Active ingredients: Candesartan cilexetil, hydrochlorothiazide
Blopressid 8 mg / 12.5 mg tablets Blopressid 16 mg / 12.5 mg tablets Blopressid 32 mg / 12.5 mg tablets Blopressid 32 mg / 25 mg tablets
Indications Why is Blopressid used? What is it for?
The name of the medicine is Blopressid. It is used to treat high blood pressure (hypertension) in adult patients. Contains two active ingredients: candesartan cilexetil and hydrochlorothiazide. These work together to lower blood pressure.
- Candesartan cilexetil belongs to a group of medicines called angiotensin II receptor antagonists. It causes blood vessels to relax and widen. This helps to reduce blood pressure.
- Hydrochlorothiazide belongs to a group of medicines called diuretics (which help you urinate). This helps the body eliminate water and salts such as sodium in the urine. This helps to reduce blood pressure.
Your doctor may prescribe Blopress Comp if your blood pressure has not been adequately controlled by candesartan cilexetil or hydrochlorothiazide alone.
Contraindications When Blopresid should not be used
Do not take Blopress Comp:
- if you are allergic to candesartan cilexetil or hydrochlorothiazide or any of the other ingredients of this medicine.
- if you are allergic to sulphonamide medicines. If you are not sure if this applies to you, consult your doctor.
- if you are more than 3 months pregnant (it is better to avoid the use of Blopress Comp also in the early stages of pregnancy - see pregnancy section).
- if you have severe kidney problems.
- if you have severe liver disease or biliary obstruction (a problem with the drainage of the bile from the gallbladder).
- if you have persistently low levels of potassium in your blood.
- if you have persistently high levels of calcium in your blood.
- if you have had gout. if you have diabetes or impaired kidney function and you are being treated with a blood pressure lowering medicine containing aliskiren.
If you are not sure if any of these apply to you, consult your doctor or pharmacist before taking Blopress Comp
Precautions for use What you need to know before taking Blopress Comp
Talk to your doctor before taking Blopress Comp:
- if you have diabetes.
- if you have heart, liver or kidney problems.
- if you have recently had a kidney transplant.
- if you are vomiting, have recently had severe vomiting or diarrhea.
- if you have a disease of the adrenal gland known as Conn's syndrome (also called primary aldosteronism).
- if you have ever had a disease called systemic lupus erythematosus (SLE).
- if you have low blood pressure.
- if you have had a stroke.
- if you have had allergies or asthma.
- tell your doctor if you think you are pregnant (or if there is a possibility of becoming pregnant). Blopress Comp is not recommended in early pregnancy, and must not be taken if you are more than 3 months pregnant, as it may cause serious harm to your baby if used at that stage (see pregnancy section).
- 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 (such as potassium) in your blood at regular intervals.
See also information under the heading "Do not take Blopress Comp".
Your doctor may need to see you more often and get tested if you have any of these conditions.
If you are about to have an operation, tell your doctor or dentist that you are taking Blopressid.
This is because Blopress Comp, when combined with some anesthetics, can cause a drop in blood pressure.
Blopress Comp can increase the skin's sensitivity to the sun.
Use in children
There is no experience with the use of Blopress Comp in children (under 18 years of age). Therefore Blopress Comp should not be given to children.
The hydrochlorothiazide contained in this drug can cause positive results in the anti-doping test.
For those who play sports: the use of the drug without therapeutic need constitutes doping and can in any case determine positive anti-doping tests
Interactions Which drugs or foods can modify the effect of Blopressid
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
Blopress Comp can affect the way some other medicines work, and some medicines can have an effect on Blopress Comp. If you are taking certain medicines, your doctor may need to have blood tests from time to time.
In particular, tell your doctor if you are taking any of the following medicines as your doctor may need to change your dose and / or take other precautions:
- Other medicines that help lower blood pressure, including beta blockers, diazoxide and ACE inhibitors such as enalapril, captopril, lisinopril or ramipril.
- Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, naproxen, diclofenac, celecoxib or etoricoxib (medicines to relieve pain and inflammation).
- Acetylsalicylic acid (if you are taking more than 3 g per day) (medicine to relieve pain and inflammation).
- Potassium supplements or potassium-containing salt substitutes (medicines that increase the level of potassium in the blood).
- Supplements of calcium or vitamin D.
- Medicines to lower cholesterol, such as colestipol or cholestyramine.
- Medicines for diabetes (oral tablets or insulin).
- Medicines to control the heartbeat (antiarrhythmic agents) such as digoxin and beta-blockers.
- Medicines whose action can be affected by blood potassium levels, such as some antipsychotic medicines.
- Heparin (a medicine to thin the blood).
- Medicines that help you pass urine (diuretics).
- Laxatives.
- Penicillin (an antibiotic).
- Amphotericin (for the treatment of fungal infections).
- Lithium (a medicine for mental health problems).
- Steroids, such as prednisolone.
- Pituitary hormone (ACTH).
- Medicines to treat cancer.
- Amantadine (to treat Parkinson's disease or for severe infections caused by viruses).
- Barbiturates (a type of sedative also used to treat epilepsy).
- Carbenoxolone (to treat esophageal disease or oral ulcers).
- Anticholinergic agents such as atropine and biperidene.
- Ciclosporin, a medicine used in organ transplants to prevent rejection.
- Other medicines which may potentiate the antihypertensive effect, such as baclofen (a medicine to relieve spasticity), amifostine (used to treat cancer) and some antipsychotic medicines.
If you are taking an ACE inhibitor or aliskiren (see also information under the headings: "Do not take Blopress Comp" and "Warnings and precautions").
Blopress Comp with food, drink and alcohol
- You can take Blopress Comp with or without food.
- When prescribed Blopress Comp, talk to your doctor before drinking alcohol. Alcohol can make you feel faint or lightheaded.
Warnings It is important to know that:
Pregnancy and breastfeeding
Pregnancy
You should tell your doctor if you think you are pregnant (or if there is a possibility of becoming pregnant). Normally your doctor will advise you to stop taking Blopress Comp before becoming pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of Blopress Comp. Blopress Comp is not recommended for women. early pregnancy, and must not be taken if you are more than 3 months pregnant, as it may cause serious harm to your baby if taken after the third month of pregnancy.
Feeding time
Tell your doctor if you are breastfeeding or about to start breastfeeding. Blopress Comp is not recommended for women who are breastfeeding and your doctor may choose another treatment for you if you wish to breastfeed, especially if the baby is newborn or was born prematurely. .
Driving and using machines
Some people may feel tired or lightheaded when taking Blopress Comp. If this happens to you, do not drive or use any tools or machines.
Blopress Comp contains lactose.
Lactose is a type of sugar. 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 Blopress Comp: Posology
Always take Blopress Comp exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist. It is important to keep taking Blopress Comp every day.
The recommended dose of Blopress Comp is one tablet once a day.
Swallow the tablet with a drink of water.
Try to take the tablet at the same time each day. This will help you remember to take it.
Blopress Comp 8 / 12.5 mg and 16 / 12.5 mg tablets: the tablets can be divided into equal doses.
Blopress Comp 32 / 12.5 mg and 32/25 mg tablets: the score line is only for dividing the tablet if you have difficulty swallowing it whole.
Overdose What to do if you have taken too much Blopress Comp
If you take more Blopress Comp than you should
If you take more Blopress Comp than prescribed by your doctor, contact a doctor or pharmacist immediately for advice.
If you forget to take Blopress Comp
Do not take a double dose to make up for a forgotten tablet. Just take the next dose as usual.
If you stop taking Blopress Comp
If you stop taking Blopress Comp, your blood pressure may rise again. So do not stop taking Blopress Comp without first talking to your doctor.
If you have any further questions on the use of Blopress Comp, ask your doctor or pharmacist.
Side Effects What are the side effects of Blopressid
Like all medicines, Blopress Comp can cause side effects, although not everybody gets them. It is important that you are aware of what these side effects may be.
Some of the side effects of Blopress Comp are caused by candesartan cilexetil and some are caused by hydrochlorothiazide.
Stop taking Blopress Comp and seek medical help immediately if you experience any of the following allergic reactions:
- difficulty in breathing, with or without swelling of the face, lips, tongue and / or throat.
- swelling of the face, lips, tongue and / or throat, which may cause difficulty in swallowing.
- severe itching of the skin (with raised blisters).
Blopress Comp can cause a reduction in the number of white blood cells. Your resistance to infection may decrease and you may notice tiredness, infection or fever. If this happens, contact your doctor. Your doctor may occasionally perform blood tests to check if Blopress Comp has had any effect on your blood (agranulocytosis).
Other possible side effects include:
Common (affects 1 to 10 users in 100)
- Changes in blood test results:
- A low amount of sodium in the blood. If this reduction is severe, then you may notice weakness, lack of energy or muscle cramps.
- An increased or decreased amount of potassium in your blood, especially if you already have kidney problems or heart failure. If this increase or decrease is severe, then you may notice tiredness, weakness, an irregular heartbeat or tingling.
- An increased amount of cholesterol, sugar or uric acid in the blood.
- Sugar in the urine.
- Feeling lightheaded / lightheaded or weak.
- Headache.
- Respiratory infection.
Uncommon (affects less than 1 user in 100)
- Low blood pressure. This can make you feel faint or lightheaded.
- Loss of appetite, diarrhea, constipation, stomach irritation.
- Skin rash, lumpy rash (hives), rash caused by sensitivity to sunlight.
Rare (affects less than 1 user in 1,000)
- Jaundice (yellowing of the skin or the whites of the eye). If this happens to you, contact your doctor immediately.
- Effects on how your kidneys work, especially if you already have kidney problems or heart failure.
- difficulty sleeping, depression, feeling of restlessness.
- Tingling or tingling in the arms or legs.
- Blurred vision for a short time.
- Abnormal heartbeat. Breathing difficulties (including lung inflammation and fluid in the lungs).
- High temperature (fever).
- Inflammation of the pancreas. This causes moderate to severe stomach pain.
- Muscle cramps.
- Damage to blood vessels causing red or purple spots to appear on the skin.
- A reduction in red or white blood cells or platelets. You may notice tiredness, infection, fever, easy swelling (bruising).
- Severe rash that develops rapidly, with blistering and peeling on the skin and sometimes in the mouth.
- Worsening of existing lupus erythematosus-like reactions or appearance of unusual skin reactions
Very rare (affects less than 1 user in 10,000)
- Swelling of the face, lips, tongue and / or throat.
- Itching.
- Back pain, pain in the joints and muscles.
- Changes in the way the liver works, including inflammation of the liver (hepatitis). You may notice tiredness, yellowing of the skin and whites of the eye and flu-like symptoms.
- Cough.
- Nausea.
Not known (frequency cannot be estimated from the available data)
- Sudden myopia
- Sudden pain in the eye (acute angle-closure glaucoma)
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse. By reporting side effects you can help provide more information on safety. of this medicine.
Expiry and Retention
- Keep out of the sight and reach of children.
- This medicine does not require any special storage conditions.
- Do not use Blopress Comp after the expiry date which is stated on the carton or blister after EXP. The expiry date refers to the last day of that month.
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.
What Blopresid contains
Blopresid tablets contain the following active ingredients: candesartan cilexetil and hydrochlorothiazide.
Blopress Comp 8 mg / 12.5 mg tablets contain 8 mg of candesartan cilexetil and 12.5 mg of hydrochlorothiazide.
Blopress Comp 16 mg / 12.5 mg tablets contain 16 mg of candesartan cilexetil and 12.5 mg of hydrochlorothiazide.
Blopress Comp 32 mg / 12.5 mg tablets contain 32 mg candesartan cilexetil and 12.5 mg hydrochlorothiazide.
Blopress Comp 32 mg / 25 mg tablets contain 32 mg of candesartan cilexetil and 25 mg of hydrochlorothiazide.
The other ingredients are calcium carmellose, hydroxypropylcellulose, lactose monohydrate, magnesium stearate, maize starch, macrogol, red iron oxide (E172) (Blopresid 16 mg / 12.5 mg and Blopressid 32 mg / 25 mg), yellow iron oxide ( E172) (Blopressid 32 mg / 12.5 mg).
Description of the appearance of Blopresid and contents of the pack
Blopress Comp 8 mg / 12.5 mg tablets are white, oval tablets approximately 8.5 mm by 5 mm with a score line and debossed with 8 / C on both sides. Blopress Comp 16 mg / 12.5 mg tablets are pale pink, oval tablets approximately 8.5 mm by 5 mm with a score line and debossed with 16 / C on both sides.Blopress Comp 32 mg / 12.5 mg tablets are light yellow, oval, approximately 11 mm by 6.5 mm flat tablets debossed with 32 / C1 on both sides.
Blopress Comp 32 mg / 25 mg tablets are light pink, oval, approximately 11 mm by 6.5 mm flat tablets debossed with 32 / C2 on both sides.
Blopress Comp tablets are presented in blister packs containing 7, 14, 20, 28, 50, 56, 98, 98x1 (single dose unit) (Blopressid 8 mg / 12.5 mg only), 100 or 300 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
BLOPRESID TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
One tablet of Blopress Comp 8 mg / 12.5 mg contains 8 mg of candesartan cilexetil and 12.5 mg of hydrochlorothiazide. Each Blopress Comp 8 mg / 12.5 mg tablet contains 76.9 mg of lactose monohydrate.
One tablet of Blopress Comp 16 mg / 12.5 mg contains 16 mg of candesartan cilexetil and 12.5 mg of hydrochlorothiazide. Each Blopress Comp 16 mg / 12.5 mg tablet contains 68.8 mg of lactose monohydrate.
One tablet of Blopress Comp 32 mg / 12.5 mg contains 32 mg of candesartan cilexetil and 12.5 mg of hydrochlorothiazide. Each Blopress Comp 32 mg / 12.5 mg tablet contains 150.2 mg of lactose monohydrate.
One tablet of Blopress Comp 32 mg / 25 mg contains 32 mg of candesartan cilexetil and 25 mg of hydrochlorothiazide. Each Blopress Comp 32 mg / 25 mg tablet contains 137.7 mg of lactose monohydrate.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Tablet.
Blopress Comp 8 mg / 12.5 mg tablets are white, oval, flat, scored with 8 / C on both sides. The tablets can be divided into equal halves.
Blopress Comp 16 mg / 12.5 mg tablets are light pink, oval, flat, scored, scored with 16 / C on both sides. The tablets can be divided into equal halves.
Blopress Comp 32 mg / 12.5 mg tablets are light yellow, oval, flat, debossed with 32 / C1 on both sides. The score line is only for dividing the tablet and facilitating swallowing and not for dividing the tablet into two equal halves.
Blopress Comp 32 mg / 25 mg tablets are light pink, oval, flat, debossed with 32 / C2 on both sides. The score line is only for dividing the tablet and facilitating swallowing and not for dividing the tablet into two equal halves.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Blopresid is indicated for:
• Treatment of essential hypertension in adult patients with blood pressure inadequately controlled by monotherapy with candesartan cilexetil or hydrochlorothiazide.
04.2 Posology and method of administration
Dosage
The recommended dose of Blopress Comp is one tablet once a day.
Dose titration with the individual components (candesartan cilexetil and hydrochlorothiazide) is recommended. If clinically appropriate, a direct switch from monotherapy to Blopress Comp may be considered. Dose titration of candesartan cilexetil is recommended when switching from hydrochlorothiazide monotherapy. Blopress Comp can be administered to patients whose blood pressure is not adequately controlled by monotherapy with candesartan cilexetil or hydrochlorothiazide or Blopress Comp at lower doses.
The maximum antihypertensive effect is usually achieved within 4 weeks of starting treatment.
Special populations
Elderly population
No dosage adjustment is necessary in elderly patients.
Patients with intravascular volume depletion
In patients at risk of hypotension, such as patients with possible intravascular volume depletion, a progressive increase of candesartan cilexetil is recommended (a starting dose of 4 mg may be considered in these patients).
Patients with impaired renal function
In these patients it is preferable to administer loop diuretics rather than thiazides. Dose titration of candesartan cilexetil is recommended in patients with mild to moderate renal impairment (creatinine clearance ≥ 30 ml / min / 1.73 m2 body surface area (BSA)) before switching to Blopress Comp (the recommended starting dose of candesartan cilexetil in these patients is 4 mg).
The use of Blopress Comp is contraindicated in patients with severe renal impairment (creatinine clearance 2 BSA) (see section 4.3).
Patients with impaired hepatic function
Dose titration of candesartan cilexetil is recommended in patients with mild to moderate hepatic impairment before switching to Blopress Comp (the recommended starting dose of candesartan cilexetil is 4 mg in these patients).
The use of Blopress Comp is contraindicated in patients with severe hepatic impairment and / or cholestasis (see section 4.3).
Pediatric population
The safety and efficacy of Blopress Comp have not been established in newborn children and up to 18 years of age. There are no data available.
Method of administration
Oral use.
Blopress Comp can be given without regard for food. The bioavailability of candesartan is not affected by food.
There is no clinically significant interaction between hydrochlorothiazide and food.
04.3 Contraindications
Hypersensitivity to the active substances or to any of the excipients or sulfonamide derivatives. Hydrochlorothiazide is a sulfonamide derivative.
Second and third trimester of pregnancy (see sections 4.4 and 4.6)
Severe renal impairment (creatinine clearance 2 BSA).
Severe impairment of liver function and / or cholestasis.
Refractory hypokalaemia and hypercalcemia.
Gout.
04.4 Special warnings and appropriate precautions for use
Altered kidney function / kidney transplant
In these patients it is preferable to administer loop diuretics rather than thiazides. When Blopressid is administered to patients with impaired renal function, it is recommended that potassium, creatinine and uric acid levels be monitored periodically.
The use of Blopress Comp in patients who have undergone a recent kidney transplant has not been tested.
Renal artery stenosis
Medicinal products that affect the renin-angiotensin-aldosterone system, including angiotensin II receptor antagonists (AIIRAs), may increase blood urea nitrogen and creatinine in patients with bilateral renal artery stenosis or renal artery stenosis in the presence of single kidney.
Intravascular volume depletion
Symptomatic hypotension may occur in patients with intravascular volume and / or sodium depletion, as described for other agents acting on the renin-angiotensin-aldosterone system. Therefore, the use of Blopress Comp is not recommended until this condition has been corrected.
Anesthesia and surgery
Hypotension due to blockade of the renin-angiotensin system may occur during anesthesia and surgery in patients treated with angiotensin II antagonists. Very rarely, hypotension can be so severe as to justify the use of intravenous fluids and / or vasopressor substances.
Altered liver function
Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, as minor disturbances in fluid and electrolyte balance can cause hepatic coma. There is no clinical experience with Blopressid in patients with impaired hepatic function.
Aortic and mitral stenosis (obstructive hypertrophic cardiomyopathy)
As with other vasodilators, special caution is recommended in patients with haemodynamically relevant aortic or mitral stenosis, or hypertrophic obstructive cardiomyopathy.
Primary hyperaldosteronism
Patients with primary aldosteronism generally do not respond to antihypertensive drugs which work by inhibiting the renin-angiotensin-aldosterone system. Therefore the use of Blopress Comp is not recommended in this population.
Electrolyte imbalance
Periodic determination of serum electrolytes should be performed at appropriate intervals. Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (hypercalcaemia, hypokalaemia, hyponatremia, hypomagnesaemia and hypochloraemic alkalosis).
Thiazide diuretics may decrease urinary calcium excretion and cause intermittent and mild increases in serum calcium concentrations. Marked hypercalcaemia may be a sign of latent hyperparathyroidism. Thiazides must be discontinued before performing parathyroid function tests.
Hydrochlorothiazide dose-dependently increases urinary excretion of potassium which may induce hypokalaemia. This effect of hydrochlorothiazide seems less evident when combined with candesartan cilexetil. The risk of hypokalaemia may be increased in patients with cirrhosis of the liver, with rapid diuresis, in patients with inadequate oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or adrenocorticotropic hormone (ACTH).
Treatment with candesartan cilexetil can cause hyperkalaemia, especially in the presence of heart failure and / or impaired renal function. Concomitant use of Blopress Comp and potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes or other drugs that may increase serum potassium levels (eg sodium heparin) may lead to increases in potassium. Monitoring should be performed. potassium, as needed.
Thiazides increase urinary excretion of magnesium, which can induce hypomagnesaemia.
Metabolic and endocrine effects
Treatment with a thiazide diuretic can impair glucose tolerance. Dosage adjustment of antidiabetic drugs, including insulin, may be necessary. Latent diabetes mellitus may become manifest during thiazide therapy. Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy. At the doses contained in Blopressid only minimal effects were reported. Thiazide diuretics increase uricaemia and can cause gout in predisposed patients.
Photosensitivity
Photosensitivity reactions have been reported during the use of thiazide diuretics (see section 4.8). In the event of a photosensitivity reaction it is recommended to discontinue the treatment. If it is necessary to restart treatment, it is recommended to protect the exposed parts of the body in sunlight or artificial UVA rays.
General aspects
In patients whose vascular tone and renal function are predominantly dependent on the activity of the renin-angiotensin-aldosterone system (eg patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with other medicinal products affecting this system, including AIIRAs, has been associated with acute hypotension, BUN, oliguria or, rarely, acute renal failure. As with other antihypertensive drugs, excessive decrease in blood pressure in patients with ischemic heart disease or atherosclerotic cerebrovascular disease can lead to myocardial infarction or stroke.
Hypersensitivity reactions to hydrochlorothiazide may occur, regardless of whether or not patients have a history of allergy or bronchial asthma, but are more likely in this type of patient.
Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide diuretics.
The antihypertensive effect of Blopress Comp can be enhanced by other antihypertensive agents.
This medicinal product contains lactose as an excipient and therefore patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption syndrome should not take this medicinal product.
Pregnancy
Angiotensin II receptor antagonist therapy (AIIRA) should not be initiated during pregnancy. Alternative antihypertensive treatments with a proven safety profile for use in pregnancy should be used for patients planning pregnancy. unless continued AIIRA therapy is considered essential. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
04.5 Interactions with other medicinal products and other forms of interaction
Compounds that have been tested in clinical pharmacokinetic studies include warfarin, digoxin, oral contraceptives (i.e. ethinyl estradiol / levonorgestrel), glibenclamide and nifedipine. No clinically relevant pharmacokinetic interactions were identified in these studies.
The potassium-depleting effect of hydrochlorothiazide could be potentiated by other drugs associated with potassium loss and hypokalaemia (eg, other kaliuretic diuretics, laxatives, amphotericin, carbenoxolone, penicillin sodium G, salicylic acid derivatives, steroids, ACTH) .
Concomitant use of Blopress Comp and potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes or other medicinal products that may raise serum potassium levels (eg sodium heparin), may lead to increases in potassium. potassium should be performed appropriately (see section 4.4).
Diuretic-induced hypokalaemia and hypomagnesaemia predispose to the potential cardiotoxic effects of digitalis glycosides and antiarrhythmics. It is recommended that potassium levels be checked periodically when Blopress Comp is administered with these drugs and with the following drugs that can induce torsades de pointes:
• Class Ia antiarrhythmics (eg quinidine, hydroquinidine, disopyramide)
• Class III antiarrhythmics (eg amiodarone, sotalol, dofetilide, ibutilide)
• Some antipsychotics (eg thioridazine, chlorpromazine, levomepromazine, trifluoperazine, ciamemazine, sulpiride, sultopride, amisulpride, thiapride, pimozide, haloperidol, droperidol)
• Others (eg bepridil, cisapride, difemanil, iv erythromycin, halofantrine, ketanserine, mizolastine, pentamidine, sparfloxacin, terfinadine, vincamine iv)
Reversible increases in serum lithium concentrations and toxic reactions have been reported during concomitant administration of lithium with Angiotensin Converting Enzyme (ACE) inhibitors or hydrochlorothiazide. A similar effect has also been reported with AIIRAs. The use of candesartan and hydrochlorothiazide with lithium is not recommended. If the combination proves necessary, careful monitoring of serum lithium levels is recommended.
When AIIRAs are administered simultaneously with non-steroidal anti-inflammatory drugs (NSAIDs) (eg, selective COX-2 inhibitors, acetylsalicylic acid (> 3g / day) and non-selective NSAIDs), "attenuation of the antihypertensive effect" may occur.
As with ACE inhibitors, concomitant use of AIIRAs and NSAIDs may lead to an increased risk of worsening of renal function including possible acute renal failure and increased serum potassium levels, especially in patients with pre-existing renal impairment. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and monitoring of renal function should be considered at the initiation of concomitant therapy and periodically thereafter. The diuretic, natriuretic and antihypertensive effect of hydrochlorothiazide is attenuated by non-steroidal anti-inflammatory drugs (NSAIDs).
Absorption of hydrochlorothiazide is reduced by colestipol or cholestyramine.
The effect of non-depolarising musculoskeletal relaxants (eg tubocurarine) can be enhanced by hydrochlorothiazide.
Thiazide diuretics can increase serum calcium levels due to decreased excretion.If calcium or vitamin D supplements are to be prescribed, serum calcium levels should be monitored and dosage adjusted accordingly.
The hyperglycemic effect of beta-blockers and diazoxide may be enhanced by thiazides.
Anticholinergic agents (e.g. atropine, biperidene) may increase the bioavailability of thiazide-type diuretics by reducing gastrointestinal motility and stomach emptying rate.
Thiazides may increase the risk of adverse events caused by amantadine.
Thiazides can reduce the renal excretion of cytotoxic drugs (eg cyclophosphamide, methotrexate) and enhance their myelosuppressive effects.
Postural hypotension can be aggravated by the simultaneous intake of alcohol, barbiturates or anesthetics.
Treatment with thiazide diuretics can reduce glucose tolerance. Dosage adjustments of antidiabetic drugs, including insulin, may be necessary. Metformin should be used with caution due to the risk of lactic acidosis induced by possible functional renal failure related to hydrochlorothiazide.
Hydrochlorothiazide may cause a decrease in the arterial response to pressor amines (eg adrenaline), but not such as to abolish the pressure effect.
Hydrochlorothiazide may increase the risk of acute renal failure, especially with high doses of iodinated contrast media.
Concomitant treatment with cyclosporine may increase the risk of hyperuricaemia and gout-type complications.
Concomitant treatment with baclofen, amifostine, tricyclic or neuroleptic antidepressants can lead to potentiation of the antihypertensive effect and induce hypotension.
04.6 Pregnancy and lactation
Pregnancy
Angiotensin II Receptor Antagonists (AIIRA)
The use of Angiotensin II Receptor Antagonists (AIIRAs) is not recommended during the first trimester of pregnancy (see section 4.4). The use of AIIRAs is contraindicated during the second and third trimesters 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 of Angiotensin II Receptor Antagonists (AIIRAs) are not available, a similar risk may also exist for this class of medicines. proven safety profile for use in pregnancy unless continued therapy with an AIIRA is considered essential.
When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately and, if appropriate, alternative therapy should be started.
Exposure to AIIRAs 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 section 5.3).
Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.
Neonates whose mothers have taken AIIRAs should be closely monitored for hypotension (see sections 4.3 and 4.4).
Hydrochlorothiazide :
Experience with the use of hydrochlorothiazide in pregnancy is limited, especially during the first trimester. Animal studies are insufficient.
Hydrochlorothiazide crosses the placenta. Considering the pharmacological mechanism of action of hydrochlorothiazide, its use during the second and third trimester of pregnancy can compromise fetal-placental perfusion and induce fetal and neonatal effects such as jaundice, alterations in electrolyte balance and thrombocytopenia.
Hydrochlorothiazide should not be used for gestational edema, gestational hypertension or preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, with no beneficial effect on the course of the disease.
Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare situations where no other treatment can be used.
Feeding time
Angiotensin II Receptor Antagonists (AIIRA)
Since no information is available on the use of Blopress Comp during breastfeeding, the use of Blopress Comp is not recommended and alternative treatments with a known better safety profile during breastfeeding are preferable, especially in the case of newborns or premature babies. .
Hydrochlorothiazide
Hydrochlorothiazide is excreted in human breast milk in minimal quantities. Thiazides, by causing intense diuresis in high doses, can inhibit milk production. The use of Blopress Comp while breastfeeding is not recommended.
04.7 Effects on ability to drive and use machines
No studies on the ability to drive and use machines have been performed. When driving vehicles or using machines, it should be taken into account that occasionally dizziness or fatigue may occur during treatment with Blopress Comp.
04.8 Undesirable effects
In controlled clinical trials with candesartan cilexetil / hydrochlorothiazide adverse reactions were mild and transient. Discontinuation of treatment due to adverse events was similar with candesartan cilexetil / hydrochlorothiazide (2.3-3.3%) and placebo (2.7-4.3%).
In clinical studies with candesartan cilexetil / hydrochlorothiazide, adverse reactions were limited to events previously observed with candesartan cilexetil and / or hydrochlorothiazide.
The table below presents the adverse reactions reported with candesartan cilexetil in clinical studies and in post-marketing experience. From a comprehensive analysis of data from clinical trials in hypertensive patients, adverse reactions with candesartan cilexetil were defined on the basis of " incidence of adverse events with candesartan cilexetil at least 1% higher than the incidence observed with placebo.
Frequencies used in the tables throughout section 4.8 are: very common (≥1 / 10), common (≥1 / 100,
1 / 10,000) and not known (frequency cannot be estimated from the available data)
The table below presents adverse reactions reported with hydrochlorothiazide alone generally at doses of 25 mg or higher.
04.9 Overdose
Symptoms
Based on pharmacological considerations, the main manifestation of candesartan cilexetil overdose should be symptomatic hypotension and dizziness. In individual reports of overdose (up to 672 mg candesartan cilexetil), the patient recovered without consequences.
The main manifestation of hydrochlorothiazide overdose is acute loss of fluids and electrolytes. Symptoms such as dizziness, hypotension, thirst, tachycardia, ventricular arrhythmias, sedation / altered consciousness and muscle cramps have also been observed.
Methods of intervention in case of overdose
No specific information is available in the treatment of overdose with Blopressid. In the event of an overdose, however, it is recommended that the following measures be taken.
When indicated, induction of vomiting or gastric lavage should be considered. If symptomatic hypotension occurs, symptomatic treatment should be instituted and vital functions monitored. The patient should be placed in a supine position with legs elevated. If this is not sufficient, the plasma volume should be increased by infusion of isotonic saline. Serum electrolytes and acid-base balance should be monitored and corrected if necessary. Sympathomimetic drugs can be administered in case the above measures are insufficient.
Candesartan cannot be removed by hemodialysis. The amount of hydrochlorothiazide that can be removed by hemodialysis is not known.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Angiotensin II antagonists + diuretics, ATC code: CO9DA06
Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and plays a role in the pathophysiology of hypertension and other cardiovascular diseases. It also plays a role in the pathogenesis of hypertrophy and organ damage. Major physiological effects of angiotensin II, such as vasoconstriction, stimulation of aldosterone, regulation of salt and water balance and stimulation of cell growth, are mediated through the type 1 receptor (AT1).
Candesartan cilexetil is a pro-drug that is rapidly converted to the active substance, candesartan, by ester hydrolysis during absorption from the gastrointestinal tract. Candesartan is a selective AIIRA for AT1 receptors, with close binding and slow dissociation from the receptor. He has no competitive activity.
Candesartan does not affect ACE or other enzyme systems usually associated with the use of ACE inhibitors. Since there is no effect on the breakdown of kinins or the metabolism of other substances, such as substance P, angiotensin II receptor antagonists (AIIRAs) are unlikely to be associated with cough. In controlled clinical trials comparing candesartan cilexetil with ACE inhibitors, the incidence of cough was lower in patients treated with candesartan cilexetil. Candesartan does not bind to or block other hormone receptors or ion channels that are important in cardiovascular regulation. L "AT1 receptor antagonism manifests itself in dose-related increases in plasma levels of renin, angiotensin I and angiotensin II, and in a decrease in plasma aldosterone concentrations.
The effects of candesartan cilexetil 8-16 mg (mean dose 12 mg), once daily, on cardiovascular morbidity and mortality were evaluated in a randomized clinical study in 4,937 elderly patients (age 70-89 years; of which 21% aged 80 years or older) with mild to moderate hypertension followed for a mean of 3.7 years (Study on Cognition and Prognosis in the Elderly). Patients received candesartan or placebo with other additional antihypertensive treatments as needed. Blood pressure was reduced from 166/90 to 145/80 mmHg in the candesartan group, and from 167/90 to 149/82 mmHg in the control group. There was no statistically significant difference in the primary end point, major cardiovascular events (cardiovascular mortality, non-fatal stroke and non-fatal myocardial infarction). There were 26.7 events per 1,000 patient-years in the candesartan group vs 30.0 events per 1,000 patient-years in the control group (relative risk 0.89, 95% CI 0.75 to 1.06, p = 0.19).
Hydrochlorothiazide inhibits the active reabsorption of sodium, mainly in the distal renal tubules and promotes the excretion of sodium, chlorine and water. Renal excretion of potassium and magnesium increases in a dose-dependent manner, while calcium is reabsorbed to a greater extent. Hydrochlorothiazide decreases plasma volume and extracellular fluids and reduces cardiac output and blood pressure. During long-term therapy, the reduction of peripheral resistance contributes to the reduction of blood pressure.
Extensive clinical studies have shown that long-term treatment with hydrochlorothiazide reduces the risk of cardiovascular morbidity and mortality.
Candesartan and hydrochlorothiazide have additive antihypertensive effects.
In hypertensive patients, Blopress Comp causes a dose-dependent and long-lasting reduction in blood pressure without reflex increases in heart rate. No severe or excessive effects of first dose hypotension or rebound effects were observed after discontinuation of treatment.
After administration of a single dose of Blopress Comp, the onset of the antihypertensive effect usually occurs within 2 hours. With continued treatment, the maximum antihypertensive effect on blood pressure is achieved within 4 weeks and is maintained during long-term treatment. Blopress Comp, administered once a day, results in an effective and homogeneous reduction in blood pressure over 24 hours, with a small difference between the peak and trough effects during the interval between doses. In a randomized study, in a double-blind manner, Blopress Comp 16 mg / 12.5 mg administered once daily significantly reduced blood pressure and controlled more patients than the combination losartan / hydrochlorothiazide 50 mg / 12.5 mg once a day.
In double-blind, randomized studies, the incidence of adverse events, especially cough, was lower during treatment with Blopress Comp than with the combination of ACE inhibitors and hydrochlorothiazide.
In two clinical trials (randomized, double-blind, placebo-controlled, parallel group) involving 275 and 1524 randomized patients, respectively, the 32 mg / 12.5 mg and 32 mg / 25 mg candesartan cilexetil / hydrochlorothiazide combinations induced blood pressure reductions of 22/15 mmHg and 21/14 mmHg, respectively, and appeared significantly more effective than their respective single components.
In a randomized, double-blind, parallel-group clinical trial comprising 1975 randomized patients inadequately controlled with 32 mg candesartan cilexetil once daily, the addition of 12.5 mg or 25 mg hydrochlorothiazide resulted in further reductions in blood pressure. blood pressure. The 32 mg / 25 mg candesartan cilexetil / hydrochlorothiazide combination was significantly more effective than the 32 mg / 12.5 mg combination, and the overall mean reductions in blood pressure were 16/10 mmHg, respectively. and 13/9 mmHg.
Candesartan cilexetil / hydrochlorothiazide is equally effective in all patients regardless of age and gender.
There are currently no data on the use of candesartan cilexetil / hydrochlorothiazide in patients with renal disease / nephropathy, reduced left ventricular function / congestive heart failure and post-myocardial infarction.
05.2 Pharmacokinetic properties
Concomitant administration of candesartan cilexetil and hydrochlorothiazide did not have a clinically significant effect on the pharmacokinetics of either substance.
Absorption and distribution
Candesartan cilexetil
Following oral administration, candesartan cilexetil is converted to the active substance candesartan. The absolute bioavailability of candesartan is approximately 40% after administration of an oral solution of candesartan cilexetil. The relative bioavailability of the tablet formulation compared to the oral solution is approximately 34% with very little variability.Mean peak concentration values (Cmax) are reached within 3-4 hours of tablet intake. Serum concentrations of candesartan increase linearly with increasing doses in the therapeutic range. No differences in candesartan pharmacokinetics were observed in either sex. The area under the curve (AUC) of serum concentration over time is not significantly affected by food.
Candesartan is highly bound to plasma proteins (more than 99%). The apparent volume of distribution of candesartan is 0.1 L / kg.
Hydrochlorothiazide
Hydrochlorothiazide is rapidly absorbed from the gastrointestinal tract with an absolute bioavailability of approximately 70%. Concomitant administration with food increases absorption by approximately 15%. Bioavailability may decrease in patients with heart failure and pronounced edema.
Plasma protein binding of hydrochlorothiazide is approximately 60%. The apparent volume of distribution is approximately 0.8 l / kg.
Biotransformation and elimination
Candesartan cilexetil
Candesartan is eliminated almost entirely unchanged via the urinary and biliary routes and only to a lesser extent via hepatic metabolism (CYP2C9). Available interaction studies indicate no effect on CYP2C9 and CYP3A4. Based on data in vitro, no interactions are expected in vivo with drugs whose metabolism depends on cytochrome P450, CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4 isoenzymes. The terminal half-life (t½) of candesartan is approximately 9 hours. No accumulation is observed following repeated dosing. The half-life of candesartan remains unchanged (approximately 9 hours) after administration of candesartan cilexetil in combination with hydrochlorothiazide. No additional accumulation of candesartan occurs after repeated administration of the combination compared to monotherapy.
Total plasma clearance of candesartan is approximately 0.37 mL / min / kg, with a renal clearance of approximately 0.19 mL / min / kg. Renal excretion occurs by both glomerular filtration and active tubular secretion. Following an oral dose of 14C-labeled candesartan cilexetil, approximately 26% of the dose is excreted in the urine as candesartan and 7% as an inactive metabolite, while approximately 56 % of the dose is found in the faeces as candesartan and 10% as the inactive metabolite.
Hydrochlorothiazide
Hydrochlorothiazide is not metabolised and is excreted almost entirely as unchanged drug by glomerular filtration and active tubular secretion. The terminal half-life (t½) of hydrochlorothiazide is approximately 8 hours. Approximately 70% of an oral dose is eliminated in the urine within 48 hours. The half-life of hydrochlorothiazide remains unchanged (approximately 8 hours) after administration of hydrochlorothiazide in combination with candesartan cilexetil. There is no additional accumulation of hydrochlorothiazide after repeated administration of the combination compared to monotherapy.
Pharmacokinetics in special populations
Candesartan cilexetil
In elderly subjects (over 65 years of age), both Cmax and AUC of candesartan are increased by approximately 50% and 80%, respectively, compared to young subjects. However, the blood pressure response and the incidence of adverse events are similar after administration of the same dose of Blopress Comp in young and elderly patients (see section 4.2).
In patients with mild and moderate renal impairment, candesartan Cmax and AUC during repeated dosing increased by approximately 50% and 70%, respectively, but t½ was not altered compared to patients with renal function. normal. Corresponding changes in patients with severe renal impairment were approximately 50% and 110%, respectively. The terminal t½ of candesartan was approximately doubled in patients with severe renal impairment. The pharmacokinetic profile in hemodialysis patients was similar to that of patients with severe renal impairment.
In two studies, both in patients with mild to moderate hepatic impairment there was an increase in mean AUC of candesartan of approximately 20% in one study and 80% in the other study (see section 4.2). experience in patients with severe hepatic impairment.
Hydrochlorothiazide
The terminal t½ of hydrochlorothiazide is prolonged in patients with renal impairment.
05.3 Preclinical safety data
No new toxic effects were observed with the combination compared to those observed with the individual components. In preclinical safety studies candesartan had effects on kidney and red cell parameters at high doses in mice, rats, dogs and monkeys. Candesartan caused a reduction in red blood cell parameters (erythrocytes, hemoglobin, hematocrit). Effects on the kidneys (such as regeneration, dilation and tubular basophilia; increased plasma concentrations of azotemia and creatinine) have been induced by candesartan and may be secondary to the hypotensive effect resulting in alterations in renal perfusion. The addition of hydrochlorothiazide enhances the nephrotoxicity of candesartan. Furthermore, candesartan induced hyperplasia / hypertrophy of the juxtaglomerular cells. These modifications can be considered as a consequence of the pharmacological action of candesartan and of little clinical relevance.
Foetotoxicity has been observed in advanced pregnancy with candesartan. The addition of hydrochlorothiazide did not significantly affect fetal development in rats, mice or rabbits (see section 4.6).
Candesartan and hydrochlorothiazide exhibit genotoxic activity at very high concentrations / doses. The genotoxicity data in vitro And in vivo indicate that candesartan and hydrochlorothiazide are unlikely to exert mutagenic or clastogenic activity under conditions of clinical use.
No carcinogenic phenomena were observed with either compound.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Calcium Carmellose Hydroxypropylcellulose
Red iron oxide E172 (Blopresid 16 mg / 12.5 mg and Blopresid 32 mg / 25 mg)
Yellow iron oxide E172 (Blopresid 32 mg / 12.5 mg)
Lactose monohydrate Magnesium stearate Maize starch
Macrogol
06.2 Incompatibility
Not relevant
06.3 Period of validity
3 years
06.4 Special precautions for storage
This medicine does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package
Blopresid 8 mg / 12.5 mg: Aluminum / Aluminum blisters or Polypropylene / Aluminum blisters inserted in a sealed Aluminum sachet of 7, 14, 20, 28, 50, 56, 98, 98x1, 100 and 300 tablets. Blopressid 16 mg / 12.5 mg: Aluminum / Aluminum blisters of 7, 14, 20, 28, 50, 56, 98, 100 and 300 tablets
Blopresid 32 mg / 12.5 mg: Aluminum blisters of 7, 14, 20, 28, 50, 56, 98, 100 and 300 tablets Blopresid 32 mg / 25 mg: Aluminum blisters of 7, 14, 20, 28, 50, 56, 98, 100 and 300 tablets
Not all pack sizes may be marketed
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
Takeda Italia SpA - Via E. Vittorini 129 - Rome
08.0 MARKETING AUTHORIZATION NUMBER
Blopressid 8 mg / 12.5 mg: 7 tablets AIC N ° 034187017 / M
Blopresid 8 mg / 12.5 mg: 14 tablets AIC N ° 034187029 / M
Blopresid 8 mg / 12.5 mg: 20 tablets AIC N ° 034187031 / M
Blopressid 8 mg / 12.5 mg: 28 tablets AIC N ° 034187043 / M
Blopresid 8 mg / 12.5 mg: 50 tablets AIC N ° 034187056 / M
Blopressid 8 mg / 12.5 mg: 56 tablets AIC N ° 034187068 / M
Blopresid 8 mg / 12.5 mg: 98 tablets AIC N ° 034187070 / M
Blopresid 8 mg / 12.5 mg: 98x1 tablets AIC N ° 034187082 / M
Blopressid 8 mg / 12.5 mg: 100 tablets AIC N ° 034187094 / M
Blopresid 8 mg / 12.5 mg: 300 tablets AIC N ° 034187106 / M
Blopresid 16 mg / 12.5 mg: 7 tablets AIC N ° 034187118 / M
Blopresid 16 mg / 12.5 mg: 14 tablets AIC N ° 034187120 / M
Blopresid 16 mg / 12.5 mg: 20 tablets AIC N ° 034187132 / M
Blopresid 16 mg / 12.5 mg: 28 tablets AIC N ° 034187144 / M
Blopresid 16 mg / 12.5 mg: 50 tablets AIC N ° 034187157 / M
Blopresid 16 mg / 12.5 mg: 56 tablets AIC N ° 034187169 / M
Blopresid 16 mg / 12.5 mg: 98 tablets AIC N ° 034187171 / M
Blopresid 16 mg / 12.5 mg: 100 tablets AIC N ° 034187183 / M
Blopresid 16 mg / 12.5 mg: 300 tablets AIC N ° 034187195 / M
Blopresid 32mg / 12.5 mg: 7 tablets AIC N ° 034187207 / M
Blopresid 32mg / 12.5mg: 14 tablets AIC N ° 034187219 / M
Blopresid 32mg / 12.5mg: 20 tablets AIC N ° 034187221 / M
Blopresid 32mg / 12.5mg: 28 tablets AIC N ° 034187233 / M
Blopresid 32mg / 12.5mg: 50 tablets AIC N ° 034187245 / M
Blopresid 32mg / 12.5mg: 56 tablets AIC N ° 034187258 / M
Blopresid 32mg / 12.5mg: 98 tablets AIC N ° 034187260 / M
Blopresid 32mg / 12.5mg: 100 tablets AIC N ° 034187272 / M
Blopresid 32mg / 12.5mg: 300 tablets AIC N ° 034187284 / M
Blopresid 32mg / 25mg: 7 tablets AIC N ° 034187296 / M
Blopresid 32mg / 25mg: 14 tablets AIC N ° 034187308 / M
Blopresid 32mg / 25mg: 20 tablets AIC N ° 034187310 / M
Blopresid 32mg / 25mg: 28 tablets AIC N ° 034187322
Blopresid 32mg / 25mg: 50 tablets AIC N ° 034187334
Blopresid 32mg / 25mg: 56 tablets AIC N ° 034187346
Blopresid 32mg / 25mg: 98 tablets AIC N ° 034187359
Blopresid 32mg / 25mg: 100 tablets AIC N ° 034187361
Blopresid 32mg / 25mg: 300 tablets AIC N ° 034187373
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Blopressid 8 mg / 12.5 mg: 18 June 1999/28 April 2007
Blopressid 16 mg / 12.5 mg: 24 August 2000/28 April 2007
Blopress Comp 32 mg / 12.5 mg and Blopress Comp 32 mg / 25 mg: 11 September 2009
10.0 DATE OF REVISION OF THE TEXT
January 2013
