Kapspargo

25 mg capsule: Light yellow opaque cap and white opaque body both imprinted with 'RL14' in black ink containing white to off-white pellets.

50 mg capsule: Dark yellow opaque cap and white opaque body both imprinted with 'RL15' in black ink containing white to off-white pellets.

100 mg capsule: White opaque cap and white opaque body both imprinted with 'RL16' in black ink containing white to off-white pellets.

200 mg capsule: Yellow opaque cap and yellow opaque body both imprinted with 'RL17' in black ink containing white to off-white pellets.

Catecholamine Depleting Drugs

Catecholamine depleting drugs (e.g., reserpine, monoamine oxidase (MAO) inhibitors) may have an additive effect when given with beta-blocking agents. Observe patients treated with metoprolol succinate plus a catecholamine depletor for evidence of hypotension or marked bradycardia, which may produce vertigo, syncope, or postural hypotension.

Epinephrine

While taking beta-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenge and may be unresponsive to the usual doses of epinephrine used to treat an allergic reaction.

CYP2D6 Inhibitors

Drugs that are strong inhibitors of CYP2D6, such as quinidine, fluoxetine, paroxetine, and propafenone, were shown to double metoprolol concentrations. While there is no information about moderate or weak inhibitors, these too are likely to increase metoprolol concentration. Increases in plasma concentration decrease the cardioselectivity of metoprolol [see Clinical Pharmacology (12.3)]. Monitor patients closely, when the combination cannot be avoided.

Digitalis, Clonidine, and Calcium Channel Blockers

Digitalis glycosides, clonidine, diltiazem and verapamil slow atrioventricular conduction and decrease heart rate. Concomitant use with beta blockers can increase the risk of bradycardia.

If clonidine and a beta blocker, such as metoprolol are coadministered, withdraw the beta-blocker several days before the gradual withdrawal of clonidine because beta-blockers may exacerbate the rebound hypertension that can follow the withdrawal of clonidine. If replacing clonidine by beta-blocker therapy, delay the introduction of beta-blockers for several days after clonidine administration has stopped.

Alcohol

Metoprolol succinate is released faster from Kapspargo Sprinkle in the presence of alcohol. This may increase the risk for adverse events associated with Kapspargo Sprinkle. Avoid alcohol consumption when taking Kapspargo Sprinkle [see Clinical Pharmacology (12.3)].

Mechanism of Action

Metoprolol is a beta1-selective (cardioselective) adrenergic receptor blocking agent. This preferential effect is not absolute, however, and at higher plasma concentrations, metoprolol also inhibits beta2-adrenoreceptors, chiefly located in the bronchial and vascular musculature.

Metoprolol 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 metoprolol slows the sinus rate and decreases AV nodal conduction.

The relative beta1-selectivity of metoprolol has been confirmed by the following: (1) In normal subjects, metoprolol 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, metoprolol 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, metoprolol 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.

Pharmacodynamics

Clinical pharmacology studies have confirmed the beta-blocking activity of metoprolol 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 metoprolol 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 metoprolol plasma concentrations from 30 to 540 nmol/L. The relative beta1‑selectivity of metoprolol diminishes and blockade of beta2-adrenoceptors increases at plasma concentration above 300 nmol/L.

In five controlled studies in normal healthy subjects, extended-release metoprolol succinate administered once a day, and immediate-release metoprolol 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 metoprolol succinate produced significantly higher total beta1-blockade over 24 hours than immediate-release metoprolol. For extended-release metoprolol 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 metoprolol administered t.i.d., and 100 mg and 200 mg extended-release metoprolol succinate once daily. Extended-release metoprolol 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 metoprolol.

In other studies, treatment with metoprolol succinate produced an improvement in left ventricular ejection fraction. Metoprolol 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.

Pharmacokinetics

The peak plasma levels following once-daily administration of extended release metoprolol succinate are reduced by 50 to 75% on average compared to a corresponding dose of immediate-release metoprolol tartrate, both when administered once daily or in divided doses. At steady state the average bioavailability of metoprolol following administration of metoprolol 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 metoprolol tartrate. The bioavailability of metoprolol shows a dose-related, although not directly proportional, increase with dose. The exposure (Cmax and AUC) of metoprolol succinate extended-release capsule are similar to that of TOPROL-XL® tablet.

Absorption

Plasma levels following oral administration of metoprolol tablet approximate 50% of levels following intravenous administration, indicating about 50% first-pass metabolism. Peak plasma concentration of metoprolol is attained at 10 hours following administration of metoprolol 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 Kapspargo Sprinkle.

Kapspargo Sprinkle (metoprolol succinate 200 mg) 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 metoprolol.

Distribution

About 12% of the drug is bound to human serum albumin.

Metoprolol crosses the blood-brain barrier and has been reported in the CSF in a concentration 78% of the simultaneous plasma concentration.

Elimination

Elimination is mainly by biotransformation in the liver, and the plasma half-life ranges from approximately 3 to 7 hours.

Metabolism

Metoprolol 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.

Excretion

Less than 5% of an oral dose of metoprolol 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 metoprolol, the urinary recovery of unchanged drug is approximately 10%.

Specific Populations

Pediatric Patients

The pharmacokinetic profile of metoprolol 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 metoprolol were similar to those described previously in adults. Age, gender, race, and ideal body weight had no significant effects on metoprolol pharmacokinetics. Metoprolol apparent oral clearance (CL/F) increased linearly with body weight. Metoprolol pharmacokinetics have not been investigated in patients < 6 years of age.

Drug Interactions

CYP2D6

Metoprolol 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 metoprolol 200 mg tripled the concentration of S-metoprolol and doubled the metoprolol elimination half-life. In four patients with cardiovascular disease, coadministration of propafenone 150 mg t.i.d. with immediate-release metoprolol 50 mg t.i.d. resulted in steady-state concentration of metoprolol 2- to 5-fold what is seen with metoprolol alone. Extensive metabolizers who concomitantly use CYP2D6 inhibiting drugs will have increased (several-fold) metoprolol blood levels, decreasing metoprolol's cardioselectivity [see Drug Interactions (7.2)].

Alcohol

An in vitro dissolution study was conducted to evaluate the impact of alcohol (5, 10, 20 and 40%), on the extended-release characteristics of Kapspargo Sprinkle. The in vitro study showed that about 89% of the total metoprolol 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 metoprolol succinate from Kapspargo Sprinkle that may increase the risk for above events associated with Kapspargo Sprinkle. Consumption of alcohol is not recommended when taking Kapspargo Sprinkle 25 mg, 50 mg, 100 mg and 200 mg.

Pharmacogenomics

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) metoprolol blood levels, decreasing metoprolol's cardioselectivity.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have been conducted to evaluate the carcinogenic potential of metoprolol tartrate. In 2-year studies in rats at three oral dosage levels of up to 800 mg/kg/day (41 times, on a mg/m2 basis, the daily dose of 200 mg for a 60 kg patient), there was no increase in the development of spontaneously occurring benign or malignant neoplasms of any type. The only histologic changes that appeared to be drug related were an increased incidence of generally mild focal accumulation of foamy macrophages in pulmonary alveoli and a slight increase in biliary hyperplasia. In a 21-month study in Swiss albino mice at three oral dosage levels of up to 750 mg/kg/day (18 times, on a mg/m2 basis, the daily dose of 200 mg for a 60-kg patient), benign lung tumors (small adenomas) occurred more frequently in female mice receiving the highest dose than in untreated control animals. There was no increase in malignant or total (benign plus malignant) lung tumors, nor in the overall incidence of tumors or malignant tumors. This 21-month study was repeated in CD-1 mice, and no statistically or biologically significant differences were observed between treated and control mice of either sex for any type of tumor.

All genotoxicity tests performed on metoprolol tartrate (a dominant lethal study in mice, chromosome studies in somatic cells, a Salmonella/mammalian-microsome mutagenicity test, and a nucleus anomaly test in somatic interphase nuclei) and metoprolol succinate (a Salmonella/mammalian-microsome mutagenicity test) were negative.

No evidence of impaired fertility due to metoprolol tartrate was observed in a study performed in rats at doses up to 22 times, on a mg/m2 basis, the daily dose of 200 mg in a 60 kg patient.

Each extended-release capsule contains 10.24 mg, 20.48 mg, 40.96 mg, and 81.92 mg of metoprolol free base, present as 23.75 mg, 47.5 mg, 95 mg, and 190 mg of metoprolol succinate and equivalent to 25 mg, 50 mg, 100 mg, and 200 mg of metoprolol tartrate, USP respectively and are supplied as follows:

25 mg capsule: Light yellow opaque cap and white opaque body both imprinted with 'RL14' in black ink containing white to off-white pellets.

50 mg capsule: Dark yellow opaque cap and white opaque body both imprinted with 'RL15' in black ink containing white to off-white pellets.

100 mg capsule: White opaque cap and white opaque body both imprinted with 'RL16' in black ink containing white to off-white pellets.

200 mg capsule: Yellow opaque cap and yellow opaque body both imprinted with 'RL17' in black ink containing white to off-white pellets.

Store at 20° C - 25° C (68° F - 77° F). [See USP Controlled Room Temperature].

Heart failure patients should be advised to consult their physician if they experience signs or symptoms of worsening heart failure such as weight gain or increasing shortness of breath.

Advise patients if a dose is missed, the patient should take only the next scheduled dose (without doubling it). Patients should not interrupt or discontinue Kapspargo Sprinkle without consulting the physician.

Advise patients (1) to avoid operating automobiles and machinery or engaging in other tasks requiring alertness until the patient's response to therapy with Kapspargo Sprinkle has been determined; (2) to contact the physician if any difficulty in breathing occurs; (3) to inform the physician or dentist before any type of surgery that he or she is taking Kapspargo Sprinkle.

Advise patients who are breastfeeding to monitor the infant for bradycardia, dry mouth, skin or eyes, and diarrhea or constipation. [see Use in Specific Population (8.2)].

Kapspargo is a trademark of Sun Pharmaceutical Industries Limited. All other trademarks are property of their respective owners.

Manufactured by:

Ohm Laboratories Inc.

New Brunswick, NJ 08901

Distributed by:

Sun Pharmaceutical Industries, Inc.

Cranbury, NJ 08512

FDA-07