Zilarbi 80

Zilarbi 80 which contains the salt Azilsartan 80 mg and is an antihypertensive agent belonging to Angiotensin II Receptor Blocker. It is approved for the treatment of Hypertension. It is also used for Heart failure and the prevention of heart attack and stroke. It may be used alone or in combination with other antihypertensive agents.

• Hypertension

Zilarbi 80 is useful for antihypertensive treatment as monotherapy or in combination therapy with other antihypertensive agents in patients aged 18 years or older. It is also commercially available as a combination therapy with chlorthalidone. Zilarbi 80 is recommended as a first-line agent when initiating antihypertensive therapy.

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

• Myocardial Infarction

Zilarbi 80 has been shown to decrease blood pressure levels more than its precursors, Olmesartan, and valsartan, and is theorized to lower mortality rates and the onset of cardiovascular disease. The benefits could be especially pertinent in the patients that have heart failure and myocardial infarction and may have potential off-label uses for these patients.

• Delay the progression of proteinuria in Diabetes mellitus

In patients with diabetes mellitus and hypertension, ARBs are effective in reducing blood pressure compared to the other first-line agents. ARBs and ACE inhibitors are considered the most efficacious in reducing the progression of moderate-to-severe albuminuria, and they may be used in an off-label fashion.

Zilarbi 80 contains the salt Azilsartan 80 mg which is an antihypertensive agent belonging to Angiotensin II Receptor Blocker and is available in the form of a tablet.

• Hypertension

Zilarbi 80 is available in an oral tablet form of 80 mg strength that is to be taken once a day, and it can be administered with or without Food. Although 80 mg is recommended as a starting dose for patients with hypertension. 40 mg may be the beginning dose for patients with concomitant high-dose diuretic therapy, as well as patients that are volume- or salt-deprived. For patients having renal or mild-to-moderate hepatic impairment, dose adjustments are not necessary; the same applies to elderly patients.

The duration and dosage of the treatment should be according to the clinical judgment of the treating physician.

• Myocardial Infarction

Azilsartan is administered at 40 mg once daily and is effective in case of myocardial infarction. It can be administered with or without Food. Azilsartan can stabilize atherosclerotic plaque and reduce cardiac fibrosis formation following myocardial infarction.

• Delay the progression of proteinuria in Diabetes mellitus

In patients with diabetes mellitus and hypertension, ARBs are effective in reducing blood pressure in addition to the other first-line agents. 20 mg daily dose of Azilsartan significantly decreased proteinuria and blood pressure. These significant reductions in proteinuria and blood pressure during Azilsartan treatment were not associated with significant increases in side effects, this is the first study of Azilsartan in which the primary outcome is proteinuria.

Hypertension:

Potassium-Rich Foods: Zilarbi 80 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. The 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 Zilarbi 80 as soon as possible.

• Hypotension In Volume- Or Salt-Depleted Patients

In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of treatment with Zilarbi 80. Correct volume or salt depletion prior to administration of Azilsartan, or start treatment at 40 mg. If hypotension does occur, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. The 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 system, changes in renal function may be anticipated in susceptible individuals treated with Zilarbi 80. In patients whose renal function may depend on the activity of the renin-angiotensin system (e.g., patients with severe congestive heart failure, renal artery stenosis, or volume depletion), treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers has been associated with oliguria or progressive azotemia and rarely with acute renal failure and death. Similar results may be anticipated in patients treated with Zilarbi 80.

Pregnancy Category C: (1st trimester); D (2nd and 3rd trimesters)

Avoid use in pregnancy. When pregnancy is detected, discontinue the use of Zilarbi 80 as soon as possible. It acts directly on the renin-angiotensin system and can cause injury and death to the developing fetus.

The food warning while consuming Zilarbi 80 is that it should be taken in concentrations during its consumption.

Potassium-Rich Foods: Zilarbi 80 may cause high blood potassium levels. Hence, avoid potassium-rich Food while taking this medicine.

The adverse reactions related to Zilarbi 80 which contains the salt Azilsartan 80 mg can be categorized as

Common Adverse effects:

• Diarrhea
• Dizziness
• Fatigue

Less Common Adverse effects:

• Nausea
• Muscle spasm
• Cough
• Asthenia
• Postural hypotension

Rare adverse effects:

• Skin rash
• Pruritus
• Angioedema

The clinically relevant drug interactions of the molecule Zilarbi 80 which contains the salt Azilsartan 80 mg are briefly summarized here.

• 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 who have compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including Zilarbi 80, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving Zilarbi 80 and NSAID therapy.

The antihypertensive effect of angiotensin II receptor antagonists, including Zilarbi 80, may be attenuated by NSAIDs, including selective COX-2 inhibitors.

• 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. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid the combined use of RAS inhibitors. Closely monitor blood pressure, renal function, and electrolytes in patients on Zilarbi 80 and other agents that affect the RAS.

Do not coadminister aliskiren with Zilarbi 80 in patients with diabetes. Avoid the use of aliskiren with Zilarbi 80 in patients with renal impairment (GFR < 60 mL/min).

• Lithium

Increases in serum lithium concentrations and lithium toxicity have been reported during the concomitant administration of lithium with angiotensin II receptor agonists. Monitor serum lithium levels during concomitant use.

The use of Zilarbi 80 contains the salt Azilsartan 80 mg should be prudent in the following group of special populations.

Pregnancy

• Pregnancy Category D

The use of Zilarbi 80 affects the renin-angiotensin system during the second and third trimesters of pregnancy, decreases fetal renal function, and increases fetal and neonatal morbidity and death. The resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. The neonatal adverse effect includes skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue the use of Zilarbi 80 as soon as possible. Most epidemiologic studies that examined fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished the drugs affecting the renin-angiotensin system from other antihypertensive agents. Proper management of maternal hypertension during pregnancy is important to optimize for both mother and the fetus.

In the unusual case, there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprising the mother of the potential risk to the fetus. Serial ultrasound examinations perform to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue the use of Zilarbi 80 unless it is considered lifesaving for the mother. Fetal testing may be appropriate during the week of pregnancy. Patients and physicians should be aware that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in-utero exposure to the Zilarbi 80 for hypotension, hyperkalemia, and oliguria.

• Nursing Mothers

It is not known if Zilarbi 80 is excreted in human milk, but low concentrations of Zilarbi 80 are excreted in the milk of lactating rats. Because of the possible adverse effects on the nursing infant, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother.

• Pediatric Use

Neonates with a history of in-utero exposure to the Zilarbi 80

If oliguria or hypotension occurs, support the blood pressure and renal function in that exchange; transfusions or dialysis may be required.

Safety and effectiveness in pediatric patients under the age of 18 years have not been established.

• Geriatric Use

No dose adjustment with the Zilarbi 80 is necessary for elderly patients. Out of the total patients in clinical studies with Zilarbi 80, 26% were elderly (65 years of age and older); 5% were 75 years of age and older. Abnormally high serum creatinine levels were more likely to be reported for patients aged 75 or older. There are no other differences in safety or effectiveness were observed between both elderly and younger patients, but the greater sensitivity of some older individuals cannot be ruled out.

• Renal Impairment

Dose adjustment is not required in patients has mild-to-severe renal impairment or end-stage renal disease. Patients having moderate to severe renal impairment are more likely to report abnormally high serum creatinine values.

• Hepatic Impairment

No dose adjustment is necessary for a patient with mild or moderate hepatic impairment. Zilarbi 80 has not been studied in patients having a severe hepatic impairment.

Pharmacodynamics:

The pressor effects of an angiotensin II infusion in a dose-related manner are inhibited by Zilarbi 80. Zilarbi 80 single dose is equivalent to 32 mg azilsartan medoxomil, which inhibited the maximal pressor effect at peak by approximately 90% and approximately 60% at 24 hours. The plasma angiotensin I and II concentrations and plasma renin activity increased while plasma aldosterone concentrations reduced after single and repeated administration of the Zilarbi 80 to healthy subjects; no significant clinical effects in the serum potassium or sodium were observed. The effect on Cardiac Repolarization: A thorough QT/QTc study was conducted to assess the potential of the Zilarbi 80 to prolong the QT/QTc interval in healthy volunteers. There was no evidence of QT/QTc prolongation at 320 mg dose of Zilarbi 80.

Pharmacokinetics:

• Absorption: In the gastrointestinal tract during absorption, Azilsartan medoxomil is hydrolyzed to Zilarbi 80, the active metabolite. Azilsartan medoxomil is not traced in plasma after oral administration. The dose proportionality in exposure was established for Zilarbi 80 in azilsartan medoxomil dose range of 20 mg to 320 mg after the single or multiple administration. The absolute bioavailability of Zilarbi 80 following the administration of azilsartan medoxomil is approximately 60%. After the oral administration of azilsartan medoxomil, peak plasma concentrations (Cmax) of Zilarbi 80 are reached within 1.5 to 3 hours. The bioavailability of Zilarbi 80 is not affected by Food.

• Distribution: The volume of distribution of the Zilarbi 80 is approximately 16L. Zilarbi 80 is highly bound about >99% of the human plasma proteins, mainly serum albumin. In rats, the minimal Zilarbi 80-associated radioactivity crossed the blood-brain barrier. Zilarbi 80 passed across the placental barrier in the pregnant rats and was distributed to the fetus.

• Metabolism and Elimination: Zilarbi 80 is metabolized into two primary metabolites. The major metabolite in the plasma is formed by O-dealkylation, referred to as M-II, and the minor metabolite is formed by decarboxylation, which is referred to as M-I. The systemic exposures to the major and minor metabolites in humans were approximately 50% and less than 1% of Zilarbi 80, respectively. Both M-I and MII do not contribute to the pharmacologic activity of Zilarbi 80. The major enzyme responsible for Zilarbi 80 metabolism is CYP2C9.

Following an oral dose of 14C-labeled azilsartan medoxomil, approximately 55% of the radioactivity was recovered in feces and about 42% in urine, with 15% of the dose excreted in urine as Zilarbi 80. The elimination half-life and renal clearance of Zilarbi 80 are approximately 11 hours and 2.3 mL/min respectively. Steady-state levels of Zilarbi 80 are achieved within 5 days and there is no accumulation in plasma that occurs with repeated once-daily dosing.