usual doses),
or calcium gluconate (10% solution). In patients with hypertrophic cardiomyopathy (IHSS), alpha-adrenergic agents
(phenylephrine, metaraminol bitartrate or methoxamine) should be used to maintain blood pressure, and isoproterenol
and levarterenol should be avoided. If further support is necessary, inotropic agents (dopamine or dobutamine) may be
administered. Actual treatment and dosage should depend on the severity and the clinical situation and the judgment
and experience of the treating physician.

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OVERDOSAGE

Treat all verapamil overdoses as serious and maintain observation for at least 48 hours (especially Isoptin SR),
preferably under continuous hospital care. Delayed pharmacodynamic consequences- may occur with the sustained
released formulation. Verapamil is known to decrease gastrointestinal transit time.
Treatment of overdosage should be supportive. Beta adrenergic stimulation or parenteral administration of calcium
solutions may increase calcium ion flux across the slow channel, and have been used effectively in treatment of
deliberate overdosage with verapamil. Verapamil cannot be removed by hemodialysis, Clinically significant hypotensive
reactions or high degree AV block should be treated with vasopressor agents or cardiac pacing, respectively. Asystole
should be handled by the usual measures including cardiopulmonary resuscitation.

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DOSAGE AND ADMINISTRATION

Essential Hypertension
The dose of ISOPTIN SR should be individualized by titration and the drug should be administered with food. Initiate
therapy with 180 mg of sustained-release verapamil HCI, ISOPTIN SR, given in the morning. Lower, initial doses of 120
mg a day may be warranted in patients who may have an increased response to verapamil (e.g., the elderly or small
people etc.). Upward titration should be based on therapeutic efficacy and safety evaluated weekly and approximately 24
hours after the previous dose. The antihypertensive effects of ISOPTIN SR are evident within the first week of therapy.
If adequate response is not obtained with 180 mg of ISOPTIN SR, the dose may be titrated upward in the following
manner:

• 240 mg each morning,
• 180 mg each morning plus 180 mg each evening, or
  240 mg each morning plus 120 mg each evening
• 240 mg every twelve hours.

 

 

When switching from immediate release ISOPTIN to ISOPTIN SR, the total daily dose in milligrams may remain the
same.

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HOW SUPPLIED

ISOPTIN® SR 240 mg tablets are supplied as light green, capsule shaped, scored, film-coated tablets containing 240 mg
of verapamil hydrochloride. The tablet is embossed with a double Knoll triangle on one side and “ISOPTIN SR” on the
other side. ISOPTIN® SR 180 mg tablets are supplied as light pink, oval shaped, scored, film-coated tablets containing
180 mg of verapamil hydrochloride. The tablet is embossed with “ISOPTIN SR” on one side, and “180 mg” on the other
side. The ISOPTIN® SR 120 mg tablets are supplied as light violet, oval shaped film-coated tablets containing 120 mg
of verapamil hydrochloride. The tablet is embossed with “KNOLL” on one side and “120 SR” on the other side.

240 mg (light green)- 	Bottle of 30-
			NDC #0044-1826-93
			Bottle of 100-
			NDC #0044-1826-02
			Hospital Unit Dose (100 Tablets- 
			Strips of 10) - NDC #0044-1 826-10
180 mg (light pink)- 	Bottle of 100-
			NDC #0044-1825-02
			Hospital Unit Dose (100 Tablets
			Strips of 10) - NDC # 0044-1825-12
120 mg (light violet)-	Bottle of 100-
			NDC #0044-1827-02
			Hospital Unit Dose (100 Tablets
			Strips of 10) - NDC #0044-1827-12

Storage: 59º-77ºF (15º-25ºC).
Protect from light and moisture.
Dispense in a tight, light-resistant container as defined in the USP.