Get your patient on Candesartan Cilexetil And Hydrochlorothiazide - Candesartan Cilexetil And Hydrochlorothiazide tablet (Candesartan Cilexetil And Hydrochlorothiazide)

Candesartan cilexitil and hydrochlorothiazide tablets are indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the class to which this drug principally belongs. There are no controlled trials demonstrating risk reduction with Candesartan cilexitil and hydrochlorothiazide tablets.
Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).
Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.
Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.
Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.
This fixed dose combination is not indicated for initial therapy (see DOSAGE AND ADMINISTRATION ).

The usual recommended starting dose of candesartan cilexetil is 16 mg once daily when it is used as monotherapy in patients who are not volume depleted. Candesartan cilexetil can be administered once or twice daily with total daily doses ranging from 8 mg to 32 mg. Patients requiring further reduction in blood pressure should be titrated to 32 mg. Doses larger than 32 mg do not appear to have a greater blood pressure lowering effect.

Hydrochlorothiazide is effective in doses of 12.5 to 50 mg once daily.

Use in Renal Impairment: Dosing recommendations for candesartan cilexetil and hydrochlorothiazide in patients with creatinine clearance < 30 mg/min cannot be provided (see SPECIAL POPULATIONS, Renal Insufficiency ).

Use in moderate to severe Hepatic Impairment: Candesartan cilexetil and hydrochlorothiazide is not recommended for initiation because the appropriate starting dose, 8 mg, cannot be given. (see SPECIAL POPULATIONS, Hepatic Insufficiency ).

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

Dose Titration by Clinical Effect: A patient whose blood pressure is not controlled on 25 mg of hydrochlorothiazide once daily can expect an incremental effect from candesartan cilexetil and hydrochlorothiazide tablets 16 mg/12.5 mg. A patient whose blood pressure is controlled on 25 mg of hydrochlorothiazide but is experiencing decreases in serum potassium can expect the same or incremental blood pressure effects from candesartan cilexetil and hydrochlorothiazide tablets 16 mg/12.5 mg and serum potassium may improve.

A patient whose blood pressure is not controlled on 32 mg of candesartan cilexetil can expect incremental blood pressure effects from candesartan cilexetil and hydrochlorothiazide tablets 32 mg/12.5 mg and then 32 mg/25 mg. The maximal antihypertensive effect of any dose of candesartan cilexetil and hydrochlorothiazide tablets can be expected within 4 weeks of initiating that dose.

Candesartan cilexetil and hydrochlorothiazide tablets may be administered with other antihypertensive agents.

Candesartan cilexetil and hydrochlorothiazide tablets may be administered with or without food.

Candesartan cilexetil and hydrochlorothiazide tablets are contraindicated in patients who are hypersensitive to candesartan, to hydrochlorothiazide or to other sulfonamide-derived drugs.
Do not co-administer aliskiren with candesartan cliexetil and hydrochlorothiazide in patients with diabetes (See PRECAUTIONS, Drug Interactions ).
Candesartan cliexetil and hydrochlorothiazide is contraindicated in patients with anuria.

Candesartan Cilexetil-Hydrochlorothiazide

Candesartan cilexitil and hydrochlorothiazide tablets has been evaluated for safety in more than 2800 patients treated for hypertension. More than 750 of these patients were studied for at least six months and more than 500 patients were treated for at least one year. Adverse experiences have generally been mild and transient in nature and have only infrequently required discontinuation of therapy. The overall incidence of adverse events reported with candesartan cilexitil and hydrochlorothiazide tablets was comparable to placebo. The overall frequency of adverse experiences was not related to dose, age, gender, or race.

In placebo-controlled trials that included 1089 patients treated with various combinations of candesartan cilexetil (doses of 2 mg to 32 mg) and hydrochlorothiazide (doses of 6.25 mg -25 mg) and 592 patients treated with placebo, adverse events, whether or not attributed to treatment, occurring in greater than 2% of patients treated with candesartan cilexitil and hydrochlorothiazide tablets and that were more frequent for candesartan cilexitil and hydrochlorothiazide tablets than placebo were:
Respiratory System Disorder: upper respiratory tract infection (3.6% vs 3.0%);

Body as a Whole: back pain (3.3% vs 2.4%); influenza-like symptoms (2.5% vs 1.9%);
Central/Peripheral Nervous System:

dizziness (2.9% vs 1.2%).

Post-Marketing Experience
The following have been very rarely reported in post-marketing experience with candesartan cilexetil:

Digestive: Abnormal hepatic function and hepatitis.

Hematologic: Neutropenia, leukopenia, and agranulocytosis.

Immunologic: Angioedema

Metabolic and Nutritional Disorders: Hyperkalemia, hyponatremia.

Respiratory System Disorders: Cough

Skin and Appendages Disorders: Pruritus, rash and urticaria.

Rare reports of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.

Hydrochlorothiazide

Other adverse experiences that have been reported with hydrochlorothiazide, without regard to causality, are listed below:

Gastrointestinal: pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, constipation, gastric irritation, anorexia

Hematologic: aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia

Hypersensitivity: anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress including pneumonitis and pulmonary edema, photosensitivity, urticaria, purpura

Musculoskeletal: muscle spasm

Non-melanoma Skin Cancer : Hydrochlorothiazide is associated with an increased risk of nonmelanoma skin cancer. In a study conducted in the Sentinel System, increased risk was predominantly for squamous cell carcinoma (SCC) and in white patients taking large cumulative doses. The increased risk for SCC in the overall population was approximately 1 additional case per 16,000 patients per year, and for white patients taking a cumulative dose of ≥50,000 mg the risk increase was approximately 1 additional SCC case for every 6,700 patients per year.

Skin: erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis, alopecia

Special Senses: transient blurred vision, xanthopsia

Urogenital: impotence.

Because candesartan is not significantly metabolized by the cytochrome P450 system and at therapeutic concentrations has no effects on P450 enzymes, interactions with drugs that inhibit or are metabolized by those enzymes would not be expected.

Interactions common to both Candesartan Cilexetil and Hydrochlorothiazide

Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including candesartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving candesartan and NSAID therapy.

The antihypertensive effect of angiotensin II receptor antagonists, including candesartan may be attenuated by NSAIDs including selective COX-2 inhibitors.

Lithium − Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists or hydrochlorothiazide. Monitor serum lithium levels during concomitant use.

Interactions with Candesartan Cilexetil

Dual Blockade of the Renin-Angiotensin System (RAS)

Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on candesartan cilexetil and hydrochlorothiazide and other agents that affect the RAS.

Coadministration of candesartan cilexetil and hydrochlorothiazide with potassium sparing diuretics, potassium supplements, potassium-containing salt substitutes or other drugs that raise serum potassium levels may result in hyperkalemia. Monitor serum potassium in such patients.

Do not co-administer aliskiren with candesartan cilexetil and hydrochlorothiazide in patients with diabetes. Avoid use of aliskiren with candesartan cilexetil and hydrochlorothiazide in patients with renal impairment (GFR <60 ml/min) (see CONTRAINDICATIONS ).

Interactions with Hydrochlorothiazide
Alcohol, barbiturates, or narcotics - Potentiation of orthostatic hypotension may occur.

Antidiabetic drugs (oral agents and insulin) - Dosage adjustment of the antidiabetic drug may be required.

Diazoxide - the hyperglycemic effect of diazoxide may be enhanced by thiazides.

Ion Exchange resins - Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively. Stagger the dosage of hydrochlorothiazide and ion exchange resins such that hydrochlorothiazide is administered at least 4 hours before or 4-6 hours after the administration of resins.

Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine) - Possible increased responsiveness to muscle relaxants such as curare derivatives.

Digitalis - Thiazide-induced hypokalemia or hypomagnesemia may predispose to digoxin toxicity.

Noradrenaline - Thiazides may decrease arterial responsiveness to noradrenaline, but not enough to preclude effectiveness of the pressor agent for therapeutic use.

Steroids or Adrenocorticotropic Hormone - Hypokalemia may develop during concomitant use of steroids or adrenocorticotropic hormone (ACTH).

Cytotoxic products - Thiazides may reduce the renal excretion of cytotoxic medicinal products (e.g. cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects.

Cyclosporine - Concomitant treatment with cyclosporine may increase the risk of hyperuricemia and gout-type complications.

Candesartan cilexetil and hydrochlorothiazide tablets combines an angiotensin II receptor (type AT ₁ ) antagonist and a diuretic, hydrochlorothiazide.

Candesartan cilexetil, USP a nonpeptide, is chemically described as (±)-1-Hydroxyethyl 2-ethoxy-1-[ p -( o -1 H -tetrazol-5- ylphenyl)benzyl]-7-benzimidazolecarboxylate, cyclohexyl carbonate (ester).

Its empirical formula is C ₃₃ H ₃₄ N ₆ O ₆ , and its structural formula is

Candesartan cilexetil USP is a white to off-white powder with a molecular weight of 610.67. It is practically insoluble in water and sparingly soluble in methanol. Candesartan cilexetil USP is a racemic mixture containing one chiral center at the cyclohexyloxycarbonyloxy ethyl ester group. Following oral administration, candesartan cilexetil USP undergoes hydrolysis at the ester link to form the active drug, candesartan, which is achiral.

Hydrochlorothiazide USP is 6-chloro-3,4-dihydro-2 H -1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C ₇ H ₈ ClN ₃ O ₄ S ₂ and its structural formula is

Hydrochlorothiazide USP is a white, or practically white, crystalline powder with a molecular weight of 297.72, which is slightly soluble in water, but freely soluble in sodium hydroxide solution.

Candesartan cilexitil and hydrochlorothiazide tablets are available for oral administration in three tablet strengths of candesartan cilexetil USP and hydrochlorothiazide USP.

Candesartan cilexetil and hydrochlorothiazide tablets 16 mg/12.5 mg contain 16 mg of candesartan cilexetil USP and 12.5 mg of hydrochlorothiazide USP.

Candesartan cilexetil and hydrochlorothiazide tablets 32 mg/12.5 mg contain 32 mg of candesartan cilexetil USP and 12.5 mg of hydrochlorothiazide USP.

Candesartan cilexetil and hydrochlorothiazide tablets 32 mg/25 mg contain 32 mg of candesartan cilexetil USP and 25 mg of hydrochlorothiazide USP.

The inactive ingredients of the tablets are carboxymethylcellulose calcium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, corn starch, glycerin, and ferric oxide (yellow). Ferric oxide (red) is also added to the 16 mg/12.5 mg and 32 mg/25 mg tablets as colorant.

Mechanism of Action

Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II).

Angiotensin II is the principal pressor agent of the renin -angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Candesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT ₁ receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is, therefore, independent of the pathways for angiotensin II synthesis.

There is also an AT ₂ receptor found in many tissues, but AT ₂ is not known to be associated with cardiovascular homeostasis. Candesartan has much greater affinity (>10,000- fold) for the AT ₁ receptor than for the AT ₂ receptor.

Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because candesartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Candesartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of candesartan on blood pressure.

Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so co-administration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with these diuretics.

The mechanism of the antihypertensive effect of thiazides is unknown.

Pharmacokinetics
General
Candesartan Cilexetil
Candesartan cilexetil is rapidly and completely bioactivated by ester hydrolysis during absorption from the gastrointestinal tract to candesartan, a selective AT ₁ subtype angiotensin II receptor antagonist. Candesartan is mainly excreted unchanged in urine and feces (via bile). It undergoes minor hepatic metabolism by O-deethylation to an inactive metabolite. The elimination half-life of candesartan is approximately 9 hours. After single and repeated administration, the pharmacokinetics of candesartan are linear for oral doses up to 32 mg of candesartan cilexetil. Candesartan and its inactive metabolite do not accumulate in serum upon repeated once-daily dosing.
Following administration of candesartan cilexetil, the absolute bioavailability of candesartan was estimated to be 15%. After tablet ingestion, the peak serum concentration (C _max ) is reached after 3 to 4 hours. Food with a high fat content does not affect the bioavailability of candesartan after candesartan cilexetil administration.

Hydrochlorothiazide
When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours.

Metabolism and Excretion
Candesartan Cilexetil
Total plasma clearance of candesartan is 0.37 mL/min/kg, with a renal clearance of 0.19 mL/min/kg. When  candesartan is administered orally, about 26% of the dose is excreted unchanged in urine. Following an oral dose of ¹⁴ C-labeled candesartan cilexetil, approximately 33% of radioactivity is recovered in urine and approximately 67% in feces. Following an intravenous dose of ¹⁴ C-labeled candesartan, approximately 59% of radioactivity is recovered in urine and approximately 36% in feces. Biliary excretion contributes to the elimination of candesartan.

Hydrochlorothiazide:
Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. At least 61% of the oral dose is eliminated unchanged within 24 hours.

Distribution
Candesartan Cilexetil
The volume of distribution of candesartan is 0.13 L/kg. Candesartan is highly bound to plasma proteins (>99%) and does not penetrate red blood cells. The protein binding is constant at candesartan plasma concentrations well above the range achieved with recommended doses. In rats, it has been demonstrated that candesartan crosses the blood-brain barrier poorly, if at all. It has also been demonstrated in rats that candesartan passes across the placental barrier and is distributed in the fetus.

Hydrochlorothiazide
Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.

Special Populations

Pediatric
The pharmacokinetics of candesartan cilexetil have not been investigated in patients <18 years of age.

Geriatric
The pharmacokinetics of candesartan have been studied in the elderly (≥65 years). The plasma concentration of candesartan was higher in the elderly (C _max was approximately 50% higher, and AUC was approximately 80% higher) compared to younger subjects administered the same dose. The pharmacokinetics of candesartan were linear in the elderly, and candesartan and its inactive metabolite did not accumulate in the serum of these subjects upon repeated, once-daily administration. No initial dosage adjustment is necessary. (See DOSAGE AND ADMINISTRATION .)

Gender
There is no difference in the pharmacokinetics of candesartan between male and female subjects.

Renal Insufficiency
In hypertensive patients with renal insufficiency, serum concentrations of candesartan were elevated. After repeated dosing, the AUC and C _max were approximately doubled in patients with severe renal impairment (creatinine clearance <30 mL/min/1.73m ² ) compared to patients with normal kidney function. The pharmacokinetics of candesartan in hypertensive patients undergoing hemodialysis are similar to those in hypertensive patients with severe renal impairment. Candesartan cannot be removed by hemodialysis.
Thiazide diuretics are eliminated by the kidney, with a terminal half-life of 5-15 hours. In a study of patients with impaired renal function (mean creatinine clearance of 19 mL/min), the half-life of hydrochlorothiazide elimination was lengthened to 21 hours. (See DOSAGE AND ADMINISTRATION .)
Safety and effectiveness of candesartan cilexetil and hydrochlorothiazide in patients with severe renal impairment (CrCL ≤30 ml/min) have not been established. No dose adjustment is required in patients with mild CrCL 60-90 ml/min) or moderate (CrCL 30-60) renal impairment.

Hepatic Insufficiency
The pharmacokinetics of candesartan were compared in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment to matched healthy volunteers following a single dose of 16 mg candesartan cilexetil. The AUC for candesartan in patients with mild and moderate hepatic impairment was increased 30% and 145% respectively. The C _max for candesartan was increased 56% and 73% respectively. The pharmacokinetics of candesartan in severe hepatic impairment have not been studied. No dose adjustment is recommended for patients with mild hepatic impairment. In patients with moderate hepatic impairment, candesartan cilexetil and hydrochlorothiazide tablets are not recommended for initiation because the appropriate starting dose, 8 mg, cannot be given. (See DOSAGE AND ADMINISTRATION ).
Monitor patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

Candesartan cilexetil and hydrochlorothiazide tablets 16 mg/12.5 mg , are Pink, oval, biconvex, uncoated tablets debossed with "ML 71" on one side and break line on both sides They are supplied as follows:

NDC 33342-131-12 unit dose package of 100

NDC 33342-131-10 bottle of 90

NDC 33342-131-51 bottle of 300
NDC 33342-131-15 bottle of 500

Candesartan cilexetil and hydrochlorothiazide tablets 32 mg/12.5 mg , are Yellow oval, biconvex, uncoated tablets debossed with "ML 58" on one side and break line on both sides. They are supplied as follows:

NDC 33342-132-12 unit dose package of 100

NDC 33342-132-10 bottle of 90

NDC 33342-132-51 bottle of 300
NDC 33342-132-15 bottle of 500

Candesartan cilexetil and hydrochlorothiazide tablets 32 mg/25 mg , are Pink, oval, biconvex, uncoated tablets debossed with "ML 57" on one side and break line on both sides. They are supplied as follows:

NDC 33342-133-12 unit dose package of 100

NDC 33342-133-10 bottle of 90

NDC 33342-133-51 bottle of 300
NDC 33342-133-15 bottle of 500

Storage:
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature]. Keep container tightly closed.

Manufactured for :
Macleods Pharma USA, Inc.
Princeton, NJ 08540

Manufactured by :
Macleods Pharmaceuticals Ltd.
Daman (U.T.), INDIA



Rev: 10/2022