Isradipine

Name: Isradipine

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Description

DynaCirc CR® contains isradipine, a calcium antagonist. It is available for once-daily oral administration as a controlled release 5 mg and 10 mg tablet for DynaCirc CR® (isradipine). DynaCirc CR® is a registered trademark for isradipine GITS (Gastrointestinal Therapeutic System) tablets.

The structural formula of isradipine is:

Chemically, isradipine is 3,5-Pyridinedicarboxylic acid, 4-(4-benzofurazanyl)-1,4-dihydro-2,6-dimethyl-, methyl 1-methylethyl ester. Isradipine is a yellow, fine crystalline powder which is odorless or has a faint characteristic odor. Isradipine is practically insoluble in water ( < 10 mg/L at 37°C), but is soluble in ethanol and freely soluble in acetone,chloroform and methylene chloride.

Active Ingredient: isradipine

Inactive Ingredients: butylated hydroxytoluene; cellulose acetate; hydroxypropyl methylcellulose; magnesium stearate; polyethylene glycol; polyethylene oxide; polysorbate 80; propylene glycol; red ferric oxide; silicon dioxide; sodium chloride; titanium dioxide; yellow ferric oxide.

System Components and Performance

Isradipine is delivered from the DynaCirc CR® (isradipine) Controlled Release Tablet as follows: a semipermeable membrane surrounds an osmotically active drug core.The core is composed of two layers: an "active"layer containing the drug, and a pharmacologically inert but osmotically active "push" layer. After ingestion, the tablet overcoating is quickly dissipated in the gastrointestinal tract,allowing water to enter the tablet through the semipermeable membrane. The polyethylene oxide polymer swells in the osmotic ("push") layer and exerts pressure against the "active"drug layer, releasing isradipine as a fine suspension through the laser-drilled tablet orifice which has been positioned on the "active" drug layer side. Drug delivery is essentially constant as long as the osmotic gradient remains constant and, after either 5 mg or 10 mg of isradipine is released, gradually falls to a negligible amount.The controlled rate of drug delivery into the gastrointestinal lumen is independent of pH or gastrointestinal motility. The delivery of isradipine in DynaCirc CR® (isradipine) Controlled Release Tablets depends on the existence of an osmotic gradient between the contents of the bilayer core and the fluid in the GI tract.The biologically inert core of the tablet remains intact and,unless it becomes trapped, is eliminated in the feces.

Overdose

Although there is no well documented experience with DynaCirc® (isradipine) overdosage,available data suggest that, as with other dihydropyridines, gross overdosage would result in excessive peripheral vasodilation with subsequent marked and probably prolonged systemic hypotension. Clinically significant hypotension overdosage calls for active cardiovascular support including monitoring of cardiac and respiratory function, elevation of lower extremities and attention to circulating fluid volume and urine output. A vasoconstrictor (such as epinephrine, norepinephrine, or levarterenol) may be helpful in restoring vascular tone and blood pressure,provided that there is no contraindication to its use.Since isradipine is highly protein bound, dialysis is not likely to be of benefit.

Significant lethality was observed in mice given oral doses of over 200 mg/kg and rabbits given about 50 mg/kg of isradipine. Rats tolerated doses of over 2000 mg/kg without effects on survival.

Uses of Isradipine

Isradipine is a prescription medication used to treat high blood pressure, known medically as hypertension.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Isradipine Dosage

Take isradipine exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The recommended dose range for isradipine is 5 to 20 mg once daily. Dose adjustments may be necessary in those with liver or kidney dysfunction.

What should I discuss with my healthcare provider before taking isradipine?

You should not take this medication if you are allergic to isradipine.

Before taking isradipine, tell your doctor if you are allergic to any drugs, or if you have:

  • kidney disease;

  • liver disease;

  • congestive heart failure; or

  • a narrowing or blockage in your digestive tract.

If you have any of these conditions, you may need a dose adjustment or special tests to safely take isradipine.

FDA pregnancy category C. This medication may be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment.

Isradipine can pass into breast milk and may harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

What should I avoid while taking isradipine?

Isradipine can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy. Get up slowly and steady yourself to prevent a fall.

Isradipine Pharmacokinetics

Absorption

Bioavailability

90–95% absorbed following oral administration, with peak plasma isradipine concentrations attained in about 1.5 hours.1

Bioavailability is approximately 15–24% due to first-pass metabolism.1

Onset

After a single dose, reduction in supine and standing BP occurs within 2–3 hours.1

Duration

Effects persist for >12 hours after administration.1

Food

Food decreases time to peak plasma concentration by about 1 hour.1

Special Populations

In patients with hepatic impairment, peak plasma concentration and AUC are increased by 32 and 52%, respectively.1

In patients with mild renal impairment (Clcr 30–80 mL/min), AUC is increased by 45%; however, in patients with severe renal failure (Clcr <10 mL/min) who have been on hemodialysis, AUC is decreased by 20–50%.1

In geriatric patients, peak plasma concentration and AUC are increased by 13 and 40%, respectively.1

Distribution

Extent

It is not known whether isradipine is distributed into milk.1

Plasma Protein Binding

95%.1

Elimination

Metabolism

Completely metabolized in the liver, apparently by CYP3A4, to inactive metabolites.1

Elimination Route

Excreted in urine (60–65%) and feces (25–30%).1

Half-life

Biphasic; initial half-life is 1.5–2 hours and terminal elimination half-life is approximately 8 hours.1

What are some side effects that I need to call my doctor about right away?

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.
  • A heartbeat that does not feel normal.
  • Very bad dizziness or passing out.
  • Swelling in the arms or legs.

Consumer Information Use and Disclaimer

  • If your symptoms or health problems do not get better or if they become worse, call your doctor.
  • Do not share your drugs with others and do not take anyone else's drugs.
  • Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
  • Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
  • Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this medicine, please talk with your doctor, nurse, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take isradipine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to isradipine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

Isradipine Description

Isradipine is a calcium antagonist available for oral administration in capsules containing 2.5 mg or 5 mg. The structural formula of Isradipine is:

Chemically, Isradipine is 3,5-Pyridinedicarboxylic acid, 4-(4-benzofurazanyl)-1,4-dihydro-2,6-dimethyl-,methyl 1-methylethyl ester. Isradipine is a yellow, fine crystalline powder which is odorless or has a faint characteristic odor. Isradipine is practically insoluble in water (<10 mg/L at 37°C), but is soluble in ethanol and freely soluble in acetone, chloroform and methylene chloride.

Active Ingredient: Isradipine

Inactive Ingredients: colloidal silicon dioxide, corn starch, gelatin, lactose monohydrate, microcrystalline cellulose, polyethylene glycol, red iron oxide (5 mg), sodium lauryl sulfate, and titanium dioxide.

Black ink contains the following ingredients: Black Iron Oxide, D&C Yellow #10 Aluminum Lake, FD&C Blue #1 Aluminum Lake, FD&C Blue #2 Aluminum Lake, FD&C Red #40 Aluminum Lake, n-Butyl Alcohol, Propylene Glycol, and Shellac Glaze in SD-45 Alcohol.

Isradipine - Clinical Pharmacology

Mechanism of Action 

Isradipine is a dihydropyridine calcium channel blocker. It binds to calcium channels with high affinity and specificity and inhibits calcium flux into cardiac and smooth muscle. The effects observed in mechanistic experiments in vitro and studied in intact animals and man are compatible with this mechanism of action and are typical of the class.

Except for diuretic activity, the mechanism of which is not clearly understood, the pharmacodynamic effects of Isradipine observed in whole animals can also be explained by calcium channel blocking activity, especially dilating effects in arterioles which reduce systemic resistance and lower blood pressure, with a small increase in resting heart rate. Although like other dihydropyridine calcium channel blockers, Isradipine has negative inotropic effects in vitro, studies conducted in intact anesthetized animals have shown that the vasodilating effect occurs at doses lower than those which affect contractility. In patients with normal ventricular function, Isradipine's afterload reducing properties lead to some increase in cardiac output.

Effects in patients with impaired ventricular function have not been fully studied.

Clinical Effects

Dose-related reductions in supine and standing blood pressure are achieved within 2-3 hours following single oral doses of 2.5 mg, 5 mg, 10 mg, and 20 mg Isradipine, with a duration of action (at least 50% of peak response) of more than 12 hours following administration of the highest dose.

Isradipine has been shown in controlled, double-blind clinical trials to be an effective antihypertensive agent when used as monotherapy, or when added to therapy with thiazide-type diuretics. During chronic administration, divided doses (b.i.d.) in the range of 5-20 mg daily have been shown to be effective, with response at trough (prior to next dose) over 50% of the peak blood pressure effect. The response is dose-related between 5-10 mg daily. Isradipine is equally effective in reducing supine, sitting, and standing blood pressure.

On chronic administration, increases in resting pulse rate averaged about 3-5 beats/min. These increases were not dose-related.

Hemodynamics

In man, peripheral vasodilation produced by Isradipine is reflected by decreased systemic vascular resistance and increased cardiac output. Hemodynamic studies conducted in patients with normal left ventricular function produced, following intravenous Isradipine administration, increases in cardiac index, stroke volume index, coronary sinus blood flow, heart rate, and peak positive left ventricular dP/dt. Systemic, coronary, and pulmonary vascular resistance was decreased. These studies were conducted with doses of Isradipine which produced clinically significant decreases in blood pressure. The clinical consequences of these hemodynamic effects, if any, have not been evaluated.

Effects on heart rate are variable, dependent upon rate of administration and presence of underlying cardiac condition. While increases in both peak positive dP/dt and LV ejection fraction are seen when intravenous Isradipine is given, it is impossible to conclude that these represent a positive inotropic effect due to simultaneous changes in preload and afterload. In patients with coronary artery disease undergoing atrial pacing during cardiac catheterization, intravenous Isradipine diminished abnormalities of systolic performance. In patients with moderate left ventricular dysfunction, oral and intravenous Isradipine in doses which reduce blood pressure by 12%-30%, resulted in improvement in cardiac index without increase in heart rate, and with no change or reduction in pulmonary capillary wedge pressure. Combination of Isradipine and propranolol did not significantly affect left ventricular dP/dtmax. The clinical consequences of these effects have not been evaluated.

Electrophysiologic Effects 

In general, no detrimental effects on the cardiac conduction system were seen with the use of Isradipine. Electrophysiologic studies were conducted on patients with normal sinus and atrioventricular node function. Intravenous Isradipine in doses which reduce systolic blood pressure did not affect PR, QRS, AH* or HV* intervals.

No changes were seen in Wenckebach cycle length, atrial, and ventricular refractory periods. Slight prolongation of QTc interval of 3% was seen in one study. Effects on sinus node recovery time (CSNRT) were mild or not seen.

In patients with sick sinus syndrome, at doses which significantly reduced blood pressure, intravenous Isradipine resulted in no depressant effect on sinus and atrioventricular node function.

*AH = conduction time from low right atrium to His bundle deflection, or AV nodal conduction

time;

HV = conduction time through His bundle and the bundle branch-Purkinje system.

Pharmacokinetics and Metabolism

Isradipine is 90%-95% absorbed and is subject to extensive first-pass metabolism, resulting in a bioavailability of about 15%-24%. Isradipine is detectable in plasma within 20 minutes after administration of single oral doses of 2.5-20 mg, and peak concentrations of approximately 1ng/mL/mg dosed occur about 1.5 hours after drug administration. Administration of Isradipine with food significantly increases the time to peak by about an hour, but has no effect on the total bioavailability (area under the curve) of the drug. Isradipine is 95% bound to plasma proteins. Both peak plasma concentration and AUC exhibit a linear relationship to dose over the 0-20 mg dose range. The elimination of Isradipine is biphasic with an early half-life of 1½-2 hours, and a terminal half-life of about 8 hours. The total body clearance of Isradipine is 1.4 L/min and the apparent volume of distribution is 3 L/kg.

Isradipine is completely metabolized prior to excretion, and no unchanged drug is detected in the urine. Six metabolites have been characterized in blood and urine, with the mono acids of the pyridine derivative and a cyclic lactone product accounting for >75% of the material identified. Approximately 60%-65% of an administered dose is excreted in the urine and 25%-30% in the feces. Mild renal impairment (creatinine clearance 30-80 mL/min) increases the bioavailability (AUC) of Isradipine by 45%. Progressive deterioration reverses this trend, and patients with severe renal failure (creatinine clearance <10 mL/min) who have been on hemodialysis show a 20%-50% lower AUC than healthy volunteers. No pharmacokinetic information is available on drug therapy during hemodialysis. In elderly patients, Cmax and AUC are increased by 13% and 40%, respectively; in patients with hepatic impairment, Cmax and AUC are increased by 32% and 52%, respectively (see DOSAGE AND ADMINISTRATION).

Precautions

General

Blood Pressure: Because Isradipine decreases peripheral resistance, like other calcium blockers Isradipine may occasionally produce symptomatic hypotension. However, symptoms like syncope and severe dizziness have rarely been reported in hypertensive patients administered Isradipine, particularly at the initial recommended doses (see DOSAGE AND ADMINISTRATION).

Use in Patients with Congestive Heart Failure: Although acute hemodynamic studies in patients with congestive heart failure have shown that Isradipine reduced afterload without impairing myocardial contractility, it has a negative inotropic effect at high doses in vitro, and possibly in some patients. Caution should be exercised when using the drug in congestive heart failure patients, particularly in combination with a beta-blocker.

Drug Interactions

Nitroglycerin: Isradipine has been safely coadministered with nitroglycerin.

Hydrochlorothiazide: A study in normal healthy volunteers has shown that concomitant administration of Isradipine and hydrochlorothiazide does not result in altered pharmacokinetics of either drug. In a study in hypertensive patients, addition of Isradipine to existing hydrochlorothiazide therapy did not result in any unexpected adverse effects, and Isradipine had an additional antihypertensive effect.

Propranolol: In a single dose study in normal volunteers, co-administration of propranolol had a small effect on the rate but no effect on the extent of Isradipine bioavailability. Significant increases in AUC (27%) and Cmax (58%) and decreases in tmax (23%) of propranolol were noted in this study. However, concomitant administration of 5 mg b.i.d. Isradipine and 40 mg b.i.d. propranolol to healthy volunteers under steady-state conditions had no relevant effect on either drug's bioavailability. AUC and Cmax differences were <20% between Isradipine given singly and in combination with propranolol, and between propranolol given singly and in combination with Isradipine.

Cimetidine: In a study in healthy volunteers, a one-week course of cimetidine at 400 mg b.i.d. with a single 5 mg dose of Isradipine on the sixth day showed an increase in Isradipine mean peak plasma concentrations (36%) and significant increase in area under the curve (50%). If Isradipine therapy is initiated in a patient currently receiving cimetidine, careful monitoring for adverse reactions is advised and downward dose adjustment may be required.

Rifampicin: In a study in healthy volunteers, a six-day course of rifampicin at 600 mg/day followed by a single 5 mg dose of Isradipine resulted in a reduction in Isradipine levels to below detectable limits. If rifampicin therapy is required, Isradipine concentrations and therapeutic effects are likely to be markedly reduced or abolished as a consequence of increased metabolism and higher clearance of Isradipine.

Warfarin: In a study in healthy volunteers, no clinically relevant pharmacokinetic or pharmacodynamic interaction between Isradipine and racemic warfarin was seen when two single oral doses of warfarin(0.7 mg/kg body weight) were administered during11 days of multiple-dose treatment with 5 mg b.i.d. Isradipine. Neither racemic warfarin nor Isradipine binding to plasma proteins in vitro was altered by the addition of the other drug.

Digoxin: The concomitant administration of Isradipine and digoxin in a single-dose pharmacokinetic study did not affect renal, nonrenal and total body clearance of digoxin.

Fentanyl Anesthesia: Severe hypotension has been reported during fentanyl anesthesia with concomitant use of a beta blocker and a calcium channel blocker. Even though such interactions have not been seen in clinical studies with Isradipine, an increased volume of circulating fluids might be required if such an interaction were to occur.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Treatment of male rats for 2 years with 2.5, 12.5, or 62.5 mg/kg/day Isradipine admixed with the diet (approximately 6, 31, and 156 times the maximum recommended daily dose based on a 50 kg man) resulted in dose dependent increases in the incidence of benign Leydig cell tumors and testicular hyperplasia relative to untreated control animals. These findings, which were replicated in a subsequent experiment, may have been indirectly related to an effect of Isradipine on circulating gonadotropin levels in the rats; a comparable endocrine effect was not evident in male patients receiving therapeutic doses of the drug on a chronic basis. Treatment of mice for two years with 2.5, 15, or 80 mg/kg/day Isradipine in the diet (approximately 6, 38, and 200 times the maximum recommended daily dose based on a 50 kg man) showed no evidence of oncogenicity. There was no evidence of mutagenic potential based on the results of a battery of mutagenic tests. No effect on fertility was observed in male and female rats treated with up to 60 mg/kg/day Isradipine.

Pregnancy

Pregnancy Category C: Isradipine was administered orally to rats and rabbits during organogenesis. Treatment of pregnant rats with doses of 6, 20, or 60 mg/kg/day produced a significant reduction in maternal weight gain during treatment with the highest dose (150 times the maximum recommended human daily dose) but with no lasting effects on the mother or the offspring. Treatment of pregnant rabbits with doses of 1, 3, or 10 mg/kg/day (2.5, 7.5, and 25 times the maximum recommended human daily dose) produced decrements in maternal body weight gain and increased fetal resorption at the two higher doses. There was no evidence of embryotoxicity at doses which were not maternotoxic and no evidence of teratogenicity at any dose tested. In a peri/postnatal administration study in rats, reduced maternal body weight gain during late pregnancy at oral doses of 20 and 60 mg/kg/day Isradipine was associated with reduced birth weights and decreased peri and postnatal pup survival.

There are no adequate and well controlled studies in pregnant women. The use of Isradipine during pregnancy should only be considered if the potential benefit outweighs potential risks.

Nursing Mothers

It is not known whether Isradipine is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for adverse effects of Isradipine on nursing infants, a decision should be made as to whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

How is Isradipine Supplied

Isradipine Capsules, USP 2.5 mg are Filled Gelatin Capsules Size #3, Cap: White Opaque/Body: White Opaque with Imprint "A-263" on cap and body. Available in bottles of 100's and 500's.

Isradipine Capsules, USP 5 mg are Filled Gelatin Capsules Size #3, Cap: Flesh Opaque/Body: Flesh Opaque with Imprint "A-264" on cap and body. Available in bottles of 100's and 500's.

Store 20°- 25°C (68°- 77°F) [see USP Controlled Room Temperature]. Dispense contents in a tight, light-resistant container as defined in the USP, with a child-resistant closure as required.

 

Manufactured By:

Elite Laboratories, Inc.

Northvale, NJ 07647

 

Distributed By:

Epic Pharma, LLC.

Laurelton, NY 11413

Manufactured in USA

Issued November 2014

MF263REV11/14

OE1511

Duration of Action

>12 hours

Half-Life Elimination

Alpha half-life: 1.5-2 hours; Terminal half-life: 8 hours

Protein Binding

95%

Storage

Store at 20°C to 25°C (68°F to 77°F) in a tight container, protected from moisture, humidity, and light.

Warnings/Precautions

Concerns related to adverse effects:

• Angina/MI: Increased angina and/or MI has occurred with initiation or dosage titration of dihydropyridine calcium channel blockers. Reflex tachycardia may occur resulting in angina and/or MI in patients with obstructive coronary disease, especially in the absence of concurrent beta-blockade.

• Hypotension/syncope: Symptomatic hypotension with or without syncope can rarely occur; blood pressure must be lowered at a rate appropriate for the patient's clinical condition.

• Peripheral edema: A common side effect is peripheral edema (dose-dependent); may begin within 2-3 weeks of starting therapy.

Disease-related concerns:

• Aortic stenosis: Use with extreme caution in patients with severe aortic stenosis; may reduce coronary perfusion resulting in ischemia.

• Heart failure (HF): The ACCF/AHA heart failure guidelines recommend to avoid use in patients with heart failure due to lack of benefit and/or worse outcomes with calcium channel blockers in general (ACCF/AHA [Yancy, 2013]).

• Hepatic impairment: Use with caution in patients with hepatic impairment; may require lower starting dose.

• Hypertrophic cardiomyopathy (HCM) with outflow tract obstruction: Use with caution in patients with HCM and outflow tract obstruction since reduction in afterload may worsen symptoms associated with this condition.

Renal Dose Adjustments

Mild renal impairment:
Initial dose: No adjustment recommended.

Precautions

Caution is recommended when using isradipine in congestive heart failure patients, especially when coadministered with a beta-blocker.

As with any other nondeformable material, caution should be used when administering controlled-release isradipine tablets in patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic).

Safety and effectiveness have not been established in pediatric patients (less than 18 years of age).

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