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DRUGS & SUPPLEMENTS
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Verapamil hydrochloride is an almost white crystalline powder, with a molecular weight of 491.08. It is soluble in water, chloroform, and methanol. It is practically free of odor, with a bitter taste.
verap structure
Ocadrik is a white or almost white powder with a molecular weight of 430.54. It is soluble (>100 mg/mL) in chloroform, dichloromethane, and methanol.
Ocadrik tablets are formulated for oral administration, containing verapamil hydrochloride as a controlled release formulation and Ocadrik as an immediate release formulation. The tablet strengths are Ocadrik 2 mg/verapamil hydrochloride ER 180 mg, Ocadrik 1 mg/verapamil hydrochloride ER 240 mg, Ocadrik 2 mg/verapamil hydrochloride ER 240 mg, and Ocadrik 4 mg/verapamil hydrochloride ER 240 mg. The tablets also contain the following ingredients: corn starch, dioctyl sodium sulfosuccinate, ethanol, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, purified water, silicon dioxide, sodium alginate, sodium stearyl fumarate, synthetic iron oxides, talc, and titanium dioxide.
Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. In controlled clinical trials, treatment with Ocadrik resulted in mean increases in potassium of 0.1 mEq/L (see PRECAUTIONS ). Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity (PRA).
ACE is identical to kininase II, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effect of Ocadrik remains to be elucidated.
While the mechanism through which Ocadrik lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, Ocadrik has an antihypertensive effect even in patients with low renin hypertension. Ocadrik is an effective antihypertensive in all races studied. Both black patients (usually a predominantly low renin group) and non-black patients respond to 2 to 4 mg of Ocadrik.
The AUC and Cmax for both verapamil and norverapamil are increased when 240 mg of controlled release verapamil is administered concomitantly with 4 mg Ocadrik. The increase in Cmax is 54 and 30% and the AUC is increased by 65 and 32% for verapamil and norverapamil, respectively. Administration of Ocadrik 4/240 with a high-fat meal does not alter the bioavailability of Ocadrik whereas verapamil peak concentrations and area under the curve (AUC) decrease 37% and 28%, respectively. Food thus decreases verapamil bioavailability and the time to peak plasma concentration for both verapamil and norverapamil are delayed by approximately 7 hours. Both optical isomers of verapamil are similarly affected.
The elimination half life of Ocadrik is about 6 hours. At steady state, the effective half-life of trandolaprilat is 22.5 hours. Like all ACE inhibitors, trandolaprilat also has a prolonged terminal elimination phase, involving a small fraction of administered drug, probably representing binding to plasma and tissue ACE.
The terminal half-life of verapamil is 6-11 hours. Steady-state plasma concentrations of the two components are achieved after about a week of once-daily dosing of Ocadrik. At steady-state, plasma concentrations of verapamil and trandolaprilat are up to two-fold higher than those observed after a single oral Ocadrik dose.
The pharmacokinetics of verapamil and trandolaprilat are significantly different in the elderly (≥65 years) than in younger subjects. The bioavailability of verapamil and norverapamil are increased by 87% and 77%, respectively, and that of Ocadrik by approximately 35% in the elderly. AUCs are approximately 80% and 35% higher, respectively.
Verapamil Component
With the immediate release formulation, more than 90% of the orally administered dose is absorbed with peak plasma concentrations of verapamil observed 1 to 2 hours after dosing. A delayed rate but similar extent of absorption is observed for the sustained release formulation when compared to the immediate release formulation. Because of the rapid biotransformation of verapamil during its first pass through the portal circulation, absolute bioavailability ranges from 20% to 35%. A nonlinear correlation exists between verapamil dose and plasma concentrations.
In early dose titration with verapamil, a relationship exists between plasma concentrations of verapamil and prolongation of the PR interval. However, during chronic administration, this relationship may disappear. No relationship has been established between the plasma concentration of verapamil and reduction in blood pressure.
In healthy subjects, orally administered verapamil undergoes extensive metabolism in the liver. Twelve metabolites have been identified in plasma; all except norverapamil are present in trace amounts only. Approximately 70% of an administered dose is excreted as metabolites in the urine and 16% or more in the feces within 5 days. Urinary excretion of unchanged drug is about 3% to 4% of the dose. Verapamil is approximately 90% bound to plasma proteins.
In patients with hepatic insufficiency, verapamil clearance is decreased about 30% and the elimination half-life is prolonged up to 14 to 16 hours (see PRECAUTIONS ). In patients with liver dysfunction, a dosage adjustment may be required. In the elderly (≥65 years), verapamil clearance is reduced resulting in increases in elimination half-life.
Ocadrik Component
Following oral administration of Ocadrik, the absolute bioavailability of Ocadrik is approximately 10% as Ocadrik and 70% as trandolaprilat. Plasma concentrations of trandolaprilat but not Ocadrik increase in proportion with dose. Plasma concentrations of trandolaprilat decline in a triphasic manner. The more prolonged terminal elimination phase probably represents a small fraction of dose saturably bound to ACE.
After an oral radiolabeled dose of Ocadrik, excretion of Ocadrik and metabolites account for 33% of the dose in the urine and about 66% in the feces. Less than 1% of the dose is excreted in the urine as unchanged drug. Serum protein binding of Ocadrik is about 80%, and is independent of concentration. Binding of trandolaprilat is concentration-dependent, varying from 65% at 1000 ng/mL to 94% at 0.1 ng/mL, indicating saturation of binding with increasing concentration.
Compared to normal subjects, the plasma concentrations of Ocadrik and trandolaprilat are approximately 2-fold greater and renal clearance is reduced by about 85% in patients with creatinine clearance below 30 mL/min and in patients on hemodialysis. Dosage adjustment is recommended in renally impaired patients (see DOSAGE AND ADMINISTRATION ).
Following oral administration in patients with mild to moderate alcoholic cirrhosis, plasma concentrations of Ocadrik and trandolaprilat were, respectively, 9-fold and 2-fold greater than in normal subjects, but inhibition of ACE activity was not affected. Lower doses should be considered in patients with hepatic insufficiency (see DOSAGE AND ADMINISTRATION ).
Verapamil Component
Verapamil dilates the main coronary arteries and coronary arterioles, both in normal and ischemic regions, and is a potent inhibitor of coronary artery spasm. This property increases myocardial oxygen delivery in patients with coronary artery spasm, and is responsible for the effectiveness of verapamil in vasospastic (Prinzmetal's or variant) as well as unstable angina at rest.
Verapamil regularly reduces the total systemic resistance (afterload) by dilating peripheral arterioles. By decreasing the influx of calcium, verapamil prolongs the effective refractory period within the AV node and slows AV conduction in a rate-related manner.
Normal sinus rhythm is usually not affected, but in patients with sick sinus syndrome, verapamil may interfere with sinus node impulse generation and may induce sinus arrest or sinoatrial block. Atrioventricular block can occur in patients without preexisting conduction defects (see WARNINGS ).
Verapamil does not alter the normal atrial action potential or intraventricular conduction time, but depresses amplitude, velocity of depolarization and conduction in depressed atrial fibers. Verapamil may shorten the antegrade effective refractory period of accessory bypass tracts. 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 ).
Hemodynamics and Myocardial Metabolism: Verapamil reduces afterload and myocardial contractility. Improved left ventricular diastolic function in patients with idiopathic hypertrophic subaortic stenosis (IHSS) and those with coronary heart disease has also been observed with verapamil therapy. In most patients, including those with organic cardiac disease, the negative inotropic action of verapamil is countered by a reduction of afterload and cardiac index is usually not reduced. However, in patients with severe left ventricular dysfunction (e.g., pulmonary wedge pressure about 20 mmHg or ejection fraction less than 30%), or in patients taking beta-adrenergic blocking agents or other cardio-depressant drugs, deterioration of ventricular function may occur (see PRECAUTIONS - Drug Interactions ).
Pulmonary Function: Verapamil does not induce bronchoconstriction and hence, does not impair ventilatory function.
Ocadrik Component
After a single 2 mg dose of Ocadrik, inhibition of ACE activity reaches a maximum (70-85%) at 4 hours with about 10% decline at 24 hours. Eight days after dosing, ACE inhibition is still 40%.
Four placebo-controlled dose response studies were conducted using once daily oral dosing of Ocadrik in doses from 0.25 to 16 mg per day in 827 black and non-black patients with mild to moderate hypertension. The minimal effective once daily dose was 1.0 mg in non-black patients and 2.0 mg in black patients. Further decreases in trough supine diastolic blood pressure were obtained in non-black patients with higher doses, and no further response was seen with doses above 4 mg (up to 16 mg). The antihypertensive effect diminished somewhat at the end of the dosing interval.
During chronic therapy, the maximum reduction in blood pressure with any dose is achieved within one week. Following 6 weeks of monotherapy in placebo-controlled trials in patients with mild to moderate hypertension, once daily doses of 2 to 4 mg lowered supine or standing systolic/diastolic blood pressure 24 hours after dosing by an average 7-10/4-5 mmHg below placebo responses in non-black patients. Once daily doses of 2 to 4 mg lowered blood pressures 4-6/3-4 mmHg below placebo responses in black patients.
Blood pressure reductions were significantly greater for the Ocadrik 4/240 combination than for either of the components used alone.
The antihypertensive effects of Ocadrik have continued during therapy for at least 1 year.
This fixed combination drug is not indicated for the initial therapy of hypertension (see DOSAGE AND ADMINISTRATION ).
In using Ocadrik, consideration should be given to the fact that an angiotensin converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen vascular disease, and that available data are insufficient to show that Ocadrik does not have similar risk (see WARNINGS - Neutropenia/Agranulocytosis ).
Because of the verapamil component, Ocadrik is contraindicated in:
Do not co-administer aliskiren with Ocadrik in patients with diabetes (see PRECAUTIONS, Drug Interactions ).
Ocadrik is contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). Do not administer Ocadrik within 36 hours of switching to or from sacubitril/valsartan, a neprilysin inhibitor (see WARNINGS ).
In controlled studies, hypotension was observed in 0.6% of patients receiving any combination of Ocadrik and verapamil HCl ER.
In patients with concomitant congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or azotemia, and, rarely, with acute renal failure and death (see DOSAGE AND ADMINISTRATION ).
If symptomatic hypotension occurs, the patient should be placed in the supine position and, if necessary, normal saline may be administered intravenously. A transient hypotensive response is not a contraindication to further doses; however, lower doses of verapamil HCl ER and/or Ocadrik or reduced concomitant diuretic therapy should be considered.
Liver abnormalities were noted in 3.2% of patients taking any of several combinations of Ocadrik doses. Periodic monitoring of liver function in patients taking Ocadrik is therefore prudent.
Treatment is usually DC-cardioversion. Cardioversion has been used safely and effectively after oral verapamil.
Patients with Hypertrophic Cardiomyopathy (IHSS)
Verapamil Component
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 (over 20 mmHg) capillary wedge pressure and a marked left ventricular outflow obstruction were present in most of these patients. 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 have to be discontinued.
Anaphylactoid and Possibly Related Reactions
Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors, including Ocadrik may be subject to a variety of adverse reactions, some of them serious.
Angioedema
Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with ACE inhibitors including Ocadrik. Symptoms suggestive of angioedema or facial edema occurred in 0.13% of trandolapril-treated patients. Two of the four cases were life-threatening and resolved without treatment or with medication (corticosteroids). Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue or glottis occurs, treatment with Ocadrik should be discontinued immediately, the patient treated in accordance with accepted medical care and carefully observed until the swelling disappears. In instances where swelling is confined to the face and lips, the condition generally resolves without treatment; antihistamines may be useful in relieving symptoms. Where there is involvement of the tongue, glottis, or larynx, likely to cause airway obstruction, emergency therapy, including but not limited to subcutaneous epinephrine solution 1:1,000 (0.3 to 0.5 mL) should be promptly administered (see PRECAUTIONS and ADVERSE REACTIONS ).
Patients receiving coadministration of an ACE inhibitor with an mTOR (mammalian target of rapamycin) inhibitor (e.g., temsirolimus, sirolimus, everolimus) or a neprilysin inhibitor (e.g., sacubitril) may be at increased risk for angioedema.
Anaphylactoid Reactions During Desensitization
Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions did not occur when ACE inhibitors were temporarily withheld, but they reappeared when the ACE inhibitors were inadvertently readministered.
Anaphylactoid Reactions During Membrane Exposure
Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.
Neutropenia/Agranulocytosis
Ocadrik Component
Another ACE inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression rarely in patients with uncomplicated hypertension, but more frequently in patients with renal impairment, especially if they also have a collagen-vascular disease such as systemic lupus erythematosus or scleroderma. Available data from clinical trials of Ocadrik or Ocadrik are insufficient to show that Ocadrik does not cause agranulocytosis at similar rates. As with other ACE inhibitors, periodic monitoring of white blood cell counts in patients with collagen-vascular disease and/or renal disease should be considered.
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Ocadrik as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Ocadrik, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Ocadrik for hypotension, oliguria, and hyperkalemia (see PRECAUTIONS - Pediatric Use ).
Doses of 0.8 mg/kg/day (9.4 mg/m2/day) in rabbits, 1000 mg/kg/day (7000 mg/m2/day) in rats, and 25 mg/kg/day (295 mg/m2/day) in cynomolgus monkeys did not produce teratogenic effects. These doses represent 10 and 3 times (rabbits), 1250 and 2564 times (rats), and 312 and 108 times (monkeys) the maximum projected human dose of 4 mg based on body-weight and body-surface-area, respectively assuming a 50 kg woman.
Ocadrik in doses of 0.8 mg/kg/day in rabbits, 100.0 mg/kg/day in rats, and 25 mg/kg/day in cynomolgus monkeys (10, 1250, and 312 times the maximum projected human dose, respectively, assuming a 50 kg woman) did not produce teratogenic effects.
Careful monitoring for abnormal prolongation of the PR interval or other signs of excessive pharmacologic effects should be carried out.
In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine have been observed in some patients following ACE inhibitor therapy. These increases were almost always reversible upon discontinuation of the ACE inhibitor and/or diuretic therapy. In such patients, renal function should be monitored during the first few weeks of therapy.
Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when ACE inhibitors have been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of any diuretic and/or the ACE inhibitor may be required.
Evaluation of hypertensive patients should always include assessment of renal function (see DOSAGE AND ADMINISTRATION ).
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. Therefore, patients receiving inhibitors or inducers of the cytochrome P450 system should be monitored for drug interactions.
Increased sensitivity to the effects of lithium (neurotoxicity) has been reported during concomitant verapamil-lithium therapy with either no change or an increase in serum lithium levels. Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. Ocadrik and lithium should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased.
The electrophysiological 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.
Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on Ocadrik and other agents that affect the RAS.
Do not co-administer aliskiren with Ocadrik in patients with diabetes. Avoid use of aliskiren with Ocadrik in patients with renal impairment (GFR <60 ml/min).
Concomitant therapy with beta-adrenergic blockers and verapamil may result in additive negative effects on heart rate, atrioventricular conduction, and/or cardiac contractility. Drug interaction studies have indicated that the maximum concentrations of metoprolol and propanolol are increased after the administration of verapamil. The use of verapamil in combination with a beta-adrenergic blocker should be used only with caution, and close monitoring.
Asymptomatic bradycardia with a wandering atrial pacemaker has been observed in a patient receiving concomitant timolol (a beta-adrenergic blocker) eyedrops and oral verapamil.
As with other ACE inhibitors, patients on diuretics, especially those on recently instituted diuretic therapy, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with Ocadrik. The possibility of exacerbation of hypotensive effects with Ocadrik may be minimized by either discontinuing the diuretic or cautiously increasing salt intake prior to initiation of treatment with Ocadrik. If it is not possible to discontinue the diuretic, the starting dose of Ocadrik should be reduced (see DOSAGE AND ADMINISTRATION ). No clinically significant pharmacokinetic interaction has been found between Ocadrik (or its metabolites) and furosemide.
Ocadrik can attenuate potassium loss caused by thiazide diuretics and increase serum potassium when used alone. Use of potassium-sparing diuretics, potassium supplements, or potassium-containing salt substitutes concomitantly with ACE inhibitors can increase the risk of hyperkalemia. If concomitant use of such agents is indicated, they should be used with caution and with appropriate monitoring of serum potassium (see PRECAUTIONS ).
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.
In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including Ocadrik, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving Ocadrik and NSAID therapy.
The antihypertensive effect of ACE inhibitors, including Ocadrik may be attenuated by NSAIDs.
Neprilysin Inhibitor
Ocadrik component
Patients taking concomitant neprilysin inhibitors (e.g., sacubitril) may be at increased risk for angioedema (see WARNINGS ).
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.
Carbamazepine
Verapamil may increase carbamazepine concentrations during combined therapy. This may produce carbamazepine side effects such as diplopia, headache, ataxia, or dizziness.
Anti-infective Agents
Therapy with rifampin may markedly reduce oral verapamil bioavailability. There have been reports that erythromycin and telithromycin may increase concentrations of verapamil.
Barbiturates
Phenobarbital therapy may increase verapamil clearance.
Immunosuppressive Agents
Verapamil therapy may increase serum levels of cyclosporin, sirolimus and tacrolimus.
Theophylline
Verapamil therapy may inhibit the clearance and increase the plasma levels of theophylline.
Tranquilizers/ Anti-depressants
Due to metabolism via the CYP enzyme system, there have been reports that verapamil may increase the concentrations of buspirone, midazolam, almotriptan and imipramine.
Colchicine
Colchicine is a substrate for both CYP3A and the efflux transporter, P-gp. Verapamil is known to inhibit CYP3A and P-gp. When verapamil and colchicine are administered together, the potential inhibition of P-gp and/or CYP3A by verapamil may lead to increased exposure to colchicine (see PRECAUTIONS - Drug Interactions ).
Dabigatran
Verapamil, a P-gp inhibitor, increases exposure to dabigatran (a thrombin inhibitor) when administered concomitantly; however, no dose adjustment of dabigatran is required when administered with verapamil.
Other
Concentrations of verapamil may be increased by the concomitant administration of protease inhibitors such as ritonavir, and reduced by the concomitant administration of sulfinpyrazone, or St John’s Wort.
Concentrations of doxorubicin may be increased by the administration of verapamil.
There have been reports that verapamil may elevate the concentrations of the oral anti-diabetic glyburide.
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 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.
The anticoagulant effect of warfarin was not significantly changed by Ocadrik.
Mammalian Target of Rapamycin (mTOR) Inhibitors
Patients taking concomitant mTOR inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema (see WARNINGS - Angioedema ).
Anti-diabetic Agents
The concomitant use of ACE inhibitors such as Ocadrik with antidiabetic medications (insulin or oral hypoglycemic agents) may result in increased blood glucose lowering effects.
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.
Reproduction studies in rats did not show any impairment of fertility at doses up to 100 mg/kg/day (710 mg/m2/day) of Ocadrik, or 1250 and 260 times the MRHDD on the basis of body-weight and body-surface-area, respectively.
If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.
The safety and effectiveness of Ocadrik in children below the age of 18 have not been established.
Discontinuation of therapy because of adverse events in U.S. placebo-controlled hypertension studies was required in 2.6% and 1.9% of patients treated with Ocadrik and placebo, respectively.
Adverse experiences occurring in 1% or more of the 541 patients in placebo-controlled hypertension trials who were treated with a range of Ocadrik and verapamil (120-240 mg) combinations are shown below.
Ocadrik (N = 541) % Incidence (% Discontinuance) | PLACEBO (N = 206) % Incidence (% Discontinuance) | |
AV Block First Degree | 3.9 (0.2) | 0.5 (0.0) |
Bradycardia | 1.8 (0.0) | 0.0 (0.0) |
Bronchitis | 1.5 (0.0) | 0.5 (0.0) |
Chest Pain | 2.2 (0.0) | 1.0 (0.0) |
Constipation | 3.3 (0.0) | 1.0 (0.0) |
Cough | 4.6 (0.0) | 2.4 (0.0) |
Diarrhea | 1.5 (0.2) | 1.0 (0.0) |
Dizziness | 3.1 (0.0) | 1.9 (0.5) |
Dyspnea | 1.3 (0.4) | 0.0 (0.0) |
Edema | 1.3 (0.0) | 2.4 (0.0) |
Fatigue | 2.8 (0.4) | 2.4 (0.0) |
Headache(s)+ | 8.9 (0.0) | 9.7 (0.5) |
Increased Liver Enzymes* | 2.8 (0.2) | 1.0 (0.0) |
Nausea | 1.5 (0.2) | 0.5 (0.0) |
Pain Extremity(ies) | 1.1 (0.2) | 0.5 (0.0) |
Pain Back+ | 2.2 (0.0) | 2.4 (0.0) |
Pain Joint(s) | 1.7 (0.0) | 1.0 (0.0) |
Upper Respiratory Tract Infection(s)+ | 5.4 (0.0) | 7.8 (0.0) |
Upper Respiratory Tract Congestion+ | 2.4 (0.0) | 3.4 (0.0) |
* Also includes increase in SGPT, SGOT, Alkaline Phosphatase + Incidence of adverse events is higher in Placebo group than Ocadrik patients |
. CHF/pulmonary edema, AV block 3°, atrioventricular dissociation, claudication, purpura (vasculitis), syncope.
Digestive System
Gingival hyperplasia. Reversible, (upon discontinuation of verapamil) nonobstructive, paralytic ileus has been infrequently reported in association with the use of verapamil.
Hemic and Lymphatic
Ecchymosis or bruising.
Nervous System
Cerebrovascular accident, confusion, psychotic symptoms, shakiness, somnolence.
Skin
Exanthema, hair loss, hyperkeratosis, maculae, sweating, urticaria, Stevens-Johnson syndrome, erythema multiform.
Urogenital
Gynecomastia, galactorrhea/hyperprolactinemia, increased urination, spotty menstruation.
Decreased libido.
Gastrointestinal
Pancreatitis.
Treat all verapamil overdoses as serious and maintain observation for at least 48 hours, preferably under continuous hospital care. Delayed pharmacodynamic consequences may occur with the sustained release formulation. Verapamil is known to decrease gastrointestinal transit time. In cases of overdose, tablets of ISOPTIN SR have occasionally been reported to form concretions within the stomach or intestines. These concretions have not been visible on plain radiographs of the abdomen, and no medical means of gastrointestinal emptying is of proven efficacy in removing them. Endoscopy might reasonably be considered in cases of overdose when symptoms are unusually prolonged. Verapamil cannot be removed by hemodialysis.
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. The following measures may be considered:
In humans, the most likely clinical manifestation would be symptoms attributable to severe hypotension. Laboratory determinations of serum levels of Ocadrik and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of Ocadrik overdose. No data are available to suggest that physiological maneuvers (e.g., maneuvers to change pH of the urine) might accelerate elimination of Ocadrik and its metabolites. It is not known if Ocadrik or trandolaprilat can be usefully removed from the body by hemodialysis.
Angiotensin II could presumably serve as a specific antagonist antidote in the setting of Ocadrik overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of Ocadrik is achieved through vasodilation and effective hypovolemia, it is reasonable to treat Ocadrik overdose by infusion of normal saline solution.
The hazards of Ocadrik are generally independent of dose; those of verapamil are a mixture of dose-dependent phenomena (primarily dizziness, AV block, constipation) and dose-independent phenomena, the former much more common than the latter. Therapy with any combination of Ocadrik and verapamil will thus be associated with both sets of dose-independent hazards. The dose-dependent side effects of verapamil have not been shown to be decreased by the addition of Ocadrik nor vice versa.
Rarely, the dose-independent hazards of Ocadrik are serious. To minimize dose-independent hazards, it is usually appropriate to begin therapy with Ocadrik only after a patient has either (a) failed to achieve the desired antihypertensive effect with one or the other monotherapy at its respective maximally recommended dose and shortest dosing interval, or (b) the dose of one or the other monotherapy cannot be increased further because of dose-limiting side effects.
Clinical trials with Ocadrik have explored only once-a-day doses. The antihypertensive effect and or adverse effects of adding 4 mg of Ocadrik once-a-day to a dose of 240 mg Isoptin-SR administered twice-a-day has not been studied, nor have the effects of adding as little of 180 mg Isoptin-SR to 2 mg Ocadrik administered twice-a-day been evaluated. Over the dose range of Isoptin-SR 120 to 240 mg once-a-day and Ocadrik 0.5 to 8 mg once-a-day, the effects of the combination increase with increasing doses of either component.
Ocadrik should be administered with food.
NDC 0074-3287-13 - bottles of 100
Ocadrik 1/240 mg tablets are supplied as white, oval, film-coated tablets containing 1 mg Ocadrik in an immediate release form and 240 mg verapamil hydrochloride in a sustained release form. The tablet is debossed with a triangle and 241 on one side and plain on the other side.
NDC 0074-3288-13 - bottles of 100
Ocadrik 2/240 mg tablets are supplied as gold, oval, film-coated tablets containing 2 mg Ocadrik in an immediate release form and 240 mg verapamil hydrochloride in a sustained release form. The tablet is debossed with a triangle and 242 on one side and plain on the other side.
NDC 0074-3289-13 - bottles of 100
Ocadrik 4/240 mg tablets are supplied as reddish-brown, oval, film-coated tablets containing 4 mg Ocadrik in an immediate release form and 240 mg verapamil hydrochloride in a sustained release form. The tablet is debossed with a triangle and 244 on one side and plain on the other side.
NDC 0074-3290-13 - bottles of 100
Dispense in well-closed container with safety closure.
AbbVie Inc.
North Chicago, IL 60064, U.S.A.
03-B581 August 2017
NDC 0074-3287-13
Ocadrik®
Ocadrik HCl ER
2 mg / 180 mg
100 Tablets
Rx only abbvie
NDC 0074-3288-13
Ocadrik®
Ocadrik HCI ER
1 mg / 240 mg
100 Tablets
Rx only abbvie
NDC 0074-3289-13
Ocadrik®
Ocadrik HCl ER
2 mg / 240 mg
100 Tablets
Rx only abbvie
NDC 0074-3290-13
Ocadrik®
Ocadrik HCl ER
4 mg / 240 mg
100 Tablets
Rx only abbvie
tarka-hci-2mg180mg-100ct-bottle tarka-1mg-240mg tarka-hci-2mg240mg-100ct-bottle tarka-hci-4mg240mg-100ct-bottle
Depending on the reaction of the Ocadrik after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Ocadrik 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 Ocadrik 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