Candesar 16

Candesar 16 which contains Candesartan 16 mg belonging to the Angiotensin II Receptor Blocker acts as an antihypertensive agent and is approved for use in the following clinical indications:

• Hypertension

Candesar 16 is indicated for the treatment of hypertension in adults and as well as for children above 1 years of age, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. Candesar 16 may be used alone or in combination with other antihypertensive agents.

• Heart Failure

Candesar 16 is indicated for the treatment of heart failure (NYHA class II-IV) in adults with left ventricular systolic dysfunction (ejection fraction ≤ 40%) to reduce cardiovascular death and to reduce heart failure hospitalizations. CANDESAR 16 also has an added effect on these outcomes when used with an ACE inhibitor.

Although not approved, there have been certain off-label indications. These include:

• Cerebrovascular accident or stroke

Long-term treatment with inhibitors of the renin–angiotensin system, Candesar 16 has been shown to reduce the risks of cognitive impairment and low quality of life after stroke.

• Diabetic nephropathy

The optimal dose of Candesartan is 16mg daily for renoprotection, as reflected by a short-term reduction in albuminuria, in hypertensive type 2 diabetic patients with nephropathy.

• Left ventricular hypertrophy

Candesar 16 use was associated with significant regression of LV hypertrophy, and improvement of LV function, symptoms, and exercise tolerance.

• Migraine

The mechanism of action of Candesar 16 as a migraine prophylaxis is not yet known. Candesar 16 reduces the effects of angiotensin II, which has several effects that may be relevant to migraines, such as direct vasoconstriction, increased sympathetic discharge, and adrenal medullary catecholamine release.

Candesar 16 which contains Candesartan 16 mg belonging to the Angiotensin II Receptor Blocker acts as an antihypertensive agent and is available in the form of tablets.

• Adult Hypertension

Adults and geriatric patients should receive an initial dose of 16mg once daily. If the patient is volume-depleted, the initial dose should be lowered to 8mg once daily. The usual dose ranges from 8 to 32mg/day.

• Paediatric Hypertension

Children above 1 year of age: Candesartan may be administered once daily or divided into two equal doses. Adjust the dosage according to blood pressure response. For patients with possible depletion of intravascular volume (e.g., patients treated with diuretics, particularly those with impaired renal function), initiate Candesartan under close medical supervision and consider administration of a lower dose.

Children 1 To < 6 years of age: The dose range is 0.05 to 0.4mg/kg per day. The recommended starting dose is 0.20mg/kg (oral suspension).

Children 6 and above years of age: For those less than 50 kg, the dose range is 2 to 16mg per day. The recommended starting dose is 4 to 8mg. For those greater than 50 kg, the dose range is 4 to 32mg per day. The recommended starting dose is 8 to 16mg. Doses above 0.4mg/kg (1 to < 6-year-olds) or 32mg (6 to < 17-year-olds) have not been studied in pediatric patients. An antihypertensive effect is usually present within 2 weeks, with full effect generally obtained within 4 weeks of treatment with Candesartan.

Children < 1 year of age: must not receive Candesartan for hypertension.

• Adult Heart Failure

The recommended initial dose for treating heart failure is 4mg once daily. The target dose is 32mg once daily, which is achieved by doubling the dose at approximately 2-week intervals, as tolerated by the patient.

• Diabetic nephropathy

The optimal dose of Candesartan is 16mg daily for renoprotection, as reflected by a short-term reduction in albuminuria, in hypertensive type 2 diabetic patients with nephropathy.

• Left ventricular hypertrophy

Hypertensive patients treated with Candesartan 16mg once daily for 24 weeks demonstrated a significant regression of LVMI, and significant improvements in left ventricular diastolic function were detected in parallel.

• Migraine

Adults should receive a 16mg dose of Candesartan once daily.

Hypertension:

• Potassium Rich Foods: Candesar 16 may cause high blood potassium levels. Hence, avoid potassium-rich Food while taking this medication.

The dietary restriction should be individualized as per patient requirements.

• Fetal Toxicity

The use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformities. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Candesar 16 as soon as possible.

• Morbidity in Infants

Children < 1 year of age must not receive Candesar 16 for hypertension. Drugs that act directly on the renin-angiotensin system (RAS) can have effects on the development of immature kidneys.

• Hypotension

Candesar 16 can cause symptomatic hypotension. Symptomatic hypotension is most likely to occur in patients who have been volume and/or salt depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Patients with symptomatic hypotension may require temporarily reducing the dose of Candesartan, diuretic, or both, and volume repletion. Volume and/or salt depletion should be corrected before initiating therapy with Candesartan.

• Major Surgery/Anaesthesia

Hypotension may occur during major surgery and anesthesia in patients treated with angiotensin II receptor antagonists, including Candesartan, due to the blockade of the renin-angiotensin system. Very rarely, hypotension may be severe such that it may warrant the use of intravenous fluids and/or vasopressors.

• Impaired Renal Function

Monitor renal function periodically in patients treated with Candesartan. Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system. Patients whose renal function may depend, in part, on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe heart failure, or volume depletion) may be at particular risk of developing oliguria, progressive azotemia or acute renal failure when treated with Candesartan. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on Candesartan.

• Hyperkalemia

Drugs that inhibit the renin-angiotensin system can cause hyperkalemia. Concomitant use of Candesar 16 with drugs that increase potassium levels may increase the risk of hyperkalemia. Monitor serum potassium periodically.

The adverse reactions related to Candesar 16 which contains Candesartan 16 mg can be categorized as

Common Adverse effects-

• Dizziness
• Diarrhea
• Fatigue
• Abdominal pain

Less Common Adverse effects-

• Nausea
• Coughing
• Back pain

Rare adverse effects-

• Peripheral edema
• Arthralgia
• Pruritus
• Skin rash
• Urticaria

• Agents Increasing Serum Potassium

Co-administration of Candesar 16 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.

• Lithium

Increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists, including Candesar 16 . Monitor serum lithium levels.

• 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 Candesar 16 and NSAID therapy. The antihypertensive effect of angiotensin II receptor antagonists, including Candesar 16 may be attenuated by NSAIDs including selective COX-2 inhibitors.

• Combination 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. A triple combination of Candesar 16 with an ACE inhibitor and a mineralocorticoid receptor antagonist is generally not recommended. Closely monitor blood pressure, renal function, and electrolytes in patients on Candesar 16 and other agents that affect the RAS.

The common side effect of Candesar 16 which contains Candesartan 16 mg includes the following:

Major side effect

• Trouble sleeping
• Back pain
• Irregular heartbeat
• Hypotension
• Headache

Minor side effect

• Hypersensitivity
• Decrease in blood cell count
• Kidney Impairment
• Shortness of breath

Pregnancy

• Pregnancy Category D

The use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Candesar 16 as soon as possible. These adverse outcomes are usually associated with the use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Candesartan, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Candesar 16 for hypotension, oliguria, and hyperkalemia.

• Nursing Mothers

It is not known whether Candesar 16 is excreted in human milk, but Candesar 16 has been shown to be present in rat milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue Candesartan, taking into account the importance of the drug to the mother.

• Pediatric Use

Neonates with a history of in-utero exposure to Candesartan: If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. The antihypertensive effects of Candesar 16 were evaluated in hypertensive children above a year of age in randomized, double-blind clinical studies. The pharmacokinetics of Candesar 16 have been evaluated in pediatric patients above 1 year of Children < 1 year of age must not receive Candesar 16 for hypertension.

Pharmacodynamics:

Candesartan inhibits the pressor effects of angiotensin II infusion in a dose-dependent manner. After 1 week of once-daily dosing with 8mg of Candesartan cilexetil, the pressor effect was inhibited by approximately 90% at peak with approximately 50% inhibition persisting for 24 hours. Plasma concentrations of angiotensin I and angiotensin II, and plasma renin activity (PRA), increased in a dose-dependent manner after single and repeated administration of Candesartan cilexetil to healthy subjects, hypertensive, and heart failure patients. ACE activity was not altered in healthy subjects after repeated Candesartan cilexetil administration. The once-daily administration of up to 16mg of Candesartan cilexetil to healthy subjects did not influence plasma aldosterone concentrations, but a decrease in the plasma concentration of aldosterone was observed when 32mg of Candesartan cilexetil was administered to hypertensive patients. In spite of the effect of Candesartan cilexetil on aldosterone secretion, very little effect on serum potassium was observed.

• Hypertension Adults

In multiple-dose studies with hypertensive patients, there were no clinically significant changes in metabolic function, including serum levels of total cholesterol, triglycerides, glucose, or uric acid. In a 12-week study of 161 patients with non-insulin-dependent (type 2) diabetes mellitus and hypertension, there was no change in the level of HbA1c.

• Heart Failure

In heart failure patients, Candesartan ≥ 8mg resulted in decreases in systemic vascular resistance and pulmonary capillary wedge pressure.

Pharmacokinetics:

• Absorption

Following administration of the Candesartan cilexetil prodrug, the absolute bioavailability of Candesartan was estimated to be 15%. After the oral administration of Candesartan cilexetil, peak plasma concentrations (Cmax) of Candesartan are reached within 3 to 4 hours. Food with a high fat content has no effect on the bioavailability of Candesartan from Candesartan cilexetil.

• Distribution

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.

• Metabolism and Excretion

The 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 the urine. Following an oral dose of 14C-labeled Candesartan cilexetil, approximately 33% of radioactivity is recovered in urine and approximately 67% in feces. Following an intravenous dose of 14C-labeled Candesartan, approximately 59% of radioactivity is recovered in urine and approximately 36% in feces. Biliary excretion contributes to the elimination of Candesartan.