Getz Pharma


Getz Pharma
Full Prescribing Info
Candesartan cilexetil.
Each tablet contains candesartan cilexetil 8 mg or 16 mg.
Candesartan cilexetil, a prodrug, is hydrolyzed to candesartan during absorption from the gastrointestinal tract. Candesartan is a selective AT1 subtype angiotensin II receptor blocker.
Candesartan cilexetil, a nonpeptide, is chemically described as 1-(cyclohexyloxycarbonyloxy)ethyl 1-((2’-(1H-tetrazol-5yl)biphenyl-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate.
Its molecular formula is C33H34N6O6.
Angiotensin II receptor blocker.
Mechanism of Action: Candesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues eg, vascular smooth muscle and the adrenal gland. Its action is, therefore, independent of the pathways for angiotensin II synthesis. There is also an AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. Candesartan has much greater affinity (>10,000-fold) for the AT1 receptor than for the AT2 receptor.
Blockade of the renin-angiotensin system with angiotensin-converting enzyme (ACE) inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. Angiotensin-converting enzyme 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.
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.
Pharmacokinetics: Absorption: Atasart is rapidly and completely bioactivated by ester hydrolysis during absorption from the gastrointestinal tract to candesartan, a selective AT1 subtype angiotensin II receptor blocker. Following administration of Atasart, the absolute bioavailability of candesartan was estimated to be 15%. After tablet ingestion, the peak serum concentration (Cmax) is reached after 3-4 hrs. Food with a high fat content does not affect the bioavailability of candesartan after Atasart administration.
Metabolism: Candesartan undergoes minor hepatic metabolism by O-deethylation to an inactive metabolite.
Distribution: After single and repeated administration, the pharmacokinetics of candesartan is linear for oral doses up to Atasart 32 mg. Candesartan and its inactive metabolite do not accumulate in serum upon repeated once-daily dosing. 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.
Excretion: When candesartan is administered orally, about 26% of the dose is excreted unchanged in urine. Total plasma clearance of candesartan is 0.37 mL/min/kg, with a renal clearance of 0.19 mL/min/kg. The elimination half-life (t½) of candesartan is approximately 9 hrs.
Special Populations: Pediatric: The pharmacokinetics of Atasart have not been investigated in patients <18 years.
Geriatric: The pharmacokinetics of candesartan had been studied in the elderly (>65 years) and in both genders. The plasma concentration of candesartan was higher in the elderly [Cmax was approximately 50% higher, and area under the concetration-time curve (AUC) was approximately 80% higher] compared to younger subjects administered with 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.
Renal Insufficiency: In hypertensive patients with renal insufficiency, serum concentrations of candesartan were elevated. After repeated dosing, the AUC and Cmax were approximately doubled in patients with severe renal impairment [creatinine clearance (CrCl) <30 mL/min/1.73 m2] 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. No initial dosage adjustment is necessary in patients with mild renal insufficiency.
Hepatic Insufficiency: The pharmacokinetics of candesartan were compared in patients with mild and moderate hepatic impairment to match healthy volunteers following a single oral dose of Atasart 16 mg. The increase in AUC for candesartan was 30% in patients with mild hepatic impairment (Child-Pugh A) and 145% in patients with moderate hepatic impairment (Child-Pugh B). The increase in Cmax for candesartan was 56% in patients with mild hepatic impairment and 73% in patients with moderate hepatic impairment. The pharmacokinetics after Atasart administration had not been investigated in patients with severe hepatic impairment.
Treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.
Dosage/Direction for Use
Dosage must be individualized. Blood pressure response is dose-related over the range of 2-32 mg. The usual recommended starting dose is 16 mg once daily when it is used as monotherapy in patients who are not volume-depleted.
Atasart can be administered once or twice daily with total daily doses ranging from 8-32 mg. Larger doses do not appear to have a greater effect, and there is relatively little experience with such doses. Most of the antihypertensive effect is present within 2 weeks and maximal blood pressure reduction is generally obtained within 4-6 weeks of treatment with Atasart. If blood pressure is not controlled by Atasart alone, a diuretic may be added.
May be administered with other antihypertensive agents. Therapy should be adjusted according to blood pressure response.
Patients with Hepatic Impairment: In patients with moderate hepatic impairment, consideration should be given to initiation of Atasart at a lower dose. No initial dose adjustment is necessary in patients with mild hepatic impairment.
Volume-depleted Patients: For patients with possible depletion of intravascular volume (eg, patients treated with diuretics, particularly those with impaired renal function), consideration should be given to initiation of Atasart at a lower dose.
Administration: Atasart my be administered with or without food.
The most likely manifestation of overdosage with Atasart would be hypotension, dizziness and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted. Candesartan cannot be removed by hemodialysis.
Hypersensitivity to candesartan or to any of the excipients of Atasart. Severe hepatic impairment and/or cholestasis.
Avoid drinking alcohol. It can lower blood pressure and may increase some of the adverse effects of Atasart.
Special Precautions
Hypotension in Volume- and Salt-Depleted Patients: In patients with an activated renin-angiotensin system eg, volume and/or salt-depleted patients (eg, those being treated with diuretics), symptomatic hypotension may occur. These conditions should be corrected prior to administration of Atasart, or the treatment should start under close medical supervision.
If hypotension occurs, the patients should be placed in the supine position and, if necessary, given an IV infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.
Impaired Renal Function: As a consequence of inhibiting the renin angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals treated with Atasart. Caution should be made while using this medication.
In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen (BUN) have been reported. There has been no long-term use of Atasart in patients with unilateral or bilateral renal artery stenosis, but similar results may be expected.
Use in lactation: It is not known whether candesartan is excreted in human milk but because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Use In Pregnancy & Lactation
Use in lactation: It is not known whether candesartan is excreted in human milk but because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Adverse Reactions
In general, treatment with Atasart was well-tolerated. However, the adverse effects reported with candesartan are usually mild and transient including headache and dizziness. Potentially important adverse events that have been reported, whether or not attributed to treatment, with an incidence of 0.5% cannot be determined whether these events were causally related to Atasart. Body as a Whole: Asthenia, fever.
Central and Peripheral Nervous System: Paresthesia, vertigo.
Gastrointestinal System Disorders: Dyspepsia, gastroenteritis.
Heart Rate and Rhythm Disorders: Tachycardia, palpitation.
Metabolic and Nutritional Disorders: Increased creatinine phosphokinase, hyperglycemia, hypertriglyceridemia, hyperuricemia.
Musculoskeletal System Disorders: Myalgia.
Platelet/Bleeding-Clotting Disorders: Epistaxis.
Psychiatric Disorders: Anxiety, depression, somnolence.
Respiratory System Disorders: Dyspnea.
If symptomatic hypotension should occur, symptomatic treatment should be instituted and vital signs monitored. The patient should be placed supine with the legs elevated. If this is not sufficient, plasma volume should be increased by infusion of eg, isotonic saline solution. Sympathomimetic medicinal products may by administered if the above mentioned measures are not sufficient.
Drug Interactions
Because candesartan is not significantly metabolized by the cytochrome P450 (CYP450) 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.
No significant drug interactions have been reported in studies of Atasart given with other drugs eg, glyburide, nifedipine, digoxin, warfarin, hydrochlorothiazide and oral contraceptives in healthy volunteers.
Since both ACE inhibitors and angiotensin receptor blockers can increase the concentrations of potassium in the blood, other medications that can increase the concentration of potassium in the blood eg, spironolactone and potassium supplements, should be used cautiously with candesartan.
Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors and with some angiotensin II receptor blockers. An increase in serum lithium concentration has been reported during concomitant administration of lithium with Atasart, so careful monitoring of serum lithium levels is recommended during concomitant use.
Store at temperatures not exceeding 30°C. Protect from light and moisture.
Shelf-Life: 36 months.
ATC Classification
C09CA06 - candesartan ; Belongs to the class of angiotensin II receptor blockers (ARBs). Used in the treatment of cardiovascular disease.
Tab 8 mg x 14's. 16 mg x 28's.
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