Active ingredients: Lisinopril (lisinopril dihydrate), Hydrochlorothiazide
ENSOR 20 mg + 12.5 mg tablets
Indications Why is Ensor used? What is it for?
PHARMACOTHERAPEUTIC CATEGORY
ACE inhibitor (Angiotensin converting enzyme inhibitor) and diuretic, in combination
THERAPEUTIC INDICATIONS
ENSOR is indicated for the treatment of essential hypertension in patients for whom combination therapy is appropriate.
Contraindications When Ensor should not be used
- History of hypersensitivity to lisinopril, to any of the excipients or to other ACE inhibitors.
- The concomitant use of ENSOR with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR <60 ml / min / 1.73 m2) (see Interactions).
- Anuria.
- History of hypersensitivity to hydrochlorothiazide or to other sulfonamides.
- Angioneurotic edema related to previous ACE inhibitor therapy.
- Hereditary / idiopathic angioneurotic edema.
- Severe renal insufficiency (creatinine clearance <30 ml / min).
- Severe impairment of liver function.
- Second and third trimester of pregnancy (see Special warnings)
Precautions for use What you need to know before you take Ensor
Lisinopril
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
There is evidence that 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 the RAAS through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see Interactions). If dual block therapy is considered absolutely necessary, this should only be done under the supervision of a specialist and with close and frequent monitoring of kidney function, electrolytes and blood pressure.
ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly in patients with diabetic nephropathy.
Symptomatic hypotension
Symptomatic hypotension has rarely been reported in patients with uncomplicated hypertension. In hypertensive patients receiving lisinopril, hypotension is more likely to occur if the patient is volume depleted, for example following diuretic therapy, low sodium diet, dialysis, diarrhea or vomiting, or with severe renal-dependent hypertension (see Interactions and Undesirable effects). Symptomatic hypotension has been observed in patients with heart failure, whether or not associated with renal insufficiency. This is more likely to occur in patients with more severe heart failure, as reflected by the administration of high doses of diuretics. loop, from hyponatremia or from impaired renal function. In patients with a high risk of symptomatic hypotension, initiation of therapy and dose adjustment should be carefully monitored. Similar considerations apply to patients with ischemic heart disease or cerebrovascular disorders, in whom a "Excessive drop in blood pressure can lead to myocardial infarction ico or a cerebrovascular event.
If hypotension occurs, the patient should be placed in the supine position and, if necessary, be given intravenous infusion of saline. A transient hypotensive response is not a contraindication to further doses, which can usually be given without difficulty once blood pressure has increased after blood volume expansion.
In some heart failure patients with normal or low blood pressure, further lowering of systemic blood pressure may occur with lisinopril. This effect is expected and generally does not constitute a reason for suspension of the treatment. If hypotension becomes symptomatic, dose reduction or discontinuation of lisinopril may be necessary.
Aortic and mitral valve stenosis / hypertrophic cardiomyopathy
Like other ACE inhibitors, lisinopril should be administered with caution in patients with mitral valve stenosis and left ventricular outflow tract obstruction, such as aortic stenosis or hypertrophic cardiomyopathy.
Impaired renal function
See Dose, method and time of administration. In patients with heart failure, hypotension following initiation of ACE inhibitor therapy may result in further impairment of renal function. Generally reversible acute renal impairment has been reported in this situation.
In some patients with bilateral renal artery stenosis or monorene artery stenosis treated with angiotensin converting enzyme inhibitors, increased blood urea nitrogen and serum creatinine, generally reversible on discontinuation of treatment, have been observed. This is especially likely in patients with renal insufficiency. The simultaneous presence of renovascular hypertension increases the risk of severe hypotension and renal insufficiency. In these patients, treatment should be initiated under strict medical supervision with reduced and carefully titrated dosages. Since treatment with diuretics may contribute to the above, the administration of diuretics should be discontinued and renal function monitored during the first weeks of lisinopril therapy.
In some hypertensive patients with no apparent prior renovascular disease, a generally mild and transient increase in blood urea nitrogen and serum creatinine was found, especially when lisinopril was administered concomitantly with a diuretic. This is more likely to occur in patients with pre -existing renal impairment A dose reduction and / or discontinuation of the diuretic and / or lisinopril may be necessary.
Kidney transplant patients
There is no experience with the administration of lisinopril to patients who have recently undergone a kidney transplant: therefore, treatment with lisinopril is not recommended in such patients.
Hypersensitivity / angioedema
Angioedema of the face, extremities, lips, tongue, glottis and / or larynx has been rarely reported in patients treated with angiotensin converting enzyme inhibitors, including lisinopril. This can occur at any time during treatment. In such cases, lisinopril should be promptly discontinued and appropriate treatment and monitoring instituted to ensure complete regression of symptoms before the patient is discharged. Even in cases where the edema is limited to the tongue, without respiratory distress, the patient may require prolonged observation as treatment with antihistamines and corticosteorides may not be sufficient.
Fatal events due to angioedema associated with edema of the larynx or tongue have been reported very rarely. Airway obstruction may occur in patients with affected tongue, glottis or larynx, especially those with previous airway surgery. In these cases, appropriate emergency therapy should be promptly administered. In this case, administration of adrenaline and / or maintenance of a patent airway should be provided. The patient should be placed under close medical surveillance until complete and prolonged resolution. symptoms.
Angiotensin converting enzyme inhibitors cause angioedema more frequently in black patients than in non-black patients.
Patients with a history of angioedema unrelated to ACE inhibitor treatment may be at increased risk of angioedema when treated with an ACE inhibitor (see Contraindications).
Anaphylactoid reactions in hemodialysis patients
Anaphylactoid reactions have been reported in patients on dialysis with high flux membranes (eg AN69) and treated concomitantly with an ACE inhibitor. The use of a different type of dialysis membrane or a different class of antihypertensive agents should be considered for these patients.
Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis
Rarely, life-threatening anaphylactoid reactions have occurred in patients receiving ACE inhibitors during low-density lipoprotein (LDL) apheresis with dextran sulfate. These reactions can be prevented by temporarily withholding ACE inhibitor treatment prior to each apheresis.
Desensitization
Cases of anaphylactoid reactions have been reported in patients treated with ACE inhibitors undergoing desensitizing treatment (e.g. hymenoptera venom). In the same patients, these reactions were prevented by temporarily stopping treatment with ACE inhibitors, but they reappeared after the medicine was inadvertently re-administered.
Hepatic insufficiency
Very rarely, treatment with ACE inhibitors has been associated with a syndrome that begins with cholestatic jaundice or hepatitis and progresses to fulminant necrosis and (sometimes) death. The mechanism of this syndrome is not known. Patients taking lisinopril and who develop jaundice or marked elevations in liver enzymes should discontinue lisinopril and undergo appropriate medical supervision.
Neutropenia / agranulocytosis
Neutropenia / agranulocytosis, thrombocytopenia and anemia have been reported in patients receiving ACE inhibitors. In patients with normal renal function and in the absence of other complicating factors, neutropenia rarely occurs. Neutropenia and agranulocytosis disappear after stopping treatment with ACE inhibitors. Lisinopril should be administered with extreme caution to patients with collagen disease, treated with immunosuppressive agents, with allopurinol or procainamide, or with a combination of these complicating factors, especially in the case of previous renal impairment. Some of these patients developed severe infections, which in a few cases did not respond to intensive antibiotic therapy. If these patients are treated with Lisinopril it is recommended that their white blood cell counts be checked periodically and that they are advised to report any episodes of infection.
Race
Angiotensin converting enzyme inhibitors cause angioedema more frequently in black patients than in non-black patients.
Like other ACE inhibitors, lisinopril may be less effective in lowering blood pressure in black patients than in patients of other races, possibly due to a higher prevalence of low renin concentrations in the black hypertensive population.
Cough
Cough has been reported following administration of ACE inhibitors. Characteristically, this cough is dry, persistent and resolves upon discontinuation of treatment. ACE inhibitor-induced cough should be considered when making the differential diagnosis of cough.
Surgery / anesthesia
In patients undergoing major surgery or undergoing anesthesia with agents that cause hypotension, lisinopril may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is believed to be related to the above mechanism, it can be corrected by volume expansion.
Hyperkalaemia
Increased serum potassium concentrations have been reported in some patients treated with ACE inhibitors, including lisinopril. Patients at risk of developing hyperkalaemia are those with renal insufficiency, diabetes mellitus or treated concomitantly with potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes; patients being treated with other drugs that cause an increase in plasma potassium (e.g. heparin). If concomitant use of the above mentioned drugs is deemed appropriate, regular monitoring of serum potassium is recommended (see Interactions).
Diabetic patients
In diabetic patients treated with oral antidiabetic agents or insulin, close blood glucose monitoring is required during the first month of treatment with an ACE inhibitor (see Interactions).
Lithium
The combination of lithium and lisinopril is generally not recommended (see Interactions).
Pregnancy
ACE inhibitor therapy should not be initiated during pregnancy. For patients planning to become pregnant, alternative antihypertensive treatments with a proven safety profile for use in pregnancy should be used, unless continued ACE inhibitor therapy is considered essential. When pregnancy is diagnosed. , treatment with ACE inhibitors should be stopped immediately and, if appropriate, alternative therapy should be started (see sections Contraindications and Special warnings).
The use of lisinopril while breastfeeding is not recommended.
Hydrochlorothiazide
Impaired renal function
In patients with renal disease, thiazides may precipitate azotaemia. In patients with impaired renal function, cumulative effects of the medicinal product may develop. "Careful evaluation of therapy, including the discontinuation of diuretics (see Contraindications).
Impaired liver function
Thiazides should be used with caution in patients with impaired liver function or progressive liver disease: minimal changes in the water-electrolyte balance can precipitate hepatic coma (see Contraindications).
Metabolic and endocrine effects
Therapy with thiazide diuretics can reduce glucose tolerance. Dose adjustments of insulin or oral hypoglycaemics may be required in diabetic patients. Latent diabetes mellitus may become apparent during thiazide therapy. Increases in cholesterol and triglyceride levels have been associated with thiazide-based diuretic therapy.
Hyperuricaemia or manifest gout may develop in some patients treated with thiazide diuretics.
Electrolyte imbalance
As with any patient on diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals.
Thiazides, including hydrochlorothiazide, can cause fluid and electrolyte imbalance (hypokalaemia, hyponatremia, and hypochloraemic alkalosis). The warning signs of fluid or electrolyte imbalance are dry mouth, thirst, weakness, lethargy, drowsiness, muscle pain, cramps or , muscle fatigue, hypotension, oliguria, tachycardia and gastrointestinal disorders such as nausea and vomiting.
Although hypokalaemia may develop following the use of thiazide diuretics, concomitant use of lisinopril may reduce diuretic-induced hypokalaemia. The risk of hypokalaemia is higher in patients with liver cirrhosis than in those who have an abrupt diuresis, inadequate oral consumption of electrolytes and in those on concomitant therapy with corticosteroids or ACTH (see Interactions).
In hot weather, edematous patients may experience hyponatremia. A chloride deficiency is usually mild and does not need treatment.
Thiazides may reduce urinary calcium excretion and cause mild and intermittent elevation of serum calcium even in the absence of known disturbances of calcium metabolism. Significant hypercalcaemia may be evidence of hidden hyperparathyroidism. Thiazides must be discontinued prior to treatment. perform tests for parathyroid function Thiazides have been shown to increase urinary excretion of magnesium, thus leading to hypomagnesaemia.
Others
Hypersensitivity reactions may occur in patients with or without episodes of allergies or bronchial asthma. The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.
Lisinopril / Hydrochlorothiazide
Hypotension and water / electrolyte imbalance:
Symptomatic hypotension may sometimes occur following administration of the first dose of lisinopril / hydrochlorothiazide. The chances of hypotension occurring in hypertensive patients are greater in the presence of water or electrolyte imbalance, eg. decreased volume, hyponatremia, hypochloraemic alkalosis, hypomagnesaemia or hypokalaemia, changes that may occur due to previous diuretic therapy, dietary salt restriction, dialysis or during intercurrent episodes of diarrhea or vomiting. In such patients, periodic checks of serum electrolytes should be performed.
Initiation of therapy and dosage adjustment in patients at increased risk of developing symptomatic hypotension should be done under close medical supervision.
Particular consideration must be given when the therapy is administered to patients with heart disease or ischemic cerebropathy, since an excessive drop in blood pressure could cause a myocardial infarction or a cerebrovascular accident.
If hypotension occurs, the patient should be placed in a supine position and infused with saline intravenously. A transient hypotensive response is not a contraindication to further doses of the drug. By restoring effective blood volume and arterial pressure, therapy can be re-established at a reduced dosage; otherwise it is possible to use one or the other member of the association individually.
As with other vasodilators, caution is warranted when lisinopril / hydrochlorothiazide is administered to patients with aortic stenosis or hypertrophic cardiomyopathy.
Impaired renal function
Thiazides are ineffective in patients with creatinine clearance values below 30 ml / min (i.e. in the presence of moderate or severe renal insufficiency) (see Contraindications).
ENSOR should not be administered to patients with a creatinine clearance of 30-80 ml / min until titration of the individual components has first demonstrated the need for the doses present in the combination tablet.
In some patients without defined pre-existing renovascular disease, when lisinopril was administered concomitantly with a diuretic, usually mild and transient increases in blood urea nitrogen and creatinine levels occurred. "association must be suspended. Restoration of therapy is possible at a reduced dosage or, if the case requires it, both components can be used appropriately alone.
Risk of hypokalemia
The combination of an ACE inhibitor and a thiazide does not exclude the onset of hypokalaemia. It is necessary to have regular potassium checks.
Neutropenia / agranulocytosis
The combination of lisinopril and fixed dose hydrochlorothiazide should be discontinued in case of evident or suspected neutropenia (neutrophils less than 1000 / mm3).
Interactions Which drugs or foods can change the effect of Ensor
Tell your doctor or pharmacist if you have recently taken any other medicines, even those without a prescription.
Interactions between ENSOR tablets, other ACE inhibitors or medicinal products containing hydrochlorothiazide are reported below.
Lisinopril
Clinical trial data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events. such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single agent active on the RAAS system (see Contraindications and Precautions for use).
Diuretics
The addition of a diuretic to the therapy of a patient already being treated with lisinopril usually results in an additional antihypertensive effect.
In patients already being treated with diuretics and especially in those who have only recently started diuretic therapy, the addition of lisinopril may occasionally cause an excessive reduction in blood pressure. The risk of symptomatic hypotension with lisinopril can be minimized by stopping treatment with diuretics before starting treatment with lisinopril (see Precautions for use).
Non-steroidal anti-inflammatory drugs (NSAIDs) including acetylsalicylic acid at a dosage of 3 g / day
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 lead to deterioration of renal function. These effects are generally reversible. Rarely, acute renal failure may occur, especially in patients with impaired renal function, such as the elderly or dehydrated patients.
Other antihypertensive agents
Concomitant administration of these drugs may increase the hypotensive effect of lisinopril. Concomitant administration of nitroglycerin and other nitrates or other vasodilators may further reduce blood pressure.
Tricyclic antidepressants / antipsychotics / anesthetics
Concomitant administration of ACE inhibitors and certain anesthetics, tricyclic antidepressants and antipsychotics may cause a further decrease in blood pressure (see Precautions for use).
Sympathomimetics
Sympathomimetics can reduce the antihypertensive effects of ACE inhibitors; patients should be carefully monitored.
Antidiabetic agents
Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetic medicinal products (insulin, oral hypoglycemic agents) may cause an increase in the blood glucose lowering effect with the risk of hypoglycaemia. This phenomenon appears to be more likely during the first weeks of combined treatment. and in patients with renal impairment.
Nitrates, acetyl-salicylic acid, thrombolytics and / or beta-blockers
Lisinopril can be administered simultaneously with acetylsalicylic acid (cardiological doses), thrombolytics, beta-blockers and / or nitrates.
Allopurinol
Concomitant administration of ACE inhibitors and allopurinol results in an increased risk of renal failure and may lead to an increased risk of leukopenia.
Cyclosporine
Concomitant administration of ACE inhibitors and cyclosporine increases the risk of renal failure and hyperkalaemia.
Lovastatin
Concomitant administration of ACE inhibitors and lovastatin increases the risk of hyperkalaemia.
Procainamide, cytostatic or immunosuppressive drugs
Concomitant use with ACE inhibitors may lead to an increased risk of leukopenia.
Hemodialysis
ENSOR is not indicated for patients requiring dialysis. A high incidence of anaphylactoid reactions has in fact been reported in patients dialysed with high flux membranes and treated concomitantly with an ACE inhibitor. This association should be avoided.
Hydrochlorothiazide
Amphotericin B (parenteral), carbenoxolone, corticosteroids, corticotropin (ACTH) or stimulant laxatives
Hydrochlorothiazide can cause electrolyte imbalance and in particular hypokalaemia.
Calcium salts
When administered concomitantly with thiazide diuretics, they can cause an increase in serum calcium levels following a decrease in excretion.
Cardiac glucosides
The possibility of digitalis toxicity associated with thiazide-induced hypokalaemia increases.
Resins of cholestyramine and colestipol
They can reduce or slow down the absorption of hydrochlorothiazide. For this reason, sulfonamide diuretics should be taken at least one hour before or four to six hours after taking these medicines.
Nondepolarizing muscle relaxants (e.g. tubocurarine chloride)
The effects of these substances can be enhanced by hydrochlorothiazide.
Drugs associated with torsades de pointes
Due to the risk of hypokalaemia, concomitant administration of hydrochlorothiazide and medicinal products that induce "torsades de pointes", such as some antipsychotics and other medicinal products known to cause torsades de pointes, should be used with caution.
Sotalol
Thiazide-induced hypokalaemia may 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 occurred in some patients. Risk factors for hyperkalaemia include renal failure, diabetes mellitus, and concomitant use of potassium-sparing diuretics (eg spironolactone, triamterene and 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 administered with potassium-dispersing diuretics, diuretic-induced hypokalaemia may be improved.
Lithium
Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium and ACE inhibitors. Concomitant use of thiazides may increase the risk of lithium toxicity and increase the already increased lithium toxicity with ACE inhibitors. Administration of Lisinopril during treatment with lithium is not recommended, however if deemed necessary, it should be performed. careful monitoring of serum lithium levels (see Precautions for use).
Trimeterprim
Concomitant administration of ACE inhibitors and thiazides with trimethoprim increases the risk of hyperkalaemia.
Warnings It is important to know that:
In the event of hospitalization, inform the medical staff and in particular the anesthetist, in the event of surgery, of the ongoing treatment with ENSOR. It will also be advisable to inform your dentist if a dental anesthetic is being administered.
The safety and efficacy of ENSOR in children has not been established, therefore the medicine should not be given to children.
The medicine is for personal use only and should never be taken by others.
Pregnancy and breastfeeding
Ask your doctor or pharmacist for advice before taking any medicine.
Pregnancy
ACE inhibitors
The use of ACE inhibitors is not recommended during the first trimester of pregnancy. The use of ACE inhibitors is contraindicated during the second and third trimester of pregnancy (see Contraindications).
ACE inhibitor therapy should not be initiated during pregnancy.
Epidemiological evidence on 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.
For patients planning pregnancy, the physician should be informed immediately as alternative antihypertensive treatments with a proven safety profile for use in pregnancy should be used, unless continued therapy with a drug is considered essential. ACE inhibitor When pregnancy is diagnosed, physicians should be informed immediately as treatment with ACE inhibitors should be stopped immediately and, if appropriate, alternative therapy should be started.
Should exposure to an ACE inhibitor have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Neonates whose mothers have taken ACE inhibitors should be closely monitored for hypotension ( see Contraindications).
Hydrochlorothiazide:
There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient.
Hydrochlorothiazide crosses the placenta. Based on its mechanism of action, the use of hydrochlorothiazide during the second and third trimester of pregnancy can compromise fetal placental perfusion and can cause fetal and neonatal effects such as jaundice, electrolyte disturbances and thrombycytopenia.
Hydrochlorothiazide should not be used for the treatment of gestational edema, 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 the treatment of hypertension in pregnant women except in rare situations where no other treatment could be used.
Feeding time
ACE inhibitors:
Since no data are available regarding the use of ACE inhibitors during lactation, ENSOR is not recommended and alternative treatments with a proven safety profile for use during lactation are preferred, especially when nursing a newborn or preterm infant. .
Hydrochlorothiazide
Hydrochlorothiazide is excreted in breast milk in small quantities. High-dose thiazide diuretics cause intense diuresis which can inhibit milk production. The use of ENSOR while breastfeeding is not recommended. If ENSOR is taken during breastfeeding, doses should be kept as low as possible.
Effects on ability to drive and use machines
When driving vehicles or machines it should be taken into account that dizziness or tiredness may occur. This can happen at the beginning of the treatment or when the dose is changed or in case of concomitant alcohol intake; these effects vary in each case according to the individual sensitivity. It is however preferable not to carry out these activities, which require particular attention, until when it is not known how the drug is tolerated.
For those who carry out sporting activities
The use of the drug without therapeutic necessity constitutes doping and can in any case determine positive anti-doping tests.
Dosage and method of use How to use Ensor: Dosage
You should follow your doctor's instructions regarding how and how often you take the tablets.
Take the tablets with a little water, at about the same time, preferably early in the morning.
Improved health should not lead to discontinuation of treatment, unless requested by the doctor.
Essential hypertension
The usual dosage is one tablet administered once a day. In general, if the desired therapeutic effect is not achieved within 2-4 weeks, the dosage can be increased to 2 tablets administered in a single daily dose.
Dosage in renal insufficiency
Thiazides may be inappropriate diuretics for use in patients with renal impairment and are ineffective at creatinine clearance values of 30 ml / min or less (ie in the presence of moderate or severe renal impairment). ENSOR should not be used as therapy. in patients with renal insufficiency In patients with creatinine clearance> 30 and <80 ml / min ENSOR should only be used after titration of the individual components.
When used alone, the recommended starting dose of lisinopril in mild renal insufficiency is 5-10 mg.
Previous diuretic therapy
Symptomatic hypotension may occur after the initial dose of ENSOR; this is more likely to occur in hypovolaemic and / or sodium-depleted patients as a result of previous diuretic therapy. Diuretic therapy should be suspended for 2-3 days before starting ENSOR therapy. If this is not possible, treatment should be started with lisinopril alone, at a dose of 5 mg.
Children
The safety and efficacy of ENSOR in children has not been established.
Use in the elderly
The efficacy and tolerability of the product in the elderly do not differ from that in adults and therefore no dose adjustments are necessary.
Overdose What to do if you have taken too much Ensor
What to do if you have forgotten to take one or more doses.
In the event that, due to forgetfulness, the intake of a dose is omitted, it is necessary to continue the therapy according to the scheduled frequency without taking any additional dose.
No specific information is available regarding the treatment of lisinopril / hydrochlorothiazide overdose.
Treatment is symptomatic and supportive. ENSOR therapy should be discontinued immediately and the patient kept under close observation. Therapeutic measures depend on the nature and severity of the symptoms. Measures should be taken to prevent absorption and to accelerate the elimination of the medicinal product.
Suggested measures include induction of vomiting and / or gastric lavage if ingestion is recent while correction of dehydration, electrolyte imbalance and hypotension should be done according to usual procedures.
Lisinopril
Limited clinical data are available regarding overdose in humans. Symptoms associated with ACE inhibitor overdose may include hypotension, circulatory shock, electrolyte disturbance, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety and cough. In the event of an overdose, treatment with an intravenous infusion of normal physiological solution is recommended.
In case of severe hypotension the patient should be placed in the shock position. Treatment with angiotensin II (if available) by infusion and / or intravenous catecholamines may be considered. If ingestion is recent, measures should be put in place to prevent absorption of lisinopril (such as vomiting, gastric lavage, administration of adsorbents and sodium sulphate). Lisinopril can be removed from the circulation by hemodialysis (see Special warnings). Pacemaker therapy is indicated for therapy resistant bradycardia. Avoid using high-flux polyacrylonitrile dialysis membranes. Vital signs, serum electrolytes, and creatinine concentration should be monitored frequently.
Hydrochlorothiazide
The most commonly observed signs and symptoms are those caused by electrolyte depletion (hypokalaemia, hypochloremia, hyponatremia) and dehydration as a result of excessive diuresis.
If digitalis has also been administered, hypokalaemia may accentuate cardiac arrhythmias.
In case of accidental ingestion / intake of an excessive dose of ENSOR, notify your doctor immediately or go to the nearest hospital.
If you have any questions about the use of ENSOR, ask your doctor or pharmacist.
Side Effects What are the side effects of Ensor
Like all medicines, ENSOR can cause side effects, although not everybody gets them. The following undesirable effects have been observed and reported during treatment with lisinopril and hydrochlorothiazide with the following frequencies: very common (≥1 / 10), common (≥1 / 100,
Disorders of the blood and lymphatic system
- Rare: anemia.
- Very rare: bone marrow depression, thrombocytopenia, leukopenia, agranulocytosis, haemolytic anemia.
Metabolism and nutrition disorders
- Not common: gout.
- Rare: hyperglycemia, hypokialiemia, hyperuricaemia, hyperkalaemia.
Nervous system disorders and psychiatric disorders
- Common: dizziness, which usually responds to dose reduction and only rarely requires discontinuation of therapy, headache, fatigue
- Uncommon: paraesthesia, anesthesia.
Cardiac and vascular diseases
- Common: hypotension (including orthostatic hypotension).
- Uncommon: palpitations, chest pain, muscle spasms and muscle weakness.
Respiratory, thoracic and mediastinal disorders
- Common: persistent dry cough, which disappears when therapy is discontinued.
Gastrointestinal disorders
- Uncommon: diarrhea, nausea, vomiting, indigestion, pancreatitis, dry mouth.
- Very rare: intestinal angioedema.
Hepatobiliary disorders
- Very rare: both hepatocellular and cholestatic hepatitis, jaundice, hepatic failure. Cases of hepatitis have very rarely been reported to have progressed to hepatic failure in some patients. Patients receiving ENSOR who experience jaundice or marked elevation of liver enzymes should discontinue treatment with ENSOR and receive appropriate medical supervision.
Skin and subcutaneous tissue disorders
- Common: skin rash.
- Rare: hypersensitivity / angioneurotic edema: angioneurotic edema of the face, extremities, lips, tongue, glottis and / or larynx.
- Very rare: cutaneous pseudolymphoma.
Complex symptoms have been reported which may include one or more of the following: fever, vasculitis, myalgia, arthralgia / arthritis, antinuclear antibody (ANA) positivity, increased erythrocyte sedimentation rate (ESR), eosinophilia and leukocytosis, rash, photosensitivity and other dermatological manifestations.
Musculoskeletal and connective tissue disorders
- Common: muscle cramps.
- Rare: muscle weakness.
Diseases of the reproductive system and breast
- Uncommon: impotence.
General disorders and administration site conditions
- Uncommon: chest tightness.
Others
A symptom complex that includes one or more of the following symptoms: fever, vasculitis, myalgia, arthralgia or arthritis, positive ANA test, increased ESR, eosinophilia, leukocytosis, rash, photosensitivity or other dermatological manifestations.
Diagnostic tests
Clinically important alterations in laboratory parameters have rarely occurred. Hyperglycaemia, hyperuricaemia, hyperkalaemia or hypokalaemia have occasionally been observed. An increase in blood cholesterol and triglyceride concentrations is possible during treatment with thiazides. Mild increases in blood urea nitrogen and blood creatinine have usually been seen in patients with no signs of pre-existing renal impairment. If such increases occur, they are usually reversible after discontinuation of treatment. Bone marrow depression, usually manifesting as anemia, has been reported. and / or thrombocytopenia and / or leukopenia. There have been rare reports of agranulocytosis: however, it has not been possible to determine a clear connection with the combination drug. Slight decreases in hemoglobin and hematocrit have frequently been reported in hypertensive patients, but they have rarely been of clinical importance unless there was "another cause of anemia". Elevations of liver enzymes and / or serum bilirubin have rarely occurred, but a causal relationship with lisinopril / hydrochlorothiazide has not been established.
There have been rare reports of haemolytic anemia.
Other side effects that have been reported with the components and which may be potential side effects of ENSOR are:
Hydrochlorothiazide:
Infections and infestations: Sialadenitis.
Blood and lymphatic system disorders: leukopenia, neutropenia / agranulocytosis, thrombocytopenia, aplastic anemia, haemolytic anemia, bone marrow depression.
Metabolism and Nutrition Disorders: Anorexia, hyperglycemia, glycosuria, hyperuricaemia, electrolyte imbalance (including hyponatremia and hypokalaemia, elevated cholesterol and triglycerides).
Psychiatric disorders: agitation, depression, sleep disturbances.
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: necrotizing angiitis (vasculitis, cutaneous vasculitis).
Respiratory, thoracic and mediastinal disorders: Respiratory distress (including pneumonia and pulmonary edema).
Gastrointestinal disorders: gastric irritation, diarrhea, constipation, pancreatitis.
Hepatobiliary disorders: jaundice (intrahepatic cholestatic jaundice).
Skin and subcutaneous tissue disorders: Photosensitivity reactions, rash, lupus erythematosus-like skin reactions, reactivation of cutaneous lupus erythematosus, urticaria, anaphylactic reactions, toxic epidermal necrolysis.
Musculoskeletal, connective tissue disorders: muscle spasms
Renal and urinary disorders: renal dysfunction, interstitial nephritis.
General Disorders and Administration Site Conditions: Fever, weakness.
Lisinopril and other ACE inhibitors:
Disorders of the blood and lymphatic system:
Rare: decrease in hemoglobin, decreases in hematocrit.
Very rare: bone marrow depression, anemia, thrombocytopenia, leukopenia, neutropenia, agranulocytosis, haemolytic anemia, lymphadenopathy, autoimmune diseases.
Metabolism and nutrition disorders
Very rare: hypoglycaemia
Nervous system disorders and psychiatric disorders:
Common: dizziness, headache
Uncommon: mood changes, paraesthesia, dizziness, taste disturbances, sleep disturbances.
Rare: mental confusion
Cardiac and vascular disorders:
Common: orthostatic effects (including hypotension)
Uncommon: myocardial infarction or cerebrovascular event, possibly secondary to excessive hypotension in high-risk patients, 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: diarrhea, vomiting
Uncommon: nausea, abdominal pain and indigestion
Rare: dry mouth
Very rare: pancreatitis, intestinal angioedema; both hepatocellular and cholestatic hepatitis, jaundice and liver failure
Skin and subcutaneous tissue disorders:
Uncommon: rash, pruritus
Rare: hypersensitivity / angioneurotic edema: angioneurotic edema of the face, extremities, lips, tongue, glottis, and / or larynx, urticaria, alopecia, psoriasis
Very rare: diaphoresis, pemphigus, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme. Symptoms have been reported which may include one or more of the following: fever, vasculitis, myalgia, arthralgia / arthritis, antinuclear antibody positive (ANA), increased erythrocyte sedimentation rate, eosinophilia and leukocytosis, rash, photosensitivity or other dermatological manifestations may occur .
Renal and urinary disorders
Common: renal dysfunction
Rare: uremia, acute renal failure.
Very rare: oliguria / anuria
Reproductive system and breast disorders:
Uncommon: impotence
Rare: gynecomastia
General disorders and administration site conditions:
Uncommon: fatigue, asthenia
Diagnostic tests:
Uncommon: blood urea increased, serum creatinine increased, liver enzymes increased, hyperkalaemia.
Rare: increased serum bilirubin, hyponatremia.
Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse
By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Expiry: see the expiry date printed on the package.
The expiry date indicated is intended for the product in intact packaging, correctly stored.
Warning: do not use the medicine after the expiry date which is stated on the blister and carton.
Special precautions for storage
The tablets should be stored in their packaging to keep them away from light.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
KEEP THE MEDICINAL PRODUCT OUT OF THE REACH AND SIGHT OF CHILDREN
COMPOSITION
Each tablet contains
Active principles: lisinopril dihydrate 21.78 mg (equivalent to 20 mg of anhydrous lisinopril) + 12.5 mg hydrochlorothiazide.
Excipients: Mannitol (E421), dibasic calcium phosphate dihydrate, maize starch, pregelatinised starch, magnesium stearate (E572).
PHARMACEUTICAL FORM AND CONTENT
Tablets Blister pack containing 14 tablets of 20 mg + 12.5 mg
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
ENSOR 20 MG + 12.5 MG TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains:
Active principles: lisinopril dihydrate 21.78 mg (equivalent to 20 mg of anhydrous lisinopril) + 12.5 mg hydrochlorothiazide.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Tablets
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
ENSOR is indicated for the treatment of essential hypertension in patients for whom combination therapy is appropriate.
04.2 Posology and method of administration
Essential hypertension
The usual dosage is one tablet administered once a day. As with other drugs given once a day, ENSOR should be taken at approximately the same time.
In general, if the desired therapeutic effect is not achieved within 2-4 weeks, the dosage can be increased to 2 tablets administered in a single daily dose.
Dosage in renal insufficiency
Thiazides may be inappropriate diuretics for use in patients with renal impairment and are ineffective at creatinine clearance values of 30 ml / min or less (ie in the presence of moderate or severe renal impairment). ENSOR should not be used as therapy. initial in patients with renal insufficiency.
In patients with creatinine clearance> 30 and titration of the individual components.
When used alone, the recommended starting dose of lisinopril in mild renal insufficiency is 5-10 mg.
Previous diuretic therapy
Symptomatic hypotension may occur after the initial dose of ENSOR; this is more likely to occur in hypovolaemic and / or sodium-depleted patients as a result of previous diuretic therapy. Diuretic therapy should be suspended for 2-3 days before starting ENSOR therapy. If this is not possible, treatment should be started with lisinopril alone, at a dose of 5 mg.
Children
The safety and efficacy of ENSOR in children has not been established.
Use in the elderly
In clinical studies, the efficacy and tolerability of lisinopril and hydrochlorothiazide administered together were similar in both the elderly and younger hypertensive patients.
Lisinopril, within a daily dosage range of 20-80 mg, was equally effective in elderly (65 years or older) and non-elderly hypertensive patients. In elderly hypertensive patients, lisinopril monotherapy was as effective in reducing diastolic blood pressure as that with hydrochlorothiazide or atenolol.
In clinical studies, age did not affect the tolerability of lisinopril.
04.3 Contraindications
Anuria.
Hypersensitivity to the active substances or to any of the excipients. History of angioedema related to previous treatment with angiotensin converting enzyme inhibitors and in patients with hereditary or idiopathic angioedema.
Hypersensitivity to other sulfonamide-derived drugs.
Second and third trimester of pregnancy (see section 4.6).
04.4 Special warnings and appropriate precautions for use
Hypotension and water / electrolyte imbalance
As with all antihypertensive therapies, symptomatic hypotension may occur in some patients. This has rarely been observed in patients with uncomplicated hypertension, but is more likely in the presence of fluid or electrolyte imbalance, eg. decreased volume, hyponatremia, hypochloraemic alkalosis, hypomagnesaemia or hypokalaemia, changes that may occur due to previous diuretic therapy, dietary salt restriction, dialysis or during intercurrent episodes of diarrhea or vomiting. In such patients, periodic checks of serum electrolytes should be performed at appropriate intervals.
In patients at risk for symptomatic hypotension, initiation of therapy and dose adjustment should be carefully monitored.
Particular consideration must be given when the therapy is administered to patients with heart disease or ischemic cerebropathy, since an excessive drop in blood pressure could cause a myocardial infarction or a cerebrovascular event.
If hypotension occurs, the patient should be placed in a supine position and, if necessary, infused with saline intravenously. A transient hypotensive response is not a contraindication to further doses of the drug. By restoring effective blood volume and arterial pressure, therapy can be re-established at a reduced dosage; otherwise it is possible to use one or the other member of the association individually.
As with other vasodilators, ENSOR should be administered with caution to patients with aortic stenosis or hypertrophic cardiomyopathy.
Surgery / anesthesia
In patients undergoing major surgery or during anesthesia with agents that produce hypotension, lisinopril may block angiotensin II formation secondary to compensatory renin release. If hypotension attributable to this mechanism occurs, this can be corrected by volume expansion.
Impaired renal function
Thiazides may not be the appropriate diuretics in the treatment of patients with renal impairment and are ineffective at creatinine clearance values of 30 ml / min or less (i.e. in the presence of moderate or severe renal impairment).
ENSOR should not be administered to patients with renal insufficiency (creatinine clearance ≤ 80 ml / min) until titration of the individual components has first demonstrated the need for the dosages present in the combination tablet.
In some patients with bilateral renal artery stenosis or monorene renal artery stenosis, increases in blood urea nitrogen and creatinine have been observed with angiotensin converting enzyme (ACE) inhibitors, usually reversible after discontinuation of therapy. This is especially true in patients with renal insufficiency. If renovascular hypertension is also present, there is an increased risk of severe hypotension and renal insufficiency. In these patients, treatment should be initiated under close medical supervision at low doses and after adequate dose titration. Since diuretic treatment may contribute to the above, renal function should be monitored during the first 4 weeks of therapy with ENSOR.
Some hypertensive patients with no apparent vascular renal disease have developed usually mild and transient elevations in blood urea nitrogen and creatinine when lisinopril was administered concomitantly with a diuretic. If this occurs during therapy with ENSOR the combination should be suspended. Restoration of therapy is possible at a reduced dosage or both components can be used appropriately alone.
In patients with severe heart failure whose renal function may be dependent on the renin-angiotensin-aldosterone system, treatment with ACE inhibitors may be associated with oliguria and / or progressive azotaemia and, rarely, with acute renal failure and / or death. In these patients, treatment with ACE inhibitors should be introduced with particular caution.
Hepatopathy
Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, as minimal alterations in the water-electrolyte balance can precipitate hepatic coma.
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 ENSOR. This can happen at any time during therapy. In such cases, ENSOR administration should be discontinued promptly and appropriate monitoring instituted to ensure complete remission of symptoms before the patient is discharged. Even in those cases where swelling only affects the tongue without respiratory distress, patients should be observed for an extended period as treatment with antihistamines and corticosteroids may not be sufficient. Fatal events due to angioedema associated with edema of the larynx or tongue have been reported very rarely. Airway obstruction may occur in patients with involvement of the tongue, glottis, or larynx, especially in people with a history of airway surgery. In these cases, emergency therapy should be given promptly. This may include the administration of epinephrine and / or measures to maintain a patent airway. The patient should be kept under close medical observation until complete and persistent resolution of symptoms. Conversion enzyme inhibitors (ACE inhibitors) cause angioedema more frequently 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 taking an ACE inhibitor (see section 4.3).
In patients taking thiazides, sensitivity reactions may occur with or without a history of allergic episodes or bronchial asthma. Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazides.
Metabolic and endocrine effects
Thiazide therapy can impair glucose tolerance; therefore, adjustment of the dosage of antidiabetic agents, including insulin, may be necessary.
Thiazides may decrease urinary calcium excretion and cause mild and intermittent increases in calcium. Marked hypercalcaemia may reveal asymptomatic hyperparathyroidism. Thiazide therapy must be discontinued before parathyroid function tests are performed.
Increases in cholesterol and triglyceride levels have been associated with diuretic therapy with thiazides.
In some patients, treatment with thiazides can precipitate hyperuricaemia and / or gout. Lisinopril may, however, induce an increase in uric acid in the urine and consequently attenuate the hyperuricaemic effect of hydrochlorothiazide.
Desensitization
Patients who received ACE inhibitors during a desensitizing treatment (eg hymenoptera venom) have suffered from anaphylactoid reactions. In the same patients these reactions were avoided when the ACE inhibitor was temporarily withdrawn, but they reappeared after the drug was inadvertently re-administered.
Hemodialysis patients
The use of ENSOR is not indicated in patients requiring dialysis for renal insufficiency.
Anaphylactotide reactions have been reported in patients undergoing certain hemodialysis procedures (e.g. with high flux membranes AN 69 and during low density lipoprotein (LDL) apheresis performed with dextran sulfate columns) treated concomitantly with ACE inhibitors. The use of different types of dialysis membranes or different types of antihypertensive agents should be considered for these patients.
Race
Conversion enzyme inhibitors (ACE inhibitors) cause angioedema more frequently in black patients than in non-black patients.
Cough
Cough has been reported with the use of ACE inhibitors. This is characteristically nonproductive, persistent and resolves upon discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.
Neutropenia and agranulocytosis
Agranulocytosis and other changes in blood count have been reported with other converting enzyme inhibitors more frequently in subjects with renal impairment, especially if accompanied by collagen disease and in those receiving immunosuppressive therapy.
Data from clinical trials are insufficient to rule out that lisinopril does not cause agranulocytosis. Rare cases of leukopenia / neutropenia and bone marrow depression have been reported in post-marketing experience, in which a causal relationship with lisinopril cannot be excluded. In patients with vascular collagen disorders and renal disease should be considered. periodic monitoring of white blood cell counts and patients themselves should be advised to immediately report any indications of infection which may be signs of neutropenia.
Aortic stenosis / hypertrophic cardiomyopathy. ACE inhibitors should be used with extreme caution.
04.5 Interactions with other medicinal products and other forms of interaction
Potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes
The potassium depletion induced by thiazide diuretics is usually attenuated by the potassium-sparing effect of lisinopril.
The use of potassium supplements, potassium-sparing agents or potassium-containing salt substitutes may lead to a significant increase in serum potassium, especially in patients with impaired renal function. If concomitant use of ENSOR and any of these agents considered appropriate, they should be used with caution and with frequent monitoring of serum potassium.
Lithium
Lithium should generally not be given with diuretics or ACE inhibitors.
Diuretic agents and ACE inhibitors reduce the renal clearance of lithium, leading to a high risk of its toxicity. Before using lithium-containing products, review their Summary of Product Characteristics.
Gold
Nitritoid reactions (symptoms of vasodilation including flushing, nausea, dizziness and hypotension, which can be very severe) have been reported more frequently in patients treated with ACE inhibitors following administration of injectable gold (e.g. sodium aurothiomalate).
Other antihypertensive agents
Concomitant use of these drugs may enhance the antihypertensive effect.
Other drugs
Co-administration with NSAIDs: When ACE inhibitors are administered simultaneously with non-steroidal anti-inflammatory drugs (eg selective COX2 inhibitors, acetylsalicylic acid starting at 325 mg / day and non-selective NSAIDs), "attenuation" may occur. of the anti-hypertensive effect.
Concomitant use of ACE inhibitors and NSAIDs may lead to an increased risk of worsening of renal function including possible acute renal failure and increased serum potassium levels especially in patients with pre-existing impaired renal function. The combination should be administered. with caution especially in the elderly. Patients should be adequately hydrated and monitoring of renal function should be considered at the initiation of concomitant therapy.
Thiazides can increase sensitivity to tubocurarine.
Allopurinol, cytostatic and immunosuppressive agents when given together with ACE inhibitors may increase the risk of leukopenia.
Potential drug interactions
Other antihypertensive agents: additive effects may occur.
When administered together, the following drugs may interact with thiazide diuretics: Alcohol-Barbiturates-Narcotics: Potentiation of the pressure drop in standing position may occur. Antidiabetic drugs (oral agents and insulin): Dosage adjustment of antidiabetic drugs may be required.
Corticosteroids, ACTH: intensified electrolyte depletion especially hypokalaemia.
Pressor amines (eg adrenaline): a decreased response to pressor amines is possible, but not such as to preclude their use.
Non-steroidal anti-inflammatory drugs (NSAIDs): in some patients the administration of NSAIDs may decrease the diuretic, natriuretic and antihypertensive effect of diuretics.
04.6 Pregnancy and lactation
Use in pregnancy
ENSOR is contraindicated in the second and third trimester of pregnancy (see section 4.3). The use of ENSOR is not recommended during the first trimester of pregnancy. If pregnancy is established, administration of lisinopril should be stopped as soon as possible.
ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to women during the second and third trimester of pregnancy. The use of ACE inhibitors during this period has been associated with fetal and neonatal damage including hypotension, renal failure, hyperkalaemia and / or cranial hypoplasia of the newborn. Maternal oligohydramniosis has occurred, presumably representing decreased renal function of the fetus. and which can result in limb contracture, craniofacial deformations and hypoplastic lung development.
In those rare cases where use during pregnancy is considered essential, serial ultrasound scans should be performed in the event of exposure to ENSOR during the second or third trimester of pregnancy to check for intra-amniotic conditions. In the event that oligohydramniosis is found, lisinopril should be discontinued unless considered lifesaving for the mother.
Doctors and patients must be aware, however, that oligohydramniosis can also be evident only after irreversible damage to the fetus has been established.
Infants whose mothers have taken lisinopril should be closely observed for hypotension, oliguria and hyperkalaemia.
Lisinopril, which crosses the placenta, has been removed from the neonatal circulation by intraperitoneal dialysis with some clinical benefit and can theoretically be removed by plasmapheresis. These adverse reactions to the embryo and fetus do not appear to occur from ACE inhibitor exposure limited to the first trimester. A retrospective epidemiological study has suggested that maternal exposure to angiotensin converting enzyme inhibitors during the first trimester of pregnancy, can lead to an increased risk of malformations, particularly on the cardiovascular and central nervous systems. If lisinopril is used during the first trimester of pregnancy, patients should be informed of the potential risks to the fetus.
Continued use of diuretics in healthy pregnant women is not recommended and exposes mother and fetus to unnecessary risk including neonatal jaundice, thrombocytopenia and other adverse reactions that have been reported in adults are also possible.
There is no experience with the removal of placenta-crossing hydrochlorothiazide from the neonatal circulation.
Feeding time
It is not known whether lisinopril is excreted in human milk; however, thiazides pass into breast milk. Because of the possible serious reactions caused by hydrochlorothiazide in breastfed babies, a decision must be made whether it is more appropriate to discontinue breastfeeding or ENSOR, taking into account the importance of the drug to the mother.
04.7 Effects on ability to drive and use machines
When driving vehicles or machines it should be taken into account that dizziness or tiredness may occur.
04.8 Undesirable effects
Clinical studies
ENSOR is generally well tolerated. In clinical studies, undesirable effects were generally mild and transient in nature; in most cases it was not necessary to interrupt therapy. The undesirable effects that were observed were limited to those previously reported with lisinopril or hydrochlorothiazide.
One of the most frequent clinical side effects was dizziness which generally responded to dose reduction and rarely required discontinuation of therapy.
Other undesirable effects were: headache, dry cough, fatigue and hypotension including orthostatic hypotension.
Even less common were: diarrhea, nausea, vomiting, dry mouth, rash, gout, palpitations, chest discomfort, muscle cramps and weakness, paraesthesia, asthenia, impotence, acute renal failure and syncope.
Post Marketing
The following undesirable effects have been observed and reported during treatment with lisinopril and hydrochlorothiazide with the following frequencies: very common (≥ 10%), common (≥ 1%,
Disorders of the blood and lymphatic system
Rare: anemia.
Very rare: bone marrow depression, thrombocytopenia, leukopenia, agranulocytosis, haemolytic anemia.
Metabolism and nutrition disorders
Uncommon: gout.
Rare: hyperglycemia, hypokalaemia, hyperuricaemia, hyperkalaemia.
Nervous system and psychiatric disorders
Common: dizziness, headache, paraesthesia.
Cardiac and vascular disorders
Common: orthostatic effects (including hypotension).
Uncommon: palpitations.
Respiratory, chest and mediastinal disorders
Common: cough.
Gastrointestinal disorders
Common: diarrhea, nausea, vomiting.
Uncommon: dry mouth.
Rare: pancreatitis.
Very rare: intestinal angioedema.
Hepatobiliary disorders
Very rare: both hepatocellular and cholestatic hepatitis, jaundice, hepatic failure. Cases of hepatitis have very rarely been reported to have progressed to hepatic failure in some patients. Patients receiving ENSOR who experience jaundice or marked elevation of liver enzymes should discontinue treatment with ENSOR and receive appropriate medical supervision.
Disorders of the skin and subcutaneous tissue
Common: rash.
Rare: hypersensitivity / angioneurotic edema: angioneurotic edema of the face, extremities, lips, tongue, glottis and / or larynx (see section 4.4).
Very rare: cutaneous pseudolymphoma.
Complex symptoms have been reported which may include one or more of the following: fever, vasculitis, myalgia, arthralgia / arthritis, antinuclear antibody (ANA) positivity, increased erythrocyte sedimentation rate (ESR), eosinophilia and leukocytosis, rash, photosensitivity and other dermatological manifestations.
Musculoskeletal disorders of connective tissue and bones
Common: muscle cramps.
Rare: muscle weakness.
Disorders of the reproductive system and breasts
Common: impotence.
General and administration site disorders
Common: fatigue, asthenia.
Uncommon: chest tightness.
Laboratory tests
Common: increased blood urea, increased serum creatinine, increased liver enzymes, decreased hemoglobin.
Uncommon: decreased hematocrit.
Rare: increase in serum bilirubin.
Other side effects that have been reported with the components and which may be potential side effects of ENSOR are:
Hydrochlorothiazide
Anorexia, gastric irritation, constipation, jaundice (intrahepatic colostatic jaundice), pancreatitis, sialadenitis, vertigo, xanthopsia, leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia, haemolytic anemia, purpura, photosensitivity, urticaria, cutaneous angiitis, vasculitis (vasculitis) , exanthema, respiratory distress including pneumonia and pulmonary edema, anaphylactic reactions, hyperglycaemia, glucosuria, hyperuricaemia, electrolyte imbalances including hyponatremia, hypomagnesaemia, muscle spasm, agitation, transient blurred vision, renal dysfunction and interstitial nephritis.
In very rare cases, Stevens-Johnson syndrome may arise.
In isolated cases: hypochloraemic alkalosis, hypercalcemia, the latter making diagnostic tests necessary to highlight a possible hyperparathyroidism. Cardiac arrhythmias and orthostatic hypotension are possible, possibly enhanced by alcohol, barbiturates, hypnotics and sedatives.
Lisinopril
Myocardial infarction or cerebrovascular event possibly secondary to excessive hypotension in high risk patients, tachycardia, abdominal pain and indigestion, mood changes, mental confusion and dizziness; as with other ACE inhibitors, changes in taste and sleep disturbances have been reported; bronchospasm, rhinitis, sinusitis, alopecia, urticaria, diaphoresis, pruritus, psoriasis and severe skin changes including pemphigus, toxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme; hyponatremia, uremia, oliguria / anuria, renal dysfunction, acute renal failure, pancreatitis, hepatitis (hepatocellular or colostatic) and jaundice. Very rarely, the development of hepatitis as an undesirable effect has been reported in some patients to progress to liver failure. Patients receiving ENSOR who develop jaundice or marked elevation of liver enzymes should discontinue ENSOR and receive appropriate medical treatment. Haemolytic anemia has been reported rarely.
04.9 Overdose
No specific information is available regarding the treatment of an overdose of ENSOR.
Treatment is symptomatic and supportive. ENSOR therapy should be discontinued and the patient closely observed. Therapeutic measures depend on the nature and severity of the symptoms. Measures should be taken to prevent absorption and to accelerate elimination of the drug.
Lisinopril
The most relevant effects of overdose are hypotension, electrolyte disturbances and renal insufficiency. In the event of severe hypotension, the patient should be placed in the shock position and rapidly administered saline by intravenous infusion. Treatment with angiotensin II (if available) may be considered. Angiotensin converting enzyme inhibitors can be removed from the circulation by hemodialysis. Avoid using high flux polyacrylonitrile dialysis membranes. Serum electrolytes and creatinine should be monitored frequently.
Hydrochlorothiazide
The most commonly observed signs and symptoms are those caused by electrolyte depletion (hypokalaemia, hypochloremia, hyponatremia) and dehydration as a result of excessive diuresis.
If digitalis has also been administered, hypokalaemia may accentuate cardiac arrhythmias.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: ACE inhibitors, combinations - ACE inhibitors and diuretics. ATC code: C09BA03. ENSOR is the fixed-dose combination of lisinopril an angiotensin converting enzyme (ACE) inhibitor and hydrochlorothiazide, a thiazide diuretic. Both components have complementary mechanisms of action and exert an additive antihypertensive effect.
When combined with other antihypertensive agents, a further decrease in blood pressure may occur.
Lisinopril is a peptidyl dipeptidase inhibitor which catalyzes the conversion of angiotensin I to angiotensin II vasoconstrictor peptide.
Angiotensin II also stimulates the secretion of aldosterone by the adrenal cortex. Inhibition of ACE results in a reduction in angiotensin II concentrations resulting in decreased vasopressor activity and aldosterone secretion. elevation of serum potassium concentration.
Although the mechanism by which lisinopril lowers blood pressure appears to be primarily the suppression of the renin-angiotensin-aldosterone system, lisinopril is also effective 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, play a role in the therapeutic effect of lisinopril.
Hydrochlorothiazide is a diuretic and antihypertensive agent. It exerts its antihypertensive action on the electrolytic reabsorption mechanism of the distal renal tubule and increases the excretion of chlorides and sodium to an equivalent extent. Natriuresis can be accompanied by loss of potassium and bicarbonates. The mechanism of the antihypertensive effect of thiazide diuretics is not known. Thiazides do not usually affect normal blood pressure. Concomitant administration of other antihypertensive drugs results in an additive reduction in blood pressure.
05.2 "Pharmacokinetic properties
Concomitant administration of lisinopril and hydrochlorothiazide has little or no effect on the bioavailability of either drug. The pre-established association is bioequivalent to the two drugs administered simultaneously.
Absorption
After oral administration of lisinopril peak plasma concentrations are observed within 7 hours, with a slight delay in patients with acute myocardial infarction. Based on urinary recovery, the extent of absorption of lisinopril is approximately 25%, with interpatient variability of 6-60% at all doses tested (5-80 mg). Absolute bioavailability is reduced by approximately 16% in patients with heart failure. Absorption of lisinopril is not affected by food.
Distribution
Lisinopril does not appear to be bound to other plasma proteins other than circulating ACE. Studies in rats indicate that lisinopril crosses the blood brain barrier poorly.
Elimination
Lisinopril is not metabolised and is excreted completely unchanged by the kidney. After multiple doses, lisinopril exhibits a storage half-life of 12.6 hours. The clearance of lisinopril in healthy subjects is approximately 50 ml / min. The decrease in serum concentrations shows a prolonged terminal phase that does not contribute to drug accumulation. This terminal phase probably represents the saturable binding at the ACE level and is not proportional to dose.
Hepatic insufficiency
Impaired liver function in cirrhotic patients leads to a decrease in the absorption of lisinopril (approximately 30% based on urinary recovery), but an increase in exposure (approximately 50%) compared to healthy subjects, due to a decrease clearance.
Kidney failure
Impaired renal function reduces the elimination of lisinopril, which is excreted by the kidney, but this reduction becomes clinically important only when the glomerular filtration rate is less than 30 ml / min.
Pharmacokinetic parameters of lisinopril in relation to renal function in different patient groups after administration of a multiple of the 5 mg dose.
With a creatinine clearance of 30-80 mL / min, the mean AUC increased by only 13%, while a 4-5 fold increase was observed with creatinine clearance 5-30 mL / min.
Lisinopril can be removed by dialysis. During a 4-hour hemodialysis, plasma concentrations of lisinopril decrease on average by 60% with a dialysis clearance between 40 and 55 ml / min.
Heart failure
Compared to healthy subjects, heart failure patients have a higher exposure to lisinopril (an average increase in AUC of 125%), but based on urinary recovery of lisinopril, a reduction in absorption of approximately 16% is noted. .
Senior citizens
Compared to young subjects, elderly patients have increases in blood concentrations and AUC (approximate 60% increase).
Hydrochlorothiazide
With monitoring of plasma levels for at least 24 hours, the plasma half-life was observed to vary in the range of 5.6-14.8 hours.
At least 61% of the oral dose is eliminated unchanged within 24 hours. After oral administration of hydrochlorothiazide the diuretic effect begins within 2 hours, peaks in approximately 4 hours and lasts for 6 to 12 hours. Hydrochlorothiazide crosses the placental but not the blood brain barrier.
05.3 Preclinical safety data
Lisinopril
The safety of lisinopril has been extensively studied in laboratory animals. The oral LD 50 of lisinopril was greater than 20 g / kg in mice and rats.
It appears that the toxicity of lisinopril in rats and dogs is mainly related to an exasperation of the pharmacological effects. There was a large gap between the therapeutic dose for humans and the toxic doses for animals.
The ratio of the non-toxic dose for dogs (5 mg / kg / day) to that recommended for humans of 40 mg / day was 6 times higher in this sensitive species.
In humans, with a dose of 40 mg / day, a maximum plasma concentration of 468 ng / ml was reached, significantly lower than the 11,370 ng / ml plasma level determined by a nephrotoxic dose in dogs.
The main signs of toxicity in dogs were related to impaired renal function (elevated BUN and creatinine levels), sometimes associated with renal tubular degeneration. The latter was not observed in rats, although increases in azotemia were noted. These changes in renal function probably represent pre-renal changes in drug-induced azotaemia related to the pharmacological activity of lisinopril. An additional saline intake improves or prevents the toxicity of lisinopril in rats as well as dogs, further supporting the hypothesis of a mechanism-based toxicity.
Carcinogenesis, mutagenesis and fertility studies
There was no evidence of oncogenic effects when lisinopril was administered to male and female rats for 105 weeks at doses up to 90 mg / kg / day (approximately 110 times the maximum recommended human daily dose). Lisinopril was also administered to 92 weeks in mice (male and female) at doses up to 135 mg / kg / day (approximately 170 times the maximum recommended human daily dose) and showed no signs of carcinogenicity. Lisinopril did not show mutagenic properties in the Ames microbial mutagenic assay with or without metabolic activation. It was negative in an "early mutation assay using Chinese hamster lung cells. Lisinopril did not produce DNA single strand breaks in an" in vitro alkaline elution assay in rat hepatocytes. In addition, lisinopril did not produce an increase in chromosomal aberrations in an in vitro test on Chinese hamster ovary cells and in an in vivo mouse bone marrow study. There were no adverse effects on reproductive capacity in male and female rats treated with lisinopril doses up to 300 mg / kg / day.
Teratogenesis
Lisinopril was not teratogenic in mice treated with doses up to 1000 mg / kg / day (1250 times the maximum recommended human daily dose) from day 6 to day 15 of gestation.
There was no increase in fetal resorptions with doses below 100 mg / kg; at doses of 1000 mg / kg this was prevented by an additional salt intake. There was no fetotoxicity or teratogenicity in rats treated with lisinopril doses up to 300 mg / kg / day (375 times the maximum recommended dose) from day 6 to day 17 of gestation.
In rats that received lisinopril from day 15 of gestation to beyond day 21 postpartum, there was an increased incidence of deaths of births between day 2 and day 7 postpartum. Day 21 post-partum, the average body weight of the offspring was lower. With an additional supply of salt to the mother there was neither an increase in deaths nor a decrease in weight in the births. In rabbits, lisinopril did not show teratogenicity when administered over the entire organogenetic period at doses up to 1 mg / kg / day in the presence of an additional salt intake.
The latter was used to eliminate the toxic effects in the mother and allow an assessment of the teratogenic potential at the highest possible dose level. It was observed that the rabbit is extremely sensitive to inhibitors of the conversion enzyme (captopril and enalapril) showing maternal and fetotoxic effects at dose levels equal to or lower than the therapeutic dose recommended for humans.
In rabbits, fetotoxicity occurred with an increased incidence of fetal resorption at doses of 1 mg / kg / day of lisinopril and with an increased incidence of incomplete ossification at the lowest tested dose (0.1 mg / kg / day). . A single 15 mg / kg / day dose of lisinopril administered intravenously to pregnant rabbits during the 16th, 21st and 26th days of gestation resulted in 88 to 100% fetal deaths.
Hydrochlorothiazide
In acute and chronic toxicology studies hydrochlorothiazide was observed to have relatively low toxicity. In acute animal toxicology studies the LD 50 in mice was greater than 10 g / kg in oral suspension.
Dogs tolerated at least 2 g / kg orally with no signs of toxicity. Hydrochlorothiazide was administered to rats in a two-litter study, to mice in a 2-generation study, and to rabbits with a positive pregnancy test. None of these studies showed teratogenic effects of hydrochlorothiazide.
Offspring raised to weaning or maturity showed no signs of treatment-related effects.
Carcinogenesis, mutagenesis and fertility studies.
Hydrochlorothiazide is currently being studied in the US Carcinogenesis Testing Program. Hydrochlorothiazide did not show mutagenic properties in vitro in the Ames microbial mutagenic assay at concentrations of up to 5 mg / plate using strains TA98 and TA100. Urine samples from patients treated with hydrochlorothiazide did not show mutagenic activity in the Ames test. The ability of some drugs to induce non-disjunction and crossing-over was measured on Aspergillus nidulans. A large number of drugs, including hydrochlorothiazide, induced nondisjunction.
Teratogenesis
Reproduction studies in rabbits, mice and rats at doses up to 100 mg / kg / day (50 times the maximum human dose) have shown no evidence of external fetal abnormalities due to hydrochlorothiazide.
Hydrochlorothiazide administered in a two-generation study in rats at doses of 4-5-6 mg / kg / day (approximately 1-2 times the maximum recommended human dose) did not alter the fertility or produce abnormalities of the offspring at birth.
Lisinopril / hydrochlorothiazide
Administration of lisinopril with hydrochlorothiazide results in toxic responses at lower doses than those observed with each compound administered alone. Since the toxicity of each component is due to its therapeutic activity (hypotension) and since there is an increase in the pharmacological activity of lisinopril when administered in combination with diuretics (hydrochlorothiazide), the increase in toxicity with the two drugs was expected. Although potentiation of toxicity secondary to potentiation of the pharmacological effect has been observed at high doses, there is no reason to predict a toxic response in humans to therapeutic doses of either drug. The safety of lisinopril and hydrochlorothiazide administered in combination with therapeutic dosages has been demonstrated in clinical studies. Lisinopril in combination with hydrochlorothiazide did not show mutagenic properties in a microbial mutagen test using Salmonella typhimurium (Ames test) or Escherichia coli with either without activation or in a mutation test using Chinese hamster lung cells. Lisinopril-hydrochlorothiazide did not produce DNA monoelic breaks in the alkaline elution fluid in the rat hepatocyte in vitro assay. Furthermore, it did not produce increases in chromosomal aberration in the in vitro Chinese hamster ovary cell test or in the in vivo mouse bone marrow study.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Mannitol (E421), dibasic calcium phosphate dihydrate, maize starch, pregelatinised starch, magnesium stearate (E572).
06.2 Incompatibility
Not known.
06.3 Period of validity
36 months
06.4 Special precautions for storage
Store the tablets in the carton in order to protect them from light.
06.5 Nature of the immediate packaging and contents of the package
PVC and aluminum blisters
Pack of 14 tablets.
06.6 Instructions for use and handling
No special instructions.
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
CRINOS S.p.A., Via Pavia, 6 - 20136 Milan
08.0 MARKETING AUTHORIZATION NUMBER
ENSOR 20 mg + 12.5 mg tablets, 14 tablets AIC No. 038520019
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
21 August 2009
10.0 DATE OF REVISION OF THE TEXT
July 2009
