Consumer medicine information

Cozavan

Losartan potassium

BRAND INFORMATION

Brand name

Cozavan

Active ingredient

Losartan potassium

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Cozavan.

SUMMARY CMI

COZAVAN®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about taking this medicine, speak to your doctor or pharmacist.

1. Why am I taking COZAVAN?

COZAVAN contains the active ingredient losartan. COZAVAN is used to lower high blood pressure, which doctors call hypertension. For more information, see Section 1. Why am I taking COZAVAN? in the full CMI.

2. What should I know before I take COZAVAN?

Do not use if you have ever had an allergic reaction to COZAVAN or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I take COZAVAN? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with COZAVAN and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I take COZAVAN?

Your doctor will tell you how many tablets you need to take each day. This depends on your condition and whether you are taking other medicines.

More instructions can be found in Section 4. How do I take COZAVAN? in the full CMI.

5. What should I know while taking COZAVAN?

Things you should do
  • Remind any doctor, dentist, or pharmacist you visit that you are taking COZAVAN.
  • Go to your doctor regularly for a check-up. Have your blood pressure checked when your doctor says, to make sure COZAVAN is working.
  • If you feel light-headed, dizzy or faint, get up slowly when getting out of bed or standing up.
  • Make sure you drink enough water during exercise and hot weather when you are taking COZAAR, especially if you sweat a lot.
  • If you have excessive vomiting and/or diarrhoea while taking COZAVAN, tell your doctor.
  • If your doctor has prescribed potassium tablets for you, continue taking them.
Things you should not do
  • Do not give COZAVAN to anyone else, even if they have the same condition as you.
Driving or using machines
  • COZAVAN may cause dizziness or light-headedness in some people. Make sure you know how you react to COZAVAN before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy or light-headed.
Drinking alcohol
  • If you drink alcohol, dizziness or light-headedness may be worse.
Looking after your medicine
  • Keep your tablets in a cool dry place where the temperature stays below 25°C.
  • Keep your tablets in the original pack until it is time to take them.

For more information, see Section 5. What should I know while taking COZAVAN? in the full CMI.

6. Are there any side effects?

Common side effects include dizziness, light-headedness, tiredness, or weakness, spinning sensation, generally feeling unwell, increased sensitivity of the skin to the sun and an inability to get or maintain an erection. Serious side effects include skin rash, shortness of breath, sore muscles not caused by exercise, bleeding or bruising more easily than normal or symptoms of an allergic reaction. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

COZAVAN®

Active ingredient(s): losartan potassium

Consumer Medicine Information (CMI)

This leaflet provides important information about taking COZAVAN. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about taking COZAVAN.

Where to find information in this leaflet:

1. Why am I taking COZAVAN?
2. What should I know before I take COZAVAN?
3. What if I am taking other medicines?
4. How do I take COZAVAN?
5. What should I know while taking COZAVAN?
6. Are there any side effects?
7. Product details

1. Why am I taking COZAVAN?

COZAVAN contains the active ingredient losartan.

COZAVAN belongs to a group of medicines, called angiotensin II receptor antagonists. It works to lower your blood pressure by relaxing your blood vessels. In addition, COZAVAN slows the progression of kidney disease in people who have type 2 diabetes mellitus with protein in the urine.

COZAVAN is used to lower high blood pressure, which doctors call hypertension.

COZAVAN is also used to slow the progression of kidney disease in people who have type 2 diabetes mellitus (also known as non-insulin dependent diabetes) with protein in their urine (which doctors call proteinuria).

Hypertension:

Everyone has blood pressure. This pressure helps get your blood all around your body. Your blood pressure may be different at different times of the day, depending on how busy or worried you are. You have hypertension (high blood pressure) when your blood pressure stays high, even when you are calm and relaxed.

There are usually no symptoms of hypertension. The only way of knowing that you have hypertension is to have your blood pressure checked on a regular basis. If high blood pressure is not treated it can lead to serious health problems. You may feel fine and have no symptoms, but eventually hypertension can cause stroke, heart disease or kidney failure. COZAVAN helps to lower your blood pressure.

Type 2 Diabetes Mellitus:

Type 2 diabetes mellitus is a condition in which the body's cells do not respond to the effects of insulin or too little insulin is produced, resulting in an elevated blood (sugar) level, known as hyperglycaemia.

Insulin maintains the appropriate level of glucose in the blood by transporting it into the body's cells so that they can produce energy or store glucose until it's needed.

Hyperglycaemia can lead to serious problems with your heart, eyes, circulation, or kidneys. When kidney damage occurs, its ability to filter blood is reduced, and proteins in the blood are lost in the urine. This may eventually lead to kidney failure. In people who have type 2 diabetes mellitus with protein in their urine, COZAVAN helps to slow the worsening of kidney disease and reduce the need for dialysis or kidney transplantation.

COZAVAN is not addictive.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

2. What should I know before I take COZAVAN?

Warnings

Do not take COZAVAN if:

  • you are pregnant or breastfeeding.
  • you are allergic to losartan, or any of the ingredients listed at the end of this leaflet.
    Some of the symptoms of an allergic reaction may include:
    - skin rash, itching or hives
    - swelling of the face, lips or tongue which may cause difficulty in swallowing or breathing
    - wheezing or shortness of breath.
    Always check the ingredients to make sure you can use this medicine.
  • you have diabetes and are taking a medicine called aliskiren to reduce blood pressure.
  • the expiry date printed on the pack has passed, or if the packaging is torn or show sign of tampering. Return it to your pharmacist for disposal.

Check with your doctor if you:

  • have, or have had, any medical conditions, especially kidney disease or liver problems.
    Your doctor may want to take special care if you have any of these conditions.
  • take any medicines for any other condition.
  • are taking other medicines that may increase serum potassium (see Section 3. What if I am taking other medicines?).
  • have recently had excessive vomiting or diarrhoea.
  • have any allergies to any other medicines or any other substances, such as foods, preservatives, or dyes.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Tell your doctor if you are pregnant or plan to become pregnant.

Tell to your doctor if you are breastfeeding or plan to breastfeed.

The use of COZAVAN while you are pregnant or breastfeeding is not recommended.

Your baby may absorb this medicine in the womb. COZAVAN can cause harm or death to an unborn baby. Talk to your doctor about other ways to lower your blood pressure if you plan to become pregnant. If you get pregnant while taking COZAVAN tell your doctor right away.

It is not known whether COZAVAN passes into breast milk, therefore it is not recommended to be taken while you are breastfeeding.

Use in children

Do not give COZAVAN to a child. There is no experience with the use of COZAVAN in children.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins, or supplements that you buy without a prescription from your pharmacy, supermarket, or health food shop.

Some medicines may interfere with COZAVAN and affect how it works.

Medicines that may increase the effect of COZAVAN include:

  • other blood pressure medicines
  • diuretic tablets, also called fluid or water tablets, including potassium-sparing diuretics
  • medicines used to relieve pain, swelling, and other symptoms of inflammation, for example indomethacin.

Medicines that may reduce the effect of COZAVAN include:

  • non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2 inhibitors, medicines used to relieve pain, swelling and other symptoms of inflammation, including arthritis.
  • grapefruit juice (which should be avoided while taking COZAVAN).

Medicines that may increase serum potassium when taken with COZAVAN include:

  • potassium tablets.
  • potassium-containing salt substitutes.
  • other medicines that may increase serum potassium (e.g., trimethoprim-containing products).

Medicines that may be affected when taken with COZAVAN include:

  • lithium (a medicine used to treat mood swings and some types of depressions).

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect COZAVAN.

You may need to take different amounts of your medicine, or you may need to take different medicines.

4. How do I take COZAVAN?

How much to take

  • Your doctor will tell you how many tablets you need to take each day. This depends on your condition and whether you are taking other medicines.
  • For high blood pressure:
    For most patients, the usual starting dose is one 50 mg tablet taken once a day. Some patients may need a lower starting dose. The dose may need to be increased depending on your blood pressure. Most patients take between 25 to 100 mg each day, taken as a single dose or in divided doses.
  • For type 2 diabetes mellitus with protein in the urine:
    The usual starting dose is one 50 mg tablet taken once a day. The dose may be increased to 100 mg once a day depending on your blood pressure.
  • COZAVAN helps control your high blood pressure but does not cure it. Therefore, COZAVAN must be taken every day. Follow the instructions provided and use COZAVAN until your doctor tells you to stop.

When to take COZAVAN

  • It does not matter whether you take COZAVAN before or after food.
  • Take your COZAVAN at about the same time each day. Taking your tablets at the same time each day will have the best effect. It will also help you remember when to take the tablets.

How to take COZAVAN

  • Swallow COZAVAN with a glass of water.

If you forget to take COZAVAN

COZAVAN should be taken regularly at the same time each day. If you miss your dose at the usual time, take it as soon as you remember, and then go back to taking your tablets as you would normally.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose you missed.

If you miss more than one dose, or are not sure what to do, check with your doctor or pharmacist.

If you have trouble remembering to take your tablets, ask your pharmacist or doctor for some hints.

If you take too much COZAVAN

If you take too many tablets, you will probably feel light-headed or dizzy.

If you think that you or anyone else has taken too much COZAVAN, urgent medical attention may be needed.

You should immediately:

  • phone the Poisons Information Centre
    (Australia telephone 13 11 26) for advice, or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while taking COZAVAN?

Things you should do

  • Have your blood pressure checked when your doctor says, to make sure COZAVAN is working.
  • Before starting any new medicine, tell your doctor or pharmacist that you are taking COZAVAN.
  • If you feel light-headed, dizzy or faint, get up slowly when getting out of bed or standing up.
    You may feel light-headed or dizzy while taking COZAVAN, especially if you are also taking a diuretic (fluid tablet). This may become worse if you stand up quickly as your blood pressure may fall. Standing up slowly, especially when you g.et up from bed or chairs, will help your body get used to the change in position and blood pressure. This problem is not common. If it occurs and gets worse or continues, talk to your doctor.
  • Tell all the doctors, dentists or pharmacists who are treating you that you are taking COZAVAN.
  • If you plan to have surgery (even at the dentist) that needs a general anaesthetic, tell your doctor or dentist that you are taking COZAVAN.
  • Make sure you drink enough water during exercise and hot weather when you are taking COZAVAN, especially if you sweat a lot.
    If you do not drink enough water while taking COZAVAN, you may faint or feel light-headed or sick. This is because your body doesn't have enough fluid and your blood pressure is low. If you continue to feel unwell, tell your doctor.
  • If you have excessive vomiting and/or diarrhoea while taking COZAVAN, tell your doctor.
    This can also mean that you are losing too much water and your blood pressure may become too low.
  • If your doctor has prescribed potassium tablets for you, continue taking them.
    COZAVAN contains a very small amount of potassium, but this does not replace any potassium tablets that you may be taking.
  • Visit your doctor regularly so they can check your progress.
    Your doctor may occasionally ask you to do a blood test to check your potassium level in the blood and to see how your kidneys are working.
  • Tell your doctor if, for any reason, you have not taken COZAVAN exactly as prescribed.
    Otherwise your doctor may adjust your treatment unnecessarily.

Call your doctor straight away if you:

  • become pregnant while taking COZAVAN. Your doctor needs to know immediately so that COZAVAN can be replaced by another medicine.

Things you should not do

  • Do not give COZAVAN to anyone else, even if they have the same condition as you.
  • Do not take COZAVAN for a longer time than your doctor has prescribed.
  • Do not let yourself run out of COZAVAN over the weekend or on holidays.
  • Do not use COZAVAN to treat any other conditions unless your doctor tells you to.

Things that would be helpful for your blood pressure

Some self-help measures suggested below may help your condition. Talk to your doctor or pharmacist about these measures and for more information.

  • Alcohol - your doctor may advise you to limit your alcohol intake.
  • Diet - eat a healthy diet which includes plenty of fresh vegetables, fruit, bread, cereals, and fish. Reducing your saturated fat intake (eat less fatty meats, full fat dairy products, butter, coconut and palm oils, most take-away foods, commercially-baked products).
  • Exercise - be active, regular exercise helps to reduce blood pressure and helps the heart get fitter, but it is important not to overdo it. Progress over time, to at least 30 minutes of moderate-intensity physical activity on 5 or more days each week. Can be accumulated in shorter bouts of 10 minutes duration. If you have been prescribed anti-angina medicine, carry it with you when being physically active. Walking is good exercise but try to find a route that is fairly flat. Before starting any exercise, ask your doctor about the best kind of program for you.
  • Salt - your doctor may advise you to watch the amount of salt in your diet. To reduce your salt intake, you should avoid using salt in cooking or at the table.
  • Smoking - your doctor may advise you to stop smoking or at least cut down and avoid second-hand smoke.
  • Weight - maintain a healthy weight. Your doctor may suggest losing some weight to help lower your blood pressure and help lessen the amount of work your heart has to do. Some people may need a dietician's help to lose weight.
  • Discuss your lifestyle and lifestyle plans with your doctor.
  • For more information and tools to improve your heart health, call Heartline, the Heart Foundation's national telephone information service, on 1300 36 27 87 (local call cost).

Driving or using machines

Be careful before you drive or use any machines or tools until you know how COZAVAN affects you.

As with many other medicines used to treat high blood pressure, COZAVAN may cause dizziness, drowsiness, light-headedness or affect alertness in some people. This effect may continue the following day. Make sure you know how you react to COZAVAN before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy or light-headed.

Particular care is recommended when you are first taking COZAVAN or if the amount of COZAVAN or any other medicine you are taking is increased or decreased.

Drinking alcohol

Tell your doctor if you drink alcohol.

If you drink alcohol, dizziness or light-headedness may be worse.

Use in elderly

Be careful if you are elderly, unwell or taking other medicines.

Some people may experience side effects such as drowsiness, confusion, dizziness and unsteadiness, which may increase the risk of a fall.

Know warning signs of heart attack and what to do:

  • Tightness, fullness, pressure, squeezing, heaviness or pain in your chest, neck, jaw, throat, shoulders, arms or back.
  • You may also have difficulty breathing or have a cold sweat or feel dizzy or light-headed or feel like vomiting (or actually vomit).
  • If you have heart attack warning signs that are severe, get worse or last for 10 minutes even if they are mild, call triple zero (000). Every minute counts.

Looking after your medicine

  • Store below 25°C.
  • Keep your tablets in the original pack until it is time to take them. If you take the tablets out the original pack, they may not keep well.

Follow the instructions on the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat, or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Heat and dampness can destroy some medicines.

Keep it where young children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Less serious side effects

Less serious side effectsWhat to do
Nervous system-related:
  • dizziness
Skin-related:
  • increased sensitivity of the skin to sun
Reproductive system or breast-related:
  • inability to get or maintain an erection.
General conditions:
  • lightheadedness
  • tiredness or weakness
  • spinning sensation
  • generally feeling unwell
Speak to your doctor if you have any of these less serious side effects and they worry you.
Respiratory-related:
  • cough
Tell your doctor if you develop cough.

Serious side effects

Serious side effectsWhat to do
Allergic reaction:
  • swelling of the face, lips, mouth, tongue, or throat which may cause difficulty in swallowing or breathing.
  • severe and sudden onset of pinkish, itchy swellings on the skin, also called hives or nettlerash
  • swelling in the intestine
Skin-related:
  • skin rash, itchiness (may be symptoms of an allergic reaction)
Muscle/skeleton-related:
  • aching muscles, not caused by exercise
Blood-related:
  • signs of anaemia, such as tiredness, being short of breath, and looking pale
  • bleeding or bruising more easily than normal
Stop taking COZAVAN immediately, call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.
Tell your doctor immediately if you notice any of these side effects. You may need medical attention.
These side effects are not common.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicines.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What COZAVAN contains

Active ingredient
(main ingredient)		losartan potassium 25 mg and 50 mg
Other ingredients
(inactive ingredients)
  • microcrystalline cellulose
  • lactose monohydrate
  • pregelatinised maize starch
  • magnesium stearate
  • Opadry complete film coating system 20A58900 White (ID 13043)
Potential allergens
  • Lactose

Do not take this medicine if you are allergic to any of these ingredients.

What COZAVAN looks like

COZAVAN 25 mg: white to off white, oval shaped biconvex film-coated tablet with "A" engraved on one side and "25" on the other side. (AUST R 156235).

COZAVAN 50 mg: white to off white, oval shaped biconvex film-coated tablet with "A50" engraved on one side and has a central break line on the other side. (AUST R 156234).

A blister pack of COZAVAN contains 10 (as starter pack) or 30 tablets.

Who distributes COZAVAN

Alphapharm Pty Ltd trading as Viatris
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.viatris.com.au
Phone: 1800 274 276

This leaflet was prepared in June 2025.

COZAVAN® is a Viatris company trademark.

COZAVAN_cmi\Jun25/00

Published by MIMS August 2025

BRAND INFORMATION

Brand name

Cozavan

Active ingredient

Losartan potassium

Schedule

S4

 

1 Name of Medicine

Losartan potassium.

2 Qualitative and Quantitative Composition

Each Cozavan film-coated tablet contains 25 mg or 50 mg of losartan potassium as the active ingredient.

Excipients with known effect.

Lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Cozavan 25 mg film-coated tablet.

White to off white, oval shaped biconvex film-coated tablet with "A" engraved on one side and "25" on the other side.

Cozavan 50 mg film-coated tablet.

White to off white, oval shaped biconvex film-coated tablet with "A50" engraved on one side and a central break line on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Hypertension.

Cozavan is indicated for the treatment of hypertension.
It may be used alone or in combination with other antihypertensive agents (e.g. thiazide diuretics).

Renal protection in type 2 diabetic patients with proteinuria.

Cozavan is indicated to delay the progression of renal disease in hypertensive type 2 diabetics with proteinuria, defined as urinary albumin to creatinine ratio ≥ 300 mg/g.

4.2 Dose and Method of Administration

The usual starting and maintenance dose is 50 mg once daily for most patients. The maximal antihypertensive effect is attained 3-6 weeks after initiation of therapy.
If the antihypertensive effect using 50 mg once daily is inadequate, 25 mg twice daily is recommended prior to increasing the dose.
For patients with intravascular volume depletion (e.g. those treated with high dose diuretics), a starting dose of 25 mg once daily should be considered (see Section 4.4 Special Warnings and Precautions for Use).
Cozavan can be administered once or twice daily. The total daily dose ranges from 25 mg to 100 mg.
No initial dosage adjustment is necessary for elderly patients or for patients with renal impairment, including patients on dialysis. A lower dose should be considered for patients with a history of hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use).
Cozavan may be administered with other antihypertensive agents.
Cozavan may be administered with or without food.

4.3 Contraindications

Cozavan is contraindicated in pregnant women and in patients who are hypersensitive to any component of this product.
Cozavan should not be administered with aliskiren in patients with diabetes (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Fetal toxicity.

Use of drugs that act on the renin angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Cozavan as soon as possible. See Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy.

Hypersensitivity.

Angioedema (see Section 4.8 Adverse Effects (Undesirable Effects)).

Hypotension and electrolyte/fluid imbalance.

In patients who are intravascularly volume depleted (e.g. those treated with high dose diuretics), symptomatic hypotension may occur. These conditions should be corrected prior to administration of Cozavan, or a lower starting dose should be used (see Section 4.2 Dose and Method of Administration).
Electrolyte imbalances are common in patients with renal impairment, with or without diabetes, and should be addressed. In a clinical study conducted in type 2 diabetic patients with proteinuria, the incidence of hyperkalaemia was higher in the group treated with Cozaar as compared to the placebo group; however, few patients discontinued therapy due to hyperkalemia (see Section 4.8 Adverse Effects (Undesirable Effects), Effects on laboratory tests).
Concomitant use of other drugs that may increase serum potassium may lead to hyperkalaemia (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Use in hepatic impairment.

Based on pharmacokinetic data which demonstrate significantly increased plasma concentrations of losartan in cirrhotic patients, a lower dose should be considered for patients with a history of hepatic impairment (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Use in renal impairment.

As a consequence of inhibiting the renin angiotensin aldosterone system, changes in renal function including renal failure have been reported in susceptible individuals. In patients whose renal function may depend on the activity of the renin aldosterone system (e.g. patients with severe congestive heart failure), treatment with angiotensin converting enzyme inhibitors has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Angiotensin II receptor antagonists would be expected to behave similarly.
Other drugs that affect the renin angiotensin system may increase blood urea and serum creatinine in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney. Similar effects have been reported with losartan potassium.

Use in the elderly.

In clinical studies there was no age related difference in the efficacy or safety profile of losartan.

Paediatric use.

Safety and effectiveness in children have not been established.

Effects on laboratory tests.

See Section 4.8 Adverse Effects (Undesirable Effects), Effects on laboratory tests.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No drug interactions of clinical significance have been identified. Compounds which have been studied in clinical pharmacokinetic trials include digoxin, warfarin, cimetidine and phenobarbital and ketoconazole. Rifampicin and fluconazole have been reported to reduce levels of active metabolite. Clinical studies have shown that concomitant use of losartan and hydrochlorothiazide may lead to potentiation of the antihypertensive effects.
As with other drugs that block angiotensin II or its effect, concomitant use of potassium-sparing diuretics (e.g. spironolactone, triamterene, amiloride), potassium supplements, salt substitutes containing potassium, or other drugs that may increase serum potassium (e.g. trimethoprim-containing products) may lead to increases in serum potassium.
As with other drugs which affect the excretion of sodium, lithium excretion may be reduced. Therefore, serum lithium levels should be monitored carefully if lithium salts are to be coadministered with angiotensin II receptor antagonists.
The antihypertensive effect of losartan may be attenuated by the nonsteroidal anti-inflammatory drug indometacin.
Nonsteroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors) may reduce the effect of diuretics and other antihypertensive drugs. Therefore, the antihypertensive effect of angiotensin II receptor antagonists or ACE inhibitors may be attenuated by NSAIDs including selective COX-2 inhibitors.
In some patients with compromised renal function (e.g. elderly patients or patients who are volume depleted, including those on diuretic therapy) who are being treated with nonsteroidal anti-inflammatory drugs, including selective cyclooxygenase-2 inhibitors, the coadministration of angiotensin II receptor antagonists or ACE inhibitors may result in a further deterioration of renal function including possible acute failure which is usually reversible. Therefore, the combination should be administered with caution in patients with compromised renal function.
These interactions should be considered in patients taking NSAIDs including selective COX-2 inhibitors concomitantly with diuretics and angiotensin II antagonists. Therefore, the combination should be administered with caution, especially in the elderly.

Combination use of ACE inhibitors or angiotensin receptor antagonists, anti-inflammatory drugs and thiazide diuretics.

The use of an ACE inhibiting drug (ACE inhibitor or angiotensin receptor antagonist), an anti-inflammatory drug (NSAID or COX-2 inhibitor) and a thiazide diuretic at the same time increases the risk of renal impairment. This includes use in fixed combination products containing more than one class of drug. Combined use of these medications should be accompanied by increased monitoring of serum creatinine, particularly at the institution of the combination. The combination of drugs from these three classes should be used with caution particularly in elderly patients or those with pre-existing renal impairment.
Dual blockade of the renin angiotensin aldosterone system (RAAS) with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function, and electrolytes in patients on losartan potassium and other agents that affect the RAAS. Do not coadminister aliskiren with losartan potassium in patients with diabetes. Avoid use of aliskiren with losartan potassium in patients with renal impairment (GFR < 60 mL/min).
Grapefruit juice contains components that inhibit CYP 450 enzymes and may lower the concentration of the active metabolite of Cozavan which may reduce the therapeutic effect. Consumption of grapefruit juice should be avoided while taking Cozavan.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Repeat dose studies in animals did not show any evidence of toxic effect on the reproductive system, and no adverse effects on fertility were observed in male or female rats at oral doses of losartan potassium up to 150-200 mg/kg/day.
(Category D)
Drugs that act directly on the renin angiotensin system can cause injury and death to the developing fetus when administered to pregnant women. Several dozen cases have been reported in the world literature in patients who were taking angiotensin converting enzyme inhibitors. When pregnancy is detected, Cozavan should be discontinued as soon as possible.
The use of drugs that act directly on the renin angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Potential neonatal adverse effects include hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with skeletal deformations, fetal limb contractures, craniofacial deformation, fetal lung hypoplasia and hypoplastic lung development. Prematurity, intrauterine growth retardation and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug. When pregnancy is detected, discontinue Cozavan as soon as possible.
These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of Cozavan as soon as possible.
These adverse outcomes are usually associated with the use of these drugs in the second and third trimesters of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. Although there is no experience with the use of Cozavan in pregnant women, animal studies with losartan potassium have demonstrated fetal and neonatal injury and death, the mechanism of which is believed to be pharmacologically mediated through effects on the renin angiotensin system. In humans, fetal renal perfusion, which is dependent upon the development of the renin angiotensin system, begins in the second trimester; thus, risk to the fetus increases if Cozavan is administered during the second or third trimesters of pregnancy.

Neonates with a history of in uterine exposure to Cozavan.

Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria and hyperkalaemia.
If oliguria or hypotension occur, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.
 It is not known whether losartan is excreted in human milk, but studies in rats indicate that both losartan and its active carboxylic acid metabolite are excreted in milk. Many drugs are excreted in human milk and because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

4.7 Effects on Ability to Drive and Use Machines

There are no data to suggest that losartan potassium affects the ability to drive and use machines. When driving vehicles or operating machines it should be taken into account that occasionally dizziness or weariness may occur (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

Losartan potassium has been evaluated for safety in more than 3300 patients treated for essential hypertension and 4058 patients overall. Over 1200 patients were treated for over 6 months and more than 800 for over one year. In general, treatment with losartan potassium was well tolerated. The overall incidence of adverse experiences reported with losartan potassium was comparable to placebo. For the most part, adverse experiences have been mild and transient in nature and have not required discontinuation of therapy. In controlled clinical trials, discontinuation of therapy due to clinical adverse experiences was required in only 2.3% and 3.7% of patients treated with losartan potassium and placebo, respectively.
In controlled clinical trials for essential hypertension, dizziness was the only adverse experience reported as drug related that occurred with an incidence greater than placebo in one percent or more of patients treated with losartan potassium. In addition, dose related orthostatic effects were seen in less than one percent of patients. Rarely, rash was reported, although the incidence in controlled clinical trials was less than placebo.
Table 1 shows adverse events based on four 6-12 week placebo controlled trials involving over 1000 patients on various doses (10-150 mg) of losartan and over 300 patients given placebo. All doses of losartan are grouped because none of the adverse events appeared to have a dose related frequency. The table includes all adverse events, whether or not attributed to the treatment, occurring in at least 1% of patients treated with losartan and that were more frequent on losartan than placebo.
The following adverse events were also reported at a rate of 1% or greater in patients treated with losartan, but were as, or more frequent, in the placebo group: asthenia/ fatigue, oedema/ swelling, abdominal pain, chest pain, nausea, headache, pharyngitis.
Adverse events occurred at about the same rates in men and women, older and younger patients, and Black and non-Black patients.
A patient with known hypersensitivity to aspirin and penicillin, when treated with losartan potassium, was withdrawn from study due to swelling of the lips and eyelids and facial rash, reported as angioedema, which returned to normal 5 days after therapy was discontinued.
Superficial peeling of palms and haemolysis was reported in one subject.
In addition to the adverse events above, potentially important events that occurred in at least two patients/ subjects exposed to losartan or other adverse events that occurred in < 1% of patients in clinical studies are listed below. It cannot be determined whether these events were causally related to losartan.

Body as a whole.

Facial oedema, fever, orthostatic effects, syncope.

Cardiovascular.

Angina pectoris, second degree AV block, CVA, hypotension, myocardial infarction, arrhythmias including atrial fibrillation, palpitation, sinus bradycardia, tachycardia, ventricular tachycardia, ventricular fibrillation.

Digestive.

Anorexia, constipation, dental pain, dry mouth, flatulence, gastritis, vomiting.

Hematologic.

Anaemia.

Metabolic.

Gout.

Musculoskeletal.

Arm pain, hip pain, joint swelling, knee pain, musculoskeletal pain, shoulder pain, stiffness, arthralgia, arthritis, fibromyalgia, muscle weakness.

Nervous system/ psychiatric.

Anxiety, anxiety disorder, ataxia, confusion, depression, dream abnormality, hypesthesia, decreased libido, memory impairment, migraine, nervousness, paraesthesia, peripheral neuropathy, panic disorder, sleep disorder, somnolence, tremor, vertigo.

Respiratory.

Dyspnoea, bronchitis, pharyngeal discomfort, epistaxis, rhinitis, respiratory congestion.

Skin.

Alopecia, dermatitis, dry skin, ecchymosis, erythema, flushing, photosensitivity, pruritus, rash, sweating, urticaria.

Special senses.

Blurred vision, burning/ stinging in the eye, conjunctivitis, taste perversion, tinnitus, decrease in visual acuity.

Urogenital.

Impotence, nocturia, urinary frequency, urinary tract infection.
The following adverse reactions have been reported in postmarketing experience.

Hypersensitivity.

Anaphylactic reactions, angioedema including swelling of the larynx and glottis causing airway obstruction and/or swelling of the face, lips, pharynx and/or tongue has been reported rarely in patients treated with losartan; some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Intestinal angioedema has been reported in patients treated with angiotensin II receptor antagonists including few cases with losartan. Vasculitis, including Henoch-Schonlein purpura, has been reported rarely.

Gastrointestinal.

Hepatitis (reported rarely), diarrhoea, liver function abnormalities, vomiting.

General disorders and administration site conditions.

Malaise.

Haematologic.

Anaemia, thrombocytopenia (reported rarely).

Musculoskeletal.

Myalgia, arthralgia.
Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.

Nervous system/ psychiatric.

Migraine, dysgeusia.

Reproductive system and breast disorders.

Erectile dysfunction/ impotence.

Respiratory.

Cough.

Skin.

Urticaria, pruritus, erythroderma, photosensitivity.

Effects on laboratory tests.

In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of losartan potassium.

Creatinine, blood urea nitrogen.

Minor increases in blood urea nitrogen (BUN) or serum creatinine were observed in less than 0.1 percent of patients with essential hypertension treated with losartan potassium alone. No patient discontinued taking losartan potassium alone due to increased BUN or serum creatinine (see Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment).

Haemoglobin and haematocrit.

Small decreases in haemoglobin and haematocrit (mean decreases of approximately 0.11 g percent and 0.09 volume percent respectively) occurred frequently in patients treated with losartan potassium alone, but were rarely of clinical importance. No patients were discontinued due to anaemia.

Liver function tests.

Occasional elevations of liver enzymes and/or serum bilirubin have occurred. In patients with essential hypertension treated with losartan potassium alone, one patient (< 0.1%) was discontinued due to these laboratory adverse experiences.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Signs and symptoms.

Limited data are available in regard to overdosage in humans. The most likely manifestation of overdosage would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation.

Treatment.

If symptomatic hypotension should occur, supportive treatment should be instituted. Neither losartan nor the active metabolite can be removed by haemodialysis.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Losartan potassium is the first nonpeptide orally active angiotensin II receptor (type AT1) antagonist to be used for the treatment of hypertension. Losartan potassium also provides a reduction in the risk of stroke in hypertensive patients with left ventricular hypertrophy and renal protection for type 2 diabetic patients with proteinuria.
Losartan is an oral angiotensin II receptor (type AT1) antagonist. Angiotensin II binds to the AT1 receptor found in many tissues (e.g. vascular smooth muscle, adrenal gland, kidneys and the heart) and elicits several important biological actions, including vasoconstriction and the release of aldosterone. Angiotensin II also stimulates smooth muscle cell proliferation. Based on binding and pharmacological bioassays, losartan binds selectively to the AT1 receptor. There is also an AT2 receptor found in many tissues. The functions of AT2 receptors have not been established. In vitro and in vivo, both losartan and its pharmacologically active carboxylic acid metabolite (E-3174) block all physiologically relevant actions of angiotensin II, regardless of the source or route of synthesis. The active metabolite is 10 to 40 times more potent by weight than losartan and appears to be a reversible, noncompetitive inhibitor of the AT1 receptor.
During losartan administration, removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. Increases in plasma renin activity lead to increases in angiotensin II in plasma. Even with these increases, antihypertensive activity and suppression of plasma aldosterone concentration are maintained, indicating effective angiotensin II receptor blockade.
Losartan binds selectively to the AT1 receptor and does not bind to or block other hormone receptors or ion channels important in cardiovascular regulation. Furthermore, losartan does not inhibit ACE (kininase II), the enzyme that degrades bradykinin. Consequently, effects not directly related to blocking the AT1 receptor, such as the potentiation of bradykinin mediated effects or the generation of oedema (losartan 1.7%, placebo 1.9%), are not associated with losartan.
Losartan has been shown to block responses to angiotensin I and angiotensin II without affecting responses to bradykinin, a finding which is consistent with the specific mechanism of action of losartan. In contrast, ACE inhibitors have been shown to block responses to angiotensin I and enhance responses to bradykinin without altering the response to angiotensin II, thus providing a pharmacodynamic distinction between losartan and ACE inhibitors.
In a study specifically designed to assess the incidence of cough in patients treated with losartan potassium as compared to patients treated with ACE inhibitors, the incidence of cough reported by patients receiving losartan potassium or hydrochlorothiazide was similar and was significantly less than in patients treated with an ACE inhibitor. In addition, in an overall analysis of 16 double blind clinical trials in 4131 patients, the incidence of spontaneously reported cough in patients treated with losartan potassium was similar (3.1%) to that of patients treated with placebo (2.6%) or hydrochlorothiazide (4.1%), whereas the incidence with ACE inhibitors was 8.8%.
In nondiabetic hypertensive patients with proteinuria, the administration of losartan potassium significantly reduces proteinuria, fractional excretion of albumin and IgG. Losartan maintains glomerular filtration rate and reduces filtration fraction. The mechanism of action of the uricosuric effect of losartan studied in normotensive subjects appears to be independent of angiotensin II blockade. Generally, in clinical trials, losartan caused a decrease in serum uric acid (usually 0.4 mg/dL) which was persistent in chronic therapy.
Losartan has no effect on autonomic reflexes and no sustained effect on plasma noradrenaline (norepinephrine).
Losartan potassium, administered in doses of up to 150 mg once daily, did not cause clinically important changes in fasting triglycerides, total cholesterol in patients with hypertension. The same doses of losartan had no effect on fasting glucose levels.
In patients with left ventricular failure, 25 mg and 50 mg doses of losartan produced positive haemodynamic and neurohormonal effects characterised by an increase in cardiac index and decreases in pulmonary capillary wedge pressure, systemic vascular resistance, mean systemic arterial pressure and heart rate and a reduction in circulating levels of aldosterone and noradrenaline (norepinephrine). The occurrence of hypotension was dose related in these heart failure patients.
The antihypertensive efficacy of losartan potassium was demonstrated in randomised, double blind, placebo controlled and comparator studies over a 12 week period and in an open label extension study for over 12 months.
Once daily administration of losartan potassium to patients with mild to moderate essential hypertension produced statistically significant reductions in systolic and diastolic blood pressure; the antihypertensive effect was maintained in clinical studies for up to one year. Measurement of blood pressure at trough (24 hours postdose) relative to peak (5-6 hours postdose) demonstrated relatively smooth blood pressure reduction over 24 hours. The antihypertensive effect paralleled the natural diurnal rhythms. Blood pressure reduction at the end of the dosing interval was approximately 70-80% of the effect seen 5-6 hours postdose. Discontinuation of losartan in hypertensive patients did not result in an abrupt rebound of blood pressure. Despite the significant decrease in blood pressure, administration of losartan potassium has no clinically significant effect on heart rate. The mechanism involved in the lack of reflex tachycardia is not clearly established.
The antihypertensive effect of losartan potassium 50 mg is similar to once daily administration of enalapril 20 mg. The antihypertensive effect of once daily administration of losartan potassium 50-100 mg is comparable to once daily administration of atenolol 50-100 mg. The effect of administration of losartan potassium 50-100 mg once daily also is equivalent to felodipine extended release 5-10 mg in older hypertensives (> 65 years) after 12 weeks of therapy.
Losartan potassium is equally effective in males and females and in younger (< 65 years) and older (> 65 years) 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. Although losartan potassium is antihypertensive in all races, as with other drugs that affect the renin angiotensin system, Black hypertensive patients have a smaller average response to losartan monotherapy than non-Black patients. Pharmacokinetic differences due to race have not been studied.
When given together with thiazide type diuretics, the blood pressure lowering effects of losartan potassium are approximately additive.
Data are currently not available to assess the long-term beneficial effect on morbidity and mortality in patients taking angiotensin II receptor antagonists.

Clinical trials.

LIFE study. The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study was a large, multicenter, multinational, randomised, triple blind, active controlled study conducted in 9193 hypertensive patients aged 55 to 80 years (mean 67 years) with ECG documented left ventricular hypertrophy. Of the patients enrolled at baseline, 1195 (13%) had diabetes; 1326 (14%), isolated systolic hypertension; 1468 (17%), coronary heart disease; and 728 (8%), cerebrovascular disease. The goal of the study was to demonstrate the cardiovascular protective effects of losartan potassium versus atenolol, over and above the benefits of blood pressure control alone (blood pressure was measured at trough). To meet this objective, the study was designed to achieve equal blood pressure in both treatment groups. Patients were randomised to receive once daily losartan potassium 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 losartan potassium 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.
In both treatment groups, blood pressure was significantly lowered to similar levels and a similar proportion of patients achieved goal blood pressure. The mean length of follow-up was 4.8 years.
The primary endpoint was the composite of cardiovascular morbidity and mortality as measured by a reduction in the combined incidence of cardiovascular death, stroke and myocardial infarction. In this trial 5% of the patients treated with losartan potassium suffered stroke compared to 7% of patients treated with atenolol, a reduction of 25% in the relative risk of stroke compared to atenolol (see Table 2). The effect of losartan potassium on stroke appeared to be over and above its beneficial effects on blood pressure control alone. The rates of cardiovascular death and myocardial infarction were not significantly different between the treatment groups. Although the results showed that treatment with losartan potassium resulted in a 13% risk reduction as compared with atenolol for patients reaching the primary composite endpoint, this effect was largely driven by a reduction in the risk on stroke.
The difference in the incidence of stroke in patients treated with losartan potassium and atenolol amounts to 1 additional stroke prevented for every 53 patients treated with losartan potassium for 5 years. The reduction in the incidence of stroke does not replace the need to adequately titrate patients to adequate blood pressure control.
The effects of losartan potassium versus atenolol on cardiovascular morbidity and mortality were examined in subgroups of patients with a baseline history of diabetes mellitus (n = 1195) or isolated systolic hypertension (ISH) (n = 1326). For the primary composite endpoint, the results seen in these subgroups were consistent with the benefit of therapy with losartan potassium seen in the overall study population: in diabetic patients, a 24% risk reduction (p = 0.03) was observed and in patients with isolated systolic hypertension, a 25% risk reduction (p = 0.06) was observed. Consistent with the results seen in the overall population, a reduction in stroke was an important contributor to the benefit observed in patients with diabetes or ISH. (See Table 3.)

Race.

Based on the LIFE study, the benefits of losartan potassium on cardiovascular morbidity and mortality compared to atenolol do not apply to Black patients with hypertension and left ventricular hypertrophy although both treatment regimens effectively lowered blood pressure in Black patients. In the LIFE study, losartan potassium decreased the risk of cardiovascular morbidity and mortality compared to atenolol in non-Black, hypertensive patients with left ventricular hypertrophy (n = 8660) as measured by the primary endpoint of the combined incidence of cardiovascular death, stroke, and myocardial infarction (p = 0.003). In this study, however, Black patients treated with atenolol were at lower risk of experiencing the primary composite endpoint compared with Black patients treated with losartan potassium (p = 0.03). In the subgroup of Black patients (n = 533; 6% of the LIFE study patients), there were 29 primary endpoints among 263 patients on atenolol (11%, 25.9 per 1000 patient years) and 46 primary endpoints among 270 patients (17%, 41.8 per 1000 patient years) on losartan potassium.
RENAAL study. The Reduction of Endpoints in NIDDM with the Angiotensin II Receptor Antagonist Losartan (RENAAL) study was a large, multicenter, randomised, placebo controlled, double blind study conducted worldwide in 1513 type 2 diabetic patients with proteinuria (assessed by a urinary albumin to creatinine ratio in 2 of 3 morning voids of greater than or equal to 300 mg/g), with or without hypertension. 751 of these patients were treated with losartan potassium. The goal of the study was to demonstrate the renal protective effects of losartan potassium over and above the benefits of blood pressure control alone. To meet this objective the study was designed to achieve equal blood pressure control in both treatment groups. Patients with proteinuria and serum creatinine of 1.3-3.0 mg/dL2 (115-265 micromol/L) (male patients over 60 kg were only enrolled if serum creatinine was > 1.5 mg/dL (> 133 micromol/L)) were randomised to receive losartan potassium 50 mg once daily titrated according to blood pressure response, or placebo, on a background of conventional antihypertensive therapy excluding ACE inhibitors and angiotensin II antagonists. Investigators were instructed to titrate study drug to 100 mg once daily as appropriate; 72% of patients were taking the 100 mg daily dose the majority of the time they were on study drug. Other antihypertensive agents (diuretics, calcium channel blockers, alpha and beta-blockers, and centrally acting agents) could be added as needed in both groups. Patients were followed for up to 4.6 years (mean of 3.4 years).
The primary endpoint of the study was the composite endpoint of doubling of serum creatinine, end stage renal disease (need for dialysis or transplantation), or death. For patients reaching the primary composite endpoint the results showed that treatment with losartan potassium as compared with placebo resulted in a reduction in the relative risk of 16.1%. For the following individual and combined components of the primary endpoint, the results also showed significant risk reduction in the group treated with losartan potassium a reduction in the relative risk of 25.3% in doubling of serum creatinine; a reduction in the relative risk of 28.6% in end stage renal disease; a reduction in the relative risk of 19.9% in end stage renal disease or death; a reduction in the relative risk of 21.0% in doubling serum creatinine or end stage renal disease (see Table 4).
There was no significant difference observed in the rate of death among patients treated with losartan potassium (21%) compared to those on placebo (20.3%). There was no significant difference observed in the incidence of cardiovascular mortality and morbidity between patients treated with losartan potassium and those who received placebo (p = 0.253).
The secondary endpoints of the study were: change in proteinuria; the rate of progression of renal disease; and the composite of morbidity and mortality from cardiovascular causes (hospitalisation for heart failure, myocardial infarction, revascularisation, stroke, hospitalisation for unstable angina, or cardiovascular death). The results showed an average reduction of 34.3% in the level of proteinuria in the group treated with losartan potassium (p < 0.001). Treatment with losartan potassium reduced the rate of decline in renal function during the chronic phase of the study by 13.9%, p = 0.003 (median rate of decline of 18.5%, p = 0.01) as measured by the reciprocal of the serum creatinine.
In this study, losartan potassium was generally well tolerated as evidenced by a similar incidence of discontinuations due to side effects compared to placebo.
There was a significant reduction in the mean number of endstage renal disease [ESRD] days with losartan potassium treatment over 3.5 years [33.6 less ESRD days with losartan potassium treatment, (-56.3, -10.9, 95% confidence interval)]. It is estimated that one case of ESRD would be prevented for every 16 patients that are treated with losartan potassium over a 3.5 year period.

5.2 Pharmacokinetic Properties

Absorption.

Following oral administration, losartan is well absorbed and undergoes first pass metabolism, forming an active carboxylic acid metabolite and other inactive metabolites. The active carboxylic metabolite (losartan acid) is responsible for most of the angiotensin II receptor antagonism.
The systemic bioavailability of losartan tablets 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 of the metabolite is about 4 times as great as that of losartan. Food slows the absorption of losartan and leads to slightly decreased levels of losartan (AUC about 18% decreased) and the active metabolite (AUC about 13% decreased). However, in each case the changes were small and there was no clinically significant effect on the plasma concentration profile of losartan.
A separate bioavailability study was conducted comparing generic losartan potassium 50 mg tablets with the innovator losartan potassium 50 mg tablets. The generic and innovator mean Cmax values for the active carboxylic metabolite were 403.051 nanogram/mL and 399.633 nanogram/mL, respectively. The point estimate of the generic to innovator ratio of the geometric means for Cmax was 1.0231 with a 90% confidence interval of [0.9813, 1.0668]. The generic and innovator mean AUC∞ values for the active carboxylic metabolite were 3167.94 nanogram.hr/mL and 3090.24 nanogram.hr/mL, respectively. The point estimate of the generic to innovator ratio of the geometric means for AUC∞ was 1.0314 with a 90% confidence interval of [1.0069, 1.0565]. The Tmax for both the generic and innovator tablets was 4 hours.

Distribution.

Both losartan and its active metabolite are > 99% bound to plasma proteins, primarily albumin. The volume of distribution of losartan is 34 L. Studies in rats indicate that losartan crosses the blood brain barrier poorly, if at all.
The volume of distribution of losartan is about 34 L and of the active metabolite is about 12 L.

Metabolism.

Losartan undergoes substantial first pass metabolism by cytochrome P450.
About 14% of an intravenously or orally administered dose of losartan is converted to its active metabolite. Following oral and intravenous administration of 14C-labelled losartan potassium, circulating plasma radioactivity primarily is attributed to losartan and its active metabolite. In vitro studies indicate that cytochrome P450 2C9 and 3A4 are involved in the biotransformation of losartan to its metabolites. Minimal conversion of losartan to its active metabolite was seen in about one percent of individuals studied.
In addition to the active metabolite, inactive metabolites are formed, including two major metabolites formed by hydroxylation of the butyl side chain and a minor metabolite, an N-2 tetrazole glucuronide.

Excretion.

Plasma clearance of losartan and its active metabolite is about 600 mL/min and 50 mL/min, respectively. Renal clearance of losartan and its active metabolite is about 74 mL/min and 26 mL/min, respectively. When losartan is administered orally, about 4% of the dose is excreted unchanged in the urine, and about 6% of the dose is excreted in the urine as active metabolite. The pharmacokinetics of losartan and its active metabolite are linear with oral losartan potassium doses up to 200 mg.
Following oral administration, plasma concentrations of losartan and its active metabolites decline polyexponentially with a terminal half-life of about 2 hours and 6-9 hours, respectively. During once daily dosing with 100 mg, neither losartan nor its active metabolite accumulates significantly in plasma.
Both biliary and urinary excretion contribute to the elimination of losartan and its metabolites. Following an oral dose of 14C-labelled losartan in man, about 35% of radioactivity is recovered in the urine and 58% in the faeces.

Characteristics in patients.

Plasma concentrations of losartan are not altered in patients with creatinine clearance above 30 mL/min. In patients with lower creatinine clearance, AUCs are about 50% greater and they are doubled in haemodialysis patients.
Plasma concentrations of the active metabolite are not significantly altered in patients with renal impairment or in haemodialysis patients. No dosage adjustment is necessary for patients with renal impairment unless they are volume depleted.
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-fold and 1.7-fold greater than those seen in young male volunteers.
Neither losartan nor the active metabolite can be removed by haemodialysis.

5.3 Preclinical Safety Data

Genotoxicity.

No evidence of genotoxic activity was observed in assays for DNA damage, gene mutations and chromosomal damage.

Carcinogenicity.

In animal studies, there was no evidence of carcinogenic activity when losartan potassium was administered orally to mice at doses up to 200 mg/kg/day for 92 weeks, or to rats at doses up to 270 mg/kg/day for 105 weeks.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each Cozavan film-coated tablet contains the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, pregelatinised maize starch, magnesium stearate, Opadry complete film coating system 20A58900 White (ID 13043).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Container type: PVDC/PE/PVC/Aluminium blisters.
25 mg tablets: Available in blister packs containing 10 (starter pack), 30 or 60 tablets.
50 mg tablets: Available in blister packs containing 10 (starter pack) or 30 tablets.
Some strengths, pack sizes and/or pack types may not be marketed.

Australian register of therapeutic goods (ARTG).

AUST R 156235 - Cozavan losartan potassium 25 mg film-coated tablet blister pack.
AUST R 156234 - Cozavan losartan potassium 50 mg film-coated tablet blister pack.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking it to your local pharmacy.

6.7 Physicochemical Properties

Losartan potassium, a nonpeptide molecule, is chemically described as 2-butyl-4-chloro- 1-[[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl] methyl]-1H-imidazole -5-methanol monopotassium salt.
Oxidation of the 5-hydroxymethyl group on the imidazole ring results in the active metabolite of losartan.

Chemical structure.


Molecular formula: C22H22ClKN6O.
Molecular weight: 461.01.

CAS number.

124750-99-8.
Losartan potassium is a white to off-white free-flowing crystalline powder. It is freely soluble in water, soluble in alcohols, and slightly soluble in common organic solvents, such as acetonitrile and methyl ethyl ketone.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

Summary Table of Changes