Valni XL 30mg prolonged release tablets

1. Name Of The Medicinal Product

VALNI XL 30 mg PROLONGED RELEASE TABLETS

2. Qualitative And Quantitative Composition

Each tablet contains 30 mg of nifedipine

For excipients see 6.1

3. Pharmaceutical Form

Prolonged release tablet

Each pale red tablet is round and biconvex and embossed with "30" on one side.

4. Clinical Particulars

4.1 Therapeutic Indications

The tablets are indicated for:

- the treatment of all grades of hypertension

- the prophylaxis of chronic stable angina pectoris, either as monotherapy or in combination with a beta-blocker

4.2 Posology And Method Of Administration

Route of Administration

For oral use

These tablets should be swallowed whole with a glass of water and not bitten, broken up or chewed.

Dosage Recommendations

It is recommended that each dose should be taken at approximately 24 hours intervals i.e., at the same time each day, preferably in the morning.

Adults: In mild to moderate hypertension the recommended initial dose is one 20 mg tablet once daily. In severe hypertension and the prophylaxis of angina pectoris the recommended initial dose is one 30 mg tablet once daily. The dose may be adjusted to a maximum of 90 mg once daily.

Prophylactic anti-anginal efficacy is maintained when patients are switched from other calcium antagonists e.g. verapamil or diltiazem. When patients are switched, the recommended initial dose is 30 mg nifedipine, once daily. Subsequent titration to a higher dosage should be according to clinical response.

Elderly: The pharmacokinetics of nifedipine may be altered in the elderly therefore, a lower maintenance dose may be necessary when treating elderly patients.

Patients With Renal Impairment: Dosage adjustments should not be required for patients with impaired renal function.

Patients With Hepatic Impairment: Nifedipine prolonged release tablets should not be administered to patients with impaired hepatic function.

Children: Nifedipine is not recommended for use in children.

Treatment with nifedipine may be continued long term.

4.3 Contraindications

VALNI XL 30 mg PROLONGED RELEASE TABLETS are contraindicated:

- in patients with a known hypersensitivity to the drug or other constituents of the tablets

- in patients with a known hypersensitivity to other dihydropyridines calcium antagonists, because of the theoretical risk of cross-reactivity

- in women who are or may become pregnant, are capable of child bearing or to nursing mothers

- in patients with clinically significant aortic stenosis, in cardiogenic shock or unstable angina or for the treatment of acute attacks of angina

- in patients with inflammatory bowel disease, Crohn's disease or with a history of gastrointestinal obstruction, oesophageal obstruction or with decreased diameter of the gastrointestinal lumen

- in patients with hepatic impairment

- for secondary prevention of myocardial infarction or during or within one month of a myocardial infarction

VALNI XL 30 mg PROLONGED RELEASE TABLETS should not be administered concomitantly with rifampicin since effective plasma levels of nifedipine may not be achieved owing to enzyme induction (see section 4.5).

The safety of nifedipine prolonged release tablets has not been established in patients with malignant hypertension.

4.4 Special Warnings And Precautions For Use

Nifedipine should be used with caution in patients with hypotension, as there is a risk of blood pressure decreasing further and in patients whose cardiac reserve is poor. Deterioration of heart failure has occasionally been observed with nifedipine.

Cardiac ischaemic pain has been reported to occur in a small proportion of patients following the introduction of nifedipine therapy. In such cases, treatment with nifedipine should be discontinued.

Caution should be exercised when nifedipine tablets are given to diabetic patients as they may require adjustment of their diabetic therapy.

In patients with malignant hypertension and hypovolaemia and who are on dialysis, a significant decrease in blood pressure can occur.

Nifedipine may be used in combined therapy with other antihypertensive agents including beta-blocker drugs, but the possibility of an additive effect resulting in postural hypotension should be borne in mind. Withdrawal of any previous antihypertensive agents should be gradual, as nifedipine will not prevent any possible rebound effects.

Nifedipine is contra-indicated in pregnancy. However, caution must be exercised when nifedipine with intravenous magnesium sulphate is given to pregnant women.

VALNI XL 30 mg PROLONGED RELEASE TABLETS must not be administered to patients with Kock pouch (ileostomy after proctocolectomy).

A false positive effect may be obtained when carrying out a barium contrast X-ray.

VALNI XL 30 mg PROLONGED RELEASE TABLETS contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance e.g. galactosaemia, the Lapp lactase deficiency or glucose-galactose malabsorption, should be advised not to take these tablets.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Known Interactions

Nifedipine should not be taken with grapefruit juice because bioavailability is increased.

Cimetidine may potentiate the antihypertensive effect of nifedipine tablets if it is administered simultaneously.

It is reported that serum quinidine levels have been reduced when it is used in combination with nifedipine, irrespective of the quinidine dose taken.

The administration of nifedipine and digoxin concurrently may lead to reduced digoxin clearance and therefore, bring about an increase in the plasma digoxin level. Close monitoring of plasma digoxin levels should take place and, if necessary, a reduction in the dosage of digoxin.

Phenytoin induces the cytochrome P450 3A4 system. When nifedipine is co-administered with phenytoin, nifedipine's bioavailability is reduced and consequently, its efficacy is weakened. In such cases, the clinical response to nifedipine should be monitored following concomitant administration and, if necessary, consideration should be given to increasing the nifedipine dose. If the nifedipine dose is increased during the co-administration of both drugs, consideration should be given to reducing the nifedipine dose when phenytoin therapy is discontinued.

Diltiazem decreases the clearance of nifedipine and hence increases plasma nifedipine levels. Caution should be exercised when both drugs are given simultaneously. A reduction of nifedipine dose may be required when the two are used together.

Nifedipine may falsely increase the spectrophotometric values of urinary vanillylmandelic acid. HPLC measurements are not affected.

Nifedipine should not be administered concomitantly with rifampicin, as effective plasma levels of nifedipine may not be achieved as a result of enzyme induction.

Simultaneous administration of cisapride and nifedipine or quinupristin / dalfopristin and nifedipine may lead to increased plasma concentration of nifedipine. Hence, the blood pressure may need to be monitored and a reduction in the nifedipine dose may be necessary.

Nifedipine enhances the effect of non-polarising muscle relaxants.

Theoretical Interactions

Nifedipine is metabolised via the cytochrome P450 3A4 system. Therefore, there are theoretical interactions with drugs such as erythromycin, ketoconazole, itraconazole, fluconazole, fluoxetine, indinavir, nelfinavir, ritonavir and saquinavir that are known to inhibit this enzyme system. Although no in vivo interaction studies with these drugs have been carried out, their co-administration with nifedipine in vitro, have shown increases in nifedipine plasma concentrations. Therefore, the blood pressure should be monitored and, if necessary, a reduction in the nifedipine dose should be considered.

Similarly, the potential interaction between nifedipine and nefazodone has not been clinically investigated. Nefazodone is known to inhibit the cytochrome P450 3A4 mediated metabolism of other drugs and therefore, co-administration with nifedipine may increase the plasma concentrations of nifedipine. Again, monitoring of the blood pressure is advised when both drugs are simultaneously administrated with, if necessary, a reduction in the nifedipine dose.

Tacrolimus is metabolised via the cytochrome P450 3A4 system. Upon co-administration with nifedipine, the plasma levels of tacrolimus should be monitored and, if necessary, consideration should be given to reducing the tacrolimus dose.

Carbamazepine, phenobarbital or valproic acid have been shown to alter the plasma levels of a structurally similar calcium channel blocker, however, no interactive studies have been carried out with these drugs and nifedipine. A decrease (with carbamazepine or phenobarbital) or an increase (with valproic acid) in nifedipine plasma concentrations, leading to a change in efficacy, can therefore not be ruled out.

Drugs Shown Not to Interact with Nifedipine

Aspirin, benazepril, candesartan cilexetil, debrisoquine, doxazosin, irbesartan, omeprazole, orlistat, pantoprazole, ranitidine, rosiglitazone and triamterene hydrochlorothiazide are drugs known not to affect the pharmacokinetics of nifedipine when they are administered concomitantly with nifedipine.

4.6 Pregnancy And Lactation

Nifedipine is contraindicated in woman capable of child-bearing.

Safe use of nifedipine during human pregnancy has not been established. Animal studies have shown reproductive toxicity (embryotoxic and teratogenic effects) at maternally toxic doses.

Nifedipine may be present in breast milk and therefore, VALNI XL 30 mg PROLONGED RELEASE TABLETS are contraindicated for use in nursing mothers.

In single reports of in vitro fertilisation, calcium antagonists like nifedipine have been associated with biochemical alterations in the head of the spermatozoa that may impair sperm function. Calcium antagonists like nifedipine should be considered as possible causes in those men who are repeatedly unsuccessful in fathering a child by in vitro fertilisation and where no other explanation can be found.

4.7 Effects On Ability To Drive And Use Machines

Reactions to nifedipine may vary in intensity in patients, especially at the onset of therapy, on changing medication or when combined with alcohol. Therefore, the patient should be warned of the possible effects and advised not to drive or operate machinery, if affected.

4.8 Undesirable Effects

Most undesirable effects are due to vasodilatory action of nifedipine and usually regress upon withdrawal of treatment.

Those commonly reported (at an incidence of (> 1 % < 10 %) in clinical studies include headache, palpitations, vasodilatation (especially at the start of therapy), lethargy, constipation, dizziness and oedema particularly peripheral oedema not connected with weight gain or heart failure.

Other side effects associated with nifedipine therapy are named below :

	Uncommon Side Effects (> 0.1 % < 1 % )	Rare Side Effects (> 0.01 % < 0.1 % )	Spontaneous Reports ( < 0.01 % )
Body as a Whole	abdominal pain, chest pain, leg pain, malaise	allergic reaction, chest pain substernal, chills, hypersensitivity-type jaundice, facial oedema fever	anaphylactic reaction, weight loss
Cardiovascular	hypotension, postural hypotension, syncope, tachycardia	cardiovascular disorder
Digestive	diarrhoea, dry mouth, dyspepsia, flatulence, nausea	anorexia, eructation, gastrointestinal disorder, gingivitis, gingival hyperplasia, vomiting	bezoar, dysphagia, oesophagitis, gum disorder, intestinal obstruction, intestinal ulcer
Haematological			leucopenia, hyperglycaemia
Hepatic		liver function test abnormalities, increase in GGT	increase in ALT, jaundice
Musculoskeletal	leg cramps	arthralgia, joint disorder, myalgia	muscle cramps
Neurological	insomnia, nervousness, paraesthesia, somnolence, vertigo	hyperaesthesia, sleep disorder, tremor, mood changes
Respiratory	dyspnoea	epistaxis
Dermatological	pruritus, rash	angioedema, maculopapular, pustular and vesiculobullous rash, sweating, urticaria	purpura, exfoliative dermatitis, photosensitive dermatitis
Special Senses		abnormal vision, eye disorder, eye pain	blurred vision
Urogenital	nocturia, polyuria	dysuria, impotence

There have also been reports of gynaecomastia in older men on long-term therapy, but this usually regresses when treatment is withdrawn.

Exacerbation of angina pectoris has been observed at the start of treatment with modified-release preparations of dihydropyridines, including nifedipine. Myocardial infarction is also known to occur although it is not possible to distinguish it from the natural course of ischaemic heart disease.

4.9 Overdose

Symptoms

There are few reports of nifedipine overdose and the symptoms are not necessarily dose-related. The most likely manifestations of overdose are severe hypotension due to vasodilatation, tachycardia or bradycardia.

The metabolic disturbances may include hyperglycaemia, metabolic acidosis and hypo- or hyperkalaemia. The cardiac effects, which may occur, include heart block, AV dissociation and asystole and cardiogenic shock with pulmonary oedema.

Other toxic effects include drowsiness, dizziness, confusion, nausea, vomiting, lethargy, flushing, hypoxia, unconsciousness and coma.

Management

In the treatment of overdose it is important to restore stable cardiovascular conditions as soon as possible and achieve total elimination of nifedipine.

Gastric lavage and charcoal instillation may be of assistance if the patient is found early after the overdose. Gastric lavage may be necessary in combination with irrigation of the small intestine. Ipecacuanha should be given to children.

To prevent the subsequent absorption of nifedipine, elimination must be complete, including from the small intestine.

Activated charcoal should be given in 4 hourly doses of 25 g for adults and 10 g for children. The blood pressure, central arterial pressure, ECG, electrolytes, pulmonary wedge pressure and urea should be carefully monitored.

Placing the patient in the supine position with the feet raised and the use of plasma expanders, as appropriate, should treat the hypotension resulting from cardiogenic shock and arterial vasodilatation. If these measures are ineffective, hypotension may be treated with 10 ml to 20 ml of 10 % calcium gluconate, administered intravenously over a period of 5 to 10 minutes. If ineffective, the therapy can be continued, with ECG monitoring.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Anatomical Therapeutic Chemical (ATC) code: C08C A05

Selective calcium channel blocker (dihydropyridine derivative), with mainly vascular effects

Nifedipine is a dihydropyridine and is a specific and potent antagonist of calcium influx through the slow channel of the cell membrane of cardiac and smooth muscle cells, both in coronary and peripheral circulation.

The antihypertensive effects of nifedipine are achieved by causing peripheral vasodilatation resulting in a reduction in peripheral resistance. Nifedipine administered once daily provides twenty-four hours control of elevated blood pressure. Nifedipine reduces blood pressure such that the percentage lowering is proportional to its initial level. In normotensive individuals, nifedipine has little or no effect.

Nifedipine produces its effects in the treatment of angina by reducing peripheral and coronary vascular resistance, leading to an increase in coronary blood flow, cardiac output and stroke volume and causing a decrease in after-load. Also, nifedipine submaximally dilates clear and atherosclerosis coronary arteries to protect the heart against coronary artery spasm and improve perfusion to the ischaemic myocardium. Nifedipine decreases the frequency of painful attacks and the ischaemic ECG changes regardless of the relative contribution from coronary artery spasm or atheroschlerosis.

5.2 Pharmacokinetic Properties

General Characteristics

VALNI XL 30 mg PROLONGED RELEASE TABLETS are formulated as prolonged release products. They are designed to control the release of nifedipine over twenty-four hours so that a clinical effect is achieved when the tablets are swallowed, once a day.

The pharmacokinetic profile is characterised by low peak-trough fluctuation. Over twenty-four hours plasma concentrations versus time profile at steady state are plateau-like, rendering the VALNI XL 30 mg PROLONGED RELEASE TABLETS suitable for once daily administration.

Absorption

Nifedipine is rapidly and almost completely absorbed from the gastrointestinal tract after oral administration. However, due to extensive hepatic first pass metabolism in the liver, the resultant bioavailability lies between 45 % and 68 %. The absorption rate is slightly changed when the tablets are taken after ingesting food but the extent of drug availability is not affected.

Distribution

Nifedipine is about 95 % bound to plasma proteins.

Metabolism

Nifedipine is almost completely metabolised in the liver by oxidative and hydrolytic processes.

Elimination

The elimination half-life is 2 to 5 hours. About 70 % to 80 % of the administered dose of nifedipine is excreted via the kidneys, mostly as its active metabolites. The rest (5% to 15%) is excreted via the bile in the faeces. The non-metabolised drug substance is only found in traces (less than 1.0%) in the urine.

Characteristics in Patients

Patients With Renal Impairment

There are no significant differences in the pharmacokinetics of nifedipine in patients with renal impairment and in healthy subjects. Therefore, dosage adjustments should not be required for patients with impaired renal function.

Patients With Hepatic Impairment

Nifedipine is primarily metabolised in the liver. The elimination half-life is markedly prolonged and there is a reduction in total clearance. Therefore, owing to the duration of action, nifedipine should not be administered to patients with reduced hepatic function.

5.3 Preclinical Safety Data

The LD₅₀ values (in mg per Kg) determined when nifedipine was given orally and intravenously to different animal species, are reported below:

Animal Species	Oral	Intravenous
Mouse	454 ( 401 - 572 ) *	4.2 ( 3.8 - 4.6 ) *
Rat	1022 ( 950 - 1087 ) *	15.5 ( 13.7 - 17.5 ) *
Rabbit	250 - 500	2 - 3
Cat	~ 100	0.5 - 8
Dog	> 250	2 - 3

* 95 % confidence interval

Subacute & Subchronic Toxicity Studies (in Rats and Dogs)

Nifedipine doses of up to 50 mg per Kg in rats and 100 mg per Kg in dogs p.o were tolerated without any damage when administered orally over periods of thirteen and four weeks, respectively.

Nifedipine doses of 2.5 mg per Kg in rats and 0.1 mg per Kg in dogs were tolerated without any damage when administered intravenously over periods of three weeks and six days, respectively.

Chronic Toxicity Studies (in Rats and Dogs)

Nifedipine doses of up to and including 100 mg per Kg in dogs p.o were tolerated without any damage when administered orally up to one year.

In rats, toxic effect occurred at nifedipine concentrations above 100 ppm in the feed (about 5 mg to 7 mg per Kg body weight).

Carcinogenic Studies (in Rats)

Studies in rats over two years produced no evidence of carcinogenic effects caused by nifedipine.

Reproductive Studies (in Rats, Mice & Rabbits)

Studies in rats, mice and rabbits maternally toxic doses of nifedipine induced some teratogenic and embryotoxic effects.

Mutagenic Studies

In vivo and in vitro studies showed that nifedipine has no mutagenic properties.

6. Pharmaceutical Particulars

6.1 List Of Excipients

In Tablet Core

Povidone K30

Lactose monohydrate

Carbomer 974P

Silica, colloidal anhydrous

In Tablet Core & Coat

Talc

Hypromellose (E. 464)

Magnesium stearate

In Tablet Coat

Dimethylaminoethyl methacrylate-Butyl methacrylate-Methyl methacrylate copolymer

Macrogol 4000

Red iron oxide (E. 172)

Titanium dioxide (E. 171)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

Shelf Life of the Medicinal Product as Packaged for Sale

36 months

Shelf Life After Dilution or Reconstitution

Not applicable

Shelf Life After First Opening the Container

Not applicable

6.4 Special Precautions For Storage

Do not store above 25 ºC. Keep blister in the outer carton.

6.5 Nature And Contents Of Container

The tablets are enclosed in blisters composed of 25 µm aluminium foil coated with 20 g m^-2 PVDC film / 250 µm PVC foil coated with 40 g m^-2 PVDC film

The blisters are boxed in cardboard cartons containing 28 tablets and a patient information leaflet.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Winthrop Pharmaceuticals UK Limited

One Onslow Street

Guildford

Surrey

GU1 4YS

United Kingdom

trading as: Winthrop Pharmaceuticals, PO Box 611, Guildford, Surrey, GU1 4YS

8. Marketing Authorisation Number(S)

PL 17780/0317

9. Date Of First Authorisation/Renewal Of The Authorisation

22/10/2007

10. Date Of Revision Of The Text

13 May 2008

SF 1.1% Gel

Generic Name: sodium fluoride (Oral route, Dental route, Oromucosal route)

SOE-dee-um FLOOR-ide

Commonly used brand name(s)

In the U.S.

• APF Gel


• Aquafresh


• CaviRinse


• Control Rx


• Denta 5000 Plus


• Dentagel


• Dentall 1100 Plus


• EtheDent


• Fluorabon


• Fluor-A-Day


• Fluoridex Daily Defense


• Fluoridex Daily Defense Enhanced Whitening

In Canada

• Fluorosol


• Koala Pals Fluoride Tooth Gel - Berrylicious Flavor


• Pdf


• Pedi-Dent

Available Dosage Forms:

• Gel/Jelly


• Tablet, Chewable


• Paste


• Solution


• Liquid


• Tablet, Enteric Coated


• Tablet


• Lozenge/Troche


• Cream

Therapeutic Class: Cariostatic

Uses For SF 1.1% Gel

Fluoride has been found to be helpful in reducing the number of cavities in the teeth. It is usually present naturally in drinking water. However, some areas of the country do not have a high enough level in the water to prevent cavities. To make up for this, extra fluoride may be added to the diet. Some children may require both dietary fluoride and topical fluoride treatments by the dentist. Use of a fluoride toothpaste or rinse may be helpful as well.

Taking extra oral fluoride does not replace good dental habits. These include eating a good diet, brushing and flossing the teeth often, and having regular dental checkups.

Fluoride may also be used for other conditions as determined by your doctor.

This medicine is available only with a prescription.

Importance of Diet

For good health, it is important that you eat a balanced and varied diet. Follow carefully any diet program your health care professional may recommend. For your specific dietary vitamin and/or mineral needs, ask your health care professional for a list of appropriate foods. If you think that you are not getting enough vitamins and/or minerals in your diet, you may choose to take a dietary supplement.

People get needed fluoride from fish, including the bones, tea, and drinking water that has fluoride added to it. Food that is cooked in water containing fluoride or in Teflon-coated pans also provides fluoride. However, foods cooked in aluminum pans provide less fluoride.

The daily amount of fluoride needed is defined in several different ways.

• For U.S.—


• Recommended Dietary Allowances (RDAs) are the amount of vitamins and minerals needed to provide for adequate nutrition in most healthy persons. RDAs for a given nutrient may vary depending on a person's age, sex, and physical condition (e.g., pregnancy).


• Daily Values (DVs) are used on food and dietary supplement labels to indicate the percent of the recommended daily amount of each nutrient that a serving provides. DV replaces the previous designation of United States Recommended Daily Allowances (USRDAs).

• For Canada—


• Recommended Nutrient Intakes (RNIs) are used to determine the amounts of vitamins, minerals, and protein needed to provide adequate nutrition and lessen the risk of chronic disease.

There is no RDA or RNI for fluoride. Daily recommended intakes for fluoride are generally defined as follows:

• Infants and children—


• Birth to 3 years of age: 0.1 to 1.5 milligrams (mg).


• 4 to 6 years of age: 1 to 2.5 mg.


• 7 to 10 years of age: 1.5 to 2.5 mg.

• Adolescents and adults—


• 1.5 to 4 mg.

Remember:

• The total amount of fluoride you get every day includes what you get from the foods and beverages that you eat and what you may take as a supplement.


• This total amount should not be greater than the above recommendations, unless ordered by your health care professional. Taking too much fluoride can cause serious problems to the teeth and bones.

Before Using SF 1.1% Gel

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Problems in children have not been reported with intake of normal daily recommended amounts. Doses of sodium fluoride that are too large or are taken for a long time may cause bone problems and teeth discoloration in children.

Geriatric

Problems in older adults have not been reported with intake of normal daily recommended amounts. Older people are more likely to have joint pain, kidney problems, or stomach ulcers which may be made worse by taking large doses of sodium fluoride. You should check with your health care professional.

Breast Feeding

Studies in women suggest that this medication poses minimal risk to the infant when used during breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

• Dairy Food

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Brown, white, or black discoloration of teeth or


• Joint pain or


• Kidney problems (severe) or


• Stomach ulcer—Sodium fluoride may make these conditions worse.

Proper Use of sodium fluoride

This section provides information on the proper use of a number of products that contain sodium fluoride. It may not be specific to SF 1.1% Gel. Please read with care.

Take this medicine only as directed by your health care professional. Do not take more of it and do not take it more often than ordered. Taking too much fluoride over a period of time may cause unwanted effects.

For individuals taking the chewable tablet form of this medicine:

• Tablets should be chewed or crushed before they are swallowed.


• This medicine works best if it is taken at bedtime, after the teeth have been thoroughly brushed. Do not eat or drink for at least 15 minutes after taking sodium fluoride.

For individuals taking the oral liquid form of this medicine:

• This medicine is to be taken by mouth even though it comes in a dropper bottle. The amount to be taken is to be measured with the specially marked dropper.


• Always store this medicine in the original plastic container. Fluoride will affect glass and should not be stored in glass containers.


• This medicine may be dropped directly into the mouth or mixed with cereal, fruit juice, or other food. However, if this medicine is mixed with foods or beverages that contain calcium, the amount of sodium fluoride that is absorbed may be reduced.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (lozenges, solution, tablets, or chewable tablets):
  
  • To prevent cavities in the teeth (not enough fluoride in the water):
    
    • Children—Dose is based on the amount of fluoride in drinking water in your area. Dose is also based on the child's age and must be determined by your health care professional.
    
    
  
  

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Precautions While Using SF 1.1% Gel

The level of fluoride present in the water is different in different parts of the U.S. If you move to another area, check with a health care professional in the new area as soon as possible to see if this medicine is still needed or if the dose needs to be changed. Also, check with your health care professional if you change infant feeding habits (e.g., breast-feeding to infant formula), drinking water (e.g., city water to nonfluoridated bottled water), or filtration (e.g., tap water to filtered tap water).

Do not take calcium supplements or aluminum hydroxide–containing products and sodium fluoride at the same time. It is best to space doses of these two products 2 hours apart, to get the full benefit from each medicine.

Inform your health care professional as soon as possible if you notice white, brown, or black spots on the teeth. These are signs of too much fluoride in children when it is given during periods of tooth development.

SF 1.1% Gel Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor as soon as possible if any of the following side effects occur:

Sodium fluoride in drinking water or taken as a supplement does not usually cause any side effects. However, taking an overdose of fluoride may cause serious problems.

• Sores in the mouth and on the lips (rare)

Stop taking this medicine and get emergency help immediately if any of the following effects occur:

• Black, tarry stools


• bloody vomit


• diarrhea


• drowsiness


• faintness


• increased watering of the mouth


• nausea or vomiting


• shallow breathing


• stomach cramps or pain


• tremors


• unusual excitement


• watery eyes


• weakness

Check with your doctor as soon as possible if any of the following side effects occur:

• Pain and aching of bones


• stiffness


• white, brown, or black discoloration of the teeth—occurs only during periods of tooth development in children

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

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Verapamil

Dosage Form: tablet
Verapamil Hydrochloride Tablets

Rx only

DESCRIPTION

Verapamil hydrochloride (Verapamil HCl) is a calcium ion influx inhibitor (slow-channel blocker or calcium ion antagonist) available for oral administration in film-coated tablets containing 80 mg or 120 mg of Verapamil hydrochloride. The structural formula of Verapamil HCl is:

C27H38N2O4• HCl                                                                                        M.W. = 491.08

Benzeneacetonitrile, α-[3-[[2-(3,4-dimethoxyphenyl)ethyl] methylamino]propyl]-3,4-dimethoxy-α-(1-methylethyl) hydrochloride 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 HCl is not chemically related to other cardioactive drugs.

Inactive ingredients include colloidal silicon dioxide, dibasic calcium phosphate dihydrate, microcrystalline cellulose, sodium starch glycolate, light mineral oil, sodium lauryl sulfate, titanium dioxide and hypromellose.

CLINICAL PHARMACOLOGY

Verapamil hydrochloride is a calcium ion influx inhibitor (slow-channel blocker or calcium ion antagonist) that 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

Angina

The precise mechanism of action of Verapamil hydrochloride as an antianginal agent remains to be fully determined, but includes the following two mechanisms:

1. Relaxation and prevention of coronary artery spasm: Verapamil hydrochloride 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 Verapamil hydrochloride 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 or dilation of coronary arteries is not an important factor in classical angina.


2. Reduction of oxygen utilization: Verapamil hydrochloride regularly reduces the total peripheral resistance (afterload) against which the heart works both at rest and at a given level of exercise by dilating peripheral arterioles. This unloading of the heart reduces myocardial energy consumption and oxygen requirements and probably accounts for the effectiveness of Verapamil hydrochloride in chronic stable effort angina.

Arrhythmia: Electrical activity through the AV node depends, to a significant degree, upon calcium influx through the slow channel. By decreasing the influx of calcium, Verapamil hydrochloride prolongs the effective refractory period within the AV node and slows AV conduction in a rate-related manner. This property accounts for the ability of Verapamil hydrochloride to slow the ventricular rate in patients with chronic atrial flutter or atrial fibrillation.

Normal sinus rhythm is usually not affected, but in patients with sick sinus syndrome, Verapamil hydrochloride 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). Verapamil hydrochloride decreases the frequency of episodes of paroxysmal supraventricular tachycardia.

Verapamil hydrochloride does not alter the normal atrial action potential or intraventricular conduction time, but in depressed atrial fibers it decreases amplitude, velocity of depolarization, and conduction velocity. Verapamil hydrochloride may shorten the antegrade effective refractory period of the accessory bypass tract. 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).

Verapamil hydrochloride 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.

Essential hypertension: Verapamil hydrochloride 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, Verapamil hydrochloride does not alter systolic cardiac function in patients with normal ventricular function.

Verapamil hydrochloride does not alter total serum calcium levels. However, one report suggested that calcium levels above the normal range may alter the therapeutic effect of Verapamil.

Pharmacokinetics and metabolism :

More than 90% of the orally administered dose of Verapamil hydrochloride 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 Verapamil HCl every 6 hours resulted in plasma levels of Verapamil ranging from 125 to 400 ng/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 concentration and 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 healthy men, orally administered Verapamil HCl 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 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 :

Verapamil hydrochloride reduces afterload and myocardial contractility. Improved left ventricular diastolic function in patients with Idiopathic Hypertrophic Subaortic Stenosis (IHSS) and those with coronary heart disease has also been observed with Verapamil hydrochloride therapy. In most patients, including those with organic cardiac disease, the negative inotropic action of Verapamil hydrochloride is countered by reduction of afterload, and cardiac index is usually not reduced. However, in patients with severe left ventricular dysfunction (eg, pulmonary wedge pressure above 20 mm Hg or ejection fraction less than 30%), or in patients taking beta-adrenergic blocking agents or other cardiodepressant drugs, deterioration of ventricular function may occur (see PRECAUTIONS, Drug interactions).

Pulmonary function:

Verapamil hydrochloride does not induce bronchoconstriction and, hence, does not impair ventilatory function.

INDICATIONS AND USAGE

Verapamil hydrochloride tablets are indicated for the treatment of the following:

Angina

1. Angina at rest including:

−

Vasospastic (Prinzmetal's variant) angina

−

Unstable (crescendo, pre-infarction) angina

2. Chronic stable angina (classic effort-associated angina)

Arrhythmias

In association with digitalis for the control of ventricular rate at rest and during stress in patients with chronic atrial flutter and/or atrial fibrillation (see WARNINGS: Accessory bypass tract)

Prophylaxis of repetitive paroxysmal supraventricular tachycardia

Essential hypertension

CONTRAINDICATIONS

Verapamil HCl tablets are contraindicated in:

1. Severe left ventricular dysfunction (see WARNINGS)


2. Hypotension (systolic pressure less than 90 mm Hg) 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 (eg, Wolff-Parkinson-White, Lown-Ganong-Levine syndromes) (see WARNINGS)


6. Patients with known hypersensitivity to Verapamil hydrochloride

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 (eg, ejection fraction less than 30%) or moderate to severe symptoms of cardiac failure and in patients with any degree of ventricular dysfunction if they are receiving a beta-adrenergic blocker (see PRECAUTIONS, Drug interactions). Patients with milder ventricular dysfunction should, if 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 with 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 elevation 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 Verapamil hydrochloride.

Atrioventricular block:

The effect of Verapamil on AV conduction and the SA node may cause asymptomatic first-degree AV block and transient bradycardia, sometimes accompanied by nodal escape rhythms. PR-interval prolongation is correlated with Verapamil plasma concentrations especially during the early titration phase 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 HCl and institution of appropriate therapy, depending on 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 (greater than 20 mm Hg) pulmonary wedge pressure and a marked left ventricular outflow obstruction were present in most of these patients. Concomitant administration of quinidine (see PRECAUTIONS, 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 use have to be discontinued.

PRECAUTIONS

General

Use in patients with impaired hepatic function: 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 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, and causes a worsening of myasthenia gravis. 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

Cytochrome inducers/inhibitors: In vitro metabolic studies indicate that Verapamil is metabolized by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. Clinically significant interactions have been reported with inhibitors of CYP3A4 (e.g., erythromycin, ritonavir) causing elevation of plasma levels of Verapamil while inducers of CYP3A4 (e.g., rifampin) have caused a lowering of plasma levels of Verapamil.

HMG-CoA reductase inhibitors: The use of HMG-CoA reductase inhibitors that are CYP3A4 substrates in combination with Verapamil has been associated with reports of myopathy/rhabdomyolysis.

Co-administration of multiple doses of 10 mg of Verapamil with 80 mg simvastatin resulted in exposure to simvastatin 2.5-fold that following simvastatin alone. Limit the dose of simvastatin in patients on Verapamil to 10 mg daily. Limit the daily dose of lovastatin to 40 mg. Lower starting and maintenance doses of other CYP3A4 substrates (e.g., atorvastatin) may be required as Verapamil may increase the plasma concentration of these drugs.

Aspirin: In a few reported cases, co-administration of Verapamil with aspirin has led to increased bleeding times greater than observed with aspirin alone.

Grapefruit juice: Grapefruit juice may increase plasma levels of Verapamil.

Alcohol : Verapamil may increase blood alcohol concentrations and prolong its effects.

Beta-blockers: Controlled studies in small numbers of patients suggest that the concomitant use of Verapamil hydrochloride and oral beta-adrenergic blocking agents may be beneficial in certain patients with chronic stable angina or hypertension, but available information is not sufficient to predict with confidence the effects of concurrent treatment in patients with left ventricular dysfunction or cardiac conduction abnormalities. Concomitant therapy with beta-adrenergic blockers and Verapamil may result in additive negative effects on heart rate, atrioventricular conduction and/or cardiac contractility.

In one study involving 15 patients treated with high doses of propranolol (median dose: 480 mg/day; range: 160 to 1,280 mg/day) for severe angina, with preserved left ventricular function (ejection fraction greater than 35%), the hemodynamic effects of additional therapy with Verapamil HCl were assessed using invasive methods. The addition of Verapamil to high-dose beta-blockers induced modest negative inotropic and chronotropic effects that were not severe enough to limit short-term (48 hours) combination therapy in this study. These modest cardiodepressant effects persisted for greater than 6 but less than 30 hours after abrupt withdrawal of beta-blockers and were closely related to plasma levels of propranolol. The primary Verapamil/beta-blocker interaction in this study appeared to be hemodynamic rather than electrophysiologic.

In other studies, Verapamil did not generally induce significant negative inotropic, chronotropic, or dromotropic effects in patients with preserved left ventricular function receiving low or moderate doses of propranolol (less than or equal to 320 mg/day); in some patients, however, combined therapy did produce such effects. Therefore, if combined therapy is used, close surveillance of clinical status should be carried out. Combined therapy should usually be avoided in patients with atrioventricular conduction abnormalities and those with depressed left ventricular function.

Asymptomatic bradycardia (36 beats/min) with a wandering atrial pacemaker has been observed in a patient receiving concomitant timolol (a beta-adrenergic blocker) eyedrops 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. However, 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 and  digitalization doses should be reduced when Verapamil is administered, and the patient should be reassessed to avoid over-or under-digitalization. Whenever over-digitalization is suspected, the daily dose of digitalis should be reduced or temporarily discontinued. On discontinuation of Verapamil hydrochloride use, the patient should be reassessed to avoid under-digitalization.

Antihypertensive agents: Verapamil administered concomitantly with oral antihypertensive agents (eg, 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 are obtained, disopyramide should not be administered within 48 hours before or 24 hours after Verapamil administration.

Flecainide: A study in 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 electrophysiologic effects of quinidine and Verapamil 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.

Other agents:

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.

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; lithium levels have been observed sometimes to increase, sometimes to decrease, and sometimes to be unchanged. 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 each 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.

Telithromycin: Hypotension and bradyarrhythmias have been observed in patients receiving concurrent telithromycin, an antibiotic in the ketolide class.

Clonidine:  Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concurrently with Verapamil. Monitor heart rate in patients receiving concomitant Verapamil and clonidine.

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/day or approximately 1, 3.5, and 12 times, respectively, the maximum recommended human daily dose (480 mg/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 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 if clearly needed. Verapamil 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 Verapamil in Europe in the treatment of cardiac side effects of beta-adrenergic agonist agents used to treat premature labor.

Nursing Mothers:

Verapamil 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 effectiveness in pediatric patients have not been established.

ANIMAL PHARMACOLOGY & OR 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 in the rat. Development of cataracts due to Verapamil has not been reported in man.

ADVERSE REACTIONS

Serious adverse reactions are uncommon when Verapamil hydrochloride 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) non-obstructive, paralytic ileus has been infrequently reported in association with the use of Verapamil. The following reactions to orally administered Verapamil 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%	Dyspnea	1.4%
Dizziness	3.3%	Bradycardia (HR <50/min)	1.4%
Nausea	2.7%	AV block total (1°, 2°, 3°)	1.2%
Hypotension	2.5%	2° and 3°	0.8%
Headache	2.2%	Rash	1.2%
Edema	1.9%	Flushing	0.6%
CHF, Pulmonary edema	1.8%
Fatigue	1.7%
Elevated liver enzymes (see WARNINGS)

In clinical trials related to the control of ventricular response in digitalized patients who had atrial fibrillation or flutter, ventricular rates below 50 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, paresthesia, psychotic symptoms, shakiness, somnolence, extrapyramidal symptoms.

Skin: arthralgia and rash, exanthema, hair loss, hyperkeratosis, macules, sweating, urticaria, Stevens-Johnson syndrome, erythema multiforme.

Special senses: blurred vision, tinnitus.

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

Treatment of acute cardiovascular adverse reactions :

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

OVERDOSAGE

Treat all Verapamil overdoses as serious and maintain observation for at least 48 hours (especially Verapamil Hydrochloride Tablets SR), preferably under continuous hospital care. Delayed pharmacodynamic consequences may occur with the sustained-release 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. In a few reported cases, overdose with calcium channel blockers has been associated with hypotension and bradycardia, initially refractory to atropine but becoming more responsive to this treatment when the patients received large doses (close to 1 gram/ hour for more than 24 hours) of calcium chloride. 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.

DOSAGE AND ADMINISTRATION

The dose of Verapamil must be individualized by titration. The usefulness and safety of dosages exceeding 480 mg/day have not been established; therefore, this daily dosage should not be exceeded. Since the half-life of Verapamil increases during chronic dosing, maximum response may be delayed.

Angina:

Clinical trials show that the usual dose is 80 mg to 120 mg three times a day. However, 40 mg three times a day may be warranted in patients who may have an increased response to Verapamil (eg, decreased hepatic function, elderly, etc). Upward titration should be based on therapeutic efficacy and safety evaluated approximately eight hours after dosing. Dosage may be increased at daily (eg, patients with unstable angina) or weekly intervals until optimum clinical response is obtained.

Arrhythmias:

The dosage in digitalized patients with chronic atrial fibrillation (see PRECAUTIONS) ranges from 240 to 320 mg/day in divided (t.i.d. or q.i.d.) doses. The dosage for prophylaxis of PSVT (non-digitalized patients) ranges from 240 to 480 mg/day in divided (t.i.d. or q.i.d.) doses. In general, maximum effects for any given dosage will be apparent during the first 48 hours of therapy.

Essential hypertension:

Dose should be individualized by titration. The usual initial monotherapy dose in clinical trials was 80 mg three times a day (240 mg/ day). Daily dosages of 360 and 480 mg have been used but there is no evidence that dosages beyond 360 mg provided added effect. Consideration should be given to beginning titration at 40 mg three times per day in patients who might respond to lower doses, such as the elderly or people of small stature. The antihypertensive effects of Verapamil hydrochloride are evident within the first week of therapy. Upward titration should be based on therapeutic efficacy, assessed at the end of the dosing interval.

HOW SUPPLIED

Verapamil Hydrochloride Tablets, USP 80 mg tablets are round, standard concave, white film-coated, scored, debossed “HP” above and “26” below on one side and plain on the reverse side, supplied as:

NDC Number	Size
23155-026-01	bottle of 100
23155-026-05	bottle of 500

Store at 20° to 25°C (68° to 77°F) [See USP controlled room temperature] and protect from light. Dispense in a tight, light-resistant container using a child-resistant closure.

MANUFACTURED FOR:

Heritage Pharmaceuticals Inc.

Edison, NJ 08837

1.866.901.DRUG (3784)

Issued: 11/11

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

Verapamil Hydrochloride Tablets, USP, 80 mg, 100 count

Verapamil HYDROCHLORIDE  Verapamil hydrochloride  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 23155-026 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Verapamil HYDROCHLORIDE (Verapamil) Verapamil HYDROCHLORIDE 80 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE   DIBASIC CALCIUM PHOSPHATE DIHYDRATE   CELLULOSE, MICROCRYSTALLINE   SODIUM STARCH GLYCOLATE TYPE A POTATO   MAGNESIUM STEARATE   MINERAL OIL   SODIUM LAURYL SULFATE   TITANIUM DIOXIDE   HYPROMELLOSE 2910 (6 MPA.S)

Product Characteristics Color WHITE Score 2 pieces Shape ROUND Size 9mm Flavor Imprint Code HP;26 Contains

Packaging # NDC Package Description Multilevel Packaging 1 23155-026-01 100 TABLET In 1 BOTTLE None 2 23155-026-05 500 TABLET In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA071880	01/07/2011

Labeler - Heritage Pharmaceuticals Inc. (780779901)

Establishment
Name	Address	ID/FEI	Operations
Emcure Pharmaceuticals USA Inc.		189630168	MANUFACTURE

Revised: 11/2011Heritage Pharmaceuticals Inc.