Angimil

Uses

Angimil Tablet:

• Essential hypertension
• Angina pectoris and prevention of re-infarction
• Supraventricular arrhythmias

Angimil Injection:

• Tachycardias such as: Paroxysmal supraventricular tachycardias
• Atrial fibrillation with rapid ventricular response (except WPWS)
• Atrial flutter with rapid conduction
• Extrasystoles
• Acute hypertension
• Acute coronary insufficiency

For the prophylaxis and / or therapy of ectopic arrhythmias (predominantly ventricular extrasystoles) in halothane anaesthesia and in the application of adrenaline in halothane anaesthesia respectively.

Angimil is also used to associated treatment for these conditions: Chronic Stable Angina Pectoris, Cluster Headache, Heart Rate, High Blood Pressure (Hypertension), Paroxysmal Supraventricular Tachycardia, Supra-ventricular Tachyarrhythmias, Unstable Angina Pectoris, Vasospastic Angina

How Angimil works

Angimil inhibits L-type calcium channels by binding to a specific area of their alpha-1 subunit,Cav1.2, which is highly expressed on L-type calcium channels in vascular smooth muscle and myocardial tissue where these channels are responsible for the control of peripheral vascular resistance and heart contractility. Calcium influx through these channels allows for the propagation of action potentials necessary for the contraction of muscle tissue and the heart's electrical pacemaker activity. Angimil binds to these channels in a voltage- and frequency-dependent manner, meaning affinity is increased 1) as vascular smooth muscle membrane potential is reduced, and 2) with excessive depolarizing stimulus.

Angimil's mechanism of action in the treatment of angina and hypertension is likely due to the mechanism described above. Inhibition of calcium influx prevents the contraction of vascular smooth muscle, causing relaxation/dilation of blood vessels throughout the peripheral circulation - this lowers systemic vascular resistance (i.e. afterload) and thus blood pressure. This reduction in vascular resistance also reduces the force against which the heart must push, decreasing myocardial energy consumption and oxygen requirements and thus alleviating angina.

Electrical activity through the AV node is responsible for determining heart rate, and this activity is dependent upon calcium influx through L-type calcium channels. By inhibiting these channels and decreasing the influx of calcium, verapamil prolongs the refractory period of the AV node and slows conduction, thereby slowing and controlling the heart rate in patients with arrhythmia.

Angimil's mechanism of action in the treatment of cluster headaches is unclear, but is thought to result from an effect on other calcium channels (e.g. N-, P-, Q-, or T-type).

Angimil is known to interact with other targets, including other calcium channels, potassium channels, and adrenergic receptors.

Dosage

Angimil dosage

Angimil Tablet:

• The dose of Angimil should be individualized by titration and the drug should be administered with food.
• For essential hypertension the initial dose should be given 180 mg in the morning. If adequate response is not obtained with 180 mg of Angimil then the dose may be titrated by following manner: 240 mg each morning. 180 mg each morning plus 180 mg each evening. 240 mg every 12 hourly.
• For angina the usual dose is 80 mg to 120 mg three times a day.
• For arrythmias in digitalized patients, Angimil should be given 240 mg to 360 mg in divided doses, depending on the severity of the condition. Divided doses up to 180 mg/day may occasionally be needed.

Angimil Injection:

Adults

: 5 mg slowly intravenously, in tachycardias and hypertensive crises, if necessary repeat after 5 to 10 minutes. Drip infusion to maintain the therapeutic effect: 5-10 mg/hour in physiological saline, glucose, laevulose or similar solutions, on average up to a total dose of 100 mg/day.

Children

:

• Newborn: 0.75-1 mg (= 0.3-0.4 ml)
• Infants: 0.75-2 mg (= 0.3-0.8 ml)
• Children age 1-5 years: 2-3 mg (= 0.8-1.2 ml)
• Age 6-14 years: 2.5-5 mg (= 1-2 ml)

of Angimil, given intravenously, depending on age and action. The injection should be made slowly under electrocardiographic control and only until onset of the effect. Intravenous infusion in hypertensive crises: initially 0.05-0.1 mg/kg/hour; if the effect proves to be insufficient, the dose is increased at 30-60 minute intervals until twice the dose or more is reached. Average total dose up to 1.5 mg/kg/day.

Side Effects

Angimil is generally well tolerated. The following reaction to orally administered Angimil appeared clearly drug related or occurred at rates greater than 1% in clinical trials with approximately 5000 patients.

• Digestive system: Constipation, nausea;
• Cardiovascular system: Hypotension, edema, CHF, pulmonary edema, bradycardia, AV block;
• Respiratory system: Upper respiratory tract infections;
• Nervous system: Dizziness, headache, fatigue;
• Skin: Rash, flashing;
• Hepatic: Elevated liver enzyme.

Toxicity

Angimil's reported oral TDLo is 14.4 mg/kg in women and 3.429 mg/kg in men. The oral LD₅₀ is 150 mg/kg in rats and 163 mg/kg in mice.

As there is no antidote for verapamil overdosage, treatment is largely supportive. Symptoms of overdose are generally consistent with verapamil's adverse effect profile (i.e. hypotension, bradycardia, arrhythmia) but instances of non-cardiogenic pulmonary edema have been observed following ingestion of large overdoses (up to 9 grams). In acute overdosage, consider the use of gastrointestinal decontamination with cathartics and/or bowel irrigation. Patients presenting with significant myocardial depression may require intravenous calcium, atropine, vasopressors, or other inotropes. Consider the formulation responsible for the overdose prior to treatment - sustained-release formulations may result in delayed pharmacodynamic effects, and these patients should be monitored closely for at least 48 hours following ingestion.

Precaution

Care should be taken in 1st degree AV block, bradycardia <50 beats/minutes, hypotension <90 mm Hg systolic pressure, atrial fibrillation/flutter and simultaneous pre-excitation syndrome e.g. WPW syndrome, heart failure (previous compensation with cardiac glycosides/diuretics required).Angimil may impair ability to drive or operate machinery, particularly in the initial stages of treatment and with concomitant consumption of alcohol. Angimil markedly slows down the elimination of alcohol and prolongs the duration of the effects of alcohol.Angimil should be given as a slow intravenous injection over at least 2 minutes under continuous ECG and blood pressure monitoring. Intravenous injection should only be given by the physician. In atrial fibrillation and simultaneous WPW syndrome there is a risk of inducing ventricular fibrillation

Interaction

May increase plasma level with CYP3A4 inhibitors (e.g. erythromycin, ritonavir), cimetidine. May decrease plasma level with CYP3A4 inducers (e.g. rifampicin), phenobarbital, sulfinpyrazone. Increased risk of bleeding with aspirin. May increase bradycardic and hypotensive effect with telithromycin. Increased AV blocking effect with clonidine. May increase plasma level of cardiac glycosides (e.g. digoxin, digitoxin), β-blockers (e.g. propranolol, metoprolol), α-blockers (e.g. terazosin, prazosin), immunosuppressants (e.g. sirolimus, ciclosporin, tacrolimus, everolimus), lipid lowering agents (e.g. lovastatin, simvastatin, atorvastatin), colchicines, quinidine, carbamazepine, imipramine, glibenclamide, doxorubicin, midazolam, buspirone, almotriptan, theophylline. May potentiate hypotensive effect with diuretics, antihypertensives, vasodilators. May increase neurotoxic effect of lithium.

Food Interaction

• Avoid alcohol. Angimil significantly inhibits the elimination of alcohol, leading to elevated blood alcohol levels.
• Avoid grapefruit products. Co-administration with grapefruit may significantly increase serum concentrations.
• Take with or without food. Recommendations vary from product to product - consult individual product monographs for additional information.

[Moderate] GENERALLY AVOID: Consumption of large quantities of grapefruit juice may be associated with significantly increased plasma concentrations of oral verapamil.

The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

One study reported no significant effect of a single administration of grapefruit juice on the pharmacokinetics of verapamil in ten hypertensive patients receiving chronic therapy.

In another study conducted in nine healthy male volunteers, administration of 120 mg oral verapamil twice daily for 3 days following pretreatment with 200 mL grapefruit juice twice daily for 5 days resulted in a 57% increase in S-verapamil peak plasma concentration (Cmax), a 36% increase in S-verapamil systemic exposure (AUC), a 40% increase in R-verapamil Cmax, and a 28% increase in R-verapamil AUC compared to administration following orange juice.

Elimination half-life and renal clearance of both S- and R-verapamil were not affected by grapefruit juice, and there were no significant effects on blood pressure, heart rate, or PR interval.

A third study reported a 1.63-fold increase in Cmax and a 1.45-fold increase in AUC of (R,S)-verapamil in 24 young, healthy volunteers given verapamil sustained-release 120 mg twice daily for 7 days with 250 mL grapefruit juice four times daily on days 5 through 7.

Two subjects developed PR interval prolongation of more than 350 ms during grapefruit juice coadministration.

A high degree of interindividual variability has been observed in these studies.

The interaction was also suspected in a case report of a 42-year-old woman who developed complete heart block, hypotension, hypoxic respiratory failure, severe anion gap metabolic acidosis, and hyperglycemia following accidental ingestion of three verapamil sustained-release 120 mg tablets over a span of six hours.

The patient's past medical history was remarkable only for migraine headaches, for which she was receiving several medications including verapamil.

Prior to admission, the patient had a 2-week history of poorly controlled migraine, and the six hours preceding hospitalization she suffered from worsening headache and palpitations progressing to altered sensorium.

An extensive workup revealed elevated verapamil and norverapamil levels more than 4.5 times above the upper therapeutic limits.

These levels also far exceeded those reported in the medical literature for patients taking verapamil 120 mg every 6 hours, or 480 mg in a 24-hour period.

The patient recovered after receiving ventilator and vasopressor support.

Upon questioning, it was discovered that the patient had been drinking large amounts of grapefruit juice (3 to 4 liters total) the week preceding her admission due to nausea.

No other sources or contributing factors could be found for the verapamil toxicity.

MANAGEMENT: Patients treated with oral verapamil should avoid the consumption of large amounts of grapefruit or grapefruit juice to prevent any undue fluctuations in serum drug levels.

Patients should be advised to seek medical attention if they experience edema or swelling of the lower extremities; sudden, unexplained weight gain; difficulty breathing; chest pain or tightness; or hypotension as indicated by dizziness, fainting, or orthostasis.

Angimil Alcohol interaction

[Moderate] GENERALLY AVOID:

Angimil may increase the blood concentrations and intoxicating effects of ethanol.

The exact mechanism of interaction is unknown but may involve verapamil inhibition of ethanol metabolism.

In 10 healthy, young volunteers, verapamil (80 mg orally every 8 hours for 6 days) increased the mean peak blood concentration (Cmax) and the 12-hour area under the concentration-time curve (AUC) of ethanol (0.8 g/kg single oral dose) by 17% and 30%, respectively, compared to placebo.

Angimil AUCs were positively correlated to increased ethanol blood AUC values.

Subjectively (i.e. each subject's perception of intoxication as measured on a visual analog scale), verapamil also significantly increased the area under the ethanol effect versus time curve but did not change the peak effect or time to peak effect.

Patients treated with verapamil should be counseled to avoid alcohol consumption.

Angimil multivitamins interaction

[Moderate] Calcium-containing products may decrease the effectiveness of calcium channel blockers by saturating calcium channels with calcium.

Calcium chloride has been used to manage acute severe verapamil toxicity.

Management consists of monitoring the effectiveness of calcium channel blocker therapy during coadministration with calcium products.

Angimil Drug Interaction

Moderate: fluticasone / salmeterol, aspirin, duloxetine, atorvastatinUnknown: diphenhydramine, rosuvastatin, omega-3 polyunsaturated fatty acids, cyclobenzaprine, furosemide, pregabalin, esomeprazole, montelukast, levothyroxine, topiramate, acetaminophen, cyanocobalamin, ascorbic acid, cholecalciferol, alprazolam, cetirizine

Angimil Disease Interaction

Major: aortic stenosis, bradyarrhythmia/AV block, cardiogenic shock/hypotension, coronary artery disease, liver disease, ventricular tachycardia, accessory AV tracts, CHF/AMI, hypertrophic cardiomyopathyModerate: neuromuscular transmission, renal dysfunction, GI narrowing

Volume of Distribution

Angimil has a steady-state volume of distribution of approximately 300L for its R-enantiomer and 500L for its S-enantiomer.

Elimination Route

More than 90% of orally administered verapamil is absorbed - despite this, bioavailability ranges only from 20% to 30% due to rapid biotransformation following first-pass metabolism in the portal circulation. Absorption kinetic parameters are largely dependent on the specific formulation of verapamil involved. Immediate-release verapamil reaches peak plasma concentrations (i.e. T_max) between 1-2 hours following administration, whereas sustained-release formulations tend to have a T_max between 6 - 11 hours.

AUC and C_max values are similarly dependent upon formulation. Chronic administration of immediate-release verapamil every 6 hours resulted in plasma concentrations between 125 and 400 ng/mL. Steady-state AUC_0-24h and C_max values for a sustained-release formulation were 1037 ng∙h/ml and 77.8 ng/mL for the R-isomer and 195 ng∙h/ml and 16.8 ng/mL for the S-isomer, respectively.

Interestingly, the absorption kinetics of verapamil are highly stereospecific - following oral administration of immediate-release verapamil every 8 hours, the relative systemic availability of the S-enantiomer compared to the R-enantiomer was 13% after a single dose and 18% at steady-state.

Half Life

Single-dose studies of immediate-release verapamil have demonstrated an elimination half-life of 2.8 to 7.4 hours, which increases to 4.5 to 12.0 hours following repetitive dosing. The elimination half-life is also prolonged in patients with hepatic insufficiency (14 to 16 hours) and in the elderly (approximately 20 hours). Intravenously administered verapamil has rapid distribution phase half-life of approximately 4 minutes, followed by a terminal elimination phase half-life of 2 to 5 hours.

Clearance

Systemic clearance following 3 weeks of continuous treatment was approximately 340 mL/min for R-verapamil and 664 mL/min for S-verapamil. Of note, apparent oral clearance appears to vary significantly between single dose and multiple-dose conditions. The apparent oral clearance following single doses of verapamil was approximately 1007 mL/min for R-verapamil and 5481 mL/min for S-verapamil, whereas 3 weeks of continuous treatment resulted in apparent oral clearance values of approximately 651 mL/min for R-verapamil and 2855 mL/min for S-verapamil.

Elimination Route

Approximately 70% of an administered dose is excreted as metabolites in the urine and ≥16% in the feces within 5 days. Approximately 3% - 4% is excreted in the urine as unchanged drug.

Pregnancy & Breastfeeding use

Angimil carries the potential to produce fetal hypoxia associated with maternal hypotension. Angimil should not be administered intravenously during the first six months of pregnancy. There are no data on use in the first and second trimester. Angimil should not be used in the final trimester unless the benefits clearly outweigh the risks. Angimil should not be administered intravenously during lactation. If a nursing mother requires intravenous Angimil, breast feeding should be discontinued for the duration of treatment.

Contraindication

• Severe left ventricular dysfunction
• Hypotension or cardiogenic shock
• Sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker)
• Second or third-degree atrioventricular (AV) block (except in patients with a functioning artificial pacemaker)
• Patients with atrial flutter or atrial fibrillation and an accessory by pass tract (eg. Wolff-Parkinson-White, Lown-Ganong-Levine syndrome)
• Patients with known hypersensitivity to verapamil hydrochloride
• Angimil injection should not be administered intravenously to patients on beta-blockers (except in an intensive care setting) and known hypersensitivity to Angimil hydrochloride.

Acute Overdose

Treatment of overdose should be supportive. Beta-adrenergic stimulation or parenteral administration of calcium solution may increase calcium ion flux across the slow channel and have been used in the treatment of overdose with Angimil. Angimil cannot be removed by haemodialysis.

Innovators Monograph

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