Lisinopril +Hct 20/12.5mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Lisinopril + HCT 20 mg/12.5 mg tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains: Lisinopril dihydrate 21.78 mg equivalent to lisinopril 20 mg and hydrochlorothiazide 12.5 mg.
Excipient with known effect: Each film-coated tablet contains 52.8mg of Mannitol.
For the full list of excipients, see section 6.1
3. PHARMACEUTICAL FORM
Tablet
Pink, round, biconvex, one-sided score notch with a diameter of 8.9-9.3mm
4 CLINICAL PARTICULARS
Treatment of essential hypertension. Lisinopril + HCT 10mg/12.5 mg tablets fixed dose combination (10 mg lisinopril and 12.5 mg hydrochlorothiazide) is indicated in patients whose blood pressure is not adequately controlled on lisinopril alone (or hydrochlorothiazide alone). (see sections 4.3, 4.4, 4.5 and
5.1)
4.2 Posology and method of administration
Posology
The selection of a suitable antihypertensive dose of lisinopril and hydrochlorothiazide will depend upon the clinical evaluation of the patient.
Lisinopril + HCT 10mg/12.5 mg tablets 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 administered in patients whose blood pressure is not adequately controlled by 10 mg lisinopril alone.
20 mg/12.5 mg tablets may be administered in patients whose blood pressure is not adequately controlled by 20 mg lisinopril alone.
A maximum daily dose of 40 mg lisinopril/25 mg hydrochlorothiazide should not be exceeded. (see sections 4.3, 4.4, 4.5 and 5.1)
Previous diuretic treatment:
Symptomatic hypotension may occur following the initial dose; this is more likely in patients who are volume and/or salt depleted because of diuretic therapy.
Diuretics should be discontinued for 2-3 days before starting Lisinopril + HCT 10 mg/12.5 mg tablets. If this is not possible, treatment should be started with lisinopril alone, in a 5 mg dose. These patients should be carefully monitored for objective and subjective symptoms of hypotension after the first dose of Lisinopril + HCT 10 mg/12.5 mg tablets (see section 4.4 Special warnings and precautions for use, hypotension and electrolyte/fluid imbalance).
Renal impairments:
The combination lisinopril/hydrochlorothiazide is contraindicated in patients with severe renal impairment (creatinine clearance <30 ml/min). In patients with creatinine clearance between 30 and 80 ml/min, it may be used only after titration of the individual components.
The recommended initial dose of lisinopril as mono-therapy for these patients is 5-10 mg (see Section 4.4 Special warnings and special precautions for use).
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 the above section on “Renal impairment”.
Paediatric use:
The safety and efficacy of Lisinopril + HCT 10 mg/12.5 mg tablets in children has not been established.
Method of administration: Oral
4.3 Contraindications
Hypersensitivity to active substance or to any of the excipients listed in section 6.1.
- Hypersensitivity to any other angiotensin converting enzyme (ACE) inhibitor or to other sulphonamide-derived medicinal product
- Lisinopril + HCT is contraindicated in patients with anuria or aortic stenosis or hyperkalaemia.
- Lisinopril + HCT is contraindicated in patients with a history of angioneurotic oedema relating to previous treatment with an ACE inhibitor
- Hereditary/idiopathic angioneurotic oedema
- Severe renal impairment (creatinine clearance < 30ml/min)
- Severe hepatic impairment
- Stenosis of the renal arteries
- Second and third trimester of pregnancy (see sections 4.4 and 4.6)
- Concomitant administration with aliskiren-containing medicines in patients with diabetes mellitus (type I or II) or with moderate to severe renal impairment (GFR < 60 ml/min/1.73m2) (see sections 4.5 and 5.1)
4.4 Special warnings and precautions for use
Symptomatic hypotension and electrolyte/fluid imbalance
Symptomatic hypotension is rarely seen in uncomplicated hypertensive patients, but is more likely to occur if the patient has been volume-depleted such as in the presence of fluid or electrolyte imbalance, e.g. salt depletion, 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, or has severe renin-dependent hypertension (see sections 4.5 and 4.8).
Regular monitoring of serum electrolytes should be performed at appropriate intervals in such patients.
In patients at increased risk of symptomatic hypotension, initiation of therapy and dose adjustment should be monitored under close medical supervision. Particular consideration should be given when therapy is administered to patients with ischaemic heart disease or cerebrovascular disease because an excessive fall in blood pressure could result in a myocardial infarction or a cerebrovascular event/ accident.
If hypotension occurs, the patient should be placed in the supine position and, if necessary, should receive an intravenous infusion of physiological/ normal saline. A transient hypotensive response is usually not a contraindication for further doses. Following restoration of effective blood/ plasma volume and pressure, reinstitution of therapy at reduced dosage may be possible; or either of the components may be used alone, as appropriate.
In some patients with heart failure who have normal or low blood pressure, additional lowering of systemic blood pressure may occur with lisinopril. This effect is anticipated and is nor usually a reason to discontinue treatment. If hypotension becomes symptomatic, a reduction of dose or discontinuation of lisinopril-hydrochlorothiazide may be necessary.
Aortic and mitral valve stenosis /hypertrophic cardiomyopathy As with other vasodilators/ ACE inhibitors Lisinopril + HCT 10 mg/12.5 mg tablets should be given with caution to patients with, mitral valve stenosis and obstruction in the outflow of the left ventricle such as aortic stenosis or hypertrophic cardiomyopathy.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1).
If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.
ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
Renal function impairment
Thiazides may not be appropriate diuretics for use in patients with renal impairment and thiazides are ineffective in patients with creatinine clearance values of 30 ml/min or below (i.e. corresponds to moderate or severe renal insufficiency).
Lisinopril + HCT 10 mg/12.5 mg tablets should not be administered to patients with renal insufficiency (creatinine clearance 30-80 ml/minutes) until titration of the individual components has shown the need for the doses present in the combination tablet.
In patients with heart failure, hypotension following the initiation of therapy with ACE inhibitors may lead to some further impairment in renal function. Acute renal failure, usually reversible, has been reported in this situation.
In some patients with bilateral renal artery stenosis or stenosis of the single artery to a solitary kidney, who have been treated with ACE 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 insufficiency. If renovascular hypertension is also present, there is an increased risk of severe hypotension and renal failure/ insufficiency. 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, renal function should be monitored during the first few weeks of lisinopril-hydrochlorothiazide therapy.
Some hypertensive patients with no apparent pre-existing renovascular disease have developed usually minor and transient increases in blood urea and serum creatinine when lisinopril has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or lisinopril may be required.
Prior diuretic therapy
The diuretic therapy should be discontinued for 2-3 days prior to initiation with lisinopril-hydrochlorothiazide. If this is not possible, treatment should be started with lisinopril alone, in a 5 mg dose.
Renal transplantation
Lisinopril + HCT should not be used, since there is no experience with patients recently transplanted with a kidney.
Anaphylactoid reactions in haemodialyticpatients
The use of Lisinopril + HCT is not indicated in patients requiring dialysis for renal failure. A high incidence of anaphylactoid reactions/Anaphylactic reactions have been reported in patients haemodialysed with high-flux dialysis membranes (e.g. AN 69) or undergoing low-density lipoprotein apheresis with dextran sulphate absorption 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 medication.
Anaphylactoid reactions related to low-density lipoproteins (LDL) apheresis In rare occasions, patients treated with ACE inhibitors during low-density lipoprotein (LDL) apheresis with dextran sulphate have shown life threatening anaphylactic reactions. These reactions/ symptoms could be avoided by temporarily discontinuation of treatment with 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 (see section 4.3).
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 the syndrome is not understood. Patients receiving ACE inhibitors/ lisinopril-hydrochlorothiazide who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor/ lisinopril-hydrochlorothiazide and receive appropriate medical follow-up.
Surgery/Anaesthesia
In patients undergoing major surgery or during anaesthesia with agents that cause 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 plasma volume expansion.
Metabolic and endocrine effects
Thiazide therapy may impair glucose tolerance and may increase cholesterol and triglyceride levels. The glycaemic levels should be closely monitored in diabetic patients previously treated with oral antidiabetic drugs or insulin, namely during the first month of treatment with an ACE inhibitor. Latent diabetes mellitus may become manifest during thiazide therapy.
Dosage adjustment of antidiabetic agents, including insulin, may be required. Thiazide therapy may precipitate hyperuricaemia and/or gout in some patients. However, lisinopril may increase urinary uric acid and thus may attenuate the hyperuricaemic effect of hydrochlorothiazide.
Electrolyte imbalance
As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals. Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (hypokalaemia, hyponatraemia, and hypochloraemic alkalosis). Warning signs of fluid or electrolyte imbalance are dryness of mouth, thirst, weakness, lethargy, drowsiness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia and gastrointestinal disturbances such as nausea or vomiting (see section 4.8). Dilutional hyponatraemia may occur in oedematous patients in hot weather. Chloride deficit is generally mild and does not require treatment. Thiazides have been shown to increase the urinary excretions of magnesium, which may result in hypomagnesaemia.
Thiazide therapy may decrease urinary calcium excretion and may cause an 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.
Hyperkalaemia
Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including lisinopril. During treatment with ACE inhibitor the following group of patients are at an increased risk for the development of hyperkalaemia: patients with impaired renal function/ insufficency, diabetes mellitus, patients who are using potassium sparing diuretics, potassium supplements and/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, frequent monitoring of serum potassium is recommended (see 4.5 Interaction with other medicinal products and other forms of interaction).
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 section 4.5).
Hypersensitivity/ angioedema
Angioneurotic oedema/angioedema of the extremities, face, lips, mucous membranes, tongue, glottis and/ or larynx has been reported uncommonly in patients treated with ACE inhibitors including lisinopril. 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 patient. Even in those instances where swelling of only the tongue is involved, without respiratory distress, patients may require prolonged observation since treatment with anti-histamines and corticosteroids may not be sufficient.
Very rarely, fatalities have been reported due to angioedema associated with laryngeal oedema or tongue oedema. However, in rare cases, severe angioedema may develop after long-term treatment with an ACE inhibitor. Treatment should be discontinued promptly and appropriate monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patient. Angioedema involving the tongue, glottis or larynx may be fatal. Emergency therapy should be instituted. The patient should be hospitalised and observed for at least 12 to 24 hours under close medical supervision and should not be discharged until complete resolution of symptoms has occurred.
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. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, especially those with a history of airway surgery, in such cases appropriate emergency 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. The patient should be under close medical supervision until complete and sustained resolution of symptoms has occurred.
Angiotensin converting enzyme inhibitors cause a higher rate of angioedema in black patients than in non-black patients.
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.
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 section 4.3).
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.
In patients receiving thiazides, hypersensitivity 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.
Desensitisation/ Anaphylactic reactions during desensitization: Sustained life-threatening anaphylactic/ anaphylactoid reactions have been rarely reported for patients undergoing desensitizing treatment with hymenoptera venom (e.g. Bee or Wasp venom) while receiving an ACE-inhibitor. In the same patients these reactions were avoided when the ACE inhibitor was temporarily withheld, but they reappeared upon inadvertent rechallenge. Therefore, caution should be used in patients treated with an ACE inhibitors undergoing such desensitization.
Neutropenia / agranulocytosis
Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported for patients receiving ACE inhibitors. In patients with normal renal function and no other complicating factors neutropenia occurs rarely. Neutropenia 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 alopurinol 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.
Serum potassium
The potassium losing effect of thiazide diuretics is usually attenuated by the potassium conserving effect of lisinopril.
Cough
Cough has been reported with the use of ACE inhibitors. As ACE-inhibitors can cause a persistent, non productive cough (resolves after discontinuation of therapy) they should be given cautiously to patients who are coughing. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.
Race
ACE inhibitors cause a higher rate of angioedema in black 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-black patients, possibly because of a higher prevalence of low-renin states in the black hypertensive population.
Lithium
The combination of ACE-inhibitors and lithium is generally not recommended (see section 4.5).
Anti-doping test
The hydrochlorothiazide contained in this medication could produce a positive analytic result in an anti-doping test.
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 antihypertensive 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
Dual blockade of the renin-angiotensin-aldosterone system
Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through the combined use of angiotensin II receptor blockers, ACE inhibitors, or direct renin inhibitors (such as aliskiren) is associated with a higher frequency of adverse events such as hypotension, hyperkalemia, and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1). Closely monitor blood pressure, renal function, and electrolytes in patients on lisinopril and other agents that affect the RAAS. Do not co-administer aliskiren with lisinopril in patients with diabetes. Avoid use of aliskiren with lisinopril in patients with renal impairment (GFR < 60 ml/min/1.73m2) (see section 4.3).
Potassium-sparing diuretics, potassium supplements and potassium-containing salt substitutes
The potassium losing effect of thiazide diuretics is usually attenuated by the potassium conserving effect of lisinopril. The use of potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes, particularly in patients with impaired renal function or diabetes mellitus, may lead to a significant increase in serum potassium. If concomitant use of Lisinopril + HCT 10 mg/12.5mg tablets and any of these agents is required, then they should be used cautiously and with frequent monitoring of serum potassium (see section 4.4).
Lithium
Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. Diuretic agents and ACE inhibitors reduce the renal clearance of lithium and add a high risk of lithium toxicity. Refer to prescribing information for lithium preparations before use of such preparations. The combination of lisinopril and hydrochlorothiazide with lithium is therefore not recommended and careful monitoring of serum lithium should be performed if the combination proves necessary (see section 4.4).
Anti-diabetics
Epidemiological studies have suggested that concomitant administration of ACE inhibitors and anti-diabetic medicines (insulins, oral hypoglycaemic agents) may cause an increased blood glucose lowering effect with an increased risk of hypoglycaemia. This phenomenon may be more likely to occur during the first weeks of combination 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. Dosage adjustment of the antidiabetic drug may be required.
NSAID (non-steroidal anti-inflammatory drugs) including acetylsalicylic acid Chronic concomitant administration with NSAID (i. e. selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day) and non-selective NSAIDs e.g. Indometacin) may reduce the antihypertensive, natriuretic and diuretic effect of ACE inhibitors and thiazide diuretics. NSAIDs and ACE inhibitors may exert an additive effect on the deterioration of renal function and an increase in serum potassium. These effects are usually reversible. Rarely, acute renal failure may occur, especially in patients with compromised renal function such as the elderly or dehydrated. The antihypertensive effect of Lisinopril + HCT may be potentiated when given concomitantly with other agents likely to cause postural hypotension. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.
Gold
Nitritoid reactions (symptoms of vasodilatation including flushing, nausea, dizziness and hypotension, which can be very severe) following injectable gold (for example, sodium aurothiomalate) have been reported more frequently in patients receiving ACE inhibitor therapy.
Allopurinol
Concomitant administration of ACE inhibitors and allopurinol increases the risk of renal damage and can lead to an increased risk of leucopenia.
Cyclosporin
Concomitant administration of ACE inhibitors and cyclosporin increases the risk of renal damage and hyperkalaemia.
Barbiturates or narcotics
Potentiation of orthostatic hypotension may occur.
Lovastatin
Concomitant administration of ACE inhibitors and lovastatin increases the risk of hyperkalaemia.
Probenecid
Concomitant administration may increase thiazide serum concentrations.
Trimethoprim
Concomitant administration of ACE inhibitors and thiazides with trimethoprim increases the risk of hyperkalaemia.
Digitalis/ cardiac glycosides
Hypokalaemia induced by thiazide treatment can increase the effect of digitalis glycosides. There is increased risk of digitalis toxicity associated with thiazide induced hypokalaemia.
Sotalol
Thiazide-induced hypokalaemia can increase the risk of sotalol-induced arrhythmias. Colestyramin, colestipol
Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Concomitant administration of colestyramin or colestipol resins bind the hydrochlorothiazide and may delay or reduces the absorption of thiazide from the gastrointestinal tract by 85% and 43% respectively. Sulphonamide diuretics should be taken at least 1 hour before or 4-6 hours after intake of these agents.
Tricyclic antidepressants/antipsychotics/Narcotics/anesthetics Concomitant use of certain anaesthetic medicinal products, tricyclic antidepressants and antipsychotics with ACE inhibitors may result in further lowering of blood pressure (see section 4.4).
Alcohol
Alcohol may enhance the hypotensive effect of any antihypertensive.
Torsades de pointes-inducing drugs
Should not be combined with HCTZ. Because of the risk of hypokalaemia, the concomitant administration of hydrochlorothiazide and medicinal products that induce torsades de pointes, e.g. some antiarrhythmias, some anti-psychotics and other drugs known to induce torsades de pointes, should be used with caution.
Corticosteroids, amphotericin B (parenteral), carbenoxolone, corticotropin (ACTH) or stimulant laxatives
HCTZ may intensify electrolyte imbalance, in particular hypokalaemia.
Pressor amines (e.g. epinephrine (adrenaline)
Possible decreased response to pressor amines but not sufficient to preclude their use. Other antihypertensive agents
Concomitant use of these agents may increase the hypotensive effect of lisinopril-hydrochlorothiazide. When combined with other antihypertensive agents, additive falls in blood pressure may occur. Concomitant use of glyceryl trinitrate and other nitrates or other vasodilators may further reduce the blood pressure.
The combination of lisinopril with aliskiren-containing medicines should be avoided (see sections 4.3 and 4.4).
Sympathomimetics
Sympathomimetics can reduce the antihypertensive effects of ACE inhibitors, patients should be carefully monitored to confirm that the desired effects are being obtained.
Procainamide, cytostatic or immunosuppressive agents
Concomitant administration with ACE inhibitors may lead to an increased risk of leucopenia (see section 4.4).
Antacids
Induce decreased bioavailability of ACE inhibitors.
Calcium salts
Increased serum calcium levels due to decreased excretion may occur when administered concurrently with thiazide diuretics.
Non-depolarizing muscle relaxants (e.g. tubocurarine chloride)
Thiazides may increase the response to tubocurarine. The effect of these agents may be potentiated by hydrochlorothiazide.
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).
4.6 Fertility, 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 contraindicated during the second and third trimester of pregnancy (see sections 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 antihypertensive 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, oligohydramnios, 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).
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, Lisinopril + HCT 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.
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.
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.
Moreover, rare case of hypoglycaemia in neonates has been reported in case of exposure near the term.
There is no experience with the removal of hydrochlorothiazide, which also crosses the placenta, from the neonatal circulation.
Breast-feeding
ACE-inhibitors
Because no information is available regarding the use of Lisinopril + HCT during breastfeeding, Lisinopril + HCT is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.
Hydrochlorthiazide
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 + HCT during breast feeding is not recommended. If Lisinopril + HCT is used during breast feeding, doses should be kept as low as possible.
Hypersensitivity to sulphonamide-derived drugs, hypokalaemia and jaundice in foetus or neonate might occur. Because of the potential for serious adverse reactions in nursing infants from both drugs, a decision should be made whether to discontinue nursing or to discontinue therapy taking into account the importance of this therapy to the mother.
4.7 Effects on ability to drive and use machines
As with other antihypertensives, lisinopril-hydrochlorothiazide combination products may have a mild to moderate effect on the ability to drive and use machines may be reduced, e.g. especially at the start of the treatment or when the dose is modified, and also when used in combination with alcohol, but these effects depend on the individual’s susceptibility. The risk of hypotension, dizziness and fainting should be considered.
When driving vehicles or operating machines it should be taken into account that occasionally dizziness or tiredness may occur.
4.8 Undesirable effects
Lisinopril + HCT 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. In clinical studies, side effects are the same as those reported previously with lisinopril or hydrochlorothiazide administered separately.
The following undesirable effects have been observed and reported during treatment with lisinopril and/or hydrochlorothiazide with the following frequencies: Very common (>10%), common (>1%, <10%), uncommon (>0.1, <1%), rare (>0.01, <0.1%), very rare (<0.01%), not known (cannot be estimated from the available data).
The most commonly reported ADRs are cough, dizziness, hypotension, and headache which may occur in 1 to 10% of treated patients.
Lisinopril
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Blood and lymphatic system disorders | |
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Rare |
Small decreases in haemoglobin and haematocrit Neutropenia |
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Very rare |
Bone marrow depression manifest as anaemia and/or thrombocytopenia and/or leucopenia, Neutropenia, agranulocytosis (see section 4.4), lymphadenopathy, autoimmune disease. Haemolytic anaemia |
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Metabolism and nutrition disorders | |
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Very rare |
Hypoglycaemia |
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Nervous system disorders and psychiatric disorders | |
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Common |
Dizziness, headache, syncope |
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Uncommon |
Paraesthesia, vertigo, taste disturbance, sleep Disturbances, mood alterations, depressive symptoms |
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Rare |
Mental confusion, Olfactory disturbance. |
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Unknown |
Hallucinations |
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Cardiac and vascular disorders | |
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Common Uncommon |
Orthostatic effects (including orthostatic hypotension) Myocardial infarction or cerebrovascular accident, possibly secondary to excessive |
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hypotension in high risk patients (see section 4.4), palpitations, tachycardia, Raynaud’s syndrome | |
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Unknown |
Flushing |
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Respiratory, thoracic and mediastinal disorders | |
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Common |
Dry and persistent Cough (see section 4.4) |
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Uncommon |
Rhinitis |
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Very rare |
Bronchospasm, sinusitis, allergic alveolitis/eosinophilic pneumonia |
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Gastrointestinal disorders | |
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Common |
Diarrhoea, vomiting |
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Uncommon |
Nausea, abdominal pain, indigestion Dry mouth |
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Rare |
Pancreatitis, intestinal angioedema |
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Very rare | |
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Hepatobiliary disorders | |
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Uncommon |
Elevations of liver enzymes and/or serum bilirubin |
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Hepatitis - either hepatocellular or cholestatic, | |
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Very rare |
Jaundice, hepatic failure (see section 4.4)* |
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Skin and subcutaneous tissue disorders | |
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Uncommon |
Rash, pruritus |
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Rare |
Hypersensitivity/angioneurotic oedema: angioneurotic oedema of the face, extremities, lips, tongue, glottis, and/or larynx (see section 4.4), urticaria, alopecia, psoriasis |
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Very rare |
Diaphoresis, pemphigus, toxic epidermal necrolysis, Stevens-Johnson Syndrome, erythema multiforme, cutaneous pseudolymphoma ** |
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Unknown |
Photosensitivity |
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Renal and urinary disorders | |
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Common |
Renal dysfunction |
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Rare |
Uraemia, acute renal failure |
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Very rare |
Oliguria/anuria |
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Unknown |
Proteinuria |
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Reproductive system and breast disorders | |
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Uncommon |
Impotence |
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Rare |
Gynaecomastia |
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Endocrine Disorders | |
|
Rare: |
Syndrome of inappropriate antidiuretic hormone secretion (SIADH) |
|
General disorders and administration site conditions | |
|
Uncommon |
Asthenia, fatigue |
|
Investigations | |
|
Uncommon |
Increases in blood urea nitrogen, serum creatinine, hyperkalaemia |
|
Rare |
Hyponatraemia |
* Very rarely, it has been reported that in some patients the undesirable development of hepatitis has progressed to hepatic failure. Patients receiving lisinopril-hydrochlorothiazide combination who develop jaundice or marked elevations of hepatic enzymes should discontinue lisinopril-hydrochlorothiazide combination and receive appropriate medical follow up.
Others: **A symptom complex which may include one or more of the following: fever, vasculitis, myalgia, arthralgia/arthritis, a positive ANA, elevated ESR, eosinophilia, leucocytosis, rash, photosensitivity or other dermatological manifestations.
Hydrochlorothiazide (frequencies unknown):
|
Infections and infestations |
Sialoadenitis |
|
Blood and lymphatic system disorders |
Leucopenia, neutropenia/agranulocytosis, thrombocytopenia, aplastic anaemia, haemolytic anaemia, bone marrow depression |
|
Metabolism and nutrition disorders |
Anorexia, hyperglycaemia, glycosuria, hyperuricaemia, electrolyte imbalance (including hyponatraemia, hypokalaemia, hypochloremic alkalosis and hypomagnesaemia), increases in blood cholesterol and triglycerides, gout, loss of appetite |
|
Psychiatric disorders |
Restlessness, depression, sleep disturbance |
|
Nervous system disorders |
Paraesthesia, light-headedness |
|
Eye disorders |
Xanthopsia, transient blurred vision, acute myopia and acute angle-closure glaucoma. |
|
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 pulmonary oedema) |
|
Gastrointestinal disorders |
Gastric irritation, diarrhoea, constipation, pancreatitis |
|
Hepatobiliary disorders |
Jaundice (intrahepatic cholestatic jaundice) |
|
Skin and subcutaneous tissue disorders |
Photosensitivity reactions, rash, systemic |
|
lupus erythematosus, cutaneous lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus, urticaria, anaphylactic reactions, toxic epidermal necrolysis, purpura | |
|
Musculo-skeletal, connective tissue and bone disorders |
Muscle spasm, muscle weakness |
|
Renal and urinary disorders |
Renal dysfunction, interstitial nephritits, renal failure |
|
General disorders |
Fever, weakness |
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
4.9 Overdose
Limited data are available for overdose in humans. No specific information is available regarding overdose with Lisinopril + HCT 10 mg/12.5 mg tablets. Treatment is symptomatic and supportive with correction of dehydration, electrolyte disturbance and hypotension. Emptying of stomach and gastric lavage after recent administration. Therapy with Lisinopril + HCT should be discontinued and patients should be kept under close supervision.
Lisinopril
Symptoms associated with overdosage of ACE inhibitors may include: Severe hypotension, circulatory shock, electrolyte disturbances and renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety and cough. After overdose, the patients should be kept under close supervision.
Treatment of overdose
The treatment is determined by the symptoms severity and nature. Measures to prevent absorption and methods to speed elimination should be employed. If severe hypotension occurs, the patients should be placed in the shock/ supine position and an intravenous infusion of physiological saline should be given rapidly. If available, treatment with angiotensin II and/or intravenous catecholamines may also 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/ lisinopril may be removed from the general circulation by haemodialysis. (See 'Special Warnings and Precautions, Haemodialysis Patients').The use of high-flux polyacrylonitrile dialysis membranes should be avoided. . Pacemaker therapy is indicated for therapy-resistant bradycardia. Vital signs, serum electrolytes and creatinine concentrations should be monitored frequently.
Hydrochlorothiazide
Additional Symptoms of hydrochlorothiazide overdose are increased diuresis, depression of consciousness (incl. coma), convulsions, paresis, cardiac arrhythmias and renal failure. Bradycardia or extensive vagal reactions should be treated by administering atropine
Symptoms are 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
Pharmacotherapeutic group: ACE inhibitor (ACE: angiotensin converting enzyme) and thiazide diuretic.
ATC-Code: C09B A03.
Mechanism of action: Both components, the ACE inhibitor and diuretic, have complementary modes of action and exert an additive antihypertensive effect. ACE catalyses the conversion of angiotensin I to angiotensin II, which has 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 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 increases 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.
Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker. ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.
These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.
ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.
5.2 Pharmacokinetic properties
The combination tablet is bioequivalent with separate administration of each of the active substances.
Absorption
Lisinopril
Approximately 25% with interpatient variability (6-60%) at all doses tested (5-80 mg). The absorption of lisinopril is not influenced by food. Maximal serum concentration is reached after 6-8 hours. Effect on blood pressure is observed after 12 hours. The effect is maximal after 6 hours and lasts for a least 24 hours. The absolute bioavailability is reduced approximately 16% in patients with heart failure.
Hydrochlorothiazide
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 dose is eliminated unchanged within 24 hours. Diuretic effect is seen within 2 hours. Maximal effect is reached after 4 hours. Clinically adequate diuretic effect lasts for 6-12 hours.
Hydrochlorothiazide crosses the placental but not the blood-brain barrier.
Distribution
Protein binding: Lisinopril is not bound to plasma proteins other than ACE. Studies in rats indicate that lisinopril crosses the blood-brain barrier poorly.
Elderly
Reduced volume of distribution in elderly can give a higher plasma concentration than in younger patients.
Half-life
Lisinopril: On multiple dosing 12 hours. Hydrochlorothiazide 5.5 - 15 hours. Metabolism/elimination
Both of the active substances are eliminated unchanged via the kidneys. Approximately 60% of hydrochlorothiazide that is administrated orally is eliminated within 24 hours.
Hepatic impairment
Impairment of hepatic function in cirrhotic patients resulted in a decrease in lisinopril absorption (about 30% as determined by urinary recovery) but an increase in exposure (approximately 50%) compared to healthy subjects due to decreased clearance.
Renal impairment
Impaired renal function decreases elimination of lisinopril, which is excreted via the kidneys, but this decrease becomes clinically important only when the glomerular filtration rate is below 30 ml/min.
Table 1 Pharmacokinetic parameters of lisinopril to different groups of renal patients after administration of a multiple 5 mg dose_
|
Renal Function Measured by creatinine clearance |
n |
Cmax (ng/ml) |
Tmax (hr) |
AUC (0-24 hrs) (ng/hr/ml) |
t1/2 (hr) |
|
>80 ml/min |
6 |
40.3 |
6 |
492+/-172 |
6.0+/-1.1 |
|
30-80 ml/min |
6 |
36.6 |
8 |
555+/-364 |
11.8+/-1.9 |
|
5-30 ml/min |
6 |
106.7 |
8 |
2228+/-938 |
19.5+/-5.2 |
With a creatinine clearance of 30-80ml/min, mean AUC was increased by 13% only, while a 4-5 fold increase in mean AUC was observed with creatinine clearance of 5-30ml/min.
Lisinopril can be removed by dialysis. During 4 hours of haemodialysis, plasma lisinopril concentrations decreased on
average by 60%, with a dialysis clearance between 40 and 55 ml/min.
5.3 Preclinical safety data
Lisinopril and hydrochlorothiazide are well established in medical use. Preclinical data is broadly consistent with clinical experience, both separately and in combination. All relevant information for the prescriber is provided elsewhere in the Summary of Product Characteristics. In animal studies ACE inhibitors gives harmful injury on the foetal development in the last phase of gestation (see 4.6 Pregnancy and lactation).
Available preclinical data indicate no other potential hazards than effects caused by the pharmacological mechanisms of action of the two compounds.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
calcium hydrogenphosphate dihydrate
croscarmellose sodium
mannitol
maize starch
magnesium stearate
ferric oxide red (E 172)
6.2 Incompatibilities
Not applicable
6.3 Shelf life
2 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
The tablets are packed in polyvinylchloride /aluminium blisters and inserted into a carton.
Package sizes: 14, 28, 30, 50, 56, 98, 100, 400.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements for disposal.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Tillomed Laboratories Ltd 3 Howard Road Eaton Socon St. Neots
Cambridgeshire PE19 8ET UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 11311//0486
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
Date of first authorisation: 19/04/2010
10 DATE OF REVISION OF THE TEXT
19/09/2016