Active ingredients: Enalapril
Enalapril 5 mg, 20 mg tablets
Why is Enalapril - Generic Drug used? What is it for?
Enalapril DOC contains an active substance called enalapril maleate.
This active substance belongs to a group of medicines called ACE inhibitors (angiotensin converting enzyme inhibitors). ENALAPRIL DOC is used:
- to treat high blood pressure (hypertension)
- to treat heart failure (weakening of heart function). May reduce the need to go to hospital and may help some patients live longer
- to prevent the signs of heart failure. The signs include: shortness of breath, tiredness after light physical activity such as walking, or swelling of the ankles and feet.
This medicine works by dilating blood vessels. This lowers blood pressure. The medicine usually starts to work within one hour, and the effect lasts for at least 24 hours. Some people will need several weeks of treatment before the best effect on blood pressure can be seen.
Contraindications When Enalapril - Generic Drug should not be used
Do not take Enalapril
- if you are allergic to enalapril maleate or any of the other ingredients of this medicine (listed in section 6).
- if you have previously had an allergic reaction to a type of medicine similar to this medicine called an ACE inhibitor.
- if you have previously had swelling of the face, lips, mouth, tongue or throat which caused difficulty in swallowing or breathing (angioedema) of an unknown or hereditary nature.
- if you have diabetes or impaired kidney function and you are being treated with a blood pressure lowering medicine containing aliskiren.
- if you have been pregnant for more than three months. It is also better to avoid Enalapril in early pregnancy (see pregnancy section).
Do not take this medicine if you have any of the above problems. If you are unsure, talk to your doctor or pharmacist before taking this medicine.
Precautions for use What you need to know before taking Enalapril - Generic Drug
Talk to your doctor or pharmacist before taking this medicine:
- if you have a heart problem.
- if you have a condition involving the blood vessels in the brain.
- if you have a blood problem such as low or lack of white blood cells (neutropenia / agranulocytosis), low platelet counts (thrombocytopenia) or low red blood cell counts (anemia).
- if you have a liver problem.
- if you are taking any of the following medicines used to treat high blood pressure:
- an 'angiotensin II receptor antagonist' (AIIRA) (also known as sartans - eg valsartan, telmisartan, irbesartan), particularly if you have diabetes-related kidney problems.
- aliskiren.
- if you have a kidney problem (including kidney transplant). This can lead to an increase in blood potassium levels which can be serious. Your doctor may need to adjust your dose of Enalapril or monitor your blood potassium levels.
- if you are on dialysis.
- if you have recently had excessive vomiting or severe diarrhea.
- if you are on a low-salt diet, are taking potassium supplements, potassium-sparing agents, or potassium-containing salt substitutes.
- if you are over 70 years of age.
- if you have diabetes. It is necessary to check carefully for lowering of blood glucose levels, especially during the first month of treatment. The level of potassium in the blood can also be higher.
- if you have ever had an allergic reaction with swelling of the face, lips, tongue or throat with difficulty in swallowing or breathing. You need to know that black patients are at higher risk for these types of ACE inhibitor reactions.
- if you have low blood pressure (you notice this when you feel faint or dizzy, especially when standing up).
- if you have collagen vascular disease (e.g. lupus erythematosus, rheumatoid arthritis or scleroderma), are undergoing therapy that suppresses the immune system, are taking the medicines allopurinol or procainamide, or combinations thereof.
Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (such as potassium) in your blood at regular intervals.
You should tell your doctor if you think you are pregnant (or if there is a possibility of becoming pregnant).
This medicine is not recommended in early pregnancy, and must not be taken if you are more than three months pregnant, as it may cause serious harm to your baby if used at that stage (see pregnancy section).
You should be aware that this medicine reduces blood pressure less effectively in black patients than in non-black patients.
If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking this medicine.
See also information under the heading "Do not take ENALAPRIL DOC".
If you are about to undergo a procedure
If you are about to have any of the following procedures, tell your doctor that you are taking Enalapril:
- any type of surgery or anesthesia (even at the dentist).
- treatment that removes cholesterol from the blood called "LDL apheresis".
- desensitization treatment to reduce the effects of an allergy to bee or wasp stings.
If any of the above apply to you, talk to your doctor or dentist before the procedure.
Interactions Which drugs or foods can change the effect of Enalapril - Generic Drug
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Herbal medicines are included. This is because Enalapril can interfere with the way some medicines work. Some other medicines can also interfere with the way Enalapril works.
Your doctor may need to change your dose and / or take other precautions:
If you are taking an angiotensin II receptor antagonist (AIIRA) or aliskiren (see also information under "Do not take Enalapril" and "Warnings and precautions").
In particular, tell your doctor or pharmacist if you are taking any of the following medicines:
- other medicines that lower blood pressure, such as beta blockers, diuretics.
- medicines containing potassium (including dietary salt substitutes).
- medicines for diabetes (including oral antidiabetic agents and insulin).
- lithium (a medicine used to treat a certain type of depression).
- medicines for depression called 'tricyclic antidepressants'.
- medicines for mental problems called "antipsychotics".
- some cough and cold medicines and medicines that reduce body weight which contain a so-called 'sympathomimetic agent'.
- some pain or arthritis medicines including gold salt therapy.
- non-steroidal anti-inflammatory drugs, including COX-2 inhibitors (medicines that reduce inflammation and can be used to help relieve pain).
- aspirin (acetylsalicylic acid).
- medicines used to dissolve blood clots (thrombolytics).
- alcohol.
If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking Enalapril.
ENALAPRIL DOC with food, drink and alcohol
Enalapril tablets can be taken with or without food, but should be taken with a sufficient amount of liquid.
Alcohol enhances the effect of ENALAPRIL DOC on high blood pressure.
Warnings It is important to know that:
Pregnancy and breastfeeding
Pregnancy
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. Your doctor will usually advise you to stop taking Enalapril before becoming pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of Enalapril.
Enalapril is not recommended in early pregnancy, and must not be taken if more than three months pregnant, as it may cause serious harm to your baby if used after the third month of pregnancy.
Feeding time
Tell your doctor if you are breastfeeding or about to start breastfeeding.
Breastfeeding of newborn babies (first weeks after birth) and especially premature babies is not recommended while you are taking Enalapril.
In the case of older infants, your doctor should advise you of the benefits and risks of taking Enalapril while breastfeeding, in comparison with other treatments.
Driving and using machines
When driving or operating machines, consider the possibility of occasional dizziness or feeling of weakness. If this happens, do not drive vehicles or use any tools or machinery.
ENALAPRIL DOC contains lactose
Lactose is a type of sugar. If you have been told by your doctor that you have "intolerance to some sugars, contact your doctor before taking this medicinal product.
Dose, Method and Time of Administration How to use Enalapril - Generic Drug: Posology
Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
The daily dose is usually taken as a single dose, in the morning, however it is also possible to divide it into two doses, in the morning and in the evening.
- It is very important to keep taking this medicine for as long as your doctor prescribes it.
- Do not take more tablets than prescribed.
For the treatment of high blood pressure
- The usual starting dose ranges from 5 to 20 mg once daily.
- Some patients may need to start treatment with a lower dose.
- The usual maintenance dose is 20 mg once daily.
- The maximum maintenance dose is 40 mg once daily.
Patients with heart failure
- The usual starting dose is 2.5 mg once daily.
- Your doctor will gradually increase the dose until the dose that is appropriate for you is reached.
- The usual maintenance dose is 20 mg per day, taken in one or two doses.
- The maximum maintenance dose is 40 mg per day, divided into two administrations.
Patients with kidney problems
The dose of the medicine will vary according to how well your kidneys are:
- moderate kidney problems - 5 to 10 mg per day.
- severe kidney problems - 2.5 mg per day.
- if you are on dialysis - 2.5 mg per day. On days when you are not on dialysis, the dose can be varied according to your blood pressure.
Elderly patients
The dose will be decided by your doctor and will be based on how well your kidneys are working.
Use in children
Experience with the use of Enalapril in children with high blood pressure is limited. If the child is able to swallow the tablets, the dose will be based on the child's weight and blood pressure. The usual starting doses are:
- weight between 20 kg and 50 kg - 2.5 mg per day.
- weight over 50 kg - 5 mg per day.
The dose can be changed according to the needs of the child:
- a maximum dose of 20 mg per day can be used in children weighing between 20 kg and 50 kg.
- a maximum dose of 40 mg per day can be used in children weighing more than 50 kg.
This medicine is not recommended in infants (first weeks of life) and children with kidney problems.
If it seems to you that the effect of Enalapril is too strong or too weak, consult your doctor or pharmacist.
If you forget to take Enalapril
If you accidentally miss a dose, skip the missed dose and take the next dose as usual.
Do not take a double dose to make up for a forgotten tablet.
If you stop taking Enalapril
Do not stop taking the medicine unless your doctor tells you to. A rebound effect (recurrence or worsening of disorders) is not usually expected when taking ENALAPRIL tablets is stopped.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Overdose What to do if you have taken too much Enalapril - Generic Drug
If you take too many tablets by mistake, contact your doctor immediately. There are limited data on overdose in humans. Symptoms of overdose may include extremely low blood pressure and renal failure.
Side Effects What are the side effects of Enalapril - Generic Drug
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Stop taking Enalapril and contact a doctor immediately if you notice any of the following:
- swelling of the face, lips, tongue or throat which may cause difficulty in breathing or swallowing.
- swelling of the hands, feet or ankles.
- development of a rash with raised red bumps (hives).
You should be aware that black patients have a higher risk of developing this type of reaction. If you notice any of these manifestations, stop taking Enalapril and contact your doctor immediately.
You may feel faint or dizzy when you start taking this medicine. If this happens, it may be helpful to lie down. This is caused by low blood pressure. It should improve as you continue to take the medicine. If you are worried please contact your doctor.
Other side effects:
Very common (may affect more than 1 in 10 people)
- feeling dizzy, weak or unwell.
- blurred vision.
- cough.
Common (may affect up to 1 in 10 people)
- low blood pressure, heart rhythm changes, fast heart rate, angina pectoris or chest pain.
- headache, fainting (syncope).
- altered sense of taste, shortness of breath.
- diarrhea or abdominal pain, rash.
- tiredness (fatigue), depression.
- allergic reactions with swelling of the face, lips, tongue or throat with difficulty in breathing or swallowing.
- increase in blood potassium levels, increase in blood creatinine levels (both are usually found in a laboratory test).
Uncommon (may affect up to 1 in 100 people)
- sudden drop in blood pressure.
- rapid or irregular heartbeats (palpitations).
- heart attack (possibly due to very low blood pressure in some high-risk patients, including those with circulatory problems in the heart or brain).
- anemia (including aplastic and haemolytic anemia).
- stroke (possibly due to very low blood pressure in high-risk patients).
- confusion, insomnia or sleepiness, nervousness.
- sensation of skin tingling or numbness.
- vertigo.
- ringing in the ears (tinnitus).
- nasal discharge, sore throat and hoarseness.
- asthma.
- slowed transit of food in the intestine (intestinal obstruction) which causes a feeling of bloating and painful cramps in the abdomen, inflammation of the pancreas.
- vomiting, difficult digestion, constipation, loss of appetite.
- upset stomach (gastric irritation), dry mouth, ulcer, impaired kidney function, kidney failure.
- increased sweating.
- itching or hives.
- hair loss.
- muscle cramps, flushing, generally feeling unwell, high body temperature (fever), impotence.
- high level of protein in the urine (measured in a laboratory test).
- low blood sugar (with an increased level of consciousness or feeling dizzy), low blood sodium, high blood urea (all measured in a blood test).
Rare (may affect up to 1 in 1,000 people)
- "Raynaud's phenomenon" in which the hands and feet can become very cold and white due to low blood flow.
- changes in blood values such as a decrease in the number of white blood cells and red blood cells, a decrease in hemoglobin, a decrease in the number of platelets.
- bone marrow depression.
- autoimmune diseases.
- altered dreams or sleep disturbances.
- pulmonary infiltrates.
- inflammation of the nose.
- pneumonia.
- inflammation of the cheeks, gums, tongue, lips, throat.
- decrease in the amount of urine produced.
- erythema multiforme.
- "Stevens-Johnson syndrome" is a serious skin condition in which there is redness and peeling of the skin, bullous or exposed ulcers, or detachment of the superficial layer of the skin from the deep layers.
- liver problems such as decreased liver function, inflammation of the liver, jaundice (yellowing of the skin or eyes), increase in liver enzymes or bilirubin (measured in a blood test).
- enlargement of the mammary glands in humans.
Very rare (may affect up to 1 in 10,000 people)
- swelling in the intestines (intestinal angioedema).
Frequency not known (cannot be estimated from the available data)
- Syndrome of inappropriate antidiuretic hormone secretion (SIADH), a condition in which the body develops an excess of water and a decreased concentration of sodium (salt), as a result of incorrect chemical signals. Patients with SIADH may become seriously ill or may have no symptoms.
- A symptom complex has been described that may be associated with some or all of the following side effects: fever, inflammation of the serous surfaces, inflammation of blood vessels, muscle and joint pain, inflammation of muscles and joints, and some changes in laboratory values ; rash, sensitivity to light and other skin reactions may occur.
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 http://www.agenziafarmaco.gov.it/it/responsabili. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton. The expiry date refers to the last day of that month.
Do not store above 30ºC. Store in the original packaging.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Deadline "> Other information
What ENALAPRIL DOC
- The active ingredient is 5 mg or 20 mg of enalapril maleate
- The other ingredients are anhydrous colloidal silica, magnesium stearate, sodium hydroxide, povidone, talc, crospovidone, microcrystalline cellulose and lactose monohydrate.
What Enalapril looks like and contents of the pack
The tablets are round, white or off-white, with ED 5 (5 mg tablets), ED 20 (20 mg tablets) on one side and a score line on the other side.
The tablets are packed in blisters (Alu / OPA-Alu-PVC).
Pack sizes of Enalapril 5 mg tablets: 28, 30, 50 or 100 tablets.
Pack sizes of Enalapril 20 mg tablets: 7, 14, 28, 30, 50 or 100 tablets.
However, not all pack sizes may be marketed.
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 -
ENALAPRIL DOC TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -
Enalapril 5 mg tablets
One tablet of ENALAPRIL DOC contains 5 mg of enalapril maleate. Excipient with known effect: 100 mg of lactose monohydrate.
Enalapril 20 mg tablets
One tablet of ENALAPRIL DOC contains 20 mg of enalapril maleate. Excipient with known effect: 90.0 mg of lactose monohydrate.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM -
Tablets.
Enalapril 5 mg tablets
The tablets are round, white or off-white, with ED 5 on one side and a score line on the other side.
The tablet can be divided into equal halves.
Enalapril 20 mg tablets
The tablets are round, white or off-white, with ED 20 on one side and a score line on the other side.
The tablet can be divided into equal halves.
04.0 CLINICAL INFORMATION -
04.1 Therapeutic indications -
• Treatment of hypertension.
• Treatment of symptomatic heart failure.
• Prevention of symptomatic heart failure in patients with asymptomatic left ventricular dysfunction (ejection fraction ≤35%).
04.2 Posology and method of administration -
Dosage
Foods do not interfere with the absorption of ENALAPRIL DOC.
The dose should be adapted to the patient profile (see section 4.4) and blood pressure response.
Hypertension
The starting dose is 5 mg to a maximum of 20 mg, depending on the degree of hypertension and the patient's condition (see below). Enalapril is given once a day. For mild hypertension the recommended starting dose is 5 to 10 mg. Patients with an intensely activated renin-angiotensin-aldosterone system (e.g., those with renovascular hypertension, salt depletion and / or hypovolemia, heart failure or severe hypertension) may experience an excessive fall in blood pressure after the initial dose. An initial dose of 5 mg or less is recommended in such patients and the initiation of therapy should be under close medical supervision.
Prior treatment with high dose diuretics may result in hypovolaemia and a risk of hypotension when initiating therapy with enalapril. An initial dose of 5 mg or less is recommended in such patients. If possible, diuretic therapy should be discontinued for 2-3 days before initiating therapy with Enalapril. Renal function and serum potassium should be monitored.
The usual maintenance dose is 20 mg / day. The maximum maintenance dose is 40 mg / day.
Heart failure / asymptomatic left ventricular dysfunction
In the management of symptomatic heart failure, Enalapril is used in conjunction with diuretics and, where appropriate, digitalis or beta-blockers. The starting dose of Enalapril in patients with symptomatic heart failure or asymptomatic left ventricular dysfunction is 2.5 mg, and should be administered under close medical observation to determine the initial effect on blood pressure. "initiation of therapy with ENALAPRIL DOC for heart failure, or after successful treatment thereof, the dose should be gradually increased, based on patient tolerability, to the usual maintenance dose of 20 mg, administered as a single or divided dose in two doses.This dose titration can be performed over a period of 2-4 weeks.The maximum dose is 40 mg per day, given in two divided doses.
Suggested dosage titration of Enalapril in patients with heart failure / asymptomatic left ventricular dysfunction
* Adequate precautions should be followed in patients receiving diuretics and those with impaired renal function (see section 4.4).
Blood pressure and renal function should be monitored closely both before and after initiation of treatment with Enalapril (see section 4.4) as hypotension and (more rarely) subsequent renal failure have been reported. In patients treated with diuretics, the dose should be reduced if possible before starting treatment with Enalapril. The onset of hypotension following the initial dose of Enalapril does not imply that hypotension will return during chronic therapy with Enalapril and does not preclude continued use of Serum potassium and renal function should also be monitored.
Dosage in renal insufficiency
In general, the intervals between enalapril dosing should be prolonged and / or the dose reduced.
* See section 4.4. Enalaprilat is dialysable. Dosage on days when patients are not on dialysis should be adjusted according to blood pressure response.
Use in the elderly
The dose should be in line with the renal function of the elderly patient (see section 4.4).
Pediatric population
There is limited experience with the use of Enalapril in clinical trials in pediatric hypertensive patients (see sections 4.4, 5.1 and 5.2).
For patients able to swallow tablets, the dose should be adjusted according to the patient profile and blood pressure response. The recommended starting dose is 2.5 mg in patients aged 20 on glomerular filtration
Method of administration
Oral use.
04.3 Contraindications -
• Hypersensitivity to the active substance or to any other ACE inhibitor or to any of the excipients listed in section 6.1.
• History of angioedema associated with ACE inhibitor therapy.
• Hereditary or idiopathic angioedema.
• Second and third trimester of pregnancy (see sections 4.4 and 4.6).
• The concomitant use of Enalapril with aliskiren-containing medicines is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate GFR
04.4 Special warnings and appropriate precautions for use -
Symptomatic hypotension
Symptomatic hypotension has rarely been reported in patients with uncomplicated hypertension. In hypertensive patients treated with Enalapril, symptomatic hypotension is more likely to occur if the patient is hypovolemic, for example those treated with diuretics, patients on a low-sodium diet, patients with hemodialysis, patients with diarrhea or vomiting (see Sections 4.5 and 4.8). Symptomatic hypotension has been observed in patients with heart failure, with or without associated renal failure. This is more likely to occur in those patients with more severe degrees of heart failure, as reflected by the use of high doses. loop diuretics, hyponatremia or impaired renal function. In these patients, therapy should be initiated under medical supervision and patients should be followed closely whenever the dose of Enalapril and / or the diuretic is adjusted. Similar considerations can be applied to patients with ischemic heart disease or with a "cerebrovascular disease, in which an excessive drop in blood pressure could lead to myocardial infarction or a cerebrovascular accident.
If hypotension occurs, the patient should be placed in the supine position and, if necessary, be given intravenous saline infusion. A transient hypotensive response is not a contraindication to further doses, which can usually be given without difficulty once blood pressure has increased after volume increase.
Treatment with Enalapril may result in further lowering of blood pressure in some heart failure patients with normal or low blood pressure. This effect is expected and generally it is not necessary to suspend the treatment. If hypotension becomes symptomatic, dose reduction and / or discontinuation of the diuretic and / or Enalapril is required.
Aortic or mitral valve stenosis / hypertrophic cardiomyopathy
Like all vasodilators, ACE inhibitors should be used with caution in patients with valvular and left ventricular outflow tract obstruction and should be avoided in case of cardiogenic shock and significant haemodynamic obstruction.
Impaired renal function
In case of renal impairment (creatinine clearance renal artery stenosis. If recognized early and adequately treated, renal insufficiency associated with enalapril therapy is usually reversible.Some hypertensive patients with no apparent pre-existing renal disease have developed increases in blood urea and creatinine when enalapril was given concomitantly with a diuretic. Dosage reductions of enalapril and / or discontinuation of the diuretic may be required. This circumstance should involve the possibility of a stenosis of the basic renal artery (see section 4.4 Renovascular hypertension).
Renovascular hypertension
In patients with bilateral renal artery stenosis or artery stenosis of the only functioning kidney treated with ACE inhibitors, there is an increased risk of hypotension and renal failure. Loss of renal function can occur with even only slight changes in serum creatinine. In these patients, therapy should be initiated under close medical supervision with low doses, careful titration and monitoring of renal function.
Kidney transplant
There is no clinical experience with the administration of Enalapril in patients with a recent kidney transplant. Treatment with Enalapril is therefore not recommended.
Hepatic insufficiency
Rarely, ACE inhibitors have been associated with a syndrome that begins with cholestatic jaundice or hepatitis and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not known. Patients taking ACE inhibitors and developing jaundice or marked elevations in liver enzymes should discontinue the ACE inhibitor and undergo appropriate medical follow-up.
Neutropenia / agranulocytosis
Neutropenia / agranulocytosis, thrombocytopenia and anemia have been reported in patients treated with ACE inhibitors. In patients with normal and uncomplicated renal function, neutropenia occurs rarely. Enalapril should be used with extreme caution in patients with vascular collagen disease, immunosuppressive therapy, allopurinol or procainamide treatments or a combination of these complications, especially if there is pre-existing renal impairment. Some of these patients have developed serious infections which in some cases have not responded to intensive antibiotic therapy.When enalapril is used in these patients, periodic monitoring of leukocytes is advised and patients should be instructed to report any signs of infection.
Hypersensitivity / angioneurotic edema
Angioneurotic edema of the face, extremities, lips, tongue, glottis and / or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including Enalapril. This can occur at any time during treatment. In such cases, Enalapril should be promptly discontinued and appropriate monitoring instituted to ensure complete regression of symptoms before the patient is discharged. Even in cases where the edema is limited to the tongue alone, without respiratory distress, patients may require prolonged observation as treatment with antihistamines and cortisones may not be sufficient.
Very rarely, deaths have been reported due to angioedema associated with laryngeal edema or tongue edema. Airway obstruction is likely to occur in patients with the tongue, glottis or larynx involved, especially if they have a positive history of airway surgery. airway obstruction is likely to occur, appropriate therapy such as epinephrine 1: 1000 subcutaneously (0.3 to 0.5ml) should be promptly administered and / or a patent airway maintained.
Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema than non-black patients.
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema during treatment with an ACE inhibitor (see also section 4.3).
Anaphylactoid reactions during desensitization to hymenoptera
Rarely, patients on ACE inhibitor therapy have reported life-threatening anaphylactoid reactions during desensitization with hymenoptera venom. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each desensitization.
Anaphylactoid reactions in the course of LDL apheresis
Rarely, some patients on ACE inhibitor therapy who underwent low-density lipoprotein (LDL) apheresis with dextran sulfate have developed
life-threatening anaphylactoid reactions. These reactions were avoided by temporarily discontinuing ACE inhibitor therapy prior to each apheresis session.
Patients on hemodialysis
Anaphylactoid reactions have been reported in patients dialysed with high flux membranes (eg AN 69) and treated at the same time with an ACE inhibitor. For such patients, the use of a different type of dialysis membrane or a different class of antihypertensive agents should be considered.
Hypoglycemia
Diabetic patients treated with oral antidiabetics or insulin initiating therapy with an ACE inhibitor should be advised to monitor carefully for hypoglycaemia, especially during the first month of concomitant use (see section 4.5).
Cough
Cough has been reported with the use of ACE inhibitors. This is usually non-productive, persistent cough and resolves upon discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.
Surgery / Anesthesia
In patients undergoing major surgery or during anesthesia with agents that cause hypotension, enalapril blocks angiotensin II formation secondary to compensatory renin release. The hypotension that occurs in these cases can be corrected by increased blood volume.
Hyperkalemia
Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including enalapril.
Risk factors for the development of hyperkalaemia include renal failure, worsening of renal function, age (> 70 years), diabetes mellitus, occurring events, particularly dehydration, acute heart failure, metabolic acidosis, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene, or amiloride), potassium supplements or potassium-containing salt substitutes; or concomitant use of other drugs associated with increases in serum potassium (eg, heparin). Particularly in patients with impaired renal function, the use of potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes may lead to a significant increase in serum potassium.
Hyperkalaemia can cause serious, sometimes fatal arrhythmias. If concomitant use of enalapril and any of the above drugs is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium (see section 4.5).
Lithium
The combination of lithium and enalapril is generally not recommended (see section 4.5).
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) Hypotension, syncope, stroke, hyperkalaemia and changes in renal function (including acute renal failure) have been reported in susceptible individuals, especially in the case of combinations of medicinal products affecting this system (see section 4.5).
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 sections 4.5 and 5.1).
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 concurrently in patients with diabetic nephropathy. The combination with aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate GFR
Lactose
Enalapril tablets contain lactose and therefore patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. Enalapril tablets contain less than 200 mg of lactose per tablet (enalapril 5 mg and 20 mg contains 100 mg and 90.0 mg of lactose monohydrate, respectively).
Pediatric population
There is limited experience in terms of efficacy and safety in hypertensive children over 6 years of age, but there is no experience for other indications. Limited pharmacokinetic data are available in children over 2 months of age (see also sections 4.2, 5.1 and 5.2). Enalapril is not recommended in children for indications other than hypertension. Enalapril is not recommended in neonates and pediatric patients with glomerular filtration rate
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 therapy with an ACE inhibitor 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 4.3 and 4.6).
Ethnic differences
As with other angiotensin converting enzyme inhibitors, enalapril appears to be less effective in lowering blood pressure in the black population than in the non-black population, possibly due to a high prevalence of low renin levels in the population. black hypertensive population.
04.5 Interactions with other medicinal products and other forms of interaction -
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
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 sections 4.3, 4.4 and 5.1).
Do not co-administer aliskiren with Enalapril in patients with diabetes or renal impairment (glomerular filtration rate GFR
Potassium-sparing diuretics or potassium supplements
ACE inhibitors reduce diuretic induced potassium loss. Potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene or amiloride), potassium supplements or potassium-containing salt substitutes may lead to significant increases in serum potassium. If concomitant use is indicated due to demonstrated hypokalaemia, they should be used with caution and with frequent monitoring of serum potassium (see section 4.4).
Diuretics (thiazides or loop diuretics)
Prior treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with enalapril (see section 4.4). The hypotensive effects may be reduced by discontinuing diuretics, by increasing blood volume or by taking salts or by initiating therapy with low dose enalapril.
Other antihypertensive agents
Concomitant use of these drugs may increase the hypotensive effect of enalapril. Concomitant use with nitroglycerin and other nitrates or other vasodilators may further reduce blood pressure.
Lithium
Reversible increases in serum lithium concentrations and episodes of lithium toxicity have been reported during concomitant administration of lithium and ACE inhibitors. Concomitant use of thiazide diuretics may further increase lithium levels and increase the risk of lithium toxicity with ACE inhibitors. The use of enalapril with lithium is not recommended, but if the combination is necessary, it should be careful monitoring of serum lithium levels (see section 4.4).
Tricyclic antidepressants / Antipsychotics / Anesthetics / Narcotics
The concomitant use of some anesthetic medicinal products, tricyclic antidepressants and antipsychotics with ACE inhibitors may result in a further reduction in blood pressure (see section 4.4).
Non-steroidal anti-inflammatory drugs (NSAIDs) including selective inhibitors cyclooxygenase-2 (COX-2)
Non-steroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors) may reduce the effect of diuretics and other antihypertensive drugs. Thus, the antihypertensive effect of angiotensin II receptor antagonists o ACE inhibitors can be attenuated by NSAIDs including selective COX-2 inhibitors.
Concomitant administration of NSAIDs (including COX-2 inhibitors) and angiotensin II receptor antagonists or ACE inhibitors has an additive effect on the increase in serum potassium and may result in deterioration of renal function. These effects are usually reversible. Acute renal failure may occur rarely, especially in patients with impaired renal function (such as the elderly or patients who are volume depleted, including those on diuretic therapy). Therefore, the combination should be administered with caution in patients with renal impairment. Patients should be adequately hydrated and renal function monitoring should be considered after initiation of concomitant therapy and thereafter. periodically.
Salt of gold
Nitritoid reactions (symptoms of which include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients receiving injectable gold salts (sodium aurothiomalate) with concomitant use of ACE inhibitors, including l "enalapril.
Sympathomimetics
Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.
Antidiabetic
Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetic medicinal products (insulins, oral hypoglycemic drugs) may cause an increase in the blood glucose lowering effect with risk of hypoglycaemia. This effect appears to be more likely to occur during the first weeks of combined treatment and in patients with renal impairment (see sections 4.4 and 4.8).
Alcohol
Alcohol increases the hypotensive effect of ACE inhibitors.
Acetylsalicylic acid, thrombolytics and beta-blockers
Enalapril can be safely administered concomitantly with acetylsalicylic acid (at cardiological dosages), thrombolytics and beta-blockers.
Pediatric population
Interaction studies have only been performed in adults.
04.6 Pregnancy and breastfeeding -
Pregnancy
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 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, 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.
Exposure to ACE inhibitors during the second and third trimesters is known to induce fetal toxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) in women (see section 5.3 ). There have been cases of oligohydramnios, which presumably indicates a decrease in fetal renal function and which can lead to limb contractures, craniofacial deformations and the development of pulmonary hypoplasia.
Should exposure to 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 sections 4.3 and 4.4).
Feeding time
Limited pharmacokinetic data demonstrate very low concentrations in breast milk (see section 5.2). Although these concentrations appear to be clinically irrelevant, the use of Enalapril in breastfeeding is not recommended for preterm infants and in the first few weeks after delivery, due to the hypothetical risk of cardiovascular and renal effects and because there is not enough clinical experience. .
In older infants, if deemed necessary for the mother, Enalapril may be taken while breastfeeding, but in this case the infant should be followed up for possible adverse effects.
04.7 Effects on ability to drive and use machines -
When driving vehicles or using machines it should be borne in mind that dizziness and tiredness have occasionally been reported.
04.8 Undesirable effects -
The following undesirable effects have been reported with enalapril in clinical trials and in post-marketing experience.
* Incidence rates were comparable with those reported in the placebo and active control groups in clinical trials.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address http://www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose -
Limited data are available on overdose in humans. The most prominent manifestations of overdose are marked hypotension, which begins approximately six hours after ingestion of the tablets, concomitant with blockade of the renin-angiotensin system, and stupor. Symptoms associated with ACE inhibitor overdose may include circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety and cough. After ingestion of 300 mg and 440 mg of enalapril, serum levels of enalaprilat were reported to be 100 and 200 times higher, respectively, than those typically observed after therapeutic doses. The recommended treatment of overdose is intravenous infusion of saline. In case of hypotension the patient should be placed in an anti-shock position. If available, treatment with angiotensin II and / or catecholamines may be considered. ingestion is recent, take measures to eliminate enalapril maleate (eg: emesis, gastric lavage, administration of adsorbents and sodium sulphate). Enalaprilat can be removed from the general circulation by hemodialysis (see section 4.4). Pacemaker treatment is indicated for therapy-refractory bradycardia. Vital signs, serum electrolytes and creatinine concentrations should be monitored continuously.
05.0 PHARMACOLOGICAL PROPERTIES -
05.1 "Pharmacodynamic properties -
Pharmacotherapeutic group: Substances acting on the renin-angiotensin system, Angiotensin converting enzyme inhibitors, unassociated, ATC code: C09A A02.
ENALAPRIL DOC (enalapril maleate) is the maleate salt of enalapril, a derivative of two amino acids, L-alanine and L-proline. The angiotensin converting enzyme (ACE) is a peptidyldipeptidase that catalyzes the conversion of angiotensin I into the pressure-acting substance, angiotensin II. After absorption, enalapril is hydrolyzed to enalaprilat, which inhibits ACE. Inhibition of ACE results in a decrease in plasma angiotensin II levels, which leads to an increase in plasma renin activity (due to removal of negative feedback exerted on renin release) and a decrease in aldosterone secretion. ACE is identical to kininase II. Therefore ENALAPRIL DOC can also block the degradation of bradykinin, a potent vasodilator peptide. The role of this action on the therapeutic effects of ENALAPRIL DOC however remains to be clarified.
Mechanism of action
Although the mechanism by which Enalapril lowers blood pressure appears to be primarily suppression of the renin-angiotensin-aldosterone system, Enalapril is antihypertensive even in patients with low-renin hypertension.
Pharmacodynamic effects
Administration of Enalapril to hypertensive patients results in a reduction in blood pressure in both supine and standing positions, without a significant increase in heart rate. Symptomatic postural hypotension is infrequent. In some patients, it may take several weeks of therapy to achieve an optimal reduction in blood pressure. Abrupt discontinuation of ENALAPRIL therapy has not been associated with a rapid rise in blood pressure. Inhibition. effective conversion enzyme activity usually begins 2 to 4 hours after oral administration of a single dose of enalapril. The onset of antihypertensive activity is usually observed after one hour and maximal activity is achieved within 4 to 6 hours of administration. The duration of the effect is dose-dependent. However, at the recommended dose the haemodynamic and antihypertensive effects appear to continue for at least 24 hours. In haemodynamic studies performed in patients with essential hypertension, the reduction in blood pressure was associated with a reduction in peripheral arterial resistance with increased cardiac output and no or minimal change in heart rate. After administration of Enalapril there was an increase in renal blood flow; the glomerular filtration rate appeared unchanged. There were no signs of water or sodium retention. However, in patients with low glomerular filtration rate prior to treatment, this usually showed an increase. Decreases in albuminuria, urinary IgG excretion and total proteinuria have been observed in short-term clinical studies in diabetic and non-diabetic renal patients after administration of enalapril.
When a thiazide diuretic is co-administered with Enalapril, the blood pressure lowering effect is at least additive. Enalapril can reduce or prevent the development of thiazide-induced hypokalaemia.
In patients with heart failure treated with digitalis and diuretics, treatment with Enalapril tablets or injectable has been associated with decreases in peripheral resistance and blood pressure. Cardiac output increased while heart rate decreased (usually elevated in patients with heart failure). Pulmonary capillary wedge pressure also decreased. Exercise tolerance and heart failure severity, measured according to the New York Heart Association criteria, have improved. These actions persisted during chronic therapy. In patients with mild or moderate heart failure, enalapril slowed the progression of heart dilation / enlargement and heart failure, as evidenced by the reduction in left ventricular systolic and end-diastolic volumes and improved ejection fraction.
Clinical efficacy and safety
A multicentre, randomized, double-blind, placebo-controlled study (SOLVD Prevention Study) examined a population with asymptomatic left ventricular dysfunction (LVEF
A multicenter, randomized, double-blind, placebo-controlled study (SOLVD Treatment Study) examined a population with congestive heart failure due to systolic dysfunction (ejection fraction myocardial infarction 23% (95% CI; 11 - 34%; 20% unstable pangina pectoris (95% CI; 9 - 29%; p
Two large randomized 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 antagonist of the angiotensin II receptor.
ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus associated with evidence of organ damage. VA NEPHRON-D was a study conducted in patients with type 2 diabetes mellitus and diabetic nephropathy.
These studies did not demonstrate any significant beneficial effect on renal and / or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute renal injury and / or hypotension was observed compared to monotherapy.
These results are also relevant for other ACE inhibitors and angiotensin II receptor antagonists, given their similar pharmacodynamic properties.
ACE inhibitors and angiotensin II receptor antagonists should therefore not be used simultaneously in patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study aimed at verifying the advantage of adding aliskiren to standard therapy of an ACE inhibitor or angiotensin II receptor antagonist in patients with diabetes mellitus. type 2 and chronic kidney disease, cardiovascular disease, or both. The study was terminated early due to an increased risk of adverse events. 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 reported more frequently in the aliskiren group than in the placebo group.
Pediatric population
There is limited experience of use in pediatric hypertensive patients over 6 years of age. In a clinical study of 110 pediatric hypertensive patients aged 6 to 16 years with body weight 20 kg and a glomerular filtration rate> 30 ml / min / 1 , 73 m², to patients with body weight
05.2 "Pharmacokinetic properties -
Absorption
Oral enalapril is rapidly absorbed; peak serum concentrations of enalapril are achieved within one hour of administration. Based on the amount excreted in the urine, the rate of absorption of enalapril from enalapril tablets is approximately 60%.
The absorption of oral ENALAPRIL is not affected by the presence of food in the gastrointestinal tract. After absorption, oral ENALAPRIL is rapidly and largely hydrolyzed to enalaprilat, a potent inhibitor of the enzyme of conversion of angiotensin. The peak serum concentration of enalaprilat occurs approximately 4 hours after an oral dose of enalapril. The effective accumulation half-life of enalaprilat after multiple oral doses of enalapril is 11 hours. In individuals with normal renal function, steady-state serum concentrations of enalaprilat were achieved after 4 days of treatment.
Distribution
Within a therapeutically relevant concentration range, human plasma protein bound enalaprilat does not exceed 60%.
Biotransformation
Except for conversion to enalaprilat, there is no evidence of significant metabolism of enalapril.
Elimination
Enalaprilat is eliminated essentially by the kidney. The main compounds in the urine are enalaprilat, which accounts for about 40% of the dose, and unchanged enalapril (about 20%).
Kidney damage
The exposure to enalapril and enalaprilat was increased in patients with renal insufficiency. In patients with mild to moderate renal insufficiency (creatinine clearance 40-60 ml / min), the steady-stage AUC of enalaprilat was twice as high. compared to patients with normal renal function after administration of 5 mg once daily. In patients with severe renal impairment (creatinine clearance 30 ml / min), the AUC is increased approximately eight-fold. The effective half-life of enalaprilat after multiple doses of enalapril maleate is prolonged at this stage of renal failure and the time required to reach steady state is greater (see section 4.2). Enalaprilat can be removed from the general circulation by hemodialysis. The clearance of dialysis is 62 ml / min.
Children and adolescents
A multiple dose pharmacokinetic study was conducted in 40 male and female hypertensive pediatric patients from 2 months to 16 years after daily oral administration of 0.07 to 0.14 mg / kg enalapril maleate. There were no major differences in the pharmacokinetics of enalaprilat in children compared with historical data in adults. The data indicate an increase in AUC (dose normalized for body weight) with increasing age; however, no increase in AUC is observed when data are normalized by body surface area. At steady state, the mean effective accumulation half-life of enalaprilat was found to be
14 hours.
Feeding time
After a single 20 mg oral dose in 5 postpartum women, the mean peak enalapril milk value was 1.7 mcg / L (range 0.54 to 5.9 mcg / L) 4 to 6 hours after postpartum. dose. The mean peak enalaprilat value was 1.7 mcg / L (range 1.2 to 2.3 mcg / L); the peaks occurred at different times over the 24-hour period. Using the peak milk level data, the maximum estimated amount ingested by an exclusively breastfed infant would be approximately 0.16% of the maternal weight-adjusted dose. A woman who had taken an oral dose of 10 mg per day of enalapril for 11 months had peak enalapril milk levels of 2 mcg / L 4 hours post dose and peak enalaprilat levels of approximately 0.75 mcg / L. 9 hours after the dose. The total amount of enalapril and enalaprilat measured in milk over the 24 hour period was 1.44 mcg / L and 0.63 mcg / L, respectively. The levels of enalaprilat in milk were undetectable (
05.3 Preclinical safety data -
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. Reproductive toxicity studies suggest that enalapril has no effect on fertility and reproductive performance in rats and is not teratogenic. In a study where the drug was administered to female rats prior to mating until gestation, a increase in the rate of deaths in offspring during lactation. The compound has been shown to cross the placental barrier and is excreted in breast milk. Angiotensin converting enzyme inhibitors, as a class, have been shown to be foetotoxic (causing damage and / or fetal death) when administered during the second or third trimester.
06.0 PHARMACEUTICAL INFORMATION -
06.1 Excipients -
Anhydrous colloidal silica,
Magnesium stearate,
Sodium hydroxide,
Povidone,
Talc,
Crospovidone,
Microcrystalline cellulose,
Lactose monohydrate.
06.2 Incompatibility "-
Not relevant.
06.3 Period of validity "-
3 years
06.4 Special precautions for storage -
Do not store above 30 ° C. Store in the original packaging.
06.5 Nature of the immediate packaging and contents of the package -
The tablets are packed in blisters (Alu / OPA-Alu-PVC).
Pack sizes of Enalapril 5 mg tablets: 28, 30, 50 or 100 tablets. Pack sizes of Enalapril 20 mg tablets: 7, 14, 28, 30, 50 or 100 tablets.
However, not all pack sizes may be marketed.
06.6 Instructions for use and handling -
Unused medicine and wastes derived from this medicine must be disposed of in accordance with local regulations.
07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -
DOC Generici S.r.l. Via Turati 40,
20121 Milan, Italy
08.0 MARKETING AUTHORIZATION NUMBER -
5 mg tablets - blister 28 tablets - AIC n. 034749097
5 mg tablets - blister 30 tablets - AIC n. 034749109
5 mg tablets - blister 50 tablets - AIC n. 034749111
5 mg tablets - blister 100 tablets - AIC n. 034749123
5 mg tablets - glass container 28 tablets - AIC n. 034749135
5 mg tablets - glass container 30 tablets - AIC n. 034749147
5 mg tablets - glass container 50 tablets - AIC n. 034749150
5 mg tablets - glass container 100 tablets - AIC n. 034749162
20 mg tablets - blister 7 tablets - AIC n. 034749349
20 mg tablets - blister 14 tablets - AIC n. 034749337
20 mg tablets - blister 28 tablets - AIC n. 034749251
20 mg tablets - blister 30 tablets - AIC n. 034749263
20 mg tablets - blister 50 tablets - AIC n. 034749275
20 mg tablets - blister 100 tablets - AIC n. 034749287
20 mg tablets - glass container 28 tablets - AIC n. 034749299
20 mg tablets - glass container 30 tablets - AIC n. 034749301
20 mg tablets - glass container 50 tablets - AIC n. 034749313
20 mg tablets - glass container 100 tablets - AIC n. 034749325
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -
Date of first authorization: March 2006.
Date of most recent renewal: November 2008.
