Azilsartan

(ay'' zil sar' tan)

PCI  : Contraindicated in pregnancy

LCaution when used during lactation : Caution when used during lactation

Molecule Info

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WARNING

WARNING: FETAL TOXICITY

  • When pregnancy is detected, discontinue Azilsartan as soon as possible.

  • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus

Contents

Azilsartan medoxomil

Indication(s)

Treatment of hypertension.  It may be used alone or in combination with other antihypertensive agents.

Dosage

Adult: Recommended Dose: 40-80 mg taken Orally once daily.  The dosage may be adjusted according to the patient's condition. Patients Treated with High-Dose Diuretics: Consider a starting dose of 40 mg. If blood pressure is not controlled with Edarbi alone, additional blood pressurereduction can be achieved by taking Azilsartan with other antihypertensive agents. Special Populations: No initial dose adjustment is recommended for elderly patients, patients with mild to severe renal impairment, end-stage renal disease, or mild-to-moderate hepatic dysfunction. Renal Impairment: Dose adjustment is not required in patients with mild to severe renal impairment or end-stage renal disease.  Patients with moderate to severe renal impairment are more likely to report abnormally high serum creatinine values. Hepatic Impairment: No dose adjustment is necessary for subjects with mild to moderate hepatic impairment. Elderly: No dose adjustment with Azilsartan is necessary in elderly patients.  Of the total patients in clinical studies with Azilsartan, 26% were elderly; 5% were ≥75 years.  Abnormally high serum creatinine values were more likely to be reported for patients ≥75 years.  No other differences in safety or effectiveness were observed between elderly patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Administration: Azilsartan may be taken with or without food.

Administration

May be taken with or without food.

Overdosage

Limited data are available related to overdosage in humans.  During controlled clinical trials in healthy subjects, once daily doses of Azilsartan up to 320 mg were administered for 7 days and were well tolerated.  In the event of an overdosage, supportive therapy should be instituted as dictated by the patient's clinical status.  Azilsartan is not dialyzable.

Warnings

When pregnancy is detected, discontinue Azilsartan as soon as possible.  Drugs that act directly on the renin-angiontensin system can cause injury and death to the developing fetus. Fetal/Neonatal Morbidity and Mortality: Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women during the 2nd and 3rd trimester.  When pregnancy is detected, Azilsartan should be discontinued as soon as possible. The use of drugs that act directly on the renin-angiotensin system during the 2nd and 3rd trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death.  Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development.  Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these were due to exposure to the drug. These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the 1st trimester.  Mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the 1st trimester should be so informed.  Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of Azilsartan as soon as possible. Rarely, no alternative to a drug acting on the renin-angiotensin system is available.  In these rare cases, the mother should be apprised of the potential hazards to the fetus and series of ultrasound examinations should be performed to assess the intra-amniotic environment. If oligohydramnios is observed, Azilsartan should be discontinued unless it is considered life-saving for the mother.  Contraction stress testing, a nonstress test or biophysical profiling may be appropriate, depending upon the week of pregnancy.  Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Infants on histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria and hyperkalemia.  If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion.  Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for impaired renal function.

Special Precautions

Hypotension in Volume- or Salt-Depleted Patients: In patients with an activated renin-angiotensin system eg, volume- and/or salt-depleted, symptomatic hypotension may occur after initiation of treatment with Azilsartan.  It is recommended to 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 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. Renal Impairment: As a consequence on inhibiting the renin-angiotensin system, changes in renal function may be anticipated in susceptible individuals treated with Azilsartan.  In patients whose renal function may depend on the activity of the renin-angiotensin system, 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 Azilsartan. In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen have been reported.  There has been no long-term use of Azilsartan in patients with unilateral or bilateral renal artery stenosis, but similar results may be expected. Azilsartan has not been studied in patients with severe hepatic impairment. Use in pregnancy & lactation: Pregnancy Category C and D.  There is no clinical experience with the use of Azilsartan in pregnant women. It is not known if azilsartan is excreted in human milk, but azilsartan is excreted at low concentrations in the milk of lactating rats.  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 children: Safety and effectiveness in pediatric patients <18 years have not been established.

Adverse Drug Reaction(s)

Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. A total of 4814 patients were evaluated for safety when treated with Azilsartan at doses of 20, 40 or 80 mg in clinical trials.  This includes 1704 patients for at least 6 months; of these, 588 were treated for at least 1 year. Treatment with Azilsartan was well-tolerated with an incidence of adverse reactions similar to placebo.  The rate of withdrawals due to adverse events in placebo-controlled monotherapy and combination therapy trials was 2. 4% for placebo, 2. 2% for Azilsartan 40 mg, and 2. 7% for Azilsartan 80 mg.  The most common adverse event leading to discontinuation, hypotension/orthostatic hypotension, was reported by 0. 4% patients randomized to Azilsartan 40 or 80 mg compared to 0% patients randomized to placebo.  Generally, adverse reactions were mild, not dose related and similar regardless of age, gender and race. In placebo-controlled monotherapy trials, diarrhea was reported up to 2% in patients treated with Azilsartan 80 mg daily compared with 0. 5% of patients on placebo. Other Adverse Reactions: Other adverse reactions with a plausible relationship to treatment that have been reported with an incidence of ≥0. 3% and greater than placebo in >3300 patients treated with Azilsartan in controlled trials are listed as follows: Gastrointestinal Disorders: Nausea. General Disorders and Administration Site Conditions: Asthenia, fatigue. Musculoskeletal and Connective Tissue Disorders: Muscle spasm. Nervous System Disorders: Dizziness, postural dizziness. Respiratory, Thoracic and Mediastinal Disorders: Cough. Clinical Laboratory Findings: In controlled clinical trials, clinically relevant changes in standard laboratory parameters were uncommon with administration of Azilsartan. Serum Creatinine: Small reversible increases in serum creatinine are seen in patients receiving Azilsartan 80 mg.  The increase may be larger when co-administered with chlorthalidone or hydrochlorothiazide. In addition, patients taking Azilsartan who had moderate to severe renal impairment at baseline or who were >75 years were more likely to report serum creatinine increases. Hemoglobin/Hematocrit: Low hemoglobin, hematocrit and RBC counts were observed in 0. 2%, 0. 4% and 0. 3% of Azilsartan treated subjects, respectively.  None of these abnormalities were reported in the placebo group.  Low and high markedly abnormal platelet and WBC counts were observed in <0. 1% of subjects.

Drug Interactions

No clinically significant drug interactions have been observed in studies of azilsartan medoxomil or azilsartan given with amlodipine, antacids, chlorthalidone, digoxin, fluconazole, glyburide, ketoconazole, metformin, pioglitazone and warfarin.  Therefore, Azilsartan may be used concomitantly with these medications. Nonsteroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors: In patients who are elderly, volume-depleted, or who have compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including Azilsartan may result in deterioration of renal function, including possible acute renal failure.  These effects are usually reversible.  Monitor renal function periodically in patients receiving azilsartan and NSAID therapy. The antihypertensive effect of angiotensin II receptor antagonists, including azilsartan, may be attenuated by NSAIDs, including selective COX-2 inhibitors.

Pregnancy Category (FDA)

Category D: There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk.

Storage

Store at temperatures not exceeding 30°C.

Pharmacology

Pharmacokinetics: Absorption: Azilsartan is hydrolyzed to azilsartan, the active metabolite, in the gastrointestinal tract during absorption.  Azilsartan medoxomil is not detected in plasma after Oral   administration.  Dose proportionality in exposure was established for azilsartan in the azilsartan medoxomil dose range of 20-320 mg after single multiple dosing. The estimated absolute bioavailability of azilsartan following administration of azilsartan medoxomil is approximately 60%.  After Oral   administration of azilsartan medoxomil, peak plasma concentrations of azilsartan are reached within 1. 5-3 hrs.  Food does not affect the bioavailability of azilsartan.  Distribution: The volume of distribution is approximately 16 L.  Azilsartan is highly bound to human plasma proteins, mainly serum albumin.  Protein-binding is constant at azilsartan plasma concentrations well above achieved with recommended doses. In rats, minimal azilsartan-associated radioactivity crossed the blood-brain barrier.  Azilsartan passed across the placental barrier in pregnant rats and was distributed to the fetus. Metabolism and Elimination: Azilsartan is metabolized to 2 primary metabolites.  The major metabolite in plasma is formed by O-dealkylation, referred to as metabolite M-II, and the minor metabolite is formed by decarboxylation, referred to as metabolite M-I.  Systemic exposures to the major and minor metabolites in humans were approximately 50% and <1% of azilsartan, respectively.  M-I and M-II do not contribute to the pharmacologic activity of Azilsartan.  The major enzyme responsible for azilsartan metabolism is CYP2C9. Following an Oral   dose of 14C-labeled azilsartan medoxomil, approximately 55% of radioactivity was recovered in feces and approximately 42% in urine, with 15% of the dose excreted in urine as azilsartan.  The elimination t½ of azilsartan is approximately 11 hrs and renal clearance is approximately 2. 3 mL/min.  Steady-state levels of azilsartan are achieved within 5 days and no accumulation in plasma occurs with repeated once-daily dosing.

ATC Classification

C09CA09 - azilsartan medoxomil.

 

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IMPORTANT WARNING:

Tell your doctor if you are pregnant or plan to become pregnant. Do not take azilsartan if you are pregnant. If you become pregnant while you are taking azilsartan, stop taking azilsartan and call your doctor immediately. Azilsartan may cause death or serious injury to the fetus when taken in the last 6 months of pregnancy.

 

Why is Azilsartan prescribed?

Azilsartan is used alone or in combination with other medications to treat high blood pressure. Azilsartan is in a class of medications called angiotensin II receptor antagonists. It works by blocking the action of certain natural substances that tighten the blood vessels, allowing the blood to flow more smoothly and the heart to pump more efficiently.

How should Azilsartan be used?

Azilsartan comes as a tablet to take by mouth. It is usually taken once a day with or without food. To help you remember to take azilsartan, take it around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take azilsartan exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Azilsartan controls high blood pressure but does not cure it. It may take about 2 weeks for you to notice the full benefit of azilsartan. Continue to take azilsartan even if you feel well. Do not stop taking azilsartan without talking to your doctor.

Other uses for Azilsartan

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

What special precautions to follow?

Before taking azilsartan,

  • tell your doctor if you are allergic to azilsartan, any other medications, or any of the ingredients in azilsartan tablets. Ask your pharmacist for a list of the ingredients.
  • tell your doctor if you have diabetes (high blood sugar) and you are taking aliskiren. Your doctor will probably tell you not to take azilsartan if you have diabetes and you are also taking aliskiren.
  • tell your doctor what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: aspirin and other nonsteroidal anti-inflammatory medications (NSAIDs) such as ibuprofen and naproxen and selective COX-2 inhibitors such as celecoxib; diuretics ('water pills'); other medications to treat high blood pressure or heart problems; and potassium supplements. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • tell your doctor if you have or have ever had heart failure, or kidney or liver disease.
  • tell your doctor if you are breast-feeding.
  • you should know that diarrhea, vomiting, not drinking enough fluids, and sweating a lot can cause a drop in blood pressure, which may cause lightheadedness and fainting. Tell your doctor if you have any of these problems or develop them during your treatment.

What special dietary instructions to follow?

Do not use salt substitutes containing potassium without talking to your doctor. If your doctor prescribes a low-salt or low-sodium diet, follow these directions carefully.

What to do if I forget a dose?

Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

What side effects can Azilsartan cause?

Azilsartan may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away 

  • diarrhea
  • dizziness
  • fainting

Some side effects can be serious. If you experience any of these symptoms below, call your doctor immediately. 

Azilsartan may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

What should I know about storage and disposal of this medication?

Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from light, excess heat and moisture (not in the bathroom). Throw away any medication that is outdated or no longer needed. Talk to your pharmacist about the proper disposal of your medication.

What other information should I know?

Keep all appointments with your doctor and the laboratory. Your blood pressure should be checked regularly to determine your response to azilsartan.

Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription.

Azilsartan tablets have a noticeable odor. Ask your pharmacist if you have any questions regarding your medication.

It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.

 Ref: U.S. Natl. Library of Medicine