Lisinopril And Hydrochlorothiazide 10mg/12.5mg Tablets
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Lisinopril and Hydrochlorothiazide 10 mg/12.5 mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 10 mg lisinopril (as dihydrate) and 12.5 mg hydrochlorothiazide.
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Tablets
Appearance of tablets:
White, round, biconvex tablets marked LHZ on one side and 22.5 on the other side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of essential hypertension.
Lisinopril and Hydrochlorothiazide 10mg/12.5mg fixed dose combination (lisinopril dihydrate 10mg and hydrochlorothiazide 12.5 mg) is indicated in patients whose blood pressure is not adequately controlled on lisinopril dihydrate alone (or hydrochlorothiazide alone)
4.2 Posology and method of administration
The selection of a suitable antihypertensive dose of lisinopril and hydrochlorothiazide will depend upon the clinical evaluation of the patient.
Lisinopril and Hydrochlorothiazide 10mg/12.5mg Tablet should be taken once daily.
The administration of the fixed combination lisinopril and hydrochlorothiazide is usually recommended after dosage titration with the individual components. When clinically appropriate a direct change from monotherapy to fixed combination may be considered.
10 mg/12.5 mg tablets may be administrated in patients whose blood pressure is not adequately controlled by 10 mg lisinopril alone.
A maximum daily dose of 40 mg lisinopril/ 25 mg hydrochlorothiazide should not be exceeded.
As with other medicines that are taken once daily, Lisinopril and Hydrochlorothiazide 10mg/12.5mg tablets should be taken at about the same time each day.
Renal impairment
The combination lisinopril/hydrochlorothiazide is contraindicated in patients with severe renal impairment.
Lisinopril and Hydrochlorothiazide 10mg/12.5mg tablets may be used in patients with creatinine clearance >30 and <80 ml/min, but only after titration of the individual components.
The recommended initial dose of lisinopril as monotherapy for these patients is 5-10 mg.
Previous diuretic treatment
Symptomatic hypotension may occur after the initial dose of Lisinopril and Hydrochlorothiazide 10mg/12.5mg tablets; this occurs more often in patients that are volume and/or salt depleted as a result of previous treatment with diuretics.
The diuretic should be discontinued 2 to 3 days before the start of treatment with Lisinopril and Hydrochlorothiazide 10mg/12.5mg tablets. If this is not possible, treatment should be started at a dose of 2.5 mg lisinopril alone.
Children and adolescents (<18 years)
The safety and efficacy of Lisinopril and Hydrochlorothiazide 10mg/12.5mg tablets in children has not been demonstrated.
Elderly patients
Clinical studies on the combination of lisinopril and hydrochlorothiazide have not shown that age is associated with any changes in efficacy or tolerability. (see [Renal Impairment])
4.3 Contraindications
■ Renal artery stenosis.
■ History of hypersensitivity to lisinopril or to any of the excipients or to any other ACE-inhibitors
■ History of hypersensitivity to hydrochlorothiazide or other sulphonamide medicinal products
■ Angioneurotic oedema relating to previous treatment with an ACE-inhibitor
■ Hereditary/idiopathic angioneurotic oedema.
■ Severe renal insufficiency (creatinine clearance <30ml/min)
■ Severe hepatic impairment
■ Second and third trimesters of pregnancy (see sections 4.4 and 4.6)
4.4 Special warnings and precautions for use Lisinopril
Patients with renal transplantation
As there is no experience with lisinopril in patients with recent renal transplantation administration of lisinopril is not recommended in these patients.
Anaphylactoid reactions in haemodialysis patients
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 different class of antihypertensive agent.
Anaphylactoid reactions during low-density lipoproteins (LDL) apheresis
Rarely, patients receiving ACE inhibitors during low-density lipoproteins (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.
Desensitization
Patients receiving ACE inhibitors during desensitisation treatment (e.g. hymenoptera venom) have sustained anaphylactoid reactions. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld but they have reappeared upon inadvertent readministration of the medicinal product.
Race
Angiotensin converting enzyme inhibitors cause a higher rate of angioedema in black patients than in non-black patients.
As with other ACE inhibitors, Lisinopril may be less effective in lowering blood pressure in black patients than in non-blacks, possibly because of a higher prevalence of low-renin states in the black hypertensive population.
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.
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.
Hyperkalaemia
Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including Lisinopril. Patients at risk for the development of hyperkalaemia include those with renal impairment, diabetes mellitus, or those using concomitant potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes, or those patients taking other drugs associated with increases in serum potassium (e.g. heparin). If concomitant use of the above-mentioned agents is deemed appropriate, regular monitoring of serum potassium is recommended (see [Interactions with other medicinal products]).
Diabetic patients
In diabetic patients treated with oral antidiabetic agents or insulin, glycaemic control should be closely monitored during the first month of treatment with an ACE inhibitor (see [Interactions with other medicinal products]).
Lithium
The combination of lithium and Lisinopril is generally not recommended (see Interactions with other medicinal products]).
Hydrochlorothiazide
Metabolic and endocrine effects
Thiazide therapy may reduce glucose tolerance. In diabetics, dose adjustments of insulin or oral hypoglycemic drugs may be necessary. Latent diabetic mellitus may become manifest during thiazide therapy.
Increases of cholesterol and triglyceride levels have been associated with thiazide diuretic therapy. In some patients treated with thiazide diuretic hyperuricaemia may occur, or manifest gout may develop.
Anti-doping test
Hydrochlorothiazide present in this medication may give a positive analysis result in anti-doping tests.
Lisinopril/hydrochlorothiazide
Hypotension and electrolyte/fluid imbalances
Symptomatic hypotension may sometimes occur following the first dose of lisinopril / hydrochlorothiazide. The odds for hypotension in hypertensive patients are greater in the presence of fluid or electrolyte imbalances, such as volume depletion, hyponatremia, hypochloremic alkalosis, hypomagnesemia or hypokalemia, that may occur as a result of a diuretic therapy, a low-sodium diet, dialysis or during intercurrent diarrhoea or vomiting. Warning signals of fluid or electrolyte imbalances are dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, myalgia or muscle cramps, muscle fatigue, hypotension, oliguria, tachycardia and gastrointestinal disorders such as nausea and vomiting. In such patients the serum electrolyte levels must be monitored on a regular basis.
Starting the therapy and adjusting the dosage for patients who are at an increased risk for symptomatic hypotension must be done under strict medical supervision.
Special attention should be given to the treatment of patients suffering from an ischaemic heart disease or cerebrovascular condition, because an excessive drop in blood pressure may trigger a myocardial infarction or a cerebrovascular accident.
If severe hypotension occurs, the patient must be put into shock position and promptly administered an intravenous infusion of a physiological saline solution. A transient hypotensive reaction is not a contraindication for future doses. If the blood volume and the blood pressure have effectively been restored, therapy may likely be resumed with a lower dosage or may very well be continued simply with one or both components.
As with other vasodilators, caution must be exercised when administering lisinopril / hydrochlorothiazide to patients suffering from aortic stenosis or hypertrophic cardiomyopathy.
Although hypokalaemia may develop through the use of thiazide diuretics, concomitant use of lisinopril may decrease diuretic-induced hypokalaemia. Regular checks of serum potassium should take place. The possibility of hypokalaemia is strongest in patients with cirrhosis of the liver, in patients experiencing rapid diuresis, in patients having an inadequate oral intake of electrolytes and in patients concomitantly treated with corticosteroids or ACTH (see [Interactions with other medicinal products]).
In hot weather hyponatraemia may occur in oedematous patients. The chloride deficiency is generally mild and does not need treatment.
Thiazides may reduce calcium excretion via urine excretion and cause a slight intermittent increase in serum calcium levels even in the absence of known disorders in calcium metabolism. Distinct hypercalcaemia may be a hint of hidden hyperparathyroidism. Thiazides should be discontinued before parathyroid function tests are performed. Thiazides have been shown to increase the renal magnesium excretion, which may result in hypomagnesemia.
Impaired renal function
Thiazides are ineffective in patients with a creatinine clearance of less than 30 ml/min (i.e. a moderate or serious renal impairment). (see [Contraindication]).
Lisinopril and Hydrochlorothiazide 10mg/12.5mg tablets should not be given to patients with a creatinine clearance of 30-80 ml/minute until dose adjustments of the separate ingredients have shown that there is a need for the doses in the combination preparation.
Some patients without a definite pre-existing renovascular disorder developed slight and transitory increases in blood urea levels and serum creatinine levels when lisinopril was given concomitantly with a diuretic. If this occurs during the use of lisinopril/hydrochlorothiazide, the treatment should be stopped. Resuming the treatment at a reduced dosage may be possible, if appropriate, one of the components may be used on its own.
In some patients with bilateral renal artery stenosis or with a stenosis of the artery to a solitary kidney, who have been treated with angiotensin converting enzyme inhibitors, increases in blood urea and serum creatinine, usually reversible upon discontinuation of therapy, have been seen. This is especially likely in patients with renal impairment. If renovascular hypertension is also present there is an increased risk of severe hypotension and renal impairment. In these patients, treatment should be started under close medical supervision with low doses and careful dose titration. Since treatment with diuretics may be a contributory factor to the above, they should be discontinued and renal function should be monitored during the first weeks of Lisinopril therapy.
In patients with renal diseases, thiazides may precipitate azotemia. In patients with impaired renal function, cumulative effects of the medication may occur. If a progressive renal insufficiency develops, characterised by an increase in non-protein nitrogen, careful evaluation of the therapy is necessary, and stopping the diuretics therapy should be considered (see [Contraindication]).
Neutropaenia/ Agranulocytosis
The fixed-dose combination of lisinopril and hydrochlorothiazide should be withdrawn if neutropenia (neutrophils less than 1000/mm ) is detected or suspected.
Neutropaenia/ Agranulocytosis, thrombocytopenia and anaemia have been reported in patients receiving ACE inhibitors. In patients with normal renal function and no other complicating factors, neutropaenia occurs rarely. Neutropaenia and agranulocytosis are reversible after discontinuation of the ACE inhibitor. Lisinopril should be used with extreme caution in patients with collagen vascular disease, immunosuppressant therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially if there is pre-existing impaired renal function. Some of these patients developed serious infections, which in a few instances did not respond to intensive antibiotic therapy. If Lisinopril is used in such patients, periodic monitoring of white blood cell counts is advised and patients should be instructed to report any sign of infection.
Hypersensitivity/Angioedema
Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported rarely in patients treated with angiotensin converting enzyme inhibitors, including Lisinopril. Patients with involvement of the tongue, glottis or larynx, are likely to experience airway obstruction, especially those with a history of airway surgery. This may occur at any time during therapy. In such cases, Lisinopril should be discontinued promptly and appropriate treatment and monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patients. Treatment may include the administration of adrenaline and/or the maintenance of a patent airway. 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.
Angiotensin converting enzyme inhibitors cause a higher rate of angioedema in black patients than in non-black patients.
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see [Contraindications]).
Hypersensitivity reactions may occur in patients with or without a history of allergic or bronchial asthma. The possibility of exacerbation or activation of Systemic Lupus Erythematosus has been reported.
Hepatic failure
Very rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice or hepatitis and progresses to fulminant necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving Lisinopril who develop jaundice or marked elevations of hepatic enzymes should discontinue Lisinopril and receive appropriate medical follow-up.
Thiazides should be used with caution in patients with impaired liver function or progressive hepatic function [disorders], as small fluctuations in the fluid and electrolyte balance may induce hepatic coma (see [Contraindication]).
Pregnancy
ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
4.5 Interaction with other medicinal products and other forms of interaction
The following interactions between Lisinopril and Hydrochlorothiazide 10mg/12.5mg tablets, other ACE-inhibitors or products containing hydrochlorothiazide have been reported.
Lisinopril
Diuretics
When a diuretic is added to the therapy of a patient receiving Lisinopril the antihypertensive effect is usually additive.
Patients already on diuretics and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure when Lisinopril is added. The possibility of symptomatic hypotension with Lisinopril can be minimised by discontinuing the diuretic prior to initiation of treatment with Lisinopril (see [Special Warnings and Precautions for Use]).
Non steroidal anti-inflammatory drugs (NSAIDs)
Chronic administration of NSAIDs may reduce the antihypertensive effect of an ACE inhibitor. NSAIDs and ACE inhibitors exert an additive effect on the increase in serum potassium and may result in a deterioration of renal function. These effects are usually reversible. Rarely, acute renal failure may occur, especially in patients with compromised renal function such as the elderly or dehydrated.
Other antihypertensive agents
Concomitant use of these agents may increase the hypotensive effects of Lisinopril. Concomitant use with glyceryl trinitrate and other nitrates, or other vasodilators, may further reduce blood pressure.
Tricyclic antidepressants / Antipsychotics /Anaesthetics Concomitant use of certain anaesthetic medicinal products, tricyclic antidepressants and antipsychotics with ACE inhibitors may result in further reduction of blood pressure (see [Special Warnings and Precautions for Use])
Sympatomimetics
Sympatomimetics may reduce the hypotensive effect of ACE-inhibitors; patients must be monitored carefully.
Antidiabetics
Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetic medicinal products (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.
Nitrates, acetylsalicylic acid, thrombolytics and/or beta blockers
Lisinopril may be used concomitantly with acetylsalicylic acid (cardiologic
doses), thrombolytics, beta blockers and/or nitrates.
Allopurinol
Concomitant administration of ACE inhibitors and allopurinol increases the risk of renal failure and may lead to an increased risk of leucopenia.
Ciclosporin
Concomitant administration of ACE inhibitors and ciclosporin increases the risk of renal failure and hyperkalaemia.
Lovastatin
Concomitant administration of ACE inhibitors and lovastatin increases the risk of hyperkalaemia.
Haemodialysis
Lisinopril and Hydrochlorothiazide 10mg/12.5mg tablets are not indicated in patients requiring dialysis as a high incidence of anaphylactoid reactions have been reported in patients dialysed with high flux membranes and treated concomitantly with an ACE inhibitor. This combination should be avoided.
Procainamide, cytostatic or immunosuppressive agents
Concomitant administration with ACE inhibitors may lead to an increased risk of leucopenia.
Hydrochlorothiazide
Amphotericin B (parenteral), carbenoxolone, corticosteroids, corticotropine (ACTH) or stimulating laxants
Hydrochlorothiazide may cause electrolyte imbalances, especially hypokalemia.
Calcium salts
Increased serum calcium levels as a result of decreased excretion may occur if concomitantly administered with thiazide diuretics.
Cardiac glycosides
Increased risk of digitalis intoxication together with thiazide induced hypokalemia.
Colestyramine resin and colestipol
These may reduce or slow down the absorption of hydrochlorothiazide. Therefore, sulphonamide diuretics should be taken at least one hour before or four to six hours after these drugs.
Non-depolarizing muscle relaxants (i.e.. tubocurarine chloride)
The effect of these medications may be increased by hydrochlorothiazide.
Medications associated with torsades de pointes
Because of the risk of hypokalemia, care should be taken if hydrochlorothiazide is administered concomitantly with medications associated with torsades de pointes, f.i. some antipsychotics and other medications which are known to induce torsades de pointes.
Sotalol
Thiazide-induced hypokalaemia can increase the risk of sotalol-induced arrhythmias.
Lisinopril/hydrochlorothiazide
Potassium supplements, potassium-sparing diuretics or potassium-containing salt substitutes
Although in clinical trials with ACE inhibitors serum potassium usually remained within normal limits, hyperkalaemia did occur in some patients. Risk factors for the development of hyperkalaemia include renal insufficiency, diabetes mellitus, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene or amiloride), potassium supplements or potassium-containing salt substitutes. 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.
If Lisinopril is given with a potassium-losing diuretic, diuretic-induced hypokalaemia may be ameliorated.
Lithium
Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and enhance the already increased lithium toxicity with ACE inhibitors. Use of Lisinopril with lithium is not recommended, but if the combination proves necessary, careful monitoring of serum lithium levels should be performed (see [Special Warnings and Precautions for Use]).
Trimethoprim
Concomitant administration of ACE inhibitors and thiazides with trimethoprim increases the risk of hyperkaleamia.
Alcohol
The ability to drive and use machines may be reduced when used in combination with alcohol.
4.6 Pregnancy and lactation
Pregnancy
ACE-inhibitors:
The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contra-indicated during the second and third trimester of pregnancy (see section 4.3 and 4.4).
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy.
When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started. Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, olidohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3).
Should exposure to ACE inhibitor have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension (see sections 4.3 and 4.4).
Hydrochlorothiazide:
There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient.
Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide its use during the second and third trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia.
Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a beneficial effect on the course of the disease.
Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare situations where no other treatment could be used.
Hydrochlorothiazide may reduce plasma volume as well as uteroplacental blood flow.
Lactation
ACE-inhibitors:
Because no information is available regarding the use of Lisinopril and Hydrochlorothiazide 10mg/12.5mg Tablets during breastfeeding, Lisinopril and Hydrochlorothiazide 10mg/12.5mg Tablets is not recommended and alternative treatments with better established safety profiles during breastfeeding
are preferable, especially while nursing a newborn or preterm infant. Hydrochlorothiazide:
Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit the milk production. The use of Lisinopril and Hydrochlorothiazide 10mg/12.5mg Tablets during breast feeding is not recommended. If Lisinopril and Hydrochlorothiazide 10mg/12.5mg Tablets is used during breast feeding, doses should be kept as low as possible.
The use of thiazide by breast feeding mothers has been associated with decreased or even suppressed milk secretion. Hypersensivity to sulphonamide-derived drugs, hypokalemia and nuclear icterus have also been observed. Because of the potential for serious adverse effects in breast-fed infants, a decision should be made to either discontinue breastfeeding or discontinue lisinopril/hydrochlorothiazide therapy. The importance of this therapy to the mother should be taken in account.
4.7 Effects on ability to drive and use machines
As with other antihypertensives, the ability to drive and use machines may be reduced, e.g. at the start of the treatment or when the dose is modified, but these effects depend on the individual’s susceptibility.
4.8 Undesirable effects
The following undesirable effects have been observed and reported during treatment with Lisinopril and Hydrochlorothiazide 10mg/12.5mg tablets with the following frequencies: very common (>1/10), common (>1/100:<1/10), uncommon (>1/1000,<1/100), rare (>1/10000;<1/1000), very rare (<1/10000) including isolated reports.
Metabolism and nutrition disorders uncommon: gout
Nervous system and psychiatric disorders
common: dizziness, which generally responded to dosage reduction and seldom required discontinuation of therapy; headache, fatigue.
uncommon: paraesthesia, asthenia
Respiratory, thoracic and mediastinal disorder
common: dry and persistent cough, which disappears after discontinuation of therapy.
Cardiac and vascular disorders:
common: hypotension including orthostatic hypotension. uncommon: palpitation, chest pain, muscle spasms and muscle weakness
Gastrointestinal disorders
uncommon: diarrhoea, nausea, vomiting, indigestion, pancreatitis, dry mouth.
Skin and subcutaneous tissue disorders uncommon: rash.
rare: angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx (see [Special Warnings and Precautions for Use]).
Reproductive system and genitals and breast disorders uncommon:impotence.
Others
rare: a complex of symptoms, consisting of one or more of the following: fever, vasculitis,
myalgia, artralgia or arthritis, positive ANA test; increased ESR, eosinophilia, leukocytosis, rash, photosensitivity or other dermatologic manifestations.
Findings in laboratory tests
Changes in laboratory values have rarely been of clinical significance. Hyperglycaemia, hyperuricaemia and hyperkalaemia or hypokalaemia are seen occasionally. Mild and temporary increases in blood nitrogen urea and serum creatinine are usually seen in patients without pre-existing kidney failure. If such increases are persistent, they generally disappear when treatment is discontinued.
Bone marrow depression, manifested as anaemia and/or thrombocytopenia and/or leucopenia, has been reported. Agranulocytosis is reported rarely, although a causal connection has not been established.
A small fall in haemoglobin and haematocrit is often reported in hypertensive patients treated with Lisinopril and Hydrochlorothiazide 10mg/12.5mg tablets, but it was rarely of clinical significance unless another cause of anaemia existed simultaneously.
An increase in liver enzymes and/or serum bilirubin is rarely seen, but a causal connection with Lisinopril and Hydrochlorothiazide 10mg/12.5mg tablets has not been established. Haemolytic anaemia has been rarely reported.
Undesirable effects reported of the individual components:
Hydrochlorothiazide:
Infections and infestations: sialdenitis
Blood and lymphatic system disorders: leucopenia,
neutropenia/agranulocytosis, thrombocytopenia, aplastic anaemia, haemolytic anaemia, bone marrow suppression.
Metabolism and nutrition disorders: anorexia, hyperglycaemia, glucosuria, hyperuricaemia, electrolyte imbalance (including hyponatraemia and hypokalaemia, increases in cholesterol and triglycerides.
Psychiatric disorders: restlessness, depression, sleep disturbance
Nervous system disorders: loss of appetite, paraesthesia, light-headedness
Eye disorders: xanthopsia, transient blurred vision
Ear and labyrinth disorders: vertigo
Cardiac disorders: Postural hypotension, cardiac arrhythmias
Vascular disorders: necrotising angiitis (vasculitis, cutaneous vasculitis)
Respiratory, thoracic and mediastinal disorders: respiratory distress (including pneumonitis and pulmonatory oedema)
Gastrointestinal disorders: gastric irritation, diarrhoea, constipation, pancreatitis
Hepato-biliary disorders: jaundice (intrahepatic cholstatic jaundice)
Skin and subcutaneous disorders: photosensitivity reactions, rash, cutaneous lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus, urticaria, anaphylactic reactions, toxic epidermal necrolysis
Musculoskeletal, connective tissue and bone disorders: muscle spasm
Renal and urinary disorders: renal dysfunction, interstital nephritis General disorders: fever, weakness
Lisinopril and other ACE inhibitors:
Blood and the lymphatic system disorders:
rare: decreases in haemoglobin, decreases in haematocrit.
very rare: bone marrow depression, anaemia, thrombocytopenia, leucopenia,
neutropenia, agranulocytosis (see [Special warnings and precautions for use]),
haemolytic anaemia, lymphadenopathy, autoimmune disease
Metabolism and nutrition disorders very rare: hypoglycaemia
Nervous system and psychiatric disorders: common: dizziness, headache
uncommon: mood alterations, paraesthesia, vertigo, taste disturbance, sleep
disturbances.
rare: mental confusion
Cardiac and vascular disorders:
common: orthostatic effects (including hypotension)
uncommon: myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients (see 4.4), palpitations, tachycardia. Raynaud’s phenomenon
Respiratory, thoracic and mediastinal disorders: common: cough uncommon: rhinitis
very rare: bronchospasm, sinusitis, allergic alveolitis/eosinophilic pneumonia
Gastrointestinal disorders:
common: diarrhoea, vomiting
uncommon: nausea, abdominal pain and indigestion
rare: dry mouth
very rare: pancreatitis, intestinal angioedema, hepatitis- either hepatocellular or cholestatic, jaundice and hepatic failure (see 4.4)
Skin and subcutaneous tissue disorders: uncommon: rash, pruritus rare: hypersensitivity/angioneurotic oedema: angioneurotic oedema of the face, extremities, lips, tongue, glottis, and/or larynx (see 4.4), urticaria, alopecia, psoriasis
very rare: diaphoresis, pemphigus, toxic epidermal necrolysis, Stevens-Johnson Syndrome, erythema multiforme.
A symptom complex has been reported which may include one or more of the following: fever, vasculitis, myalgia, arthralgia/arthritis, positive antinuclear antibodies (ANA), elevated red blood cell sedimentation rate (ESR), eosinophilia and leucocytosis, rash, photosensitivity or other dermatological manifestations may occur.
Renal and urinary disorders: common: renal dysfunction rare: uraemia, acute renal failure very rare: oliguria/anuria
Reproductive system and breast disorders: uncommon: impotence rare: gynaecomastia
General disorders and administration site conditions: uncommon: fatigue, asthenia
Investigations:
uncommon: increases in blood urea, increases in serum creatinine, increases in liver enzymes, hyperkalaemia
rare: increases in serum bilirubin, hyponatraemia.
4.9 Overdose
No specific information is available on the treatment of overdose of Lisinopril and Hydrochlorothiazide 10mg/12.5mg tablets. Treatment is symptomatic and supportive. Treatment with Lisinopril and Hydrochlorothiazide 10mg/12.5mg tablets should be discontinued and the patient should be monitored very closely. Therapeutic measures depend on the nature and the severity of the symptoms. Measures should be instituted to prevent absorption and to promote elimination. The recommended measures include inducing vomiting and/or gastric lavage if the drug was ingested recently, while dehydration, disturbances of the electrolyte balance and hypotension should be treated in the usual manner.
Lisinopril: Limited data are available for overdose in humans. Typical symptoms of overdose may be severe hypotension, circulatory shock, electrolyte disorders, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, cough and kidney failure.
If severe hypotension occurs the patient should be placed in a shock position, and an intravenous infusion of normal saline should be administered rapidly. Treatment with angiotensin II infusion and/or intravenous catecholamines (if it is available) may be considered. If ingestion is recent, take measures aimed at eliminating Lisinopril (e.g. emesis, gastric lavage, administration of absorbents and sodium sulphate).
ACE inhibitors may be removed from the blood circulation by haemodialysis (see [Special warnings and precautions for use]). Pacemaker therapy is indicated for therapy-resistant bradycardia.
Serum electrolytes, vital signs and creatinine should be monitored regularly.
Hydrochlorothiazide: the most common signs and symptoms are those that are due to electrolyte reduction (hypokalaemia, hypochloraemia, hyponatraemia) and dehydration due to significant diuresis. If digitalis has also been taken hypokalaemia may also be accompanied by accentuate arrhythmia.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: ACE inhibitor (ACE: angiotensin converting enzyme) and thiazide diuretic, ATC-code: C09B A03
Mechanism of action: Both components, Lisinopril, the ACE inhibitor and Hydrochlorothiazide, a diuretic, have complementary modes of action and exert an additive antihypertensive effect. ACE catalyses the conversion of angiotension I to angiotension II, which has a strong vasoconstrictor effect and stimulates aldosterone secretion. The antihypertensive effect of Lisinopril is mainly due to the suppression of the renin angiotensin-aldosterone system with reduction of plasma concentration of angiotension II (resulting in decreased vasopressor activity) and aldosterone. Lisinopril exerts an antihypertensive effect even in patients with low-renin hypertension. ACE is identical to kininase II, an enzyme that degrades bradykinin. It remains unclear whether increased levels of bradykinin (a potent vasodilator) plays a role in the therapeutic effect of lisinopril.
Hydrochlorothiazide is a thiazide diuretic and an antihypertensive that increase the plasma-renin activity. Hydrochlorothiazide suppresses the renal reabsorption of electrolytes in the renal distal tubule and increases the excretion of sodium, chloride, potassium, magnesium, bicarbonates and water. The excretion of calcium may be reduced. Concomitant administration of lisinopril and hydrochlorothiazide gives a greater reduction in blood pressure than monotherapy. Lisinopril normally attenuates the potassium loss associated with hydrochlorothiazide.
The effects of the fixed dose combination of lisinopril and hydrochlorothiazide on mortality and cardiovascular morbidity are currently unknown.
5.2 Pharmacokinetic properties
The combined tablet is bio-equivalent to monotherapy with each of the active ingredients.
Absorption
Lisinopril: Approx 25%, with an interindividual variability of 6-60% on all the tested dosages (5-80 mg). The absorption of lisinopril is not affected by food. Peak serum concentrations are reached within 6-8 hours. Effect on blood pressure was observed after 1-2 hours. The peak effect is obtained after 6 hours and lasts for at least 24 hours.
Hydrochlorothiazide: The diuretic effect is observed within 2 hours. The maximum effect is attained after 4 hours. Clinically noticeable effect will last 6-12 hours.
Distribution
Protein binding: Lisinopril is not bound to plasma proteins except to ACE. A reduced distribution volume may result in higher plasma concentrations in older patients than in younger patients.
Half-life
Lisinopril: after multiple dosing 12 hours. Hydrochlorothiazide 5^ - 15 hours.
Metabolism/elimination
Both active components are excreted unchanged via the kidneys. Approx. 60% of the orally administered hydrochlorothiazide is eliminated within 24 hours.
5.3 Preclinical safety data
Preclinical safety data show no particular risk to humans on the basis of traditional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenicity and toxicity in connection with reproduction.
In animal tests angiotensin converting enzyme inhibitors induce adverse effects on the late foetal development, resulting in foetal death and congenital effects, in particular affecting the skull. Fetotoxicity, intrauterine growth retardation and patent ductus arteriosus have also been reported. These developmental anomalies are thought to be partly due to a direct action of ACE inhibitors on the fetal renin-angiotensin system and partly due to the ischemia resulting from maternal hypotension and decreases in foetal-placental blood flow and oxygen/nutrients delivery to the foetus.
(see [Pregnancy and lactation])
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Calcium hydrogen phosphate dihydrate
Mannitol
Maize starch
Pregelatinized starch
Magnesium stearate
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
PVC/aluminium blister: 10, 14, 28, 30, 50, 56, and 100 tablets,
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Generics [UK] Limited t/a Mylan
Station Close
Potters Bar
Hertfordshire
EN6 1TL
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 04569/0694
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
09/12/2008
10 DATE OF REVISION OF THE TEXT
16/11/2012