Azisan Plus40 mg+12.5 mg

Azisan Plus is indicated for the treatment of hypertension (high blood pressure), to lower blood pressure in adults. It is FDA-approved for two established uses:

• Add-on/substitution therapy: In patients whose blood pressure is not adequately controlled on a single antihypertensive agent (such as an angiotensin II receptor blocker alone or a thiazide-type diuretic alone).
• Initial (first-line) therapy: In patients who are likely to need multiple drugs to achieve their blood pressure goals, as an initial combination therapy.

Azisan Plus is not indicated for the initial treatment of hypertensive emergencies. Lowering blood pressure with this combination has been shown to reduce the risk of fatal and non-fatal cardiovascular events, primarily stroke and myocardial infarction, consistent with the benefits of blood pressure reduction in general. Azisan Plus is generally not used as monotherapy for mild, newly diagnosed hypertension where a single agent may be tried first, and its use should be guided by a physician's overall assessment of cardiovascular risk.

Each tablet of Azilsartan Medoxomil + Chlorthalidone contains two active ingredients:

• Azilsartan medoxomil - an angiotensin II receptor blocker (ARB), commonly available in strengths equivalent to 40 mg azilsartan.
• Chlorthalidone - a thiazide-like diuretic, commonly available as 12.5 mg or 25 mg.

Azilsartan Medoxomil + Chlorthalidone is typically formulated as fixed-dose combination tablets (for example, 40/12.5 mg and 40/25 mg strengths), combining the two active substances in a single oral dosage form.

Azisan Plus is a fixed-dose combination oral antihypertensive medicine that pairs an angiotensin II receptor blocker (azilsartan medoxomil) with a thiazide-like diuretic (chlorthalidone). Azilsartan medoxomil is a prodrug that is hydrolyzed during absorption to its active form, azilsartan, which blocks the vasoconstricting and aldosterone-secreting effects of angiotensin II. Chlorthalidone increases excretion of sodium, chloride, and water by inhibiting sodium reabsorption in the distal renal tubule, and also has direct vasodilating effects. By combining two complementary mechanisms, Azisan Plus produces a greater reduction in blood pressure than either component alone and is used when a single antihypertensive agent is insufficient to control blood pressure.

Azisan Plus belongs to the therapeutic class of combination antihypertensive agents, specifically an Angiotensin II Receptor Blocker (ARB) combined with a thiazide-like diuretic.

Mechanism of Action

Azilsartan Medoxomil + Chlorthalidone combines two agents with complementary and additive blood-pressure-lowering actions:

• Azilsartan (from azilsartan medoxomil): Selectively blocks the binding of angiotensin II to the AT1 receptor in vascular smooth muscle and the adrenal gland, blocking the vasoconstrictive and aldosterone-secreting effects of angiotensin II. This reduces peripheral vascular resistance without the reflex tachycardia typically seen with direct vasodilators.
• Chlorthalidone: A thiazide-like diuretic that inhibits sodium and chloride reabsorption at the distal convoluted tubule of the nephron, increasing excretion of sodium, chloride, and water, thereby reducing plasma and extracellular fluid volume. It may also have a direct arterial vasodilatory effect that contributes to its antihypertensive action.

Pharmacokinetics

Azilsartan medoxomil is rapidly converted to the active moiety azilsartan during absorption in the gastrointestinal tract, reaching peak plasma concentration in about 1.5 to 3 hours, and is highly protein bound; it is metabolized in the liver and eliminated via biliary/renal routes with an effective half-life of approximately 11 hours. Chlorthalidone is well absorbed orally, is extensively bound to erythrocytes and plasma proteins, undergoes minimal hepatic metabolism, and is eliminated largely unchanged by the kidneys, with a long elimination half-life (approximately 40-60 hours), permitting once-daily dosing.

Azisan Plus is administered orally, once daily, at approximately the same time each day to maintain consistent blood levels. It can be taken with or without food. Tablets should be swallowed whole with a glass of water and should not be crushed or chewed unless a physician or pharmacist advises otherwise. If a dose is missed, it should be taken as soon as remembered unless it is close to the time of the next dose, in which case the missed dose should be skipped; doses should not be doubled.

Azisan Plus should be used with caution alongside the following agents:

• Aliskiren: Concomitant use in patients with diabetes is contraindicated due to increased risk of hyperkalemia, hypotension, and renal impairment (see Contraindications).
• Other ARBs, ACE inhibitors, or direct renin inhibitors: Concurrent use increases the risk of hyperkalemia, hypotension, and renal function changes without added cardiovascular benefit; dual blockade of the renin-angiotensin system is generally not recommended.
• Potassium-sparing diuretics, potassium supplements, or salt substitutes containing potassium: May increase the risk of hyperkalemia when combined with the azilsartan component.
• NSAIDs (including selective COX-2 inhibitors): May reduce the antihypertensive and diuretic effect of Azisan Plus and increase the risk of renal impairment, particularly in volume-depleted or elderly patients.
• Lithium: Diuretics reduce renal clearance of lithium, increasing the risk of lithium toxicity; concurrent use requires close monitoring of lithium levels.
• Other antihypertensive agents: Additive blood-pressure-lowering effect, which is often used therapeutically but requires monitoring for excessive hypotension.
• Corticosteroids, ACTH, or amphotericin B: May intensify electrolyte depletion (particularly hypokalemia) caused by the chlorthalidone component.
• Digoxin: Chlorthalidone-induced hypokalemia or hypomagnesemia may increase the risk of digoxin toxicity and cardiac arrhythmias.
• Antidiabetic drugs (insulin/oral agents): The chlorthalidone component may raise blood glucose, requiring dose adjustment of antidiabetic therapy.

Most patients tolerate Azisan Plus well. Reported adverse effects include:

Common

• Dizziness
• Fatigue
• Headache
• Diarrhea or nausea

Less Common but Clinically Important

• Symptomatic hypotension, particularly after the first dose or with volume depletion
• Syncope (fainting)
• Electrolyte disturbances: hypokalemia, hyponatremia, hypomagnesemia, hypochloremic alkalosis (see Precautions and Warnings)
• Hyperuricemia and gout flares
• Elevated blood glucose
• Muscle cramps or weakness (related to electrolyte changes)

Rare but Serious

• Angioedema (swelling of face, lips, tongue, or throat)
• Acute kidney injury, particularly in susceptible patients
• Severe allergic/hypersensitivity reactions, including in patients with sulfonamide allergy
• Blood dyscrasias (rare, associated with the thiazide-like component)

Patients should seek immediate medical attention for signs of angioedema, severe dizziness/fainting, or signs of significant electrolyte imbalance (e.g. severe muscle weakness, irregular heartbeat).

Boxed Warning - Fetal Toxicity

Azisan Plus can cause injury and death to the developing fetus when used during pregnancy. Drugs that act directly on the renin-angiotensin system, such as the azilsartan component of Azisan Plus, can cause oligohydramnios, fetal lung hypoplasia, skeletal deformations, and neonatal renal failure, particularly with use in the second and third trimesters. Azisan Plus must be discontinued as soon as pregnancy is detected, and it should not be used in women who are pregnant or planning pregnancy unless there is no suitable alternative.

Lactation

It is not known whether the components of Azisan Plus pass into human breast milk in clinically significant amounts. Because of the potential for serious adverse effects in a nursing infant, a decision should be made whether to discontinue breastfeeding or discontinue Azisan Plus, taking into account the importance of the drug to the mother. Azisan Plus should be used during breastfeeding only if clearly needed and after consultation with a physician, since safer alternatives are usually preferred during lactation.

• Hypotension: Symptomatic hypotension may occur, especially at treatment initiation, after dose increases, or in volume- or salt-depleted patients (e.g. from prior diuretic therapy, vomiting, diarrhea, or a low-salt diet). Correct volume depletion before starting Azisan Plus where possible.
• Renal function changes: Azisan Plus can cause changes in renal function; monitor periodically, particularly in patients with renal artery stenosis, volume depletion, or concurrent use of NSAIDs, as acute kidney injury may occur.
• Hyperkalemia: The azilsartan component can raise serum potassium, especially in patients with renal impairment, diabetes, or those taking potassium-sparing diuretics, potassium supplements, or salt substitutes; monitor potassium levels periodically.
• Electrolyte and metabolic disturbances: Chlorthalidone can cause hypokalemia, hyponatremia, hypomagnesemia, and hypochloremic alkalosis; periodic monitoring of serum electrolytes is recommended, particularly in the elderly or those on other medications affecting electrolytes.
• Hyperuricemia/gout: Chlorthalidone can raise serum uric acid and precipitate gout attacks in susceptible individuals.
• Hyperglycemia: Thiazide-like diuretics may impair glucose tolerance; monitor blood glucose in patients with diabetes or prediabetes.
• Sulfonamide hypersensitivity: Chlorthalidone is chemically related to sulfonamides; use caution in patients with a history of sulfonamide allergy due to possible cross-sensitivity.
• Dual renin-angiotensin system blockade: Avoid combining Azisan Plus with other ARBs, ACE inhibitors, or aliskiren, as this increases the risk of hyperkalemia, hypotension, and renal impairment without added benefit.
• Angioedema: Discontinue immediately and seek emergency care if swelling of the face, lips, tongue, or throat, or difficulty breathing occurs.

Overdose of Azisan Plus is most likely to present as pronounced hypotension, dizziness, electrolyte disturbances (particularly hypokalemia and hyponatremia), dehydration, and possible bradycardia or tachycardia. There is no specific antidote. In case of suspected overdose, seek immediate medical attention or contact emergency services/poison control. Management is generally supportive, involving monitoring of vital signs, correction of fluid and electrolyte imbalances, and symptomatic treatment as directed by medical professionals; do not attempt home treatment for a suspected overdose.

Store at room temperature (below 30°C), away from light and moisture. Keep out of reach of children.

• Elderly: No overall dosage adjustment is generally required, but elderly patients may be more sensitive to blood-pressure-lowering and electrolyte effects; use with caution and monitor closely.
• Renal impairment: Use with caution; thiazide-type diuretics tend to be less effective as renal function worsens, and closer monitoring of renal function and electrolytes is warranted (see Dosage and Administration and Precautions and Warnings).
• Hepatic impairment: Azisan Plus is contraindicated in hepatic coma or precoma; use with caution in other hepatic impairment as minor alterations in fluid and electrolyte balance may precipitate complications.
• Pregnancy: Contraindicated; discontinue immediately upon detection of pregnancy (see Pregnancy and Lactation).
• Lactation: Use only if clearly needed, weighing benefits against potential infant risk (see Pregnancy and Lactation).
• Pediatric patients: Safety and efficacy have not been established (see Pediatric Uses).

Azisan Plus is intended for long-term, ongoing management of hypertension rather than short-term use. Treatment is typically continued indefinitely as part of chronic blood pressure control, with periodic physician follow-up to reassess blood pressure control, renal function, and electrolytes. Azisan Plus should not be stopped abruptly without medical advice, and any change in duration or dose should be directed by the prescribing physician.

Angiotensin II Receptor Blocker (ARB) + Thiazide-like Diuretic (combination antihypertensive)

Azilsartan Medoxomil + Chlorthalidone works through two complementary mechanisms. Azilsartan (the active form of azilsartan medoxomil) selectively and competitively blocks angiotensin II from binding to the AT1 receptor, preventing angiotensin II-mediated vasoconstriction and aldosterone release, which lowers blood pressure and reduces sodium/water retention. Chlorthalidone inhibits sodium and chloride reabsorption in the distal convoluted tubule of the kidney, promoting diuresis (loss of sodium, chloride, and water), which reduces circulating blood volume and further lowers blood pressure; it may also have a direct vasodilating effect on arterial smooth muscle. Together, these mechanisms produce a synergistic antihypertensive effect greater than either agent alone.

Category D

Safety and efficacy of Azisan Plus in pediatric patients have not been established. Azisan Plus is not recommended for use in children or adolescents, and it should only be used in adults for the treatment of hypertension under the guidance of a physician.