Date of approval.
Date of revision.
Verapamil Hydrochloride Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Verapamil Hydrochloride Tablets
English name: Verapamil Hydrochloride Tablets
Hanyu Pinyin：Yansuan Weilapami Pian
Ingredients
The main ingredient of this product is verapamil hydrochloride, whose chemical name is (±)-α-[3-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino]propyl]-3,4-dimethoxy-α-isopropylbenzeneacetonitrile hydrochloride
Chemical structure formula.
Molecular formula: C27H38N2O4-HCl
Molecular weight: 491.07
Properties
This product is a film-coated tablet, which appears white after removing the coating.
Indications
1. angina pectoris: variant angina pectoris, unstable angina pectoris, chronic stable angina pectoris.
2. Arrhythmias: Combined with digoxin to control ventricular rate in chronic atrial fibrillation and/or atrial flutter (except WPW syndrome or L-G-L syndrome) and to prevent recurrent episodes of paroxysmal supraventricular tachycardia.
3. primary hypertension.
【Specification】.
40 mg
Dosage]
Individualized treatment is achieved by dose adjustment. The safe and effective dose is no more than 480 mg/day.
1. Angina pectoris: the general dose is 80-120 mg/dose orally three times a day. The effective dose for hepatic insufficiency and the elderly is 40 mg/dose orally three times a day. The decision to increase the dose is made approximately 8 hours after the drug based on efficacy and safety assessment.
2. Arrhythmias: For patients with chronic atrial fibrillation treated with digitalis, the total daily dose is 240 to 320 mg orally in three or four doses/day. The total daily dose for the prevention of paroxysmal supraventricular tachycardia (in patients not taking digitalis) in adults is 240 to 480 mg orally three or four times a day. Age 1 to 5 years: daily amount of 4 to 8 mg/kg orally three times a day; or 40 to 80 mg orally every 8 hours. > 5 years: 80 mg orally every 6 to 8 hours.
3. primary hypertension: the general starting dose is 80 mg orally three times a day. The use of doses up to 360-480 mg per day. for low doses that respond to the elderly or thin body size, should consider the starting dose of 40 mg, three times a day orally.
Adverse reactions]
Adverse reactions reported from clinical trials, post-marketing experience or phase IV clinical trials are listed below by MedDRA system organ classification.
The frequency of adverse reactions is defined as follows: very common (≥10%), common (≥1% to <10%), occasional (≥0.1% to <1%), rare (≥0.01% to <0.1%), very rare (<0.01%), unknown (frequency cannot be estimated from available data).
The most common adverse reactions were headache, dizziness, gastrointestinal disorders (nausea, constipation, abdominal discomfort), bradycardia, tachycardia, palpitations, hypotension, flushing, peripheral edema, and fatigue.
Adverse reactions in clinical trials and post-marketing surveillance of verapamil
MedDRA Systemic Organ Classification Common Occasional Rare Very Rare Unknown Immune System Disorders Allergic reactions. Neurologic disorders Dizziness, headache, neuropathy Sensory abnormalities, tremor Extrapyramidal symptoms, paralysis (tetraplegia)1, convulsions Metabolic and nutritional disorders Reduced glucose tolerance Hyperkalemia Psychiatric disorders Nervousness Drowsiness Ear and vagus disorders Tinnitus Vertigo Cardiac disorders Bradycardia, onset or exacerbation of heart failure, excessive drop in blood pressure and/or uprightness regulation disorders Palpitations, tachycardia AV block I, II, III degrees, heart failure, sinus arrest, sinus bradycardia, cardiac arrest Vascular disease flushing, hypotension Peripheral edema due to dilatation of small arteries may be present. Respiratory, thoracic, and mediastinal disorders Bronchospasm, dyspnea Gastrointestinal disorders Constipation, nausea Abdominal pain Vomiting Abdominal discomfort, gingival hyperplasia, intestinal obstruction Liver and biliary tract disorders Reversible rise in liver enzymes, possibly a manifestation of allergic hepatitis Skin and subcutaneous tissue disorders Erythema acuminata Hyperhidrosis Photodermatitis Angioedema, Stevens-Johnson syndrome syndrome, erythema multiforme, alopecia, pruritus, purpura, maculopapular rash, urticaria Musculoskeletal and connective tissue disorders Exacerbation: myasthenia gravis, Lambert-Eaton syndrome, advanced Duchenne muscular dystrophy Arthralgia, muscle weakness, myalgia Renal and urinary disorders Renal insufficiency Genital and breast disorders Erectile dysfunction, breast overflow, male gynecomastia General disorders and drug administration Departmental conditions Peripheral edema Fatigue Examination Elevated blood levels of prolactin1 Regarding paralysis (quadriplegia), one case of post-marketing verapamil in combination with colchicine has been reported. This may be due to inhibition of CYP3A4 and P-gp by verapamil allowing colchicine to cross the blood-brain barrier (see [Drug Interactions]).
Caution
Patients with pacemakers may experience increased pacing and sensory thresholds with verapamil hydrochloride.
In patients with cardiovascular disease, such as severe cardiomyopathy, congestive heart failure, or recent myocardial infarction, the combination of an intravenous beta-blocker or propyzamide with intravenous verapamil increases the risk of serious adverse reactions due to the cardiac depressant effects of both classes of drugs (see [Drug Interactions]).
Contraindications
This product is contraindicated in the following cases.
1. hypersensitivity to the active ingredient (verapamil hydrochloride) or to any of the excipients of this product.
2. Cardiogenic shock or hypotension (systolic blood pressure below 90 mmHg).
3. acute myocardial infarction complicated by bradycardia, hypotension, left heart failure.
4. Severe cardiac conduction dysfunction (e.g., second or third degree sinus or atrioventricular block), sick sinus syndrome. Patients with pacemaker implantation are excluded.
5. Congestive heart failure (unless due to supraventricular tachycardia responsive to verapamil).
6. Atrial fibrillation/atrial flutter combined with a pre-excitation syndrome (e.g. WPW or L-G-L syndrome). In these patients, verapamil therapy is associated with an increased risk of developing ventricular tachycardia, including ventricular fibrillation.
7. Combine with ivabradine (see [Drug Interactions]).
8. Combined intravenous administration of beta-blockers should not be used in patients receiving verapamil therapy (exception: intensive care, see [Drug Interactions]).
9. Take with grapefruit juice.
[Precautions].
1. Heart failure
The negative inotropic effect of verapamil can be compensated by its reduction of afterload (lowering circulatory vascular resistance), and the net effect does not impair ventricular function. However, avoid verapamil in patients with severe left ventricular insufficiency (pulmonary wedge pressure >20 mmHg or ejection fraction <30%), moderate-to-severe heart failure, and patients with any degree of ventricular dysfunction already treated with beta-blockers. Patients with mild cardiac insufficiency in whom verapamil must be used need to have controlled clinical symptoms prior to treatment.
2. Pre-excitation syndrome
Verapamil accelerates the antegrade conduction of the atrioventricular bypass. Intravenous treatment with verapamil in patients with atrioventricular bypass combined with atrial flutter or atrial fibrillation can cause increased ventricular rate and even induce ventricular fibrillation by accelerating the antegrade conduction of the atrioventricular bypass. Although oral verapamil has not been reported as described above, it may be dangerous for such patients to receive oral verapamil and is therefore contraindicated.
3. Atrioventricular block
Verapamil may cause AV node and sinus node conduction block associated with increased plasma concentrations, particularly during the early incremental phase of treatment. It may cause first-degree AV block, transient sinus bradycardia, sometimes accompanied by nodal escape. High degree AV block is uncommon (0.8%). When significant degree I AV block occurs or progresses to degree II or III AV block, dose reduction or discontinuation is required.
Antiarrhythmics (e.g., flecainide, propyzamide), beta-adrenergic receptor blockers (e.g., metoprolol, propranolol), and inhalational anesthetics, when combined with verapamil hydrochloride, may result in cardiovascular effects (higher grade of AV block, higher grade of heart rate reduction, heart failure, greater reduction in blood pressure) (see [Drug Interactions]). Asymptomatic bradycardia (36 beats/min) with wandering atrial pacing was observed in a patient who was co-administered timolol eye drops (beta-blocker) and verapamil.
4. Hepatic impairment
Use verapamil with caution in patients with hepatic impairment due to its extensive metabolism in the liver. In severe hepatic insufficiency, the clearance half-life of verapamil is prolonged to 14-16 hours, and only 30% of the normal dose is required for this group of patients. (See [Drug Interactions]).
5. Renal Impairment
Although comparative studies consistently show that impaired renal function in patients with end-stage renal failure has no effect on the pharmacokinetics of verapamil, individual case reports suggest that it should be used with caution and carefully monitored in patients with impaired renal function (ECG, blood pressure). Verapamil cannot be removed by hemodialysis.
6. HMG-CoA reductase inhibitors (“statins”)
In patients taking verapamil in combination with an HMG-CoA reductase inhibitor (e.g., simvastatin, atorvastatin, or lovastatin), the HMG-CoA reductase inhibitor should be started and the dose adjusted at the lowest possible dose. Patients being treated with HMG-CoA reductase inhibitors (e.g., simvastatin, atorvastatin, or lovastatin) should consider lowering the dose of a statin if they are combined with verapamil and the serum cholesterol concentration to be adjusted is reassessed (see [Drug Interactions]).
The risk of myopathy/rhabdomyolysis is increased when verapamil and simvastatin are combined at higher doses. The dose of simvastatin should be adjusted accordingly (see [Drug Interactions]).
7. Diseases with impaired neuromuscular transmission
Verapamil has been reported to attenuate neuromuscular transmission in patients with muscular dystrophy. Verapamil should be used with caution in the presence of impaired neuromuscular conduction (myasthenia gravis, Lambert-Eaton syndrome, late-stage Duchenne muscular dystrophy).
8. Serum calcium
Verapamil does not alter serum calcium concentrations, but there have been reports of higher than normal range blood calcium levels that may affect the efficacy of verapamil.
9. Monitor liver function
Because verapamil may cause an increase in transaminases, it is prudent to monitor liver function regularly in patients treated with verapamil.
10. Idiopathic hypertrophic subaortic stenosis
Studies have found multiple adverse events with verapamil titrated to 720 mg/day in patients who are mostly propranolol intolerant or refractory, with most adverse events improving after dose reduction and rare discontinuations.
Other Precautions
Effects on the ability to drive and use machines
Verapamil therapy requires regular medical supervision. The ability to respond may be altered due to individual differences in response, resulting in impaired ability to actively drive, operate machinery, or work without safety precautions. The extent of this effect is greater at the start of treatment, at increasing doses, at changes in formulation, and in combination with alcohol. Verapamil may increase the blood concentration of alcohol and delay its elimination, which may increase the effects of alcohol.
Pregnant and lactating women]
Pregnancy
Verapamil can cross the placental barrier. The plasma concentration in the umbilical vein is 20%-92% of the plasma concentration in pregnant women. There is insufficient experience with the use of the drug in pregnant women, and the limited data on oral treatment in pregnant women do not suggest teratogenic effects. Animal studies have shown reproductive toxicity (see [Pharmacologic Toxicology]).
Therefore, verapamil hydrochloride should not be administered during the first and second trimesters of pregnancy. It should be administered in late pregnancy only when clearly needed, taking into account the risks to the pregnant woman and the fetus, and when the benefits to the pregnant woman outweigh the risks to the fetus.
Lactation
Verapamil is secreted into breast milk (the concentration in breast milk is approximately 23% of the maternal plasma concentration). There are limited data in humans following oral administration showing that verapamil is only present in small amounts in the infant (0.1% to 1% of the maternal dose) and therefore administration of verapamil may be compatible with breastfeeding.
Risk cannot be excluded in neonates/infants. Due to the risk of serious adverse reactions in infants, verapamil should be used during breastfeeding only when it is essential for maternal health.
There are indications that verapamil may cause hyperprolactinemia and overflow in isolated cases.
[Pediatric Use].
For children, use only for cardiac arrhythmias and at reduced doses as described in [Dosage] and related in [Pharmacokinetics].
Geriatric use
The dose should be reduced in elderly patients, see [Dosage], see [Precautions], [Pharmacokinetics].
Drug Interactions]
In vitro studies have shown that verapamil is metabolized by the cytochrome P450 isozymes CYP3A4, CYP1A2, CYP2C8, CYP2C9, and CYP2C18. Verapamil inhibits CYP3A4 and P-glycoprotein (P-gp).
CYP3A4 inhibitors elevate plasma levels of verapamil hydrochloride, and clinically significant interactions have been reported; whereas CYP3A4 inducers decrease plasma levels of verapamil hydrochloride. Therefore, patients should be monitored for drug interactions.
The following table contains some possible pharmacokinetic interactions.
Interactions Effect of Combination Drugs on Verapamil or Combination Drugs Remarks alpha-blocker prazosin prazosin Cmax ↑ (~40%), no effect on half-life additional antihypertensive effect terazosin terazosin AUC ↑ (~24%) and Cmax ↑ (~25%) antiarrhythmic drug flecainide minimal effect on plasma clearance of flecainide (<~10%)
No effect on plasma clearance of verapamil For more information see [Precautions] in Antiarrhythmics, beta-blockers, and inhaled anesthetics Quinidine Oral Quinidine clearance ↓ (~35%) Hypotension.
In patients with hypertrophic obstructive cardiomyopathy, pulmonary edema may occur Amiodarone Increased plasma concentrations of amiodarone Calming agent Theophylline Oral and systemic clearance ↓ (~20%) Insignificant reduction in clearance in smokers (~11%) Anticonvulsants/antiepileptics Carbamazepine Patients with refractory partial epilepsy, carbamazepine AUC ↑ (~46%) Increased levels of carbamazepine.
This may trigger adverse effects of carbamazepine such as diplopia, headache, ataxia, dizziness Decreased plasma concentration of verapamil hydrochloride Phenytoin verapamil plasma concentration ↓ AUC ↑ (~15%) of antidepressant promethazine Promethazine has no effect on the level of the active metabolite desipramine Increased plasma concentration of verapamil hydrochloride Antidiabetic glibenclamide Glibenclamide Cmax ↑ (~28%) and AUC ↑ (~26%) Increased plasma concentrations of verapamil hydrochloride Antigout colchicine colchicine AUC ↑ (~2.0-fold) and Cmax ↑ (~1.3-fold) Reduced dose of colchicine (combination of colchicine and verapamil hydrochloride not recommended) Anti-infectives clarithromycin verapamil levels may ↑ Erythromycin verapamil levels may ↑ Rifampin oral verapamil, verapamil AUC ↓ (~97%) and Cmax ↓ (~94%), oral bioavailability ↓ (~92%) Antihypertensive effect may be reduced intravenous verapamil, PK unchanged Telithromycin verapamil levels may ↑ Antitumor agent doxorubicin oral verapamil, AUC ↑ (104%) and Cmax ↑ (61%) small cell lung cancer patients intravenous verapamil, doxorubicin PK No significant changes in advanced tumor patients Azole antifungals Clotrimazole verapamil hydrochloride plasma concentrations increased Ketoconazole verapamil hydrochloride plasma concentrations increased Itraconazole verapamil hydrochloride plasma concentrations increased Barbiturates Phenobarbital oral verapamil clearance ↑ (~5 times) Benzodiazepines and other anxiolytics Butroconazole butroconazole AUC and Cmax ↑ (~3.4 times) Verapamil hydrochloride Increased plasma concentrations of midazolam Midazolam plasma concentrations of midazolam ↑ (~3-fold) and Cmax ↑ (~2-fold) Increased plasma concentrations of verapamil hydrochloride Patients with the beta-blocker metoprolol angina, metoprolol AUC ↑ (~32.5%) and Cmax ↑ (~41%) See [caution] Increased plasma concentrations of verapamil hydrochloride Patients with propranolol angina, propranolol AUC ↑ (~65%) and Cmax↑ (~94%) Increased plasma concentrations of verapamil hydrochloride Total clearance of cardiac glycosides digitalis toxins digitalis toxins ↓ (~27%) and extrarenal clearance ↓ (~29%) Digoxin healthy subjects: digoxin Cmax↑ (~44%), digoxin C12h↑ (~53%), digoxin CSS↑ (~44%), digoxin AUC↑ (~ (50%) Decrease digoxin dose (see [Caution]) H2 receptor antagonist cimetidine R-verapamil AUC↑ (~25%) and S-verapamil AUC↑ (~40%) corresponding to R- and S-verapamil clearance ↓ After intravenous administration of verapamil, cimetidine decreases verapamil clearance Immunologic agents/immunosuppressive agents cyclosporine cyclosporine AUC, CSS, and Cmax ↑ (~45%) Everolimus Everolimus: AUC ↑ (~3.5-fold), Cmax ↑ (~2.3-fold)
Verapamil: C trough concentration ↑ (~2.3-fold) It may be necessary to determine the concentration of everolimus and dose adjustment sirolimus sirolimus: AUC ↑ (~2.2-fold)
S-verapamil: AUC ↑ (~1.5-fold) may be necessary to determine the concentration and dose adjustment of sirolimus tacrolimus tacrolimus levels may ↑ Lipid-lowering agents/ HMG-CoA reductase inhibitors atorvastatin may atorvastatin levels ↑
Verapamil AUC ↑ (~43%) For more information see more information in this section: HMG-CoA reductase inhibitors (statins) Lovastatin possible Lovastatin levels ↑
Verapamil AUC ↑ (~63%) and Cmax ↑ (~32%) Simvastatin Simvastatin AUC ↑ (~2.6-fold) and Cmax ↑ (~4.6-fold) Serotonin receptor agonists Almotriptan Almotriptan AUC ↑ (~20%) and Cmax ↑ (~24%) Verapamil hydrochloride Increased plasma concentrations Pro-uric acid excretory agents Benzedrine Oral Verapamil: Verapamil Clearance ↑ (~3-fold), bioavailability ↓ (~60%) possible reduction in antihypertensive effect IV verapamil: no change in PK Other cardiac therapeutics Ivabradine Due to additional heart rate lowering effect of verapamil on ivabradine, contraindicated in combination with ivabradine see [contraindication] Other grapefruit juice R-verapamil AUC ↑ (~49%) or S-verapamil AUC ↑ (~37% )
Elimination half-life and renal clearance are not affected by R-verapamil Cmax↑ (~75%) or S-verapamil AUC↑ (~51%).
When using this product, avoid foods and beverages containing grapefruit juice St. John’s wort (through-leaf canary) R-verapamil AUC ↓ (~78%) or S-verapamil AUC ↓ (~80%) with a corresponding decrease in Cmax More information
1. Anti-HIV antiviral drugs
The plasma concentration of verapamil may be increased due to the potential inhibitory effects of certain anti-HIV antiviral drugs (e.g., ritonavir). Therefore, it should be used with caution when combined and the dose of verapamil may be reduced if necessary.
Similarly, by affecting degradation, verapamil may increase the plasma levels of these drugs.
2. Lithium
Increased sensitivity to lithium effects (neurotoxicity) has been reported with combined lithium treatment; lithium levels remain unchanged or increase.
However, the use of verapamil also resulted in decreased serum levels of lithium in patients on continuous oral lithium therapy. Therefore, patients should be closely monitored when combining these two drugs.
3. Muscle relaxants
Clinical and animal data suggest that verapamil can potentiate the effects of muscle relaxants (arrow toxicity and depolarization). Therefore it may be necessary to reduce the dose of verapamil and/or the dose of muscle relaxants when combined.
4. Acetylsalicylic acid
Increased propensity for hemorrhage.
5. dabigatran
Dabigatran Cmax and AUC increased when oral verapamil was combined with dabigatranate (150 mg), a P-gp substrate, but the extent of these changes depended on the prescription of verapamil and the timing of administration.
The combination of immediate-release verapamil 120 mg 1 hour prior to a single dose of dabigatranate increased the Cmax of dabigatran by approximately 180% and the AUC by approximately 150%. No significant interaction was observed when verapamil was combined with dabigatranate 2 hours after dabigatran administration (Cmax increased by approximately 10% and AUC increased by approximately 20% for dabigatran).
Close clinical monitoring is recommended when verapamil is combined with dabigatranate, especially in the setting of bleeding, and especially in patients with mild to moderate renal insufficiency.
6. Ethanol (alcohol)
Delays ethanol degradation and increases the plasma concentration of ethanol, thereby enhancing the effects of ethanol.
7. HMG-CoA reductase inhibitors (statins)
In patients taking verapamil in combination with an HMG-CoA reductase inhibitor (e.g., simvastatin, atorvastatin, or lovastatin), the HMG-CoA reductase inhibitor should be started and dose adjusted at the lowest possible dose. Patients being treated with an HMG-CoA reductase inhibitor (e.g., simvastatin, atorvastatin, or lovastatin) should consider lowering the dose of a statin if the combination of verapamil is used to reassess the serum cholesterol concentration that needs to be adjusted.
The risk of myopathy/rhabdomyolysis is increased when verapamil and simvastatin are combined at higher doses. The dose of simvastatin should be adjusted accordingly (see [Precautions]).
Fluvastatin, pravastatin, and resrivastatin are not metabolized by the cytochrome P450 isoenzyme CYP3A4 and are unlikely to interact with verapamil.
8. Antihypertensives, diuretics, vasodilators
Enhanced antihypertensive effect, risk of excessive hypotension.
9. Anti-arrhythmics (e.g., flecainide, propyzamide), beta-blockers (e.g., metoprolol, propranolol), inhalation anesthetics
Cardiovascular effects are mutually reinforcing (higher AV blockade levels, higher heart rate reduction levels, heart failure, more blood pressure reduction).
Patients receiving intravenous verapamil should not be coadministered with intravenous beta-blockers (exception: intensive care, see [contraindications]). The combination of intravenous verapamil and an antiepinephrine agent may result in excessive hypotension. Particularly in patients with cardiovascular disease such as severe cardiomyopathy, congestive heart failure, or recent myocardial infarction, the combination of an intravenous beta-blocker or propiamine with intravenous verapamil increases the risk of these adverse effects because both classes of drugs inhibit myocardial contractility and AV conduction (see [ADVERSE REACTIONS]).
10. Cytotoxic drugs
Cytotoxic drugs such as cyclophosphamide, vincristine, methylphenidate, prednisone, vincristine amide, adriamycin, and cisplatin reduce the absorption of verapamil.
11. beta-lactone, vitamin D, and remifentan
Decrease the plasma concentration of verapamil by increasing hepatic metabolism.
12. Antihypertensive agents such as vasodilators, angiotensin-converting enzyme inhibitors, diuretics
The antihypertensive effect is superimposed and patients on combined antihypertensive therapy should be monitored appropriately.
13. Amiodarone
Combined use may increase cardiotoxicity.
14. flecainide
The combination of verapamil and flecainide may superimpose negative inotropic effects and prolong atrioventricular conduction.
15. Inhalational anesthetics
Animal studies suggest that when inhalational anesthetics are used concomitantly with verapamil, the dose of both drugs needs to be carefully adjusted to avoid excessive cardiac depression.
16. Propyzamide
Avoid concomitant use of verapamil and propyzamide.
[Drug overdose].
1. Symptoms of drug overdose.
Symptoms of intoxication following verapamil poisoning depend on the dose taken, the time of initiation of detoxification measures, and myocardial contractility (age dependence). The following symptoms were observed in cases of severe poisoning.
Severe hypotension, cardiac insufficiency, bradycardia or tachycardic arrhythmias (e.g. atrioventricular separation, high atrioventricular block, cardiac arrest), which can lead to cardiovascular shock and cardiac arrest. Unconsciousness to coma, hyperglycemia, hypokalemia, metabolic acidosis, hypoxia, cardiogenic shock with pulmonary edema, impaired renal function, and convulsions. Death is sometimes reported.
2. Therapeutic measures for drug overdose.
Treatment involves removal of toxins and restoration of previously stable cardiovascular status.
Therapeutic measures depend on the timing and manner of administration of the drug and the type and severity of the symptoms of poisoning.
In case of poisoning with a large quantity of extended-release preparations, it should be noted that the release and absorption of the drug in the intestine can continue for more than 48 hours after the dose.
Gastric lavage is recommended after oral poisoning with verapamil, even after more than 12 hours of dosing, if no gastrointestinal motility (bowel sounds) is detected. In case of suspected poisoning with extended-release preparations, extensive elimination measures such as emetic, endoscopically controlled absorption of gastric and small intestinal contents, colonic lavage, drainage, and high enema should be performed.
Hemodialysis does not clear verapamil, but hemofiltration and plasma replacement (calcium antagonists highly bound to plasma proteins) are recommended.
Commonly used intensive medical resuscitation measures, such as extra-thoracic cardiac massage, mechanical ventilation, defibrillation or pacemaker therapy.
3. Special measures for drug overdose.
Removal of cardiac depression, correction of hypotension and bradycardia.
Bradyarrhythmias can be treated symptomatically with atropine and/or beta-adrenoceptor agonists (isoprenaline, m-hydroxyisoprenaline) and require temporary pacing therapy in the case of bradyarrhythmias. Cardiac arrest should be treated by conventional methods, including the use of beta-adrenoceptor agonists (isoprenaline).
Calcium is a specific antidote, e.g. 10-20 ml of 10% calcium gluconate solution (2.25-4.5 mmol) can be pushed intravenously and repeated if needed or given as a continuous intravenous drip (e.g. 5 mmol/hour).
Cardiogenic shock and arterial vasodilation can lead to hypotension, which can be treated with dopamine (up to 25 μg/kg body weight/minute), dobutamine (up to 15 μg/kg body weight/minute), epinephrine, or norepinephrine.
The dose of these drugs can be adjusted only according to the patient’s responsiveness to the drug. Serum calcium levels should be maintained at or slightly above the upper limit of normal. Due to arterial vasodilation, rehydration therapy (Ringer’s solution or sodium chloride solution) should be administered early in treatment.
【Pharmacology and Toxicology】.
Pharmacological effects
Verapamil blocks the entry of calcium ions into the cells through the cell membranes of the heart and vascular muscle. It directly reduces myocardial oxygen demand by intervening in the metabolic process of intracellular energy expenditure, while indirectly reducing afterload. The calcium ion blocking effect of verapamil on coronary vascular smooth muscle tissue increases myocardial perfusion, even in post-stenotic tissue, and also relieves coronary artery spasm. The mechanism of the anti-hypertensive effect of verapamil is to reduce peripheral vascular resistance without causing an increase in rebound heart rate and generally without affecting normotension.
Verapamil has anti-arrhythmic effects, especially in supraventricular arrhythmias. It slows conduction in the atrioventricular node. Depending on the type of arrhythmia, the therapeutic effect of verapamil may be to restore sinus rhythm and/or to bring the ventricular rate to normal levels. Verapamil has no significant effect on normal heart rate or causes only a mild decrease in heart rate.
Toxicological studies
Repeated oral administration of verapamil at doses ≥30 mg/kg/day in dogs was associated with changes in the lens and/or eyelids and symptomatic cataracts at ≥62.5 mg/kg/day.
Genotoxicity.
Results of both in vitro and in vivo genotoxicity tests with verapamil hydrochloride were negative.
Reproductive toxicity.
Oral administration of verapamil up to 15 mg/kg/day in rabbits and 60 mg/kg/day in rats did not show significant effects on offspring growth and development; when the dose was increased to maternal toxicity, embryonic death and growth retardation were seen.
Pharmacokinetics]
Verapamil hydrochloride is a racemic mixture consisting of equal amounts of the R-enantiomer and S-enantiomer.
Absorption
After oral administration, more than 90% of verapamil is rapidly absorbed into the small intestine. Due to the significant hepatic first-pass metabolism effect of verapamil, the average bioavailability after a single dose of verapamil tablets is approximately 22% (in the original form of verapamil), respectively. The bioavailability of multiple doses was approximately twice that of a single dose. Maximum plasma concentrations were reached at 1 to 2 hours for verapamil and at 1 hour for desmethyl verapamil after oral administration of verapamil tablets.
Food has no effect on the bioavailability of verapamil.
Distribution
Verapamil is widely distributed in all tissues, with a volume of distribution ranging from 1.8-6.8 L/kg in healthy subjects. the plasma protein binding of verapamil is approximately 90%.
Metabolism
Verapamil is extensively metabolized in vivo. In vitro metabolism studies have shown that verapamil is metabolized by the cytochrome P450 isozymes CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18. The major metabolites of verapamil are various N- and O-dealkylated products. The majority of oral verapamil hydrochloride in healthy men is metabolized in the liver, and 12 metabolites can be detected, most of which are trace amounts, with desmethylverapamil being one of the 12 metabolites detected in urine. Of these metabolites only desmethylverapamil showed significant pharmacological effects in the dog test (approximately 10-20% of verapamil).
Steady-state plasma concentrations of desmethyl verapamil and verapamil were similar. Steady-state was reached after 3-4 days of once-daily dosing.
Excretion
Following oral administration of verapamil, approximately 50% of the dose is excreted in the urine within 24 hours and approximately 70% within 5 days. 16% or more of the dose is excreted in the feces. Approximately 3-4% of the active substance excreted by the kidneys is excreted in the unchanged form (prototype drug), and desmethyl verapamil accounts for approximately 6% of the active substance excreted.
Elimination
After intravenous infusion of verapamil, verapamil is rapidly eliminated in an exponential form, including a faster early distribution phase (half-life of 4 minutes) and a slower terminal elimination phase (half-life of 2-5 hours). After oral administration of verapamil, the elimination half-life of verapamil is 3-7 hours.
The total clearance of verapamil is as large as the hepatic blood flow, approximately 1 L/h/kg (range: 0.7-1.3 L /h/kg). Inter-individual variation in clearance rates is significant.
Special Populations
Children
Pharmacokinetic information for children is limited. The mean half-life of verapamil after intravenous administration is 9.17 hours and the mean clearance is 30 L/h, compared to a mean clearance of approximately 70 L/h in adults at 70 kg. Steady-state plasma concentrations following oral administration of verapamil in children are slightly lower than in adults.
Geriatric patients
Age affects the pharmacokinetics of verapamil after administration in elderly patients with hypertension. The clearance half-life may be prolonged in elderly patients. The antihypertensive effect of verapamil is not affected by age.
In renal insufficiency
Controlled studies in patients with end-stage renal disease and in subjects with healthy kidneys have shown that renal impairment does not affect the pharmacokinetics of verapamil.
Verapamil and desmethyl verapamil are not cleared by hemodialysis.
In hepatic insufficiency
The half-life of verapamil is prolonged in patients with hepatic impairment because of reduced oral clearance and increased volume of distribution.
Storage]
Keep sealed.
Packaging
PVC solid pharmaceutical tablet and aluminum foil for pharmaceutical packaging, 20 tablets/plate x 1 plate/box.
Expiration date
24 months
Execution standard
Approval number】
State Drug Certificate H12020051
Manufacturer
Company Name: Tianjin Central Pharmaceutical Co.
Production Address: No. 1 Fujin Road, Beichen District, Tianjin
Postal Code: 300400
After-sales service: 8008180768 (call from a landline); 4006010268