Pharmacotherapeutic Group: Beta-receptor blocker, selective. ATC Code: C07A B02
Pharmacology: Pharmacodynamics: Topme is a beta1-selective receptor blocker, i.e. Topme affects the beta1-receptors of the heart in lower doses than needed to affect beta2-receptors in peripheral vessels and bronchi. At increasing doses the beta1-selectivity may decrease.
Topme has no beta-stimulating effect and has little membrane-stimulating effect. Beta-receptor blockers have negative inotropic and chronotropic effect.
Topme therapy reduces the effect of catecholamines in association with physical and psychic strain and gives lower heart rate, cardiac output and blood pressure. In stress situations with an increased release of adrenaline from the adrenal glands, Topme does not prevent the normal physiological vascular dilation. In therapeutic doses, Topme has less contractile effect on the bronchial muscles than non-selective beta-blockers. This property enables treatment of patients with bronchial asthma or other pronounced obstructive lung diseases with Topme in combination with beta2-receptor stimulants. Topme influences insulin release and carbohydrate metabolism to less extent than non-selective beta-blockers and therefore it can also be given to patients with diabetes mellitus. The cardiovascular reaction in hypoglycaemia eg, tachycardia, is less influenced by Topme and the return of blood sugar level to normal is faster than for non-selective beta-receptor blockers.
In hypertension, Topme lowers the blood pressure significantly for more than 24 hours both in lying and standing position as well as during exercise. In treatment with Topme an increase in the peripheral vascular resistance is observed initially. In long-term treatment, however, the obtained lowering in blood pressure may be due to reduced peripheral vascular resistance and unchanged cardiac output. In males with moderate/severe hypertension, Topme reduces the risk of cardiovascular death. There is no electrolyte imbalance.
In tachyarrhythmias the effect of increased sympatholytic activity is blocked and this gives a lower heart rate primarily by reduced automatisation in the pacemaker cells, but also through a prolonged supraventricular conduction time.
Topme reduces the risk of reinfarction and cardiac death, especially sudden death after myocardial infarction.
Pharmacokinetics: The bioavailability of Topme is 40-50%. Maximal beta-blockade is reached after 1-2 hours. After per oral once-daily dosage of 100 mg the effect on the heart rate is still pronounced after 12 hours. Topme is metabolised in the liver mainly by CYP2D6. Three main metabolites have been identified, though none has a beta-blocking effect of clinical importance. The half-life in plasma is 3-5 hours. Topme is excreted to approximately 5% in unchanged form via the kidneys, the remaining dose as metabolites.
Take Topme only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. Your dose may need to be changed several times in order to find out what works best for you.
In addition to the use of Topme, treatment for your high blood pressure may include weight control and changes in the types of foods you eat, especially foods high in sodium (salt). Your doctor will tell you which of these are most important for you. You should check with your doctor before changing your diet.
Many patients who have high blood pressure will not notice any signs of the problem. In fact, many patients feel normal. It is very important that you take your medicine exactly as directed and that you keep your appointments with your doctor even if you feel well.
Remember that Topme will not cure your high blood pressure, but it does help control it. You must continue to take it as directed if you expect to lower your blood pressure and keep it down. You may have to take high blood pressure medicine for the rest of your life. If high blood pressure is not treated, it can cause serious problems such as heart failure, blood vessel disease, strokes, or kidney disease.
Take Topme with a meal or just after you eat. You may break the extended-release tablet into two pieces, but swallow the two pieces whole and do not crush or chew them.
Swallow the tablet whole with a glass of water. Do not crush, break, or chew it.
The dose of Topme will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of Topme. If your dose is different, do not change it unless your doctor tells you to do so.
The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.
If you miss a dose of Topme, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.
Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.
Keep out of the reach of children.
Do not keep outdated medicine or medicine no longer needed.
Ask your healthcare professional how you should dispose of any medicine you do not use.
Immediate release (Topme): Administer with or immediately following meals.
Extended release (Topme succinate): According to the manufacturer, it is preferable to administer with or immediately following meals; however, may also administer without regard to meals (Tangeman 2003; van den Berg 1990; Wikstrand 2003). May divide tablets in half; do not crush or chew.
Bariatric surgery: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. ER tablet (Topme succinate) may be divided in half but not crushed or chewed. IR tablet, oral solution, and injectable formulations are available. If safety and efficacy can be effectively monitored, no change in formulation or administration is required after bariatric surgery; however, selection of IR formulation or alternative therapy is advised for cardiovascular and other high-risk labeled and off-label indications.
Sprinkle capsule: May be swallowed whole or the capsule may be opened and contents sprinkled on a small amount (1 teaspoonful) of soft food (eg, applesauce, pudding, or yogurt) to be used within 60 minutes (do not store for future use).
Nasogastric tube administration: Open capsule and add contents to an all plastic oral tip syringe; add 15 mL of water. Gently shake the syringe for ~10 seconds. Immediately deliver mixture through a ≥12 French nasogastric tube. No granules should remain in the syringe; rinse syringe with additional water if necessary.
IV: May administer undiluted by rapid infusion (IV push) over 1 minute for acute treatment. May also be administered by slow infusion (ie, 5 to 10 mg of Topme in 50 mL of fluid) over ~30 to 60 minutes during less urgent situations (eg, substitution for oral Topme).
Topme is a beta1-selective (cardioselective) adrenergic receptor blocking agent. This preferential effect is not absolute, however, and at higher plasma concentrations, Topme also inhibits beta2-adrenoreceptors, chiefly located in the bronchial and vascular musculature.
Topme has no intrinsic sympathomimetic activity, and membrane-stabilizing activity is detectable only at plasma concentrations much greater than required for beta-blockade. Animal and human experiments indicate that Topme slows the sinus rate and decreases AV nodal conduction.
The relative beta1-selectivity of Topme has been confirmed by the following: (1) In normal subjects, Topme is unable to reverse the beta2-mediated vasodilating effects of epinephrine. This contrasts with the effect of nonselective beta-blockers, which completely reverse the vasodilating effects of epinephrine. (2) In asthmatic patients, Topme reduces FEV1 and FVC significantly less than a nonselective beta-blocker, propranolol, at equivalent beta1-receptor blocking doses.
Hypertension: The mechanism of the antihypertensive effects of beta-blocking agents has not been elucidated. However, several possible mechanisms have been proposed: (1) competitive antagonism of catecholamines at peripheral (especially cardiac) adrenergic neuron sites, leading to decreased cardiac output; (2) a central effect leading to reduced sympathetic outflow to the periphery; and (3) suppression of renin activity.
Angina Pectoris: By blocking catecholamine-induced increases in heart rate, in velocity and extent of myocardial contraction, and in blood pressure, Topme reduces the oxygen requirements of the heart at any given level of effort, thus making it useful in the long-term management of angina pectoris.
Heart Failure: The precise mechanism for the beneficial effects of beta-blockers in heart failure has not been elucidated.
Clinical pharmacology studies have confirmed the beta-blocking activity of Topme in man, as shown by (1) reduction in heart rate and cardiac output at rest and upon exercise, (2) reduction of systolic blood pressure upon exercise, (3) inhibition of isoproterenol-induced tachycardia, and (4) reduction of reflex orthostatic tachycardia.
The relationship between plasma Topme levels and reduction in exercise heart rate is independent of the pharmaceutical formulation. Beta1-blocking effects in the range of 30 to 80% of the maximal effect (approximately 8 to 23% reduction in exercise heart rate) correspond to Topme plasma concentrations from 30 to 540 nmol/L. The relative beta1‑selectivity of Topme diminishes and blockade of beta2-adrenoceptors increases at plasma concentration above 300 nmol/L.
In five controlled studies in normal healthy subjects, extended-release Topme succinate administered once a day, and immediate-release Topme administered once to four times a day, provided comparable total beta1-blockade over 24 hours (area under the beta1-blockade versus time curve) in the dose range 100 to 400 mg. In another controlled study, 50 mg once daily for each product, extended-release Topme succinate produced significantly higher total beta1-blockade over 24 hours than immediate-release Topme. For extended-release Topme succinate, the percent reduction in exercise heart rate was relatively stable throughout the entire dosage interval and the level of beta1-blockade increased with increasing doses from 50 to 300 mg daily.
A controlled cross-over study in heart failure patients compared the plasma concentrations and beta1-blocking effects of 50 mg immediate-release Topme administered t.i.d., and 100 mg and 200 mg extended-release Topme succinate once daily. Extended-release Topme succinate 200 mg once daily produced a larger effect on suppression of exercise-induced and Holter-monitored heart rate over 24 hours compared to 50 mg t.i.d. of immediate-release Topme.
In other studies, treatment with Topme succinate produced an improvement in left ventricular ejection fraction. Topme succinate was also shown to delay the increase in left ventricular end-systolic and end-diastolic volumes after 6 months of treatment.
Although beta-adrenergic receptor blockade is useful in the treatment of angina, hypertension, and heart failure there are situations in which sympathetic stimulation is vital. In patients with severely damaged hearts, adequate ventricular function may depend on sympathetic drive. In the presence of AV block, beta-blockade may prevent the necessary facilitating effect of sympathetic activity on conduction. Beta2-adrenergic blockade results in passive bronchial constriction by interfering with endogenous adrenergic bronchodilator activity in patients subject to bronchospasm and may also interfere with exogenous bronchodilators in such patients.
The peak plasma levels following once-daily administration of extended release Topme succinate are reduced by 50 to 75% on average compared to a corresponding dose of immediate-release Topme, both when administered once daily or in divided doses. At steady state the average bioavailability of Topme following administration of Topme succinate, across the dosage range of 50 to 400 mg once daily, was reduced by 25% relative to the corresponding single or divided doses of immediate-release Topme. The bioavailability of Topme shows a dose-related, although not directly proportional, increase with dose. The exposure (Cmax and AUC) of Topme succinate extended-release capsule are similar to that of TOPROL-XL® tablet.
Plasma levels following oral administration of Topme tablet approximate 50% of levels following intravenous administration, indicating about 50% first-pass metabolism. Peak plasma concentration of Topme is attained at 10 hours following administration of Topme succinate extended-release capsule.
Effect of food
Compared to fasted state administration, high-fat, high-calorie meal (54.3% fat, 15.6% proteins and 30.1% carbohydrates) did not have a significant effect on the absorption of Topme succinate extended-release capsule.
200 mg Topme succinate extended release capsule administered under fasting conditions to healthy adults by sprinkling the entire contents on one-tablespoon (15 mL) of applesauce did not significantly affect Tmax, Cmax, and AUC of Topme.
About 12% of the drug is bound to human serum albumin.
Topme crosses the blood-brain barrier and has been reported in the CSF in a concentration 78% of the simultaneous plasma concentration.
Elimination is mainly by biotransformation in the liver, and the plasma half-life ranges from approximately 3 to 7 hours.
Topme is a racemic mixture of R- and S- enantiomers, and is primarily metabolized by CYP2D6. When administered orally, it exhibits stereoselective metabolism that is dependent on oxidation phenotype.
Less than 5% of an oral dose of Topme is recovered unchanged in the urine; the rest is excreted by the kidneys as metabolites that appear to have no beta-blocking activity.
Following intravenous administration of Topme, the urinary recovery of unchanged drug is approximately 10%.
The pharmacokinetic profile of Topme succinate was studied in 120 pediatric hypertensive patients (6 to 17 years of age) receiving doses ranging from 12.5 to 200 mg once daily. The pharmacokinetics of Topme were similar to those described previously in adults. Age, gender, race, and ideal body weight had no significant effects on Topme pharmacokinetics. Topme apparent oral clearance (CL/F) increased linearly with body weight. Topme pharmacokinetics have not been investigated in patients < 6 years of age.
Topme is metabolized predominantly by CYP2D6. In healthy subjects with CYP2D6 extensive metabolizer phenotype, coadministration of quinidine 100 mg, a potent CYP2D6 inhibitor, and immediate-release Topme 200 mg tripled the concentration of S-Topme and doubled the Topme elimination half-life. In four patients with cardiovascular disease, coadministration of propafenone 150 mg t.i.d. with immediate-release Topme 50 mg t.i.d. resulted in steady-state concentration of Topme 2- to 5-fold what is seen with Topme alone. Extensive metabolizers who concomitantly use CYP2D6 inhibiting drugs will have increased (several-fold) Topme blood levels, decreasing Topme's cardioselectivity.
An in vitro dissolution study was conducted to evaluate the impact of alcohol (5, 10, 20 and 40%), on the extended-release characteristics of Topme succinate extended-release capsules. The in vitro study showed that about 89% of the total Topme succinate dose was released at 2 hour at the highest alcohol level (40%), and about 17% of total drug was released at 2 hour with 5% alcohol. Alcohol causes a rapid release of Topme succinate from the extended-release capsules that may increase the risk for above events associated with Topme succinate extended-release capsules. Consumption of alcohol is not recommended when taking Topme succinate extended-release capsules 25 mg, 50 mg, 100 mg and 200 mg.
CYP2D6 is absent in about 8% of Caucasians (poor metabolizers) and about 2% of most other populations. CYP2D6 can be inhibited by several drugs. Poor metabolizers of CYP2D6 will have increased (several-fold) Topme blood levels, decreasing Topme's cardioselectivity.
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Information checked by Dr. Sachin Kumar, MD Pharmacology