Solu-Medrone 40mg, 125mg, 500mg and 1 gram

1. Name Of The Medicinal Product

Solu-Medrone 40 mg

Solu-Medrone 125mg

Solu-Medrone 500mg

Solu-Medrone 1gram

2. Qualitative And Quantitative Composition

Solu-Medrone 40 mg : Methylprednisolone sodium succinate 53.0 mg equivalent to 40 mg of methylprednisolone.

Solu-Medrone 125mg: Methylprednisolone sodium succinate 165.8 mg equivalent to 125 mg of methylprednisolone.

Solu-Medrone 500mg: Methylprednisolone sodium succinate 663.0 mg equivalent to 500 mg of methylprednisolone.

Solu-Medrone 1g: Methylprednisolone sodium succinate 1.326 gm equivalent to 1.0 g of methylprednisolone.

3. Pharmaceutical Form

Powder for injection.

4. Clinical Particulars

4.1 Therapeutic Indications

Solu

1. Dermatological disease

Severe erythema multiforme (Stevens

2. Allergic states

Bronchial asthma

Severe seasonal and perennial allergic rhinitis

Angioneurotic oedema

Anaphylaxis

3. Gastro

Ulcerative colitis

Crohn's disease

4. Respiratory diseases

Aspiration of gastric contents

Fulminating or disseminated tuberculosis (with appropriate antituberculous chemotherapy)

5. Neurological disorders

Cerebral oedema secondary to cerebral tumour

Acute exacerbations of multiple sclerosis superimposed on a relapsing-remitting background.

6. Miscellaneous

T.B. meningitis (with appropriate antituberculous chemotherapy)

Transplantation

4.2 Posology And Method Of Administration

Solu

For intravenous infusion the initially prepared solution may be diluted with 5% dextrose in water, isotonic saline solution, or 5% dextrose in isotonic saline solution. To avoid compatibility problems with other drugs Solu

Undesirable effects may be minimised by using the lowest effective dose for the minimum period (see Other special warnings and precautions).

Parenteral drug products should wherever possible be visually inspected for particulate matter and discoloration prior to administration.

Adults: Dosage should be varied according to the severity of the condition, initial dosage will vary from 10 to 500 mg. In the treatment of graft rejection reactions following transplantation, a dose of up to 1 g/day may be required. Although doses and protocols have varied in studies using methylprednisolone sodium succinate in the treatment of graft rejection reactions, the published literature supports the use of doses of this level, with 500 mg to 1 g most commonly used for acute rejection. Treatment at these doses should be limited to a 48

Children: In the treatment of high dose indications, such as haematological, rheumatic, renal and dermatological conditions, a dosage of 30 mg/kg/day to a maximum of 1 g/day is recommended. This dosage may be repeated for three pulses either daily or on alternate days. In the treatment of graft rejection reactions following transplantation, a dosage of 10 to 20 mg/kg/day for up to 3 days, to a maximum of 1 g/day, is recommended. In the treatment of status asthmaticus, a dosage of 1 to 4 mg/kg/day for 1

Elderly patients: Solu

Detailed recommendations for adult dosage are as follows:

In anaphylactic reactions adrenaline or noradrenaline should be administered first for an immediate haemodynamic effect, followed by intravenous injection of Solu

In sensitivity reactions Solu

In graft rejection reactions following transplantation doses of up to 1 g per day have been used to suppress rejection crises, with doses of 500 mg to 1 g most commonly used for acute rejection. Treatment should be continued only until the patient's condition has stabilised; usually not beyond 48

In cerebral oedema corticosteroids are used to reduce or prevent the cerebral oedema associated with brain tumours (primary or metastatic).

In patients with oedema due to tumour, tapering the dose of corticosteroid appears to be important in order to avoid a rebound increase in intracranial pressure. If brain swelling does occur as the dose is reduced (intracranial bleeding having been ruled out), restart larger and more frequent doses parenterally. Patients with certain malignancies may need to remain on oral corticosteroid therapy for months or even life. Similar or higher doses may be helpful to control oedema during radiation therapy.

The following are suggested dosage schedules for oedemas due to brain tumour.

Schedule A (1)	Dose (mg)	Route	Interval in hours	Duration
Pre-operative:	20	IM	3-6
During Surgery:	20 to 40	IV	hourly
Post operative:	20	IM	3	24 hours
	16	IM	3	24 hours
	12	IM	3	24 hours
	8	IM	3	24 hours
	4	IM	3	24 hours
	4	IM	6	24 hours
	4	IM	12	24 hours

Schedule B (2)	Dose (mg)	Route	Interval in hours	Duration
Pre-operative:	40	IM	6	2-3
Post operative:	40	IM	6	3-5
	20	Oral	6	1
	12	Oral	6	1
	8	Oral	8	1
	4	Oral	12	1
	4	Oral		1

Aim to discontinue therapy after a total of 10 days.

REFERENCES

1. Fox JL, MD. "Use of Methylprednisolone in Intracranial Surgery" Medical Annals of the District of Columbia, 34:261

2. Cantu RC, MD Harvard Neurological Service, Boston, Massachusetts. Letter on file, The Upjohn Company (February 1970).

In the treatment of acute exacerbations of multiple sclerosis in adults, the recommended dose is 1 g daily for 3 days. Solu-Medrone should be given as an intravenous infusion over at least 30 minutes.

In other indications, initial dosage will vary from 10 to 500 mg depending on the clinical problem being treated. Larger doses may be required for short

4.3 Contraindications

Solu

4.4 Special Warnings And Precautions For Use

Warnings and Precautions:

1. A Patient Information Leaflet is provided in the pack by the manufacturer.

2. Undesirable effects may be minimised by using the lowest effective dose for the minimum period. Frequent patient review is required to appropriately titrate the dose against disease activity (see Posology and method of administration).

3. Adrenal cortical atrophy develops during prolonged therapy and may persist for months after stopping treatment. In patients who have received more than physiological doses of systemic corticosteroids (approximately 6 mg methylprednisolone) for greater than 3 weeks, withdrawal should not be abrupt. How dose reduction should be carried out depends largely on whether the disease is likely to relapse as the dose of systemic corticosteroids is reduced. Clinical assessment of disease activity may be needed during withdrawal. If the disease is unlikely to relapse on withdrawal of systemic corticosteroids, but there is uncertainty about HPA suppression, the dose of systemic corticosteroid may be reduced rapidly to physiological doses. Once a daily dose of 6 mg methylprednisolone is reached, dose reduction should be slower to allow the HPA-axis to recover.

Abrupt withdrawal of systemic corticosteroid treatment, which has continued up to 3 weeks is appropriate if it considered that the disease is unlikely to relapse. Abrupt withdrawal of doses up to 32 mg daily of methylprednisolone for 3 weeks is unlikely to lead to clinically relevant HPA-axis suppression, in the majority of patients. In the following patient groups, gradual withdrawal of systemic corticosteroid therapy should be considered even after courses lasting 3 weeks or less:

• Patients who have had repeated courses of systemic corticosteroids, particularly if taken for greater than 3 weeks.

• When a short course has been prescribed within one year of cessation of long-term therapy (months or years).

• Patients who may have reasons for adrenocortical insufficiency other than exogenous corticosteroid therapy.

• Patients receiving doses of systemic corticosteroid greater than 32 mg daily of methylprednisolone.

• Patients repeatedly taking doses in the evening.

4. Patients should carry 'Steroid Treatment' cards which give clear guidance on the precautions to be taken to minimise risk and which provide details of prescriber, drug, dosage and the duration of treatment.

5. Although Solu

6. There have been a few reports of cardiac arrhythmias and/or circulatory collapse and/or cardiac arrest associated with the rapid intravenous administration of large doses of Solu

7. Corticosteroids may mask some signs of infection, and new infections may appear during their use. Suppression of the inflammatory response and immune function increases the susceptibility to fungal, viral and bacterial infections and their severity. The clinical presentation may often be atypical and may reach an advanced stage before being recognised.

8. Chickenpox is of serious concern since this normally minor illness may be fatal in immunosuppressed patients. Patients (or parents of children) without a definite history of chickenpox should be advised to avoid close personal contact with chickenpox or herpes zoster and if exposed they should seek urgent medical attention. Passive immunization with varicella/zoster immunoglobin (VZIG) is needed by exposed non-immune patients who are receiving systemic corticosteroids or who have used them within the previous 3 months; this should be given within 10 days of exposure to chickenpox. If a diagnosis of chickenpox is confirmed, the illness warrants specialist care and urgent treatment. Corticosteroids should not be stopped and the dose may need to be increased.

9. Exposure to measles should be avoided. Medical advice should be sought immediately if exposure occurs. Prophylaxis with normal intramuscular immuneglobulin may be needed.

10. Live vaccines should not be given to individuals with impaired immune responsiveness. The antibody response to other vaccines may be diminished.

11. The use of Solu

12. Rarely anaphylactoid reactions have been reported following parenteral Solu

13. Care should be taken for patients receiving cardioactive drugs such as digoxin because of steroid induced electrolyte disturbance/potassium loss (see Undesirable effects).

14. Corticosteroids should not be used for the management of head injury or stroke because it is unlikely to be of benefit and may even be harmful.

Special precautions:

Particular care is required when considering the use of systemic corticosteroids in patients with the following conditions and frequent patient monitoring is necessary.

1. Osteoporosis (post-menopausal females are particularly at risk).

2. Hypertension or congestive heart failure.

3. Existing or previous history of severe affective disorders (especially previous steroid psychosis).

4. Diabetes mellitus (or a family history of diabetes).

5. History of tuberculosis.

6. Glaucoma (or a family history of glaucoma).

7. Previous corticosteroid-induced myopathy.

8. Liver failure or cirrhosis.

9. Renal insufficiency.

10. Epilepsy.

11. Peptic ulceration.

12. Fresh intestinal anastomoses.

13. Predisposition to thrombophlebitis.

14. Abscess or other pyogenic infections.

15. Ulcerative colitis.

16. Diverticulitis.

17. Myasthenia gravis.

18. Ocular herpes simplex, for fear of corneal perforation.

19. Hypothyroidism.

20. Recent myocardial infarction (myocardial rupture has been reported).

21. Kaposi's sarcoma has been reported to occur in patients receiving corticosteroid therapy. Discontinuation of corticosteroids may result in clinical remission

22. Patients and/or carers should be warned that potentially severe psychiatric adverse reactions may occur with systemic steroids (see section 4.8). Symptoms typically emerge within a few days or weeks of starting treatment. Risks may be higher with high doses/systemic exposure (see also section 4.5 Interaction with Other Medicaments and Other Forms of Interaction that can increase the risk of side effects), although dose levels do not allow prediction of the onset, type, severity or duration of reactions. Most reactions recover after either dose reduction or withdrawal, although specific treatment may be necessary. Patients/carers should be encouraged to seek medical advice if worrying psychological symptoms develop, especially if depressed mood or suicidal ideation is suspected. Patients/carers should be alert to possible psychiatric disturbances that may occur either during or immediately after dose tapering/withdrawal of systemic steroids, although such reactions have been reported infrequently.

Particular care is required when considering the use of systemic corticosteroids in patients with existing or previous history of severe affective disorders in themselves or in their first degree relatives. These would include depressive or manic-depressive illness and previous steroid psychosis.

Use in children: Corticosteroids cause growth retardation in infancy, childhood and adolescence, which may be irreversible. Treatment should be limited to the minimum dosage for the shortest possible time. In order to minimise suppression of the hypothalamo

Use in the elderly: The common adverse effects of systemic corticosteroids may be associated with more serious consequences in old age, especially osteoporosis, hypertension, hypokalaemia, diabetes, susceptibility to infection and thinning of the skin. Close clinical supervision is required to avoid life-threatening reactions.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

1. Convulsions have been reported with concurrent use of methylprednisolone and ciclosporin. Since concurrent administration of these agents results in a mutual inhibition of metabolism, it is possible that convulsions and other adverse events associated with the individual use of either drug may be more apt to occur.

2. Drugs that induce hepatic enzymes, such as rifampicin, rifabutin, carbamazepine, phenobarbitone, phenytoin, primidone, and aminoglutethimide enhance the metabolism of corticosteroids and its therapeutic effects may be reduced.

3. Drugs which inhibit the CYP3A4 enzyme, such as cimetidine, erythromycin, ketoconazole, itraconazole, diltiazem and mibefradil, may decrease the rate of metabolism of corticosteroids and hence increase the serum concentration.

4. Steroids may reduce the effects of anticholinesterases in myasthenia gravis. The desired effects of hypoglycaemic agents (including insulin), anti-hypertensives and diuretics are antagonised by corticosteroids, and the hypokalaemic effects of acetazolamide, loop diuretics, thiazide diuretics and carbenoxolone are enhanced.

5. The efficacy of coumarin anticoagulants may be enhanced by concurrent corticosteroid therapy and close monitoring of the INR or prothrombin time is required to avoid spontaneous bleeding.

6. The renal clearance of salicylates is increased by corticosteroids and steroid withdrawal may result in salicylate intoxication. Salicylates and non-steroidal anti-inflammatory agents should be used cautiously in conjunction with corticosteroids in hypothrombinaemia.

7. Steroids have been reported to interact with neuromuscular blocking agents such as pancuronium with partial reversal of the neuromuscular block.

4.6 Pregnancy And Lactation

Pregnancy

The ability of corticosteroids to cross the placenta varies between individual drugs, however, methylprednisolone does cross the placenta.

Administration of corticosteroids to pregnant animals can cause abnormalities of foetal development including cleft palate, intra-uterine growth retardation and affects on brain growth and development. There is no evidence that corticosteroids result in an increased incidence of congenital abnormalities, such as cleft palate in man, however, when administered for long periods or repeatedly during pregnancy, corticosteroids may increase the risk of intra-uterine growth retardation. Hypoadrenalism may, in theory , occur in the neonate following prenatal exposure to corticosteroids but usually resolves spontaneously following birth and is rarely clinically important. As with all drugs, corticosteroids should only be prescribed when the benefits to the mother and child outweigh the risks. When corticosteroids are essential, however, patients with normal pregnancies may be treated as though they were in the non-gravid state.

Lactation

Corticosteroids are excreted in small amounts in breast milk, however, doses of up to 40 mg daily of methylprednisolone are unlikely to cause systemic effects in the infant. Infants of mothers taking higher doses than this may have a degree of adrenal suppression, but the benefits of breastfeeding are likely to outweigh any theoretical risk.

4.7 Effects On Ability To Drive And Use Machines

None stated.

4.8 Undesirable Effects

Under normal circumstances Solu

PARENTERAL CORTICOSTEROID THERAPY

GASTRO-INTESTINAL

Increases in alanine transaminase (ALT, SGPT) aspartate transaminase (AST, SGOT) and alkaline phosphatase have been observed following corticosteroid treatment. These changes are usually small, not associated with any clinical syndrome and are reversible upon discontinuation.

ANTI-INFLAMMATORY AND IMMUNOSUPPRESSIVE EFFECTS - Increased susceptibility and severity of infections with suppression of clinical symptoms and signs, opportunistic infections, may suppress reactions to skin tests, recurrence of dormant tuberculosis (see Special warnings and special precautions for use).

MUSCULOSKELETAL

FLUID AND ELECTROLYTE DISTURBANCE

DERMATOLOGICAL

ENDOCRINE/METABOLIC

NEUROPSYCHIATRIC

OPHTHALMIC

CARDIOVASCULAR – Myocardial rupture following a myocardial infarction.

GENERAL

WITHDRAWAL SYMPTOMS

A 'withdrawal syndrome' may also occur including, fever, myalgia, arthralgia, rhinitis, conjunctivitis, painful itchy skin nodules and loss of weight.

4.9 Overdose

There is no clinical syndrome of acute overdosage with Solu

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Medrone is a corticosteroid with an anti-inflammatory activity at least five times that of hydrocortisone. An enhanced separation of glucocorticoid and mineralocorticoid effect results in a reduced incidence of sodium and water retention.

5.2 Pharmacokinetic Properties

Methylprednisolone is extensively bound to plasma proteins, mainly to globulin and less so to albumin. Only unbound corticosteroid has pharmacological effects or is metabolised. Metabolism occurs in the liver and to a lesser extent in the kidney. Metabolites are excreted in the urine.

Mean elimination half-life ranges from 2.4 to 3.5 hours in normal healthy adults and appears to be independent of the route of administration.

Total body clearance following intravenous or intramuscular injection of methylprednisolone to healthy adult volunteers is approximately 15-16l/hour. Peak methylprednisolone plasma levels of 33.67 mcg/100 ml were achieved in 2 hours after a single 40 mg i.m. injection to 22 adult male volunteers.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium biphosphate and sodium phosphate.

The 40 mg vial also contains lactose.

6.2 Incompatibilities

None stated.

6.3 Shelf Life

Shelf-life of the medicinal product as packaged for sale: 60 months.

After reconstitution with Sterile Water for injections, use immediately, discard any remainder.

6.4 Special Precautions For Storage

Store below 25°C.

Refer to Section 4.2 Dosage and Administration. No diluents other than those referred to are recommended. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

6.5 Nature And Contents Of Container

Type I clear glass vial with butyl rubber plug and flip top seal.

Each vial of Solu-Medrone 40 mg contains the equivalent of 40 mg of methylprednisolone as the sodium succinate for reconstitution with 1 ml of Sterile Water for Injections.

Each vial of Solu-Medrone 125 mg contains the equivalent of 125 mg of methylprednisolone as the sodium succinate for reconstitution with 2 ml of Sterile Water for Injections.

Each vial of Solu-Medrone 500 mg contains the equivalent of 500 mg of methylprednisolone as the sodium succinate for reconstitution with 7.8 ml of Sterile Water for Injections.

Each vial of Solu-Medrone 1 g contains the equivalent of 1 g of methylprednisolone as the sodium succinate for reconstitution with 15.6 ml of Sterile Water for Injections.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Pharmacia Limited

Ramsgate Road

Sandwich

Kent

CT13 9NJ

United Kingdom

8. Marketing Authorisation Number(S)

Solu-Medrone 40 mg PL 0032/0033

Solu-Medrone 125mg PL 0032/0034

Solu-Medrone 500mg PL 0032/0035

Solu-Medrone 1g PL 0032/0039

9. Date Of First Authorisation/Renewal Of The Authorisation

2^nd February 2005

10. Date Of Revision Of The Text

3^rd April 2008

Legal category: POM

SM 3_0 UK

Famotidine Suspension

Pronunciation: fa-MOE-tih-deen
Generic Name: Famotidine
Brand Name: Pepcid Oral Suspension

Famotidine Suspension is used for:

Treating and preventing ulcers. It is also used to treat conditions that cause increased acid secretion (eg, Zollinger-Ellison syndrome), gastroesophageal reflux disease (GERD), and esophagitis. It may also be used for other conditions as determined by your doctor.

Famotidine Suspension is an H₂ (histamine) blocker. It works by reducing stomach acid by blocking one of the chemicals (histamine) that stimulates the release of acid into the stomach.

Do NOT use Famotidine Suspension if:

• you are allergic to any ingredient in Famotidine Suspension or to other H₂ blockers (eg, ranitidine)


• you are taking dasatinib

Contact your doctor or health care provider right away if any of these apply to you.

Before using Famotidine Suspension:

Some medical conditions may interact with Famotidine Suspension. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have kidney or liver problems.

Some MEDICINES MAY INTERACT with Famotidine Suspension. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Dasatinib because its effectiveness may be decreased by Famotidine Suspension

This may not be a complete list of all interactions that may occur. Ask your health care provider if Famotidine Suspension may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Famotidine Suspension:

Use Famotidine Suspension as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Take Famotidine Suspension by mouth with or without food.


• Shake well before each use.


• Use a measuring device marked for medicine dosing. Ask your pharmacist for help if you are unsure of how to measure this dose.


• If you take atazanavir, erlotinib, itraconazole, ketoconazole, or rilpivirine, ask your doctor or pharmacist how to take it with Famotidine Suspension.


• Ask your doctor before taking antacids or other acid reducers with Famotidine Suspension.


• If you miss a dose of Famotidine Suspension, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Famotidine Suspension.

Important safety information:

• Famotidine Suspension may cause dizziness. This effect may be worse if you take it with alcohol or certain medicines. Use Famotidine Suspension with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.


• Notify your doctor if you have any symptoms of a bleeding ulcer, such as black, tarry stools, or vomit that looks like coffee grounds.


• You may need to make significant diet and lifestyle changes to help treat and prevent ulcers and other digestive problems, including stress-reduction programs, exercise, and diet changes.


• Use Famotidine Suspension with caution in the ELDERLY; they may be more sensitive to its effects.


• PREGNANCY and BREAST-FEEDING: If you become pregnant, contact your doctor. You will need to discuss the benefits and risks of using Famotidine Suspension while you are pregnant. Famotidine Suspension is found in breast milk. Do not breast-feed while taking Famotidine Suspension.

Possible side effects of Famotidine Suspension:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Constipation; diarrhea; dizziness; headache.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); irregular heartbeat; seizures.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Famotidine side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.

Proper storage of Famotidine Suspension:

Store mixed suspension at 77 degrees F (25 degrees C). Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Do not freeze. Keep Famotidine Suspension in original container. Do not store in the bathroom. Throw away unused suspension after 30 days. Keep Famotidine Suspension out of the reach of children and away from pets.

General information:

• If you have any questions about Famotidine Suspension, please talk with your doctor, pharmacist, or other health care provider.


• Famotidine Suspension is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Famotidine Suspension. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

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Calan

verapamil hydrochloride

Dosage Form: tablet, film coated
Calan®

verapamil hydrochloride tablets

Calan Description

Calan (verapamil HCl) is a calcium ion influx inhibitor (slow-channel blocker or calcium ion antagonist) available for oral administration in film-coated tablets containing 40 mg, 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 microcrystalline cellulose, corn starch, gelatin, hydroxypropyl cellulose, hypromellose, iron oxide colorant, lactose, magnesium stearate, polyethylene glycol, talc, and titanium dioxide.

Calan - Clinical Pharmacology

Calan 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 Calan as an antianginal agent remains to be fully determined, but includes the following two mechanisms:

1. Relaxation and prevention of coronary artery spasm: 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.


2. Reduction of oxygen utilization: Calan 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 Calan 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, Calan 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 Calan 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, 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 decreases the frequency of episodes of paroxysmal supraventricular tachycardia.

Calan 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. 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.

Essential hypertension

Calan 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.

Pharmacokinetics and metabolism

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 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 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 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

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 therapy. 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.

Indications and Usage for Calan

Calan 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

1. 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)


2. 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 Calan.

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, 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 Calan 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 Calan use, the patient should be reassessed to avoid under-digitalization.

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 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.

Cyclosporine

Verapamil therapy may increase serum levels of cyclosporine.

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 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 in the rat. Development of cataracts due to verapamil has not been reported in man.

Adverse Reactions

Serious adverse reactions are uncommon when Calan 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 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.

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.

Calan 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 Calan 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 is Calan Supplied

Calan 40 mg tablets are round, pink, film coated, with Calan debossed on one side and 40 on the other, supplied as:

NDC Number	Size
0025-1771-31	bottle of 100

Calan 80 mg tablets are oval, peach colored, scored, film coated, with Calan debossed on one side and 80 on the other, supplied as:

NDC Number	Size
0025-1851-31	bottle of 100

Calan 120 mg tablets are oval, brown, scored, film coated, with Calan 120 debossed on one side, supplied as:

NDC Number	Size
0025-1861-31	bottle of 100

Store at 59° to 77°F (15° to 25°C) and protect from light. Dispense in tight, light-resistant containers.

LAB-0269-8.0

October 2011

PRINCIPAL DISPLAY PANEL - 80 mg Label

NDC 0025-1851-31

100 Tablets

Rx only

Calan®

verapamil hydrochloride

tablets

80 mg

Pfizer

Distributed by

G.D. Searle LLC

Division of Pfizer Inc, NY, NY 10017

PRINCIPAL DISPLAY PANEL - 120 mg Label

NDC 0025-1861-31

100 Tablets

Rx only

Calan®

verapamil hydrochloride

tablets

120 mg

Pfizer

Distributed by

G.D. Searle LLC

Division of Pfizer Inc, NY, NY 10017

Calan  verapamil hydrochloride  tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0025-1771 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength verapamil hydrochloride (verapamil) verapamil hydrochloride 40 mg

Inactive Ingredients Ingredient Name Strength cellulose, microcrystalline   starch, corn   gelatin   hydroxypropyl cellulose   hypromelloses   lactose   magnesium stearate   polyethylene glycols   talc   titanium dioxide

Product Characteristics Color PINK Score no score Shape ROUND Size 6mm Flavor Imprint Code Calan;40 Contains

Packaging # NDC Package Description Multilevel Packaging 1 0025-1771-31 100 TABLET In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA018817	09/10/1984	01/20/2011

Calan  verapamil hydrochloride  tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0025-1851 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 cellulose, microcrystalline   starch, corn   gelatin   hydroxypropyl cellulose   hypromelloses   lactose   magnesium stearate   polyethylene glycols   talc   titanium dioxide

Product Characteristics Color ORANGE (peach) Score 2 pieces Shape OVAL Size 11mm Flavor Imprint Code Calan;80 Contains

Packaging # NDC Package Description Multilevel Packaging 1 0025-1851-31 100 TABLET In 1 BOTTLE None 2 0025-1851-51 500 TABLET In 1 BOTTLE None 3 0025-1851-52 1000 TABLET In 1 BOTTLE None

Marketing Information
Marketing Category	Application Number or Monograph Citation

Purdue Pharma LP

Address Purdue Pharma LP, One Stamford Forum 201 Tresser Boulevard Stamford, CT 06901-3431 Contact Details Phone: (203) 588-8000 Website: http://www.purduepharma.com/ Careers: http://www.purduepharma.com/Working-at-Purdue...

Sodium Fluoride Dental Rinse

Neutral Sodium Fluoride 0.2% Dental Rinse

NDC 60258-158-16


Neutral Sodium Fluoride 0.2%


Dental Rinse


Mint Flavor


Rx Only


Cypress Pharmaceutical, Inc.


16 fl oz (1 pt) (473 mL)


Description: Neutral Sodium Fluoride 0.2% Dental Rinse is a mint-flavored, neutral, aqueous solution containing 6% alcohol.


ACTIVE INGREDIENT: Sodium Fluoride 0.2% (w/v).  Contains: FD and C Blue #1.


INACTIVE INGREDIENT: Purified water, Glycerin, Alcohol 6% (v/v), Xylitol, Sodium Benzoate, Flavor, Magna Sweet, FD and C Blue #1.


CLINICAL PHARMACOLOGY: Topical application of sodium fluoride increases tooth resistance to acid dissolution, promotes remineralzation, and inhibits the cariogenic microbial process.


INDICATIONS AND USAGE: For once-weekly use as a dental caries preventative in pediatric patients.


WARNINGS: DO NOT SWALLOW.  Keep out of reach of infants and children.


DOSAGE AND ADMINISTRATION: For caries- Adults and pediatric patients over 6 years, 2 teaspoonfuls (10mL) once a week, preferably at bedtime after thoroughly brushing teeth, rinse vigorously around and between teeth for one minute, then expectorate.  DO NOT SWALLOW.  For maximum benefit, do not eat, drink, or rinse mouth for at least 30 minutes after treatment.


STORAGE: Store at controlled room temperature, 20-25oC (68-77oF).


See package insert for additional information.


CNRG06


7/2008


Rev 6/06


Manufactured for:


Cypress Pharmaceutical, Inc.,


Madison, MS 39110

Sodium Fluoride Dental Rinse Description

Neutral Sodium Fluoride 0.2% Dental Rinse is a mint-flavored, neutral, aqueous solution containing 6% alcohol.


Active ingredient: Sodium Fluoride 0.2% (w/v).  Contains: FD and C Blue #1.


Inactive ingredients: Purified water, Glycerin, Alcohol 6% (v/v), Xylitol, Sodium Benzoate, Flavor, Magna Sweet, FD and C Blue #1.

Sodium Fluoride Dental Rinse - Clinical Pharmacology

Topical application of sodium fluoride increases  tooth resistance to acid dissolution, promotes remineralzation, and inhibits the cariogenic microbial process.

Indications and Usage for Sodium Fluoride Dental Rinse

A dental caries preventative for weekly self-applied topical use.  Weekly rinsing with a neutral 0.2% sodium fluoride solution protects against dental caries in pediatric patients.  Neutral Sodium Fluoride 0.2% Dental Rinse provides a ready- to-use preparation for convenient administration and favorable compliance.  May be used in areas where drinking water is fluoridated since topical fluoride cannot produce fluorosis.  (See WARNINGS for exception.)

Contraindications

Do not use in patients with dyaphagia.  Do not use in pediatric patients under age 6 years unless recommended by a dentist or physician.

Warnings

Keep out of reach of infants and children.  Pediatric patients under age 12 should be supervised in the use of this product.  Patients under age 6 require special supervision to prevent repeated swallowing of rinse since they frequently swallow significant amounts while rinsing.  Prolonged daily ingestion may result in dental fluorosis in patients under age 6, especially if water fluoridation exceeds 0.6 ppm.  Read directions carefully before using.

PRECAUTIONS

General: Not for systemic treatment.  DO NOT SWALLOW.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

No carcinogenesis was found in mice or female  rats treated with fluoride at doses ranging from 4.1 to 9.1 mg/kg of body weight.  Equivocal  evidence of carcinogenesis was reported in rats treated with 2.5 and 4.1 mg/kg of body weight.  In another study, no carcinogenesis was observed in rats treated with fluoride up to 11.3 mg/kg of body weight.  Epidemiological data provide no credible evidence for an association between fluoride, either naturally occurring or added to drinking water, and risk of human cancer.


Fluoride ion is not mutagenic in standard bacterial systems but has been associated with chromosome aberrations in cultured human and rodent cells at doses much higher than expected human exposures.  Some in vivo studies report chromosome damage in rodents while other studies using similar protocols report negative results.


Potential adverse reproductive effects of fluoride exposure in humans has not been adequately evaluated.  Adverse effects on reproduction were reported for rats, mice, fox, and cattle exposed to 100 ppm or greater concentrations of fluoride in their diet or drinking water.  Other studies conducted in rats demonstrated that lower concentrations of fluoride (5 mg/kg of body weight) did not result in impaired fertility and reproductive capabilities.

Pregnancy

Teratogenic Effects: Pregnancy Category B.  It has been shown that fluoride crosses the placenta of rats, but only 0.01% of the amount administered is incorporated in fetal tissue.  Animal studies (rats, mice, rabbits) have shown that fluoride is not a teratogen.  Maternal exposure to 12.2 mg fluoride/kg of body weight (rats) or 13.1 mg/kg of body weight (rabbits) did not affect litter size or fetal weight and did not increase frequency of skeletal or visceral malformations.  There are no adequate and well-controlled studies in pregnant women.  However, epidemiological studies conducted in areas with high levels of naturally fluoridated water showed no increase in birth defects.  Heavy exposure to fluoride during in utero development may result in skeletal fluorosis which becomes evident in childhood.

Nursing Mothers

It is not known if fluoride is excreted in human milk.  However, many drugs are excreted in milk and caution should be exercised when products containing fluoride are administered to a nursing woman.  Reduced milk production was reported in farm-raised fox when the animals were fed a diet containing a high concentration of fluoride (98-137 mg/kg of body weight).  No adverse effects on parturition, lactation, or offspring were seen in rats administered fluoride up to 5 mg/kg of body weight.

Pediatric Use

The use of Neutral Sodium Fluoride 0.2% Dental Rinse as a weekly caries preventative in pediatric patients aged 6 to 16 years is supported by adequate and well-controlled clinical studies in students aged 6 to 12 years.1-3 Safety and effectiveness in pediatric patients below the ages of 6 years have not been established.  Please refer to the CONTRAINDICATIONS and WARNINGS sections.

Geriatric Use

Of the total number of subjects in clinical studies of 1.1% (w/v) sodium fluoride, 15 percent were 65 and over, while 1 percent were 75 and over.  No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients but greater sensitivity of some older individuals cannot be ruled out.  This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.  Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Adverse Reactions

In patients with mucositis, gingival tissues may be hypersensitive to flavor or alcohol present in formulation.  Allergic reactions and other idiosyncrasies are rarely reported.

Overdosage

Accidental ingestion of large amounts of fluoride may result in acute burning in the mouth and sore tongue.  Nausea, vomiting, and diarrhea may occur soon after ingestion (within 30 minutes) and are accompanied by salivation, hematemesis and epigastric cramping abdominal pain.  These symptoms may persist for 24 hours. If less than 5 mg fluoride/kg body weight (i.e. less than 2.3 mg fluoride/lb body weight)has been ingested, give calcium (e.g. milk) orally to relieve gastrointestinal symptoms and observe for a few hours.  If more than 5 mg fluoride/kg body weight (i.e. more than 2.3 mg fluoride/lb body weight) has been ingested, induce vomiting give orally soluble calcium (e.g.milk, 5% calcium gluconate or calcium lactate solution) and immediately seek medical assistance.  For accidental ingestion of more than 15 mg fluoride/kg of body weight (i.e. more than 6.9 mg fluoride/lb body weight) induce vomiting and admit immediately to a hospital facility.


A treatment dose (10 mL or two teaspoonfuls) of Neutral Sodium Fluoride 0.2% Dental Rinse contains approximately 9 mg of fluoride one 16 fl oz bottle contains approximately 429 mg fluoride.

Sodium Fluoride Dental Rinse Dosage and Administration

For caries- Adults and pediatric patients over age 6 years, 2 teaspoonfuls (10mL) once a week, preferably at bedtime after thoroughly brushing teeth, rinse vigorously around and between teeth for one minute, then expectorate.  DO NOT SWALLOW.  For maximum benefit, do not eat, drink, or rinse mouth for at least 30 minutes afterwards.

How is Sodium Fluoride Dental Rinse Supplied

Plastic bottle with child-resistant closure containing 16 fl oz (473 mL) (NDC 60258-158-16).

STORAGE

Store at Controlled Room Temperature, 20-25oC (68-77oF).

REFERENCES

1. American Dental Association, Accepted Dental Therapeutics,

Ed. 40, Chicago(1984): 403. 2. Ibid., p. 405-407. 3. L.W. Ripa, G.S.

Leske, and A. Sposato, "Supervised Weekly Rinsing with a 0.2% Neutral

NaF Solution: Final Results of a Demonstration Program after Six School

Years" J. Pub. Health Dent, 43 (1983):

53-62. 4. Driscoll WS, et al. "Caries- preventative effects on school

children daily and weekly fluoride mouthrinsing in a fluoridated

community: final results after 30 months" JADA. 1982;105:1010-1013.


Cypress Pharmaceutical, Inc.


6/06


I327


Manufactured for:


Cypress Pharmaceutical, Inc.,


Madison, MS 39110

NEUTRAL SODIUM FLUORIDE 0.2%   DENTAL RINSE sodium fluoride  rinse

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 60258-158 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SODIUM FLUORIDE (FLUORIDE ION) SODIUM FLUORIDE 9 mg  in 10 mL

Inactive Ingredients Ingredient Name Strength No Inactive Ingredients Found

Product Characteristics Color      Score      Shape Size Flavor MINT Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 60258-158-16 473 mL In 1 BOTTLE, PLASTIC None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
unapproved other		08/01/2006

Labeler - Cypress Pharmaceutical, Inc. (790248942)

Registrant - Cypress Pharmaceutical, Inc. (790248942)

Establishment
Name	Address	ID/FEI	Operations
Emerald 3 Enterprises, Inc.		000000000	manufacture

Revised: 11/2009Cypress Pharmaceutical, Inc.

More Sodium Fluoride Dental Rinse resources

• Sodium Fluoride Dental Rinse Use in Pregnancy & Breastfeeding
• Sodium Fluoride Dental Rinse Support Group
• 3 Reviews for Sodium Fluoride - Add your own review/rating

Compare Sodium Fluoride Dental Rinse with other medications

• Prevention of Dental Caries

Indiaral

Indiaral may be available in the countries listed below.

Ingredient matches for Indiaral

Loperamide

Loperamide hydrochloride (a derivative of Loperamide) is reported as an ingredient of Indiaral in the following countries:

• France

International Drug Name Search

Robinul Powder

1. Name Of The Medicinal Product

Robinul Powder

2. Qualitative And Quantitative Composition

Robinul Powder consists of Glycopyrrolate (glycopyrronium bromide) 100% w/w.

3. Pharmaceutical Form

White, crystalline powder.

4. Clinical Particulars

4.1 Therapeutic Indications

Iontophoretic treatment of the plantar and palmar skin for idiopathic hyperhidrosis.

4.2 Posology And Method Of Administration

Route of Administration: Iontophoresis

Dosage and Administration:

A 0.05% solution in distilled water of Glycopyrrolate USP is applied to palmar or plantar skin. When treating the foot or hand, sufficient solution to cover the palm or sole is placed in a non-metallic container and the anode, of sheet metal larger in area than the part being treated, is placed in the solution. The sole or palm is separated from the anode by 5mm of plastic foam or a layer of lint or sponge sheet.

In all cases an electrical circuit is completed by placing another limb in lukewarm tap water containing the cathode, similarly shielded from direct contact with the skin.

Recommended average conditions are 90 volts DC at 10-20 mA for adults (including older patients) and 2-10 mA for children, for 12 minutes at each site, depending on the patient's skin tolerance, body weight and size. Only one site should be treated at a time and only two sites in any one day. Treatments should not be repeated within seven days, but may be repeated later varying the precise conditions according to the recurrence and severity of hyperhidrosis. See also 'Special warnings and special precautions for use' below.

4.3 Contraindications

Glaucoma. Do not use during pregnancy.

4.4 Special Warnings And Precautions For Use

Glycopyrrolate may cause tachycardia.

This product should be used with great caution in patients with cardiovascular disease, thyrotoxicosis and obstructive disorders of the lower urinary tract. Patients with mycotic or other skin infections should not be treated.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Not applicable.

4.6 Pregnancy And Lactation

Do not use during pregnancy, as safety in this condition has not been established. Reproduction studies in rats and rabbits revealed no teratogenic effects from glycopyrrolate. However, diminished rates of conception and of survival at weaning were observed in rats, in a dose related manner. Studies in dogs suggest that this may be due to diminished seminal secretion, which is evident at high doses of glycopyrrolate. The significance of this for man is not clear.

4.7 Effects On Ability To Drive And Use Machines

Since this drug may cause drowsiness, patients receiving glycopyrrolate should not drive or operate machinery immediately after treatment unless it has been shown not to affect their physical or mental ability.

4.8 Undesirable Effects

Dryness of the mouth, blurred vision and mild abdominal discomfort may occur. Exercise care in patients with prostatic hypertrophy. Due to the effect of anticholinergics on mucous secretions, it is advisable not to treat people with chronic bronchitis. Occasionally difficulty in eating may occur and micturition may be temporarily affected for some hours after treatment. A mild tingling feeling may occur in the immersed areas during treatment and any recent cuts or cracks in the skin may smart when the current is increased at the start of iontophoresis. The latter can be avoided by covering the lesion with a thin smear of petroleum jelly. Avoid over-exertion especially in hot weather, until any side effects have disappeared.

4.9 Overdose

Not appropriate for the product.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Glycopyrrolate is an anticholinergic agent. The pharmacological particulars of anticholinergic drugs are well documented in the scientific literature.

5.2 Pharmacokinetic Properties

This product is indicated for use by Topical Iontophoresis for hyperhidrosis. Glycopyrrolate is a Quaternary Ammonium Compound and as such is absorbed through the skin in negligible amounts only.

5.3 Preclinical Safety Data

Nothing of relevance to the prescriber.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Not applicable - no other constituents present.

6.2 Incompatibilities

None.

6.3 Shelf Life

48 months unopened. 14 days after reconstitution.

6.4 Special Precautions For Storage

There are no special storage precautions for this product.

6.5 Nature And Contents Of Container

The product is presented in a screw cap amber bottle containing 3, 5 or 10g of glycopyrrolate USP.

6.6 Special Precautions For Disposal And Other Handling

The product should only be used by specialist units experienced in IONTOPHORETIC technique. The electrodes and treated skin areas must be placed in non-metallic containers and separated carefully by layers of, for example, sponge or lint. Direct contact between electrodes and skin must be avoided otherwise burns may result. The current must be very slowly increased from zero mA and decreased to zero mA at the beginning and end of the treatment period respectively to avoid any Faradic discharge between the electrode and skin on removal of the patient's limb from the container of solution. Instruct patient that contact must not be broken during treatment. Prior to use in iontophoresis a stock solution of Robinul powder (glycopyrrolate) may be made up with freshly boiled and cooled distilled or deionised water. Glycopyrrolate does hydrolyse slowly at pH 7 and it is recommended that stock solutions be discarded after not more than 14 days.

The solution must not be alkaline otherwise glycopyrrolate will hydrolyse more rapidly.

ADMINISTRATION DETAILS

7. Marketing Authorisation Holder

Anpharm Limited

Roscrea

Co. Tipperary

Ireland

8. Marketing Authorisation Number(S)

PL 15372/0003

9. Date Of First Authorisation/Renewal Of The Authorisation

1^st July, 1997.

10. Date Of Revision Of The Text

May, 2003.