When to take losartan?

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Taking blood pressure pills at bedtime best for cardiovascular health

New research suggests that the best time for people with hypertension to take their blood pressure pills is at bedtime rather than in the morning.

Share on PinterestTaking blood pressure medication at bedtime is most likely to reduce cardiovascular risk, new research suggests.

It appears that not only does this timing result in better blood pressure control, but that it also markedly reduces the risk of cardiovascular death and events such as a heart attack or stroke.

Researchers came to these conclusions after analyzing data from the Hygia Chronotherapy Trial.

Hygia is the largest and longest lasting clinical trial to examine the effects of antihypertensive medication timing on the risk of cardiovascular events.

The investigators behind the present findings randomly assigned 19,084 adults to take the blood pressure pills that their doctors had prescribed either when they woke up in the morning or at bedtime. The participants were of Caucasian Spanish descent, and 8,470 were female.

During an average follow-up of 6 years, all individuals underwent 48-hour ambulatory blood pressure monitoring at least once per year.

“The results of this study,” says Ramón C. Hermida, Ph.D., the leader of the Hygia project, “show that patients who routinely take their antihypertensive medication at bedtime, as opposed to when they wake up, have better-controlled blood pressure and, most importantly, a significantly decreased risk of death or illness from heart and blood vessel problems.”

Hermida is a professor at the University of Vigo, in Spain, and director of its bioengineering and chronobiology labs.

He and colleagues report the recent findings in the European Heart Journal.

Markedly lower risk of cardiovascular events

The new study shows that, compared with individuals who took their blood pressure pills in the morning, those who took them before retiring to bed at night had a 45% lower risk of dying from or experiencing cardiovascular events, such as a heart attack, stroke, or heart failure.

The team adjusted the results to remove the effect of potential influencing factors. These factors include sex, age, cholesterol levels, smoking status, and presence of kidney disease or type 2 diabetes.

The researchers also examined the effect of medication timing on the risk of certain individual cardiovascular events.

These analyses showed that, compared with taking blood pressure pills in the morning, taking them at bedtime can reduce the risk of:

  • death due to heart or blood vessel conditions by 66%
  • stroke by 49%
  • heart attack by 44%
  • heart failure by 42%
  • coronary revascularization by 40%

Coronary revascularization is a procedure that unblocks or widens a vessel that supplies the heart to restore blood flow.

No mention of timing in current guidelines

Prof. Hermida explains that the current guidelines on how to treat high blood pressure do not mention or give advice about the best time of day to take the pills.

“Morning ingestion has been the most common recommendation by physicians, based on the misleading goal of reducing morning blood pressure levels,” he observes.

However, previous findings from the Hygia project have shown that the most significant independent marker of people’s cardiovascular risk is their average systolic blood pressure during sleep.

This link is independent of blood pressure readings taken during waking hours or at visits to the doctor, notes Prof. Hermida.

“Furthermore,” he adds, “there are no studies showing that treating hypertension in the morning improves the reduction in the risk of cardiovascular disease.”

A limitation that he and his colleagues highlight is that, because the participants came from one ethnic group, they cannot say how true the findings might be for other populations.

Origins of these benefits are unclear

Paul Leeson, Ph.D., a professor of cardiovascular medicine at the University of Oxford, in the United Kingdom, was not involved in the trial.

He commends the findings and describes the scale, length of follow-up, and effect size as “impressive.”

“Where the benefit comes from remains unclear,” Prof. Leeson observes.

Do these effects arise because the drugs improve sleep patterns or because side effects present less of a problem at night? he muses.

Or, could it be that overnight blood pressure is a better marker of heart health?

Prof. Leeson remarks that other studies looking into the timing of blood pressure medication are about to complete and report findings.

It will be interesting to see whether they confirm these recent results and shed any insights on the underlying mechanisms of these effects.

“This study has the potential to transform how we prescribe blood pressure medication.”

Prof. Paul Leeson

About losartan

Type of medicine An angiotensin-II receptor antagonist
Used for High blood pressure; heart failure; kidney disease associated with diabetes
Also called Cozaar® and Cozaar-Comp® (which also contains hydrochlorothiazide)
Available as Tablets and oral liquid suspension

Losartan is an angiotensin receptor blocker. It is also called an angiotensin-II receptor antagonist, or an AIIRA. You will have been prescribed losartan for one of the following reasons:

  • To lower blood pressure if your blood pressure is too high (hypertension).
  • To help your heart if it is not beating as well as it should (heart failure).
  • To help protect your kidneys if you have kidney disease associated with type 2 diabetes mellitus.

Losartan works by blocking the effect of a substance in your body called angiotensin II. Angiotensin II causes your blood vessels to narrow and also leads to the production of another substance called aldosterone, which increases the amount of fluid in your blood. By preventing the action of angiotensin II, losartan reduces how much work your heart has to do and lowers your blood pressure. It also has a protective effect on your kidneys.

You may be prescribed losartan to take on its own, or alongside other medicines to help your condition. There is a combination tablet available called Cozaar-Comp® which contains losartan with a diuretic called hydrochlorothiazide. This combination tablet can be prescribed to people with high blood pressure to help reduce the total number of tablets that need to be taken each day.

Before taking losartan

Some medicines are not suitable for people with certain conditions, and sometimes a medicine can only be used if extra care is taken. For these reasons, before you start taking losartan it is important that your doctor knows:

  • If you are pregnant or breastfeeding.
  • If you know you have a blockage of the artery which supplies blood to your kidneys, a condition called renal artery stenosis.
  • If you have any problems with your heart valves or heart muscle.
  • If you have a problem with the way your liver works.
  • If you are taking any other medicines. This includes any medicines you are taking which are available to buy without a prescription, as well as herbal and complementary medicines.
  • If you have ever had an allergic reaction to a medicine, or if you have had any other type of allergic reaction.

How to take losartan

  • Before you start the treatment, read the manufacturer’s printed information leaflet from inside the pack. It will give you more information about losartan and will provide you with a full list of the side-effects which you could experience from taking it.
  • Take losartan once each day, exactly as your doctor tells you to. There are several different strengths of tablet available. When you first start treatment your doctor may gradually increase the strength of the tablets to suit your condition. Each time you collect a fresh supply, it’s a good idea to check the strength on the packet to make sure they are what you are expecting.
  • Try to take losartan at the same time of day each day. For most people this will be in the morning. Taking your doses at the same time each day will help you to remember to take losartan regularly.
  • Swallow the tablet whole with a drink of water. You can take losartan either before or after a meal.
  • If you forget to take a dose, take it as soon as you remember. If you do not remember until the following day, miss out the forgotten dose. Do not take two doses at the same time to make up for a forgotten dose.

Getting the most from your treatment

  • Try to keep your regular appointments with your doctor. This is so your progress can be monitored. Your doctor may want you to have some blood tests from time to time to check on your kidneys, and also how much potassium is in your blood.
  • If you buy any medicines, check with a pharmacist that they are suitable to take with losartan. This is because some anti-inflammatory painkillers (such as aspirin and ibuprofen) can interfere with the way it works, and also may increase the risk of side-effects.
  • It is very important that you follow any dietary and lifestyle advice that you have been given by your doctor, such as eating a healthy diet, not smoking, and taking regular exercise.
  • If you drink alcohol, ask your doctor for advice. Your doctor may recommend that you do not drink alcohol while you are on losartan because it will increase the risk of side-effects, such as feeling dizzy or faint.
  • Try to avoid salt substitutes which contain potassium. This is because the substitutes will increase the amount of potassium in your blood and this can cause problems.
  • If you are having an operation or dental treatment, tell the person carrying out the treatment that you are taking losartan. This is because your blood pressure may drop too low if you are given some anaesthetics.
  • Treatment with losartan is usually long-term unless you experience an adverse effect. Continue to take the tablets regularly, unless you are advised otherwise by your doctor.

If you are also taking hydrochlorothiazide in combination with this medicine

  • Studies have suggested that taking higher doses of hydrochlorothiazide for long periods of time may increase the risk of certain skin cancers.
  • Tell your doctor if you have ever been treated for skin cancer before.
  • Tell your doctor about any new or changed moles or worrying marks on your skin.
  • Use a sunscreen in strong sunlight. Do not use sunbeds.

Can losartan cause problems?

Along with their useful effects, most medicines can cause unwanted side-effects although not everyone experiences them. The table below contains some of the most common ones associated with losartan. You will find a full list in the manufacturer’s information leaflet supplied with your medicine. The unwanted effects often improve as your body adjusts to the new medicine, but speak with your doctor or pharmacist if any of the following continue or become troublesome.

Common losartan side-effects (these affect less than 1 in 10 people) What can I do if I experience this?
Feeling tired, or dizzy and light-headed when you stand up (due to low blood pressure) Getting up and moving more slowly should help. If you begin to feel dizzy, sit for a few minutes before you stand up again
Changes in the amount of potassium in your blood You will have blood tests from time to time to check for this

If you experience any other symptoms which you think may be due to the medicine, speak with your doctor or pharmacist for further advice.

How to store losartan

  • Keep all medicines out of the reach and sight of children.
  • Store the tablets in a cool, dry place, away from direct heat and light.
  • Store the liquid medicine in a refrigerator and do not use it after the expiry date on the bottle. The expiry date is four weeks after it has been made up by the pharmacy.

Important information about all medicines

Never take more than the prescribed dose. If you suspect that you or someone else might have taken an overdose of this medicine, go to the accident and emergency department of your local hospital at once. Take the container with you, even if it is empty.

This medicine is for you. Never give it to other people even if their condition appears to be the same as yours.

Do not keep out-of-date or unwanted medicines. Take them to your local pharmacy which will dispose of them for you.

If you have any questions about this medicine ask your pharmacist.

WEDNESDAY, Oct. 23, 2019 (HealthDay News) — Taking blood pressure medications at bedtime rather than in the morning nearly halves the risk of dying from a heart attack, stroke or heart failure, a large, new study finds.

Researchers in Spain followed more than 19,000 adults with high blood pressure. They found that people who took all their blood pressure meds at night had lower blood pressure around the clock compared to volunteers who took their medication in the morning.

“The findings are highly consistent regardless of sex, age, presence of diabetes or kidney disease, and other major known factors of increased risk,” said study lead author Ramon Hermida.

Hermida is director of bioengineering and chronobiology at the University of Vigo’s Atlantic Research Center for Information and Communication Technologies.

“Conventionally, most patients ingest their medication in the morning,” said Hermida, “although no single trial ever documented this to be preferable.” No guidelines are currently in place regarding the best time to take the drugs, he added.

A New York City heart doctor believes consistency in taking your blood pressure pills will deliver optimal protection.

“The key here is routines,” said Dr. Satjit Bhusri, a cardiologist at Lenox Hill Hospital. “Not missing a dose. We know one thing worse than an elevated blood pressure is swings in blood pressure due to periodic non-compliance.”

To achieve compliance, it’s important to stick to a routine, Bhusri said.

Besides compliance, factors such as emotions and simultaneous use of other medications can affect a drug’s effectiveness, Bhusri noted.

The investigation — called the Hygia Chronotherapy Trial — ran between 2008 and 2018. It involved about 10,600 men and 8,500 women in northern Spain, aged 18 and older.

All had been diagnosed with high blood pressure prior to the study. The patients were tracked for a little over six years on average.

Study participants were randomly assigned to take all of their blood pressure pills just once a day, either in the morning or at bedtime.

Blood pressure was repeatedly assessed throughout the study. At least once a year, participants also wore a mobile monitor, which logged multiple blood pressure readings over two days.

Cozaar

Generic Name: losartan (loe SAR tan)
Brand Names: Cozaar

Medically reviewed by P. Thornton, DipPharm Last updated on May 1, 2019.

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What is Cozaar?

Cozaar (losartan) belongs to a group of drugs called angiotensin II receptor antagonists (sometimes called ARB blockers). It keeps blood vessels from narrowing, which lowers blood pressure and improves blood flow.

Cozaar is used to treat high blood pressure (hypertension) in adults and children who are at least 6 years old. It is also used to lower the risk of stroke in certain people with heart disease.

Cozaar is also used to slow long-term kidney damage in people with type 2 diabetes who also have high blood pressure.

Important Information

Do not use Cozaar if you are pregnant, and tell your doctor right away if you become pregnant. Losartan can cause injury or death to the unborn baby during your second or third trimester.

If you have diabetes, do not use Cozaar together with any medication that contains aliskiren (a blood pressure medicine).

You may also need to avoid taking Cozaar with aliskiren if you have kidney disease.

In rare cases, Cozaar can cause a condition that results in the breakdown of skeletal muscle tissue, leading to kidney failure. Call your doctor right away if you have unexplained muscle pain, tenderness, or weakness especially if you also have fever, unusual tiredness, and dark colored urine.

Before taking this medicine

You should not use Cozaar if you are allergic to losartan.

Do not use Cozaar if you are pregnant, and tell your doctor right away if you become pregnant. Losartan can cause injury or death to the unborn baby if you take the medicine during your second or third trimester.

To make sure Cozaar is safe for you, tell your doctor if you have:

  • kidney disease;

  • liver disease;

  • congestive heart failure;

  • an electrolyte imbalance (such as high levels of potassium in your blood);

  • if you are on a low-salt diet; or

  • if you are dehydrated.

You should not breast-feed while using Cozaar.

Cozaar is not approved for use by anyone younger than 6 years old.

How should I take Cozaar?

Take Cozaar exactly as prescribed by your doctor. Follow all directions on your prescription label and read all medication guides or instruction sheets. Your doctor may occasionally change your dose.

You may take Cozaar with or without food.

Call your doctor if you are sick with vomiting or diarrhea, or if you are sweating more than usual. You can easily become dehydrated while taking Cozaar. This can lead to very low blood pressure, a serious electrolyte imbalance, or kidney failure.

Your blood pressure will need to be checked often and you may need other blood and urine tests.

It may take 3 to 6 weeks before your blood pressure is under control. For best results, keep using the medicine as directed. Talk with your doctor if your condition does not improve after 3 weeks of treatment.

If you have high blood pressure, keep using this medicine even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medicine for the rest of your life.

Store at room temperature away from moisture, heat, and light.

Cozaar dosing information

Usual Adult Dose for Diabetic Nephropathy:

Initial dose: 50 mg orally once a day
Maximum dose: 100 mg orally once a day

-If hypertensive patients with left ventricular hypertrophy or type 2 diabetic nephropathy patients require titration from initial dose, increase to 100 mg orally once a day.
-Antihypertension is substantially present within 1 week but in some studies the maximal effect occurred in 3 to 6 weeks.
Uses:
-Treatment of hypertension.
-To reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy.
-Treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria (urinary albumin to creatinine ratio 300 mg/g or greater) in patients with type 2 diabetes and a history of hypertension.

Usual Adult Dose for Hypertension:

Initial dose: 50 mg orally once a day
Maximum dose: 100 mg orally once a day

-If hypertensive patients with left ventricular hypertrophy or type 2 diabetic nephropathy patients require titration from initial dose, increase to 100 mg orally once a day.
-Antihypertension is substantially present within 1 week but in some studies the maximal effect occurred in 3 to 6 weeks.
Uses:
-Treatment of hypertension.
-To reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy.
-Treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria (urinary albumin to creatinine ratio 300 mg/g or greater) in patients with type 2 diabetes and a history of hypertension.

Usual Pediatric Dose for Hypertension:

6 Years or Older:
Initial dose: 0.7 mg/kg orally once a day (up to 50 mg total)

-May be given as a tablet or suspension.
-Doses above 1.4 mg/kg (or 100 mg) daily have not been studied in pediatric patients.

What happens if I miss a dose?

Take the medicine as soon as you can, but skip the missed dose if it is almost time for your next dose. Do not take two doses at one time.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What should I avoid while taking Cozaar?

Drinking alcohol can further lower your blood pressure and may increase certain side effects of Cozaar.

Do not use potassium supplements or salt substitutes, unless your doctor has told you to.

Avoid getting up too fast from a sitting or lying position, or you may feel dizzy.

Cozaar side effects

Get emergency medical help if you have signs of an allergic reaction to Cozaar: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

  • a light-headed feeling, like you might pass out;

  • pain or burning when you urinate;

  • high potassium level – nausea, weakness, tingly feeling, chest pain, irregular heartbeats, loss of movement; or

  • kidney problems – little or no urination, rapid weight gain, painful or difficult urination, swelling in your hands, feet, or ankles.

Common Cozaar side effects may include:

  • dizziness;

  • back pain; or

  • cold symptoms such as stuffy nose, sneezing, sore throat.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Cozaar?

Tell your doctor about all your other medicines, especially:

This list is not complete. Other drugs may interact with losartan, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible drug interactions are listed here.

Further information

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use Cozaar only for the indication prescribed.

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Copyright 1996-2020 Cerner Multum, Inc. Version: 16.01.

Related questions

  • Are losartan and losartan potassium the same drug or two different ones?
  • Does losartan cause rapid heart rate, irregular heartbeat or low blood pressure?
  • Losartan vs Valsartan – What’s the difference between them?

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How does this medication work? What will it do for me?

Losartan belongs to a family of medications known as angiotensin II receptor blockers. These medications are used in adults and children over the age of six to lower mild-to-moderate hypertension (high blood pressure).

Angiotensin II is a chemical that the body releases to cause the constriction of blood vessels. Losartan blocks the action of angiotensin II, resulting in the relaxation of the blood vessels. This relaxation causes the blood pressure to drop. The full effects of losartan are usually seen within 3 to 6 weeks after treatment has started. Losartan may be used alone or in combination with a diuretic (water pill).

Losartan may also be taken by adults who have type 2 diabetes along with hypertension and protein in the urine (proteinuria). In these cases, losartan is used to protect the kidneys from further damage due to diabetes.

This medication may be available under multiple brand names and/or in several different forms. Any specific brand name of this medication may not be available in all of the forms or approved for all of the conditions discussed here. As well, some forms of this medication may not be used for all of the conditions discussed here.

Your doctor may have suggested this medication for conditions other than those listed in these drug information articles. If you have not discussed this with your doctor or are not sure why you are taking this medication, speak to your doctor. Do not stop taking this medication without consulting your doctor.

Do not give this medication to anyone else, even if they have the same symptoms as you do. It can be harmful for people to take this medication if their doctor has not prescribed it.

What form(s) does this medication come in?

25 mg
Each white, oval-shaped, unscored, film-coated tablet, with code “951” on one side and plain on the other, contains losartan potassium 25 mg. Nonmedicinal ingredients: carnauba wax, corn starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, microcrystalline cellulose, and titanium dioxide.

50 mg
Each white, oval-shaped, film-coated tablet, with code “952” on one side and scored on the other, contains losartan potassium 50 mg. The splitting of COZAAR 50 mg tablets is not advised. Nonmedicinal ingredients: carnauba wax, corn starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, microcrystalline cellulose, and titanium dioxide.

100 mg
Each white, teardrop-shaped, unscored, film-coated tablet, with code “960” on one side and plain on the other, contains losartan potassium 100 mg. Nonmedicinal ingredients: carnauba wax, corn starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, microcrystalline cellulose, and titanium dioxide.

How should I use this medication?

The usual recommended dose of losartan for adults is 50 mg or 100 mg once daily. The usual starting dose is 50 mg once daily. In some cases, a lower starting dose of 25 mg once daily may be advisable. A dose of 100 mg once daily should not be exceeded. Your doctor will adjust the dosage according to individual needs.

The usual recommended dose of losartan for children, aged 6 – 16 years, is based on body weight. The dose is 25 mg once daily for children weighing between 20 kg and 49 kg. This dose may be increased to 50 mg once daily. In children weighing more than 50 kg, the starting dose is 50 mg taken once daily. This dose may be increased to 100 mg once daily.

Losartan may be taken with or without food, but should be taken the same way each day.

Many things can affect the dose of a medication that a person needs, such as body weight, other medical conditions, and other medications. If your doctor has recommended a dose different from the ones listed here, do not change the way that you are taking the medication without consulting your doctor.

It is important that this medication be taken exactly as prescribed by your doctor. If you miss a dose, skip the missed dose and continue with your regular dosing schedule. Do not take a double dose to make up for a missed one. If you are not sure what to do after missing a dose, contact your doctor or pharmacist for advice.

Do not dispose of medications in wastewater (e.g. down the sink or in the toilet) or in household garbage. Ask your pharmacist how to dispose of medications that are no longer needed or have expired.

Who should NOT take this medication?

Losartan should not be taken by anyone who:

  • is allergic to losartan or to any of the ingredients of the medication
  • is pregnant

What side effects are possible with this medication?

Many medications can cause side effects. A side effect is an unwanted response to a medication when it is taken in normal doses. Side effects can be mild or severe, temporary or permanent. The side effects listed below are not experienced by everyone who takes this medication. If you are concerned about side effects, discuss the risks and benefits of this medication with your doctor.

The following side effects have been reported by at least 1% of people taking this medication. Many of these side effects can be managed, and some may go away on their own over time.

Contact your doctor if you experience these side effects and they are severe or bothersome. Your pharmacist may be able to advise you on managing side effects.

  • abdominal pain
  • back pain
  • cough
  • diarrhea
  • dizziness
  • headache
  • stuffy nose
  • trouble sleeping

Although most of these side effects listed below don’t happen very often, they could lead to serious problems if you do not check with your doctor or seek medical attention.

Check with your doctor as soon as possible if any of the following side effects occur:

  • fainting
  • heart palpitations (abnormal heartbeat with a feeling of thumping, fluttering, or pounding in the chest)
  • skin rash – especially if you also have joint pain
  • signs of liver problems (e.g., nausea, vomiting, diarrhea, loss of appetite, weight loss, yellowing of the skin or whites of the eyes, dark urine, pale stools)
  • signs of too much potassium in the body (e.g., irregular heartbeat, muscle weakness, generally feeling unwell)
  • unexplained muscle pain

Stop taking the medication and seek immediate medical attention if any of the following occur:

  • signs of a serious allergic reaction (e.g., swelling of face or throat, hives, or difficulty breathing)

Some people may experience side effects other than those listed. Check with your doctor if you notice any symptom that worries you while you are taking this medication.

Are there any other precautions or warnings for this medication?

HEALTH CANADA ADVISORY

February 4, 2014

Health Canada has issued new restrictions concerning the use of losartan. To read the full Health Canada Advisory, visit Health Canada’s web site at www.hc-sc.gc.ca.

Before you begin using a medication, be sure to inform your doctor of any medical conditions or allergies you may have, any medications you are taking, whether you are pregnant or breast-feeding, and any other significant facts about your health. These factors may affect how you should use this medication.

Blood pressure: Occasionally, a larger-than-expected drop in blood pressure occurs after taking losartan, in some cases after the first dose. It is more likely to occur if you take diuretics (water pills), have reduced salt intake, are on dialysis, or are experiencing diarrhea or vomiting. Blood pressure should be checked more often in these situations. If you have low blood pressure or are just starting to take this medication, you should move slowly when you are rising from a reclining to an upright position to reduce the risk of dizziness.

Dizziness: Losartan may cause dizziness, affecting your ability to drive or operate machinery. Avoid these and other hazardous tasks until you have determined how this medication affects you.

Kidney problems: The use of losartan may affect the function of the kidneys, especially for those who already have kidney problems. Certain people have experienced changes in kidney function (e.g., people with narrowed blood vessels in their kidneys, or those with severe congestive heart failure). The use of diuretics (water pills), nonsteroidal anti-inflammatory drugs (NSAIDs) or aliskiren may further increase risk of kidney problems for people already at risk for this problem. If you have kidney function problems, your doctor will likely closely monitor your condition while you are taking this medication.

Liver function: Losartan is removed from the body by the liver. Liver disease or reduced liver function may cause this medication to build up in the body, causing side effects. If you have liver problems, discuss with your doctor how this medication may affect your medical condition, how your medical condition may affect the dosing and effectiveness of this medication, and whether any special monitoring is needed. Your doctor may want to test your liver function regularly with blood tests while you are taking this medication.

Pregnancy: Losartan should not be taken by pregnant women as it can cause harm to an unborn child. If you are planning to become pregnant, discuss alternative medications for blood pressure control with your doctor.

If you become pregnant while taking this medication, stop taking it and tell your doctor at once.

Breast-feeding: It is not known if losartan passes into breast milk. If you are a breast-feeding mother and are taking this medication, it may affect your baby. Talk to your doctor about whether you should continue breast-feeding.

Children: The safety and effectiveness of using this medication have not been established for children less than 6 years of age.

What other drugs could interact with this medication?

There may be an interaction between losartan and any of the following:

  • aliskiren
  • alpha blockers (e.g., alfuzosin, doxazosin, tamsulosin)
  • alpha agonists (e.g., clonidine, methyldopa)
  • amifostine
  • amphetamines (e.g., dextroamphetamine)
  • angiotensin converting enzyme inhibitors (ACEIs; e.g., captopril, lisinopril, ramipril)
  • other angiotensin receptor blockers (ARBs; e.g., candasartan, irbesartan, losartan)
  • aprepitant
  • “azole” antifungals (e.g., itraconazole, ketoconazole, voriconazole)
  • barbiturates (e.g., pentobarbital, phenobarbital)
  • beta-adrenergic blockers (e.g., atenolol, propranolol, sotalol)
  • bosentan
  • calcium channel blockers (e.g., amlodipine, diltiazem, nifedipine, verapamil)
  • canagliflozin
  • capecitabine
  • carbamazepine
  • cyclosporine
  • delaviridine
  • dexamethasone
  • diabetes medications (e.g., chlorpropamide, glipizide, glyburide, pioglitazone, repaglinide)
  • diuretics (water pills; e.g., furosemide, hydrochlorothiazide, indapamide)
  • efavirenz
  • epelernone
  • ephedra
  • epoprostenol
  • fluorouracil
  • gemfibrozil
  • ginger
  • ginseng (American)
  • heparin and low-molecular weight heparins (e.g., dalteparin, tinzaparin)
  • lithium
  • methylphenidate
  • monoamine oxidase inhibitors (MAOIs; e.g., moclobemide, phenelzine, rasagiline, selegiline, tranylcypromine)
  • medications that increase the level of potassium in the blood (e.g., spironolactone, amiloride, triamterene, or salt substitutes that contain potassium)
  • nevirapine
  • non-steroidal anti-inflammatory medications (NSAIDs; e.g., diclofenac, ibuprofen, naproxen)
  • oxcarbazepine
  • pentoxifylline
  • phenytoin
  • phosphodiesterase 5 inhibitors (e.g., sildenafil, tadalafil, vardenafil)
  • pimozide
  • primidone
  • quinine
  • rifabutin
  • rifampin
  • rituximab
  • St. John’s wort
  • sodium phosphates
  • sulfadiazine
  • tamoxifen
  • tegafur
  • tolvaptan
  • trimethoprim
  • yohimbine
  • zopiclone

If you are taking any of these medications, speak with your doctor or pharmacist. Depending on your specific circumstances, your doctor may want you to:

  • stop taking one of the medications,
  • change one of the medications to another,
  • change how you are taking one or both of the medications, or
  • leave everything as is.

An interaction between two medications does not always mean that you must stop taking one of them. Speak to your doctor about how any drug interactions are being managed or should be managed.

Medications other than those listed above may interact with this medication. Tell your doctor or prescriber about all prescription, over-the-counter (non-prescription), and herbal medications you are taking. Also tell them about any supplements you take. Since caffeine, alcohol, the nicotine from cigarettes, or street drugs can affect the action of many medications, you should let your prescriber know if you use them.

All material copyright MediResource Inc. 1996 – 2020. Terms and conditions of use. The contents herein are for informational purposes only. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Source: www.medbroadcast.com/drug/getdrug/Cozaar

CLINICAL PHARMACOLOGY

Mechanism Of Action

Angiotensin II is a potent vasoconstrictor, the primary vasoactive hormone of the renin-angiotensin system, and an important component in the pathophysiology of hypertension. It also stimulates aldosterone secretion by the adrenal cortex. Losartan and its principal active metabolite block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor found in many tissues, (e.g., vascular smooth muscle, adrenal gland). There is also an AT2 receptor found in many tissues but it is not known to be associated with cardiovascular homeostasis. Neither losartan nor its principal active metabolite exhibits any partial agonist activity at the AT1 receptor, and both have much greater affinity (about 1000-fold) for the AT1 receptor than for the AT2 receptor. In vitro binding studies indicate that losartan is a reversible, competitive inhibitor of the AT1 receptor. The active metabolite is 10 to 40 times more potent by weight than losartan and appears to be a reversible, non-competitive inhibitor of the AT1 receptor.

Neither losartan nor its active metabolite inhibits ACE (kininase II, the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin), nor do they bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

Pharmacodynamics

Losartan inhibits the pressor effect of angiotensin II (as well as angiotensin I) infusions. A dose of 100 mg inhibits the pressor effect by about 85% at peak with 25-40% inhibition persisting for 24 hours. Removal of the negative feedback of angiotensin II causes a doubling to tripling in plasma renin activity and consequent rise in angiotensin II plasma concentration in hypertensive patients. Losartan does not affect the response to bradykinin, whereas ACE inhibitors increase the response to bradykinin. Aldosterone plasma concentrations fall following losartan administration. In spite of the effect of losartan on aldosterone secretion, very little effect on serum potassium was observed.

The effect of losartan is substantially present within one week but in some studies the maximal effect occurred in 3-6 weeks. In long-term follow-up studies (without placebo control) the effect of losartan appeared to be maintained for up to a year. There is no apparent rebound effect after abrupt withdrawal of losartan. There was essentially no change in average heart rate in losartan-treated patients in controlled trials.

Pharmacokinetics

Absorption

Following oral administration, losartan is well absorbed and undergoes substantial first-pass metabolism. The systemic bioavailability of losartan is approximately 33%. Mean peak concentrations of losartan and its active metabolite are reached in 1 hour and in 3-4 hours, respectively. While maximum plasma concentrations of losartan and its active metabolite are approximately equal, the AUC (area under the curve) of the metabolite is about 4 times as great as that of losartan. A meal slows absorption of losartan and decreases its Cmax but has only minor effects on losartan AUC or on the AUC of the metabolite (~10% decrease). The pharmacokinetics of losartan and its active metabolite are linear with oral losartan doses up to 200 mg and do not change over time.

Distribution

The volume of distribution of losartan and the active metabolite is about 34 liters and 12 liters, respectively. Both losartan and its active metabolite are highly bound to plasma proteins, primarily albumin, with plasma free fractions of 1.3% and 0.2%, respectively. Plasma protein binding is constant over the concentration range achieved with recommended doses. Studies in rats indicate that losartan crosses the blood-brain barrier poorly, if at all.

Metabolism

Losartan is an orally active agent that undergoes substantial first-pass metabolism by cytochrome P450 enzymes. It is converted, in part, to an active carboxylic acid metabolite that is responsible for most of the angiotensin II receptor antagonism that follows losartan treatment. About 14% of an orally-administered dose of losartan is converted to the active metabolite. In addition to the active carboxylic acid metabolite, several inactive metabolites are formed. In vitro studies indicate that cytochrome P450 2C9 and 3A4 are involved in the biotransformation of losartan to its metabolites.

Elimination

Total plasma clearance of losartan and the active metabolite is about 600 mL/min and 50 mL/min, respectively, with renal clearance of about 75 mL/min and 25 mL/min, respectively. The terminal half-life of losartan is about 2 hours and of the metabolite is about 6-9 hours. After single doses of losartan administered orally, about 4% of the dose is excreted unchanged in the urine and about 6% is excreted in urine as active metabolite. Biliary excretion contributes to the elimination of losartan and its metabolites. Following oral 14C-labeled losartan, about 35% of radioactivity is recovered in the urine and about 60% in the feces. Following an intravenous dose of 14C-labeled losartan, about 45% of radioactivity is recovered in the urine and 50% in the feces. Neither losartan nor its metabolite accumulates in plasma upon repeated once-daily dosing.

Special Populations

Pediatric

Pharmacokinetic parameters after multiple doses of losartan (average dose 0.7 mg/kg, range 0.36 to 0.97 mg/kg) as a tablet to 25 hypertensive patients aged 6 to 16 years are shown in Table 4 below. Pharmacokinetics of losartan and its active metabolite were generally similar across the studied age groups and similar to historical pharmacokinetic data in adults. The principal pharmacokinetic parameters in adults and children are shown in the table below.

Table 2: Pharmacokinetic Parameters in Hypertensive Adults and Children Age 6-16 Following Multiple Dosing

The bioavailability of the suspension formulation was compared with losartan tablets in healthy adults. The suspension and tablet are similar in their bioavailability with respect to both losartan and the active metabolite .

Geriatric And Gender

Losartan pharmacokinetics have been investigated in the elderly (65-75 years) and in both genders. Plasma concentrations of losartan and its active metabolite are similar in elderly and young hypertensives. Plasma concentrations of losartan were about twice as high in female hypertensives as male hypertensives, but concentrations of the active metabolite were similar in males and females. No dosage adjustment is necessary .

Race

Pharmacokinetic differences due to race have not been studied .

Renal Insufficiency

Following oral administration, plasma concentrations and AUCs of losartan and its active metabolite are increased by 50-90% in patients with mild (creatinine clearance of 50 to 74 mL/min) or moderate (creatinine clearance 30 to 49 mL/min) renal insufficiency. In this study, renal clearance was reduced by 55-85% for both losartan and its active metabolite in patients with mild or moderate renal insufficiency. Neither losartan nor its active metabolite can be removed by hemodialysis .

Hepatic Insufficiency

Following oral administration in patients with mild to moderate alcoholic cirrhosis of the liver, plasma concentrations of losartan and its active metabolite were, respectively, 5-times and about 1.7-times those in young male volunteers. Compared to normal subjects the total plasma clearance of losartan in patients with hepatic insufficiency was about 50% lower and the oral bioavailability was about doubled. Use a starting dose of 25 mg for patients with mild to moderate hepatic impairment. COZAAR has not been studied in patients with severe hepatic impairment .

Drug Interactions

No clinically significant drug interactions have been found in studies of losartan potassium with hydrochlorothiazide, digoxin, warfarin, cimetidine and phenobarbital. However, rifampin has been shown to decrease the AUC of losartan and its active metabolite by 30% and 40%, respectively. Fluconazole, an inhibitor of cytochrome P450 2C9, decreased the AUC of the active metabolite by approximately 40%, but increased the AUC of losartan by approximately 70% following multiple doses. Conversion of losartan to its active metabolite after intravenous administration is not affected by ketoconazole, an inhibitor of P450 3A4. The AUC of active metabolite following oral losartan was not affected by erythromycin, an inhibitor of P450 3A4, but the AUC of losartan was increased by 30%.

The pharmacodynamic consequences of concomitant use of losartan and inhibitors of P450 2C9 have not been examined. Subjects who do not metabolize losartan to active metabolite have been shown to have a specific, rare defect in cytochrome P450 2C9. These data suggest that the conversion of losartan to its active metabolite is mediated primarily by P450 2C9 and not P450 3A4.

Clinical Studies

Hypertension

Adult Hypertension

The antihypertensive effects of COZAAR were demonstrated principally in 4 placebo-controlled, 6- to 12- week trials of dosages from 10 to 150 mg per day in patients with baseline diastolic blood pressures of 95-115. The studies allowed comparisons of two doses (50-100 mg/day) as once-daily or twice-daily regimens, comparisons of peak and trough effects, and comparisons of response by gender, age, and race. Three additional studies examined the antihypertensive effects of losartan and hydrochlorothiazide in combination.

The 4 studies of losartan monotherapy included a total of 1075 patients randomized to several doses of losartan and 334 to placebo. The 10- and 25-mg doses produced some effect at peak (6 hours after dosing) but small and inconsistent trough (24 hour) responses. Doses of 50, 100 and 150 mg once daily gave statistically significant systolic/diastolic mean decreases in blood pressure, compared to placebo in the range of 5.5-10.5/3.5-7.5 mmHg, with the 150-mg dose giving no greater effect than 50-100 mg. Twice-daily dosing at 50-100 mg/day gave consistently larger trough responses than once-daily dosing at the same total dose. Peak (6 hour) effects were uniformly, but moderately, larger than trough effects, with the trough-to-peak ratio for systolic and diastolic responses 50-95% and 60-90%, respectively.

Addition of a low dose of hydrochlorothiazide (12.5 mg) to losartan 50 mg once daily resulted in placeboadjusted blood pressure reductions of 15.5/9.2 mmHg.

Analysis of age, gender, and race subgroups of patients showed that men and women, and patients over and under 65, had generally similar responses. COZAAR was effective in reducing blood pressure regardless of race, although the effect was somewhat less in Black patients (usually a low-renin population).

Pediatric Hypertension

The antihypertensive effect of losartan was studied in one trial enrolling 177 hypertensive pediatric patients aged 6 to 16 years old. Children who weighed <50 kg received 2.5, 25 or 50 mg of losartan daily and patients who weighed ≥50 kg received 5, 50 or 100 mg of losartan daily. Children in the lowest dose group were given losartan in a suspension formulation . The majority of the children had hypertension associated with renal and urogenital disease. The sitting diastolic blood pressure (SiDBP) on entry into the study was higher than the 95th percentile level for the patient’s age, gender, and height. At the end of three weeks, losartan reduced systolic and diastolic blood pressure, measured at trough, in a dose-dependent manner. Overall, the two higher doses (25 to 50 mg in patients <50 kg; 50 to 100 mg in patients ≥50 kg) reduced diastolic blood pressure by 5 to 6 mmHg more than the lowest dose used (2.5 mg in patients <50 kg; 5 mg in patients ≥50 kg). The lowest dose, corresponding to an average daily dose of 0.07 mg/kg, did not appear to offer consistent antihypertensive efficacy. When patients were randomized to continue losartan at the two higher doses or to placebo after 3 weeks of therapy, trough diastolic blood pressure rose in patients on placebo between 5 and 7 mmHg more than patients randomized to continuing losartan. When the low dose of losartan was randomly withdrawn, the rise in trough diastolic blood pressure was the same in patients receiving placebo and in those continuing losartan, again suggesting that the lowest dose did not have significant antihypertensive efficacy. Overall, no significant differences in the overall antihypertensive effect of losartan were detected when the patients were analyzed according to age (<, ≥12 years old) or gender. While blood pressure was reduced in all racial subgroups examined, too few non-White patients were enrolled to compare the dose-response of losartan in the non-White subgroup.

Hypertensive Patients With Left Ventricular Hypertrophy

The LIFE study was a multinational, double-blind study comparing COZAAR and atenolol in 9193 hypertensive patients with ECG-documented left ventricular hypertrophy. Patients with myocardial infarction or stroke within six months prior to randomization were excluded. Patients were randomized to receive once daily COZAAR 50 mg or atenolol 50 mg. If goal blood pressure (<140/90 mmHg) was not reached, hydrochlorothiazide (12.5 mg) was added first and, if needed, the dose of COZAAR or atenolol was then increased to 100 mg once daily. If necessary, other antihypertensive treatments (e.g., increase in dose of hydrochlorothiazide therapy to 25 mg or addition of other diuretic therapy, calcium-channel blockers, alpha-blockers, or centrally acting agents, but not ACE inhibitors, angiotensin II antagonists, or beta-blockers) were added to the treatment regimen to reach the goal blood pressure.

Of the randomized patients, 4963 (54%) were female and 533 (6%) were Black. The mean age was 67 with 5704 (62%) age ≥65. At baseline, 1195 (13%) had diabetes, 1326 (14%) had isolated systolic hypertension, 1469 (16%) had coronary heart disease, and 728 (8%) had cerebrovascular disease. Baseline mean blood pressure was 174/98 mmHg in both treatment groups. The mean length of follow-up was 4.8 years. At the end of study or at the last visit before a primary endpoint, 77% of the group treated with COZAAR and 73% of the group treated with atenolol were still taking study medication. Of the patients still taking study medication, the mean doses of COZAAR and atenolol were both about 80 mg/day, and 15% were taking atenolol or losartan as monotherapy, while 77% were also receiving hydrochlorothiazide (at a mean dose of 20 mg/day in each group). Blood pressure reduction measured at trough was similar for both treatment groups but blood pressure was not measured at any other time of the day. At the end of study or at the last visit before a primary endpoint, the mean blood pressures were 144.1/81.3 mmHg for the group treated with COZAAR and 145.4/80.9 mmHg for the group treated with atenolol; the difference in systolic blood pressure (SBP) of 1.3 mmHg was significant (p<0.001), while the difference of 0.4 mmHg in diastolic blood pressure (DBP) was not significant (p=0.098).

The primary endpoint was the first occurrence of cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction. Patients with nonfatal events remained in the trial, so that there was also an examination of the first event of each type even if it was not the first event (e.g., a stroke following an initial myocardial infarction would be counted in the analysis of stroke). Treatment with COZAAR resulted in a 13% reduction (p=0.021) in risk of the primary endpoint compared to the atenolol group (see Figure 1 and Table 3); this difference was primarily the result of an effect on fatal and nonfatal stroke. Treatment with COZAAR reduced the risk of stroke by 25% relative to atenolol (p=0.001) (see Figure 2 and Table 3).

Figure 1: Kaplan-Meier estimates of the primary endpoint of time to cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction in the groups treated with COZAAR and atenolol. The Risk Reduction is adjusted for baseline Framingham risk score and level of electrocardiographic left ventricular hypertrophy.

Figure 2: Kaplan-Meier estimates of the time to fatal/nonfatal stroke in the groups treated with COZAAR and atenolol. The Risk Reduction is adjusted for baseline Framingham risk score and level of electrocardiographic left ventricular hypertrophy.

Table 3 shows the results for the primary composite endpoint and the individual endpoints. The primary endpoint was the first occurrence of stroke, myocardial infarction or cardiovascular death, analyzed using an ITT approach. The table shows the number of events for each component in two different ways. The Components of Primary Endpoint (as a first event) counts only the events that define the primary endpoint, while the Secondary Endpoints count all first events of a particular type, whether or not they were preceded by a different type of event.

Table 3: Incidence of Primary Endpoint Events

Although the LIFE study favored COZAAR over atenolol with respect to the primary endpoint (p=0.021), this result is from a single study and, therefore, is less compelling than the difference between COZAAR and placebo. Although not measured directly, the difference between COZAAR and placebo is compelling because there is evidence that atenolol is itself effective (vs. placebo) in reducing cardiovascular events, including stroke, in hypertensive patients.

Other clinical endpoints of the LIFE study were: total mortality, hospitalization for heart failure or angina pectoris, coronary or peripheral revascularization procedures, and resuscitated cardiac arrest. There were no significant differences in the rates of these endpoints between the COZAAR and atenolol groups.

For the primary endpoint and stroke, the effects of COZAAR in patient subgroups defined by age, gender, race and presence or absence of isolated systolic hypertension (ISH), diabetes, and history of cardiovascular disease (CVD) are shown in Figure 3 below. Subgroup analyses can be difficult to interpret and it is not known whether these represent true differences or chance effects.

Figure 3: Primary Endpoint Events† within Demographic Subgroups

Nephropathy In Type 2 Diabetic Patients

The RENAAL study was a randomized, placebo-controlled, double-blind, multicenter study conducted worldwide in 1513 patients with type 2 diabetes with nephropathy (defined as serum creatinine 1.3 to 3.0 mg/dL in females or males ≤60 kg and 1.5 to 3.0 mg/dL in males >60 kg and proteinuria ).

Patients were randomized to receive COZAAR 50 mg once daily or placebo on a background of conventional antihypertensive therapy excluding ACE inhibitors and angiotensin II antagonists. After one month, investigators were instructed to titrate study drug to 100 mg once daily if the trough blood pressure goal (140/90 mmHg) was not achieved. Overall, 72% of patients received the 100-mg daily dose more than 50% of the time they were on study drug. Because the study was designed to achieve equal blood pressure control in both groups, other antihypertensive agents (diuretics, calcium-channel blockers, alpha- or beta-blockers, and centrally acting agents) could be added as needed in both groups. Patients were followed for a mean duration of 3.4 years.

The primary endpoint of the study was the time to first occurrence of any one of the following events: doubling of serum creatinine, end-stage renal disease (ESRD) (need for dialysis or transplantation), or death. Treatment with COZAAR resulted in a 16% risk reduction in this endpoint (see Figure 4 and Table 4). Treatment with COZAAR also reduced the occurrence of sustained doubling of serum creatinine by 25% and ESRD by 29% as separate endpoints, but had no effect on overall mortality (see Table 4).

The mean baseline blood pressures were 152/82 mmHg for COZAAR plus conventional antihypertensive therapy and 153/82 mmHg for placebo plus conventional antihypertensive therapy. At the end of the study, the mean blood pressures were 143/76 mmHg for the group treated with COZAAR and 146/77 mmHg for the group treated with placebo.

Figure 4: Kaplan-Meier curve for the primary composite endpoint of doubling of serum creatinine, end stage renal disease (need for dialysis or transplantation) or death.

Table 4: Incidence of Primary Endpoint Events

The secondary endpoints of the study were change in proteinuria, change in the rate of progression of renal disease, and the composite of morbidity and mortality from cardiovascular causes (hospitalization for heart failure, myocardial infarction, revascularization, stroke, hospitalization for unstable angina, or cardiovascular death). Compared with placebo, COZAAR significantly reduced proteinuria by an average of 34%, an effect that was evident within 3 months of starting therapy, and significantly reduced the rate of decline in glomerular filtration rate during the study by 13%, as measured by the reciprocal of the serum creatinine concentration. There was no significant difference in the incidence of the composite endpoint of cardiovascular morbidity and mortality.

The favorable effects of COZAAR were seen in patients also taking other anti-hypertensive medications (angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors were not allowed), oral hypoglycemic agents and lipid-lowering agents.

For the primary endpoint and ESRD, the effects of COZAAR in patient subgroups defined by age, gender and race are shown in Table 5 below. Subgroup analyses can be difficult to interpret and it is not known whether these represent true differences or chance effects.

Table 5: Efficacy Outcomes within Demographic Subgroups

ARTICLES

Development and evaluation of sustained release losartan potassium matrix tablet using kollidon SR as release retardant

Md. Shahid Sarwar; Mohammad Salim Hossain

Department of Pharmacy, Noakhali Science and Technology University, Sonapur, Bangladesh

ABSTRACT

The present study was undertaken to develop sustained release (SR) matrix tablets of losartan potassium, an angiotensin-II antagonist for the treatment of hypertension. The tablets were prepared by direct compression method, along with Kollidon SR as release retardant polymer. The amount of losartan potassium remains fixed (100 mg) for all the three formulations whereas the amounts of Kollidon SR were 250 mg, 225 mg, and 200 mg for F-1, F-2, and F-3 respectively. The evaluation involves three stages: the micromeritic properties evaluation of granules, physical property studies of tablets, and in-vitro release kinetics studies. The USP apparatus type II was selected to perform the dissolution test, and the dissolution medium was 900 mL phosphate buffer pH 6.8. The test was carried out at 75 rpm, and the temperature was maintained at 37 ºC ± 0.5 ºC. The release kinetics was analyzed using several kinetics models. Higher polymeric content in the matrix decreased the release rate of drug. At lower polymeric level, the rate and extent of drug release were enhanced. All the formulations followed Higuchi release kinetics where the Regression co-efficient (R2) values are 0.958, 0.944, and 0.920 for F-1, F-2, and F-3 respectively, and they exhibited diffusion dominated drug release. Statistically significant (P<0.05) differences were found among the drug release profile from different level of polymeric matrices. The release mechanism changed from non-fickian (n=0.489 for F-1) to fickian (n=0.439 and 0.429 for F-2, and F-3 respectively) as a function of decreasing the polymer concentration. The Mean Dissolution Time (MDT) values were increased with the increase in polymer concentration.

Uniterms: Losartan potassium/sustained release/development. Losartan potassium/sustained release/evaluation. Tablets/direct compression. Kollidon SR./use/release retardant.

RESUMO

O presente estudo foi realizado para desenvolver (SR) matriz de comprimidos de liberação sustentada de losartana, um antagonista da angiotensina II, para o tratamento da hipertensão arterial. Os comprimidos foram preparados pelo método de compressão direta com Kollidon SR como polímero de liberação lenta. A quantidade de losartana potássica permanece fixa (100 mg) para todas as três formulações enquanto que as quantidades de Kollidon SR foram de 250 mg, 225 mg e 200 mg para F-1, F-2 e F-3, respectivamente. A avaliação envolve três etapas- propriedades micromeríticas dos grânulos, estudo das propriedades físicas dos comprimidos e estudos de cinética de liberação in vitro.. Selecionoou-se o aparelho USP tipo II para realizar o teste de dissolução em meio com 900 mL de tampão fosfato pH 6,8 . O teste foi realizado em 75 rpm e a temperatura foi mantida a 37 ºC ± 0.5 ºC. Analisou-se a cinética de liberação utilizando-se vários modelos cinéticos. Conteúdo mais alto de polímero na matriz reduziu a taxa de liberação do fármaco. Em níveis mais baixos de polímero, a taxa e a extensão de liberação do fármaco foram aumentados. Todas as formulações seguiram a cinética de liberação de Higuchi, em que os valores do coeficiente de regressão (R2) foram 0,958 , 0,944 e 0,920 para F-1, F-2 e F-3, respectivamente, e elas apresentaram liberação do fármaco dominada pela difusão. Encontraram-se diferenças estatisticamente significativas (P<0,05) entre os perfis de liberação do fármaco com diferentes níveis de matrizes poliméricas. O mecanismo de liberação mudou de não-fickiano(n=0,489 para F-1) para fickiano(n=0,439 e 0,429 para F-2 e F-3, respectivamente) em função da diminuição da concentração de polímero. Os valores do Tempo de Dissolução Média (TDM) aumentaram com o aumento da concentração polímero.

Unitermos: Losartana/liberação sustentada/desenvolvimento. Losartana/liberação sustentada/avaliação. Comprimidos/compressão direta. Kollidon SR./uso/retardador de liberação.

INTRODUCTION

The objective of an ideal drug delivery system is to deliver adequate amount of drug for an extended period for its optimum therapeutic activity. Most drugs are inherently not long-lasting in the body, and require multiple daily dosing to achieve the desired blood concentration to produce therapeutic activity. To overcome such problems greater attention has been focused on sustained release drug delivery system (Chien, 1992).

Losartan potassium is an orally active angiotensin-II receptor antagonist used in the treatment of hypertension due to mainly blockade of AT1 receptor. It is freely soluble in water, slightly soluble in acetonitrile, and soluble in isopropyl alcohol. It is readily absorbed from the gastrointestinal tract with oral bioavailability of about 33 per cent and a plasma elimination half-life ranging from 1.5 to 2.5 hours. Administration of losartan potassium in a sustained release dosage form with dual characteristics, that is, burst release, followed by an extended release over 8 hours would be more desirable; as these characteristics would allow a rapid onset followed by protracted anti-hypertensive effect by maintaining the plasma concentration of the drug. Previously, several studies were conducted on losartan potassium by using various hydrophilic and hydrophobic polymers for their in-vitro evaluation (Chithaluru et al., 2011; Shanmugam et al., 2011).

The objective of the present investigation were to prepare sustained release matrix tablets of losartan Potassium by using Kollidon SR at three different concentrations, and to compare the in-vitro characteristics (weight variation, thickness and diameter, hardness, friability, drug content, release kinetics, etc.) of the developed matrix tablets. Kollidon SR is polyvinyl acetate and povidone based matrix-retarding agent. Polyvinyl acetate is insoluble in water. The povidone content is gradually leached out after introduction into water. Kollidon SR is completely soluble in N-methylpyrrolididone. It is particularly suitable for the manufacture of pH independent sustained release matrix tablets. Polyvinyl acetate is a plastic material that produces a coherent matrix even under low compression forces. When the tablets are introduced into gastric or intestinal fluid, the water-soluble povidone is leached out to form pores through which the active ingredient slowly diffuse outwards. Kollidon SR contains no ionic groups and is, therefore, inert to the drug substance (Reza, Quadir, Haider, 2003).

MATERIAL AND METHODS

Material

Losartan Potassium was kindly supplied by Globe Pharmaceuticals Limited, Noakhali, Bangladesh, as a gift sample. Kollidon SR was procured from BASF, Dhaka, Bangladesh Limited. Potassium di-hydrogen phosphate (Merck, Darmstadt, Germany), and sodium hydroxide (Merck, Darmstadt, Germany) were used as dissolution medium. Magnesium stearate and lactose were obtained from Novo Healthcare Limited, Dhaka, Bangladesh. Solvents and all other chemicals were of analytical grade.

Methods

Preparation of matrix tablet

Various methods are available for producing sustained release Losartan Potassium tablet preparation. In our experiment, direct compression technique was followed to prepare sustained release Losartan Potassium matrix tablet from the formulations mentioned in Table I.

The active ingredient (losartan potassium), release retardant (Kollidon SR), filler (lactose), and lubricant (magnesium stearate) were blended together by dry mixing. The dried granules were then sized through 40-mesh sieve. Finally, the granules were weighed to adjust the final weight of individual tablet considering its loss during operational handling. Then, the granules were made into tablets by direct compression at fixed compression force (5 ton) for specific period of time (2 minutes) by using hydraulic press (PIKE Technologies, India; Model: M-15) fitted with 13 mm dies.

Micromeritic properties of granules

• Bulk density

LBD (loose bulk density) and TBD (tapped bulk density) were determined by 5 g of powder from each formula-previously lightly shaken to break any agglomerates formed; and was placed into a 10 ml measuring cylinder. After the initial volume was observed, the cylinder was allowed to fall under its own weight onto a hard surface from a height of 2.5 cm at 2-second intervals. The reading of tapping was continued until no further change in volume was noted. LBD and TBD were determined by using following equations (Shah, Rampradhan, 1997):

LBD = Weight of the powder (W) /volume of the packing (V)

TBD = Weight of the powder/Tapping volume of the packing

• Carr’s index

The Carr’s Index (CI) is an indication of the compressibility of a powder. It is calculated by the formula:

CI = {(BD-TD)/BD} x 100

where, BD is the freely settled bulk density of the powder, and TD is the tapped bulk density of the powder (Rawlins, 1977).

• Hausner’s ratio

The Hausner’s ratio is a number that is correlated to the flowability of powder or granular material. It is calculated by:

H = BD/TD

• Angle of repose

The angle of repose of granules was determined by the funnel method. The accurately weighed granules were taken in a funnel. The height of the funnel was adjusted in such a way that the tip of the funnel just touched the apex of the heap of the granules. The granules were allowed to flow through the funnel freely onto the surface. The diameter of the powder cone was measured, and angle of repose was calculated using (Botz et al., 2003):

Angle of repose θ = tan-1 (h/r)

where, ‘h’ is height of the powder cone, and ‘r’ is the radius of the powder cone.

Physical parameters and drug content

• Weight variation

For weight variation test, the weights of 10 tablets (Electronic balance AR2140, India) of each batch were taken individually, and calculated the average weight of 10 tablets of each batch. Then the percentage of weight variation was determined of each tablet by using (Rashid et al., 2009):

% Weight variation = {(Average weight – Individual weight)/Average weight} × 100

• Thickness and diameter

The thickness and diameter of the tablets of all of the three formulations were determined with digital calipers (Range: 0-150 mm).

• Hardness

Tablet hardness was determined with tablet hardness tester EH-OIP Electrolab, India (Kaushik, Dureja, Saini, 2004).

• Friability

The friability of the tablets was measured in a Roche friabilator (EF2 Electrolab, India). Tablets of a known weight (W1) were de-dusted in a drum for a fixed time (25 rpm for 4 minutes), and weighed (W2) again. The weight loss should not be more than 1 per cent (Reddy et al., 2011).

Friability = {(W1 – W2)/W1} × 100

• Drug content

10 tablets were weighed and powdered; then, 176.5 mg tablet powder (equivalent to 100 mg) was dissolved in buffer solution and made the volume up to 100 mL. The solution was diluted 100 times, and absorbance was measured at 205 nm by using SHIMADZU UV-1800 spectrophotometer, Japan; and drug content was determined (Mansoor, Sharma, Dhakal, 2007).

In vitro release studies

• Dissolution study procedure

The in-vitro dissolution studies were performed using USP type-II dissolution apparatus (Rotating Peddle method) at 75 rpm. The dissolution medium consisted of potassium di-hydrogen phosphate buffer of pH 6.8 up to 900 mL, maintained at 37 ºC ± 0.5 ºC; where the tablets were completely in sink condition in the dissolution vessel. An aliquot (5 ml) was withdrawn at specific time intervals, which replaced by equivalent amount of buffer solution. The drug content was determined by UV-visible spectrophotometer (SHIMADZU UV-1800 spectrophotometer) at 205 nm. The release studies were conducted in triplicate.

• Drug release kinetics

To analyze the mechanism of drug release from the matrix tablets, the release data were fitted to the following equations:

Zero-order equation: (Cooper and Gunn, 1986) Q = k0 t where, Q is the amount of drug released at time t, and k0 is the release rate.

First-order equation (Hadjiioannou, Christian, Koupparis, 1993):

Log Q = Log Q0 – k1t/ 2.303

where, Q is the amount of drug un-dissolved at t time, Q0 is drug concentration at t = 0 and k1 is the release rate constant.

Higuchi’s equation (Higuchi, 1963);

Q = k2t1/2

where, Q is the percent of drug release at time t, and k2 is the diffusion rate constant.

Hixson-Crowell equation:

Qo1/3 – Qt 1/3 = Kot

where, Qt is the initial amount of drug, Qo is cumulative amount of drug release at time t, Ko is Hixson-Crowell release constant and t is time in hours.

Korsmeyer-Peppas equation (Korsmeyer et al., 1983):

Log (M t / M f) = Log k + n Log t

where, Mt is the amount of drug release at time t; Mf is the amount of drug release after infinite time; k is a release rate constant incorporating structural and geometric characteristics of the tablet; and n is the diffusional exponent indicative of the mechanism of drug release.

To clarify the diffusion exponent (n) for different batches of matrix tablet, the log value of percentage drug released was plotted against log time for each batch. A value of n < 0.45 indicates Fickian (case I) release; > 0.45 but < 0.89 for non-Fickian (anomalous) release; and > 0.89 indicates super case II type of release. Case II generally refers to the erosion of the polymeric chain, and anomalous transport (Non-Fickian) refers to a combination of both diffusion and erosion-controlled drug release (Shato et al., 1997). Mean dissolution time (MDT) was calculated from dissolution data using the equation: (Mockel, Lippold, 1993)

MDT = (n / n + 1) k -1/n

where, n = diffusion exponent and k = release rate constant.

RESULTS AND DISCUSSION

The Micromeritic properties of granules are indicated in Table II. The results of bulk densities were 0.522, 0.459, and 0.454 g/mL and the results of tapped bulk densities were 0.669, 0.677, and 0.708 g/mL for F-1, F-2, and F-3 respectively. The bulk densities of granules of the proposed formulation F-1 were quite higher than that of other granules. This may be due to the presence of more fine granules (Nellore et al., 1998). The Hausner’s Ratio for F-1, F-2, and F-3 were 1.34, 1.49, and 1.54 respectively. A Hausner’s Ratio greater than 1.25 is considered an indication of poor flowability (Li, 2004). The angle of repose for F-1, F-2, and F-3 were 50º, 48.7º, and 45.6º respectively. The results of angle of repose (> 30) indicate unsatisfactory flow properties of granules (Rashid et al., 2009). A Carr’s Index greater than 25 is considered an indication of poor flowability, and below 15 is of good flowability (Patel, Baria, 2009).

The mechanical properties of the Losartan Potassium tablets were improved (increased hardness and reduced friability) as the polymer concentration were increased. The produced tablets had thickness (n=3) about 3±0.01 mm, and diameter (n=3) of about 13 mm. Therefore, the polymer and other additives had no effect on the dimensions (thickness and diameter) of the Losartan Potassium matrix tablet, if the total weight is same, and the die and punch size is fixed. The weight variation (n=10) test of the tablet meet the USP specification as indicated in Table II.

To establish the sink condition, we did not carry out the experiment directly, but in some reports (Bonfilio et al., 2010) have stated that the drug does not possess sufficient solubility in 0.1 N hydrochloric acid, whereas, it shows satisfactory solubility in phosphate buffer. In some reports (Bonfilio et al., 2010), it has been stated that the use of water as a dissolution medium is discouraged because test condition such as pH and surface tension can vary depending on water source, and may change during the dissolution test itself. For this reason, the phosphate buffer pH 6.8 was chosen as dissolution medium.

The calibration curve of analytical method exhibited excellent linearity (R2 = 0.996) within the range of 1 µg/mL to 10 µg/mL. For the UV spectroscopic method, the relative standard deviation (RSD) values for intraday system and method precision were 0.25 and 1.04 per cent, respectively. The specificity study indicated that no interference from the matrix and excipients was found in the placebo of the tablets. The sample was found to be stable at 25 ºC for 24 h and the overall RSD percentage was found to be 0.99.

The drug content (n=3) of the formulated tablet among different batches ranged from 99.7±1.2% to 102.5±1.3% which meet USP specification (100±5%). It was noticed that Kollidon SR has a unique character of maintaining tablets geometric shape (Sakr, Alanazi, 2011). This is one of the most common reasons for choosing the Kollidon SR as release retardant polymer as compared to all others hydrophobic polymer.

To know the mechanism of drug release from these formulations, the data were treated according to zero order (cumulative amount of drug released vs time), first-order (log cumulative percentage of drug remaining vs time), Higuchi’s (cumulative percentage of drug released vs square root of time), Korsmeyer-Peppas (log cumulative percentage of drug released vs log time), and Hixson-Crowell (cubic root of percent drug release vs time) pattern for kinetics of drug release during dissolution process (Reddy, Mutalik, 2003).

As clearly indicated in Table III, the formulations did not follow a zero-order release pattern (Figure 1) where the regression values are 0.808, 0.782, and 0.753 for F-1, F-2, and F-3 respectively. When the data were plotted according to the first-order equation, the tablets showed a first order release, with regression value of 0.898, 0.918, and 0.911. The formulations showed to be best expressed by Higuchi’s equation, as the plots showed high linearity with regression value of 0.958, 0.944, 0.920 for Kollidon SR, indicating that the drug releases follow the Higuchi release kinetics (Figure 2), and diffusion is the dominating drug release mechanism. This finding is similar to that of previously investigated work (Reza, Quadir, Haider, 2003; Shanmugam et al., 2011).

The dissolution data was also fitted to the well-known exponential equation (Korsmeyer-Peppas equation), which is often used to describe the drug release behavior from polymeric systems. As indicated in the Table III, F-1 exhibited non-fickian type drug release, whereas, F-2 and F-3 exhibited fickian-type drug release from the tablet matrix. The percentage of drug release differs significantly at P<0.05 from different amount of polymer matrices.

MDT values are used to characterize drug release rate from a dosage form and release retarding efficiency of the polymer. MDT value is higher for F-1 and lower for F-3 as shown in Table IV. Moreover, we calculated the t75% values for all batches, and the data showed marked enhancement of t75% values from 3.64 to 7.93 (Table IV) indicating that the F-1 is the best formulation among the developed formulations. This finding indicates considerable release retarding potentiality of the Kollidon SR that was also reported by previous work (Sakr, Alanazi, 2011). The relationship between release rate and polymer content is shown in Figure 3.

CONCLUSION

The release rate of losartan potassium decreased with increase in polymer concentration. Therefore, it can be concluded that Kollidon SR is potential candidates for the development of sustained release losartan potassium matrix tablets. The best-proposed formulation F-1 may be used for the development of sustained release losartan potassium matrix tablet to meet the patient’s demand for the management of hypertension.

ACKNOWLEDGEMENTS

The authors are thankful to Globe Pharmaceuticals Limited, Novo Healthcare Limited and BASF Limited, Bangladesh for their generous gift of the necessary ingredients.

CHIEN, Y.W. Novel drug delivery systems. 2.ed. New York: Marcel Dekker, 1992. p.139-196.

COOPER, J.; GUNN, C. Tutorial pharmacy. 6.ed. New Delhi: CBS Publishers and Distributors, 1986. p.225.

MOCKEL, J.E.; LIPPOLD, B.C. Zero order release from hydrocolloid matrices. Pharm. Res., v.10, p.1066-1070, 1993.

RAWLINS, E.A. Bentley’s text book of pharmaceutics. 5.ed. London: Cassell and Collier MacMillan, 1977. p.24-248.

Received for publication on 10th July 2011
Accepted for publication on 13th July 2012

A comparative trial of controlled-onset, extended-release verapamil, enalapril, and losartan on blood pressure and heart rate changes*

Abstract

Background:

The excess morning risk of myocardial infarction and stroke may be attributable to the rapid rise in blood pressure (BP) and heart rate in the hours after awakening. The aim of this randomized, double-blinded, placebo-controlled, multicenter study was to compare once-daily, controlled-onset, extended-release (COER-24) verapamil to enalapril and losartan on BP and heart rate during the postawakening morning phase as well as throughout the 24-h period.

Methods:

A total of 406 patients were randomized to an 8-week forced-titration period with one of the following: 1) COER-24 verapamil 240 mg/day titrated to 360 mg/day; 2) enalapril 10 mg/day titrated to 20 mg/day, 3) losartan 50 mg/day titrated to 100 mg/day, or 4) placebo. Office BP and heart rate and ambulatory 24-h BP monitoring was performed at baseline, 4 weeks, and 8 weeks.

Results:

Each active treatment, as compared with placebo, lowered BP both during the morning hours as well as the entire 24-h period. COER-24 verapamil was more effective in lowering morning systolic (−16.6 mm Hg) and diastolic (−11.9 mm Hg) BP than either enalapril or losartan (P < .001). For the entire 24-h period, the effects of COER-24 verapamil (−11.6/−8.4 mm Hg) were comparable to enalapril (−13.4/−8.3 mm Hg; P = NS). Losartan achieved a similar 24-h effect on systolic pressure (−9.3 mm Hg) but was less effective on diastolic pressure (−5.4 mm Hg; P = .004 ν COER-verapamil). Unlike losartan or enalapril, COER-24 verapamil was the only treatment to lower the heart rate over both the 24-h period (−4.6 beats/min; P < .001) and during waking hours (−4.6 beats/min; P < .001). A blunted rate of rise in BP, heart rate, and rate–pressure product occurred during the postawakening period with COER-verapamil (P = .03) but not with either of the other treatment arms. Lastly, the decline in BP at night was similar for COER-verapamil and losartan and greater with enalapril (P = .014)

Conclusions:

COER-24 verapamil produces changes in BP and pulse that more closely match the normal circadian hemodynamic rhythms than either do enalapril or losartan.

Major cardiovascular events including myocardial infarction (MI), stroke, and sudden death occur in distinctive circadian patterns. These events occur with greater frequency in the early morning hours as compared with other times of the day.1–4 Paralleling this is a pattern of hemodynamic changes that may provide the pathophysiologic link for the circadian pattern of clinical events.5–8 The rapid rise in blood pressure (BP) and heart rate that occurs after awakening exerts a substantial hemodynamic stress, which may precipitate myocardial ischemia or stroke.5–8 Consequently, therapy targeted to offset the hemodynamic stress may be particularly effective at addressing both the physiologic events and their attendant morbidity.9 Controlled-onset, extended-release (COER-24) verapamil (Covera-HS, Pharmacia Corp., Peapack, NJ) is a unique delivery system that modulates, and therefore maximizes, the delivery of verapamil to coincide with the morning rise in BP and heart rate.10,11

The aim of the present study was to compare the efficacy of COER-24 verapamil, administered at bedtime, with two classes of commonly used hypertensive medications, angiotensin converting enzyme (ACE) inhibitors (enalapril) and angiotensin-receptor blockers (losartan), administered in the morning. We examined the effects of these three drugs on hemodynamic parameters in the morning as well as throughout the entire 24-h period.

Materials and methods

Study population

A total of 406 patients were randomized at 30 sites in the United States and Canada. All patients provided written informed consent, and the protocol was approved by the Institutional Review Board of all participating institutions.

Patients who were enrolled were between 21 and 80 years of age and had stage I to III essential hypertension (defined as an untreated diastolic BP between 95 and 114 mm Hg on two consecutive visits). In addition, all patients underwent ambulatory BP monitoring and were required to have a diastolic pressure of ≥85 mm Hg during normal daily activities between 10 AM and 6 PM. Patients on active treatment for hypertension before enrollment were eligible but first underwent a 1- to 2-week screening period during which their active medication was discontinued.

Patients were excluded if any of the following conditions were present: MI, unstable angina, stroke, or transient ischemic attack within the past 6 months, a history of New York Heart Association class II to IV heart failure, hypertrophic cardiomyopathy, secondary hypertension due to any identifiable cause, renal allografts, renal insufficiency (creatinine >2.5 mg/dL), poorly controlled diabetes, active hepatic disease, required use of any other hypertensive medication, or known hypersensitivity to any of the study medications.

Study methods

Patients underwent a screening period of 1 to 2 weeks during which their current medications were discontinued. They then entered a placebo lead-in period of 2 to 4 weeks to allow complete washout of their prior antihypertensive medications. They were subsequently randomized in a 2:2:2:1 ratio to one of four treatment arms: 1) COER-verapamil, 2) enalapril, 3) losartan, or 4) placebo. Patients were then started on a lower dose of the active medication for 4 weeks and underwent upward titration for an additional 4 weeks, for a total of 8 weeks of therapy. The doses employed for each of the active medications for the first and second treatment phase were as follows: 1) COER-verapamil (240 mg/day titrated to 360 mg/day); 2) enalapril (10 mg/day titrated to 20 mg/day); or 3) losartan (50 mg/day titrated to 100 mg/day). Enalapril and losartan were administered in the morning, whereas COER-verapamil was administered in the evening. Patients received matching placebo drug at the alternate time to maintain the double blind. Patients assigned to the placebo arm received an “upward titration” to maintain the double blind.

Seated and standing vital signs and 24-h ambulatory BP monitoring (ABPM) (SpaceLabs monitor, model 90207; SpaceLabs, Redmond, WA) were repeated after 4 weeks and 8 weeks of active treatment. The primary end point was BP during the morning acceleration phase, defined as the 4 h after awakening. Secondary objectives of the study were to compare the effects of the three medications on the rate of rise in BP and heart rate during the morning acceleration phase, and to compare the effects of treatment during the entire 24-h dosing interval.

Statistical analysis used analysis of covariance to compare treatment groups with respect to each efficacy variable. Comparison of demographic and baseline data was performed with χ2 methods for categoric data and nonparametric Kruskal-Wallis methods for continuous-value data. Statistical significance was defined as P < .05. During the course of the study, ongoing testing revealed that the stability of one lot of losartan could not be guaranteed. Patients and investigators remained blinded to the medication under suspicion. The medication supplies were replenished with lots of losartan the stability of which was adequate. Subsequently, at the end of the study, patients who had received medication from the suspect losartan were excluded from analysis. All other batches of losartan and all batches of the other study medications passed all stability testing. To compensate for the loss of patients and the attendant loss of statistical power, overall enrollment was boosted to reestablish the original statistical power. The sample size calculations were performed with the intent of an 80% power to detect a mean difference of ≥3 mm Hg in the morning diastolic pressure between active treatment groups using a two-tailed α = 0.05.

Results

The baseline demographic and clinical variables are summarized in Table 1. There were no significant differences in age, ethnicity, gender, or baseline BPs among the four treatment groups. Similarly, the groups were comparable for baseline ABPM recordings for the entire 24-h period as well as for each of the time periods (morning, daytime, nighttime) (Table 2).

Table 1

Baseline patient characteristics

COER = controlled-onset, extended-release; BP = blood pressure.

Table 1

Baseline patient characteristics

COER = controlled-onset, extended-release; BP = blood pressure.

Table 2

Baseline ambulatory BP recordings

Abbreviation as in Table 1.

Table 2

Baseline ambulatory BP recordings

Abbreviation as in Table 1.

Morning lowering of BP

Although all three active treatments, in comparison to placebo, reduced BP (as measured by ABPM) during the morning acceleration phase, COER-verapamil reduced both diastolic and systolic BP to a greater degree than did either enalapril or losartan (Fig. 1). The mean reductions in systolic and diastolic BP for COER-verapamil were −16.6/−11.9 mm Hg, ν −10.4/−6.0 mm Hg for enalapril (P < .001) and −8.9/−5.2 mm Hg for losartan (P < .001). Paralleling these ABPM measurements, BP as recorded by cuff during the morning office visit revealed a greater reduction with COER-verapamil (systolic/diastolic change, −18.2/−13.7 mm Hg) than with either enalapril (−11.1/−7.5 mm Hg; P = .003 for systolic and P < .001 for diastolic) or losartan (−9.1/−7.7 mm Hg; P < .001 for both systolic and diastolic).

The change from baseline to week 8 in systolic and diastolic blood pressure during the postawakening morning hours induced by COER-verapamil, enalapril, losartan, and placebo. COER = controlled-onset, extended-release.

Fig 1. Fig 1.

Twenty-four-hour BP lowering

The BP–lowering effects for the entire 24-h period were comparable for COER-verapamil and enalapril. COER-verapamil lowered the systolic and diastolic pressure by −11.6/−8.4 mm Hg, ν −13.1/−8.3 mm Hg for enalapril (P = .07 and P = .80 for systolic and diastolic, respectively). Losartan achieved comparable lowering of the systolic BP for the 24-h period (−9.3 mm Hg; P = .20 ν COER-verapamil) but was less effective in lowering the diastolic pressure (−5.4 mm Hg; P = .004 ν COER-verapamil).

Nighttime lowering of BP

During the nighttime hours, enalapril lowered the systolic BP to a greater degree (−11.3 mm Hg) than COER-verapamil (−8.9 mm Hg; P =.014). The effects of losartan on systolic pressure (−7.6 mm Hg) were comparable to COER-verapamil (P = 0.80). All three agents had comparable effects, which were not significantly different on nighttime diastolic pressure (−6.5 mm Hg with COER-verapamil; −7.0 mm Hg with enalapril; −4.6 mm Hg with losartan).

Circadian pattern of BP lowering

The complete circadian pattern of BP lowering by the three active agents is illustrated in Figs. 2 and 3. COER-verapamil exerted its most prominent effect in the postawakening morning hours and its least effect during nighttime hours. The effect of enalapril peaked in the afternoon hours but continued to exert the greatest effect of the three agents during the nighttime hours. Losartan demonstrated the flattest circadian effect of the three agents, with approximately equal lowering of BP throughout the 24-h period.

The 24-h effects of COER-verapamil, enalapril, and losartan on diastolic blood pressure (BP). The effects of the drugs are shown as change in BP from baseline to week 8. Abbreviation as in Fig. 1.

Fig 2. Fig 2.

The 24-h effects of COER-verapamil, enalapril, and losartan on systolic BP. The effects of the drugs are shown as change in BP from baseline to week 8. Abbreviation as in Figs. 1 and 2.

Fig 3. Fig 3.

Heart rate reduction

COER-verapamil significantly reduced heart rate for both the 24-h period (−4.7 beats/min; P < .001 ν placebo) and the daytime hours (−4.6 beats/min; P < .001 ν placebo). Neither enalapril nor losartan had a significant effect on heart rate. Consequently, the double product (systolic pressure × heart rate) was significantly reduced by all three agents in comparison to placebo, but was reduced to a greater degree by COER-verapamil for both the morning acceleration phase (−2025 mm Hg·beats/min) and the entire 24-h period (−1505 mm Hg·beats/min) than either enalapril or losartan.

Blunted rise in BP in morning

COER-verapamil blunted the rate of rise in BP during the morning hours. COER-verapamil reduced the rate of rise of diastolic pressure by −1.0 mm Hg/h (P = .03 ν placebo), whereas enalapril (−0.1 mm Hg/h) and losartan (−0.02 mm Hg/h) did not reduce this rate in comparison to placebo.

Adverse events

The overall incidence of adverse events was comparable in the four treatment groups: 63% for COER-verapamil, 61% for enalapril, 54% for losartan, and 53% for placebo. Serious adverse events were reported in one patient receiving COER-verapamil (cholelithiasis), one patient receiving enalapril (aggravated hypertension), and five events in two patients receiving losartan (syncope, chest pain, MI, epistaxis, and acute renal failure). The most common adverse event in all groups was headache: 26% of the COER-verapamil group, 16% of enalapril, 20% of losartan, and 16% of placebo. Other adverse events reported included constipation in 11% of COER-verapamil patients and upper respiratory infections in 12% of enalapril patients.

Discussion

The present study demonstrated that the antihypertensive effects of COER-verapamil are better matched to normal circadian rhythms of BP than either enalapril or losartan. COER-verapamil reduced BP during the morning acceleration phase to a greater degree than either enalapril or losartan; had a similar degree of overall BP–lowering effects over the entire 24-h period in comparison to enalapril, and a superior 24-h effect in comparison to losartan; and had less impact than enalapril on nocturnal BP when BP is already at its lowest.

The importance of the circadian BP patterns is their association with important clinical events.5–8 The postawakening surge in morning BP has been implicated as one potential mechanism contributing to the morning excess of serious cardiovascular events such as MI and strokes.5–8 The ability to lower the rising BP during these critical morning hours is thus a desirable feature in antihypertensive therapy, and may offer an important physiologic approach.9

Conversely, there are potential substantial benefits in avoiding nocturnal hypotension. The BP patterns during sleeping hours have been implicated in the development of end-organ damage. The normal pattern of BP during sleep is a dip of ≥10%. Although the absence of “dipping” is associated with certain forms of end-organ effects such as left ventricular hypertrophy, more recent data have implicated an exaggeration of the nocturnal dipping pattern (“overdipping”) with cerebrovascular and optic nerve–head ischemic lesions.12–14 Thus, an exaggeration of the normal dipping pattern by antihypertensive therapy is not desirable and may contribute to recurrent cerebral ischemic episodes.15

The effects of COER-verapamil in lowering heart rate may also be of clinical relevance. Although recent controversy has focused on the possibility that rapidly acting dihydropyridine calcium antagonists may aggravate myocardial ischemia via a reflex tachycardia, the effect of nondihydropyridines such as verapamil in slowing heart rate has been invoked as an important distinguishing mechanism.16

1. Muller JE , Stone PH , Turi ZG , Rutherford JD , Czeisler CA , Parker C , Poole WK , Passamani E , Roberts R , Robertson T , Sobel BE , Willerson JT , Braunwald E : Circadian variation in the frequency of onset of acute myocardial infarction. N Engl J Med 1985;313:1315–1322. 2. Cohen MC , Rohtla KM , Lavery CE , Muller JE , Mittelman MA : Meta-analysis of the morning excess of acute myocardial infarction and sudden cardiac death. Am J Cardiol 1997;11:1512–1516. 3. Elliott WJ : Circadian variation in the timing of stroke onset. Stroke 1998;29:992–996. 4. Willich SN , Levy D , Rocco MB , Tofler GH , Stone PH , Muller JE : Circadian variation in the incidence of sudden cardiac death in the Framingham Heart Study population. Am J Cardiol 1987;60:801–806. 5. Asmar R , Benetos A , Pannier B , Agnes E , Topouchian J , Laloux B , Safar M : Prevalence and circadian variations of ST-segment depression and its concomitant blood pressure changes in asymptomatic systemic hypertension. Am J Cardiol 1996;77:384–390. 6. Parati G , DiRienzo M , Ulian L , Santuccio C , Girard A , Elghozi JL , Mancia G : Clinical relevance of blood pressure variability. J Hypertens 1998;16:S25–S33. 7. Rehman A , Zalos G , Andrews NP , Mulcahy D , Quyyumi AA : Blood pressure changes during transient myocardial ischemia: insights into mechanisms. J Am Coll Cardiol 1997;30:1249–1255. 8. Trenkwalder P , Dobrindt R , Plaschke M , Lydtin H : Usefulness of simultaneous ambulatory electrocardiographic and blood pressure monitoring in detecting myocardial ischemia in patients >70 years of age with systemic hypertension. Am J Cardiol 1993;72:927–931. 9. Anwar YA , White WB : Chronotherapeutics for cardiovascular disease. Drugs 1998;55:631–643. 10. White WB , Black HB , Weber MA , Elliott WJ , Bryzinski B , Fakouhi TD : Comparison of effects of controlled onset extended release verapamil at bedtime and nifedipine gastrointestinal therapeutic system on arising on early morning blood pressure, heart rate, and the heart rate-blood pressure product. Am J Cardiol 1998;81:424–431. 11. White WB , Anders RJ , MacIntyre JM , Black HR , Sica DA : Nocturnal dosing of a novel delivery system of verapamil for systemic hypertension. Am J Cardiol 1995;76:375–380. 12. Hayreh SS , Zimmerman MB , Podhajsky P , Alward WLM : Nocturnal arterial hypotension and its role in optic nerve head and ocular ischemic disorders. Am J Opthalmol 1994;117:603–624. 13. Watanabe N , Imai Y , Nagai K , Tsuji I , Satoh H , Sakuma M , Sakuma H , Kato J , Onodera-Kikuchi N , Yamada M , Abe F , Hisamichi S , Abe K : Nocturnal blood pressure and silent cerebrovascular lesions in elderly Japanese. Stroke 1996;27:1319–1327. 14. Kario K , Matsuo T , Kobayashi H , Imiya M , Matsuo M , Shimada K : Nocturnal fall of blood pressure and silent cerebrovascular damage in elderly hypertensive patients: advanced silent cerebrovascular damage in extreme dippers. Hypertension 1996;27:130–135. 15. Nakamura K , Oita J , Yamaguchi T : Nocturnal blood pressure dip in stroke survivors. Stroke 1995;26:1373–1378. 16. Gibson RS , Hansen JF , Messerli F , Schechtman KB , Boden WE : Long-term effects of diltiazem and verapamil on mortality and cardiac events in non-Q-wave acute myocardial infarction without pulmonary congestion: post hoc subset analysis of the Multicenter Diltiazem Postinfarction Trial and the Second Danish Verapamil Infarction Trial studies. Am J Cardiol 2000;86:275–279.

Author notes

* This study was supported by Pharmacia Corporation. © 2002 by the American Journal of Hypertension, Ltd. American Journal of Hypertension, Ltd.

What is losartan used for?

  • Lowering high blood pressure with no known cause (essential hypertension) in adults and in children and adolescents aged 6 to 18 years.
  • Reducing the risk of stroke in adults with high blood pressure and an enlarged heart (left ventricular hypertrophy).
  • Treating diabetic kidney disease (diabetic nephropathy) in adults with type 2 diabetes.
  • Treating chronic heart failure in adults who can’t take medicines called ACE inhibitors.

How does losartan work?

Losartan potassium is a type of medicine called an angiotensin II receptor antagonist. It works by blocking angiotensin II receptors and preventing the action of a hormone called angiotensin II.

Angiotensin II is involved in regulating blood pressure and fluid balance. It has two main actions. It causes the blood vessels to constrict and narrow; it also reduces the amount of salt and water that the kidneys filter out of the blood. Both these actions increase the pressure in the blood vessels.

By blocking the action of angiotensin II, losartan allows the blood vessels to widen and more fluid to be filtered out of the blood by the kidneys. This lowers blood pressure.

When the pressure in the blood vessels is reduced, it makes it easier for the heart to pump the blood around the body. This means that losartan can be used to improve the symptoms of heart failure, where the heart isn’t pumping as efficiently as it should be.

Losartan is used in diabetic kidney disease because it lowers high blood pressure (which can damage the kidneys) but also because it can help protect the kidneys and slow down the progression of the disease.

What should I know before taking losartan?

  • Some people may find that taking losartan makes them feel tired, dizzy or faint. If you feel dizzy you should lie down until the symptoms pass. Try getting up slowly if you find you feel dizzy when you stand up. If you frequently feel dizzy let your doctor know, as your losartan dose may need reducing.
  • If you’re due to have an operation or dental treatment, it’s important to tell the person carrying out the treatment that you’re taking losartan. This is particularly important if you’re likely to be given an anaesthetic.

Can I drive while taking losartan?

Usually yes, but as losartan can make some people feel dizzy you should make sure you know how you react to it before driving or operating machinery. Avoid doing these potentially hazardous activities if affected.

Can I drink alcohol while taking losartan?

Although alcohol doesn’t directly affect the medicine itself, drinking alcohol can increase the blood pressure lowering effect of losartan, which could make you more likely to feel dizzy. If you find losartan makes you feel dizzy it’s best to avoid drinking alcohol. Also remember that alcohol can increase blood pressure and make heart failure worse, so it’s important to minimise the amount of alcohol that you drink.

Do I need to avoid any food or drinks while taking losartan?

  • You shouldn’t use salt substitutes such as Lo-Salt while you’re taking losartan. This is because these have a high content of potassium, which together with the losartan can make the amount of potassium in your blood rise too high.
  • Other than alcohol, there’s nothing else you specifically need to avoid while taking losartan. Just make sure you are eating a healthy, balanced diet to help your condition.
  • How do I take losartan?
  • Who shouldn’t take losartan?
  • What are the possible side effects of losartan?
  • Can I take other medicines with losartan?

What branded medicines contain losartan?

Losartan is a generic medicine, available as losartan 12.5 mg tablets, losartan 25 mg tablets, losartan 50 mg tablets and losartan 100 mg tablets. Losartan tablets and liquid are also available under the brand name Cozaar.

Cozaar comp tablets contain losartan in combination with a diuretic medicine called hydrochlorothiazide.

Last updated: 24.03.2017

Helen Marshall, BPharm, MRPharmS Helen Marshall, BPharm, MRPharmS A UK registered pharmacist with a background in hospital pharmacy.

Differential effects of losartan and doxazosin on vascular function in senescent spontaneously hypertensive rats*

We evaluated the effects of treatment for 12 weeks with 10 mg/kg/day of either losartan or doxazosin on vascular function in senescent spontaneous hypertensive rats (SHR). Both doxazosin and losartan reduced blood pressure, although the former was more effective. In contrast, both drugs reduced relative aortic weight and increased plasma nitrates to a similar extent. Losartan, but not doxazosin, increased the magnitude of the response to acetylcholine (10−9 to 10−5 mol/L). Both treatments increased relaxations to sodium nitroprusside (10−10 to 10−6 mol/L). These data show that losartan may possess advantages over doxazosin in improving vascular function in senescent SHR. This report emphasizes the importance of angiotensin II in vascular function alterations induced by aging in SHR.

Clinical and experimental studies have shown that hypertension is associated with endothelial dysfunction mainly characterized by a reduction in endothelium-dependent relaxations.1,2 These functional changes can be magnified by aging, probably attributable to a longer duration of hypertension and, therefore, to a longer exposure of the responsible mechanisms to endothelial dysfunction.3,4,5 Indeed, we have previously observed a lower vasorelaxing response not only to acetylcholine (Ach) but also to sodium nitroprusside (SNP) in senescent as compared to adult spontaneous hypertensive rats (SHR).3 Moreover, we have also found a greater response to both angiotensin II and phenylephrine (PE) in aged SHR than in adult animals.3,6 This suggests the possibility that the renin-angiotensin system and cathecholamines can play a role in the alterations of vascular function associated with aging in SHR. In fact, captopril and losartan can improve relaxations to Ach and SNP in senescent SHR, thus supporting the notion that angiotensin II participates in these alterations. However, it is not yet well established whether cathecholamines can also participate in functional changes in the vascular wall produced by aging in SHR. Therefore, the aim of this study was to evaluate the effect of an α1-adrenergic receptor antagonist on vascular function in senescent SHR. As a control, we studied the effect of losartan.

Methods

Animals

Senescent male SHR 20 to 22 months old (Charles River, Barcelona, Spain) were treated for 12 consecutive weeks with 10 mg/kg per day of either losartan or doxazosin in drinking water. A group of untreated animals was run in parallel. The animals were maintained under controlled light and temperature conditions, and were fed a normal rat chow (A.04, Panlab, Barcelona, Spain). All experimental procedures were approved by the Institutional Animal Care and Use Committee, according to the guidelines for ethical care of experimental animals of the European Community.

Blood pressure measurement procedure

Systolic blood pressure (SBP) was estimated basally and at the end of the study by use of a tail–cuff plethysmograph (Narco Bio-Systems, Houston, TX) in unrestrained animals. Rats were trained daily before the beginning of measurements of blood pressure, as described elsewhere.3 The method was previously validated by comparing the values with direct measurements obtained in chronically catheterized animals.3

Plasma nitrates concentration

Plasma samples were obtained in tubes containing citrate (3.8%) when the animals were killed. Plasma nitrite concentrations were measured using Griess reagent after the quantitative conversion of nitrates to nitrites by using dihydronicotinamide adenine dinucleotide (NADH)-dependent nitrate reductase. Thus, the results are expressed in terms of plasma concentrations of nitrates plus nitrites ( in mmoles per liter).

Vascular measurements

Concentration–response curves to Ach (10−9 to 10−5 mol/L) and SNP (10−10 to 10−6 mol/L) were studied in aortic rings contracted with a submaximal dose of PE and prepared as described elsewhere. The degree of preconstriction of rings was similar in all groups. As an index of aortic hypertrophy the weight per 10-mm length per 100 g body weight ratio was used.7

Data analysis

Single-variable comparisons were made using a one-way analysis of variance; all other data were analyzed by two-way analysis of variance for multiple comparisons, followed by a Newman-Keuls test if differences were noted. Values of P < .05 were considered statistically significant. Results are presented as mean ± SEM of 6 rats.

Chronic treatment with either losartan or doxazosin decreased SBP levels as compared with the untreated group (157.6 ± 6.9, 133.7 ± 9.6, 195.5 ± 7.7 mm Hg, respectively), although the effect of doxazosin tended to be more prominent than that observed with losartan (in the limit of significance). This hypotensive effect was associated with a similar reduction (P < .05) in the relative weight of the aortic rings as compared with the control group (1.49 ± 0.08, 1.45 ± 0.06, 1.88 ± 0.08 mg/10 mm/100 g body weight, losartan, doxazosin, and control group, respectively). Likewise, both losartan and doxazosin treatment increased (P < .05) plasma nitrate levels to the same extent as compared with the untreated group (49.1 ± 8.3, 45.0 ± 10.3, 18.6 ± 4.9 μmol/L, respectively).

As shown in Figure 1 (right top), losartan administration increased the magnitude of the response to Ach, as suggested by the increase in the maximal response. Likewise, rings from losartan-treated animals were more sensitive to acetylcholine, as shown by a higher pD2 value (7.8 ± 0.2 v 6.9 ± 0.1; P < .05). In contrast, doxazosin treatment enhanced the sensitivity to this agent only (7.6 ± 0.1 v 6.9 ± 0.1; P < .05). Both treatments increased the relaxation to SNP as shown by an increase in maximal response (Figure 1, bottom) and pD2 value (7.9 ± 0.2, 7.8 ± 0.1, 7.3 ± 0.04, losartan, doxazosin, and control group, respectively).

Figure 1. Figure 1.

The present study shows that losartan, the AT1 receptor antagonist, was more effective than doxazosin in improving vascular function in senescent SHR. This suggests the importance of angiotensin II in the alterations of vascular function in senescent SHR. Moreover, these data confirm previous observations indicating that a reduction in blood pressure is not always associated with amelioration of endothelial dysfunction.8,9

Several mechanisms can be underlying the beneficial effects induced by doxazosin and losartan on the relaxation induced by Ach and SNP. The first could be attributable to a decrease in blood pressure, which implies a reduction in the physical stress targeting the vascular wall. This effect could also account for the reduction in the aortic hypertrophy induced by both drugs. Moreover, these changes in the vascular wall can also participate in the amelioration of vascular function by reducing the response to vasoconstrictor agents, which can antagonize the responses to vasodilatadory factors. An enhancement in NO availability, as suggested by an increase in plasma nitrates, could be an additional mechanism involved in the amelioration of the endothelial function induced by both drugs. This increase could be the consequence of an elevation in the synthesis or a reduction in its degradation. In fact, it has been shown that doxazosin is not only able to increase nitric oxide synthase (NOS) activity,10 but also reduce NO degradation through its antioxidant ability.11 Likewise, losartan can prevent NO degradation by inhibiting the vascular production of superoxide via NADH/NADPH oxidase activation.12 Indeed, we have provided supporting evidence for the involvement of NO in the actions of losartan in SHR.13,14

The fact that losartan was more effective than doxazosin in improving relaxation to Ach could be explained by a major production or sensitivity to angiotensin II in senescent SHR, which, in turn, antagonizes the actions of NO. Indeed, we have previously reported a greater response to angiotensin II in senescent SHR as compared with that in adult animals in both conduit and resistance arteries.3,6 This response was reduced by losartan. Likewise, aging increases the activity of angiotensin converting enzyme in resistance arteries from SHR.15

In summary, these data show that in senescent SHR, blocking of AT1 receptors with losartan may improve vascular function to a greater extent than by blocking α1-adrenergic receptors with doxazosin, and emphasize the importance of angiotensin II in vascular function alterations observed in senescent SHR.

1. De Mey JG , Gray DD : Endothelium-dependent reactivity in resistance vessels. Prog Appl Microcirc 1985;88:181–187. 2. Linder L , Kiowki W , Bühler FRR , Luscher LF : Indirect evidence for release of endothelium-derived relaxing factor in human forearm circulation in vivo: blunted response in essential hypertension. Circulation 1990;81:1762–1767. 3. Maeso R , Rodrigo E , Muñoz-García R et al. Chronic treatment with losartan ameliorates vascular dysfunction induced by aging in spontaneously hypertensive rats. J Hypertens 1998;16:665–672. 4. Taddei S , Virdis A , Mattei P et al. Aging and endothelial function in normotensive subjects and essential hypertension patients. Circulation 1995;91:1981–1987. 5. Küng CF , Lüscher TF : Different mechanisms of endothelial dysfunction with aging and hypertension in rat aorta. Hypertension 1995;14:S42–S48. 6. Maeso R , Rodrigo E , Muñoz-García R , Navarro-Cid J , Ruilope LM , Cachofeiro V , Lahera V ,Factors involved in the effects of an AT1 receptor antagonist on endothelial dysfunction induced by aging in SHR. Kidney Int 1998;54: (Suppl 8) S30–S35. 7. Hayakawa H , Raij L : The link among nitric oxide synthase activity, endothelial function, and aortic and ventricular hypertrophy in hypertension. Hypertension 1997;29: (part 2): 235–241. 8. Schiffrin EL , Deng LY : Comparison of effects of angiotensin I-converting enzyme inhibition and beta-blockade for 2 years on function of small arteries from hypertensive patients. Hypertension 1995;25:699–703. 9. Cockcroft JR , Chowienczyk FJ , Reniamin N et al. Preserved endothelium-dependent vasodilation in patients with essential hypertension. N Engl J Med 1994;330:1036–1040. 10. Tojo A , Kobayashi N , Kimura K et al. Effects of antihypertensive drugs on nitric oxide synthase activity in rat kidney. Kidney Int 1996;49:S138–S140. 11. Chait A , Gilmore M , Kawamura M : Inhibition of low density lipoprotein oxidation in vitro by the 6- and 7-hydroxy-metabolites of doxazosin, an α1-adrenergic antihypertensive agent. Am J Hypertens 1994;7:159–164. 12. Rajagopalan S , Kurz S , Munzel T , Tarpey M , Freeman BA , Griendling KK , Harrison DG : Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone. J Clin Invest 1996;97: (8): 1916–1923. 13. Cachofeiro V , Maeso R , Rodrigo E et al. Nitric oxide and prostaglandins in the prolonged effects of losartan and ramipril in hypertension. Hypertension 1995;26:236–243. 14. Maeso R , Navarro-Cid J , Muñoz-García R et al. Losartan reduces phenylephrine constrictor response in aortic rings from spontaneously hypertensive rats. Role of nitric oxide and angiotensin II type 2 receptors. Hypertension 1996;28:967–972. 15. Lang M , Noll G , Lüscher TF : Effect of aging and hypertension on contractility of resistance arteries: modulation by endothelial factors. Am J Physiol 1995;269:H837–H844. * This study was supported by grants from the Comisión Interministerial de Ciencia y Tecnología, Spain (SAF-1549-C02-01) and the Comunidad Autónoma de Madrid, Spain (08.4/0003/1997). © 1999 by the American Journal of Hypertension, Ltd. American Journal of Hypertension, Ltd.

This information from Lexicomp® explains what you need to know about this medication, including what it’s used for, how to take it, its side effects, and when to call your healthcare provider.

Brand Names: US

Hyzaar

Brand Names: Canada

Warning

  • Do not take if you are pregnant. Use during pregnancy may cause birth defects or loss of the unborn baby. If you get pregnant or plan on getting pregnant while taking this drug, call your doctor right away.

What is this drug used for?

  • It is used to treat high blood pressure.
  • It is used to prevent strokes.
  • It may be given to you for other reasons. Talk with the doctor.

What do I need to tell my doctor BEFORE I take this drug?

  • If you are allergic to this drug; any part of this drug; or any other drugs, foods, or substances. Tell your doctor about the allergy and what signs you had.
  • If you have a sulfa allergy.
  • If you are taking dofetilide.
  • If you are not able to pass urine.
  • If you are dehydrated, talk with your doctor.
  • If you are taking a drug that has aliskiren in it and you also have diabetes or kidney problems.
  • If you are breast-feeding or plan to breast-feed.

This is not a list of all drugs or health problems that interact with this drug.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this drug with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

What are some things I need to know or do while I take this drug?

  • Tell all of your health care providers that you take this drug. This includes your doctors, nurses, pharmacists, and dentists.
  • Avoid driving and doing other tasks or actions that call for you to be alert until you see how this drug affects you.
  • To lower the chance of feeling dizzy or passing out, rise slowly if you have been sitting or lying down. Be careful going up and down stairs.
  • If you have high blood sugar (diabetes), you will need to watch your blood sugar closely.
  • Check your blood pressure as you have been told.
  • Have blood work checked as you have been told by the doctor. Talk with the doctor.
  • This drug may affect certain lab tests. Tell all of your health care providers and lab workers that you take this drug.
  • If you are taking a salt substitute that has potassium in it, a potassium-sparing diuretic, or a potassium product, talk with your doctor.
  • If you are on a low-salt or salt-free diet, talk with your doctor.
  • Talk with your doctor before using OTC products that may raise blood pressure. These include cough or cold drugs, diet pills, stimulants, ibuprofen or like products, and some natural products or aids.
  • Talk with your doctor before you drink alcohol or use other drugs and natural products that slow your actions.
  • Be careful in hot weather or while being active. Drink lots of fluids to stop fluid loss.
  • Tell your doctor if you have too much sweat, fluid loss, throwing up, or loose stools. This may lead to low blood pressure.
  • If you take cholestyramine or colestipol, talk with your pharmacist about how to take them with this drug.
  • Watch for gout attacks.
  • This drug may cause high cholesterol and triglyceride levels. Talk with the doctor.
  • If you have lupus, this drug can make your lupus active or get worse. Tell your doctor right away if you get any new or worse signs.
  • This drug may not work as well in black patients. Talk with the doctor.
  • If you are 65 or older, use this drug with care. You could have more side effects.

What are some side effects that I need to call my doctor about right away?

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Signs of high blood sugar like confusion, feeling sleepy, more thirst, more hungry, passing urine more often, flushing, fast breathing, or breath that smells like fruit.
  • Signs of kidney problems like unable to pass urine, change in how much urine is passed, blood in the urine, or a big weight gain.
  • Signs of fluid and electrolyte problems like mood changes, confusion, muscle pain or weakness, a heartbeat that does not feel normal, very bad dizziness or passing out, fast heartbeat, more thirst, seizures, feeling very tired or weak, not hungry, unable to pass urine or change in the amount of urine produced, dry mouth, dry eyes, or very bad upset stomach or throwing up.
  • Swelling in the arms or legs.
  • Any skin change.
  • This drug can cause certain eye problems. If left untreated, this can lead to lasting eyesight loss. If eye problems happen, signs like change in eyesight or eye pain most often happen within hours to weeks of starting this drug. Call your doctor right away if you have these signs.

What are some other side effects of this drug?

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

  • Dizziness.
  • Signs of a common cold.
  • Back pain.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to your national health agency.

How is this drug best taken?

Use this drug as ordered by your doctor. Read all information given to you. Follow all instructions closely.

  • Take with or without food.
  • Keep taking this drug as you have been told by your doctor or other health care provider, even if you feel well.
  • This drug may cause you to pass urine more often. To keep from having sleep problems, try not to take too close to bedtime.
  • Drink lots of noncaffeine liquids unless told to drink less liquid by your doctor.

What do I do if I miss a dose?

  • Take a missed dose as soon as you think about it.
  • If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
  • Do not take 2 doses at the same time or extra doses.

How do I store and/or throw out this drug?

  • Store at room temperature protected from light. Store in a dry place. Do not store in a bathroom.
  • Keep lid tightly closed.
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Throw away unused or expired drugs. Do not flush down a toilet or pour down a drain unless you are told to do so. Check with your pharmacist if you have questions about the best way to throw out drugs. There may be drug take-back programs in your area.

General drug facts

  • If your symptoms or health problems do not get better or if they become worse, call your doctor.
  • Do not share your drugs with others and do not take anyone else’s drugs.
  • Some drugs may have another patient information leaflet. If you have any questions about this drug, please talk with your doctor, nurse, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Consumer Information Use and Disclaimer

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

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