Orloc Comp

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DESCRIPTION

Orloc Comp tablets are indicated for the treatment of hypertension. It combines two antihypertensive agents in a once-daily

Dosage: a synthetic beta1-selective (cardioselective) adrenoceptor blocking agent (bisoprolol fumarate) and a benzothiadiazine diuretic (hydrochlorothiazide).

Orloc Comp USP is chemically described as (±)-1-[4-[[2-(1-methylethoxy) ethoxy]methyl]phenoxy]-3-[(1-methylethyl)amino]-2-propanol(E)-2-butenedioate (2:1) (salt). It possesses an asymmetric carbon atom in its structure and is provided as a racemic mixture. The S(-) enantiomer is responsible for most of the beta-blocking activity. Its empirical formula is (C18H31NO4)2-C4H4O4 and it has a molecular weight of 766.97. Its structural formula is:

Orloc Comp USP is a white crystalline powder, approximately equally hydrophilic and lipophilic, and readily soluble in water, methanol, ethanol, and chloroform.

Hydrochlorothiazide USP (HCTZ) is 6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. It is a white, or practically white, practically odorless crystalline powder. It is slightly soluble in water, sparingly soluble in dilute sodium hydroxide solution, freely soluble in n-butylamine and dimethylformamide, sparingly soluble in methanol, and insoluble in ether, chloroform, and dilute mineral acids. Its empirical formula is C7H8CIN3O4S2 and it has a molecular weight of 297.73. Its structural formula is:

Each Orloc Comp Tablet, 2.5 mg/6.25 mg for oral administration contains:

Orloc Comp USP....................................................................................................2.5 mg

Hydrochlorothiazide USP................................................................................................6.25 mg

Each Orloc Comp Tablet, 5 mg/6.25 mg for oral administration contains:

Orloc Comp USP........................................................................................................5 mg

Hydrochlorothiazide USP..................................................................................................6.25 mg

Each Orloc Comp Tablet, 10 mg/6.25 mg for oral administration contains:

Orloc Comp USP.....................................................................................................10 mg

Hydrochlorothiazide USP.................................................................................................6.25 mg

Inactive ingredients include: colloidal silicon dioxide, corn starch, dibasic calcium phosphate, magnesium stearate, microcrystalline cellulose, hypromellose, titanium dioxide, polyethylene glycol, polysorbate 80. Both the 2.5 mg/6.25 mg and the 5 mg/6.25 mg tablets contain FD&C yellow No. 6 aluminum lake. In addition, the 5 mg/6.25 mg tablets contain FD&C red No. 40 aluminium lake.

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CLINICAL PHARMACOLOGY

Orloc Comp have been used individually and in combination for the treatment of hypertension. The antihypertensive effects of these agents are additive; hydrochlorothiazide 6.25 mg significantly increases the antihypertensive effect of Orloc Comp. The incidence of hypokalemia with the Orloc Comp 6.25 mg combination is significantly lower than with hydrochlorothiazide 25 mg. In clinical trials of bisoprolol and hydrochlorothiazide, mean changes in serum potassium for patients treated with Orloc Comp 2.5 mg/6.25 mg, 5 mg/6.25 mg, 10 mg/6.25 mg or placebo were less than ± 0.1 mEq/L. Mean changes in serum potassium for patients treated with any dose of bisoprolol in combination with hydrochlorothiazide 25 mg ranged from -0.1 mEq/L to -0.3 mEq/L.

Orloc Comp is a beta1-selective (cardioselective) adrenoceptor blocking agent without significant membrane stabilizing or intrinsic sympathomimetic activities in its therapeutic dose range. At higher doses (>20 mg) Orloc Comp USP also inhibits beta2-adrenoreceptors located in bronchial and vascular musculature. To retain relative selectivity, it is important to use the lowest effective dose.

Hydrochlorothiazide USP is a benzothiadiazine diuretic. Thiazides affect renal tubular mechanisms of electrolyte reabsorption and increase excretion of sodium and chloride in approximately equivalent amounts. Natriuresis causes a secondary loss of potassium.

Pharmacokinetics and Metabolism

Orloc Comp

In healthy volunteers, both Orloc Comp are well absorbed following oral administration of Orloc Comp. No change is observed in the bioavailability of either agent when given together in a single tablet. Absorption is not affected whether Orloc Comp is taken with or without food. Mean peak Orloc Comp plasma concentrations of about 9.0 ng/mL, 19 ng/mL and 36 ng/mL occur approximately 3 hours after the administration of the 2.5 mg/6.25 mg, 5 mg/6.25 mg and 10 mg/6.25 mg combination tablets, respectively. Mean peak plasma hydrochlorothiazide concentrations of 30 ng/mL occur approximately 2.5 hours following the administration of the combination. Dose proportional increases in plasma bisoprolol concentrations are observed between the 2.5 mg and 5 mg, as well as between the 5 mg and 10 mg doses. The elimination T1/2 of bisoprolol ranges from 7 to 15 hours, and that of hydrochlorothiazide ranges from 4 to 10 hours. The percent of dose excreted unchanged in urine is about 55% for bisoprolol and about 60% for hydrochlorothiazide.

Orloc Comp USP

The absolute bioavailability after a 10 mg oral dose of Orloc Comp USP is about 80%. The first pass metabolism of Orloc Comp is about 20%.

The pharmacokinetic profile of Orloc Comp has been examined following single doses and at steady state. Binding to serum proteins is approximately 30%. Peak plasma concentrations occur within 2 to 4 hours of dosing with 2.5 mg to 20 mg, and mean peak values range from 9.0 ng/mL at 2.5 mg to 70 ng/mL at 20 mg. Once-daily dosing with Orloc Comp results in less than two-fold intersubject variation in peak plasma concentrations. Plasma concentrations are proportional to the administered dose in the range of 2.5 mg to 20 mg. The plasma elimination half-life is 9 to 12 hours and is slightly longer in elderly patients, in part because of decreased renal function. Steady state is attained within 5 days with once-daily dosing. In both young and elderly populations, plasma accumulation is low; the accumulation factor ranges from 1.1 to 1.3, and is what would be expected from the half-life and once-daily dosing. Bisoprolol is eliminated equally by renal and nonrenal pathways with about 50% of the dose appearing unchanged in the urine and the remainder in the form of inactive metabolites. In humans, the known metabolites are labile or have no known pharmacologic activity. Less than 2% of the dose is excreted in the feces. The pharmacokinetic characteristics of the two enantiomers are similar. Bisoprolol is not metabolized by cytochrome P450 II D6. In subjects with creatinine clearance less than 40 mL/min, the plasma half-life is increased approximately threefold compared to healthy subjects.

In patients with liver cirrhosis, the rate of elimination of bisoprolol is more variable and significantly slower than that in healthy subjects, with a plasma half-life ranging from 8 to 22 hours.

In elderly subjects, mean plasma concentrations at steady state are increased, in part attributed to lower creatinine clearance. However, no significant differences in the degree of bisoprolol accumulation is found between young and elderly populations.

Hydrochlorothiazide USP

Hydrochlorothiazide USP is well absorbed (65% to 75%) following oral administration. Absorption of hydrochlorothiazide USP is reduced in patients with congestive heart failure. Peak plasma concentrations are observed within 1 to 5 hours of dosing, and range from 70 ng/mL to 490 ng/mL following oral doses of 12.5 mg to 100 mg. Plasma concentrations are linearly related to the administered dose. Concentrations of hydrochlorothiazide USP are 1.6 to 1.8 times higher in whole blood than in plasma. Binding to serum proteins has been reported to be approximately 40% to 68%. The plasma elimination half-life has been reported to be 6 to 15 hours. Hydrochlorothiazide USP is eliminated primarily by renal pathways. Following oral doses of 12.5 mg to 100 mg, 55% to 77% of the administered dose appears in urine and greater than 95% of the absorbed dose is excreted in urine as unchanged drug. Plasma concentrations of hydrochlorothiazide USP are increased and the elimination half-life is prolonged in patients with renal disease.

Pharmacodynamics

Orloc Comp USP

Findings in clinical hemodynamics studies with bisoprolol fumarate are similar to those observed with other beta-blockers. The most prominent effect is the negative chronotropic effect, giving a reduction in resting and exercise heart rate. There is a fall in resting and exercise cardiac output with little observed change in stroke volume, and only a small increase in right atrial pressure, or pulmonary capillary wedge pressure at rest or during exercise. In normal volunteers, Orloc Comp therapy resulted in a reduction of exercise- and isoproterenol-induced tachycardia. The maximal effect occurred within 1 to 4 hours post-dosing. Effects generally persisted for 24 hours at doses of 5 mg or greater. In controlled clinical trials, Orloc Comp given as a single daily dose has been shown to be an effective antihypertensive agent when used alone or concomitantly with thiazide diuretics.

The mechanism of bisoprolol fumarate's antihypertensive effect has not been completely established. Factors that may be involved include:

1) Decreased cardiac output,

2) Inhibition of renin release by the kidneys,

3) Diminution of tonic sympathetic outflow from vasomotor centers in the brain. Beta1-selectivity of Orloc Comp has been demonstrated in both animal and human studies. No effects at therapeutic doses on beta2-adrenoreceptor density have been observed. Pulmonary function studies have been conducted in healthy volunteers, asthmatics, and patients with chronic obstructive pulmonary disease (COPD). Doses of Orloc Comp ranged from 5 mg to 60 mg, atenolol from 50 mg to 200 mg, metoprolol from 100 mg to 200 mg, and propranolol from 40 mg to 80 mg. In some studies, slight, asymptomatic increases in airway resistance (AWR) and decreases in forced expiratory volume (FEV1) were observed with doses of Orloc Comp USP 20 mg and higher, similar to the small increases in AWR noted with other cardioselective beta-blocking agents. The changes induced by beta-blockade with all agents were reversed by bronchodilator therapy.

Electrophysiology studies in man have demonstrated that Orloc Comp significantly decreases heart rate, increases sinus node recovery time, prolongs AV node refractory periods, and with rapid atrial stimulation, prolongs AV nodal conduction.

Hydrochlorothiazide USP

Acute effects of thiazides are thought to result from a reduction in blood volume and cardiac output, secondary to a natriuretic effect, although a direct vasodilatory mechanism has also been proposed. With chronic administration, plasma volume returns toward normal, but peripheral vascular resistance is decreased.

Thiazides do not affect normal blood pressure. Onset of action occurs within 2 hours of dosing, peak effect is observed at about 4 hours, and activity persists for up to 24 hours.

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CLINICAL STUDIES

In controlled clinical trials, Orloc Comp 6.25 mg has been shown to reduce systolic and diastolic blood pressure throughout a 24-hour period when administered once daily. The effects on systolic and diastolic blood pressure reduction of the combination of Orloc Comp were additive. Further, treatment effects were consistent across age groups (<60 years, >60 years), racial groups (black, nonblack), and gender (male, female).

In two randomized, double-blind, placebo-controlled trials conducted in the U.S., reductions in systolic and diastolic blood pressure and heart rate 24 hours after dosing in patients with mild-to-moderate hypertension are shown below. In both studies mean systolic/diastolic blood pressure and heart rate at baseline were approximately 151/101 mm Hg and 77 bpm.

Study 1 Study 2
Placebo

B5/

H6.25 mg

Placebo H6.25 mg

B2.5/

H6.25 mg


B10/

H6.25 mg

n= 75 150 56 23 28 25
Total ∆ BP (mm Hg) -2.9/-3.9 -15.8/-12.6 -3.0/-3.7 -6.6/-5.8 -14.1/-10.5 -15.3/-14.3
Drug EffectObserved mean change from baseline minus placebo. -/- -12.9/-8.7 -/- -3.6/-2.1 -11.1/-6.8 -12.3/-10.6
Total ∆ HR (bpm) -0.3 -6.9 -1.6 -0.8 -3.7 -9.8
Drug Effect - -6.6 - +0.8 -2.1 -8.2

Blood pressure responses were seen within 1 week of treatment but the maximum effect was apparent after 2 to 3 weeks of treatment. Overall, significantly greater blood pressure reductions were observed on Orloc Comp than on placebo. Further, blood pressure reductions were significantly greater for each of the Orloc Comp plus hydrochlorothiazide combinations than for either of the components used alone regardless of race, age, or gender. There were no significant differences in response between black and nonblack patients.

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INDICATIONS AND USAGE

Orloc Comp tablets are indicated in the management of hypertension.

CONTRAINDICATIONS

Orloc Comp is contraindicated in patients in cardiogenic shock, overt cardiac failure, second or third degree AV block, marked sinus bradycardia, anuria, and hypersensitivity to either component of this product or to other sulfonamide-derived drugs.

WARNINGS

Cardiac Failure

In general, beta-blocking agents should be avoided in patients with overt congestive failure. However, in some patients with compensated cardiac failure, it may be necessary to utilize these agents. In such situations, they must be used cautiously.

Patients Without a History of Cardiac Failure

Continued depression of the myocardium with beta-blockers can, in some patients, precipitate cardiac failure. At the first signs or symptoms of heart failure, discontinuation of Orloc Comp should be considered. In some cases Orloc Comp therapy can be continued while heart failure is treated with other drugs.

Abrupt Cessation of Therapy

Exacerbations of angina pectoris and, in some instances, myocardial infarction or ventricular arrhythmia, have been observed in patients with coronary artery disease following abrupt cessation of therapy with beta-blockers. Such patients should, therefore, be cautioned against interruption or discontinuation of therapy without the physician’s advice. Even in patients without overt coronary artery disease, it may be advisable to taper therapy with Orloc Comp over approximately 1 week with the patient under careful observation. If withdrawal symptoms occur, beta-blocking agent therapy should be reinstituted, at least temporarily.

Peripheral Vascular Disease

Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in such individuals.

Bronchospastic Disease

PATIENTS WITH BRONCHOSPASTIC PULMONARY DISEASE SHOULD, IN GENERAL, NOT RECEIVE BETA-BLOCKERS. Because of the relative beta1-selectivity of Orloc Comp, Orloc Comp may be used with caution in patients with bronchospastic disease who do not respond to, or who cannot tolerate other antihypertensive treatment. Since beta1-selectivity is not absolute, the lowest possible dose of Orloc Comp should be used. A beta2 agonist should be made available.

Major Surgery

Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.

Diabetes and Hypoglycemia

Beta-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective beta-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. Because of its beta1-selectivity, this is less likely with Orloc Comp. However, patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned about these possibilities. Also, latent diabetes mellitus may become manifest and diabetic patients given thiazides may require adjustment of their insulin dose. Because of the very low dose of hydrochlorothiazide employed, this may be less likely with Orloc Comp.

Thyrotoxicosis

Beta-adrenergic blockade may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of beta-blockade may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate thyroid storm.

Renal Disease

Cumulative effects of the thiazides may develop in patients with impaired renal function. In such patients, thiazides may precipitate azotemia. In subjects with creatinine clearance less than 40 mL/min, the plasma half-life of Orloc Comp is increased up to threefold, as compared to healthy subjects. If progressive renal impairment becomes apparent, Orloc Comp should be discontinued.

Hepatic Disease

Orloc Comp should be used with caution in patients with impaired hepatic function or progressive liver disease. Thiazides may alter fluid and electrolyte balance, which may precipitate hepatic coma. Also, elimination of Orloc Comp is significantly slower in patients with cirrhosis than in healthy subjects (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism ).

Acute Myopia and Secondary Angle-Closure Glaucoma

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

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PRECAUTIONS

General

Electrolyte and Fluid Balance Status

Although the probability of developing hypokalemia is reduced with Orloc Comp because of the very low dose of hydrochlorothiazide employed, periodic determination of serum electrolytes should be performed, and patients should be observed for signs of fluid or electrolyte disturbances, i.e., hyponatremia, hypochloremic alkalosis, hypokalemia, and hypomagnesemia. Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.

Warning signs or symptoms of fluid and electrolyte imbalance include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

Hypokalemia may develop, especially with brisk diuresis when severe cirrhosis is present, during concomitant use of corticosteroids or adrenocorticotropic hormone or after prolonged therapy. Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia and hypomagnesemia can provoke ventricular arrhythmias or sensitize or exaggerate the response of the heart to the toxic effects of digitalis. Hypokalemia may be avoided or treated by potassium supplementation or increased intake of potassium-rich foods.

Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction rather than salt administration, except in rare instances when the hyponatremia is life-threatening. In actual salt depletion, appropriate replacement is the therapy of choice.

Parathyroid Disease

Calcium excretion is decreased by thiazides, and pathologic changes in the parathyroid glands, with hypercalcemia and hypophosphatemia, have been observed in a few patients on prolonged thiazide therapy.

Hyperuricemia

Hyperuricemia or acute gout may be precipitated in certain patients receiving thiazide diuretics. Orloc Comp, alone or in combination with hydrochlorothiazide, has been associated with increases in uric acid. However, in U.S. clinical trials, the incidence of treatment-related increases in uric acid was higher during therapy with hydrochlorothiazide 25 mg than with B/H 6.25 mg (10%). Because of the very low dose of hydrochlorothiazide employed, hyperuricemia may be less likely with Orloc Comp.

Drug Interactions

Orloc Comp may potentiate the action of other antihypertensive agents used concomitantly. Orloc Comp should not be combined with other beta-blocking agents. Patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, should be closely monitored because the added beta-adrenergic blocking action of Orloc Comp may produce excessive reduction of sympathetic activity. In patients receiving concurrent therapy with clonidine, if therapy is to be discontinued, it is suggested that Orloc Comp be discontinued for several days before the withdrawal of clonidine.

Orloc Comp should be used with caution when myocardial depressants or inhibitors of AV conduction, such as certain calcium antagonists (particularly of the phenylalkylamine [verapamil] and benzothiazepine [diltiazem] classes), or antiarrhythmic agents, such as disopyramide, are used concurrently.

Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.

Orloc Comp USP

Concurrent use of rifampin increases the metabolic clearance of Orloc Comp, shortening its elimination half-life. However, initial dose modification is generally not necessary. Pharmacokinetic studies document no clinically relevant interactions with other agents given concomitantly, including thiazide diuretics and cimetidine. There was no effect of Orloc Comp on prothrombin times in patients on stable doses of warfarin.

Risk of Anaphylactic Reaction

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

Hydrochlorothiazide USP

When given concurrently the following drugs may interact with thiazide diuretics.

Alcohol, barbiturates or narcotics: potentiation of orthostatic hypotension may occur.

Antidiabetic drugs : dosage adjustment of the antidiabetic drug may be required.

Other antihypertensive drugs: additive effect or potentiation.

Cholestyramine and colestipol resins: Absorption of hydrochlorothiazide USP is impaired in the presence of anionic exchange resins. Single doses of cholestyramine and colestipol resins bind the hydrochlorothiazide USP and reduce its absorption in the gastrointestinal tract by up to 85% and 43%, respectively.

Corticosteroids, ACTH: Intensified electrolyte depletion, particularly hypokalemia.

Pressor amines (e.g., norepinephrine): possible decreased response to pressor amines but not sufficient to preclude their use.

Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine): possible increased responsiveness to the muscle relaxant.

Lithium: generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Refer to the package insert for lithium preparations before use of such preparations with Orloc Comp.

Nonsteroidal anti-inflammatory drugs: In some patients, the administration of a nonsteroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium sparing, and thiazide diuretics. Therefore, when Orloc Comp and non-steroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.

In patients receiving thiazides, sensitivity reactions may occur with or without a history of allergy or bronchial asthma. Photosensitivity reactions and possible exacerbation or activation of systemic lupus erythematosus have been reported in patients receiving thiazides. The antihypertensive effects of thiazides may be enhanced in the post-sympathectomy patient.

Laboratory Test Interactions

Based on reports involving thiazides, Orloc Comp may decrease serum levels of protein-bound iodine without signs of thyroid disturbance.

Because it includes a thiazide, Orloc Comp should be discontinued before carrying out tests for parathyroid function (see PRECAUTIONS, Parathyroid Disease).

Information For Patients

Patients, especially those with coronary artery disease, should be warned against discontinuing use of bisoprolol and hydrochlorothiazide without a physician’s supervision. Patients should also be advised to consult a physician if any difficulty in breathing occurs, or if they develop other signs or symptoms of congestive heart failure or excessive bradycardia. Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned that beta-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia, and Orloc Comp should be used with caution.

Patients should know how they react to this medicine before they operate automobiles and machinery or engage in other tasks requiring alertness. Patients should be advised that photosensitivity reactions have been reported with thiazides.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Orloc Comp

Long-term studies have not been conducted with the Orloc Comp combination.

Orloc Comp USP

Long-term studies were conducted with oral Orloc Comp administered in the feed of mice and rats (26 months). No evidence of carcinogenic potential was seen in mice dosed up to 250 mg/kg/day or rats dosed up to 125 mg/kg/day. On a body-weight basis, these doses are 625 and 312 times, respectively, the maximum recommended human dose (MRHD) of 20 mg, or 0.4 mg/kg/day, based on 50 kg individuals; on a body-surface-area basis, these doses are 59 times (mice) and 64 times (rats) the MRHD.

Hydrochlorothiazide USP

Two-year feeding studies in mice and rats, conducted under the auspices of the National Toxicology Program (NTP), treated mice and rats with doses of hydrochlorothiazide USP up to 600 mg/kg/day and 100 mg/kg/day, respectively. On a body-weight basis, these doses are 2,400 times (in mice) and 400 times (in rats) the MRHD of hydrochlorothiazide USP (12.5 mg/day) in Orloc Comp. On a body-surface-area basis, these doses are 226 times (in mice) and 82 times (in rats) the MRHD. These studies uncovered no evidence of carcinogenic potential of hydrochlorothiazide USP in rats or female mice, but there was equivocal evidence of hepatocarcinogenicity in male mice.

Mutagenesis

Orloc Comp

The mutagenic potential of the Orloc Comp combination was evaluated in the microbial mutagenicity test, the point mutation and chromosomal aberration assays in Chinese hamster V79 cells, and the micronucleus test in mice. There was no evidence of mutagenic potential in these in vitro and in vivo assays.

Orloc Comp USP

The mutagenic potential of Orloc Comp was evaluated in the microbial mutagenicity (Ames) test, the point mutation and chromosome aberration assays in Chinese hamster V79 cells, the unscheduled DNA synthesis test, the micronucleus test in mice, and the cytogenetics assay in rats. There was no evidence of mutagenic potential in these in vitro and in vivo assays.

Hydrochlorothiazide USP

Hydrochlorothiazide USP was not genotoxic in in vitro assays using strains TA 98, TA 100, TA 1535, TA 1537 and TA 1538 of Salmonella typhimurium ; in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations; or in in vivo assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) test and in the mouse Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide USP of 43 µg/mL to 1300 µg/mL. Positive test results were also obtained in the Aspergillus nidulans non-disjunction assay, using an unspecified concentration of hydrochlorothiazide USP.

Impairment of Fertility

Orloc Comp

Reproduction studies in rats did not show any impairment of fertility with the Orloc Comp combination doses containing up to 30 mg/kg/day of Orloc Comp USP in combination with 75 mg/kg/day of hydrochlorothiazide USP. On a body-weight basis, these doses are 75 and 300 times, respectively, the MRHD of Orloc Comp. On a body-surface-area basis, these study doses are 15 and 62 times, respectively, MRHD.

Orloc Comp USP

Reproduction studies in rats did not show any impairment of fertility at doses up to 150 mg/kg/day of Orloc Comp USP or 375 and 77 times the MRHD on the basis of body-weight and body-surface-area, respectively.

Hydrochlorothiazide USP

Hydrochlorothiazide USP had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 mg/kg/day and 4 mg/kg/day, respectively, prior to mating and throughout gestation. Corresponding multiples of maximum recommended human doses are 400 and 16 (rats) on the basis of body-weight and 38 (mice) and 3.3 (rats) on the basis of body-surface-area.

Pregnancy

Teratogenic Effects-Pregnancy Category C

Orloc Comp

In rats, the Orloc Comp combination was not teratogenic at doses up to 51.4 mg/kg/day of Orloc Comp in combination with 128.6 mg/kg/day of hydrochlorothiazide. Orloc Comp doses used in the rat study are, as multiples of the MRHD in the combination, 129 and 514 times greater, respectively, on a body-weight basis, and 26 and 106 times greater, respectively, on the basis of body-surface-area. The drug combination was maternotoxic (decreased body weight and food consumption) at B5.7/H14.3 (mg/kg/day) and higher, and fetotoxic (increased late resorptions) at B17.1/H42.9 (mg/kg/day) and higher. Maternotoxicity was present at 14/57 times the MRHD of B/H, respectively, on a body-weight basis, and 3/12 times the MRHD of B/H doses, respectively, on the basis of body-surface-area. Fetotoxicity was present at 43/172 times the MRHD of B/H, respectively, on a body-weight basis, and 9/35 times the MRHD of B/H doses, respectively, on the basis of body-surface-area. In rabbits, the B/H combination was not teratogenic at doses of B10/H25 (mg/kg/day). Orloc Comp used in the rabbit study were not teratogenic at 25/100 times the B/H MRHD, respectively, on a body-weight basis, and 10/40 times the B/H MRHD, respectively, on the basis of body-surface-area. The drug combination was maternotoxic (decreased body weight) at B1/H2.5 (mg/kg/day) and higher, and fetotoxic (increased resorptions) at B10/H25 (mg/kg/day). The multiples of the MRHD for the B/H combination that were maternotoxic are, respectively, 2.5/10 (on the basis of body-weight) and 1/4 (on the basis of body-surface-area), and for fetotoxicity were, respectively 25/100 (on the basis of body-weight) and 10/40 (on the basis of body-surface-area).

There are no adequate and well-controlled studies with Orloc Comp in pregnant women. Orloc Comp should be used during pregnancy only if the potential benefit justifies the risk to the fetus.

Orloc Comp USP

In rats, Orloc Comp USP was not teratogenic at doses up to 150 mg/kg/day, which were 375 and 77 times the MRHD on the basis of body-weight and body-surface area, respectively. Orloc Comp USP was fetotoxic (increased late resorptions) at 50 mg/kg/day and maternotoxic (decreased food intake and body-weight gain) at 150 mg/kg/day. The fetotoxicity in rats occurred at 125 times the MRHD on a body-weight basis and 26 times the MRHD on the basis of body-surface-area. The maternotoxicity occurred at 375 times the MRHD on a body-weight basis and 77 times the MRHD on the basis of body-surface-area. In rabbits, Orloc Comp USP was not teratogenic at doses up to 12.5 mg/kg/day, which is 31 and 12 times the MRHD based on body-weight and body-surface-area, respectively, but was embryolethal (increased early resorptions) at 12.5 mg/kg/day.

Hydrochlorothiazide USP

Hydrochlorothiazide USP was orally administered to pregnant mice and rats during respective periods of major organogenesis at doses up to 3000 mg/kg/day and 1000 mg/kg/day, respectively. At these doses, which are multiples of the MRHD equal to 12,000 for mice and 4,000 for rats, based on body-weight, and equal to 1,129 for mice and 824 for rats, based on body-surface-area, there was no evidence of harm to the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nonteratogenic Effects

Thiazides cross the placental barrier and appear in the cord blood. The use of thiazides in pregnant women requires that the anticipated benefit be weighed against possible hazards to the fetus. These hazards include fetal or neonatal jaundice, pancreatitis, thrombocytopenia, and possibly other adverse reactions that have occurred in the adult.

Nursing Mothers

Orloc Comp alone or in combination with hydrochlorothiazide has not been studied in nursing mothers. Thiazides are excreted in human breast milk. Small amounts of Orloc Comp have been detected in the milk of lactating rats. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness of Orloc Comp in pediatric patients have not been established.

Geriatric Use

In clinical trials, at least 270 patients treated with Orloc Comp plus hydrochlorothiazide were 60 years of age or older. Hydrochlorothiazide added significantly to the antihypertensive effect of bisoprolol in elderly hypertensive patients. No overall differences in effectiveness or safety were observed between these patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

ADVERSE REACTIONS

Orloc Comp

Bisoprolol fumarate/H6.25 mg is well tolerated in most patients. Most adverse effects have been mild and transient. In more than 65,000 patients treated worldwide with Orloc Comp, occurrences of bronchospasm have been rare. Discontinuation rates for AEs were similar for bisoprolol fumarate/H6.25 mg and placebo-treated patients.

In the United States, 252 patients received Orloc Comp (2.5 mg, 5 mg, 10 mg or 40 mg)/H6.25 mg and 144 patients received placebo in two controlled trials. In Study 1, Orloc Comp 5 mg/H6.25 mg was administered for 4 weeks. In Study 2, Orloc Comp 2.5 mg, 10 mg or 40 mg/H6.25 mg was administered for 12 weeks. All adverse experiences, whether drug related or not, and drug related adverse experiences in patients treated with Orloc Comp 2.5 mg to 10 mg/H6.25 mg, reported during comparable, 4 week treatment periods by at least 2% of bisoprolol fumarate/H6.25 mg-treated patients (plus additional selected adverse experiences) are presented in the following table:


Body System/

Adverse Experience


All Adverse

Experiences


Drug Related

Adverse Experiences


PlaceboCombined across studies.

(n=144)

%


B2.5-

40/H6.25

(n=252)

%


Placebo

(n=144)

%


B2.5-

10/H6.25

(n=221)

%


Cardiovascular

  • bradycardia
  • arrhythmia
  • peripheral ischemia
  • chest pain

0.7

1.4

0.9

0.7


1.1

0.4

0.7

1.8


0.7

0.0

0.9

0.7


0.9

0.0

0.4

0.9


Respiratory

  • bronchospasm
  • cough
  • rhinitis
  • URI

0.0

1.0

2.0

2.3


0.0

2.2

0.7

2.1


0.0

0.7

0.7

0.0


0.0

1.5

0.9

0.0


Body as a Whole

  • asthenia
  • fatigue
  • peripheral edema

0.0

2.7

0.7


0.0

4.6

1.1


0.0

1.7

0.7


0.0

3.0

0.9


Central Nervous System

  • dizziness
  • headache

1.8

4.7


5.1

4.5


1.8

2.7


3.2

0.4


Musculoskeletal

  • muscle cramps
  • myalgia

0.7

1.4


1.2

2.4


0.7

0.0


1.1

0.0


Psychiatric

  • insomnia
  • somnolence
  • loss of libido
  • impotence

2.4

0.7

1.2

0.7


1.1

1.1

0.4

1.1


2.0

0.7

1.2

0.7


1.2

0.9

0.4

1.1


Gastrointestinal

  • diarrhea
  • nausea
  • dyspepsia

1.4

0.9

0.7


4.3

1.1

1.2


1.2

0.9

0.7


1.1

0.9

0.9


Other adverse experiences that have been reported with the individual components are listed below.

Orloc Comp USP

In clinical trials worldwide, or in post-marketing experience, a variety of other AEs, in addition to those listed above, have been reported. While in many cases it is not known whether a causal relationship exists between bisoprolol and these AEs, they are listed to alert the physician to a possible relationship.

Central Nervous System: Unsteadiness, dizziness, vertigo, headache, syncope, paresthesia, hypoesthesia, hyperesthesia, sleep disturbance/vivid dreams, insomnia, somnolence, depression, anxiety/restlessness, decreased concentration/memory.

Cardiovascular: Bradycardia, palpitations and other rhythm disturbances, cold extremities, claudication, hypotension, orthostatic hypotension, chest pain, congestive heart failure, dyspnea on exertion.

Gastrointestinal: Gastric/epigastric/abdominal pain, peptic ulcer, gastritis, dyspepsia, nausea, vomiting, diarrhea, constipation, dry mouth.

Musculoskeletal: Arthralgia, muscle/joint pain, back/neck pain, muscle cramps, twitching/tremor.

Skin: Rash, acne, eczema, psoriasis, skin irritation, pruritus, purpura, flushing, sweating, alopecia, dermatitis, exfoliative dermatitis (very rarely), cutaneous vasculitis.

Special Senses: Visual disturbances, ocular pain/pressure, abnormal lacrimation, tinnitus, decreased hearing, earache, taste abnormalities.

Metabolic: Gout.

Respiratory : Asthma, bronchospasm, bronchitis, dyspnea, pharyngitis, rhinitis, sinusitis, URI (upper respiratory infection).

Genitourinary: Decreased libido/impotence, Peyronie’s disease (very rarely), cystitis, renal colic, polyuria.

General: Fatigue, asthenia, chest pain, malaise, edema, weight gain, angioedema.

In addition, a variety of adverse effects have been reported with other beta-adrenergic blocking agents and should be considered potential adverse effects:

Central Nervous System: Reversible mental depression progressing to catatonia, hallucinations, an acute reversible syndrome characterized by disorientation to time and place, emotional lability, slightly clouded sensorium.

Allergic: Fever, combined with aching and sore throat, laryngospasm, and respiratory distress.

Hematologic: Agranulocytosis, thrombocytopenia.

Gastrointestinal: Mesenteric arterial thrombosis and ischemic colitis.

Miscellaneous: The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with Orloc Comp during investigational use or extensive foreign marketing experience.

Hydrochlorothiazide USP

The following adverse experiences, in addition to those listed in the above table, have been reported with hydrochlorothiazide USP.

General: Weakness.

Central Nervous System: Vertigo, paresthesia, restlessness.

Cardiovascular: Orthostatic hypotension (may be potentiated by alcohol, barbiturates, or narcotics).

Gastrointestinal: Anorexia, gastric irritation, cramping, constipation, jaundice (intrahepatic cholestatic jaundice), pancreatitis, cholecystitis, sialadenitis, dry mouth.

Musculoskeletal: Muscle spasm.

Hypersensitive Reactions: Purpura, photosensitivity, rash, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), fever, respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions.

Special Senses: Transient blurred vision, xanthopsia.

Metabolic: Gout.

Genitourinary: Sexual dysfunction, renal failure, renal dysfunction, interstitial nephritis.

Skin: Erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis.

Laboratory Abnormalities

Orloc Comp

Because of the low dose of hydrochlorothiazide in Orloc Comp, adverse metabolic effects with bisoprolol fumarate/H6.25 mg are less frequent and of smaller magnitude than with hydrochlorothiazide 25 mg. Laboratory data on serum potassium from the U.S. placebo-controlled trials are shown in the following table:


PlaceboCombined across studies.


B2.5/

H6.25 mg

(n=28)


B5/

H6.25 mg

(n=149)


B10/

H6.25 mg

(n=28)


HCTZ

25 mg

(n=142)

Potassium
Mean ChangeMean change from baseline at Week 4.(mEq/L) +0.04 +0.11 -0.08 0.00 -0.30
HypokalemiaPercentage of patients with abnormality at Week 4. 0.0% 0.0% 0.7% 0.0% 5.5%

Treatment with both beta blockers and thiazide diuretics is associated with increases in uric acid. However, the magnitude of the change in patients treated with B/H 6.25 mg was smaller than in patients treated with hydrochlorothiazide 25 mg. Mean increases in serum triglycerides were observed in patients treated with Orloc Comp 6.25 mg. Total cholesterol was generally unaffected, but small decreases in HDL cholesterol were noted. Other laboratory abnormalities that have been reported with the individual components are listed below.

Orloc Comp USP

In clinical trials, the most frequently reported laboratory change was an increase in serum triglycerides, but this was not a consistent finding. Sporadic liver test abnormalities have been reported. In the U.S. controlled trials experience with Orloc Comp treatment for 4 to 12 weeks, the incidence of concomitant elevations in SGOT and SGPT from 1 to 2 times normal was 3.9%, compared to 2.5% for placebo. No patient had concomitant elevations greater than twice normal.

In the long-term, uncontrolled experience with Orloc Comp treatment for 6 to 18 months, the incidence of one or more concomitant elevations in SGOT and SGPT from 1 to 2 times normal was 6.2%. The incidence of multiple occurrences was 1.9%. For concomitant elevations in SGOT and SGPT of greater than twice normal, the incidence was 1.5%. The incidence of multiple occurrences was 0.3%. In many cases these elevations were attributed to underlying disorders, or resolved during continued treatment with Orloc Comp. Other laboratory changes included small increases in uric acid, creatinine, BUN, serum potassium, glucose, and phosphorus and decreases in WBC and platelets. There have been occasional reports of eosinophilia. These were generally not of clinical importance and rarely resulted in discontinuation of Orloc Comp.

As with other beta-blockers, ANA conversions have also been reported on Orloc Comp. About 15% of patients in long-term studies converted to a positive titer, although about one-third of these patients subsequently reconverted to a negative titer while on continued therapy.

Hydrochlorothiazide USP

Hyperglycemia, glycosuria, hyperuricemia, hypokalemia and other electrolyte imbalances (see PRECAUTIONS ), hyperlipidemia, hypercalcemia, leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia, and hemolytic anemia have been associated with hydrochlorothiazide therapy.

OVERDOSAGE

There are limited data on overdose with Orloc Comp. However, several cases of overdose with Orloc Comp have been reported (maximum: 2000 mg). Bradycardia and/or hypotension were noted. Sympathomimetic agents were given in some cases, and all patients recovered.

The most frequently observed signs expected with overdosage of a beta-blocker are bradycardia and hypotension. Lethargy is also common, and with severe overdoses, delirium, coma, convulsions, and respiratory arrest have been reported to occur. Congestive heart failure, bronchospasm, and hypoglycemia may occur, particularly in patients with underlying conditions. With thiazide diuretics, acute intoxication is rare. The most prominent feature of overdose is acute loss of fluid and electrolytes. Signs and symptoms include cardiovascular (tachycardia, hypotension, shock), neuromuscular (weakness, confusion, dizziness, cramps of the calf muscles, paresthesia, fatigue, impairment of consciousness), gastrointestinal (nausea, vomiting, thirst), renal (polyuria, oliguria, or anuria [due to hemoconcentration]), and laboratory findings (hypokalemia, hyponatremia, hypochloremia, alkalosis, increased BUN [especially in patients with renal insufficiency]).

If overdosage of Orloc Comp is suspected, therapy with bisoprolol and hydrochlorothiazide should be discontinued and the patient observed closely. Treatment is symptomatic and supportive; there is no specific antidote. Limited data suggest Orloc Comp is not dialyzable; similarly, there is no indication that hydrochlorothiazide USP is dialyzable. Suggested general measures include induction of emesis and/or gastric lavage, administration of activated charcoal, respiratory support, correction of fluid and electrolyte imbalance, and treatment of convulsions. Based on the expected pharmacologic actions and recommendations for other beta-blockers and hydrochlorothiazide USP, the following measures should be considered when clinically warranted:

Bradycardia: Administer IV atropine. If the response is inadequate, isoproterenol or another agent with positive chronotropic properties may be given cautiously. Under some circumstances, transvenous pacemaker insertion may be necessary.

Hypotension, Shock: The patient’s legs should be elevated. IV fluids should be administered and lost electrolytes (potassium, sodium) replaced. Intravenous glucagon may be useful. Vasopressors should be considered.

Heart Block (second or third degree): Patients should be carefully monitored and treated with isoproterenol infusion or transvenous cardiac pacemaker insertion, as appropriate.

Congestive Heart Failure: Initiate conventional therapy (i.e., digitalis, diuretics, vasodilating agents, inotropic agents).

Bronchospasm: Administer a bronchodilator such as isoproterenol and/or aminophylline.

Hypoglycemia: Administer IV glucose.

Surveillance: Fluid and electrolyte balance (especially serum potassium) and renal function should be monitored until normalized.

DOSAGE AND ADMINISTRATION

Bisoprolol is an effective treatment of hypertension in once-daily doses of 2.5 mg to 40 mg, while hydrochlorothiazide is effective in doses of 12.5 mg to 50 mg. In clinical trials of bisoprolol/hydrochlorothiazide combination therapy using bisoprolol doses of 2.5 mg to 20 mg and hydrochlorothiazide doses of 6.25 mg to 25 mg, the antihypertensive effects increased with increasing doses of either component.

The adverse effects (see WARNINGS ) of bisoprolol are a mixture of dose-dependent phenomena (primarily bradycardia, diarrhea, asthenia, and fatigue) and dose-independent phenomena (e.g., occasional rash); those of hydrochlorothiazide are a mixture of dose-dependent phenomena (primarily hypokalemia) and dose-independent phenomena (e.g., possibly pancreatitis); the dose-dependent phenomena for each being much more common than the dose-independent phenomena. The latter consist of those few that are truly idiosyncratic in nature or those that occur with such low frequency that a dose relationship may be difficult to discern. Therapy with a combination of bisoprolol and hydrochlorothiazide will be associated with both sets of dose-independent adverse effects, and to minimize these, it may be appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy. On the other hand, regimens that combine low doses of bisoprolol and hydrochlorothiazide should produce minimal dose-dependent adverse effects, e.g., bradycardia, diarrhea, asthenia and fatigue, and minimal dose-dependent adverse metabolic effects, i.e., decreases in serum potassium.

Therapy Guided by Clinical Effect: A patient whose blood pressure is not adequately controlled with 2.5 mg to 20 mg bisoprolol daily may instead be given Orloc Comp. Patients whose blood pressures are adequately controlled with 50 mg of hydrochlorothiazide USP daily, but who experience significant potassium loss with this regimen, may achieve similar blood pressure control without electrolyte disturbance if they are switched to Orloc Comp.

Initial Therapy: Antihypertensive therapy may be initiated with the lowest dose of Orloc Comp, one 2.5 mg/6.25 mg tablet once daily. Subsequent titration (14 day intervals) may be carried out with Orloc Comp up to the maximum recommended dose 20 mg/12.5 mg (two 10 mg/6.25 mg tablets) once daily, as appropriate.

Replacement Therapy: The combination may be substituted for the titrated individual components.

Cessation of Therapy: If withdrawal of Orloc Comp therapy is planned, it should be achieved gradually over a period of about 2 weeks. Patients should be carefully observed.

Patients with Renal or Hepatic Impairment: As noted in the WARNINGS section, caution must be used in dosing/titrating patients with hepatic impairment or renal dysfunction. Since there is no indication that hydrochlorothiazide USP is dialyzable, and limited data suggest that bisoprolol is not dialyzable, drug replacement is not necessary in patients undergoing dialysis.

Geriatric Patients: Dosage adjustment on the basis of age is not usually necessary, unless there is also significant renal or hepatic dysfunction (see above and WARNINGS section).

Pediatric Patients: There is no pediatric experience with Orloc Comp.

HOW SUPPLIED

Orloc Comp Tablets, for oral administration, are available as:

2.5 mg/6.25 mg: Round, convex, orange, film-coated tablets, plain on one side and debossed "E" over "701" on the other side and supplied as:

NDC 0185-0701-30 bottles of 30

NDC 0185-0701-01 bottles of 100

NDC 0185-0701-05 bottles of 500

5 mg/6.25 mg: Round, convex, red, film-coated tablets, plain on one side and debossed "E" over "704" on the other side and supplied as:

NDC 0185-0704-30 bottles of 30

NDC 0185-0704-01 bottles of 100

NDC 0185-0704-05 bottles of 500

10 mg/6.25 mg: Round, convex, white, film-coated tablets, plain on one side and debossed "E" over "707" on the other side and supplied as:

NDC 0185-0707-30 bottles of 30

NDC 0185-0707-01 bottles of 100

NDC 0185-0707-05 bottles of 500

Store at 20° to 25°C (68° to 77°F).

To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Sandoz Inc.

Princeton, NJ 08540

OS7596

Rev. 05/11

MF0701REV05/11

MG #16359

Bisoprolol Fumarate/Hctz 5/6.25 Tablet

Chemical Structure 1 Chemical Structure 2

Orloc Comp pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Orloc Comp available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Orloc Comp destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Orloc Comp Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Orloc Comp pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."HYDROCHLOROTHIAZIDE TABLET [QUALITEST PHARMACEUTICALS]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."BISOPROLOL FUMARATE TABLET [BRYANT RANCH PREPACK]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. Dailymed."AMLODIPINE BESYLATE; HYDROCHLOROTHIAZIDE; OLMESARTAN MEDOXOMIL: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Orloc Comp?

Depending on the reaction of the Orloc Comp after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Orloc Comp 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 Orloc Comp 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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Review

sdrugs.com conducted a study on Orloc Comp, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Orloc Comp consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Arunabha Ray, MD Pharmacology

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