Calan SR

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. An overdose of verapamil can be fatal.

Get emergency medical help if you have signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• chest pain, fast or slow heart rate;

• a light-headed feeling, like you might pass out;

• shortness of breath (even with mild exertion), swelling, rapid weight gain;

• lung problems--anxiety, sweating, pale skin, wheezing, gasping for breath, cough with foamy mucus; or

• liver problems--loss of appetite, upper stomach pain, tiredness, easy bruising or bleeding, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

Common side effects may include:

• constipation;

• headache, dizziness; or

• abnormal liver function tests.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

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

Appropriate studies have not been performed on the relationship of age to the effects of verapamil in the pediatric population. Safety and efficacy have not been established .

Geriatric

Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of verapamil in the elderly. However, elderly patients are more likely to have age-related heart, liver, or kidney problems which may require an adjustment of dose in patients receiving verapamil .

Pregnancy

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. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. 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 medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Colchicine
• Dofetilide
• Flibanserin
• Lomitapide

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acebutolol
• Adenosine
• Afatinib
• Alprenolol
• Amiodarone
• Apixaban
• Aprepitant
• Atazanavir
• Atenolol
• Atorvastatin
• Betaxolol
• Betrixaban
• Bevantolol
• Bisoprolol
• Bosutinib
• Brexpiprazole
• Bucindolol
• Bupivacaine
• Bupivacaine Liposome
• Carbamazepine
• Carteolol
• Carvedilol
• Celiprolol
• Ceritinib
• Cilostazol
• Clarithromycin
• Clonidine
• Clopidogrel
• Cobimetinib
• Conivaptan
• Crizotinib
• Cyclobenzaprine
• Dabigatran Etexilate
• Dantrolene
• Deflazacort
• Digoxin
• Dilevalol
• Domperidone
• Doxorubicin
• Doxorubicin Hydrochloride Liposome
• Dronedarone
• Eliglustat
• Eplerenone
• Erythromycin
• Esmolol
• Everolimus
• Fingolimod
• Fosaprepitant
• Hydrocodone
• Ibrutinib
• Idelalisib
• Ifosfamide
• Ivabradine
• Ivacaftor
• Ketoconazole
• Labetalol
• Lacosamide
• Levobunolol
• Lovastatin
• Lurasidone
• Mepindolol
• Mepivacaine
• Metipranolol
• Metoprolol
• Morphine
• Morphine Sulfate Liposome
• Nadolol
• Naloxegol
• Nebivolol
• Netupitant
• Nilotinib
• Olaparib
• Oxprenolol
• Penbutolol
• Pindolol
• Piperaquine
• Pixantrone
• Propranolol
• Ranolazine
• Simeprevir
• Simvastatin
• Sonidegib
• Sotalol
• Tacrolimus
• Talinolol
• Tertatolol
• Timolol
• Tizanidine
• Tolvaptan
• Topotecan
• Venetoclax
• Vincristine
• Vincristine Sulfate Liposome

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Buspirone
• Cyclosporine
• Dalfopristin
• Digitoxin
• Dutasteride
• Flecainide
• Fosphenytoin
• Indinavir
• Lithium
• Metformin
• Midazolam
• Nevirapine
• Oxcarbazepine
• Pancuronium
• Phenobarbital
• Phenytoin
• Quinidine
• Quinupristin
• Sirolimus
• St John's Wort
• Suvorexant
• Tedisamil
• Telithromycin
• Tubocurarine
• Vecuronium

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 is usually not recommended, 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.

• Tobacco

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.

• Ethanol
• Grapefruit Juice

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:

• Congestive heart failure or
• Muscle disease (e.g., Duchenne's muscular dystrophy, myasthenia gravis) or
• Pulmonary edema (fluid in the lungs)—Use with caution. May make these conditions worse .

• Heart block (type of abnormal heart rhythm) or
• Heart problems (e.g., Wolff-Parkinson-White syndrome, Lown-Ganong-Levine syndrome) or
• Low blood pressure (hypotension) or
• Sick sinus syndrome (heart rhythm problem, can use if have a pacemaker that works properly)—Should not be used in patients with these conditions .

• Kidney problems or
• Liver problems—Use with caution. The effects may be increased because of slower removal of the medicine from the body .

It is very important that your doctor check your progress at regular visits to make sure this medicine is working properly and to check for unwanted effects .

Low blood pressure (hypotension) may occur while taking this medicine. Check with your doctor right away if you have the following symptoms: blurred vision; confusion; severe dizziness, faintness, or lightheadedness when getting up from a lying or sitting position suddenly; sweating; or unusual tiredness or weakness .

While you are taking this medicine be careful to limit the amount of alcohol that you drink. Alcohol increases dizziness and drowsiness and also lowers blood pressure .

• It is used to treat high blood pressure.
• It may be given to you for other reasons. Talk with the doctor.

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

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

CALAN (verapamil HCl) 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

Verapamil 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, CALAN does not alter systolic cardiac function in patients with normal ventricular function.

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

CALAN 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 CALAN 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.

CALAN 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, CALAN 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, CALAN 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).

CALAN does not alter the normal atrial action potential or intraventricular conduction time, but depresses amplitude, velocity of depolarization, and conduction in depressed atrial fibers. CALAN 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).

CALAN 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 CALAN 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 level does exist. 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. No relationship has been established between the plasma concentration of verapamil and a reduction in blood pressure.

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 Calan SR was similar to CALAN (immediate release); rates of absorption were of course different.

In a randomized, single-dose, crossover study using healthy volunteers, administration of 240 mg Calan 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 Calan 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 Calan SR have shown effectiveness of doses similar to the effective doses of CALAN (immediate release).

In healthy men, orally administered CALAN 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.

In ten healthy males, administration of oral verapamil (80 mg every 8 hours for 6 days) and a single oral dose of ethanol (0.8 g/kg) resulted in a 17% increase in mean peak ethanol concentrations (106.45 ± 21.40 to 124.23 ± 24.74 mg∙hr/dL) compared to placebo. The area under the blood ethanol concentration versus time curve (AUC over 12 hours) increased by 30% (365.67 ± 93.52 to 475.07 ± 97.24 mg∙hr/dL). Verapamil AUCs were positively correlated (r=0.71) to increased ethanol blood AUC values (see PRECAUTIONS, Drug interactions).

Hemodynamics and myocardial metabolism

CALAN 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 CALAN. In most patients, including those with organic cardiac disease, the negative inotropic action of CALAN 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

CALAN does not induce bronchoconstriction and, hence, does not impair ventilatory function.

Verapamil HCl caplets 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

Overdose with verapamil may lead to pronounced hypotension, bradycardia, and conduction system abnormalities (eg, junctional rhythm with AV dissociation and high degree AV block, including asystole). Other symptoms secondary to hypoperfusion (eg, metabolic acidosis, hyperglycemia, hyperkalemia, renal dysfunction, and convulsions) may be evident.

Treat all verapamil overdoses as serious and maintain observation for at least 48 hours (especially Calan SR), preferably under continuous hospital care. Delayed pharmacodynamic consequences may occur with the sustained-release formulation. Verapamil is known to decrease gastrointestinal transit time.

In overdose, caplets of Calan SR have occasionally been reported to form concretions within the stomach or intestines. These concretions have not been visible on plain radiographs of the abdomen, and no medical means of gastrointestinal emptying is of proven efficacy in removing them. Endoscopy might reasonably be considered in cases of massive overdose when symptoms are unusually prolonged.

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. Continued treatment with large doses of calcium may produce a response. In a few reported cases, overdose with calcium channel blockers that was initially refractory to atropine became more responsive to this treatment when the patients received large doses (close to 1 g/hr for more than 24 hr) 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.

Common side effects of Calan SR include: sinus bradycardia. Other side effects include: pulmonary edema, severe hypotension, and second degree atrioventricular block. See below for a comprehensive list of adverse effects.