Active ingredients: Losartan (Losartan sodium)
NEO-LOTAN 12.5 mg film-coated tablets
NEO-LOTAN 50 mg film-coated tablets
NEO-LOTAN 100 mg film-coated tablets
Neo-Lotan package inserts are available for pack sizes: - NEO-LOTAN 12.5 mg film-coated tablets, NEO-LOTAN 50 mg film-coated tablets, NEO-LOTAN 100 mg film-coated tablets
- NEO-LOTAN 2.5 mg / ml powder and solvent for oral suspension
Indications Why is Neo-Lotan used? What is it for?
Losartan (Neo-lotan) belongs to a group of medicines known as angiotensin II receptor antagonists. Angiotensin II is a substance produced in the body that binds to receptors in blood vessels, causing the blood vessel to narrow. This causes blood pressure to rise. Losartan prevents angiotensin II from binding to these receptors, causing the blood vessels to relax, resulting in lowering of blood pressure. Losartan slows the decrease in kidney function in patients with high blood pressure and type 2 diabetes.
Neo-lotan is used
- to treat adult patients and children and adolescents aged 6 to 18 years with high blood pressure (hypertension)
- to protect the kidney in hypertensive patients with type 2 diabetes who have laboratory tests showing abnormal kidney function and proteinuria ≥ 0.5g per day (a condition in which the urine has an abnormal amount of protein)
- to treat patients with chronic heart failure when therapy with specific medicines called angiotensin converting enzyme inhibitors (ACE inhibitors, medicines used to lower high blood pressure) is not considered adequate by your doctor. If your heart failure has been stabilized by ACE inhibitor therapy you should not be switched to losartan therapy.
- in patients with high blood pressure and thickening of the left ventricular walls, Neolotan has been shown to decrease the risk of stroke ("LIFE indication").
Contraindications When Neo-Lotan should not be used
Do not take Neo-lotan:
- if you are allergic to losartan or any of the other ingredients of this medicine (listed in section 6),
- if you have been pregnant for more than 3 months. (It is also preferable to avoid taking Neo-lotan in early pregnancy - see Pregnancy), - if you have severe liver impairment.
- if you have diabetes or impaired kidney function and you are being treated with a blood pressure lowering medicine containing aliskiren.
Precautions for use What you need to know before taking Neo-Lotan
Talk to your doctor, pharmacist, or nurse before taking Neo-lotan.
You should tell your doctor if you think you are (or might get) pregnant. Neo-lotan is not recommended in early pregnancy, and must not be taken if you are more than 3 months pregnant, as it can cause serious harm to your baby if used during this period (see pregnancy section).
Before taking Neo-lotan it is important that you tell your doctor:
- if you have a history of angioedema (swelling of the face, lips, throat, and / or tongue) (see also section 4 "Possible side effects"),
- if you suffer from excessive vomiting or diarrhea which has caused a large loss of body fluids and / or salt,
- if you are being treated with diuretics (drugs that increase the amount of water eliminated through the kidneys) or if you are on a diet with a restricted salt intake which causes a large loss of fluid and salt from the body (see section 3 "Dosage in particular groups of patients "),
- if you know that you have a narrowing or blockage of the blood vessels that carry blood to the kidneys or if you have recently had a kidney transplant,
- if you have impaired liver function (see sections 2 "Do not take Neo-lotan" and 3 "Dosage in special patient groups"),
- if you suffer from heart failure with or without impaired kidney function or concomitant severe life-threatening cardiac arrhythmias. Particular care should be taken when simultaneously being treated with a beta blocker,
- if you have problems with your heart valves or heart muscle,
- if you have coronary heart disease (caused by reduced blood flow in the blood vessels of the heart) or if you have cerebrovascular disease (caused by reduced blood circulation in the brain),
- if you suffer from primary hyperaldosteronism (a syndrome associated with increased secretion of the hormone aldosterone by the adrenal gland, caused by an abnormality within the gland),
- if you are taking any of the following medicines used to treat high blood pressure:
- an ACE inhibitor (for example enalapril, lisinopril, ramipril), particularly if you have diabetes-related kidney problems,
- aliskiren.
Your doctor may check your kidney function, blood pressure and the amount of electrolytes (for example potassium) in your blood at regular intervals.
See also information under the heading "Do not take Neo-lotan"
Children and adolescents
Neo-lotan has been studied in children. For more information, consult your doctor.
Neo-lotan is not recommended in children suffering from kidney or liver problems, as the data available in this patient group are limited. Neo-Lotan is not recommended for use in children under 6 years of age as it has not been shown to work in this age group.
Interactions Which drugs or foods can modify the effect of Neo-Lotan
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
Take special care if you are taking the following medicines while being treated with Neo-lotan:
- other medicines to lower blood pressure because they can further reduce your blood pressure. Blood pressure can also be lowered by one of the following drugs / drug class: tricyclic antidepressants, antipsychotics, baclofen, amifostine,
- medicines that retain potassium or that may increase potassium levels (e.g. potassium supplements, potassium-containing salt substitutes or potassium-sparing drugs such as some diuretics [amiloride, triamterene, spironolactone] or heparin),
- non-steroidal anti-inflammatory drugs such as indomethacin, including cox-2 inhibitors (drugs that reduce inflammation and can be used to relieve pain) because they may decrease the effect of losartan in lowering blood pressure.
Your doctor may need to change your dose and / or take other precautions:
- if you are taking an ACE inhibitor or aliskiren (see also information under "Do not take Neo-lotan" and "Warnings and precautions".
- If your kidney function is impaired, concomitant use of these drugs can lead to worsening of kidney function.
Medicines containing lithium should not be taken in combination with losartan without close medical supervision. Appropriate precautionary measures (e.g. blood tests) may be indicated.
Neo-lotan with food and drink
Neo-lotan can be taken with or without food.
Warnings It is important to know that:
Pregnancy and breastfeeding
Pregnancy
You should tell your doctor if you think you are (or might get) pregnant. Your doctor will normally advise you to stop taking Neo-lotan before you become pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of Neo-lotan.
Neo-lotan is not recommended in the early period of pregnancy, and should not be taken if you are more than 3 months pregnant, as it can 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. Neo-lotan is not recommended for mothers who are breastfeeding, and your doctor may choose another treatment if you wish to breastfeed. Especially if your baby is a newborn or premature baby.
Consult your doctor or pharmacist before taking this medicine.
Driving and using machines
No studies on the effects on the ability to drive and use machines have been performed.
Neo-lotan is unlikely to affect the ability to drive and use machines.
However, as with other blood pressure lowering drugs, losartan can cause dizziness or sleepiness in some people. If you experience dizziness or sleepiness, you should consult your doctor before undertaking these activities.
Neo-lotan contains lactose
Neo-lotan contains lactose monohydrate. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.
Dose, Method and Time of Administration How to use Neo-Lotan: Posology
Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist. Your doctor will decide on the appropriate dosage of Neo-lotan, based on your disease and any other medicines you are taking. It is important to continue taking Neo-lotan for the duration of your prescription as this will keep your blood pressure control stable.
Adult patients with high blood pressure
Treatment usually starts with 50 mg losartan (one Neo-lotan 50 mg tablet) once a day. The maximum effect in reducing blood pressure is reached 3-6 weeks after the start of treatment. In some patients the dose may subsequently be increased to 100 mg losartan (two tablets of Neo-lotan 50 mg or one tablet of Neo-Lotan 100 mg) once a day.
If you have the impression that the effect of losartan is too strong or too weak, contact your doctor or pharmacist.
Use in children and adolescents
Children under the age of 6
Neo-Lotan is not recommended for use in children under 6 years of age as it has not been shown to work in this age group.
Children between the ages of 6 and 18
The recommended starting dose in patients weighing between 20 and 50 kg is 0.7 mg of losartan per kg of body weight once daily (up to a maximum of 25 mg of Neo-lotan). Your doctor may increase the dose if your blood pressure is not controlled.
Another formulation (s) of this medicine may be more suitable for children; ask your doctor or pharmacist.
Adult patients with high blood pressure and type 2 diabetes
Treatment usually starts with 50 mg losartan (one Neo-lotan 50 mg tablet) once a day. The dose may subsequently be increased to 100 mg losartan (two Neolotan 50 mg tablets or one Neo-Lotan 100 mg tablet) once daily based on blood pressure response to therapy.
Losartan tablets can be administered with other blood pressure lowering medicines (e.g. diuretics, calcium channel blockers, alpha or beta blockers, and centrally acting medicines) as well as with insulin and other commonly used medicines that lower blood glucose levels. blood (e.g. sulfonylureas, glitazones, and glucosidase inhibitors).
Adult patients with heart failure
Treatment usually starts with 12.5 mg losartan (one Neo-lotan 12.5 mg tablet) once a day. The dose should be gradually increased on a weekly basis (i.e. 12.5 mg per day during the first week, 25 mg per day during the second week, 50 mg per day during the third week, 100 mg per day during the fourth week, 150 mg per day mg per day during the fifth week) up to the maintenance dose determined by your doctor. A maximum dose of 150 mg losartan (for example, three Neo-lotan 50 mg tablets or one Neo-lotan 100 mg tablet and one Neo-Lotan 50 mg tablet) may be used once a day.
In the treatment of heart failure, losartan is usually combined with a diuretic (medicine that increases the amount of fluid excreted through the kidneys) and / or digitalis (medicine that helps make the heart stronger and more efficient) and / or beta-blockers .
Dosage in particular patient groups
Your doctor may recommend a lower dose, especially when starting treatment in some patients such as those treated with high-dose diuretics, in patients with impaired liver function, or in patients over 75 years of age. The use of losartan is not recommended in patients with severe hepatic impairment (see section "Do not take Neo-lotan").
Administration
The tablets should be swallowed with a glass of water. You should try to take your daily dose at the same time each day. It is important to continue taking Neo-lotan until your doctor tells you otherwise.
If you forget to take Neo-lotan
If you accidentally forget to take your daily dose, take the next tablet at the scheduled time the next day.
Do not take a double dose to make up for a forgotten tablet. If you have any questions on the use of this medicine, consult your doctor, pharmacist or nurse.
Overdose What to do if you have taken too much Neo-Lotan
If you accidentally take too many tablets, contact your doctor immediately. Symptoms of overdose are low blood pressure, increased heart rate, possibly decreased heart rate.
Side Effects What are the side effects of Neo-Lotan
Like all medicines, this medicine can cause side effects, although not everybody gets them.
If you experience any of the following side effects, stop taking losartan tablets and consult your doctor immediately or go to the nearest hospital emergency department:
A severe allergic reaction (skin rash, itching, swelling of the face, lips, mouth or throat which may cause difficulty in swallowing or breathing).
This is a serious but rare side effect, affecting more than 1 in 10,000 patients but less than 1 in 1,000 patients. You may need urgent medical attention or hospitalization.
The following side effects have been reported with Neo-lotan:
Common (may affect up to 1 in 10 people):
- dizziness,
- lowering of blood pressure (especially after "excessive loss of fluid from the body into the blood vessels" eg in patients with severe heart failure or being treated with high doses of diuretics),
- dose-related orthostatic effects such as lowering of blood pressure which occurs when rising from a lying or sitting position,
- weakness,
- fatigue,
- low blood glucose (hypoglycemia),
- too much potassium in the blood (hyperkalaemia).
- changes in kidney function including kidney failure,
- reduced number of red blood cells (anemia),
- increase in blood urea, creatinine and serum potassium in patients with heart failure.
Uncommon (may affect up to 1 in 100 people):
- drowsiness,
- headache,
- sleep disorders,
- feeling of heart beating fast (palpitations),
- severe chest pain (angina pectoris),
- shortness of breath (dyspnoea),
- abdominal pain,
- constipation,
- diarrhea,
- nausea,
- He retched,
- urticaria,
- itch,
- rash,
- localized swelling (edema),
- cough.
Rare (may affect up to 1 in 1,000 people):
- hypersensitivity
- angioedema
- inflammation of blood vessels (vasculitis including Henoch-Schonlein purpura),
- feeling numb or tingling (paraesthesia),
- fainting (syncope),
- very fast and irregular heartbeat (atrial fibrillation),
- brain attack (stroke),
- inflammation of the liver (hepatitis),
- high blood levels of alanine aminotranferase (ALT), usually resolvable upon discontinuation of treatment.
Not known (frequency cannot be estimated from the available data):
- reduction in the number of platelets,
- migraine,
- abnormal liver function (liver),
- muscle and joint pain,
- flu-like symptoms,
- back pain and urinary tract infection,
- increased sensitivity to the sun (photosensitivity),
- unexplained muscle pain with dark (tea-like) discoloration of the urine (rhabdomyolysis),
- impotence,
- inflammation of the pancreas (pancreatitis),
- low levels of sodium in the blood (hyponatremia),
- depression,
- general feeling of not feeling well (malaise),
- perception of sounds, buzzing, ringing, creaking in the ears (tinnitus),
- taste disturbances (dysgeusia).
Side effects in children are similar to those seen in adults.
Reporting of side effects
If you get any side effects, including any possible side effects not listed in this leaflet, talk to your doctor, pharmacist or nurse. You can also report side effects directly via the national reporting system at 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 Neo-lotan out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton or bottle label. The expiry date refers to the last day of the month.
Blister:
Store Neo-lotan in the original package to protect from light and moisture.
Do not open the blister pack until you are ready to take the tablet.
Bottles:
Store Neo-lotan in the original package in order to protect from light.
Do not store above 25 ° C. Keep the bottle tightly closed to protect from moisture.
Do not throw away 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 Neo-lotan contains
The active substance is losartan potassium.
Each Neo-lotan 12.5 mg tablet contains 12.5 mg of losartan potassium.
Each Neo-lotan 50 mg tablet contains 50 mg of losartan potassium.
Each Neo-lotan 100 mg tablet contains 100 mg of losartan potassium.
The other ingredients are microcrystalline cellulose (E460), lactose monohydrate, pregelatinised maize starch, magnesium stearate (E572), hyprolose (E463), hypromellose (E464).
Neo-lotan 12.5 mg, 50 mg and 100 mg contain potassium in the following quantities: 1.06 mg (0.027 mEq), 4.24 mg (0.108 mEq) and 8.48 mg (0.216 mEq) respectively.
Neo-lotan 12.5 mg tablets also contain carnauba wax (E903), titanium dioxide (E171), indigo carmine aluminum lake (E132).
Neo-lotan 50 mg tablets also contain carnauba wax (E903), titanium dioxide (E171).
Neo-lotan 100 mg tablets also contain carnauba wax (E903), titanium dioxide (E171).
Description of the appearance of Neo-lotan and contents of the pack
Neo-lotan 12.5 mg is supplied as non-breakable film-coated tablets containing 12.5 mg of losartan potassium.
Neo-lotan 50 mg is supplied as scored film-coated tablets containing 50 mg of losartan potassium. The tablet can be divided into equal halves.
Neo-lotan 100 mg is supplied as non-breakable film-coated tablets containing 100 mg of losartan potassium.
Neo-lotan is supplied in the following packages:
- Neo-lotan 12.5 mg - The tablets are contained in PVC / PE / PVDC blisters and aluminum foil cover in packs of 7, 14, 21, 28, 50, 98, 210 or 500 tablets and a single-dose pack of 28 tablets for hospital use. HDPE bottles of 100 tablets.
- Neo-lotan 50 mg - Tablets are contained in PVC / PE / PVDC blister and aluminum foil cover in packs of 7, 10, 14, 20, 28, 30, 50, 56, 84, 90, 98, 280 o 500 tablets and a single-dose pack of 28, 56 and 98 tablets for hospital use. HDPE bottles of 100 or 300 tablets.
- Neo-lotan 100 mg - PVC / PE / PVDC blister and aluminum foil cover in packs of 7, 10, 14, 15, 20, 28, 30, 50, 56, 84, 90, 98 or 280 tablets and one single-dose packs of 28, 56 and 98 tablets for hospital use. HDPE bottles of 100 tablets.
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 -
NEO-LOTAN TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -
Each Neo-lotan 12.5 mg tablet contains 12.5 mg of losartan potassium.
Each Neo-lotan 50 mg tablet contains 50 mg of losartan potassium.
Each Neo-lotan 100 mg tablet contains 100 mg of losartan potassium.
Each Neo-lotan 12.5 mg tablet contains 25.25 mg of lactose monohydrate.
Each Neo-lotan 50 mg tablet contains 25.5 mg of lactose monohydrate.
Each Neo-lotan 100 mg tablet contains 51.0 mg of lactose monohydrate.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM -
Film-coated tablets.
Neo-lotan 12.5 mg tablet
Blue, oval film-coated tablets debossed with 11 on one side and plain on the other side.
Neo-lotan 50 mg tablet
White, oval film-coated tablets debossed with 952 on one side and a fracture mark on the other.
The tablet can be divided into equal halves.
100 mg Neo-lotan tablet
White, teardrop-shaped film-coated tablets debossed with 960 on one side and plain on the other side.
04.0 CLINICAL INFORMATION -
04.1 Therapeutic indications -
• Treatment of essential hypertension in adults and in children and adolescents aged 6 to 18 years.
• Treatment of renal disease in adult patients with hypertension and type 2 diabetes mellitus with proteinuria ≥ 0.5 g / day in the context of antihypertensive therapy (see sections 4.3, 4.4, 4.5 and 5.1).
• Treatment of chronic heart failure in adult patients, when treatment with angiotensin converting enzyme (ACE) inhibitors is not considered suitable due to incompatibility, especially cough, or contraindication. Patients with heart failure who have been stabilized on an ACE inhibitor should not be transferred to losartan. Patients must have a left ventricular ejection fraction ≤ 40% and must be clinically stable and on a stabilized chronic heart failure treatment regimen.
• Reduction of the risk of stroke in adult hypertensive patients with left ventricular hypertrophy documented by ECG (see section 5.1 LIFE Study, Race).
04.2 Posology and method of administration -
Dosage
Hypertension
For most patients, the usual starting and maintenance dosage is 50 mg once daily. The maximum antihypertensive effect is obtained 3-6 weeks after the start of therapy. Some patients may benefit further by increasing the dose to 100 mg once daily (in the morning).
Losartan can be administered with other antihypertensive drugs, especially with diuretics (e.g. hydrochlorothiazide) (see sections 4.3, 4.4, 4.5 and 5.1).
Hypertensive patients with type II diabetes and proteinuria ≥ 0.5 g / day
The usual dosage is 50 mg once daily. Dosage can be increased to 100 mg once daily based on blood pressure response from one month after initiation of therapy. Losartan can be administered with other antihypertensive agents (eg, diuretics, calcium channel blockers, alpha or beta blockers, and centrally acting medicinal products) (see sections 4.3, 4.4, 4.5 and 5.1) and with insulin and other commonly used hypoglycemic agents (eg sulfonylureas, glitazones and glycosidase inhibitors).
Heart failure
The starting dose of losartan in patients with heart failure is usually 12.5 mg once daily. Dosage should generally be titrated at weekly intervals (i.e. 12.5 mg per day, 25 mg per day, 50 mg per day, 100 mg per day, up to a maximum dose of 150 mg once daily), based on the patient tolerability.
Reduction of the risk of stroke in hypertensive patients with left ventricular hypertrophy documented on ECG
The starting dosage is usually 50 mg of losartan once daily. Based on blood pressure response, a low dose of hydrochlorothiazide should be added and / or the dose of losartan should be increased to 100 mg once daily.
Special populations
Use in patients with intravascular volume depletion
For patients with intravascular volume depletion (e.g. those treated with high-dose diuretics), a starting dose of 25 mg once daily should be considered (see section 4.4).
Use in patients with renal impairment and hemodialysis patients
No initial dosage adjustment is necessary in patients with renal impairment and on hemodialysis patients.
Use in patients with impaired hepatic function
A lower dosage should be considered for patients with a history of hepatic impairment. There is no therapeutic experience in patients with severe hepatic impairment. Therefore, losartan is contraindicated in patients with severe hepatic impairment (see sections 4.3 and 4.4).
Pediatric population
6 months - less than 6 years
Safety and efficacy in children aged 6 months to less than 6 years have not been established. Currently available data are described in sections 5.1 and 5.2 but no recommendation on a posology can be made.
From 6 years to 18 years
For patients who can swallow tablets, the recommended dosage is 25 mg once daily in patients weighing> 20 to
The dosage should be adjusted according to the blood pressure response.
In patients weighing> 50 kg the usual dosage is 50 mg once daily. In exceptional cases the dosage can be adjusted up to a maximum of 100 mg once daily. Dosages greater than 1.4 mg / kg (or greater than 100 mg) per day have not been studied in pediatric patients.
Losartan is not recommended for use in children less than 6 years of age as limited data are available in this patient group.
It is not recommended in children with glomerular filtration rate
Losartan is also not recommended in children with hepatic impairment (see also section 4.4).
Use in the elderly
Although consideration should be given to initiating therapy with 25 mg in patients over 75 years of age, dosage adjustment is not usually necessary in the elderly.
Method of administration
Losartan tablets should be swallowed with a glass of water.
Neo-lotan can be given with or without meals.
04.3 Contraindications -
• Hypersensitivity to the active substance or to any of the excipients (listed in sections 4.4 and 6.1).
• Second and third trimester of pregnancy (see sections 4.4 and 4.6).
• Severe impairment of liver function.
• The concomitant use of Neo-lotan with aliskiren-containing medicines is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate VFG
04.4 Special warnings and appropriate precautions for use -
Hypersensitivity
Angioedema. Patients with a history of angioedema (swelling of the face, lips, throat, and / or tongue) should be closely monitored (see section 4.8).
Hypotension and water and electrolyte imbalance
In volume-and / or sodium-depleted patients following strong diuretic therapy, low-sodium diet, diarrhea or vomiting, especially after the first dose and after dose escalation, symptomatic hypotension is likely to occur. These conditions should be corrected prior to administration of losartan or the latter should be used at a lower starting dose (see section 4.2). This also applies to children aged 6 to 18 years.
Electrolyte imbalance
Electrolyte imbalances are common in patients with impaired renal function, with or without diabetes, and should be considered. In a clinical study conducted in type 2 diabetic patients with nephropathy, the incidence of hyperkalaemia was higher in the losartan group than in the placebo group (see section 4.8). Therefore, plasma potassium concentrations and values creatinine clearance should be closely monitored, especially in patients with heart failure and creatinine clearance between 30 and 50 ml / min. Concomitant use of potassium-sparing diuretics, potassium supplements and salt substitutes is not recommended with losartan containing potassium (see section 4.5).
Hepatic impairment
Based on pharmacokinetic data demonstrating significant increases in plasma concentrations of losartan in cirrhotic patients, a lower dose should be considered for patients with a history of hepatic impairment. There is no therapeutic experience with losartan in patients with severe hepatic impairment. Losartan should therefore not be administered to patients with severe hepatic impairment (see sections 4.2, 4.3 and 5.2).
Losartan is not recommended in children with hepatic impairment (see section 4.2).
Kidney damage
As a consequence of inhibition of the renin-angiotensin system, changes in renal function including renal failure have been reported (in particular, in patients whose renal function is dependent on the renin-angiotensin-aldosterone system such as those with severe heart failure or dysfunction pre-existing renal). As with other medicinal products that affect the renin-angiotensin-aldosterone system, increases in blood urea and serum creatinine have also been reported in patients with bilateral renal artery stenosis or tributary artery stenosis of a single kidney; these changes of renal function may be reversible upon discontinuation of therapy. Losartan should be used with caution in patients with bilateral renal artery stenosis or tributary artery stenosis of a single kidney.
Use in pediatric patients with renal impairment
Losartan is not recommended in children with glomerular filtration rate
Renal function should be monitored regularly during losartan therapy as it may deteriorate.
This is particularly the case when losartan is administered in the presence of other conditions (fever, dehydration) which may impair kidney function.
Impaired renal function has been seen with the concomitant use of losartan and ACE inhibitors. Therefore, their concomitant use is not recommended (see section 4.5).
Kidney transplant
There is no experience in patients with recent kidney transplantation.
Primary hyperaldosteronism
Patients with primary aldosteronism generally unresponsive to antihypertensive medicinal products which act through inhibition of the renin-angiotensin system. Therefore, the use of losartan is not recommended.
Coronary heart disease and cerebrovascular disease
As with other antihypertensive agents, an excessive reduction in blood pressure in patients with cardiovascular ischaemia and cerebrovascular disease can cause myocardial infarction or stroke.
Heart failure
As with other medicinal products that affect the renin-angiotensin system, there is a risk of severe arterial hypotension, and (often acute) renal impairment in patients with heart failure with or without renal impairment.
There is limited therapeutic experience with losartan in patients with heart failure and concomitant severe renal impairment, in patients with severe heart failure (NYHA class IV) as well as in patients with heart failure and symptomatic life-threatening cardiac arrhythmias. Losartan should therefore be used with caution in these patient groups. The combination of losartan with a beta blocker should be used with caution (see section 5.1).
Stenosis of the aortic and mitral valves, obstructive hypertrophic cardiomyopathy
As with other vasodilator drugs, special caution should be exercised in patients with aortic or mitral valve stenosis, or with obstructive hypertrophic cardiomyopathy.
Excipients
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
Pregnancy
Losartan therapy should not be initiated during pregnancy. Unless continued losartan therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive therapy that has an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with losartan should be discontinued immediately and, if necessary, alternative therapy initiated (see sections 4.3 and 4.6).
Other warnings and precautions
As observed for angiotensin converting enzyme inhibitors, losartan and the other angiotensin antagonists are apparently less effective in lowering blood pressure in the black population than in the non-black population, possibly due to a higher prevalence of a low-renin condition in the black hypertensive population.
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 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 concomitantly in patients with diabetic nephropathy.
04.5 Interactions with other medicinal products and other forms of interaction -
Other antihypertensive agents may increase the hypotensive action of losartan. Concomitant use with other substances which may induce hypotension as an adverse reaction (such as tricyclic antidepressants, antipsychotics, baclofen and amifostine) may increase the risk of hypotension.
Losartan is predominantly metabolised by cytochrome P450 (CYP2C9) to the active carboxyacid metabolite. In a clinical study, fluconazole (inhibitor of CYP2C9) was found to decrease exposure to the active metabolite by approximately 50%. Concomitant treatment of losartan with rifampicin (inducer of metabolic enzymes) was shown to result in a 40% reduction in plasma concentration of the active metabolite. The clinical relevance of this effect is unknown. No difference in exposure was seen with concomitant treatment with fluvastatin (weak inhibitor of CYP2C9).
As with other medicines that block angiotensin II or its effects, concomitant use of other medicines that cause potassium retention (eg potassium-sparing diuretics: amiloride, triamterene, spironolactone) or may increase potassium levels (eg e.g. heparin), potassium supplements or potassium-containing salt substitutes may lead to increases in serum potassium. Simultaneous administration is not recommended.
Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. Very rare cases have also been reported with angiotensin II receptor antagonists. Co-administration of lithium with losartan should be undertaken with caution. If this combination is deemed essential, monitoring of serum lithium levels during concomitant use is recommended. .
When angiotensin II antagonists are administered simultaneously with non-steroidal anti-inflammatory drugs (such as selective COX-2 inhibitors, acetylsalicylic acid in anti-inflammatory doses and non-selective NSAIDs), "attenuation of the antihypertensive effect" may occur. Concomitant administration of antagonists of angiotensin II or diuretics and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and to an increase in serum potassium, especially in patients with pre-existing renal dysfunction. Co-administration should be done with caution, especially in the elderly patient. Patients should be adequately hydrated and monitoring of renal function should be considered after initiation of concomitant therapy and should then be performed periodically.
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).
04.6 Pregnancy and breastfeeding -
Pregnancy
The use of losartan is not recommended during the first trimester of pregnancy (see section 4.4). The use of losartan 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. Although controlled epidemiological data on the risk with Angiotensin II Receptor Inhibitors (AIIRAs) are not available, a similar risk may also exist for this class of medicinal products. For patients planning pregnancy, alternative antihypertensive treatment with a proven safety profile for use in pregnancy should be used unless continued AIIRA therapy is considered essential. When pregnancy is diagnosed, Losartan treatment should be stopped immediately and, if appropriate, alternative therapy should be initiated.
Exposure to AIIA therapy during the second and third trimester of pregnancy is known to induce fetal toxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) in women ( see also paragraph 5.3).
In case of exposure to losartan from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.
Neonates whose mothers have taken losartan should be closely monitored for hypotension (see also sections 4.3 and 4.4).
Feeding time
Since no information is available on the use of losartan during breastfeeding, the use of losartan is not recommended and alternative treatments with a proven better safety profile for use during breastfeeding are preferred, especially while breastfeeding an infant or premature infant.
04.7 Effects on ability to drive and use machines -
No studies on the ability to drive or use machines have been performed. However, it should be taken into account that occasionally dizziness or somnolence may occur when driving vehicles or operating machines during antihypertensive therapy, particularly at the start of treatment or with increasing dosage.
04.8 Undesirable effects -
Losartan was evaluated in clinical studies as follows:
• in controlled clinical trials in essential hypertension in> 3,000 adult patients 18 years of age and older
• in a controlled clinical study in 177 hypertensive pediatric patients aged 6 to 16 years
• in a controlled clinical study in> 9,000 hypertensive patients aged 55 to 80 years with left ventricular hypertrophy (see LIFE study, section 5.1)
• in a controlled clinical study in> 7,700 adult patients with chronic heart failure (see ELITE I, ELITE II and HEAAL studies, section 5.1)
• in a controlled clinical study in> 1,500 type 2 diabetic patients aged 31 years and older with proteinuria (see RENAAL study, section 5.1)
In these clinical studies, the most common adverse reaction was dizziness.
The frequency of adverse reactions listed below is defined using the following convention: very common (≥ 1/10); common (≥ 1/100,
Table 1. The frequency of adverse reactions identified from placebo-controlled clinical trials and from post marketing experience
* Including swelling of the larynx, glottis, face, lips, pharynx and / or tongue (causing airway obstruction); in some of these patients, angioedema had already occurred in the past with the administration of other medicines, including ACE inhibitors
** Including Henoch-Schönlein purpura
|| Especially in patients with intravascular depletion, eg. patients with severe heart failure or under treatment with a "high dose diuretics"
† Common in patients receiving 150 mg losartan instead of 50 mg
‡ In a clinical study in type 2 diabetic patients with nephropathy, hyperkalaemia> 5.5 mmol / l developed 9.9% of patients treated with losartan tablets and 3.4% of patients treated with placebo
§ Usually resolved with abort
The following additional adverse reactions occurred more frequently in patients receiving losartan than in those receiving placebo (frequencies not known): back pain, urinary tract infection and flu-like symptoms.
Renal and urinary disorders:
As a consequence of inhibition of the renin-angiotensin-aldosterone system, changes in renal function including renal failure have been reported in patients at risk; these changes in renal function may be reversible upon discontinuation of therapy (see section 4.4).
Pediatric population
The adverse reaction profile for pediatric patients appears to be similar to that seen in adult patients. Data in the pediatric population are limited.
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 www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose -
Symptoms of intoxication
Limited data are available on overdose in humans. The most likely manifestations of overdose would be hypotension and tachycardia. Parasympathetic (vagal) stimulation-induced bradycardia may occur.
Treatment of intoxication
Should symptomatic hypotension occur, supportive treatment should be undertaken.
The measures to be taken vary according to the timing of drug intake and the type and severity of symptoms. Stabilization of the cardiovascular system should be given priority. Following oral intake, administration of a sufficient dose of activated charcoal is indicated. . Thereafter, close monitoring of vital signs should be performed. Vital signs should be corrected if necessary.
Neither losartan nor the active metabolite can be removed by hemodialysis.
05.0 PHARMACOLOGICAL PROPERTIES -
05.1 "Pharmacodynamic properties -
Pharmacotherapeutic group: Angiotensin II antagonists, common.
ATC code: C09CA01.
Losartan is a synthetic angiotensin II (type AT1) receptor antagonist, for oral use. Angiotensin II, a potent vasoconstrictor, is the primary active hormone of the renin / angiotensin system and is a determining factor in the pathophysiology of hypertension. Angiotensin II binds to the AT1 receptor found in many tissues (eg vascular smooth muscle, adrenal glands, kidneys and heart) and stimulates several important biological processes, including vasoconstriction and the release of aldosterone. In addition, angiotensin II stimulates the proliferation of smooth muscle cells.
Losartan selectively blocks the AT1 receptor. In vitro And in vivo, both losartan and its pharmacologically active carboxylic acid metabolite E-3174 block any physiologically relevant activity of angiotensin II, regardless of origin and synthesis process.
Losartan has no agonist effect or blocks other hormone receptors or ion channels important for cardiovascular regulation. Furthermore, losartan does not inhibit ACE (kininase II), the enzyme that degrades bradykinin. Consequently, potentiation of bradykinin-mediated undesirable effects does not occur.
During administration of losartan, the removal of angiotensin II negative feedback on renin secretion leads to an increase in plasma renin activity (ARP). An increase in ARP results in an increase in plasma angiotensin II. Despite these increases, antihypertensive activity and suppression of plasma aldosterone concentration are maintained, indicating effective blockade of angiotensin II receptors. After discontinuation of losartan, ARP and angiotensin II values return to normal. baseline within three days.
Both losartan and its main active metabolite have a much greater affinity for the AT1 receptor than for the AT2 receptor. Weight equal, the active metabolite is 10 to 40 times more active than losartan.
Hypertension Studies
In controlled clinical trials, once daily administration of losartan to patients with mild to moderate essential hypertension produced statistically significant reductions in systolic and diastolic blood pressure. Measurement of blood pressure 24 hours post dose versus 5 - 6 hours post dose showed a reduction in blood pressure over 24 hours; the natural diurnal rhythm was maintained. The reduction in blood pressure at the end of the interval of dosage was equal to 70 - 80% of the effect observed 5 - 6 hours after the dose.
Discontinuation of losartan in hypertensive patients did not result in a rebound in blood pressure. Despite the marked decrease in blood pressure, losartan had no clinically significant effect on heart rate.
Losartan is equally effective in both genders, and in younger (under 65) and older hypertensive patients.
LIFE study
The Losartan Intervention For Endpoint Reduction in Hypertension [LIFE study] was a randomized, triple-blind, active-controlled study in 9,193 hypertensive patients aged 55 to 80 years with left ventricular hypertrophy documented on ECG. Patients were randomized. to receive Losartan 50 mg once daily or atenolol 50 mg once daily. In case of failure to achieve the desired blood pressure level (atenolol was subsequently increased to 100 mg once daily. Other antihypertensive drugs were added if necessary, except for ACE inhibitors, angiotensin II antagonists or beta-blockers to achieve the desired blood pressure level.
The mean duration of follow up was 4.8 years.
The primary endpoint was the composite endpoint of cardiovascular mortality and morbidity as measured by the reduction in the combined incidence of cardiovascular death, stroke and myocardial infarction. Blood pressure was significantly decreased to similar levels in the two groups. Treatment with losartan has resulted in a 13.0% risk reduction (p = 0.021, 95% confidence interval 0.77-0.98) compared to atenolol in patients who met the primary composite endpoint. This finding was mainly attributable to a reduction in the incidence of stroke.Treatment with losartan reduced the risk of stroke by 25% compared with atenolol (p = 0.001 95% confidence interval 0.63-0.89). The rates of cardiovascular death and myocardial infarction were not significantly different between the treatment groups.
Race
In the LIFE study, black patients treated with losartan had a higher risk of incurring the primary composite endpoint, i.e. of suffering a cardiovascular event (e.g. myocardial infarction, cardiovascular death) and especially stroke compared to black patients. Therefore the results observed with losartan compared to atenolol in the LIFE study with respect to cardiovascular morbidity / mortality are not applicable to black patients with hypertension and left ventricular hypertrophy.
RENAAL study
The Reduction of Endpoints in NIDDM with the Angiotensin II Receptor Antagonist Losartan study, RENAAL study, was a controlled clinical study conducted worldwide in 1,513 type 2 diabetes patients with proteinuria, with or without hypertension. 751 patients were treated with losartan. The aim of the study was to demonstrate a nephroprotective effect of losartan potassium against and in addition to the benefits associated with blood pressure control alone.
Patients with proteinuria and a serum creatinine of 1.3 - 3.0 mg / dl were randomized to treatment with losartan 50 mg once daily, titrated if necessary to achieve a blood pressure response, or with placebo, in the setting of conventional antihypertensive therapy which excluded ACE inhibitors and angiotensin II antagonists.
The researchers were instructed to titrate the study drug to 100 mg per day as appropriate; 72% of patients took the 100 mg daily dose most of the time. Other antihypertensive agents (diuretics, calcium channel blockers, alpha and beta blockers, and also centrally acting antihypertensive agents) were permitted as additional treatment depending on the requirements in both groups. Patients were followed up for up to 4.6 years (3.4 years on average).
The primary endpoint of the study was a composite endpoint of doubling of serum creatinine, end-stage renal failure (need for dialysis or transplantation) or death.
The results showed that treatment with losartan (327 events) compared to placebo (359 events) resulted in a 16.1% risk reduction (p = 0.022) in the number of patients reaching the primary composite endpoint. For the following individual and combined components of the primary endpoint, the results showed a significant risk reduction in the losartan group: 25.3% risk reduction for doubling serum creatinine (p = 0.006); 28.6% risk reduction for end-stage renal failure (p = 0.002); 19.9% risk reduction for end-stage renal failure or death (p = 0.009); 21.0% risk reduction for doubling of serum creatinine or end-stage renal failure (p = 0.01).
The all-cause mortality rate was not significantly different in the two treatment groups. Losartan was generally well tolerated in this study, as shown by the discontinuation rate due to adverse reactions which was comparable to the placebo group.
HEAAL study
The Heart Failure Endpoint Evaluation of Angiotensin II Antagonist Losartan (HEAAL) study was a controlled clinical study conducted worldwide in 3,834 patients aged 18 to 98 years with heart failure (NYHA class II-IV) who were intolerant to treatment with ACE inhibitor. Patients were randomized to receive losartan 50 mg once daily or losartan 150 mg, in addition to conventional therapy not containing ACE inhibitors.
Patients were followed up for over 4 years (median 4.7 years). The primary endpoint of the study was a composite endpoint of all cause death or hospitalization for heart failure.
The results showed that treatment with 150 mg losartan (828 events) compared to treatment with 50 mg losartan (889 events) resulted in a 10.1% risk reduction (p = 0.027 95% confidence interval 0 , 82-0.99) in the number of patients who met the primary composite endpoint. This was primarily attributable to a reduction in the incidence of hospitalization for heart failure. Treatment with 150 mg losartan reduced the risk of hospitalization for heart failure by 13.5% compared to treatment with 50 mg losartan (p = 0.025 95% confidence interval 0.76-0.98). The all-cause death rate was not significantly different between the treatment groups. Renal impairment, hypotension, and hyperkalaemia were more common in the 150 mg group than in the 50 mg group, but these adverse events did not result in significantly higher interruptions in therapy in the 150 mg group.
ELITE I and ELITE II studies
In the ELITE study conducted over 48 weeks in 722 patients with heart failure (NYHA class II-IV), no difference was observed between patients treated with losartan and those treated with captopril with respect to the primary endpoint of a long-term change in function. The observation from the ELITE I study, that losartan reduced the risk of mortality compared to captopril, was not confirmed by the subsequent ELITE II study, described below.
In ELITE II study, losartan 50 mg once daily (starting dose 12.5 mg, increased to 25 mg, then to 50 mg once daily) was compared with captopril 50 mg three times daily (starting dose 12.5 mg , increased to 25 mg and then to 50 mg three times a day). The primary endpoint of this prospective study was all cause mortality.
In this study, 3,152 patients with heart failure (NYHA class II-IV) were followed for nearly two years (median: 1.5 years) to determine whether losartan was superior to captopril in reducing all cause mortality. The primary endpoint showed no statistically significant difference between losartan and captopril in reducing all cause mortality.
In both comparator-controlled (non-placebo-controlled) clinical trials in patients with heart failure, the tolerability of losartan was superior to that of captopril as measured by a significantly lower incidence of discontinuation of therapy due to adverse reactions and a significantly lower cough frequency.
An increase in mortality was observed in the ELITE II study in a small subgroup (22% of all patients with heart failure) of patients taking beta-blockers at baseline.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
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)) 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 concurrently 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
Pediatric hypertension
The antihypertensive effects of losartan were demonstrated in a clinical study of 177 hypertensive pediatric patients aged 6 to 16 years with body weight> 20 kg and a glomerular filtration rate> 30 ml / min / 1.73m². Patients with body weight> 20 kg to 50 kg were given 5, 50 or 100 mg / day of losartan. At the end of three weeks, once-daily administration of losartan decreased trough blood pressure in a dose-dependent manner.
In general, there was a dose-response. The dose-response relationship was very evident when comparing the low-dose and medium-dose treatment groups (period I: -6.2 mmHg vs -11.65 mmHg), but was attenuated when comparing the medium-dose group to the high-dose group (period I: -11.65 mmHg vs -12.21 mmHg). The lowest doses studied, 2.5 mg and 5 mg , corresponding to an average daily dosage of 0.07 mg / kg, did not appear to be able to provide consistent antihypertensive efficacy.
These results were confirmed during period II of the study in which patients were randomized to continue losartan or placebo after three weeks of therapy. The difference in "blood pressure increase compared to the placebo group was greater in the medium dose treatment group (6.70 mmHg in the medium dose treatment group vs 5.38 in the high dose treatment group)." increase in trough diastolic blood pressure was however the same in patients treated with placebo and in those who continued losartan at the lowest dose in each group, again suggesting that the lowest dose in each group did not have a significant antihypertensive effect. .
The long-term effects of losartan on growth, puberty and general development have not been studied. The long-term efficacy of antihypertensive therapy with losartan in childhood in reducing cardiovascular morbidity and mortality has also not been established.
The effect of losartan on proteinuria was evaluated in a 12-week placebo and active (amlodipine) controlled clinical study in hypertensive (n = 60) and normotensive (n = 246) children with proteinuria. was defined as urinary protein / creatinine ratio ≥0.3. Hypertensive patients (aged 6 to 18 years) were randomized to treatment with losartan (n = 30) or amlodipine (n = 30). Normotensive patients ( aged 1 to 18 years) were randomized to treatment with losartan (n = 122) or placebo (n = 124). Losartan was given at doses ranging from 0.7 mg / kg to 1.4 mg / kg ( up to a maximum dose of 100 mg per day) Amlodipine was administered at doses ranging from 0.05 mg / kg to 0.2 mg / kg (up to a maximum dose of 5 mg per day).
Overall, after 12 weeks of treatment, patients receiving losartan had a statistically significant reduction from baseline in proteinuria of 36% versus a 1% increase in the placebo / amlodipine group (p≤0.001). Hypertensive patients receiving losartan had a reduction from baseline in proteinuria of -41.5% (95% CI -29.9; -51.1) versus + 2.4% (95% CI -22 , 2; 14.1) had in the amlodipine group. The reduction in both systolic and diastolic blood pressure was greater in the losartan group (-5.5 / -3.8 mmHg) than in the amlodipine group (-0.1 / + 0.8 mmHg) A small decrease in blood pressure (-3.7 / -3.4 mmHg) was observed in the losartan group compared to placebo in normotensive children. No significant correlation was noted between the decrease in proteinuria and blood pressure, however it is possible that the reduction in blood pressure is responsible, in pa rte, reduction of proteinuria in the losartan group.
The long-term effects of losartan in children with proteinuria were studied for up to 3 years in the open-label safety extension phase of the same study, in which all patients who completed 12 weeks of baseline were invited to participate. of study. A total of 268 patients entered the open-label extension phase and were re-randomized to losartan (n = 134) or enalapril (n = 134) and 109 patients had ≥3 years of follow-up (designated end point ≥ 100 patients who had completed 3 years of follow-up in the extension period). The intervals between the doses of losartan and enalapril, administered at the investigator's discretion, were 0.30 to 4.42 mg / kg / day and 0.02 to 1.13 mg / kg / day, respectively. During the extension phase of the study, the maximum daily doses of 50 mg per body weight 50 kg were not exceeded for most patients.
In summary, the results from the safety extension phase show that losartan was well tolerated and led to sustained reductions in proteinuria with no appreciable change in glomerular filtration rate (GFR) over 3 years. In normotensive patients (n = 205), enalapril had a numerically greater effect than losartan on proteinuria (-33.0% (95% CI -47.2, -15.0) vs -16.6% (95% CI -34.9, 6.8)) and GFR (9.4 (95% CI 0.4, 18.4) vs -4.0 (95% CI -13.1, 5.0) ml / min / 1.73 m²). In hypertensive patients (n = 49), losartan had a numerically greater effect on proteinuria (-44.5% (95% CI -64.8; -12.4) vs -39.5% (95% CI -62 , 5, -2.2)) and GFR (18.9 (95% CI 5.2, 32.5) vs -13.4 (95% CI -27.3, 0.6)) ml / min / 1.73m².
An open-label, dose-ranging clinical study was conducted to investigate the safety and efficacy of losartan in pediatric patients aged 6 months to 6 years with hypertension. A total of 101 patients were randomized to one of three different Initial doses of losartan administered open label: a low dose of 0.1 mg / kg / day (n = 33), a mean dose of 0.3 mg / kg / day (n = 34) or a high dose of 0, 7 mg / kg / day (n = 34). Of these patients, 27 were infants who were defined as children aged 6 months to 23 months. Study drug was titrated to the next dose level at 3 weeks, 6, and 9 in patients who had not reached the blood pressure goal and who were not yet on the maximum dose (1.4 mg / kg / day, not to exceed 100 mg / day) of losartan.
Of the 99 patients treated with study drug, 90 (90.9%) patients continued in the extension study with follow-up visits every 3 months. The mean duration of therapy was 264 days.
In summary, mean decrease from baseline in blood pressure was similar across all treatment groups (change from baseline in PAS (systolic blood pressure) at week 3 was -7.3, -7.6, and -6 , 7 mmHg for the low, medium, and high dose randomized groups, respectively; the decrease from baseline in PAD (diastolic blood pressure) at week 3 was -8.2, -5.1, and 6.7 mmHg for randomized low, medium and high dose groups); however, there was no statistically significant effect on dose-dependent response for PAS and PAD.
Losartan, at doses of 1.4 mg / kg, was generally well tolerated in hypertensive children aged 6 months to 6 years after 12 weeks of treatment. The overall safety profile appeared comparable between the treatment groups.
05.2 "Pharmacokinetic properties -
Absorption
Following oral administration, losartan is well absorbed and undergoes a first pass metabolism, from which an active carboxylic acid metabolite and other inactive metabolites are formed. The systemic bioavailability of losartan tablets is approximately 33%. Losartan and its active metabolite reach average concentration peaks in 1 hour and 3-4 hours, respectively.
Distribution
Both losartan and its active metabolite are ≥ 99% bound to plasma proteins, primarily albumin. The volume of distribution of losartan is 34 liters.
Biotransformation
Approximately 14% of an intravenously or orally administered dose of losartan is converted to its active metabolite. Following oral or intravenous administration of 14C-labeled losartan potassium, circulating radioactivity in plasma is mainly attributed to losartan and its active metabolite. Minimal conversion of losartan to its active metabolite was observed in approximately one percent of the individuals under study.
In addition to the active metabolite, inactive metabolites are also formed.
Elimination
Plasma clearances of losartan and its active metabolite are approximately 600 ml / min and 50 ml / min, respectively. Renal clearances of losartan and its active metabolite are approximately 74 mL / min and 26 mL / min, respectively.When losartan is administered orally, approximately 4% of the dose is excreted unchanged in the urine and approximately 6% of the dose is excreted as an active metabolite in the urine. The pharmacokinetics of losartan and its active metabolite are linear with oral doses of losartan potassium up to 200 mg.
After oral administration, the plasma concentrations of losartan and its active metabolite decrease in a polyexponential manner, with a terminal half-life of approximately 2 hours and 6-9 hours, respectively. With a dose of 100 mg once daily no accumulation occurs. significant in plasma neither of losartan nor its active metabolite.
Losartan and its metabolites are eliminated both via the bile and the urine. Following oral / intravenous administration of 14C-labeled losartan in humans, about 35% / 43% of radioactivity is recovered in the urine and 58% / 50% in the faeces.
Characteristics of patients
The plasma concentrations of losartan and its active metabolite observed in elderly hypertensive patients are not significantly different from those observed in young hypertensive patients.
Plasma levels of losartan were twice as high in hypertensive patients as in hypertensive men, while plasma levels of the active metabolite are not different between men and women.
In patients with mild to moderate alcoholic liver cirrhosis, the plasma levels of losartan and its active metabolite following oral administration were respectively 5 and 1.7 times higher than in young male volunteers (see sections 4.2 and 4.4).
Plasma concentrations of losartan are not altered in patients with a creatinine clearance above 10 ml / minute. Compared to patients with normal renal function, the AUC of losartan is approximately 2 times higher in patients on hemodialysis.
Plasma concentrations of the active metabolite are not altered in patients with renal impairment or in hemodialysis patients.
Neither losartan nor the active metabolite can be removed by hemodialysis.
Pharmacokinetics in pediatric patients
The pharmacokinetics of losartan were studied in 50 pediatric hypertensive patients> 1 month of age up to
The results showed that the active metabolite is formed from losartan in all age groups. The results showed that the pharmacokinetics of losartan following oral administration were generally similar in infants and toddlers, preschool children, school age children and adolescents. The pharmacokinetics of the metabolite differ most between the age groups. When comparing preschool children with adolescents these differences become statistically significant. Exposure in infants / young children was relatively high.
05.3 Preclinical safety data -
Non-clinical data reveal no special hazards for humans based on conventional studies of general pharmacology, genotoxicity and potential carcinogenicity. In repeat dose toxicity studies, administration of losartan resulted in a reduction in red blood cell parameters (erythrocytes, hemoglobin, hematocrit), an increase in serum N-urea levels and occasional increases in serum creatinine, a decrease in heart weight (without histological correlates) and gastrointestinal changes (mucosal lesions, ulcers, erosions, hemorrhages). substances acting directly on the renin-angiotensin system, losartan has been shown to induce adverse reactions in late fetal development, resulting in fetal death and malformations.
06.0 PHARMACEUTICAL INFORMATION -
06.1 Excipients -
Microcrystalline cellulose (E460);
lactose monohydrate;
pregelatinised maize starch;
magnesium stearate (E572);
hyprolose (E463);
hypromellose (E464).
Neo-lotan 12.5 mg, 50 mg and 100 mg contain potassium in the following quantities: 1.06 mg (0.027 mEq), 4.24 mg (0.108 mEq) and 8.48 mg (0.216 mEq) respectively.
Neo-lotan 12.5 mg tablets also contain Carnauba wax (E903), titanium dioxide (E171), indigo carmine aluminum lake (E132).
Neo-lotan 50 mg tablets also contain Carnauba wax (E 903), titanium dioxide (E171).
Neo-lotan 100 mg tablets also contain Carnauba wax (E 903), titanium dioxide (E171).
06.2 Incompatibility "-
Not relevant.
06.3 Period of validity "-
3 years.
06.4 Special precautions for storage -
Blisters: Store in the original package in order to protect from light and moisture.
HDPE bottles: Do not store above 25 ° C. Store in the original container in order to protect from light. Keep the bottle tightly closed to protect from moisture.
06.5 Nature of the immediate packaging and contents of the package -
NEO-LOTAN 12.5 mg - PVC / PE / PVDC blister and aluminum foil cover in cartons containing 7, 14, 21, 28, 50, 98, 210 and 500 tablets and a single dose pack of 28 tablets for hospital use . HDPE bottles of 100 tablets.
NEO-LOTAN 50 mg - PVC / PE / PVDC blister and aluminum foil cover in cartons containing 7, 10, 14, 20, 28, 30, 50, 56, 84, 90, 98, 280 and 500 tablets and one single-dose packs of 28, 56 and 98 tablets for hospital use. HDPE bottles of 100 and 300 tablets.
NEO-LOTAN 100 mg - PVC / PE / PVDC blister and aluminum foil cover in cartons containing 7, 10, 14, 15, 20, 28, 30, 50, 56, 84, 90, 98 and 280 tablets and one single-dose packs of 28, 56 and 98 tablets for hospital use. HDPE bottles of 100 tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling -
No special instructions.
07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -
Neopharmed Gentili S.r.l.
Via S.G. Cottolengo, 15 - 20143 Milan
08.0 MARKETING AUTHORIZATION NUMBER -
NEO-LOTAN 12.5 mg film-coated tablets
7 tablets n. 029385034
21 tablets n. 029385022
NEO-LOTAN 50 mg film-coated tablets
28 divisible tablets n. 029385010
NEO-LOTAN 100 mg film-coated tablets
28 tablets n. 029385046
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -
Date of first authorization: May 1995
Date of most recent renewal: May 2000
10.0 DATE OF REVISION OF THE TEXT -
May 2015
