Binosto - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Unwanted Effects Shelf Life and Storage Other Information

Active ingredients: Alendronic acid

Binosto 70 mg Effervescent Tablets

Why is Binosto used? What is it for?

What is Binosto?

Alendronate, the active substance in Binosto, belongs to a group of non-hormonal medicines called bisphosphonates. Binosto prevents the bone loss that occurs in women after the menopause and helps rebuild bone. Reduces the risk of spine and hip fractures.

What is Binosto used for?

Your doctor has prescribed Binosto for the treatment of osteoporosis. Binosto reduces the risk of fractures of the spine and hip.

Binosto must be taken once a week

What is osteoporosis?

Osteoporosis is a thinning and weakening of the bones. It is common in women after menopause. In menopause, the ovaries stop producing the female hormone, estrogen, which helps keep a woman's skeleton healthy. As a result, it occurs. bone loss and bone becomes weaker. The risk of osteoporosis is greater the earlier the woman reaches menopause.

In the early stages, osteoporosis usually has no symptoms. However, if treatment is not taken, fractures can occur. Although fractures are usually painful, fractures of the bones of the spine may not be felt until they are found. in a decrease in stature. Fractures can occur during normal daily activities such as lifting weights, or with minor injuries that would not be able to cause fractures in normal bone.Fractures normally occur in the hip, spine or wrist and can be not only painful but can lead to significant problems, such as a bowed back (widow's hump) and limitations in movement.

How can osteoporosis be treated?

Osteoporosis can be treated and it is never too late to start treatment. Binosto not only prevents bone loss but helps rebuild bone that may have been lost and reduces the risk of spine and spine fractures. hip.

Along with treatment with Binosto, your doctor may suggest lifestyle changes to improve the condition of the disease, such as:

  • Quitting smoking Smoking appears to increase the rate at which bone is lost and, therefore, may increase the risk of fractures.
  • Exercise Like muscles, bones need exercise to stay strong and healthy. Consult your doctor before starting any exercise program.
  • Balanced diet your doctor can advise you on your diet or tell you if you should take food supplements (especially calcium and Vitamin D).

Contraindications When Binosto should not be used

Do not take Binosto

  • if you are allergic (hypersensitive) to alendronate or any of the other ingredients of this medicine (listed in section 6)
  • if you have certain problems with your esophagus (the tube that connects your mouth with your stomach), such as narrowing and difficulty swallowing
  • if you are unable to stand or sit upright for at least 30 minutes
  • if your doctor has told you that you have low blood calcium levels.

If you think that any of these apply to you, do not take the effervescent tablets. Consult your doctor first and follow the directions given.

Precautions for use What you need to know before you take Binosto

Talk to your doctor or pharmacist or nurse before taking Binosto if:

  • suffer from kidney problems;
  • has difficulty swallowing or problems with the digestive system;
  • your doctor has told you that you have Barrett's esophagus (a disease associated with changes in the cells that line the lower part of the esophagus);
  • you have been told that you have low blood calcium levels;
  • have poor dental health, have gum disease, are planning to have a tooth extraction or do not have regular dental check-ups;
  • have cancer;
  • are undergoing chemotherapy or radiotherapy;
  • you are taking corticosteroids (such as prednisone or dexamethasone);
  • you are or have been a smoker (as this may increase the risk of dental problems).

You may be asked to have a dental check-up before starting treatment with Binosto.

It is important to maintain good oral hygiene while being treated with Binosto. You should have regular dental check-ups throughout your treatment and you should contact your doctor or dentist if you experience any kind of mouth or tooth problem such as loosening, pain or swelling.

There may be irritation, inflammation or ulceration of the esophagus (the tube that connects the mouth to the stomach) often with symptoms of chest pain, heartburn or difficulty or pain in swallowing, especially if patients have not used enough water to dissolve the effervescent tablets and / or if they spread during the first 30 minutes after taking Binosto These side effects may get worse if patients continue to take Binosto after experiencing these symptoms.

Children and adolescents:

Binosto should not be given to children and adolescents

Interactions Which drugs or foods may change the effect of Binosto

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Calcium supplements, antacids, and some oral medications are likely to interfere with the absorption of alendronate if taken at the same time.

It is therefore important to follow the instructions given in section 3. HOW TO TAKE BINOSTO.

Binosto with food and drink

Food and drinks (including mineral water) are likely to make Binosto less effective if taken at the same time. It is therefore important to follow the instructions given in section 3. HOW TO TAKE BINOSTO.

Warnings It is important to know that:

Pregnancy, breastfeeding and fertility

Binosto is only indicated for women after menopause. Do not take Binosto if you are pregnant or think you may be or if you are breastfeeding.

Driving and using machines

Side effects (for example, blurred vision, dizziness and severe bone, joint or muscle pain) have been reported with alendronate which may interfere with your ability to drive or use machines. Your individual response to alendronate may vary ( see section 4. POSSIBLE SIDE EFFECTS).

Binosto contains sodium

This medicinal product contains 26.2 mmol (or 602.54 mg) sodium per dose. This should be taken into consideration by patients on a low sodium diet.

Dose, Method and Time of Administration How to use Binosto: Posology

Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.

Binosto must be dissolved in half a glass of tap water before being taken. Do not chew or swallow the tablet whole.

Take one Binosto effervescent tablet once a week, as an oral solution.

To obtain benefits from treatment with Binosto it is necessary to carefully follow the instructions below:

  1. Choose the day of the week that best fits your activities. Take one effervescent tablet as an oral solution of Binosto each week on your chosen day. It is very important that you follow instructions 2), 3), 4) and 5) to facilitate the quick entry of the effervescent tablet, as an oral solution, of Binosto into the stomach and to help reduce the possibility of irritating the esophagus (the canal connecting the mouth to the stomach).
  2. After getting out of bed to start the day, and before taking any food, drink or other medication, dissolve the Binosto effervescent tablet in half a glass of tap water (not less than 120ml) (not mineral water). Once you have finished fizzing and the effervescent tablet has completely dissolved giving rise to a clear and colorless solution, drink this solution and then at least 30 ml of tap water (one sixth of a glass). You can drink additional water. If you see undissolved parts of the tablet, you can mix the solution until it is clear and colorless.
    • Do not take with mineral water (still or sparkling).
    • Do not take with coffee or tea.
    • Do not take with juice or milk.
    Do not swallow the undissolved effervescent tablet or chew or let the effervescent tablet dissolve in the mouth.
  3. Do not lie down - keep your torso upright (sitting, standing, walking) - for at least 30 minutes after drinking the oral solution containing the dissolved effervescent tablet. Do not relax until you have eaten something.
  4. You should not take Binosto at bedtime or before getting out of bed at the beginning of the day.
  5. If you experience difficulty or pain in swallowing, chest pain or develop or worsen heartburn, stop taking Binosto and contact your doctor.
  6. After drinking the oral solution containing the Binosto dissolved effervescent tablet, wait at least 30 minutes before eating, drinking or taking any other medicines of the day, including antacids, calcium supplements and vitamins. Binosto is only effective when taken on an empty stomach.

If you forget to take Binosto

If you forget to take a dose, simply take one effervescent tablet dissolved in tap water the next morning of the day you remember, following the instructions above in points 2), 3), 4), 5) and 6) . Do not take two effervescent tablets for oral solution on the same day.

Thereafter, resume taking the effervescent tablet for oral solution once a week, on your chosen day.

If you stop taking Binosto

It is important to continue taking Binosto for as long as your doctor prescribes it. Binosto is only effective for treating osteoporosis if you continue to take the effervescent tablets dissolved in tap water.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist or nurse.

Overdose What to do if you have taken too much Binosto

If you have accidentally taken too many Binosto effervescent tablets, drink a full glass of milk and contact your doctor immediately. Do not induce vomiting and do not lie down.

Side Effects What are the side effects of Binosto

Like all medicines, Binosto can cause side effects, although not everybody gets them.

All medicines can cause allergic reactions, although severe allergic reactions are very rare. Stop taking Binosto and contact your doctor immediately if you experience any of the following symptoms:

  • sudden wheezing, difficulty in breathing, swelling of the eyelids, face, throat, tongue, lips, rash or itching (especially if it affects the whole body)
  • a rash that gets worse with sunlight; blistering of the skin, eyes, mouth or genitals, itching or high fever (symptoms of severe skin reactions called Stevens-Johnson syndrome or toxic epidermal necrolysis).

If you have difficulty swallowing and / or pain when swallowing, feel pain behind your breastbone or if you notice your heartburn developing or worsening, stop taking Binosto and contact your doctor immediately. If you ignore these symptoms and continue to take your effervescent tablet, as an oral solution, these esophageal reactions are likely to get worse.

The following side effects have been reported:

Very common (may affect more than 1 in 10 people):

  • bone, muscle and / or joint pain which is sometimes severe.

Common (may affect up to 1 in 10 people):

  • heartburn, difficulty swallowing, pain on swallowing, ulceration of the esophagus (the tube that connects your mouth to your stomach) which can cause chest pain, heartburn or difficulty or pain in swallowing;
  • joint swelling;
  • abdominal pain, uncomfortable feeling in the stomach or belching after meals, constipation, feeling of fullness or bloating in the stomach, diarrhea, flatulence;
  • hair loss, itching;
  • headache, dizziness;
  • tiredness, swelling of the hands or legs.

Uncommon (may affect up to 1 in 100 people):

  • nausea, vomiting;
  • irritation or inflammation of the esophagus (the tube that connects your mouth to your stomach) or stomach
  • black or dark stools;
  • blurred vision, pain or redness of the eyes;
  • rash, redness of the skin;
  • transient flu-like symptoms, such as body aches, generally feeling unwell and sometimes with fever usually at the start of treatment;
  • change in taste.

Rare (may affect up to 1 in 1,000 people):

  • allergic reactions such as hives, swelling of the face, lips, tongue and / or throat, possibly causing difficulty in breathing and swallowing;
  • symptoms of low blood calcium levels including muscle cramps or spasms and / or a tingling sensation in the fingers or around the mouth;
  • stomach or peptic ulcers (sometimes severe or with bleeding);
  • narrowing of the esophagus (the tube that connects the mouth to the stomach);
  • rash made worse by exposure to sunlight, severe skin reactions;
  • pain in the mouth, and / or jaw, swelling or ulcers inside the mouth, numbness or a feeling of heaviness in the jaw, or loosening of a tooth. These could be signs of bone damage in the jaw ( osteonecrosis) usually associated with delayed healing and infection, often after tooth extraction Contact your doctor and dentist if you experience such symptoms;
  • an unusual fracture of the femur may rarely occur particularly in patients on long-term treatment for osteoporosis. Contact your doctor if you experience pain, weakness or discomfort in the thigh, hip or groin as this may be an early indication. of a possible fracture of the femur;
  • mouth ulcers when the tablets are chewed or sucked.

Very rare (may affect up to 1 in 10,000 people):

  • talk to your doctor if you have ear pain, ear discharge and / or ear infection. These episodes could be signs of bone damage in your ear.

Contact your doctor or pharmacist promptly if you experience these or any other unusual symptoms. It may be helpful to note which symptom occurs, when it begins, and how long it lasts.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at www.agenziafarmaco.gov. it / it / responsible. By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

Keep this medicine out of the sight and reach of children.

Do not use Binosto after the expiry date which is stated on the carton and strip after EXP. The expiry date refers to the last day of that month.

This medicinal product does not require any special storage temperatures. Store in the original package to protect from moisture. Do not remove the effervescent tablet from the strip until you are ready to take the medicine.

Do not throw any medicines in the drainage water 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 Binosto contains

The active ingredient is alendronate sodium trihydrate.

  • Each effervescent tablet contains 70 mg of alendronic acid as 91.37 mg of alendronate sodium trihydrate.
  • The other ingredients are: sodium citrate dihydrate, anhydrous citric acid, sodium hydrogen carbonate, anhydrous sodium carbonate, strawberry flavor [maltodextrin (maize), gum arabic, propylene glycol (E 1520), naturally identical flavoring substances], acesulfame potassium, sucralose.

What Binosto looks like and contents of the pack

Binosto is available as white to off-white, flat, round effervescent tablets with a diameter of 25 mm and with beveled edges. After dissolution of the tablet the solution is clear and colorless.

The effervescent tablets are supplied in composite foil strips. Each strip contains 2 individually packaged effervescent tablets. The strips are packaged in cardboard boxes in packs of 4, 12 or 24 effervescent 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.

Further information on Binosto can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT - 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION - 03.0 PHARMACEUTICAL FORM - 04.0 CLINICAL PARTICULARS - 04.1 Therapeutic indications - 04.2 Posology and method of administration - 04.3 Contraindications - 04.4 Special warnings and appropriate precautions for use - 04.5 Interactions with other medicinal products and other forms of interaction - 04.6 Pregnancy and lactation - 04.7 Effects on the ability to drive and use machines - 04.8 Undesirable effects - 04.9 Overdose - 05.0 PHARMACOLOGICAL PROPERTIES - 05.1 "Pharmacodynamic properties - 05.2 Pharmacokinetic properties" - 05.3 Preclinical safety data - 06.0 PHARMACEUTICAL PARTICULARS - 06.1 Excipients - 06.2 Incompatibility "- 06.3 Shelf life" - 06.4 Special precautions for storage - 06.5 Nature of the primary packaging and contents of the package - 06.6 Instructions for use and handling - 07.0 AUTHORIZATION HOLDER ALL "PLACING ON THE MARKET - 08.0 MARKETING AUTHORIZATION NUMBER - 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION - 10.0 DATE OF REVISION OF THE TEXT - 11.0 FOR RADIO DRUGS, COMPLETE DATA ON INTERNAL RADIATION DOSIMETRY - 12.0 INSTRUCTIONS FOR RADIOPHONES ON EXTEMPORARY PREPARATION AND QUALITY CONTROL -

01.0 NAME OF THE MEDICINAL PRODUCT -

BINOSTO 70 MG EFFERVESCENT TABLETS

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -

Each effervescent tablet contains 70 mg of alendronic acid as 91.37 mg of alendronate sodium trihydrate.

Excipients:

Each effervescent tablet contains 602.54 mg of sodium.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM -

Effervescent tablet.

White to off-white, flat, round effervescent tablets with a diameter of 25 mm and with beveled edges.After dissolution, the solution has a pH of 4.8 - 5.4.

04.0 CLINICAL INFORMATION -

04.1 Therapeutic indications -

Treatment of postmenopausal osteoporosis.

Binosto reduces the risk of vertebral and hip fractures.

04.2 Posology and method of administration -

Dosage

The recommended dose is one 70 mg effervescent tablet once weekly.

Patients should be advised that if they miss a dose of Binosto 70 mg,

they should take one effervescent tablet the morning after the day they notice it. You should not take two effervescent tablets on the same day but you must restart taking one effervescent tablet once a week, on the chosen day as previously established.

The optimal duration of bisphosphonate treatment for osteoporosis has not been established. The need for continued treatment should be reassessed in each individual patient periodically based on the potential benefits and risks of Binosto, particularly after 5 or more years of use. .

Pediatric population:

Alendronate sodium is not recommended for use in children below 18 years of age as there are insufficient data on safety and efficacy in conditions associated with pediatric osteoporosis (see also section 5.1).

Use in the elderly:

In clinical studies, no age-related difference in the efficacy or safety profiles of alendronate was demonstrated. Therefore, no dose adjustment is necessary in elderly patients.

Use in patients with renal impairment:

No dosage adjustment is necessary in patients with glomerular filtration rate (GFR) greater than 35 mL / min. Alendronate is not recommended in patients with impaired renal function when the GFR is less than 35 ml / min, as there is no experience in this regard.

Method of administration

To obtain adequate absorption of alendronate:

Binosto 70 mg should be taken at least 30 minutes before any food, drink or medicine of the day, with tap water only. Other beverages (including mineral water), food and some medicinal products are likely to reduce the absorption of alendronate (see section 4.5).

To facilitate reaching the stomach and thereby minimize the risk of local and oesophageal irritation and related adverse reactions (see section 4.4):

• Binosto 70 mg should only be taken after getting out of bed to start the day, dissolved in half a glass of tap water (not less than 120 ml). Dissolving the tablet in water produces a buffered solution at pH 4.8 - 5.4. The buffered solution must be drunk when it has finished fizzing and the effervescent tablet has completely dissolved giving rise to a buffered solution, clear and colorless, followed by at least 30 ml of tap water (one sixth of a glass). Additional tap water can be taken.

• Patients should not swallow the undissolved effervescent tablet, should not chew the effervescent tablet or let the effervescent tablet dissolve in their mouth due to the risk of oropharyngeal irritation (see sections 4.4 and 4.8).

• If the tablet does not dissolve completely, the buffered solution can be mixed until it is clear and colorless.

• Patients should not lie down until they have eaten something, which should be at least 30 minutes after drinking the oral solution.

• Patients should not lie down for at least 30 minutes after drinking the oral solution.

• Binosto 70 mg should not be taken at bedtime or before getting out of bed at the beginning of the day.

• Binosto 70 mg can be given to patients who are unable or refuse to swallow tablets.

Patients should take calcium and vitamin D supplements if dietary intake is inadequate (see section 4.4).

Binosto 70 mg has not been studied for the treatment of glucocorticoid-induced osteoporosis.

04.3 Contraindications -

• Hypersensitivity to alendronate or to any of the excipients listed in section 6.1.

• Disorders of the esophagus and other factors that delay oesophageal emptying, such as stricture or achalasia.

• Inability to stand or sit upright for at least 30 minutes.

• Hypocalcemia.

• See also section 4.4.

04.4 Special warnings and appropriate precautions for use -

Alendronate may cause local irritation of the upper gastrointestinal mucosa. Due to the potential for worsening of the underlying disease, caution should be exercised when administering alendronate to patients with active upper gastrointestinal disorders such as dysphagia, oesophageal, gastritis, duodenitis, ulcers or with a recent (1 year) history of major gastrointestinal disease such as peptic ulcer or active gastrointestinal bleeding or upper gastrointestinal surgery excluding pyloroplasty (see section 4.3). In patients with known Barrett's esophagus, prescribers should weigh the potential benefits and risks of alendronate on an individual basis.

Esophageal reactions (some severe and requiring hospitalization) such as esophagitis, esophageal erosions and esophageal ulcers, rarely followed by esophageal strictures, have been reported in patients receiving alendronate. The physician should, therefore, be alert for any signs or symptoms that indicate a possible esophageal reaction and advise the patient to discontinue alendronate and seek medical attention if symptoms of esophageal irritation such as dysphagia, pain or swelling occur. retrosternal pain, new or worsening heartburn.

The risk of severe esophageal adverse experiences appears to be greater in patients who do not take alendronate properly and / or who continue to take alendronate after developing symptoms suggestive of oesophageal irritation. It is very important that the patient knows and understands how to take the drug (see section 4.2). The patient should be advised that if these precautions are not followed, the risk of esophageal problems may increase.

While no increased risk was observed in large clinical trials with alendronate tablets, rare (post-marketing) cases of gastric and duodenal ulcers, some serious and associated with complications, have been reported.

Osteonecrosis of the jaw, usually associated with tooth extraction and / or local infection (including osteomyelitis), has been reported in cancer patients receiving regimens including bisphosphonates administered primarily intravenously. Many of these patients were also treated with chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported in patients with osteoporosis being treated with oral bisphosphonates.

When assessing the individual's risk of developing osteonecrosis of the jaw, the following risk factors should be considered:

• potency of the bisphosphonate (highest for zoledronic acid), route of administration (see

above) and cumulative dose.

• cancer, chemotherapy, radiotherapy, corticosteroids, smoking.

• a history of dental disease, poor oral hygiene, periodontal disease, procedures

invasive dentistry and dentures with poor adherence.

Before starting bisphosphonate treatment in patients with poor dental health, the need for a dental examination with appropriate preventive dental procedures should be considered.

During treatment, these patients should, if possible, avoid invasive dental procedures. In patients who have developed osteonecrosis of the jaw during bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest that discontinuation of treatment with bisphosphonates reduce the risk of osteonecrosis of the jaw. The clinical judgment of the physician must guide the management program of each patient, based on the individual assessment of the risk / benefit ratio.

During treatment with bisphosphonates, all patients should be encouraged to maintain good oral hygiene, to undergo periodic dental check-ups, and to report any type of oral symptoms such as tooth mobility, pain, or swelling.

Bone, joint and / or muscle pain has been reported in patients treated with bisphosphonates. In post-marketing experience these symptoms have rarely been severe and / or have caused disability (see section 4.8). The time to onset of symptoms ranged from one day to several months after initiation of treatment. Discontinuation resulted in symptom relief in most patients. Following re-administration of the same drug or another bisphosphonate, a subset of patients experienced symptom relapse.

Atypical fractures of the femur

Atypical subtrochanteric and diaphyseal fractures of the femur have been reported, mainly in patients on long-term bisphosphonate therapy for osteoporosis. These short transverse or oblique fractures can occur anywhere in the femur from just below the lesser trochanter to above the supracondylar line. These fractures occur spontaneously or after minimal trauma and some patients experience thigh or groin pain, often associated with imaging evidence of stress fractures, weeks or months before a hip fracture occurs. complete. Fractures are often bilateral; therefore, in patients treated with bisphosphonates who have sustained a fracture of the femoral shaft, the contralateral femur should be examined. Limited healing of these fractures has also been reported. In patients with suspected atypical femoral fracture, consideration should be given to discontinuing bisphosphonate therapy pending an assessment of the patient based on the individual benefit-risk ratio.

During treatment with bisphosphonates, patients should be advised to report any pain in the thigh, hip or groin and any patient who exhibits such symptoms should be evaluated for the presence of an incomplete femur fracture.

In post-marketing experience with alendronate there have been rare reports of severe skin reactions, including Stevens Johnson syndrome and toxic epidermal necrolysis.

Osteonecrosis of the external auditory canal has been reported in conjunction with the use of bisphosphonates, predominantly in association with long-term therapy. Possible risk factors for osteonecrosis of the external auditory canal include the use of steroids and chemotherapy and / or local risk factors such as infection or trauma. Osteonecrosis of the external auditory canal should be considered in patients treated with bisphosphonates who have ear symptoms, including chronic ear infections.

The use of alendronate is not recommended in patients with renal impairment when the GFR is less than 35 ml / min (see section 4.2).

Pediatric population:

Alendronate sodium is not recommended for use in children below 18 years of age as there are insufficient data on safety and efficacy in conditions associated with pediatric osteoporosis (see also sections 4.2 and 5.1).

Causes of osteoporosis other than estrogen deficiency and age or use of glucocorticoids must be carefully considered.

Hypocalcaemia must be corrected prior to initiation of alendronate therapy (see section 4.3). Other disorders of mineral metabolism (such as vitamin D deficiency and hypoparathyroidism) should also be adequately treated before starting treatment with Binosto. In patients with these clinical conditions, monitoring of serum calcium levels and symptoms of hypocalcaemia should be performed during therapy with Binosto 70 mg.

Due to the positive effect of alendronate on increased bone mineralization, decreases in serum calcium and phosphates may occur especially in patients taking glucocorticoids in whom calcium absorption may be reduced. Such decreases are usually limited and asymptomatic However, there have been rare reports of symptomatic hypocalcaemia, occasionally serious and often in patients with predisposing conditions (eg hypoparathyroidism, vitamin D deficiency and calcium malabsorption).

In patients receiving glucocorticoids it is particularly important to ensure an adequate intake of calcium and vitamin D.

Excipients

This drug contains 26.2 mmol (or 602.54 mg) of sodium per dose. To be taken into consideration in people on a low sodium diet.

04.5 Interactions with other medicinal products and other forms of interaction -

Food and beverages (including mineral water), calcium supplements, antacids and other oral medications, when taken at the same time as alendronate, are likely to interfere with the absorption of alendronate. Consequently, patients should allow at least 30 minutes after 'taking' alendronate before taking any other oral medication (see sections 4.2 and 5.2).

In healthy volunteers, prednisone administered orally (20 mg three times daily for five days) did not produce a clinically significant change in the oral bioavailability of alendronate (a mean increase of between 20% and 44%).

No other clinically relevant interactions with medicinal products are expected. During clinical trials a number of patients took estrogen (intravaginally, transdermally or orally) while taking alendronate. No adverse reactions attributable to their concomitant use have been identified.

Since the use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) is associated with gastrointestinal irritation, caution should be exercised during concomitant treatment with alendronate.

Although no specific interaction studies have been conducted, alendronate has been used in clinical studies concomitantly with a wide range of medicinal products with no evidence of adverse clinical interactions.

04.6 Pregnancy and breastfeeding -

Pregnancy

Alendronate should not be used during pregnancy. There are no adequate data on the use of alendronate in pregnant women. Animal studies do not indicate direct harmful effects with respect to pregnancy, embryo / fetal development or postnatal development. L "alendronate caused dystocia due to hypocalcaemia in pregnant rats (see section 5.3).

Feeding time

It is not known whether alendronate is excreted in human milk. Given the indications, alendronate should not be used by breastfeeding women.

Fertility

Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over a period of years. The amount of bisphosphonates incorporated into adult bone, and therefore, the amount available for release into the systemic circulation, is directly related to the dose and duration of bisphosphonate use (see section 5.2). There are no data on risk. fetal in man. However, there is a theoretical risk of fetal harm, mainly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact on risk of variables such as the time from cessation of bisphosphonate therapy to conception, the type of bisphosphonate used, and the route of administration (intravenous versus oral) has not been studied.

04.7 Effects on ability to drive and use machines -

No studies on the effects on the ability to drive and use machines have been performed. However, some adverse reactions that have been reported with alendronate may affect the ability to drive or use machines in some patients. Individual responses to alendronate may vary (see section 4.8).

04.8 Undesirable effects -

In a one-year study in postmenopausal women with osteoporosis, the overall safety profile of alendronate 70 mg once weekly (n = 519) and alendronate 10 mg / day (n = 370) were similar. .

In two 3-year studies with approximately the same design, in postmenopausal women (alendronate 10 mg: n = 196, placebo: n = 397), the overall safety profile of alendronate 10 mg and that of the placebo group are similar results.

Adverse reactions reported by investigators as possible, probable, or certain drug related reactions are presented below if they occurred in> 1% in one of the groups treated in the one-year study, or in> 1% of patients treated with alendronate 10 mg / day and with a higher incidence than placebo-treated patients in the three-year studies.

1 YEAR STUDY 3 YEAR STUDY alendronate 70 mg once weekly (n = 519)% alendronate 10 mg / day (n = 370)% alendronate 10mg / day (n = 196)% placebo (n = 397)% Gastro-intestinal abdominal pain 3.7 3.0 6.6 4.8 dyspepsia 2.7 2.2 3.6 3.5 acid regurgitation 1.9 2.4 2.0 4.3 nausea 1.9 2.4 3.6 4.0 abdominal distension 1.0 1.4 1.0 0.8 constipation 0.8 1.6 3.1 1.8 diarrhea 0.6 0.5 3.1 1.8 dysphagia 0.4 0.5 1.0 0.0 flatulence 0.4 1.6 2.6 0.5 gastritis 0.2 1.1 0.5 1.3 gastric ulcer 0.0 1.1 0.0 0.0 esophageal ulcer 0.0 0.0 1.5 0.0 Musculoskeletal Musculoskeletal pain (bone, muscle or joint) 2.9 3.2 4.1 2.5 Muscle cramps 0.2 1.1 0.0 1.0 Neurological Headache 0.4 0.3 2.6 1.5

The following adverse reactions have been reported during clinical trials and / or post-marketing use of alendronate tablets for oral use:

Adverse reactions Very common (≥1 / 10) Common (≥ 1/100, Uncommon (≥1 / 1000, Rare (≥1 / 10,000, Very Rare ( Disorders of the immune system hypersensitivity reactions including urticaria and angioedema Metabolism and nutrition disorders: symptomatic hypocalcemia, often in association with predisposing conditions #. Nervous system disorders: headache, dizziness dysgeusia§ Eye disorders inflammation of the eye (uveitis, scleritis, or episcleritis) Ear and labyrinth disorders vertigo§ ‡ Gastrointestinal disorders abdominal pain, dyspepsia, constipation, diarrhea, flatulence, oesophageal ulcer *, dysphagia *, abdominal distension, acid regurgitation nausea, vomiting, gastritis, oesophagitis *, esophageal erosions *, melaena§ oesophageal stricture *, oropharyngeal ulceration *, upper gastrointestinal UP (Bleeding, Ulcers, Perforation) # Skin and subcutaneous tissue disorders alopecia§, pruritus§ rash, erythema Rash with photosensitivity, severe skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis + Musculoskeletal, connective tissue and bone disorders musculoskeletal (bone, muscle or joint) pain which is sometimes severe # § joint swelling § Atypical subtrochanteric and diaphyseal fractures of the femur (bisphosphonate class adverse reaction) #, osteonecrosis of the jaw§ +, stress fractures of the proximal femoral shaft§ + Osteonecrosis of the external auditory canal (adverse reaction for the bisphosphonate class) General disorders and administration site conditions asthenia§, peripheral edema§ transient symptoms as in the acute phase response (myalgia, malaise and rarely fever), typically associated with the initiation of treatment.

# See section 4.4

§ The frequency in clinical trials was similar in both the drug and placebo groups.

* See sections 4.2 and 4.4

+ This adverse reaction was identified through post-marketing monitoring. The frequency of "rare" was estimated based on relevant clinical studies

‡ These adverse reactions have been identified with the tablet formulation and may not apply to Binosto 70 mg, which is taken as a buffered oral solution.

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 -

Hypocalcaemia, hypophosphataemia and upper gastrointestinal adverse events such as gastric disturbances, heartburn, esophagitis, gastritis or ulcer, may be the consequence of oral overdose.

No specific information is available on the treatment of an overdose with alendronate. Milk or antacids that bind to alendronate should be given. Due to the risk of esophageal irritation, do not induce vomiting and the patient must remain strictly erect.

05.0 PHARMACOLOGICAL PROPERTIES -

05.1 "Pharmacodynamic properties -

Pharmacotherapeutic group: drugs acting on bone structure and mineralization, bisphosphonates.

ATC code: M05BA04.

The active substance in Binosto 70 mg is alendronate sodium trihydrate.

It is a bisphosphonate which acts as an osteoclast-mediated bone resorption inhibitor with no direct effect on bone formation. Preclinical studies have shown that alendronate preferentially localizes to sites of active resorption. Activity is inhibited, but osteoclast recruitment and adhesion are not affected. The bone tissue formed during treatment with alendronate is qualitatively normal.

Esophageal toxicity associated with alendronate treatment, also known as drug esophagitis, is a multifactorial effect that appears to be mediated primarily by local irritation of the esophageal mucosa due to a crystalline substance. Gastroesophageal acid reflux may be a concomitant risk factor, as acid blockade is one of the main treatments when alendronate-associated "esophagitis" occurs. Binosto 70 mg effervescent tablets, administered as a buffered solution, was developed to completely solubilize alendronate in a drinkable solution at high pH, ​​with the ability to neutralize the acid, to minimize the contact of particulate alendronate with the mucosa and to prevent the presence of strong gastric acidity in the stomach, decreasing the potential damage in cases of esophageal reflux. Please refer to section 4.8 for post marketing data collected in the United States.

Treatment of postmenopausal osteoporosis

Osteoporosis is defined as bone mineral density (BMD) of the spine or hip 2.5 SD (standard deviations) below the mean of a normal young population or as a previous fragility fracture, independent of BMD.

The therapeutic equivalence of alendronate 70 mg once weekly (n = 519) and alendronate 10 mg / day (n = 370) was demonstrated in a one-year multicenter study of postmenopausal women with osteoporosis. mean lumbar spine BMD from baseline at one year was 5.1% (95% CI 4.8, 5.4%) in the 70 mg once-weekly group and 5.4% (95 % CI 5.0, 5.8%) in the 10 mg / day group. Mean increases in BMD were 2.3% and 2.9% at the femoral neck and 2.9% and 3.1% across the hip for the 70 mg once weekly and 10 mg once daily groups, respectively. The two treatment groups were also similar with regard to increases in DMO in other bone districts.

The effects of alendronate on bone mass and fracture incidence in postmenopausal women were investigated in two initial efficacy studies of identical design (n = 994) and in the Fracture Intervention Trial (FIT: n = 6,459). ).

In the initial efficacy studies, mean increases in bone mineral density (BMD) with alendronate 10 mg / day compared with placebo at three years were 8.8%, 5.9% and 7.8%. respectively at the level of the vertebral column, the neck of the femur and the trochanter. Also the BMD of the organism in full it increased significantly. C "was a reduction of 48% (alendronate 3.2% vs placebo 6.2%) in the proportion of alendronate-treated patients with one or more vertebral fractures compared to those treated with placebo. Over the two-year extension of these studies, BMD continued to increase in the spine and the trochanter and remained stable at the level of the femoral neck and body in full.

The FIT consists of two placebo-controlled studies of alendronate once daily (5 mg per day for two years and 10 mg per day for one or two additional years):

• FIT 1: A three-year study of 2,027 patients with at least one vertebral (compression) fracture at baseline. In this study, daily intake of alendronate reduced the incidence of ≥1 new vertebral fracture by 47% (alendronate 7.9% vs placebo 15.0%). There was also a statistically significant reduction in the incidence of hip fractures (1.1% vs 2.2%, a reduction of 51%).

• FIT 2: A four-year study of 4,432 patients with low bone mass but without vertebral fractures at baseline. In this study, a significant difference was observed in the subgroup analysis of osteoporotic women (37% of the overall study population, with osteoporosis as defined above) in the incidence of ≥1 vertebral fracture (2.9% vs 5.8%, a reduction of 50%) and in the incidence of hip fractures (alendronate 1.0% vs placebo 2.2%, a reduction of 56%).

Clinical efficacy of Binosto 70 mg effervescent tablets for oral solution

BC-118-07: A clinical study with Binosto 70 mg performed in 12 healthy female volunteers. This clinical study evaluated gastric emptying and gastric pH after administration of a conventional tablet and Binosto 70 mg, effervescent tablet, with a high buffering capacity. The buffered solution has the potential to improve gastric tolerance. Both formulations tested rapidly cleared the esophagus and there were no statistically significant or physiologically relevant differences in gastric emptying times.

Exposure of the mucosa to alendronate at a pH less than 3 is irritating to the gastroesophageal tissue. Ingestion of a conventional tablet resulted in alendronate being present in the stomach at a pH below 3 within minutes. Following administration of Binosto 70 mg, gastric pH generally increased to about 5 and remained at a plateau for 30 minutes, then gradually decreased. The time it took for gastric pH to drop below 3 after ingestion of the drug was significantly longer with the effervescent tablets than with the conventional tablet.

Therefore Binosto 70 mg minimizes the possibility of exposure of the esophagus (in case of reflux) and stomach to acidified alendronate.

Laboratory data

In clinical studies, asymptomatic, mild and transient decreases in serum calcium and phosphate were observed in approximately 18% and 10% of patients treated with alendronate 10 mg / day, respectively, compared with approximately 12% and 3% of those treated. with placebo, however, the incidences of serum calcium decreases up to values

Pediatric population

Alendronate sodium has been studied in a small number of patients under 18 years of age with osteogenesis imperfecta. The results are insufficient to support the use of alendronate sodium in pediatric patients with osteogenesis imperfecta.

05.2 "Pharmacokinetic properties -

Absorption

Compared to a reference intravenous dose, the mean oral bioavailability of alendronate tablets in women was 0.64% for doses ranging from 5 to 70 mg given after overnight fasting and 2 hours before a standard breakfast. Similar bioavailability. it decreased to an estimated 0.46% and 0.39% when alendronate was given an "hour or half" before a standard breakfast.

The bioavailability of Binosto 70 mg including effervescent is equivalent to that of alendronate tablets, but the intra-individual variation in excretion (and therefore absorption) is smaller for effervescent tablets (cumulative excretion in the first 48 hours: CV 32.0 vs 42.1%, maximum rate of excretion: CV 37.5 vs 45.6%).

In osteoporosis studies, alendronate was effective when given at least 30 minutes before the first food or drink of the day.

Bioavailability was negligible when alendronate was taken with a standard breakfast or up to 2 hours later. Concomitant administration of alendronate with coffee or orange juice reduced bioavailability by approximately 60%.

Distribution

Studies in rats show that alendronate temporarily distributes to soft tissues after intravenous administration of 1 mg / kg, but is then rapidly redistributed to bone or excreted in urine. The mean volume of distribution at steady state, excluding bone, is at least 28 liters in humans. The plasma concentrations of the drug, after oral administration of therapeutic doses, are too low for an analytical evaluation (plasma protein in humans is about 78%.

Biotransformation

There is no evidence of metabolism of alendronate in animals or humans.

Elimination

After a single intravenous dose of 14C-radiolabelled alendronate, approximately 50% of the radioactivity is excreted in the urine within 72 hours and very little or no radioactivity in faeces is found. Renal clearance of alendronate is 71. ml / min after a single 10 mg intravenous dose and systemic clearance does not exceed 200 ml / min. Within 6 hours after intravenous administration the plasma concentration decreases to more than 95%. Due to the release of alendronate from the skeleton, the terminal half-life in humans is estimated to be greater than 10 years. In rats, alendronate is not excreted via the acid-base transport system of the kidneys and therefore is not expected. that it interferes with the excretion of other medicines through these systems in humans.

Characteristics in patients

Pre-clinical studies show that drug that is not deposited in bone is rapidly excreted in the urine. No evidence of saturation of bone absorption has been demonstrated after chronic administration of cumulative intravenous doses up to 35 mg / kg in Although no clinical data are available, it is likely that, as in animals, renal elimination of alendronate will be reduced in patients with renal impairment. Consequently, increased accumulation of alendronate in bone is expected in subjects with impaired renal function (see section 4.2).

05.3 Preclinical safety data -

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential.

Studies in rats showed that alendronate treatment during pregnancy was associated with female dystocia during parturition related to hypocalcaemia. In trials, rats that received high doses showed an "increased incidence of incomplete fetal ossification. It is unknown whether this is relevant to humans."

06.0 PHARMACEUTICAL INFORMATION -

06.1 Excipients -

Sodium citrate dihydrate

Anhydrous citric acid

Sodium hydrogen carbonate

Sodium carbonate anhydrous

Strawberry flavor [maltodextrin (corn), gum arabic, propylene glycol (E 1520), nature-identical flavoring substances]

Acesulfame potassium

Sucralose

06.2 Incompatibility "-

Not relevant.

06.3 Period of validity "-

4 years.

06.4 Special precautions for storage -

This medicinal product does not require any special storage temperatures.

Store in the original package to protect from moisture.

06.5 Nature of the immediate packaging and contents of the package -

The effervescent tablets are supplied in strips of composite sheets (paper / polyethylene / aluminum / zinc ionomer), with 2 effervescent tablets packed in unit strips.

Packs of 4, 12 or 24 effervescent tablets.

Not all pack sizes may be marketed.

06.6 Instructions for use and handling -

No special instructions for disposal.

Unused medicine and wastes derived from this medicine must be disposed of in accordance with local regulations.

The appearance of the medicinal product after dissolution is a clear and colorless solution.

07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -

Abiogen Pharma S.p.A.

Via Meucci, 36

Ospedaletto - Pisa

08.0 MARKETING AUTHORIZATION NUMBER -

AIC n. 040246011 "70 mg effervescent tablets"

AIC n. 040246023 "70 mg effervescent tablets"

AIC n. 040246035 "70 mg effervescent tablets"

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -

February 2013

10.0 DATE OF REVISION OF THE TEXT -

March 2016

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY -

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL -

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