CARACE 20 PLUS Tablets

1. Name Of The Medicinal Product

Carace^®20 Plus

2. Qualitative And Quantitative Composition

'Carace' 20 Plus: Each tablet contains 20 mg lisinopril and 12.5 mg hydrochlorothiazide.

3. Pharmaceutical Form

Tablets

'Carace' 20 Plus: Yellow, hexagonal scored tablet with the product code 'MSD 140' on one side.

4. Clinical Particulars

4.1 Therapeutic Indications

For the management of mild to moderate hypertension in patients who have been stabilised on the individual components given in the same proportions.

4.2 Posology And Method Of Administration

Route of administration: Oral

Adults

Essential hypertension: The usual dosage of 'Carace' Plus is 1 tablet, administered once daily. If necessary, the dosage may be increased to 2 tablets, administered once daily.

Dosage in renal insufficiency: Thiazides may not be appropriate diuretics for use in patients with renal impairment and are ineffective at creatinine clearance values of 30 ml/min or below (i.e. moderate or severe renal insufficiency).

'Carace' Plus is not to be used as initial therapy in any patient with renal insufficiency.

In patients with creatinine clearance of >30 and <80 ml/min, 'Carace' Plus may be used, but only after titration of the individual components.

Prior diuretic therapy:

Symptomatic hypotension may occur following the initial dose of 'Carace' Plus: this is more likely in patients who are volume and/or salt depleted as a result of prior diuretic therapy. If possible, the diuretic therapy should be discontinued for 2-3 days prior to initiation of therapy with lisinopril alone, in a 2.5 mg dose.

Use in the elderly

Lisinopril was equally effective in elderly (65 years or older) and non-elderly hypertensive patients. In elderly hypertensive patients, monotherapy with lisinopril was as effective in reducing diastolic blood pressure as monotherapy with either hydrochlorothiazide or atenolol. In clinical studies, age did not affect the tolerability of lisinopril.

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

Paediatric Use

Safety and effectiveness in children have not been established.

4.3 Contraindications

'Carace' Plus is contraindicated in patients with anuria or aortic stenosis or hyperkalaemia.

'Carace' Plus is contraindicated in patients who are hypersensitive to any component of the product.

'Carace' Plus is contraindicated 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.

'Carace' Plus is contraindicated in patients who are hypersensitive to other sulphonamide-derived drugs.

The use of 'Carace' Plus during pregnancy is not recommended. When pregnancy is detected 'Carace' Plus should be discontinued as soon as possible, unless it is considered life-saving for the mother.

'Carace' Plus is contraindicated in lactating women who are breast-feeding infants. It is not known whether lisinopril is excreted in human milk. Thiazides do appear in human milk. See also 'Breast-feeding mothers' under 'Pregnancy and Lactation'.

4.4 Special Warnings And Precautions For Use

Hypotension and electrolyte/fluid imbalance: As with all antihypertensive therapy, symptomatic hypotension may occur in some patients. This was rarely seen in uncomplicated hypertensive patients but is more likely in the presence of fluid or electrolyte imbalance, e.g. volume depletion, hyponatraemia, hypochloraemic alkalosis, hypomagnesaemia or hypokalaemia which may occur from prior diuretic therapy, dietary salt restriction, dialysis, or during intercurrent diarrhoea or vomiting. Periodic determination of serum electrolytes should be performed at appropriate intervals in such patients.

Particular consideration should be given when therapy is administered to patients with ischaemic heart or cerebrovascular disease, because 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.

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.

Renal function impairment: Thiazides may not be appropriate diuretics for use in patients with renal impairment and are ineffective at creatinine clearance values of 30 ml/min or below (i.e. moderate or severe renal insufficiency). 'Carace' Plus should not be administered to patients with renal insufficiency (creatinine clearance <80 ml/min) until titration of the individual components has shown the need for the doses present in the combination tablet.

Some hypertensive patients, with no apparent pre-existing renal disease, have developed usually minor and transient increases in blood urea and serum creatinine when lisinopril has been given concomitantly with a diuretic. If this occurs during therapy with 'Carace' Plus, 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 single 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.

Haemodialysis patients: The use of 'Carace' Plus is not indicated in patients requiring dialysis for renal failure. A high incidence of anaphylactoid reactions has 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.

Anaphylactoid reactions during LDL apheresis: Rarely, patients receiving ACE inhibitors during low-density lipoprotein (LDL) apheresis with dextran sulphate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each apheresis.

Hepatic disease: 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.

Surgery/anaesthesia: In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, lisinopril may block 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.

Metabolic and endocrine effects: Thiazide therapy may impair glucose tolerance. Dosage adjustment of antidiabetic agents, including insulin, may be required.

Thiazides may decrease urinary calcium excretion and may cause intermittent and slight elevation of serum calcium. Marked hypercalcaemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.

Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.

Thiazide therapy may precipitate hyperuricaemia and/or gout in certain patients. However, lisinopril may increase urinary uric acid and thus may attenuate the hyperuricaemic effect of hydrochlorothiazide.

Hypersensitivity/angioneurotic oedema: Angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported rarely in patients treated with angiotensin-converting enzyme inhibitors, including lisinopril. This may occur at anytime during treatment. In such cases, 'Carace' Plus should be discontinued promptly, and appropriate monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patient.

In those instances where swelling has been confined to the face and lips, the condition generally resolved without treatment, although antihistamines have been useful in relieving symptoms. Angioneurotic oedema associated with laryngeal oedema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy (which may include subcutaneous ephinephrine (adrenaline) solution 1:1,000 (0.3 ml to 0.5 ml) and/or measures to ensure a patent airway) should be administered promptly.

Intestinal angioedema has also been reported very rarely in patients treated with ACE inhibitors and should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to non-blacks.

Patients with a history of angioedema unrelated to ACE-inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor. (See also 'Contraindications').

In patients receiving thiazides, sensitivity reactions may occur with or without a history of allergy or bronchial asthma. Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazides.

Anaphylactoid Reactions during Hymenoptera Desensitisation: Rarely, patients receiving ACE inhibitors during desensitisation with hymenoptera venom (e.g. Bee or Wasp venom) have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each desensitisation.

Cough: Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is non-productive, persistent, and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Serum potassium: The potassium-losing effect of thiazide diuretics is usually attenuated by the potassium-conserving effect of lisinopril.

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 'Carace' Plus and any of these agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium.

Antidiabetic drugs: Epidemiological studies have suggested that concomitant administration of ACE-inhibitors and antidiabetic medicines (insulins, oral hypoglycaemic agents) may cause an increased blood-glucose-lowering effect with risk of hypoglycaemia. This phenomenon appeared to be more likely to occur during the first weeks of combined treatment and in patients with renal impairment. Long term controlled clinical trials with lisinopril have not confirmed these findings and do not preclude the use of lisinopril in diabetic patients. It is advised, however that these patients be monitored. (See below for information regarding antidiabetic drugs and thiazide diuretics.)

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. Refer to prescribing information for lithium preparations before use of such preparations.

Narcotic drugs/antipsychotics: Postural hypotension may occur with ACE inhibitors.

Alcohol: Alcohol may enhance the hypotensive effect of any antihypertensive.

Other agents: Indometacin may diminish the antihypertensive effect of concomitantly administered 'Carace' Plus. In some patients with compromised renal function who are being treated with non-steroidal anti-inflammatory drugs the co-administration of ACE inhibitors may result in further deterioration of renal function. These effects are usually reversible. The antihypertensive effect of 'Carace' Plus may be potentiated when given concomitantly with other agents likely to cause postural hypotension.

Non-depolarising muscle relaxants: Thiazides may increase the responsiveness to tubocurarine.

Allopurinol, cytostatic or immunosuppressive agents, systemic corticosteroids, or procainamide: Concomitant administration with ACE inhibitors may lead to an increased risk of leucopenia.

Antacids: Induce decreased bioavailability of ACE inhibitors.

Sympathomimetics: May reduce the antihypertensive effects of ACE inhibitors; patients should be carefully monitored to confirm that the desired effect is being obtained.

Ciclosporin: Increase the risk of hyperkalaemia with ACE inhibitors.

When administered concurrently, the following drugs may interact with thiazide diuretics:

Barbiturates or narcotics: Potentiation of orthostatic hypotension may occur.

Antidiabetic drugs (oral agents and insulin): Dosage adjustment of the antidiabetic drug may be required. (See above for information regarding antidiabetic drugs and lisinopril).

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: Intensified electrolyte depletion, particularly hypokalaemia.

Pressor amines (e.g. epinephrine (adrenaline)): Possible decreased response to pressor amines but not sufficient to preclude their use.

Non-steroidal anti-inflammatory drugs: In some patients, the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of diuretics.

4.6 Pregnancy And Lactation

Pregnancy

The use of 'Carace' Plus during pregnancy is not recommended. When pregnancy is detected 'Carace' Plus should be discontinued as soon as possible, unless it is considered life-saving for the mother.

ACE inhibitors can cause foetal and neonatal morbidity and mortality when administered to pregnant women during the second and third trimesters. Use of ACE inhibitors during this period has been associated with foetal and neonatal injury including hypotension, renal failure, hyperkalaemia, and/or skull hypoplasia in the newborn. Maternal oligohydramnios, presumably representing decreased foetal renal function, has occurred and may result in limb contractures, craniofacial deformations and hypoplastic lung development.

These adverse effects to the embryo and foetus do not appear to have resulted from intrauterine ACE inhibitor exposure limited to the first trimester.

The routine use of diuretics in otherwise healthy pregnant women is not recommended and exposes mother and foetus to unnecessary hazard including foetal or neonatal jaundice, thrombocytopenia and possibly other adverse reactions which have occurred in the adult.

If 'Carace' Plus is used during pregnancy, the patient should be apprised of the potential hazard to the foetus. In those rare cases where use during pregnancy is deemed essential, serial ultrasound examinations should be performed to assess the intraamniotic environment. If oligohydramnios is detected, 'Carace' Plus should be discontinued unless it is considered life-saving for the mother. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the foetus has sustained irreversible injury.

Infants whose mothers have taken 'Carace' Plus should be closely observed for hypotension, oliguria and hyperkalaemia. Lisinopril, which crosses the placenta, has been removed from the neonatal circulation by peritoneal dialysis with some clinical benefit, and theoretically may be removed by exchange transfusion. There is no experience with the removal of hydrochlorothiazide, which also crosses the placenta, from the neonatal circulation.

Lactation

Breast-feeding mothers: It is not known whether lisinopril is secreted in human milk; however, thiazides do appear in human milk. Because of the potential for serious reactions in nursing infants, a decision should be made whether to discontinue breast-feeding or to discontinue 'Carace' Plus, taking into account the importance of the drug to the mother.

4.7 Effects On Ability To Drive And Use Machines

Usually 'Carace' Plus does not interfere with the ability to drive and to operate machinery. Patients should be instructed to first determine how they respond to 'Carace' Plus before performing hazardous tasks.

4.8 Undesirable Effects

'Carace' Plus 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 side effects that have been observed have been limited to those reported previously with lisinopril or hydrochlorothiazide.

One of the most common clinical side effects was dizziness, which generally responded to dosage reduction and seldom required discontinuation of therapy. Other, less frequent, side effects were headache, dry cough, fatigue, and hypotension including orthostatic hypotension.

Still less common were diarrhoea, nausea, vomiting, pancreatitis, dry mouth, rash, gout, palpitation, chest discomfort, muscle cramps and weakness, paraesthesia, asthenia, and impotence.

Hypersensitivity/angioneurotic oedema: Angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported rarely. Intestinal angioedema has also been reported very rarely in patients treated with ACE inhibitors. (see 'Precautions').

A symptom complex has been reported which may include some or all of the following: fever, vasculitis, myalgia, arthralgia/arthritis, a positive ANA, elevated ESR, eosinophilia, and leucocytosis. Rash, photosensitivity, or other dermatological manifestations may occur.

Laboratory test findings: Laboratory side effects have rarely been of clinical importance. Occasional hyperglycaemia, hyperuricaemia and hyperkalaemia or hypokalaemia have been noted. Usually minor and transient increases in blood urea nitrogen and serum creatinine have been seen in patients without evidence of pre-existing renal impairment. If such increases persist, they are usually reversible upon discontinuation of 'Carace' Plus. Small decreases in haemoglobin and haematocrit have been reported frequently in hypertensive patients treated with 'Carace' Plus but were rarely of clinical importance unless another cause of anaemia co-existed. Rarely, elevation of liver enzymes and/or serum bilirubin have occurred, but a causal relationship to 'Carace' Plus has not been established.

Other side effects reported with the individual components alone, and which may be potential side effects with 'Carace' Plus, are:

Lisinopril: Myocardial infarction or cerebrovascular accident possibly secondary to excessive hypotension in high-risk patients (see 'Precautions'), tachycardia, abdominal pain, hepatitis - either hepatocellular or cholestatic jaundice, mood alterations, mental confusion, bronchospasm, urticaria, pruritis, diaphoresis, alopecia, uraemia, oliguria/anuria, renal dysfunction, acute renal failure, bone marrow depression manifest as anaemia and/or thrombocytopenia and/or leucopenia, hyponatraemia. Rare cases of neutropenia have been reported, although no causal relationship has been established. There have been reports of haemolytic anaemia in patients taking lisinopril, although no causal relationship has been established.

Hydrochlorothiazide: Anorexia, gastric irritation, constipation, jaundice (intrahepatic cholestatic jaundice), sialoadenitis, vertigo, xanthopsia, leucopenia, agranulocytosis, thrombocytopenia, aplastic anaemia, haemolytic anaemia, purpura, photosensitivity, urticaria, necrotising angiitis (vasculitis, cutaneous vasculitis), fever, respiratory distress including pneumonitis and pulmonary oedema, anaphylactic reactions, toxic epidermal necrolysis, hyperglycaemia, glycosuria, hyperuricaemia, electrolyte imbalance including hyponatraemia, muscle spasm, restlessness, transient blurred vision, renal failure, renal dysfunction, and interstitial nephritis.

4.9 Overdose

No specific information is available on the treatment of overdosage with 'Carace' Plus. Treatment is symptomatic and supportive. Therapy with 'Carace' Plus should be discontinued and the patient observed closely. Suggested measures include induction of emesis and/or gastric lavage, if ingestion is recent, and correction of dehydration, electrolyte imbalance and hypotension by established procedures.

Lisinopril: The most likely features of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of normal saline solution, if available angiotensin II may be beneficial.

Lisinopril may be removed from the general circulation by haemodialysis. (See 'Special Warnings and Precautions, Haemodialysis Patients').

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.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

'Carace' Plus contains antihypertensive and diuretic activity. Lisinopril and hydrochlorothiazide have been used alone and concurrently for the treatment of hypertension where their effects are approximately additive.

Lisinopril is an inhibitor of the angiotensin-converting enzyme (ACE). Inhibition of the formation of angiotensin II results in vasodilation and a fall in blood pressure.

Hydrochlorothiazide is a diuretic and antihypertensive agent. Use of this agent alone results in increased renin secretion. Although lisinopril alone is antihypertensive, even in patients with low renin hypertension, concomitant administration with hydrochlorothiazide results in a greater reduction in blood pressure. Lisinopril attenuates the potassium loss associated with hydrochlorothiazide.

5.2 Pharmacokinetic Properties

In clinical studies, peak serum concentrations of lisinopril occurred within about 6 to 8 hours following oral administration. Declining serum concentrations exhibited a prolonged terminal phase which did not contribute to drug accumulation. This terminal phase probably represents saturable binding to ACE and was not proportional to dose. Lisinopril did not appear to be bound to other plasma proteins.

Lisinopril does not undergo significant metabolism and is excreted unchanged predominantly in the urine. Based on urinary recovery in clinical studies, the extent of absorption of lisinopril was approximately 25%. Lisinopril absorption was not influenced by the presence of food in the gastrointestinal tract.

On multiple dosing, lisinopril exhibited an effective accumulation half-life of 12 hours.

In patients with renal insufficiency, disposition of lisinopril was similar to that in patients with normal renal function until glomerular filtration rate reached 30 ml/min or less; peak and trough lisinopril levels, and time to peak then increased and time to steady state was sometimes prolonged. Animal studies indicate lisinopril crosses the blood-brain barrier poorly. No clinically significant pharmacokinetic interactions occurred when lisinopril was used concomitantly with propranolol, digoxin or hydrochlorothiazide.

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

Concomitant multiple doses of lisinopril and hydrochlorothiazide have little or no effect on the bioavailability of these drugs. The combination tablet is bioequivalent to concomitant administration of the separate entities.

5.3 Preclinical Safety Data

Lisinopril and hydrochlorothiazide are well established in medical use. Preclinical data is broadly consistent with clinical experience. For reproduction toxicity, see section 4.6.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Mannitol BP

Calcium Hydrogen Phosphate BP

Blue FD & C Aluminium Lake (E132) ('Carace' 10 Plus)

Yellow Ferric Oxide (E172) ('Carace' 20 Plus)

Maize Starch BP

Pregelatinised Starch BP

Magnesium Stearate EP

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

30 months - Bottles

36 months - Blisters

6.4 Special Precautions For Storage

Store in a dry place below 25°C.

6.5 Nature And Contents Of Container

HDPE bottles of 30, 56 or 100 tablets.

Blister packs of 2, 28, 30, 56, 84 or 100 tablets.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Merck Sharp & Dohme Limited

Hertford Road

Hoddesdon

Hertfordshire

EN11 9BU

8. Marketing Authorisation Number(S)

Carace 20 Plus           PL 00025/0535

9. Date Of First Authorisation/Renewal Of The Authorisation

11 February 2009

10. Date Of Revision Of The Text

November 2011

LEGAL CATEGORY

POM

© Merck Sharp & Dohme Limited 2011. All rights reserved.

SPC.CARPLUS.11.UK.3526