Consumer medicine information

Mizart HCT

Telmisartan; Hydrochlorothiazide

BRAND INFORMATION

Brand name

Mizart HCT

Active ingredient

Telmisartan; Hydrochlorothiazide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Mizart HCT.

What is in this leaflet

This leaflet answers some common questions about Mizart HCT. It does not contain all available information.

It does not take the place of talking to your doctor or pharmacist.

This leaflet was last updated on the date at the end of this leaflet.

More recent information may be available.

The latest Consumer Medicine Information is available from your pharmacist, doctor, or from www.medicines.org.au and may contain important information about the medicine and its use of which you should be aware.

Keep this information with your Mizart HCT tablets. You may need to read it again later.

To find out more about Mizart HCT

Ask your doctor or pharmacist if you have any questions about your medicine if you have any concerns or if you have any trouble before, during or after using Mizart HCT.

What Mizart HCT is used for

Mizart HCT lowers high blood pressure, also called hypertension.

Everyone has blood pressure. This pressure helps your blood move 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 when your blood pressure stays higher than normal, even when you are calm or relaxed.

There are usually no signs of hypertension. The only way of knowing that you have hypertension is to have your blood pressure checked on a regular basis. You may feel fine and have no symptoms, but if high blood pressure is not treated, it can lead to serious health problems (such as stroke, heart disease and kidney failure).

Mizart HCT helps to lower your blood pressure but does not cure hypertension.

Mizart HCT contains telmisartan and hydrochlorothiazide. Both medicines reduce blood pressure in different ways. Telmisartan belongs to a group of medicines called angiotensin II receptor antagonists. It works by widening the blood vessels of the body, and therefore helping to lower your blood pressure.

Hydrochlorothiazide belongs to the group of medicines called diuretics. Diuretics cause an increase in the volume of urine. They also help with lowering blood pressure particularly when combined with other blood pressure reducing medicines.

Mizart HCT may be used either alone or in combination with other medicines used to treat high blood pressure.

Mizart HCT may have been prescribed for you for another reason.

Ask your doctor if you have any questions about why Mizart HCT has been prescribed for you.

Mizart HCT is not addictive.

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

Before you take Mizart HCT

When you must not take it

Only take Mizart HCT if it has been prescribed for you by a doctor.

Never give it to someone else even if their symptoms seem to be the same as yours.

Do not take Mizart HCT if you are allergic to telmisartan, hydrochlorothiazide, sulfonamide-derived medicines or to any of the other ingredients in Mizart HCT. These ingredients are listed in full at the end of this leaflet. If you are uncertain as to whether you have these allergies you should raise those concerns with your doctor.

Do not take Mizart HCT if you suffer from:

  • severe liver disease
  • severe kidney disease
  • cholestasis or biliary obstructive disorders (problem with the flow of bile from the gall bladder)
  • low potassium levels in the blood
  • high calcium levels in the blood
  • diabetes or kidney problems and you are taking aliskiren (a medicine used to treat high blood pressure).

Do not take Mizart HCT if you have rare hereditary condition of fructose intolerance.

The maximum recommended daily dose of Mizart HCT contains 170 mg of mannitol (in the 40/12.5 mg tablets) and approximately 340 mg of mannitol (in the 80/12.5 mg and 80/25 mg tablets).

Do not take Mizart HCT if you have rare hereditary condition of galactose intolerance.

The maximum recommended daily dose of Mizart HCT contains 84 mg of lactose monohydrate in the 40/12.5 mg tablets, 180.5 mg of lactose monohydrate in the 80/12.5 mg tablets, and 169.4 mg of lactose monohydrate in the 80/25 mg tablets.

If you are uncertain as to whether you have these conditions you should raise those concerns with your doctor

Do not take Mizart HCT if you are pregnant or breastfeeding. Like other similar medicines, it may affect your developing baby if you take it during pregnancy.

It is not known if telmisartan or hydrochlorothiazide, the active ingredients in Mizart HCT, pass into breast milk and there is a possibility your baby may be affected.

Do not take Mizart HCT after the EXPIRY DATE on the carton or blister strips has passed.

Do not take Mizart HCT if the packaging is torn or shows signs of tampering.

If you are not sure whether you should start taking Mizart HCT, talk to your doctor.

Before you start to take it

It is essential that your doctor knows your medical history before prescribing Mizart HCT.

Before taking Mizart HCT, tell your doctor if you have, or have had, any of the following conditions:

  • kidney problems
  • a kidney transplant
  • liver problems
  • heart problems
  • primary hyperaldosteronism (raised aldosterone levels also known as Conn's syndrome)
  • diabetes
  • gout
  • fructose intolerance
  • galactose intolerance
  • a low salt diet
  • recent severe diarrhoea or vomiting
  • have a history of allergy or asthma
  • systemic lupus erythematosus (a disease affecting the skin, joints and kidney)
  • eye problems

If you are uncertain as to whether you have, or have had, any of these conditions you should raise those concerns with your doctor.

Before taking Mizart HCT it is advisable to tell your doctor if you are taking any other medicines, obtained with or without a doctor's prescription from your pharmacy, supermarket or health food shop.

In particular, tell your doctor if you are taking:

  • any other medicines used to treat high blood pressure
  • lithium, a medicine used to treat certain mental illnesses
  • other diuretics or fluid tablets
  • laxatives
  • potassium tablets (potassium supplements)
  • potassium containing salt substitutes
  • medicines or salt substitutes which may increase your potassium levels
  • amphotericin B (amphotericin), a medicine used to treat fungal infections
  • penicillin antibiotics used to treat bacterial infections
  • heart medicines such as digoxin, a medicine used to treat heart failure or antiarrhythmic medicines
  • alcohol
  • sleeping tablets
  • strong pain killing medicines
  • medicines for diabetes (oral tablets or capsules or insulin)
  • powder or granules used to help reduce cholesterol
  • corticosteroid medicines such as prednisolone, cortisone or ACTH
  • aspirin
  • nonsteroidal anti-inflammatory agents (medicines used to relieve pain, swelling and other symptoms of inflammation including arthritis)
  • medicines used to treat gout
  • calcium supplements or medicines containing calcium
  • beta-blockers (a type of medicine used to treat high blood pressure or other heart conditions)
  • anticholinergic medicines, which can be used to treat Parkinson's disease, relieve stomach cramps or prevent travel sickness
  • amantadine, a medicine used to treat Parkinson's disease or to prevent influenza
  • medicines used to treat cancer (cytotoxic medicines)

These medicines may be affected by Mizart HCT, or may affect the way it works. Also, other medicines used to treat high blood pressure may have an additive effect with Mizart HCT in lowering your blood pressure. Therefore, you may need different amounts of your medicines.

Your doctor or pharmacist will be able to tell you what to do if you are taking Mizart HCT with other medicines.

Pregnancy

Ask for your doctor's advice if you are pregnant, or likely to become pregnant during your course of medication. Mizart HCT should not be taken if you are pregnant.

Breastfeeding

Ask for your doctor's advice if you are breastfeeding or likely to breastfeed during the course of your medication. Mizart HCT should not be taken if you are breastfeeding.

Children

Mizart HCT is not recommended for use in children and teenagers up to 18 years of age.

How to take Mizart HCT

How much to take

The usual recommended dose for adults is one Mizart HCT 40/12.5 mg tablet once a day.

If your blood pressure is still too high after 4-8 weeks of starting treatment, your doctor may increase your dose to one Mizart HCT 80/12.5 mg tablet once a day.

If your blood pressure is still not satisfactorily controlled with Mizart HCT 80/12.5 mg, your doctor may increase your dose to one Mizart HCT 80/25 mg tablet once a day.

Follow all directions given to you by your doctor or pharmacist. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the label, ask your doctor or pharmacist for help.

The amount of Mizart HCT you have to take will depend on your condition and whether or not you are taking any other medicines.

How to take it

Take Mizart HCT at about the same time each day.

Mizart HCT should be swallowed with a glass of water.

Mizart HCT can be taken with or without food.

Do not take extra doses of Mizart HCT without consulting your doctor.

If you forget to take a dose

It is important to take Mizart HCT as directed.

If you miss a dose, take it as soon as you remember. However, if you remember when it is almost time for your next dose, take only your usual dose at that time.

Do not take a double dose of Mizart HCT to make up for a dose that you missed.

How long to take it for

Mizart HCT helps control your high blood pressure but does not cure it. Therefore Mizart HCT must be taken every day.

Continue taking Mizart HCT for as long as your doctor prescribes it.

If you have taken too much (overdose)

Seek medical advice if you have taken more than the recommended or prescribed dose of Mizart HCT. Advice can be provided by a doctor, pharmacist or Poisons Information Centre (telephone 13 11 26).

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Signs of overdose may include increased or slower heart rate, low blood pressure (dizziness, lightheadedness), dehydration, nausea, drowsiness and muscle spasm.

While taking Mizart HCT

Things you must do Tell your doctor immediately if you become pregnant while taking Mizart HCT.

Tell your doctor or pharmacist if you begin using any other medicine while you are taking Mizart HCT.

If you feel dizzy or lightheaded, and you wish to stand up, you should do so slowly.

You may feel dizzy or lightheaded when you begin to take Mizart HCT, especially if you are also taking a diuretic or fluid tablet. If this problem occurs, talk to your doctor.

If you exercise, or if you sweat, or if the weather is hot, you should drink plenty of water.

If you plan to have surgery or other treatment (even at the dentist) that needs an anaesthetic, make sure you tell your doctor or dentist that you are taking Mizart HCT.

Tell your doctor if you develop an unexpected abnormal lump, bump, ulcer, sore or coloured area on the skin (skin lesion) during the treatment.

Treatment with hydrochlorothiazide, particularly long-term use with high doses, may increase the risk of some types of skin and lip cancer (non-melanoma skin cancer).

Protect your skin from sun exposure and UV rays while taking Mizart HCT.

Ability to drive or operate machinery

It is advisable to be careful when driving or operating machinery until you know how Mizart HCT affects you. It is always possible that Mizart HCT, like other medicines used to treat high blood pressure, may cause dizziness or drowsiness in some people.

When taken as recommended, and when there are no side effects, Mizart HCT is not known to have any effect on the ability to drive or operate machinery.

Lifestyle measures that help reduce heart disease risk

By following these simple measures, you can further reduce the risk from heart disease.

  • Quit smoking and avoid second-hand smoke.
  • Limit alcohol intake.
  • Enjoy healthy eating by:
    - eating plenty of vegetables and fruit;
    - 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).
  • Be active. 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.
  • Maintain a healthy 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).

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.

Side effects

You should be aware that all prescription medicines carry some risks and that all possible risks may not be known at this stage despite thorough testing. Your doctor has weighed the risks of you taking Mizart HCT against the benefits they expect it will have for you.

Ask for the advice of your doctor or pharmacist if you have any concerns about the effects of using this medicine.

Most side effects of Mizart HCT are mild and temporary. The overall frequency of side effects reported by patients taking Mizart HCT is similar to patients taking a placebo (sugar tablet).

The following side effects have been reported by patients taking Mizart HCT.

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

It is not known if these side effects are caused by Mizart HCT:

  • 'flu-like' symptoms
  • fainting, dizziness or spinning sensation
  • a feeling of tension or fullness in the nose, cheeks and behind the eyes, sometimes with a throbbing ache (sinusitis)
  • infections of the air passages
  • shortness of breath or difficulty breathing
  • eye pain, abnormal or blurred vision
  • back pain
  • changes in heart rhythm or increased heart rate
  • rash or redness or itchiness of skin
  • increased sweating
  • dizziness or lightheadedness when you stand up (postural hypotension)
  • stomach pain or discomfort (abdominal pain, dyspepsia, gastritis)
  • wind or excessive gas in the stomach or bowel
  • vomiting
  • diarrhoea or constipation
  • dry mouth
  • pins and needles
  • sleep disturbances or trouble sleeping
  • feeling anxious
  • depression
  • impotence
  • leg pain or cramps in legs
  • aching muscles or aching joints not caused by exercise or muscle spasms
  • chest pain
  • pain
  • liver problems
  • changes in the levels of potassium or sodium or uric acid in your blood (such changes are usually detected by a blood test)

Tell your doctor as soon as possible if you experience any side effects during or after taking Mizart HCT, so that these may be properly treated.

Symptoms such as feeling very thirsty, sleepy, sick or vomiting, a dry mouth, general weakness, muscle pain or cramps, a very fast heart rate, may mean that the hydrochlorothiazide part of Mizart HCT is having an excessive effect. You should tell your doctor if you experience any of these symptoms.

Tell your doctor as soon as possible if you notice any unexpected changes to your skin, including your lips. This could be a type of skin or lip cancer (non-melanoma skin cancer).

If any of the following happens, stop taking Mizart HCT and either tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • 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 nettle rash
  • developing or worsening of a disease called systemic lupus erythematosus which affects the skin, joints and kidney.

These are rare but serious side effects and may indicate a severe allergic reaction. You may need urgent medical attention or hospitalisation.

In addition, other side effects not listed above may occur in some patients. Tell your doctor or pharmacist if you notice anything unusual, during or after taking Mizart HCT.

After taking Mizart HCT

Storage

Leave the tablets in the blister strip until it is time to take a dose. The blister pack protects the tablets from light and moisture.

Mizart HCT should be kept in a cool, dry place where the temperature stays below 25°C.

Do not store Mizart HCT or any other medicine in the bathroom or near a sink. Do not leave it in the car or on window sills. Heat and dampness can destroy some medicines.

Keep Mizart HCT where young children cannot reach it.

Disposal

If you have been told by your doctor that you will not be needing Mizart HCT anymore, or the tablets have passed their expiry date, the unused medicine should be returned to your pharmacist so that it can be disposed of safely.

Product description

What Mizart HCT is

Mizart HCT is the brand name of your medicine.

Mizart HCT tablets are available in three strengths: 40/12.5 mg, 80/12.5 mg and 80/25 mg tablets.

Mizart HCT 40/12.5 mg tablets are pink mottled and white to off-white biconvex, oval shaped, two layer tablets. The white to off-white layer may contain pink specks.

The pink mottled face of Mizart HCT 40/12.5 mg tablets are marked with L199.

Mizart HCT 80/12.5 mg tablets are pink mottled and white to off-white, biconvex, oval shaped, two layer tablets. The white to off-white layer may contain pink specks.

The pink mottled face of Mizart HCT 80/12.5 mg tablets are marked with L200.

Mizart HCT 80/25 mg tablets are yellow mottled and white to off-white biconvex, oval shaped, two layer tablets. The white to off-white layer may contain yellow specks.

The white face of Mizart HCT 80/25 mg tablets are marked with L201.

Mizart HCT tablets are available in blister packs of 28 tablets.

Ingredients

Each Mizart HCT 40/12.5 mg tablet contains 40 mg telmisartan and 12.5 mg hydrochlorothiazide.

Each Mizart HCT 80/12.5 mg tablet contains 80 mg telmisartan and 12.5 mg hydrochlorothiazide.

Each Mizart HCT 80/25 mg tablet contains 80 mg telmisartan and 25 mg hydrochlorothiazide.

The other ingredients found in the tablets are:

  • povidone
  • lactose monohydrate
  • magnesium stearate
  • meglumine
  • sodium hydroxide
  • sodium stearylfumarate
  • mannitol

Mizart HCT 40/12.5 mg and 80/12.5 mg tablets also contain Pigment Blend PB-24880 Pink and Mizart HCT 80/25 mg tablets also contain Pigment Blend PB-52290 Yellow, as colouring agent.

Mizart HCT tablets contain lactose.

Sponsor

Mizart HCT is supplied in Australia by:

Alphapharm Pty Ltd
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.mylan.com.au

Australian registration numbers:

Mizart HCT 40/12.5 mg (blister)-

AUST R 246472

Mizart HCT 80/12.5 mg (blister)-

AUST R 246473

Mizart HCT 80/25 mg (blister)-

AUST R 246474

This leaflet was prepared in May 2020.

Mizart HCT_cmi\May20/00

Published by MIMS July 2020

BRAND INFORMATION

Brand name

Mizart HCT

Active ingredient

Telmisartan; Hydrochlorothiazide

Schedule

S4

 

1 Name of Medicine

Telmisartan and hydrochlorothiazide.

6.7 Physicochemical Properties

Telmisartan is an off-white to yellowish crystalline powder. It is practically insoluble in water, very slightly soluble in ethanol, slightly soluble in methanol and soluble in a mixture of chloroform and methanol (1:1).
Hydrochlorothiazide is a white, or practically white, odourless crystalline powder. It is very slightly soluble in water, and freely soluble in sodium hydroxide solution.

Chemical structure.


Molecular formula.

Telmisartan: C33H30N4O2.
Hydrochlorothiazide: C7H8ClN3O4S2.

Molecular weight.

Telmisartan: 514.6.
Hydrochlorothiazide: 297.73.

Chemical name.

Telmisartan: 4'-[(1,4'-dimethyl-2'-propyl [2,6'-bi-1H-benzimidazol]-1'-yl)-methyl]-[1,1'-biphenyl]-2-carboxylic acid (IUPAC nomenclature).
Hydrochlorothiazide: 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide.

CAS number.

Telmisartan: 144701-48-4.
Hydrochlorothiazide: 58-9305.

2 Qualitative and Quantitative Composition

Each Mizart HCT 40/12.5 tablet contains telmisartan 40 mg and hydrochlorothiazide 12.5 mg.
Each Mizart HCT 80/12.5 tablet contains telmisartan 80 mg and hydrochlorothiazide 12.5 mg.
Each Mizart HCT 80/25 tablet contains telmisartan 80 mg and hydrochlorothiazide 25 mg.

Excipient with known effect.

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

3 Pharmaceutical Form

Tablet.

40/12.5 mg tablet.

Each tablet is a pink mottled and white to off-white biconvex, oval shaped, two layer tablet. The white to off-white layer may contain pink specks. The pink mottled face of tablets are marked with L199.

80/12.5 mg tablet.

Each tablet is a pink mottled and white to off-white biconvex, oval shaped, two layer tablet. The white to off-white layer may contain pink specks. The pink mottled face of tablet is marked with L200.

80/25 mg tablet.

Each tablet is a yellow mottled and white to off-white biconvex, oval shaped, two layer tablet. The white to off-white layer may contain yellow specks. The white face of tablets are marked with L201.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Mizart HCT is a combination of an angiotensin II receptor antagonist (type AT1), telmisartan, and a benzothiadiazine (thiazide) diuretic, hydrochlorothiazide. The combination of these ingredients has an additive antihypertensive effect, reducing blood pressure to a greater degree than either component alone. Mizart HCT once daily produces effective and smooth reductions in blood pressure across the therapeutic dose range.

Telmisartan.

Telmisartan displaces angiotensin II with very high affinity from its binding site at the AT1 receptor subtype, which is responsible for the known actions of angiotensin II. Telmisartan does not exhibit any partial agonist activity at the AT1 receptor. Telmisartan binds selectively with the AT1 receptor and does not reveal relevant affinity for other receptors nor does it inhibit human plasma renin or block ion channels. The clinically relevant effect of AT1 receptor blockade is to lower blood pressure by inhibition of angiotensin II mediated vasoconstriction leading to reduction of systemic vascular resistance. During administration with telmisartan, removal of angiotensin II negative feedback on renin secretion results in increased plasma renin activity, which in turn leads to increases in angiotensin II in plasma. Despite these increases, antihypertensive activity and suppressed aldosterone levels indicate effective angiotensin II receptor blockade. Telmisartan does not inhibit angiotensin converting enzyme (kininase II), the enzyme which also degrades bradykinin. Therefore it is not expected to potentiate bradykinin mediated adverse effects or cause oedema.
In humans, an 80 mg dose of telmisartan almost completely inhibits the angiotensin II evoked increase in blood pressure. The inhibitory effect is maintained over 24 hours and still measurable up to 48 hours.
After administration of the first dose of telmisartan/hydrochlorothiazide, onset of antihypertensive activity occurs gradually within 3 hours. The maximal reduction in blood pressure is generally attained 4-8 weeks after the start of treatment and is sustained during long-term therapy. The antihypertensive effect persists constantly over 24 hours after dosing and includes the last 4 hours before the next dose. With ambulatory blood pressure monitoring and conventional blood pressure measurements, the 24 hour trough to peak ratio for 40-80 mg doses of telmisartan was > 80% for both systolic blood pressure (SBP) and diastolic blood pressure (DBP).
In patients with hypertension, telmisartan reduces both systolic and diastolic blood pressure without affecting pulse rate. The antihypertensive efficacy of telmisartan is independent of gender or age, and has been compared to antihypertensive drugs such as amlodipine, atenolol, enalapril, hydrochlorothiazide, lisinopril and valsartan.
Upon abrupt cessation of treatment, blood pressure gradually returns to pretreatment values over a period of several days without evidence of rebound hypertension.
The incidence of dry cough was significantly lower in patients treated with telmisartan than in those given angiotensin converting enzyme inhibitors in clinical trials directly comparing the two antihypertensive treatments.

Prevention of cardiovascular morbidity and mortality.

ONTARGET (ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) compared the effects of telmisartan, ramipril and the combination of telmisartan and ramipril on cardiovascular outcomes in 25,620 patients aged 55 years or older with a history of coronary artery disease, stroke, transient ischaemic attack, peripheral vascular disease, or diabetes mellitus accompanied by evidence of end organ damage (e.g. retinopathy, left ventricular hypertrophy, macro or microalbuminuria), which represents a broad cross section of patients at high risk of cardiovascular events.
The coprimary objectives of the ONTARGET trial were to determine if (a) the combination of telmisartan 80 mg and ramipril 10 mg is superior to ramipril 10 mg alone and if (b) telmisartan 80 mg is not inferior to ramipril 10 mg alone in reducing the primary composite endpoint of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalisation for congestive heart failure. Hypothesis tests were performed using hazard ratios and time to event analyses (Kaplan-Meier).
The principal patient exclusion criteria included: symptomatic heart failure or other specific cardiac diseases, syncopal episodes of unknown aetiology or planned cardiac surgery within 3 months of the start of study, uncontrolled hypertension or haemorrhagic stroke.
Patients were randomised to one of the three following treatment groups: telmisartan 80 mg (n = 8542), ramipril 10 mg (n = 8576), or the combination of telmisartan 80 mg plus ramipril 10 mg (n = 8502), and followed for a mean observation time of 4.5 years. The population studied was 73% male, 74% Caucasian, 14% Asian and 43% were 65 years of age or older. Hypertension was present in nearly 83% of randomised patients: 69% of patients had a history of hypertension at randomisation and an additional 14% had actual blood pressure readings ≥ 140/90 mmHg. At baseline, the total percentage of patients with a medical history of diabetes was 38% and an additional 3% presented with elevated fasting plasma glucose levels. Baseline therapy included acetylsalicylic acid (76%), statins (62%), beta-blockers (57%), calcium channel blockers (34%), nitrates (29%) and diuretics (28%).
Adherence to treatment was better for telmisartan than for ramipril or the combination of telmisartan and ramipril, although the study population had been prescreened for tolerance to treatment with an ACE inhibitor. During the study, significantly less telmisartan patients (22.0%) discontinued treatment, compared to ramipril patients (24.4%) and telmisartan/ramipril patients (25.3%). The analysis of adverse events leading to permanent treatment discontinuation and of serious adverse events showed that cough and angioedema were less frequently reported in patients treated with telmisartan than in patients treated with ramipril, whereas hypotension was more frequently reported with telmisartan.

Comparison of telmisartan versus ramipril.

The choice of the noninferiority margin of 1.13 was solely based on the results of the HOPE (Heart Outcomes Prevention Evaluation) study. Telmisartan showed a similar effect to ramipril in reducing the primary composite endpoint of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalisation for congestive heart failure. The incidence of the primary endpoint was similar in the telmisartan (16.7%) and ramipril (16.5%) groups. In the intention to treat (ITT) analysis, the hazard ratio for telmisartan versus ramipril was 1.01 (97.5% CI 0.93-1.10, p (noninferiority) = 0.0019). The noninferiority result was confirmed in the per protocol (PP) analysis, where the hazard ratio was 1.02 (97.5% CI 0.93-1.12, p (noninferiority) = 0.0078). Since the upper limit of the 97.5% CI was below the predefined noninferiority margin of 1.13 and the p-value for noninferiority was below 0.0125 in both the ITT and PP analyses, the trial succeeded in demonstrating the noninferiority of telmisartan versus ramipril in the prevention of the composite primary endpoint. The noninferiority conclusion was found to persist following corrections for differences in systolic blood pressure at baseline and over time. There was no difference in the primary endpoint in subgroups based on age, gender, race, baseline concomitant therapies or underlying diseases.
Telmisartan was also found to be similarly effective to ramipril in several prespecified secondary endpoints, including a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke, the primary endpoint in the reference study HOPE, which had investigated the effect of ramipril versus placebo. The ITT hazard ratio of telmisartan versus ramipril for this endpoint in ONTARGET was 0.99 (97.5% CI 0.90-1.08, p (noninferiority) = 0.0004), and confirmed by the PP hazard ratio of 1.00 (97.5% CI 0.91-1.11, p (noninferiority) = 0.0041.

Comparison of telmisartan plus ramipril combination versus ramipril monotherapy alone.

Combining telmisartan with ramipril did not add further benefit over ramipril or telmisartan alone, thus superiority of the combination could not be demonstrated. The incidence of the primary endpoint was 16.3% in the telmisartan plus ramipril combination group, compared to the telmisartan (16.7%) and ramipril (16.5%) groups. In addition, there was a significantly higher incidence of hyperkalaemia, renal failure, hypotension and syncope in the combination group. Therefore the use of a combination of telmisartan and ramipril is not recommended in this population.

Hydrochlorothiazide.

Hydrochlorothiazide is a thiazide diuretic. The mechanism of the antihypertensive effect of thiazide diuretics is not fully known. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. The diuretic action of hydrochlorothiazide reduces plasma volume, increases plasma renin activity, increases aldosterone secretion, with consequent increases in urinary potassium and bicarbonate loss, and decreases in serum potassium. Coadministration with telmisartan tends to reverse the potassium loss associated with these diuretics, presumably through blockade of the renin angiotensin aldosterone system. With hydrochlorothiazide, onset of diuresis occurs in 2 hours, and peak effect occurs at about 4 hours, while the action persists for approximately 6-12 hours.
Epidemiological studies have shown that long-term treatment with hydrochlorothiazide reduces the risk of cardiovascular mortality and morbidity. There are no data regarding the effects of telmisartan and telmisartan/hydrochlorothiazide on morbidity and mortality in hypertensive patients.

Clinical trials.

The antihypertensive effects of telmisartan/hydrochlorothiazide were examined in three pivotal 8 week randomised, double blind clinical trials.
One of the pivotal studies compared telmisartan/hydrochlorothiazide 40/12.5 mg to telmisartan 40 mg, in patients who failed to respond adequately to treatment with telmisartan 40 mg. Following a 4 week run in period, patients who failed to respond to telmisartan 40 mg monotherapy (DBP > 90 mmHg) were randomised to receive either telmisartan 40 mg (167 patients) or telmisartan/hydrochlorothiazide 40/12.5 mg (160 patients) for 8 weeks. Seated blood pressure was taken 24 hours postdose at each visit.
Treatment with telmisartan/hydrochlorothiazide 40/12.5 mg lowered DBP by an additional 3.5 mmHg and SBP by 7.4 mmHg compared to telmisartan 40 mg. Both results were highly statistically significant (p < 0.01). Most of the additional effect was seen at 4 weeks of treatment. Changes in DBP for telmisartan 40 mg monotherapy were -4.8 mmHg at week 4 and -4.3 mmHg at week 8. Changes in DBP for telmisartan/hydrochlorothiazide 40/12.5 mg were -6.1 mmHg at week 4 and -7.4 mmHg at week 8.
Patients in the telmisartan/hydrochlorothiazide 40/12.5 mg arm had a normalised blood pressure response rate (SBP < 140 mmHg and DBP < 90 mmHg) of 51.6% compared to 23.5% for patients in the telmisartan 40 mg monotherapy arm. The DBP response rate (DBP < 90 mmHg) was 64.8% for the telmisartan/hydrochlorothiazide 40/12.5 mg compared to 40.1% in the monotherapy arm. The SBP response rate (reduction in SBP ≥ 10 mmHg from start of active treatment) was 63.5% for the telmisartan/hydrochlorothiazide 40/12.5 mg compared to 42.6% in the monotherapy arm.
In the other pivotal study, telmisartan/hydrochlorothiazide 80/12.5 mg was compared to telmisartan 80 mg. Patients received telmisartan 40 mg (open label) for 4 weeks. At the end of 4 weeks, patients who failed to respond adequately to telmisartan 40 mg (DBP ≥ 90 mmHg) were titrated to telmisartan 80 mg. At the end of this 4 week period, patients who failed to respond adequately to telmisartan 80 mg (DBP ≥ 90 mmHg) were randomised to receive either telmisartan 80 mg (245 patients) or telmisartan/hydrochlorothiazide 80/12.5 mg (246 patients). Seated blood pressure was recorded 24 hours postdose at each visit.
Treatment with telmisartan/hydrochlorothiazide 80/12.5 mg lowered DBP by an additional 3.1 mmHg and SBP by 5.7 mmHg compared to telmisartan 80 mg in this group of nonresponders to telmisartan 80 mg monotherapy. Both were statistically significant (p < 0.01). Similar results were seen with standing blood pressure. Most of the additional effect was seen at 4 weeks of treatment. Patients in the telmisartan/hydrochlorothiazide 80/12.5 mg arm had a significantly greater blood pressure response rate (SBP < 140 mmHg and DBP < 90 mmHg) of 41.5% compared to 26.1% for patients in the telmisartan 80 mg arm (p < 0.05).
In the third pivotal study (n = 687 patients evaluated for efficacy), telmisartan/hydrochlorothiazide 80/25 mg was compared to telmisartan/hydrochlorothiazide 80/12.5 mg in patients who failed to respond adequately to treatment with telmisartan/hydrochlorothiazide 80/12.5 mg. Following a 6 week run in period, patients who failed to respond to telmisartan/hydrochlorothiazide 80/12.5 mg (DBP ≥ 90 mmHg) were randomised to either continue treatment with telmisartan/hydrochlorothiazide 80/12.5 mg (347 patients) or to receive telmisartan/hydrochlorothiazide 80/25 mg (340 patients) for 8 weeks. Seated blood pressure was recorded 24 hours postdose at each visit.
In this group of nonresponders to telmisartan/hydrochlorothiazide 80/12.5 mg, treatment with telmisartan/hydrochlorothiazide 80/25 mg demonstrated an incremental blood pressure lowering effect on DBP by an additional 1.6 mmHg and on SBP by 2.7 mmHg compared to continued treatment with telmisartan/hydrochlorothiazide 80/12.5 mg (difference in adjusted mean changes from baseline, respectively). Both were statistically significant (p < 0.01). Patients in the telmisartan/hydrochlorothiazide 80/25 mg arm had a significantly greater blood pressure response rate compared to patients in the telmisartan/hydrochlorothiazide 80/12.5 mg arm. The DBP response rate (DBP < 90 mmHg or reduction in DBP ≥ 10 mmHg from baseline) was 59.7% for telmisartan/hydrochlorothiazide 80/25 mg compared to 51.9% for telmisartan/hydrochlorothiazide 80/12.5 mg and the SBP response rate (SBP < 140 mmHg or reduction in SBP ≥ 10 mmHg from baseline) was 65.9% for telmisartan/hydrochlorothiazide 80/25 mg compared to 57.3% for telmisartan/hydrochlorothiazide 80/12.5 mg (both p < 0.05).
An open label follow-up study was conducted at the study end of the telmisartan/hydrochlorothiazide 80/25 mg pivotal study, where all patients received telmisartan/hydrochlorothiazide 80/25 mg for 6 months. In this follow-up study, trough seated blood pressure was further decreased by 4.6/3.6 mmHg (SBP/DBP) with telmisartan/hydrochlorothiazide 80/25 mg treatment, resulting in a total reduction of 11.4/9.7 mmHg (SBP/DBP) from baseline of the preceding study. Overall, the DBP response rate (DBP < 90 mmHg or reduction in DBP ≥ 10 mmHg from baseline of the preceding study) was achieved in 74.3% of patients and the SBP response rate (SBP < 140 mmHg or reduction in SBP ≥ 10 mmHg from baseline of the preceding study) was achieved in 77.8% of patients at study end.
In a pooled analysis of two similar 8 week double blind placebo controlled clinical trials (n = 2121 patients evaluated for efficacy) comparing telmisartan 80 mg/ hydrochlorothiazide 25 mg (942 patients) with valsartan 160 mg/hydrochlorothiazide 25 mg (952 patients), a significantly greater blood pressure lowering effect of 2.2/1.2 mmHg (SBP/DBP) was demonstrated (difference in adjusted mean changes from baseline, respectively) in favour of telmisartan 80 mg/hydrochlorothiazide 25 mg combination. Both were statistically significant (p < 0.01).
No statistical differences were found with regard to gender between the different treatment groups in all three pivotal studies. No differences were observed concerning age in the first pivotal study discussed. However, for the second and third pivotal studies, although there were no age differences between treatment groups for DBP response/lowering effect, a trend was observed for a greater SBP response/lowering effect in the elderly. This in part could be due to the fact that the elderly generally respond well to hydrochlorothiazide.
In summary, the data showed that the benefits of telmisartan and hydrochlorothiazide appear to be additive and the blood pressure reduction of telmisartan/hydrochlorothiazide was larger than the blood pressure reduction achieved by either monotherapy component.

Non-melanoma skin cancer.

Based on available data from epidemiological studies, cumulative dose-dependent association between hydrochlorothiazide and NMSC has been observed. One study included a population comprised of 71,553 cases of BCC and of 8,629 cases of SCC matched to 1,430,883 and 172,462 population controls, respectively. High hydrochlorothiazide use (≥ 50,000 mg cumulative) was associated with an adjusted OR of 1.29 (95% CI: 1.23-1.35) for BCC and 3.98 (95% CI: 3.68-4.31) for SCC. A clear cumulative dose response relationship was observed for both BCC and SCC. Another study showed a possible association between lip cancer (SCC) and exposure to hydrochlorothiazide: 633 cases of lip-cancer were matched with 63,067 population controls, using a risk-set sampling strategy. A cumulative dose-response relationship was demonstrated with an adjusted OR 2.1 (95% CI: 1.7-2.6) increasing to OR 3.9 (3.0-4.9) for high use (~25,000 mg) and OR 7.7 (5.7-10.5) for the highest cumulative dose (~100,000 mg). [See Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)].

5.2 Pharmacokinetic Properties

Absorption.

Following oral administration of the fixed dose combination tablets, the tmax values for telmisartan vary from 0.5 to 4 hours. Absolute bioavailability of telmisartan was shown to be dose dependent. The mean absolute bioavailability of 40 mg telmisartan was 40%, whereas the mean absolute bioavailability of the 160 mg dose amounted to about 60%.
The maximum plasma concentration (Cmax) and, to a smaller extent, area under the plasma concentration time curve (AUC) increase disproportionately with dose. In a phase II clinical trial, 40, 80 and 120 mg of telmisartan were administered (in capsules) for 28 days to hypertensive subjects. Maximum plasma concentrations at steady state, Cmax,ss, and AUCss were determined in 37-39 subjects per dose group.
In this trial, the mean Cmax showed a more than proportional increase with dose, increasing 4.4-fold for a twofold increase in dose from 40 to 80 mg, and increasing 2.4-fold with a 1.5-fold increase in dose from 80 to 120 mg. The mean AUCss were nearly proportional with increasing dose, increasing 2.3-fold for a twofold increase in dose from 40 to 80 mg, and increasing 1.5-fold with a 1.5-fold increase in dose from 80 to 120 mg.
There is no evidence of clinically relevant accumulation of telmisartan taken at the recommended dose.
When telmisartan is taken with food, the reduction in the area under the plasma concentration time curve (AUC0-∞) of telmisartan varies from approximately 6% (40 mg dose) to approximately 19% (160 mg dose). The small reduction in AUC should not cause a reduction in the therapeutic efficacy. Therefore, Mizart HCT may be taken with or without food.
Following oral administration of hydrochlorothiazide, peak concentrations of hydrochlorothiazide are reached in approximately 1.0-2.5 hours after dosing. The absolute oral bioavailability for hydrochlorothiazide is documented as 50 to 80%.

Distribution.

Telmisartan is highly bound to plasma protein (> 99.5%), mainly albumin and alpha-1-acid glycoprotein. The mean steady-state apparent volume of distribution (Vdss) is approximately 6.6 L/kg.
Hydrochlorothiazide is 68% protein bound in the plasma and its apparent volume of distribution is 0.83-1.14 L/kg.

Metabolism.

Telmisartan undergoes substantial first-pass metabolism by conjugation to the acylglucuronide. No pharmacological activity has been shown for the conjugate. Telmisartan is not metabolised by the cytochrome P450 system.
Hydrochlorothiazide is not metabolised in man.

Excretion.

Telmisartan is characterised by biexponential decay pharmacokinetics with a terminal elimination half-life of 18.3-23.0 hours.
After oral (and intravenous) administration telmisartan is nearly exclusively excreted with the faeces, mainly as unchanged compound. Cumulative urinary excretion is < 1% of dose. Total plasma clearance (CLtot) is high (approximately 1000 mL/min) when compared with hepatic blood flow (about 1500 mL/min).
Hydrochlorothiazide is excreted almost entirely as unchanged drug in urine. At least 61% of the oral dose is eliminated as unchanged drug within 24 hours. Renal clearance is about 250-300 mL/min. The terminal elimination half-life of hydrochlorothiazide is 8-10 hours.

Special populations.

Elderly patients.

The pharmacokinetics of telmisartan do not differ between younger and elderly patients (i.e. patients older than 65 years of age).

Patients with renal impairment.

Renal excretion does not contribute to the clearance of telmisartan. Based on modest experience in patients with mild to moderate renal impairment (creatinine clearance of 30-60 mL/min, mean about 50 mL/min) no dosage adjustment is necessary in patients with decreased renal function. Telmisartan is not removed from blood by haemodialysis. In patients with impaired renal function the rate of hydrochlorothiazide elimination is reduced. In a typical study in patients with a mean creatinine clearance of 60 mL/min the elimination half-life of hydrochlorothiazide was increased. In functionally anephric patients the elimination half-life is about 34 hours.

Patients with hepatic impairment.

Pharmacokinetic studies of telmisartan in patients with hepatic impairment showed an increase in absolute bioavailability up to nearly 100%. The elimination half-life is not changed in patients with hepatic impairment.

Gender.

Plasma concentrations of telmisartan are generally 2-3 times higher in females than in males. In clinical trials, however, no clinically significant increases in blood pressure response or incidences of orthostatic hypotension were found in females. No dosage adjustment is necessary. There was a trend towards higher plasma concentrations of hydrochlorothiazide in females than in males. This is not considered to be of clinical relevance.

Children.

Pharmacokinetic studies of telmisartan have not been investigated in patients less than 18 years of age.

5.3 Preclinical Safety Data

Genotoxicity.

The genotoxic potential of telmisartan in combination with hydrochlorothiazide has not been evaluated in animal studies.

Telmisartan.

Telmisartan was not genotoxic in a battery of tests for gene mutations and clastogenicity.

Hydrochlorothiazide.

Hydrochlorothiazide was not genotoxic in a gene mutation assay in bacterial cells, or in tests for clastogenic activity in vitro and in vivo. However, hydrochlorothiazide had mutagenic activity in a mammalian cell assay (mouse lymphoma cells) and caused an increase in chromosomal aberrations in vitro (Chinese hamster lung cells). Hydrochlorothiazide also had a genotoxic activity in the sister chromatid exchange assay in Chinese hamster ovary cells and a nondisjunction assay in Aspergillus nidulans. However, the extensive human experience with hydrochlorothiazide has failed to show an association between its use and an increase in neoplasms.

Carcinogenicity.

The carcinogenic potential of telmisartan in combination with hydrochlorothiazide has not been evaluated in animal studies.

Telmisartan.

Two year studies in mice and rats did not show any increases in tumour incidences when telmisartan was administered in the diet at doses up to 1000 and 100 mg/kg/day, respectively. Plasma AUC values at the highest dose levels were approximately 60 and 15 times greater, respectively, than those anticipated in humans at the maximum recommended dose.

Hydrochlorothiazide.

Two year feeding studies in mice and rats showed no evidence of carcinogenic potential in female mice at doses up to approximately 600 mg/kg/day, or in male and female rats at doses up to approximately 100 mg/kg/day. However, there was equivocal evidence for hepatocarcinogenicity in male mice treated with hydrochlorothiazide alone at approximately 600 mg/kg/day.

4 Clinical Particulars

4.1 Therapeutic Indications

Mizart HCT is indicated for the treatment of hypertension. Treatment should not be initiated with these combinations.

4.3 Contraindications

Hypersensitivity to any of the components of the product or sulphonamide derived substances.
Pregnancy.
Lactation.
Cholestasis and biliary obstructive disorders.
Severe hepatic impairment.
Severe renal impairment (creatinine clearance < 30 mL/min).
Anuria.
Refractory hypokalaemia, hypercalcaemia.
The concomitant use of Mizart HCT with aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m2).
In case of rare hereditary conditions that may be incompatible with an excipient of the product, the use of the product is contraindicated (see Section 4.4 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

Renovascular hypertension.

There is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the renin angiotensin aldosterone system.

Use in renal impairment and kidney transplantation.

Experience with telmisartan/hydrochlorothiazide is modest in patients with mild to moderate renal impairment and therefore periodic monitoring of potassium, creatinine and uric acid serum levels is recommended. Mizart HCT should not be used in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see Section 4.3 Contraindications). Thiazide diuretic associated azotaemia may occur in patients with impaired renal function. There is no experience regarding the administration of telmisartan/hydrochlorothiazide in patients with a recent kidney transplant.
Increases in serum creatinine have been observed in studies with ACE inhibitors in patients with single or bilateral renal artery stenosis. An effect similar to that observed with ACE inhibitors should be anticipated with Mizart HCT.

Other conditions with stimulation of the renin angiotensin aldosterone system.

In patients whose vascular tone and renal function depend predominantly on the activity of the renin angiotensin aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with other medicinal products that affect this system has been associated with acute hypotension, hyperazotaemia, oliguria, or rarely acute renal failure.

Dual blockade of the renin angiotensin aldosterone system.

As a consequence of inhibiting the renin angiotensin aldosterone system, changes in renal function (including acute renal failure) have been reported in susceptible individuals, especially if combining medicinal products that affect this system. Dual blockade of the renin angiotensin aldosterone system (e.g. by adding an ACE inhibitor or the direct renin inhibitor aliskiren to an angiotensin II receptor antagonist) should therefore be limited to individually defined cases with close monitoring of renal function (see Section 4.3 Contraindications).

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

The use of an 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.

Primary aldosteronism.

Patients with primary aldosteronism generally will not respond to antihypertensive medicinal products acting through inhibition of the renin angiotensin system. Therefore, the use of Mizart HCT is not recommended.

Diabetes mellitus.

Exploratory post hoc analyses of two placebo controlled telmisartan trials suggested an increased risk of fatal myocardial infarction and unexpected cardiovascular death (death occurring within 24 hours of the onset of symptoms without confirmation of cardiovascular cause, and without clinical or post mortem evidence of other etiology) in patients with diabetes mellitus who have no documented medical history of either coronary heart disease or myocardial infarction. In patients with diabetes mellitus, coronary heart disease may be asymptomatic and can therefore remain undiagnosed. Treatment with blood pressure lowering agent telmisartan may further reduce coronary perfusion in these patients. For this reason, patients with diabetes mellitus should undergo specific diagnostics and be treated accordingly before initiating therapy with Mizart HCT.

Aortic and mitral valve stenosis, and obstructive hypertrophic cardiomyopathy.

As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral valve stenosis, or obstructive hypertrophic cardiomyopathy.

Metabolic and endocrine effects.

Thiazide therapy may impair glucose tolerance. In diabetic patients dosage adjustments of insulin or oral hypoglycaemic agents may be required. Latent diabetes mellitus may become manifest during thiazide therapy.
An increase in cholesterol and triglyceride levels has been associated with thiazide diuretic therapy; however, at the 12.5 mg dose contained in telmisartan/hydrochlorothiazide 40/12.5 mg and 80/12.5 mg tablets, minimal or no effects were reported.
Hyperuricaemia may occur or frank gout may be precipitated in some patients receiving thiazide therapy.
In the clinical trials conducted with telmisartan/hydrochlorothiazide, an increase in uric acid levels and triglyceride levels were observed with increasing dose of hydrochlorothiazide. Consideration should be taken if monitoring of lipids and uric acid levels is needed in patients at risk of metabolic disturbances when titrated to the highest dose of Mizart HCT.

Electrolyte imbalance.

As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals including when the patient is vomiting excessively or receiving parenteral fluids.
Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (hypokalaemia, hyponatraemia, and hypochloraemic alkalosis). Warning signs of fluid or electrolyte imbalance are dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, seizure, confusion, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea or vomiting.
Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy with telmisartan may reduce diuretic induced hypokalaemia. The risk of hypokalaemia is greatest in patients with liver cirrhosis, in patients experiencing brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or ACTH. Conversely, due to the antagonism of the AT1 receptors by the telmisartan component of telmisartan/hydrochlorothiazide, hyperkalaemia might occur. Although clinically significant hyperkalaemia has not been documented with telmisartan/hydrochlorothiazide, risk factors for the development of hyperkalaemia include renal insufficiency and/or heart failure, and diabetes mellitus. Potassium sparing diuretics, potassium supplements or potassium containing salt substitutes should be coadministered cautiously with Mizart HCT (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
There is no evidence that telmisartan/hydrochlorothiazide would reduce or prevent diuretic induced hyponatraemia. Chloride deficit is generally mild and usually does not require treatment.
Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.
Thiazides have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesaemia.

Use in hepatic impairment.

The majority of telmisartan is eliminated in the bile. Patients with cholestasis, biliary obstructive disorders or severe hepatic insufficiency can be expected to have reduced clearance. Mizart HCT is, therefore, contraindicated for use in these patients.
Mizart HCT should only be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. There is no clinical experience with telmisartan/hydrochlorothiazide in patients with hepatic impairment.

Lactose monohydrate.

The maximum recommended daily dose of telmisartan/hydrochlorothiazide contains 84 mg of lactose monohydrate in the dose strength 40/12.5 mg, 180.5 mg in the dose strength 80/12.5 mg, and 169.4 mg of lactose monohydrate in the dose strength 80/25 mg.
Patients with rare hereditary condition of galactose intolerance e.g. galactosaemia should not take this medicine.

Mannitol.

The maximum recommended daily dose of telmisartan and hydrochlorothiazide combination tablet contains 170 mg mannitol in the dose strength 40/12.5 mg and 340 mg mannitol in the dose strengths 80/12.5 mg and 80/25 mg.
Patients with rare hereditary condition of fructose intolerance should not take this medicine.

Sodium and/or volume depleted patients.

Symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before the administration of Mizart HCT.

Acute myopia and secondary angle closure glaucoma.

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle closure glaucoma may include a history of sulfonamide or penicillin allergy.

Non-melanoma skin cancer.

An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide exposure has been observed in two epidemiological studies based on the Danish National Cancer Registry (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Photosensitising actions of hydrochlorothiazide could act as a possible mechanism for NMSC.
Patients taking hydrochlorothiazide should be informed of the risk of NMSC and advised to regularly check their skin for any new lesions and promptly report any suspicious skin lesions. Possible preventive measures such as limited exposure to sunlight and UV rays and, in case of exposure, adequate protection should be advised to the patients in order to minimise the risk of skin cancer. Suspicious skin lesions should be promptly examined potentially including histological examinations of biopsies. The use of hydrochlorothiazide may also need to be reconsidered in patients who have experienced previous NMSC [see Section 4.8 Adverse Effects (Undesirable Effects)].

Other.

As with any antihypertensive agent, excessive reduction of blood pressure in patients with ischaemic cardiopathy or ischaemic cardiovascular disease could result in a myocardial infarction or stroke.

General.

Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history.
Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide diuretics.

Use in the elderly.

See Section 5.2 Pharmacokinetic Properties, Special populations, Elderly patients.

Paediatric use.

Safety and efficacy of telmisartan/hydrochlorothiazide have not been established in children and adolescents up to 18 years.

Effects on laboratory tests.

See Section 4.8 Adverse Effects (Undesirable Effects), Clinical laboratory findings.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Telmisartan may increase the hypotensive effect of other antihypertensive agents. Other interactions of clinical significance have not been identified. Compounds which have been studied in pharmacokinetic trials include digoxin, warfarin, hydrochlorothiazide, glibenclamide, ibuprofen, paracetamol, simvastatin and amlodipine. For digoxin a 20% increase in median plasma digoxin trough concentration has been observed (39% in a single case), monitoring of plasma digoxin levels should be considered.
Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors. Cases have also been reported with angiotensin II receptor antagonists, including telmisartan. Furthermore, renal clearance of lithium is reduced by thiazides so the risk of lithium toxicity could be increased with Mizart HCT. Lithium and Mizart HCT should be coadministered with caution. Therefore, serum lithium level monitoring is advisable during concomitant use.
The potassium depleting effect of hydrochlorothiazide is attenuated by the potassium sparing effect of telmisartan. However, this effect of hydrochlorothiazide on serum potassium would be expected to be potentiated by other drugs associated with potassium loss and hypokalaemia (e.g. other kaliuretic diuretics, laxatives, corticosteroids, ACTH, amphotericin B (amphotericin), carbenoxolone, penicillin G sodium, salicylic acid and derivatives). Conversely, based on the experience with the use of other drugs that blunt the renin angiotensin system, concomitant use of potassium sparing diuretics, potassium supplements, salt substitutes containing potassium or other drugs that may increase serum potassium levels (e.g. heparin sodium) may lead to increases in serum potassium. If these drugs are to be prescribed with Mizart HCT, monitoring of potassium plasma levels is advisable.
Treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin at anti-inflammatory dosage regimens, COX-2 inhibitors and nonselective NSAIDs is associated with the potential for acute renal insufficiency in patients who are dehydrated. Compounds acting on the renin angiotensin aldosterone system like telmisartan may have synergistic effects. Patients receiving NSAIDs and Mizart HCT should be adequately hydrated and be monitored for renal function at the beginning of combined treatment. The coadministration of NSAIDs may reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics in some patients.
Periodic monitoring of serum potassium is recommended when Mizart HCT is administered with drugs affected by serum potassium disturbances (e.g. digitalis glycosides, antiarrhythmics and drugs known to induce torsades de pointes).
Telmisartan is not metabolised by the cytochrome P450 system and had no effects in vitro on cytochrome P450 enzymes, except for some inhibition of CYP2C19. Telmisartan is not expected to interact with drugs that inhibit, or are metabolised by cytochrome P450 enzymes.
In one study, the coadministration of telmisartan 80 mg once daily and ramipril 10 mg once daily to healthy subjects increases steady-state Cmax and AUC of ramipril 2.3- and 2.1-fold, respectively, and Cmax and AUC of ramiprilat 2.4 and 1.5-fold, respectively. In contrast, Cmax and AUC of telmisartan decrease by 31% and 16% respectively. The clinical relevance of this observation is not fully known. When coadministering telmisartan and ramipril, the response may be greater because of the possibly additive pharmacodynamics effects of the combined drugs and also because of the increased exposure to ramipril and ramiprilat in the presence of telmisartan. Combining telmisartan with ramipril in the ONTARGET trial resulted in a significantly higher incidence of hyperkalaemia, renal failure, hypotension and syncope compared to telmisartan alone or ramipril alone (see Section 5.1 Pharmacodynamic Properties, Telmisartan). Concomitant use of telmisartan and ramipril is therefore not recommended in patients with already controlled blood pressure and should be limited to individually defined cases with close monitoring of renal function.
The following drugs may interact with thiazide diuretics when administered concurrently:

Alcohol, barbiturates, or narcotics.

Potentiation of orthostatic hypotension may occur.

Antidiabetic drugs (oral agents and insulins).

Dosage adjustment of the antidiabetic drug may be required (see Section 4.4 Special Warnings and Precautions for Use).

Metformin.

There is a risk of lactic acidosis when coadministered with hydrochlorothiazide.

Colestyramine and colestipol resins.

Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either colestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85 and 43 percent, respectively.

Corticosteroids, ACTH.

Electrolyte depletion, particularly hypokalaemia, may be increased.

Digitalis glycosides.

Thiazide induced hypokalaemia or hypomagnesaemia favour the onset of digitalis induced cardiac arrhythmias (see Section 4.4 Special Warnings and Precautions for Use).

Pressor amines (e.g. noradrenaline (norepinephrine)).

The effect of pressor amines may be decreased.

Nondepolarizing skeletal muscle relaxants (e.g. tubocurarine).

The effect of nondepolarizing skeletal muscle relaxants may be potentiated by hydrochlorothiazide.

Treatment for gout.

Dosage adjustment of uricosuric medications may be necessary as hydrochlorothiazide may raise the level of serum uric acid. Increase in dosage of probenecid or sulfinpyrazone may be necessary. Coadministration of thiazide may increase the incidence of hypersensitivity reactions of allopurinol.

Calcium salts.

Thiazide diuretics may increase serum calcium levels due to the decreased excretion. If calcium supplements must be prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly.

Other interactions.

The hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by thiazides. Anticholinergic agents (e.g. atropine, biperiden) may increase the bioavailability of thiazide type diuretics by decreasing gastrointestinal motility and stomach emptying rate. Thiazides may increase the risk of adverse effects caused by amantadine. Thiazides may reduce the renal excretion of cytotoxic drugs (e.g. cyclophosphamide monohydrate, methotrexate) and potentiate their myelosuppressive effects.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No studies on fertility in humans have been performed. The effects on fertility of telmisartan in combination with hydrochlorothiazide have not been evaluated in animal studies.

Telmisartan.

The fertility of male and female rats was unaffected at oral telmisartan doses up to 100 mg/kg/day.

Hydrochlorothiazide.

No animal fertility studies with hydrochlorothiazide are available for evaluation.
(Category D)

Telmisartan.

Angiotensin II receptor antagonists should not be initiated during pregnancy. The use of angiotensin II receptor antagonists is not recommended during the first trimester of pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started. The use of angiotensin II receptor antagonists is contraindicated during the second and third trimesters of pregnancy.
Although there is no clinical experience with telmisartan/hydrochlorothiazide in pregnant women, in utero exposure to drugs that act directly on the renin angiotensin system can cause fetal and neonatal morbidity and even death. Several dozen cases have been reported in the world literature in patients who were taking angiotensin converting enzyme inhibitors. Therefore, when pregnancy is detected, Mizart HCT should be discontinued as soon as possible.
Preclinical studies with telmisartan do not indicate teratogenic effect, but have shown fetotoxicity.
Angiotensin II receptor antagonists exposure during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). Oligohydramnios reported in this setting, presumably resulting from decreased fetal renal function, has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug.
These adverse effects do not appear to occur when drug exposure 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. Women of childbearing age should be warned of the potential hazards to their fetus should they become pregnant.
Unless continued angiotensin II receptor antagonist therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped immediately, and if appropriate, alternative therapy should be started.
Should exposure to angiotensin II receptor antagonists have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken angiotensin II receptor antagonists should be closely observed for hypotension, oliguria and hyperkalaemia.
Telmisartan has been shown to cross the placenta in rats. There were no teratogenic effects when telmisartan alone or telmisartan in combination with hydrochlorothiazide were administered orally to rats and rabbits during the period of organogenesis at doses up to 50 mg/kg/day telmisartan and 15.6 mg/kg hydrochlorothiazide. Telmisartan was not teratogenic in rabbits at oral doses up to 45 mg/kg/day, but fetal resorptions were observed at the highest dose level. Administration of 50 mg/kg/day telmisartan to rats during pregnancy and lactation caused a decrease in birthweight and suppression of postnatal growth and development of the offspring. The no effect dose level in rabbits was 15 mg/kg/day, and corresponded to a plasma AUC value that was about 9 times higher than that anticipated in women at the highest recommended dose. Plasma AUC values of telmisartan and hydrochlorothiazide in rats at the highest dose were both about 5 times that anticipated in women at the highest recommended dose.

Hydrochlorothiazide.

There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester.
Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide its use during the second and third trimester may compromise fetoplacental perfusion and may cause fetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia.
Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or pre-eclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a beneficial effect on the course of the disease.
Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare situations where no other treatment could be used.
Mizart HCT is contraindicated during lactation. It is not known whether telmisartan is excreted in human milk. Animal studies have shown excretion of telmisartan in breast milk. Thiazides appear in human milk and may inhibit lactation. Lactating women should either not be prescribed Mizart HCT or should discontinue breastfeeding if Mizart HCT is administered.
Telmisartan is excreted in the milk of lactating rats. When administered orally to lactating rats at 50 mg/kg/day, telmisartan suppressed postnatal growth and development of the offspring.

4.8 Adverse Effects (Undesirable Effects)

Telmisartan/hydrochlorothiazide has been evaluated for safety in over 1700 patients, including 716 treated for over six months and 420 for over one year. In clinical trials with telmisartan/hydrochlorothiazide, no unexpected adverse events have been observed. Adverse experiences have been limited to those that have been previously reported with telmisartan and/or hydrochlorothiazide. The overall incidence of adverse experiences reported with the combination was comparable to placebo. Most adverse experiences were mild in intensity and transient in nature and did not require discontinuation of therapy.
The overall incidence and pattern of adverse events reported with telmisartan/hydrochlorothiazide 80/25 mg was comparable with telmisartan/hydrochlorothiazide 80/12.5 mg. A dose-relationship of undesirable effects was not established and they showed no correlation with gender, age or race of the patients.
Adverse events occurring at an incidence of 2% or more in patients treated with telmisartan/hydrochlorothiazide and at a greater rate than in patients treated with placebo, irrespective of their causal association, are presented in Table 1.
The following adverse events were reported at a rate of 2% or greater in patients treated with telmisartan/hydrochlorothiazide, but were as, or more common in the placebo group: pain, headache, cough, urinary tract infection (including cystitis).
Adverse events occurred at approximately the same rates in men and women, older and younger patients, and Black and non-Black patients.
The adverse reactions reported in clinical trials with telmisartan/hydrochlorothiazide (including the dose strengths 40/12.5 mg, 80/12.5 mg and 80/25 mg) are listed below:

Cardiac disorders.

Cardiac arrhythmias, tachycardia.

Eye disorders.

Abnormal vision, transient blurred vision.

Ear and labyrinth disorders.

Vertigo.

Gastrointestinal disorders.

Diarrhoea, dry mouth, flatulence, abdominal pain, constipation, dyspepsia, vomiting, gastritis.

General disorders and administration site conditions.

Chest pain, influenza-like symptoms, pain.

Hepato-biliary disorders.

Abnormal hepatic function/ liver disorder*.

Infections and infestations.

Bronchitis, pharyngitis, sinusitis.

Investigations.

Increase in creatinine, increase in liver enzymes, increase in blood creatine phosphokinase, increase in uric acid.

Metabolism and nutrition disorders.

Hypokalaemia, hyponatraemia, hyperuricaemia.

Musculoskeletal, connective tissue and bone disorders.

Back pain, muscle spasm, myalgia, arthralgia, leg pain, cramps in legs.

Nervous system disorders.

Syncope/ faint, dizziness, paraesthesia, sleep disturbances, insomnia.

Psychiatric disorders.

Anxiety, depression.

Reproductive system and breast disorders.

Impotence.

Respiratory, thoracic and mediastinal disorders.

Respiratory distress (including pneumonitis and pulmonary oedema), dyspnoea.

Skin and subcutaneous tissue disorders.

Angioedema (with fatal outcome), erythema, pruritus, rash, sweating increased, urticaria.

Vascular disorders.

Hypotension (including orthostatic hypotension).
In controlled trials (n=1017), 0.2% of patients treated with telmisartan/hydrochlorothiazide 40/12.5 mg or 80/12.5 mg discontinued due to orthostatic hypotension, and the incidence of dizziness was 4% and 7%, respectively.

Telmisartan.

Other adverse experiences that have been reported with telmisartan in the indication of hypertension treatment or in patients aged 50 years or older at high risk of developing major cardiovascular events, without regard to causality, are listed below:

Blood and lymphatic system disorders.

Anaemia, eosinophilia, thrombocytopenia.

Cardiac disorders.

Palpitation, angina pectoris, abnormal ECG, bradycardia.

Ear and labyrinth disorders.

Tinnitus, ear ache.

Endocrine disorders.

Diabetes mellitus.

Eye disorders.

Conjunctivitis.

Gastrointestinal disorders.

Haemorrhoids, gastroenteritis, enteritis, gastroesophageal reflux, toothache, non-specific gastrointestinal disorders (e.g. stomach upset).

General disorders and administration site conditions.

Fever, malaise, leg oedema, peripheral oedema, asthenia (weakness).

Immune system disorders.

Allergy, anaphylactic reaction, hypersensitivity.

Infections and infestations.

Sepsis including fatal outcome, upper respiratory tract infections, urinary tract infections (including cystitis), infection, fungal infection, abscess, otitis media.

Investigations.

Decrease in haemoglobin.

Metabolism and nutrition disorders.

Gout, hypercholesterolaemia, hyperkalaemia, hypoglycaemia (in diabetic patients).

Musculoskeletal, connective tissue and bone disorders.

Arthrosis, arthritis, tendon pain (tendinitis like symptoms).

Nervous system disorders.

Somnolence, migraine, hypoaesthesia.

Psychiatric disorders.

Nervousness.

Renal and urinary disorders.

Micturition frequency, renal impairment including acute renal failure (see Section 4.4 Special Warnings and Precautions for Use).

Respiratory, thoracic and mediastinal disorders.

Asthma, rhinitis, epistaxis.

Skin and subcutaneous tissue disorders.

Dermatitis, eczema, drug eruption, toxic skin eruption.

Vascular disorders.

Cerebrovascular disorder, flushing, dependent oedema, hypertension.

Hydrochlorothiazide.

Other adverse experiences that have been reported with hydrochlorothiazide, without regard to causality, are listed below:

Blood and the lymphatic system disorders.

Anaemia (including aplastic anaemia, haemolytic anaemia), agranulocytosis, bone marrow depression, neutropenia/ leukopenia, thrombocytopenia (sometimes with purpura).

Eye disorders.

Xanthopsia, acute myopia, acute angle-closure glaucoma.

Endocrine disorders.

Loss of diabetic control.

Gastrointestinal disorders.

Nausea, pancreatitis, stomach upset, cramping, gastric irritation.

General disorders and administration site conditions.

Fever.

Hepatobiliary disorders.

Jaundice (hepatocellular or cholestatic jaundice).

Immune system disorders.

Anaphylactic reactions, allergy.

Infections and infestations.

Sialadenitis.

Investigations.

Increase in triglycerides.

Metabolism and nutrition disorders.

Hyperglycaemia, cause or exacerbate volume depletion, electrolyte imbalance, hypercholesterolaemia, anorexia, loss of appetite, hypomagnesaemia, hypercalcaemia, hypochloraemic alkalosis.

Musculoskeletal, connective tissue and bone disorders.

Weakness.

Nervous system disorders.

Headache, light-headedness.

Psychiatric disorders.

Restlessness.

Renal and urinary disorders.

Renal failure, renal dysfunction, interstitial nephritis, glycosuria.

Skin and subcutaneous tissue disorders.

Cutaneous lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus, erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis, purpura, photosensitivity reactions, cutaneous vasculitis.

Vascular disorders.

Necrotizing angiitis (vasculitis).

Clinical laboratory findings.

In controlled trials, clinically relevant changes in standard laboratory test parameters were rarely associated with administration of telmisartan/hydrochlorothiazide tablets.

Haemoglobin and haematocrit.

Decreases in haemoglobin (≥ 2 g/dL) and haematocrit (≥ 9%) were observed in 1.2% and 0.6% of telmisartan/hydrochlorothiazide patients, respectively, in controlled trials. Changes in haemoglobin and haematocrit were not considered clinically significant and there were no discontinuations due to anaemia.

Creatinine, blood urea nitrogen (BUN).

Increases in BUN (≥ 11.2 mg/dL) and serum creatinine (≥ 0.5 mg/dL) were observed in 2.8% and 1.4%, respectively, of patients with hypertension treated with telmisartan/hydrochlorothiazide in controlled trials. No patient discontinued treatment with telmisartan/hydrochlorothiazide due to an increase in BUN or creatinine.

Liver function tests.

Occasional elevations of liver enzymes and/or serum bilirubin have occurred. No telmisartan/hydrochlorothiazide treated patients discontinued therapy due to abnormal hepatic function.

Electrolyte imbalance.

See Section 4.4 Special Warnings and Precautions for Use.

Post-marketing experience.

In addition, the following have also been reported based on post-marketing experience:

Telmisartan and hydrochlorothiazide.

Immune system disorders.

Exacerbation or activation of systemic lupus erythematosus.
* Most cases of hepatic function/ liver disorder from post-marketing experience with telmisartan occurred in patients in Japan, who are more likely to experience these adverse reactions.

Hydrochlorothiazide.

Neoplasms benign, malignant and unspecified (including cysts and polyps).

Frequency 'not known': Non-melanoma skin cancer (Basal cell carcinoma and Squamous cell carcinoma) (see Section 4.4 Special Warnings and Precautions for Use; Section 5.1 Pharmacodynamic Properties, Clinical trials).

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.

4.2 Dose and Method of Administration

Adults.

The recommended dose is one tablet once daily.
The dose of telmisartan can be increased before switching to Mizart HCT. Direct change from monotherapy to the fixed combinations may be considered.
Mizart HCT 40/12.5 mg may be administered in patients whose blood pressure is not adequately controlled by telmisartan 40 mg or hydrochlorothiazide.
Mizart HCT 80/12.5 mg may be administered in patients whose blood pressure is not adequately controlled by telmisartan 80 mg or by Mizart HCT 40/12.5 mg.
Mizart HCT 80/25 mg may be administered in patients whose blood pressure is not adequately controlled by Mizart HCT 80/12.5 mg or in patients who have been previously stabilised on telmisartan and hydrochlorothiazide given separately.
The maximum antihypertensive effect with Mizart HCT is generally attained 4-8 weeks after the start of treatment.
Mizart HCT may be administered with or without food.

Elderly.

No dosing adjustment is necessary.

Renal impairment.

Due to the hydrochlorothiazide component, Mizart HCT should not be used by patients with severe renal dysfunction (creatinine clearance < 30 mL/min, see Section 4.3 Contraindications). Loop diuretics are preferred to thiazides in this population. Experience in patients with mild to moderate renal impairment has not suggested adverse renal effects and dose adjustment is not considered necessary. Periodic monitoring of renal function is advised (see Section 4.4 Special Warnings and Precautions for Use).

Hepatic impairment.

In patients with mild to moderate hepatic impairment, the dosage should not exceed Mizart HCT 40/12.5 mg once daily. Mizart HCT is not indicated in patients with severe hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use).

4.7 Effects on Ability to Drive and Use Machines

The effect of telmisartan/hydrochlorothiazide on ability to drive and use machines has not been studied. However, when driving or operating machinery it should be taken into account that with antihypertensive therapy, occasionally dizziness or drowsiness may occur.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
Limited information is available for telmisartan/hydrochlorothiazide with regard to overdose in humans.
The most prominent manifestations of telmisartan overdose were hypotension and tachycardia; bradycardia also occurred.
Overdose with hydrochlorothiazide is associated with electrolyte depletion (hypokalaemia, hypochloraemia, hyponatraemia) and dehydration resulting from excessive diuresis. The most common signs and symptoms of overdose are nausea and somnolence. Hypokalaemia may result in muscle spasm and/or accentuate cardiac arrhythmias associated with the concomitant use of digitalis glycosides or certain antiarrhythmic drugs.
No specific information is available on the treatment of overdose with Mizart HCT. The patient should be closely monitored, and the treatment should be symptomatic and supportive depending on the time since ingestion and the severity of the symptoms. Serum electrolytes and creatinine should be monitored frequently. If hypotension occurs, the patient should be placed in a supine position, with salt and volume replacements given quickly.
Telmisartan is not removed by haemodialysis. The degree to which hydrochlorothiazide is removed by haemodialysis has not been established.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

6 Pharmaceutical Particulars

6.1 List of Excipients

Tablet core: povidone (K25), lactose monohydrate, magnesium stearate, meglumine, sodium hydroxide, sodium stearyl fumarate and mannitol. Mizart HCT 40/12.5 mg and 80/12.5 mg tablets also contain Pigment Blend PB-24880 Pink and Mizart HCT 80/25 mg tablets also contain Pigment Blend PB-52290 Yellow, as colouring agent.

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. Protect from light and moisture.
These tablets should not be removed from their foil pack until required for administration.

6.5 Nature and Contents of Container

Blister packs (Aluminium/ Aluminium silver foil) of 28 tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

Summary Table of Changes