Candesartan Cilexetil

ATACAND (candesartan cilexetil), a prodrug, is hydrolyzed to candesartan during absorption from the gastrointestinal tract. Candesartan is a selective AT1 subtype angiotensin II receptor antagonist.

Candesartan cilexetil, a nonpeptide, is chemically described as (±)-1-Hydroxyethyl 2-ethoxy-1-[p-(o-1H-tetrazol-5ylphenyl)benzyl]-7-benzimidazolecarboxylate, cyclohexyl carbonate (ester).

Its empirical formula is C33H34N6O6, and its structural formula is:

Candesartan cilexetil is a white to off-white powder with a molecular weight of 610.67. It is practically insoluble in water and sparingly soluble in methanol. Candesartan cilexetil is a racemic mixture containing one chiral center at the cyclohexyloxycarbonyloxy ethyl ester group. Following oral administration, candesartan cilexetil undergoes hydrolysis at the ester link to form the active drug, candesartan, which is achiral.

ATACAND is available for oral use as tablets containing either 4 mg, 8 mg, 16 mg, or 32 mg of candesartan cilexetil and the following inactive ingredients: hydroxypropyl cellulose, polyethylene glycol, lactose, corn starch, carboxymethylcellulose calcium, and magnesium stearate. Ferric oxide (reddish brown) is added to the 8-mg, 16-mg, and 32-mg tablets as a colorant.

Clinical Studies Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

ATACAND has been evaluated for safety in more than 3600 patients/subjects, including more than 3200 patients treated for hypertension. About 600 of these patients were studied for at least 6 months and about 200 for at least 1 year. In general, treatment with ATACAND was well tolerated. The overall incidence of adverse events reported with ATACAND was similar to placebo.

The rate of withdrawals due to adverse events in all trials in patients (7510 total) was 3.3% (i.e., 108 of 3260) of patients treated with ATACAND as monotherapy and 3.5% (i.e., 39 of 1106) of patients treated with placebo. In placebo-controlled trials, discontinuation of therapy due to clinical adverse events occurred in 2.4% (i.e., 57 of 2350) of patients treated with ATACAND and 3.4% (i.e., 35 of 1027) of patients treated with placebo.

The most common reasons for discontinuation of therapy with ATACAND were headache (0.6%) and dizziness (0.3%).

The adverse events that occurred in placebo-controlled clinical trials in at least 1% of patients treated with ATACAND and at a higher incidence in candesartan cilexetil (n = 2350) than placebo (n = 1027) patients included back pain (3% vs. 2%), dizziness (4% vs. 3%), upper respiratory tract infection (6% vs. 4%), pharyngitis (2% vs. 1%), and rhinitis (2% vs. 1%).

Among children in clinical studies, 1 in 93 children age 1 to < 6 and 3 in 240 age 6 to < 17 experienced worsening renal disease. The association between candesartan and exacerbation of the underlying condition could not be excluded.

The adverse event profile of ATACAND in adult heart failure patients was consistent with the pharmacology of the drug and the health status of the patients. In the CHARM program, comparing ATACAND in total daily doses up to 32 mg once daily (n=3803) with placebo (n=3796), 21.0% of patients discontinued ATACAND for adverse events vs. 16.1% of placebo patients.

Postmarketing Experience

The following adverse reactions were identified during post-approval use of ATACAND. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following have been very rarely reported in post-marketing experience:

Digestive: Abnormal hepatic function and hepatitis.

Hematologic: Neutropenia, leukopenia, and agranulocytosis.

Immunologic: Angioedema

Metabolic and Nutritional Disorders: Hyperkalemia, hyponatremia.

Respiratory system disorders: Cough

Skin and Appendages Disorders: Pruritus, rash and urticaria.

Rare reports of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.

Included as part of the PRECAUTIONS section.

No lethality was observed in acute toxicity studies in mice, rats, and dogs given single oral doses of up to 2000 mg/kg of candesartan cilexetil. In mice given single oral doses of the primary metabolite, candesartan, the minimum lethal dose was greater than 1000 mg/kg but less than 2000 mg/kg.

The most likely manifestation of overdosage with ATACAND 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.

Treatment: To obtain up-to-date information about the treatment of overdose, consult your Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians' Desk Reference (PDR). In managing overdose, consider the possibilities of multiple-drug overdoses, drug-drug interactions, and altered pharmacokinetics in your patient.

ATACAND®
(at-a-cand)
(candesartan cilexetil) Tablets

Read the Patient information that comes with ATACAND before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or your treatment. If you have any questions about ATACAND, ask your doctor or pharmacist.

What is the most important information I should know about ATACAND?

ATACAND can cause harm or death to an unborn baby. Talk to your doctor about other ways to lower your blood pressure if you plan to become pregnant. If you get pregnant while taking ATACAND, tell your doctor right away.

What is ATACAND?

ATACAND is a prescription medicine called an angiotensin receptor blocker (ARB).

ATACAND is used to:

• treat high blood pressure in adults and children, 1 to 17 years of age
• treat certain types of heart failure in adults, to reduce death and hospitalization for heart damage and heart failure

Heart failure is a condition where the heart does not pump blood as well as it should.

ATACAND must not be used in children less than 1 year of age for high blood pressure.

Who should not take ATACAND?

Do not take ATACAND if you:

• are allergic to any of the ingredients in ATACAND. See the end of this leaflet for a complete list of ingredients in ATACAND.
• are diabetic and taking aliskiren.

What should I tell my doctor before taking ATACAND?

Before you take ATACAND, tell your doctor if you:

• have heart problems
• have liver problems
• have kidney problems
• currently have vomiting or diarrhea
• are scheduled for surgery or anesthesia. Low blood pressure can happen in people who take ATACAND and have major surgery and anesthesia.
• have any other medical conditions
• are pregnant or planning to become pregnant. See “What is the most important information I should know about ATACAND?”
• are breast-feeding or plan to breast-feed. It is not known if ATACAND passes into your breast milk. You and your doctor should decide if you will take ATACAND or breast-feed. You should not do both.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. ATACAND and other medicines may affect each other causing serious side effects. ATACAND may affect the way other medicines work, and other medicines may affect how ATACAND works.

Especially tell your doctor if you take:

• lithium carbonate (Lithobid) or lithium citrate, medicines used in some types of depression • other medicines for high blood pressure, especially water pills (diuretics)
• potassium supplements
• salt substitutes
• non-steroidal anti-inflammatory drugs (NSAIDs)

Know the medicines you take. Keep a list of your medications with you to show your doctor and pharmacist when a new medication is prescribed. Talk to your doctor or pharmacist before you start taking any new medicine. Your doctor or pharmacist will know what medicines are safe to take together.

How should I take ATACAND?

• Take ATACAND exactly as prescribed by your doctor.
• Do not change your dose or stop ATACAND without talking to your doctor, even if you are feeling well.
• If your child cannot swallow tablets, or if tablets are not available in the prescribed strength, your pharmacist will prepare ATACAND as a liquid suspension for your child. If your child switches between taking the tablet and the suspension, your doctor will change the dose as needed. Shake the bottle of suspension well before each dose.
• ATACAND is taken by mouth with or without food.
• If you miss a dose of ATACAND, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose. Take the next dose on time. Do not take 2 doses at one time. If you are not sure about your dosing call your doctor or pharmacist.
• If you take more ATACAND than prescribed, call your doctor, local poison control center, or go to the nearest emergency room.

What should I avoid while taking ATACAND?

ATACAND can cause you to feel dizzy or tired. Do not drive, operate machinery, or do other dangerous activities until you know how ATACAND affects you.

What are the possible side effects of ATACAND?

ATACAND may cause serious side effects, including:

• Injury or death to your unborn baby. See “What is the most important information I should know about ATACAND?
• Low blood pressure (hypotension). Low blood pressure is most likely to happen if you:
  • take water pills (diuretics)
  • are on a low salt diet
  • get dialysis treatments
  • are dehydrated (decreased body fluids) due to vomiting and diarrhea
  • have heart problems

If you feel dizzy or faint lie down and call your doctor right away.

Low blood pressure can also happen if you have major surgery or anesthesia. You will be monitored for this and treated if needed. See “What should I tell my doctor before taking ATACAND?”

• Worsening kidney problems. Kidney problems may get worse in people that already have kidney disease or heart problems. Your doctor may do blood tests to check for this.
• Increased potassium in your blood. Your doctor may do a blood test to check your potassium levels as needed.
  • Symptoms of allergic reaction. Call your doctor right away if you have any of these symptoms of an allergic reaction:
  • swelling of your face, lips, tongue or throat
  • rash
  • hives and itching

The most common side effects of ATACAND are:

• back pain
• dizziness
• cold or flu symptoms (upper respiratory tract infection)
• sore throat (pharyngitis)
• nasal congestion and stuffiness (rhinitis)

Tell your doctor or pharmacist about any side effect that bothers you or that does not go away.

These are not all the side effects of ATACAND. Ask your doctor or pharmacist for more information.

Call your doctor for medical advice about side effects. You can report side effects to FDA at 1-800-FDA-1088.

How should I store ATACAND?

• Do not keep medicine that is out of date or that you no longer need.
• Store ATACAND Tablets at room temperature below 86°F (30°C).
• Store ATACAND oral suspension at room temperature below 86°F (30°C).
• Use the oral suspension within 30 days after first opening the bottle. Do not use after the expiration date stated on the bottle.
• Do not freeze.
• Keep the container of ATACAND closed tightly.

Keep ATACAND and all medicine out of the reach of children.

General information about ATACAND.

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use ATACAND for a condition for which it was not prescribed. Do not give ATACAND to other people, even if they have the same problem you have. It may harm them.

This leaflet summarizes the most important information about ATACAND. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about ATACAND that is written for health professionals.

For more information, go to www.atacand-us.com or call 1 800-236-9933.

What are the ingredients in ATACAND?

Active ingredient: candesartan cilexetil.

Inactive ingredients in ATACAND tablets and ATACAND oral suspension are: hydroxypropyl cellulose, polyethylene glycol, lactose, corn starch, carboxymethylcellulose calcium, and magnesium stearate. Ferric oxide (reddish brown) is added to the 8-mg, 16-mg, and 32-mg tablets as a colorant.

In addition to the above, ATACAND oral suspension also includes the following inactive ingredients: Ora Plus, Ora Sweet or Ora-Blend.

How does ATACAND work?

ATACAND is a type of medicine called angiotensin receptor blocker, which blocks the effect of the hormone angiotensin II, causing the blood vessels to relax. This helps lower blood pressure. Medicines that lower your blood pressure lower your chance of having a stroke or heart attack.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Hypertension

Management of hypertension (alone or in combination with other classes of antihypertensive agents).1 2 3 16 17 18 19 20 21 500

Angiotensin II receptor antagonists are recommended as one of several preferred agents for the initial management of hypertension; other options include ACE inhibitors, calcium-channel blockers, and thiazide diuretics.501 502 503 504 While there may be individual differences with respect to specific outcomes, these antihypertensive drug classes all produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes.501 502 503 504 Individualize choice of therapy; consider patient characteristics (e.g., age, ethnicity/race, comorbidities, cardiovascular risk) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, cost).500 501 502 503 504 515

Angiotensin II receptor antagonists or ACE inhibitors may be preferred in hypertensive patients with diabetes mellitus or chronic kidney disease; angiotensin II receptor antagonists also may be preferred, as an alternative to ACE inhibitors, in hypertensive patients with heart failure or ischemic heart disease and/or post-MI.500 501 502 504 520 523 524 527 534 535 536 543

Black hypertensive patients generally tend to respond better to monotherapy with calcium-channel blockers or thiazide diuretics than to angiotensin II receptor antagonists.500 501 504 However, diminished response to an angiotensin II receptor antagonist is largely eliminated when administered concomitantly with a calcium-channel blocker or thiazide diuretic.500 504

The optimum BP threshold for initiating antihypertensive drug therapy is controversial.501 504 505 506 507 508 515 523 530 Further study needed to determine optimum BP thresholds/goals; individualize treatment decisions.501 503 507 515 526 530

JNC 7 recommends initiation of drug therapy in all patients with uncomplicated hypertension and BP ≥140/90 mm Hg;500 JNC 8 panel recommends SBP threshold of 150 mm Hg for patients ≥60 years of age.501 Although many experts agree that SBP goal of <150 mm Hg may be appropriate for patients ≥80 years of age,502 504 505 530 application of this goal to those ≥60 years of age is controversial, especially for those at higher cardiovascular risk.501 502 505 506 508 511 515

In the past, initial antihypertensive drug therapy was recommended for patients with diabetes mellitus or chronic kidney disease who had BP ≥130/80 mm Hg;500 503 current hypertension management guidelines generally recommend a BP threshold of 140/90 mm Hg for these individuals (same as for the general population of patients without these conditions), although a goal of <130/80 mm Hg may still be considered.501 502 503 504 520 530 535 536 541

Heart Failure

Used in the management of heart failure.1 52 53 524 800

Because of their established benefits, ACE inhibitors have been the preferred drugs for inhibition of the renin-angiotensin-aldosterone (RAA) system in patients with heart failure and reduced left ventricular ejection fraction (LVEF); 524 however, some evidence indicates that therapy with an ACE inhibitor (enalapril) may be less effective than angiotensin receptor-neprilysin inhibitor (ARNI) therapy (e.g., sacubitril/valsartan) in reducing cardiovascular death and heart failure-related hospitalization.702 800

Angiotensin II receptor antagonists may be used as an alternative for those patients in whom use of an ACE inhibitor or ARNI is inappropriate.524 528 800

No additional therapeutic benefit when angiotensin II receptor antagonist used in combination with an ACE inhibitor.a

ACCF, AHA, and the Heart Failure Society of America (HFSA) recommend that patients with chronic symptomatic heart failure and reduced LVEF (NYHA class II or III) who are able to tolerate an ACE inhibitor or angiotensin II receptor antagonist be switched to therapy containing an ARNI to further reduce morbidity and mortality.800

Diabetic Nephropathy

A recommended agent in the management of patients with diabetes mellitus and persistent albuminuria† who have modestly elevated (30–300 mg/24 hours) or higher (>300 mg/24 hours) levels of urinary albumin excretion; slows rate of progression of renal disease in such patients.25 26 27 28 29 30 31 32 36 37 39 40 41 520 535 536

• Risks of use during pregnancy.1 2 55 56

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1 2

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.