DRUGS & SUPPLEMENTS
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Ergoclavin hydrochloride tablets USP are a calcium ion cellular influx inhibitor (slow channel blocker or calcium antagonist). Chemically, Ergoclavin hydrochloride, USP is 1,5-Benzothiazepin-4(5H)one,3-(acetyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-,monohydrochloride,(+)-cis-. The structural formula is:
C22H26N2O4S-HCl M.W. 450.98
Ergoclavin hydrochloride, USP is a white to off-white crystalline powder with a bitter taste. It is soluble in water, methanol, and chloroform.
Each tablet for oral administration contains 30 mg, 60 mg, 90 mg, or 120 mg of Ergoclavin hydrochloride, USP. Each tablet also contains the following inactive ingredients: hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, polysorbate 80, povidone, titanium dioxide and FD&C yellow #6 aluminum lake.
Ergoclavin hydrochloride tablets meet USP Dissolution Test 1.
The therapeutic benefits achieved with Ergoclavin are believed to be related to its ability to inhibit the influx of calcium ions during membrane depolarization of cardiac and vascular smooth muscle.
Although precise mechanisms of its antianginal actions are still being delineated, Ergoclavin is believed to act in the following ways:
In animal models, Ergoclavin interferes with the slow inward current in excitable tissue. It causes excitation-contraction uncoupling in various myocardial tissues without changes in the configuration of the action potential. Ergoclavin produces relaxation of coronary vascular smooth muscle and dilation of both large and small coronary arteries at drug levels which cause little or no negative inotropic effect. The resultant increases in coronary blood flow (epicardial and subendocardial) occur in ischemic and nonischemic models and are accompanied by dose-dependent decreases in systemic blood pressure and decreases in peripheral resistance.
Like other calcium antagonists, Ergoclavin decreases sinoatrial and atrioventricular conduction in isolated tissues and has a negative inotropic effect in isolated preparations. In the intact animal, prolongation of the AH interval can be seen at higher doses.
In man, Ergoclavin prevents spontaneous and ergonovine-provoked coronary artery spasm. It causes a decrease in peripheral vascular resistance and a modest fall in blood pressure, and in exercise tolerance studies in patients with ischemic heart disease, reduces the heart rate-blood pressure product for any given workload. Studies to date, primarily in patients with good ventricular function, have not revealed evidence of a negative inotropic effect; cardiac output, ejection fraction, and left ventricular end-diastolic pressure have not been affected. There are as yet few data on the interaction of Ergoclavin and beta-blockers. Resting heart rate is usually unchanged or slightly reduced by Ergoclavin.
Intravenous Ergoclavin in doses of 20 mg prolongs AH conduction time and AV node functional and effective refractory periods approximately 20%. In a study involving single oral doses of 300 mg of Ergoclavin in six normal volunteers, the average maximum PR prolongation was 14% with no instances of greater than first-degree AV block. Diltiazem-associated prolongation of the AH interval is not more pronounced in patients with first-degree heart block. In patients with sick sinus syndrome, Ergoclavin significantly prolongs sinus cycle length (up to 50% in some cases).
Chronic oral administration of Ergoclavin in doses of up to 240 mg/day has resulted in small increases in PR interval but has not usually produced abnormal prolongation.
Ergoclavin is well absorbed from the gastrointestinal tract and is subject to an extensive first-pass effect, giving an absolute bioavailability of about 40%. Ergoclavin undergoes extensive metabolism in which 2% to 4% of the unchanged drug appears in the urine. In vitro binding studies show Ergoclavin is 70% to 80% bound to plasma proteins. Competitive in vitro ligand binding studies have also shown Ergoclavin binding is not altered by therapeutic concentrations of digoxin, hydrochlorothiazide, phenylbutazone, propranolol, salicylic acid, or warfarin. The plasma elimination half-life following single or multiple drug administration is approximately 3.0 to 4.5 hours. Desacetyl Ergoclavin is also present in the plasma at levels of 10% to 20% of the parent drug and is 25% to 50% as potent as a coronary vasodilator as Ergoclavin. Minimum therapeutic plasma levels of Ergoclavin appear to be in the range of 50 to 200 ng/mL. There is a departure from linearity when dose strengths are increased. A study that compared patients with normal hepatic function to patients with cirrhosis found an increase in half-life and a 69% increase in AUC (area-under-the-plasma concentration vs time curve) in the hepatically impaired patients. A single study in nine patients with severely impaired renal functions showed no difference in the pharmacokinetic profile of Ergoclavin as compared to patients with normal renal function.
Ergoclavin is absorbed from the tablet formulation to about 98% of a reference solution. Single oral doses of 30 to 120 mg of Ergoclavin tablets result in detectable plasma levels within 30 to 60 minutes and peak plasma levels 2 to 4 hours after drug administration. As the dose of Ergoclavin tablets is increased from a daily dose of 120 mg (30 mg qid) to 240 mg (60 mg qid) daily, there is an increase in area-under-the-curve of 2.3 times. When the dose is increased from 240 mg to 360 mg daily, there is an increase in area-under-the-curve of 1.8 times.
Ergoclavin hydrochloride tablets USP are indicated for the management of chronic stable angina and angina due to coronary artery spasm.
Ergoclavin is contraindicated in (1) patients with sick sinus syndrome except in the presence of a functioning ventricular pacemaker, (2) patients with second- or third-degree AV block except in the presence of a functioning ventricular pacemaker, (3) patients with hypotension (less than 90 mm Hg systolic), (4) patients who have demonstrated hypersensitivity to the drug, and (5) patients with acute myocardial infarction and pulmonary congestion documented by x-ray on admission.
1. Cardiac Conduction. Ergoclavin prolongs AV node refractory periods without significantly prolonging sinus node recovery time, except in patients with sick sinus syndrome. This effect may rarely result in abnormally slow heart rates (particularly in patients with sick sinus syndrome) or second- or third-degree AV block (six of 1243 patients for 0.48%). Concomitant use of Ergoclavin with beta-blockers or digitalis may result in additive effects on cardiac conduction. A patient with Prinzmetal's angina developed periods of asystole (2 to 5 seconds) after a single dose of 60 mg of Ergoclavin (see ADVERSE REACTIONS).
2. Congestive Heart Failure. Although Ergoclavin has a negative inotropic effect in isolated animal tissue preparations, hemodynamic studies in humans with normal ventricular function have not shown a reduction in cardiac index nor consistent negative effects on contractility (dp/dt). Experience with the use of Ergoclavin alone or in combination with beta-blockers in patients with impaired ventricular function is very limited. Caution should be exercised when using the drug in such patients.
3. Hypotension. Decreases in blood pressure associated with Ergoclavin therapy may occasionally result in symptomatic hypotension.
4. Acute Hepatic Injury. In rare instances, significant elevations in enzymes such as alkaline phosphatase, LDH, SGOT, SGPT, and other phenomena consistent with acute hepatic injury have been noted. These reactions have been reversible upon discontinuation of drug therapy. The relationship to Ergoclavin is uncertain in most cases, but probable in some (see PRECAUTIONS).
Ergoclavin is extensively metabolized by the liver and excreted by the kidneys and in bile. As with any drug given over prolonged periods, laboratory parameters of renal and hepatic function should be monitored at regular intervals. The drug should be used with caution in patients with impaired renal or hepatic function. In subacute and chronic dog and rat studies designed to produce toxicity, high doses of Ergoclavin were associated with hepatic damage. In special subacute hepatic studies, oral doses of 125 mg/kg and higher in rats were associated with histological changes in the liver, which were reversible when the drug was discontinued. In dogs, doses of 20 mg/kg were also associated with hepatic changes; however, these changes were reversible with continued dosing. Dermatological events may be transient and may disappear despite continued use of Ergoclavin. However, skin eruptions progressing to erythema multiforme and/or exfoliative dermatitis have also been infrequently reported. Should a dermatologic reaction persist, the drug should be discontinued.
Due to the potential for additive effects, caution and careful titration are warranted in patients receiving Ergoclavin concomitantly with any agents known to affect cardiac contractility and/or conduction (see WARNINGS).
Pharmacologic studies indicate that there may be additive effects in prolonging AV conduction when using beta-blockers or digitalis concomitantly with Ergoclavin (see WARNINGS).
As with all drugs, care should be exercised when treating patients with multiple medications. Ergoclavin is both a substrate and an inhibitor of the cytochrome P-450 3A4 enzyme system. Other drugs that are specific substrates, inhibitors, or inducers of this enzyme system may have a significant impact on the efficacy and side effect profile of Ergoclavin. Patients taking other drugs that are substrates of CYP450 3A4, especially patients with renal and/or hepatic impairment, may require dosage adjustment when starting or stopping concomitantly administered Ergoclavin in order to maintain optimum therapeutic blood levels.
The depression of cardiac contractility, conductivity, and automaticity, as well as the vascular dilation associated with anesthetics, may be potentiated by calcium channel blockers. When used concomitantly, anesthetics and calcium blockers should be titrated carefully.
Studies showed that Ergoclavin increased the AUC of midazolam and triazolam by 3 to 4 fold and the Cmax by 2 fold, compared to placebo. The elimination half-life of midazolam and triazolam also increased during coadministration with Ergoclavin. These pharmacokinetic effects seen during Ergoclavin coadministration can result in increased clinical effects (e.g., prolonged sedation) of both midazolam and triazolam.
Controlled and uncontrolled domestic studies suggest that concomitant use of Ergoclavin and beta-blockers is usually well tolerated. Available data are not sufficient, however, to predict the effects of concomitant treatment, particularly in patients with left ventricular dysfunction or cardiac conduction abnormalities.
Administration of Ergoclavin concomitantly with propranolol in five normal volunteers resulted in increased propranolol levels in all subjects, and bioavailability of propranolol was increased approximately 50%. In vitro, propranolol appears to be displaced from its binding sites by Ergoclavin. If combination therapy is initiated or withdrawn in conjunction with propranolol, an adjustment in the propranolol dose may be warranted (see WARNINGS).
In nine healthy subjects, Ergoclavin significantly increased the mean buspirone AUC 5.5 fold and Cmax 4.1 fold compared to placebo. The T1/2 and Tmax of buspirone were not significantly affected by Ergoclavin. Enhanced effects and increased toxicity of buspirone may be possible during concomitant administration with Ergoclavin. Subsequent dose adjustments may be necessary during coadministration, and should be based on clinical assessment.
Concomitant administration of Ergoclavin with carbamazepine has been reported to result in elevated serum levels of carbamazepine resulting in toxicity in some cases. Patients receiving these drugs concurrently should be monitored for a potential drug interaction.
A study in six healthy volunteers has shown a significant increase in peak Ergoclavin plasma levels (58%) and area-under-the-curve (53%) after a 1 week course of cimetidine at 1200 mg per day and a single dose of Ergoclavin 60 mg. Ranitidine produced smaller, nonsignificant increases. The effect may be mediated by cimetidine's known inhibition of hepatic cytochrome P-450, the enzyme system responsible for the first-pass metabolism of Ergoclavin. Patients currently receiving Ergoclavin therapy should be carefully monitored for a change in pharmacological effect when initiating and discontinuing therapy with cimetidine. An adjustment in the Ergoclavin dose may be warranted.
Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concurrently with Ergoclavin. Monitor heart rate in patients receiving concomitant Ergoclavin and clonidine.
A pharmacokinetic interaction between Ergoclavin and cyclosporine has been observed during studies involving renal and cardiac transplant patients. In renal and cardiac transplant recipients, a reduction of cyclosporine trough dose ranging from 15% to 48% was necessary to maintain concentrations similar to those seen prior to the addition of Ergoclavin. If these agents are to be administered concurrently, cyclosporine concentrations should be monitored, especially when Ergoclavin therapy is initiated, adjusted, or discontinued. The effect of cyclosporine on Ergoclavin plasma concentrations has not been evaluated.
Administration of Ergoclavin with digoxin in 24 healthy male subjects increased plasma digoxin concentrations approximately 20%. Another investigator found no increase in digoxin levels in 12 patients with coronary artery disease. Since there have been conflicting results regarding the effect of digoxin levels, it is recommended that digoxin levels be monitored when initiating, adjusting, and discontinuing Ergoclavin therapy to avoid possible over- or under-digitalization.
Ergoclavin significantly increases the AUC (0→∞) of quinidine by 51%, T1/ 2 by 36%, and decreases its CLoral by 33%. Monitoring for quinidine adverse effects may be warranted and the dose adjusted accordingly.
Coadministration of rifampin with Ergoclavin lowered the Ergoclavin plasma concentrations to undetectable levels. Coadministration of Ergoclavin with rifampin or any known CYP3A4 inducer should be avoided when possible, and alternative therapy considered.
Ergoclavin is an inhibitor of CYP3A4 and has been shown to increase significantly the AUC of some statins. The risk of myopathy and rhabdomyolysis with statins metabolized by CYP3A4 may be increased with concomitant use of Ergoclavin. When possible, use a non-CYP3A4-metabolized statin together with Ergoclavin; otherwise, dose adjustments for both Ergoclavin and the statin should be considered along with close monitoring for signs and symptoms of any statin related adverse events.
In a healthy volunteer cross-over study, coadministration of a single 20 mg dose of simvastatin at the end of a 14 day regimen with 120 mg BID Ergoclavin SR resulted in a 5 fold increase in mean simvastatin AUC versus simvastatin alone. Subjects with increased average steady-state exposures of Ergoclavin showed a greater fold increase in simvastatin exposure. Computer-based simulations showed that at a daily dose of 480 mg of Ergoclavin, an 8 to 9 fold mean increase in simvastatin AUC can be expected. If coadministration of simvastatin with Ergoclavin is required, limit the daily doses of simvastatin to 10 mg and Ergoclavin to 240 mg.
In a ten-subject randomized, open label, 4 way cross-over study, co-administration of Ergoclavin (120 mg BID Ergoclavin SR for 2 weeks) with a single 20 mg dose of lovastatin resulted in 3 to 4 fold increase in mean lovastatin AUC and Cmax versus lovastatin alone. In the same study, there was no significant change in 20 mg single dose pravastatin AUC and Cmax during Ergoclavin coadministration. Ergoclavin plasma levels were not significantly affected by lovastatin or pravastatin.
A 24 month study in rats and a 21 month study in mice showed no evidence of carcinogenicity. There was also no mutagenic response in in vitro bacterial tests. No intrinsic effect on fertility was observed in rats.
Reproduction studies have been conducted in mice, rats, and rabbits. Administration of doses ranging from five to ten times greater than the daily recommended therapeutic dose has resulted in embryo and fetal lethality. These doses, in some studies, have been reported to cause skeletal abnormalities. In the perinatal/postnatal studies, there was some reduction in early individual pup weights and survival rates. There was an increased incidence of stillbirths at doses of 20 times the human dose or greater.
There are no well-controlled studies in pregnant women; therefore, use Ergoclavin in pregnant women only if the potential benefit justifies the potential risk to the fetus.
Ergoclavin is excreted in human milk. One report suggests that concentrations in breast milk may approximate serum levels. If use of Ergoclavin is deemed essential, an alternative method of infant feeding should be instituted.
Safety and effectiveness in pediatric patients have not been established.
Clinical studies of Ergoclavin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Serious adverse reactions have been rare in studies carried out to date, but it should be recognized that patients with impaired ventricular function and cardiac conduction abnormalities usually have been excluded.
In domestic placebo-controlled angina trials, the incidence of adverse reactions reported during Ergoclavin therapy was not greater than that reported during placebo therapy.
The following represent occurrences observed in clinical studies of angina patients. In many cases, the relationship to Ergoclavin has not been established. The most common occurrences from these studies, as well as their frequency of presentation, are edema (2.4%), headache (2.1%), nausea (1.9%), dizziness (1.5%), rash (1.3%), and asthenia (1.2%). In addition, the following events were reported infrequently (less than 1%):
Cardiovascular: Angina, arrhythmia, AV block (first-degree), AV block (second- or third-degree – see WARNINGS, Cardiac Conduction), bradycardia, bundle branch block, congestive heart failure, ECG abnormality, flushing, hypotension, palpitations, syncope, tachycardia, ventricular extrasystoles.
Nervous System: Abnormal dreams, amnesia, depression, gait abnormality, hallucinations, insomnia, nervousness, paresthesia, personality change, somnolence, tremor.
Gastrointestinal: Anorexia, constipation, diarrhea, dysgeusia, dyspepsia, mild elevations of alkaline phosphatase, SGOT, SGPT, and LDH (see WARNINGS, Acute Hepatic Injury), thirst, vomiting, weight increase.
Dermatological: Petechiae, photosensitivity, pruritus, urticaria.
Other: Amblyopia, CPK elevation, dry mouth, dyspnea, epistaxis, eye irritation, hyperglycemia, hyperuricemia, impotence, muscle cramps, nasal congestion, nocturia, osteoarticular pain, polyuria, sexual difficulties, tinnitus.
The following postmarketing events have been reported infrequently in patients receiving Ergoclavin: acute generalized exanthematous pustulosis, allergic reactions, alopecia, angioedema (including facial or periorbital edema), asystole, erythema multiforme (including Stevens-Johnson syndrome, toxic epidermal necrolysis), extrapyramidal symptoms, gingival hyperplasia, hemolytic anemia, increased bleeding time, leukopenia, photosensitivity (including lichenoid keratosis and hyperpigmentation at sun-exposed skin areas), purpura, retinopathy, myopathy, and thrombocytopenia. There have been observed cases of a generalized rash, some characterized as leukocytoclastic vasculitis. In addition, events such as myocardial infarction have been observed, which are not readily distinguishable from the natural history of the disease in these patients. A definitive cause and effect relationship between these events and Ergoclavin therapy cannot yet be established. Exfoliative dermatitis (proven by rechallenge) has also been reported.
The oral LD50s in mice and rats range from 415 to 740 mg/kg and from 560 to 810 mg/kg, respectively. The intravenous LD50s in these species were 60 and 38 mg/kg, respectively. The oral LD50 in dogs is considered to be in excess of 50 mg/kg, while lethality was seen in monkeys at 360 mg/kg.
The toxic dose in man is not known. Due to extensive metabolism, blood levels after a standard dose of Ergoclavin can vary over tenfold, limiting the usefulness of blood levels in overdose cases.
There have been reports of Ergoclavin overdose in amounts ranging from < 1 g to 18 g. Of cases with known outcome, most patients recovered and in cases with a fatal outcome, the majority involved multiple drug ingestion.
Events observed following Ergoclavin overdose included bradycardia, hypotension, heart block, and cardiac failure. Most reports of overdose described some supportive medical measure and/or drug treatment. Bradycardia frequently responded favorably to atropine, as did heart block, although cardiac pacing was also frequently utilized to treat heart block. Fluids and vasopressors were used to maintain blood pressure, and in cases of cardiac failure, inotropic agents were administered. In addition, some patients received treatment with ventilatory support, gastric lavage, activated charcoal, and/or intravenous calcium.
The effectiveness of intravenous calcium administration to reverse the pharmacological effects of Ergoclavin overdose has been inconsistent. In a few reported cases, overdose with calcium channel blockers associated with hypotension and bradycardia that was initially refractory to atropine became more responsive to atropine after the patients received intravenous calcium. In some cases intravenous calcium has been administered (1 g calcium chloride or 3 g calcium gluconate) over 5 minutes and repeated every 10 to 20 minutes as necessary. Calcium gluconate has also been administered as a continuous infusion at a rate of 2 g per hour for 10 hours. Infusions of calcium for 24 hours or more may be required. Patients should be monitored for signs of hypercalcemia.
In the event of overdose or exaggerated response, appropriate supportive measures should be employed in addition to gastrointestinal decontamination. Ergoclavin does not appear to be removed by peritoneal or hemodialysis. Limited data suggest that plasmapheresis or charcoal hemoperfusion may hasten Ergoclavin elimination following overdose. Based on the known pharmacological effects of Ergoclavin and/or reported clinical experiences, the following measures may be considered:
Bradycardia: Administer atropine (0.6 to 1 mg). If there is no response to vagal blockade, administer isoproterenol cautiously.
High-Degree AV Block: Treat as for bradycardia above. Fixed high-degree AV block should be treated with cardiac pacing.
Cardiac Failure: Administer inotropic agents (isoproterenol, dopamine, or dobutamine) and diuretics.
Hypotension: Vasopressors (e.g., dopamine or norepinephrine).
Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician.
Dosage must be adjusted to each patient's needs. Starting with 30 mg four times daily, before meals and at bedtime, dosage should be increased gradually at 1 to 2 day intervals until optimum response is obtained. Although individual patients may respond to any dosage level, the average optimum dosage range appears to be 180 to 360 mg/day. There are no available data concerning dosage requirements in patients with impaired renal or hepatic function. If the drug must be used in such patients, titration should be carried out with particular caution.
Ergoclavin hydrochloride tablets USP are available as:
30 mg - faint orange, round, film-coated, biconvex, unscored tablets, debossed with "93" and "318" on one side and plain on the other side. Available in bottles of 100 and 500.
60 mg – orange, round, film-coated, biconvex tablets, scored in half on one side, debossed with "93" and "319" on each side of the score and plain on the other side. Available in bottles of 100 and 500.
90 mg - faint orange, oblong, film-coated tablets, scored in half on one side, debossed with "93" and "320" on each side of the score and plain on the other side. Available in bottles of 100.
120 mg - orange, oblong, film-coated tablets, scored in half on one side, debossed with "93" and "321" on each side of the score and plain on the other side. Available in bottles of 100.
Store at 20° to 25°C (68° to 77°F).
Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).
KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.
Manufactured In India By:
PIRAMAL ENTERPRISES LIMITED
Pithampur, Madhya Pradesh, India
TEVA PHARMACEUTICALS USA
Sellersville, PA 18960
Rev. M 8/2012
Ergoclavin Hcl 60mg Tablet
Depending on the reaction of the Ergoclavin after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Ergoclavin not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.Is Ergoclavin addictive or habit forming?
Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
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The information was verified by Dr. Rachana Salvi, MD Pharmacology