Consumer medicine information

Enalapril/HCT Sandoz

Enalapril maleate; Hydrochlorothiazide

BRAND INFORMATION

Brand name

Enalapril/HCT Sandoz

Active ingredient

Enalapril maleate; Hydrochlorothiazide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Enalapril/HCT Sandoz.

What is in this leaflet

This leaflet answers some common questions about Enalapril/HCT Sandoz 20 mg/6 mg. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Enalapril/HCT Sandoz 20 mg/6 mg against the benefits it is expected to have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Enalapril/HCT Sandoz 20 mg/6 mg is used for

The name of your medicine is Enalapril/HCT Sandoz 20 mg/6 mg. It contains the active ingredients enalapril maleate and hydrochlorothiazide.

It is used to treat mild to moderate high blood pressure (hypertension).

Hypertension
Everyone has blood pressure. This pressure helps to circulate the 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 higher than is needed, 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 and kidney failure. Enalapril/HCT Sandoz 20 mg/6 mg helps to lower your blood pressure.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

How Enalapril/HCT Sandoz 20 mg/6 mg works

Enalapril/HCT Sandoz 20 mg/6 mg contains two active ingredients. One of these is enalapril maleate. It belongs to a group of medicines called angiotensin converting enzyme (ACE) inhibitors. It works by widening your blood vessels. This means that blood is able to pass through them more easily and the heart doesn't have to pump as hard to move blood around the body.

The other active ingredient is hydrochlorothiazide, which is a fluid tablet or diuretic. It helps reduce the amount of fluid in the body by making your kidneys pass more water and salt.

Both of these active ingredients help to lower high blood pressure.

There is no evidence that Enalapril/HCT Sandoz 20mg/6mg is addictive.

Before you take Enalapril/HCT Sandoz 20 mg/6 mg

When you must not take it

Do not take this medicine if:

  • you are allergic to the active ingredients or any of the inactive ingredients mentioned at the end of this leaflet under Product Description. Some of the symptoms of an allergic reaction may include shortness of breath; wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.
  • you have an allergy to any sulfur medicines or sulfonamide antibiotics.
    One of the active ingredients in this medicine, hydrochlorothiazide, is a sulfur-containing medicine (a sulfonamide). Therefore, if you are allergic to sulfur medicines, such as some antibiotics or some tablets used to treat diabetes, you are likely to be allergic to Enalapril/HCT Sandoz 20 mg/6 mg. Check with your doctor or pharmacist if you are not sure whether you are allergic to sulfur medicines.
  • you have taken any other 'ACE inhibitor' medicines for high blood pressure or heart failure before, which caused your face, lips, tongue, throat, hands or feet to swell up, or made it hard for you to breathe.
    If you have had an allergic reaction to an ACE inhibitor before, you may be allergic to this medicine.
  • you have a history of swelling of the face, lips, tongue, throat, hands or feet, for no apparent reason
  • you have renal artery stenosis, a disease of the kidney
  • you are not passing urine
  • you have diabetes and are taking a medicine called aliskiren to reduce blood pressure
  • you are taking a medicine containing a neprilysin inhibitor (e.g., sacubitril). Do not take Enalapril/HCT Sandoz 20 mg/6 mg for at least 36 hours before or after you take sacubitril/valsartan, a medicine containing a neprilysin inhibitor.
  • you are pregnant or breastfeeding. Your baby may absorb this medicine in the womb or from breast milk and therefore there is a possibility of harm to the baby.
  • it is past its expiry date or the packaging appears to have been tampered with.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Do not give Enalapril/HCT Sandoz 20mg/6mg to a child. Its safety in children has not been established.

Before you start to take it

Tell your doctor if:

  • you plan on becoming pregnant or will be breastfeeding while you are using this medicine. It should not be used during pregnancy or while breastfeeding.
  • you have or have had any medical conditions, especially the following:
    - kidney disease, or if you are undergoing dialysis
    - passing less urine than is normal
    - liver disease
    - heart problems
    - diabetes.
  • you are following a very low salt diet
  • you are taking potassium supplements, potassium-sparing agents, potassium-containing salt substitutes or other drugs that may increase serum potassium (eg. Trimethoprim-containing products)
  • you have an allergy to any other medicines, especially if they are in the same drug class as enalapril maleate or hydrochlorothiazide
  • you have had an allergy to any other substances, including foods, preservatives or dyes
  • you have recently suffered from excessive vomiting or diarrhoea
  • you suffer from low blood pressure (you may notice this as faintness or dizziness, especially when standing)
  • surgery and anaesthesia (even at the dentist office) are scheduled, as there may be a sudden fall in blood pressure associated with anaesthesia
  • you are taking a medicine containing a neprilysin inhibitor (e.g., sacubitril).
  • You have had skin cancer or if you develop a new skin lesion during the treatment. Treatment with hydrochlorothiazide, particularly long-term use with high doses, may increase the risk of some types of skins and lip cancer (non-melanoma skin cancer). Discuss with your doctor how to protect your skin from sun exposure, and avoid artificial tanning.

If you have not told your doctor about any of the above, tell them before you start taking Enalapril/HCT Sandoz 20mg/6mg tablets.

Taking other medicines

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

Some medicines and Enalapril/HCT Sandoz 20mg/6mg may interfere with each other. These include:

  • other fluid tablets (diuretics)
  • other medicines used to treat high blood pressure
  • lithium, used to treat severe mood swings and some types of depression
  • potassium tablets or potassium-containing salt substitutes
  • potassium-sparing agents (e.g. spironolactone, eplerenone, triamterene, amiloride)
  • medicines that may increase potassium levels such as heparin, trimethoprim/sulfamethoxazole
  • steroid medicines such as cortisone, prednisone
  • insulin and tablets used to treat diabetes
  • barbiturates, used to treat epilepsy, such as phenobarbitone
  • strong pain killers such as codeine, morphine, dextropropoxyphene
  • non-steroidal anti-inflammatory drugs (NSAIDs or COX-2 inhibitors) used to treat inflammation, pain, arthritis
  • arthritis medicines including gold therapy
  • insulin or oral antidiabetic medicines. You should be closely monitored for low blood glucose levels, especially during the first month of treatment with Enalapril/HCT Sandoz 20 mg/6 mg.
  • mammalian target of rapamycin inhibitors (e.g. temsirolimus, sirolimus, everolimus) or a medicine containing a neprilysin inhibitor (e.g. sacubitril)
  • cholestyramine and colestipol, used to treat high cholesterol
  • medicines used to relax muscles before or during surgery
  • medicines used in emergency situations, such as adrenaline
  • alcohol.

These medicines may be affected by Enalapril/HCT Sandoz 20mg/6mg, or may affect how well it works. You may need to use different amounts of your medicine, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take Enalapril/HCT Sandoz 20 mg/6 mg

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

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

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 most patients, the usual dose is one tablet a day.

When to take Enalapril/HCT Sandoz 20 mg/6 mg

Take Enalapril/HCT Sandoz 20 mg/6 mg at about the same time each day. This is best in the morning, for example, at breakfast time. Taking it 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 it

Swallow the tablet whole with a full glass of water.

How long to take it

Enalapril/HCT Sandoz 20 mg/6 mg helps control your high blood pressure but does not cure it. Therefore it must be taken every day. Continue taking this medicine for as long as your doctor prescribes.

If you forget to take it

If it is less than six hours until your next dose, skip the dose you missed and take your next dose when you are meant to. Otherwise, take it as soon as you remember, and then go back to taking your tablet(s) as you would normally.

Do not take a double dose to make up for the dose you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering when to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think you or anyone else has taken too much Enalapril/HCT Sandoz 20 mg/6 mg. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

If you take too many tablets, you will probably feel light-headed or dizzy, or you may faint. You may also become very thirsty, confused, have a change in the amount of urine passed or have a fast heart beat.

While you are taking Enalapril/HCT Sandoz 20 mg/6 mg

Things you must do

Always follow your doctor's instructions carefully.

Tell your doctor immediately if you become pregnant while taking this medicine.

If you are about to start taking a new medicine, tell your doctor and pharmacist that you are taking Enalapril/HCT Sandoz 20 mg/6 mg.

Have your blood pressure checked when your doctor says, to make sure this medicine is working.

If you feel any light-headedness or dizziness after you take your first dose of Enalapril/HCT Sandoz 20 mg/6 mg or if your dose is increased, tell your doctor immediately.

If you feel light-headed, dizzy or faint, get up slowly when getting out of bed or standing up. This may be because your blood pressure is falling suddenly. Standing up slowly, especially when you get up from bed or chairs, will help your body get used to the change in position and blood pressure. If this problem gets worse or continues, talk to your doctor.

If you have excessive vomiting and/or diarrhoea while taking this medicine, or you have any of the following symptoms, tell your doctor:

  • dry mouth, thirst
  • weakness, tiredness, drowsiness
  • muscle pains or cramps
  • fast heart beat
  • passing less urine than normal.

You may be dehydrated because you are losing too much water. This may also drop your blood pressure too much.

Make sure you drink enough water during exercise and hot weather when you are taking this medicine, especially if you sweat a lot. If you do not drink enough water while taking it, you may faint or feel light-headed or sick. This is because your blood pressure is dropping suddenly. If you continue to feel unwell, tell your doctor.

If you plan to have surgery (even at the dentist) that needs a general anaesthetic, tell your doctor or dentist that you are taking Enalapril/HCT Sandoz 20 mg/6 mg. Your blood pressure may drop suddenly.

Go to your doctor regularly for a check-up. Your doctor may occasionally do a blood test to check your potassium level in the blood and to see how your kidneys are working.

Things you must not do

Do not stop taking this medicine without your doctor's permission.

Do not use it to treat any other complaints unless your doctor says so.

Do not give this medication to anyone else, even if their symptoms seem similar to yours.

Things to be careful of

Be careful driving or operating machinery until you know how this medicine affects you. It may cause dizziness or light-headedness in some people, especially after the first dose or if the dose is increased. Make sure you know how you react to Enalapril/HCT Sandoz 20 mg/6 mg before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy or light-headed. If you drink alcohol, dizziness or light-headedness may be worse.

Side Effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while taking Enalapril/HCT Sandoz 20 mg/6 mg.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Hydrochlorothiazide, a component of this medicine, increases sensitivity of the skin to the sun and may increase the risk of some types of skin and lip cancer (non-melanoma skin cancer).

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

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following and they worry you:

  • headache
  • dry cough
  • light-headedness or dizziness because blood pressure is too low
  • tiredness or weakness
  • feeling sick (nausea), vomiting, loss of appetite
  • diarrhoea, constipation, stomach upset, pains or cramps
  • restlessness
  • muscle cramps
  • transient blurred vision or yellow vision.

These are the more common side effects of Enalapril/HCT Sandoz 20 mg/6 mg. Mostly, these are mild and short-lived.

Tell your doctor immediately if you notice any of the following:

  • changes in the way your heart beats, for example, if you notice it beating faster
  • fainting
  • severe dizziness, spinning sensation
  • skin rash, itchiness or other skin problems
  • signs of worrying or frequent infections such as fever, severe chills, sore throat or mouth ulcers
  • signs of anaemia such as tiredness, headache, being short of breath when exercising, looking pale
  • passing less urine than is normal for you
  • yellowing of the skin and/or eyes, also called jaundice
  • numbness or tingling in the hands or feet
  • signs of dehydration such as nausea, vomiting, muscle cramps, headache, drowsiness and tiredness. If untreated, mental confusion and fits may develop. Your doctor may need to monitor your blood sodium levels.

These may be serious side effects of Enalapril/HCT Sandoz 20 mg/6 mg. You may need urgent medical attention. Serious side effects are rare.

If any of the following happen, stop taking this medicine and tell your doctor immediately, or go to Accident and Emergency at your nearest hospital:

  • swelling of the face, lips, mouth, throat or tongue which may cause difficulty in swallowing or breathing
  • swelling of the hands, feet, or ankles
  • pinkish, itchy swelling on the skin, also called hives or nettle rash
  • chest pain, angina
  • wheeziness due to chest tightness, shortness of breath
  • collapse, numbness or weakness of arms and legs.

These are very serious side effects. You may need urgent medical attention or hospitalisation.

All of these side effects are very rare.

Tell your doctor or pharmacist if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some people.

After taking Enalapril/HCT Sandoz 20 mg/6 mg

Storage

Keep your medicine in the original container.

If you take it out of its original container it may not keep well.

Keep your medicine in a cool dry place where the temperature stays below 25°C. Protect from light.

Do not store Enalapril/HCT Sandoz 20 mg/6 mg tablets or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car.

Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product Description

What it looks like

Enalapril/HCT Sandoz 20 mg/6 mg tablets are white, oval, biconvex tablets with a snap tab on one side, scored and marked "EN20" on the other side. This medicine is available in blister packs of 30 tablets.

Ingredients

Active ingredients:

Each Enalapril/HCT Sandoz 20 mg/6 mg tablet contains 20 mg enalapril maleate and 6 mg hydrochlorothiazide.

Inactive Ingredients:

  • lactose monohydrate
  • magnesium stearate
  • maize starch
  • sodium bicarbonate
  • purified talc.

Supplier

Sandoz Pty Ltd
ABN 60 075 449 553
54 Waterloo Road
Macquarie Park, NSW 2113
Australia
Tel: 1800 726 369

This leaflet was revised in August 2019.

Australian Register Number:

Enalapril/HCT Sandoz 20 mg/6 mg tablets: AUST R 126490

Published by MIMS October 2019

BRAND INFORMATION

Brand name

Enalapril/HCT Sandoz

Active ingredient

Enalapril maleate; Hydrochlorothiazide

Schedule

S4

 

1 Name of Medicine

Enalapril maleate/ hydrochlorothiazide.

6.7 Physicochemical Properties

Enalapril maleate.

Enalapril maleate is the ethyl ester of the parent diacid, enalaprilat.
Enalapril maleate is a white to off white crystalline powder. It is sparingly soluble in water, soluble in ethanol and freely soluble in methanol and dimethyl formamide.
Chemical formula: (S)-1-[N-[1- (ethoxycarbonyl)-3-phenylpropyl]-L-alanyl]-L-proline, (Z)-2-butenedioate salt (1:1).
Molecular formula: C20H28N2O5.C4H4O4. Molecular weight: 492.53.

Hydrochlorothiazide.

Hydrochlorothiazide is a white, or practically white, crystalline powder. It is slightly soluble in water, but freely soluble in sodium hydroxide solution.
Chemical formula: 6-chloro-3,4-dihydro- 2H-1,2,4-benzo-thiadiazine-7- sulfonamide-1,1-dioxide.
Molecular formula: C7H8ClN3O4S2. Molecular weight: 297.74.

Chemical structure.


CAS number.

Enalapril maleate.

76095-16-4.

Hydrochlorothiazide.

58-93-5.

2 Qualitative and Quantitative Composition

Each Enalapril/HCT Sandoz 20 mg/6 mg tablet contains enalapril maleate 20 mg and hydrochlorothiazide 6 mg.

Excipient with known effect.

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

3 Pharmaceutical Form

Enalapril/HCT Sandoz 20 mg/6 mg are white, oval, biconvex tablets with snap tab on one side, scored and marked "EN20" on the other side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Enalapril/HCT (enalapril maleate and hydrochlorothiazide) is a combination of an angiotensin converting enzyme inhibitor (enalapril maleate) and a diuretic (hydrochlorothiazide).
Enalapril/HCT 20 mg/6 mg provides antihypertensive activity. Enalapril maleate and hydrochlorothiazide have been used singly and concomitantly for the treatment of hypertension. Although 6 mg of hydrochlorothiazide alone does not produce a clinically significant antihypertensive effect compared with placebo, when 6 mg of hydrochlorothiazide is combined with enalapril a clinically synergistic effect on blood pressure is achieved. The antihypertensive effect is maintained for at least 24 hours.

Enalapril maleate.

Angiotensin converting enzyme (ACE) is a peptidyl dipeptidase which catalyses the conversion of angiotensin I to the pressor substance angiotensin II. After absorption, enalapril is hydrolysed to enalaprilat, which inhibits ACE. Inhibition of ACE results in decreased plasma angiotensin II, which leads to increased plasma renin activity (due to removal of negative feedback of renin release) and decreased aldosterone secretion.
ACE is identical to kininase II. Thus, enalapril may also block the degradation of bradykinin, a potent vasodepressor peptide. However, the role that this plays in the therapeutic effects of enalapril remains to be elucidated.
While the mechanism through which enalapril lowers blood pressure is believed to be primarily suppression of the renin angiotensin aldosterone system, which plays a major role in the regulation of blood pressure, enalapril is antihypertensive even in patients with low renin hypertension.
Administration of enalapril maleate to patients with hypertension results in a reduction of both supine and standing blood pressure without a significant increase in heart rate.
Symptomatic postural hypotension is infrequent. In some patients, the development of optimal blood pressure reduction may require several weeks of therapy. Abrupt withdrawal of enalapril maleate has not been associated with rapid increase in blood pressure.
Effective inhibition of ACE activity usually occurs two to four hours after oral administration of an individual dose of enalapril. Onset of antihypertensive activity was usually seen at one hour, with peak reduction of blood pressure achieved by four to six hours after administration. The duration of effect is dose related. However, at recommended doses, antihypertensive and haemodynamic effects have been shown to be maintained for at least 24 hours.
In haemodynamic studies in patients with essential hypertension, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance with an increase in cardiac output and little or no change in heart rate. Following administration of enalapril maleate there was an increase in renal blood flow; glomerular filtration rate was unchanged. However, in patients with low pretreatment glomerular filtration rates, the rates were usually increased.

Hydrochlorothiazide.

Hydrochlorothiazide is a diuretic and antihypertensive agent, which increases plasma renin activity. The mechanism of the antihypertensive effect of thiazides is unknown. Hydrochlorothiazide usually does not affect normal blood pressure.

Enalapril maleate and hydrochlorothiazide.

Although enalapril alone is antihypertensive even in patients with low renin hypertension, concomitant administration of hydrochlorothiazide in these patients leads to greater reduction of blood pressure. The mechanism for this synergy is unknown.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Enalapril maleate.

Oral enalapril maleate is rapidly absorbed, with peak serum concentrations of enalapril occurring within one hour. Based on urinary recovery, the extent of absorption of enalapril from oral enalapril maleate is approximately 60%. The extent of absorption of enalapril is similar for the various doses in the recommended therapeutic range.

Distribution.

Peak serum concentrations of enalaprilat occur three to four hours after an oral dose of enalapril maleate. Protein binding is approximately 50%. The serum concentration profile of enalaprilat exhibits a prolonged terminal phase, apparently associated with binding to ACE. In subjects with normal renal function, steady-state serum concentrations of enalaprilat were achieved by the fourth day of administration of enalapril maleate. The plasma concentration time profile of enalaprilat was complex with several exponentials including a very prolonged terminal phase (t1/2 > 30 hours). The effective half-life for accumulation of enalaprilat following multiple doses of oral enalapril maleate is eleven hours.

Metabolism.

Following absorption, oral enalapril is rapidly and extensively hydrolysed to enalaprilat, a potent angiotensin converting enzyme inhibitor. Except for conversion to enalaprilat, there is no evidence for significant metabolism of enalapril. The extent of hydrolysis of enalapril is similar for the various doses in the recommended therapeutic range.

Excretion.

Excretion of enalapril is primarily renal. The principal components in urine are enalaprilat, accounting for about 40% of the dose, and intact enalapril.

Hydrochlorothiazide.

Hydrochlorothiazide is not metabolised but is eliminated rapidly by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours. At least 61% of the oral dose is eliminated unchanged within 24 hours.

Enalapril maleate/ hydrochlorothiazide.

There are no bioavailability data on the enalapril/HCT 20 mg/6 mg combination tablet. Concomitant multiple doses of enalapril maleate and hydrochlorothiazide have little or no effect on the bioavailability of these drugs. Various tablet combinations of enalapril and hydrochlorothiazide have been shown in studies to be bioequivalent to concomitant administration of the separate entities. However, in a study comparing the bioavailability of a 10 mg enalapril/25 mg hydrochlorothiazide combination tablet and the single entity tablets given concomitantly, both the AUC and Cmax for enalaprilat were approximately 20% lower in the combination tablet than in the single enalapril tablet. This suggests that hydrochlorothiazide may have an effect on the pharmacokinetics of enalapril when they are given in a combination tablet. Enalapril/HCT 20 mg/6 mg may be assumed to be clinically bioequivalent to the separate entities.
There are no data on the possible pharmacokinetic interactions between enalapril and hydrochlorothiazide in the enalapril/HCT 20 mg/6 mg combination tablet. There are no pharmacokinetic data on the use of enalapril/HCT 20 mg/6 mg in patients with hepatic or renal failure.
The absorption of oral enalapril maleate was not influenced by the presence of food in the gastrointestinal tract when examined in studies of the single agent enalapril maleate tablet. No food interaction studies have been performed with the combination enalapril maleate/ hydrochlorothiazide tablets.

5.3 Preclinical Safety Data

Genotoxicity.

Enalapril maleate.

Enalapril was also negative in the following genotoxicity studies: rec-assay, reverse mutation assay with E. coli, sister chromatid exchange with cultured mammalian cells, and the micronucleus test with mice, as well as in an in vivo cytogenic study using mouse bone marrow.

Hydrochlorothiazide.

Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay of Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537 and TA 1538 and in the Chinese hamster ovary (CHO) test for chromosomal aberrations, or in vivo in assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes and the Drosophila sex linked recessive lethal trait gene. Positive test results were obtained only in the in vitro CHO sister chromatid exchange (clastogenicity) and in the mouse lymphoma cell (mutagenicity) assays, using concentrations of hydrochlorothiazide from 43 to 1,300 microgram/mL, and in the Aspergillus nidulans nondisjunction assay at an unspecified concentration.

Carcinogenicity.

Enalapril maleate.

There was no evidence of a carcinogenic effect when enalapril was administered for 106 weeks to rats at doses up to 90 mg/kg/day. Enalapril has also been administered for 94 weeks to male and female mice at doses up to 90 and 180 mg/kg/day, respectively, and showed no evidence of carcinogenicity.
Neither enalapril maleate nor the active diacid was mutagenic in the Ames microbial mutagen test with or without metabolic activation.
At least one ACE inhibitor has caused an increase in the incidence of oxyphilic renal tubular cells and oncocytomas in rats. The potential for ACE inhibitors to cause this effect in humans is unknown. Moreover, the progression of oxyphilic cells to oncocytomas is rare in humans and when it does occur, it is considered benign.

Hydrochlorothiazide.

Two year feeding studies in mice and rats uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses up to approximately 600 mg/kg/day) or in male and female rats (at doses of up to approximately 100 mg/kg/day). The studies, however, uncovered equivocal evidence for hepatocarcinogenicity in male mice.

Enalapril maleate and hydrochlorothiazide.

Neither enalapril nor enalaprilat, nor enalapril in combination with hydrochlorothiazide, was mutagenic in the Ames microbial mutagen test with or without metabolic activation.
The combination of enalapril and hydrochlorothiazide was also negative in an in vitro alkaline elution assay in rat hepatocytes and in an in vitro chromosome aberration assay.

4 Clinical Particulars

4.1 Therapeutic Indications

Mild to moderate hypertension. Treatment should not be initiated with this fixed dose combination.

4.3 Contraindications

Enalapril/HCT 20 mg/6 mg is contraindicated in:
Patients with anuria;
Patients who are hypersensitive to any component of this product and in patients with a history of angioneurotic oedema relating to previous treatment with an angiotensin converting enzyme inhibitor, and in patients with hereditary or idiopathic angioedema;
Patients who have shown hypersensitivity to other sulphonamide derived drugs;
Patients with renal artery stenosis;
Severe renal and hepatic impairment;
Use during pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy);
Use during lactation (see Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation).
Enalapril/HCT 20 mg/6 mg should not be administered with aliskiren in patients with diabetes (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Enalapril/HCT 20 mg/6 mg is contraindicated in combination with a neprilysin inhibitor (e.g. sacubitril). Do not administer enalapril/HCT 20 mg/6 mg within 36 hours of switching to or from sacubitril/ valsartan, a product containing a neprilysin inhibitor. (See Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.)

4.4 Special Warnings and Precautions for Use

Enalapril maleate.

Hypersensitivity/ angioneurotic edema.

Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including enalapril maleate. In such cases, enalapril maleate should be promptly discontinued and the patient carefully observed until the swelling disappears. Even in those instances where swelling of only the tongue is involved, without respiratory distress, patients may require prolonged observation since treatment with antihistamines and corticosteroids may not be sufficient. Very rarely, fatalities have been reported due to angioedema associated with laryngeal oedema or tongue oedema. Patients with involvement of the tongue, glottis or larynx are likely to experience airway obstruction, especially those with a history of airway surgery.
Where there is involvement of the tongue, glottis or larynx likely to cause airway obstruction appropriate therapy, which may include subcutaneous adrenaline solution 1:1000 (0.3 to 0.5 mL) and/or measures to ensure a patent airway, should be promptly administered. (See Section 4.8 Adverse Effects (Undesirable Effects)).
Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to non-blacks.
Patients receiving coadministration of ACE inhibitor and mTOR (mammalian target of rapamycin) inhibitor (e.g. temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment).
Patients receiving concomitant ACE inhibitor and neprilysin inhibitor therapy may be at increased risk for angioedema (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
The onset of angioedema associated with use of ACE inhibitors may be delayed for weeks or months. Patients may have multiple episodes of angioedema with long symptom free intervals. Angioedema may occur with or without urticaria.

Hypotension.

As with all antihypertensive therapy, excessive hypotension may occur in some patients. In patients with heart failure, with or without associated renal insufficiency, excessive hypotension has been observed and may be associated with oliguria and/or progressive azotaemia, and rarely with acute renal failure and/or death. Because of the potential fall in blood pressure in these patients, therapy should be started under very close medical supervision. Such patients should be followed closely for the first two weeks of treatment and if the dose of enalapril/HCT 20 mg/6 mg is increased.
Similar considerations may apply to patients with ischaemic heart or cerebrovascular disease, in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.
If hypotension occurs, the patient should be placed in the supine position and, if necessary, should receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses. Following restoration of effective blood volume and pressure reinstitution of therapy at reduced dosage may be possible; or either of the components may be used appropriately alone.

Neutropenia/ agranulocytosis.

Another angiotensin converting enzyme inhibitor has been shown to cause agranulocytosis and bone marrow depression (including leucopenia/ neutropenia). These reports generally involve patients who have pre-existing renal dysfunction and/or collagen vascular disease, some of whom have received concomitant immunosuppressant therapy. Most reports describe transient episodes for which a causal relationship to the ACE inhibitor could not be established. Available data from clinical trials of enalapril are insufficient to show that enalapril does not cause agranulocytosis at similar rates. International marketing experience has revealed cases of neutropenia or agranulocytosis in which a causal relationship to enalapril cannot be excluded.
It is recommended that periodic haematological monitoring be considered in patients with diseases known to affect bone marrow function (e.g. renal dysfunction, collagen vascular disease, etc.) and/or who are taking concomitant therapy known to be associated with bone marrow depression.

Aortic stenosis/ hypertrophic cardiomyopathy.

As with all vasodilators, ACE inhibitors should be given with caution to patients with obstruction in the outflow tract of the left ventricle.

Surgery/ anaesthesia.

In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, enalapril blocks angiotensin II formation, secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.

Hyperkalaemia.

(See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Serum potassium.)
Risk factors for the development of hyperkalaemia include renal insufficiency, worsening of renal function, age (> 70 years), diabetes mellitus, intercurrent events, in particular dehydration, acute cardiac decompensation, metabolic acidosis and concomitant use of potassium sparing diuretics (e.g. spironolactone, eplerenone, triamterene, or amiloride), potassium supplements, or potassium containing salt substitutes; or those patients taking other drugs associated with increases in serum potassium (e.g. heparin, co-trimoxazole also known as trimethoprim/ sulfamethoxazole).
The use of potassium supplements, potassium sparing diuretics, or potassium containing salt substitutes particularly in patients with impaired renal function may lead to a significant increase in serum potassium. Hyperkalaemia can cause serious, sometimes fatal, arrhythmias.
If concomitant use of enalapril/HCT 20 mg/6 mg and any of the above-mentioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium.
The combination of enalapril and a low dose diuretic cannot exclude the possibility of hyperkalaemia to occur.

Non-melanoma skin cancer.

An increased risk of non-melanoma skin cancer (basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)) with increasing cumulative dose of hydrochlorothiazide has been observed in epidemiological studies. Photosensitising actions of hydrochlorothiazide could act as a possible mechanism for non-melanoma skin cancer.
Patients taking hydrochlorothiazide should be informed of the risk of non-melanoma skin cancer and advised to take preventive measures to reduce sun and artificial UVA exposure. Patients should regularly check their skin for new lesions and promptly report suspicious skin lesions to their physicians for evaluation. The use of hydrochlorothiazide may also need to be reconsidered in patients who have experienced previous non-melanoma skin cancer. (See Section 4.8 Adverse Effects (Undesirable Effects)).

Anaphylactoid reactions during hymenoptera desensitisation.

Rarely, patients receiving ACE inhibitors during desensitisation with hymenoptera venom have experienced life threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each desensitisation.

Cough.

A persistent, nonproductive, ticklish cough has been reported in some patients undergoing treatment with enalapril and other ACE inhibiting drugs. The cough is often worse when lying down. The cough is more common in women (who account for about two-thirds of reported cases). The patients who cough may have increased bronchial reactivity compared to those who do not cough. It may disappear in some patients with continued use or diminish or disappear if the dose of the drug is reduced.
In those in whom cough persists, the drug should be discontinued. The cough usually returns on rechallenge. No residual effects have been reported.

Primary aldosteronism.

Patients with primary aldosteronism will generally not respond to antihypertensive medicines acting through inhibition of the renin angiotensin system.

Hydrochlorothiazide.

Fluid/ electrolyte imbalance.

Patients should be observed for clinical signs of fluid or electrolyte imbalance, e.g. volume depletion, hyponatraemia, hypochloraemic alkalosis, hypomagnesaemia or hypokalaemia which may occur during intercurrent diarrhoea or vomiting. Periodic determination of serum electrolytes should be performed at appropriate intervals in such patients.

Acute myopia and secondary angle closure glaucoma.

Hydrochlorothiazide, a sulphonamide, has been associated with 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 treatment may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle closure glaucoma may include a history of sulphonamides or penicillin allergy.

Postsympathectomy.

The antihypertensive effects of thiazide diuretics may be increased in the postsympathectomy patient.

Systemic lupus erythematosus.

Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide diuretics.

Enalapril maleate and hydrochlorothiazide.

Metabolic and endocrine effects.

Experience with therapeutic doses of hydrochlorothiazide higher than that contained in enalapril/HCT 20 mg/6 mg indicates that thiazide therapy may impair glucose tolerance, increase cholesterol and triglyceride levels and decrease serum sodium, magnesium and potassium levels. In clinical studies with 6 mg of hydrochlorothiazide, however, no clinically significant effect on glucose, cholesterol, triglycerides, sodium, magnesium or potassium was reported.
Thiazide therapy has been associated with the development of hyperuricaemia and/or gout in certain patients. This hyperuricaemic effect appears to be dose related and is not clinically significant at the 6 mg dose contained in enalapril/HCT 20 mg/6 mg. In addition, enalapril may increase urinary uric acid and thus attenuate the hyperuricaemic effect of hydrochlorothiazide.
Although no data exist for enalapril/HCT 20 mg/6 mg, thiazide therapy may decrease urinary calcium excretion. Marked hypercalcaemia may be evidence of occult hyperparathyroidism. Thiazides should be discontinued before performing tests for parathyroid function.

Preclinical safety data.

Enalapril/HCT 20 mg/6 mg has greater toxicity than that of the component agents. In particular, studies in rats, dogs and monkeys showed that the renal toxic effects of enalapril maleate are increased when the drug is given in combination with hydrochlorothiazide. The combination of enalapril maleate and hydrochlorothiazide produced gastrointestinal toxicity (haemorrhage, erosion and necrosis) in dogs, but similar effects have not been observed with enalapril, and these were considered to be secondary to uraemia as a result of renal toxicity in dogs given high doses of enalapril.

Haemodialysis patients.

The use of enalapril/HCT 20 mg/6 mg is not indicated in patients requiring dialysis for renal failure (see Section 4.2 Dose and Method of Administration). Anaphylactoid reactions have been reported in patients dialysed with high flux membranes (e.g. AN 69) and treated concomitantly with an ACE inhibitor. In these patients, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.

Use in hepatic impairment.

Enalapril maleate.

Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice or hepatitis and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.

Hydrochlorothiazide.

Thiazides should 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.

Use in renal impairment.

Thiazides may not be appropriate diuretics for use in patients with renal impairment and are ineffective at creatinine clearance values of 30 mL/minute or below (i.e. moderate or severe renal insufficiency).
Enalapril/HCT 20 mg/6 mg should not be administered to patients with renal insufficiency (creatinine clearance < 80 mL/minute) until titration of enalapril has shown the need for the doses present in the combination tablet. (See Section 4.2 Dose and Method of Administration.)
Azotaemia may be precipitated or increased by hydrochlorothiazide. Cumulative effects of the drug may develop in patients with impaired renal function. If increasing azotaemia and oliguria occur during treatment of renal disease, the diuretic should be discontinued.
Some hypertensive patients with no apparent pre-existing renal disease have developed usually minor and transient increases in blood urea and serum creatinine when enalapril has been given concomitantly with a diuretic. If this occurs during therapy with enalapril/HCT 20 mg/6 mg, the combination should be discontinued. Reinstitution of therapy at reduced dosage may be possible; or either of the components may be used appropriately alone.
In some patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, increases in blood urea and serum creatinine, usually reversible upon discontinuation of therapy, have been seen with angiotensin converting enzyme (ACE) inhibitors.
There are no data on the use of enalapril/HCT 20 mg/6 mg in patients with renal function impairment.
Evaluation of the hypertensive patient should always include assessment of renal function (see Section 4.2 Dose and Method of Administration).

Use in the elderly.

In clinical studies, the efficacy and tolerability of enalapril maleate and hydrochlorothiazide, administered concomitantly, were similar in both elderly and younger hypertensive patients.

Paediatric use.

Safety and effectiveness in children have not been established.

Effects on laboratory tests.

Laboratory test findings which have been reported with the use of enalapril alone include:

Serum electrolytes.

Hyperkalaemia (see Section 4.4 Special Warnings and Precautions for Use), hyponatraemia.

Creatinine, blood urea nitrogen.

In controlled clinical trials minor increases in blood urea nitrogen and serum creatinine, reversible upon discontinuation of therapy, were observed in some patients with essential hypertension treated with enalapril alone. Increases are more likely to occur in patients receiving concomitant diuretics or in patients with renal artery stenosis (see Section 4.4 Special Warnings and Precautions for Use).

Haemoglobin and haematocrit.

Small decreases in haemoglobin and haematocrit occur frequently in hypertensive patients treated with enalapril but are rarely of clinical importance unless another cause of anaemia coexists.

Other (causal relationship unknown).

In marketing experience, rare cases of pancreatitis, neutropenia, thrombocytopenia, bone marrow depression, and agranulocytosis have been reported. A few cases of haemolysis have been reported in patients with G6PD deficiency.

Liver function tests.

Elevations of liver enzymes and/or serum bilirubin have occurred.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Other antihypertensive therapy.

The antihypertensive effect of enalapril/HCT 20 mg/6 mg is augmented by antihypertensive agents that cause renin release (e.g. diuretics).
The combination of enalapril maleate with beta-adrenergic blocking agents, methyldopa or calcium entry blockers has been shown to improve the efficacy of lowering the blood pressure.
Ganglionic blocking agents or adrenergic blocking agents, combined with enalapril, should only be administered under careful observation of the patient.

Serum potassium. (See Section 4.4 Special Warnings and Precautions for Use, Hyperkalaemia.)

Serum potassium usually remains within normal limits. The use of potassium supplements, potassium sparing agents or potassium containing salt substitutes, particularly in patients with impaired renal function, may lead to a significant increase in serum potassium. If concomitant use of enalapril/HCT 20 mg/6 mg and any of these agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium.

Lithium.

Diuretic agents and ACE inhibitors reduce the renal clearance of lithium and add a high risk of lithium toxicity. Concomitant use is not recommended. See the package inserts for lithium preparations before use of such preparations.

Nonsteroidal anti-inflammatory drugs including selective cyclooxygenase-2 inhibitors.

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 renal failure. These effects are usually reversible.
These interactions should be considered in patients taking NSAIDs including selective COX-2 inhibitors concomitantly with diuretics and ACE inhibitors. Therefore, the combination should be administered with caution in patients with compromised renal function.
In some patients, the administration of a nonsteroidal anti-inflammatory agent including a selective cyclooxygenase-2 inhibitor can reduce the diuretic, natriuretic and antihypertensive effects of diuretics.

Combination use of angiotensin converting enzyme 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.

It has been reported in the literature that in patients with established atherosclerotic disease, heart failure, or with diabetes with end organ damage, dual blockade of the renin angiotensin aldosterone system is associated with a higher frequency of hypotension, syncope, hyperkalaemia, and changes in renal function (including acute renal failure) as compared to use of a single renin angiotensin aldosterone system agent. Dual blockade (e.g. by adding an ACE inhibitor to an angiotensin II receptor antagonist) should be limited to individually defined cases with close monitoring of renal function. Closely monitor blood pressure, renal function, and electrolytes in patients on enalapril/HCT 20 mg/6 mg and other agents that affect the RAAS. Do not coadminister aliskiren with enalapril/HCT 20 mg/6 mg in patients with diabetes. Avoid use of aliskiren with Enalapril/HCT 20 mg/6 mg in patients with renal impairment (GFR < 60 mL/min).

Nondepolarising muscle relaxants.

Thiazides may increase the responsiveness to tubocurarine.

Gold.

Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including enalapril.

Mammalian target of rapamycin (mTOR) inhibitors.

Patients taking concomitant mTOR inhibitor (e.g. temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema (see Section 4.4 Special Warnings and Precautions for Use).

Neprilysin inhibitors.

Patients taking a concomitant neprilysin inhibitor (e.g. sacubitril) may be at increased risk for angioedema (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

Co-trimoxazole (trimethoprim/ sulfamethoxazole).

Patients taking concomitant co-trimoxazole (trimethoprim/ sulfamethoxazole) may be at increased risk for hyperkalaemia (see Section 4.4 Special Warnings and Precautions for Use).

Increasing the QT interval (e.g. quinidine, procainamide, amiodarone, sotalol).

Increased risk of torsades de pointes.

Alcohol, barbiturates or narcotics.

Potentiation of orthostatic hypotension may occur.

Antidiabetic drugs.

For oral agents and insulin, dosage adjustment of the antidiabetic drug may be required as thiazides can increase blood glucose concentration.

Cholestyramine and colestipol resins.

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

Corticosteroids, ACTH (adrenocorticotrophic hormone).

Intensified electrolyte depletion, particularly hypokalaemia, may occur when corticosteroids or ACTH are used with thiazide diuretics.

Kaliuretic diuretics (e.g. furosemide), carbenoxolone, or laxative abuse.

Hydrochlorothiazide may increase the loss of potassium and/or magnesium.

Pressor amines (e.g. adrenaline).

Possible decreased response to pressor amines may occur but not sufficiently to preclude their use.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There were no adverse effects on reproductive performance in male and female rats treated with 10 to 90 mg/kg/day of enalapril. The effects of hydrochlorothiazide or the enalapril maleate/ hydrochlorothiazide combination on fertility and reproductive performance have not been evaluated.
(Category D)
Enalapril/HCT 20 mg/6 mg contains an ACE inhibitor and, therefore, should not be used during pregnancy.

Enalapril maleate.

As with all ACE inhibitors, enalapril should not be taken during pregnancy. Pregnancy should be excluded before starting treatment with enalapril/HCT 20 mg/6 mg and avoided during the treatment.
If a patient intends to become pregnant, treatment with ACE inhibitors must be discontinued and replaced by another form of treatment.
If a patient becomes pregnant while on ACE inhibitors, she must immediately inform her doctor to discuss a change in medication and further management.
There are no adequate and well controlled studies of enalapril in pregnant women. Data, however, show that enalapril crosses the human placenta. Post marketing experience with all ACE inhibitors suggest that exposure in utero may be associated with hypotension and decreased renal perfusion in the foetus. ACE inhibitors have also been associated with foetal death in utero. There have been reports of foetal and neonatal damage, including hypotension, anuria, reversible or irreversible renal failure, hyperkalaemia, skull hypoplasia and death when ACE inhibitors have been used during the second and third trimesters of pregnancy.
A historical cohort study in over 29,000 infants born to nondiabetic mothers has shown 2.7 times higher risk for congenital malformations in infants exposed to any ACE inhibitor during first trimester compared to no exposure. The risk ratios for cardiovascular and central nervous system malformations were 3.7 times (95% confidence interval 1.89 to 7.3) and 4.4 times (95% confidence interval 1.37 to 14.02), respectively, compared to no exposure.
There is a potential risk of foetal hypotension, decreased birthweight and decreased renal perfusion or anuria in the foetus from in utero exposure to ACE inhibitors.
Oligohydramnios in the mother has also been reported, presumably representing decreased renal function in the foetus. Oligohydramnios in this setting has been associated with foetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these were due to ACE inhibitor exposure. In addition, use of ACE inhibitors during the first trimester of pregnancy has been associated with a potentially increased risk of birth defects.
Any neonate exposed to enalapril in utero should be observed closely for adequate urine output, blood pressure and hyperkalaemia. If required, appropriate medical measures should be initiated including administration of fluids or dialysis to remove enalaprilat from the circulatory system.
The maternal and foetal toxicity occurred in some rabbits at doses of 1 mg/kg/day or more. Saline supplementation prevented the maternal and foetal toxicity seen at doses of 3 and 10 mg/kg/day, but not at 30 mg/kg/day. Enalapril was not teratogenic in rabbits. There was no foetotoxicity or teratogenicity in rats treated with up to 200 mg/kg/day of enalapril. Foetotoxicity expressed as a decrease in average foetal weight occurred in rats given 1,200 mg/kg/day of enalapril, but did not occur when these animals were supplemented with saline.

Hydrochlorothiazide.

Thiazides, related diuretics and loop diuretics enter the foetal circulation and may cause electrolyte disturbances. Neonatal thrombocytopenia has been reported with thiazides and related diuretics. Loop diuretics like frusemide and bumetanide are probably also associated with this risk. During the latter part of pregnancy products of this type should, therefore, only be given on sound indications, and then in the lowest effective dose.
The routine use of diuretics in otherwise healthy pregnant women with or without mild oedema is not indicated and exposes mother and foetus to unnecessary hazard. Diuretics do not prevent development of toxaemia of pregnancy and there is no satisfactory evidence that they are useful in the treatment of toxaemia.
Thiazides cross the placental barrier and appear in cord blood. Therefore, the use of hydrochlorothiazide when pregnancy is present or suspected requires that the benefits of the drug be weighed against possible hazards to the foetus. These hazards include foetal or neonatal jaundice, thrombocytopenia and possibly other adverse reactions which occurred in the adult.

Enalapril maleate and hydrochlorothiazide.

Reproductive toxicity studies in rats, mice and rabbits suggested that maternal toxicity and foetal toxicity (based on decreased foetal weight) may be increased when enalapril maleate and hydrochlorothiazide are given in combination than when each drug is given alone.
Both enalapril and thiazides appear in human milk. If use of the drug is deemed essential, the patient should stop breastfeeding.

4.8 Adverse Effects (Undesirable Effects)

Enalapril/HCT 20 mg/6 mg is usually well tolerated. In clinical studies, side effects have usually been mild and transient and in most instances have not required interruption of therapy. The most common side effects reported during clinical study with enalapril/HCT 20 mg/6 mg were headache (1%) and cough (3%).
No clinically important changes in standard laboratory parameters were associated with administration of enalapril/HCT 20 mg/6 mg.
The following undesirable effects have been reported for enalapril hydrochlorothiazide, enalapril alone or hydrochlorothiazide alone either during clinical studies or after the drug was marketed include:
Very common (> 1/10); common (> 1/100, < 1/10); uncommon (> 1/1,000, < 1/100); rare (> 1/10,000, < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data).

Blood and the lymphatic system disorders.

Uncommon: anemia (including aplastic and hemolytic).
Rare: neutropenia, decreases in hemoglobin, decreases in hematocrit, thrombocytopenia, agranulocytosis, bone marrow depression, leukopenia, pancytopenia, lymphadenopathy, autoimmune diseases.

Endocrine disorders.

Very rare: syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Metabolism and nutrition disorders.

Common: hypokalemia, increase of cholesterol, increase of triglycerides, hyperuricemia.
Uncommon: hypoglycemia, hypomagnesemia, gout*.
Rare: increase in blood glucose.
Very rare: hypercalcemia.

Nervous system and psychiatric disorders.

Common: headache, depression, syncope, taste alteration.
Uncommon: confusion, somnolence, insomnia, nervousness, paraesthesia, vertigo, decreased libido*.
Rare: dream abnormality, sleep disorders, paresis (due to hypokalemia), hallucinations.

Eye disorders.

Very common: blurred vision.

Ear and labyrinth disorders.

Uncommon: tinnitus.

Cardiac and vascular disorders.

Very common: dizziness.
Common: hypotension, orthostatic effects including hypotension, rhythm disturbances, angina pectoris, tachycardia.
Uncommon: flushing, palpitations, myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients.
Rare: Raynaud's phenomenon.

Respiratory, thoracic and mediastinal disorders.

Very common: cough.
Common: dyspnea, pharyngeal pain.
Uncommon: rhinorrhea, sore throat and hoarseness, bronchospasm/ asthma.
Rare: respiratory distress (including pneumonitis and pulmonary edema), pulmonary infiltrates, rhinitis, allergic alveolitis/ eosinophillic pneumonia.

Gastrointestinal disorders.

Very common: nausea.
Common: diarrhea, abdominal pain.
Uncommon: ileus, pancreatitis, vomiting, dyspepsia, constipation, anorexia, gastric irritations, dry mouth, flatulence*, peptic ulcer.
Rare: stomatitis/ aphthous ulcerations, glossitis, taste disturbances.
Very rare: intestinal angioedema.

Hepatobiliary disorders.

Rare: hepatic failure, hepatic necrosis (maybe fatal), hepatitis, either hepatocellular or cholestatic jaundice, cholecystitis (in particular in patients with pre-existing cholelithiasis).

Skin and subcutaneous tissue disorders.

Common: rash (exanthema), angioneurotic edema of the face, extremities, lips, tongue, glottis and/or larynx.
Uncommon: pruritus, urticaria, alopecia.
Rare: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, purpura, hyperhidrosis, cutaneous lupus erythematosus, erythroderma, pemphigus, diaphoresis.
A symptom complex has been reported which may include some or all of the following: fever, serositis, vasculitis, myalgia/ myositis, arthralgia/ arthritis, a positive ANA, elevated ESR, eosinophilia, and leukocytosis. Rash, photosensitivity or other dermatologic manifestations may occur. These symptoms have disappeared after discontinuation of therapy.

Musculoskeletal, connective tissue and bone disorders.

Common: muscle cramps+.
Uncommon: arthralgia*.

Renal and urinary disorders.

Uncommon: renal dysfunction, renal failure, proteinuria.
Rare: oliguria, interstitial nephritis.

Reproductive system and breast disorders.

Uncommon: impotence.
Rare: gynaecomastia.

General disorders and administration site conditions.

Very common: asthenia.
Common: chest pain, fatigue.
Uncommon: malaise, fever.

Investigations.

Common: hyperkalemia, increases in serum creatinine.
Uncommon: increases in blood urea, hyponatremia.
Rare: elevations of liver enzymes, elevations of serum bilirubin.
*These ADRs are only relevant for doses of hydrochlorothiazide 12.5 mg and 25 mg.
+The frequency of muscle cramps as common pertains to doses of hydrochlorothiazide 12.5 mg and 25 mg, whereas, the frequency of the event is uncommon as it pertains to 6 mg doses of hydrochlorothiazide.

Angioedema.

Angioedema has been reported in patients receiving enalapril maleate. Angioedema associated with laryngeal oedema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis and/or larynx occurs, treatment with enalapril/HCT 20 mg/6 mg should be discontinued and appropriate therapy instituted immediately (see Section 4.4 Special Warnings and Precautions for Use). In very rare cases, intestinal angioedema has been reported with angiotensin converting enzyme inhibitors including enalapril.
Additional side effects seen post marketing are myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients (see Section 4.4 Special Warnings and Precautions for Use, Hypotension), angina pectoris and muscle cramps.

Potential adverse effects.

Additional side effects which have been seen with other combinations of enalapril and hydrochlorothiazide or with hydrochlorothiazide alone and may be potential side effects with Enalapril/HCT 20 mg/6 mg are the following:

Other combinations of enalapril and hydrochlorothiazide.

Tachycardia, flatulence, decreased libido, dry mouth, gout, arthralgia, hyperglycemia, hyperuricemia, hypokalemia, nonorthostatic hypotension.

Hydrochlorothiazide.

Gastric irritation, cramping, diarrhoea, sialoadenitis, xanthopsia, leukopenia, agranulocytosis, aplastic anemia, hemolytic anemia, purpura, photosensitivity, fever, necrotizing angiitis (vasculitis), respiratory distress (including pneumonitis and pulmonary oedema), interstitial nephritis, anaphylactic reaction, hyperglycemia, glycosuria, hyperuricemia, electrolyte imbalance (including hypokalemia), restlessness, muscle spasm, weakness, transient blurred vision.

Neoplasms.

Non-melanoma skin cancer (basal cell carcinoma, squamous cell carcinoma).
Based on available data from epidemiological studies, a cumulative dose-dependent association between hydrochlorothiazide and non-melanoma skin cancer (BCC and SCC) has been observed.
The largest study included a population comprised of 71,553 cases of BCC and 8,629 cases of SCC matched to 1,430,883 and 172,462 population controls, respectively. High cumulative hydrochlorothiazide use (≥ 50,000 mg) was associated with an adjusted odds ratio (OR) of 1.29 (95% CI: 1.23-1.35) for BCC and 3.98 (95% CI: 3.68-4.31) for SCC. A cumulative dose-response relationship was observed for both BCC and SCC. Another study evaluated the association between lip cancer (SCC) and exposure to hydrochlorothiazide: 633 cases of lip cancer were matched with 63.067 population controls. A cumulative dose-response relationship was demonstrated with an adjusted OR of 2.1 (95% CI: 1.7-2.6) for ever-use, increasing to an OR of 3.9 (95% CI: 3.0-4.9) for high use (≥ 25,000 mg) and an OR of 7.7 (95% CI: 5.7-10.5) for the highest cumulative dose (≥ 100,000 mg).

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 http://www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Dosage.

Treatment with enalapril/HCT 20 mg/6 mg should only be commenced after titration of the enalapril component has been shown not to be effective in achieving the required lowering of blood pressure.

Hypertension.

In hypertension, the usual dosage of enalapril/HCT 20 mg/6 mg is one tablet, administered once daily.

Prior diuretic therapy.

Symptomatic hypotension may occur following the initial dose of enalapril/HCT 20 mg/6 mg; this is more likely in patients who are volume or salt depleted as a result of prior diuretic therapy. The diuretic therapy should be discontinued for two to three days prior to initiation of therapy with enalapril/HCT 20 mg/6 mg. Patients receiving concomitant diuretic and ACE inhibitor therapy in doses greater than or equal to those contained in enalapril/HCT 20 mg/6 mg may be transferred to enalapril/HCT 20 mg/6 mg without discontinuation of the diuretic.

Method of administration.

Enalapril/HCT 20 mg/6 mg is supplied as tablets for oral administration.

Dosage adjustment in renal impairment.

Thiazides may not be appropriate diuretics for use in patients with renal impairment and are ineffective at creatinine clearance values of 30 mL/minute or below (i.e. moderate or severe renal insufficiency).
In patients with creatinine clearance of > 30 and < 80 mL/minute, enalapril/HCT 20 mg/6 mg should be used only after titration of the enalapril component.
The recommended initial dose of enalapril maleate, when used alone, in mild renal insufficiency is 5 mg.

4.7 Effects on 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)).

4.9 Overdose

No specific information is available on the treatment of overdosage with enalapril/HCT 20 mg/6 mg. Treatment is symptomatic and supportive. Therapy with enalapril/HCT 20 mg/6 mg should be discontinued and the patient observed closely. Suggested measures include induction of emesis if ingestion is recent, and correction of dehydration, electrolyte imbalance and hypotension by established procedures.

Enalapril maleate.

The most prominent features of overdosage reported to date are marked hypotension, beginning some six hours after ingestion of tablets, concomitant with blockade of the renin angiotensin system and stupor. Symptoms associated with overdosage of ACE inhibitors may include circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough. Serum enalaprilat levels 100 and 200-fold higher than usually seen after therapeutic doses have been reported after ingestion of 300 and 440 mg of enalapril maleate, respectively.
The recommended treatment of overdosage is intravenous infusion of normal saline solution. Enalaprilat may be removed from the general circulation by haemodialysis. (See Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment, Haemodialysis patients.)
Vital signs, serum electrolytes and creatinine concentrations should be monitored continuously.

Hydrochlorothiazide.

The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalaemia, hypochloraemia, hyponatraemia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalaemia may accentuate cardiac arrhythmias.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate, magnesium stearate, maize starch, sodium bicarbonate, purified talc.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
For information on interactions with other medicines and other forms of interactions, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

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.

6.5 Nature and Contents of Container

Enalapril/HCT Sandoz 20 mg/6 mg are packed in aluminium/aluminium blisters of 30 tablets.

6.6 Special Precautions for Disposal

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

Summary Table of Changes