Bonasol - 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

Bonasol 70mg Weekly oral solution

Why is Bonasol used? What is it for?

Bonasol oral solution belongs to a group of non-hormonal medicines called bisphosphonates. Bonasol oral solution is used for:

  • Prevent bone loss (osteoporosis) that occurs in postmenopausal women and helps rebuild bone.
  • Reduce the risk of vertebral and hip fractures.

Your doctor has prescribed Bonasol oral solution to treat your osteoporosis and to reduce the risk of vertebral and hip fractures.

What is osteoporosis?

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

Osteoporosis usually has no symptoms at first. However, if left untreated, it can result in bone fractures. Although such fractures usually produce pain, vertebral fractures can also go unnoticed until they cause a decrease in stature. Bone fractures can occur during normal daily activities such as lifting a weight, or as a result of minor injuries, which generally would not cause a fracture in normal bones. Bone fractures usually occur in the hip, spine, or wrist and can not only be painful but can also lead to significant problems such as bowing of the back (hump) and limited range of motion.

How can osteoporosis be treated?

Osteoporosis can be cured and it is never too late to start treatment. Alendronate not only prevents bone loss, it also helps to rebuild any lost bone tissue, and reduces the risk of vertebral and bone fractures. hip.

In addition to treatment with Bonasol Oral Solution, your doctor may suggest that you change your lifestyle for your own good, for example:

Quitting smoking. Smoking appears to increase the rate of bone loss, and consequently, may increase the risk of fractures.

Doing exercise. Like muscles, bones also need exercise to keep them strong and healthy. Before starting any exercise program, consult your doctor.

By adopting a balanced diet. Your doctor may advise you on the correct diet or tell you if you need to take any supplements (especially calcium and vitamin D).

Contraindications When Bonasol should not be used

Do not take Bonasol oral solution:

  • if you are allergic (hypersensitive) to alendronate or any of the other ingredients of Bonasol 70 mg Oral Solution. See section 6: Further information.
  • if you have problems with your esophagus (the tube that connects your mouth with your stomach) such as a narrowing or difficulty swallowing fluids
  • if your doctor has told you that you have low blood calcium
  • if you are unable to stand or sit upright for at least 30 minutes. If you think any of these apply to you, do not take the solution. Talk to your doctor first and follow their instructions.

Precautions for use What you need to know before taking Bonasol

Take special care with Bonasol oral solution

Before taking Bonasol Oral Solution it is important that you tell your doctor if:

  • have any kidney problems
  • suffer from any allergies
  • have problems with swallowing or digestion
  • your doctor told you that you have Barrett's esophagus (a disorder associated with changes in the cells lining the lower esophagus)
  • have low levels of calcium in the blood
  • have gum disease
  • has planned a "tooth extraction

Before treatment with Bonasol oral solution, a dental examination should be considered if any of the following conditions exist:

  • suffer from cancer
  • you are undergoing chemotherapy or radiotherapy
  • he's on steroid therapy
  • does not undergo routine dental care
  • suffer from gum disease

During the treatment, preventive dental care should be performed, according to the dentist's instructions.

Irritation, inflammation or ulceration of the esophagus (the tube that connects the mouth to the stomach) may occur, often accompanied by symptoms such as chest pain, heartburn or difficulty or pain in swallowing, especially if patients lie on their back after taking Bonasol. oral solution These side effects may be aggravated if patients continue to take Bonasol oral solution after experiencing these symptoms.

Interactions Which drugs or foods can modify the effect of Bonasol

Calcium supplements, antacids and some oral medications are likely to interfere with the absorption of Bonasol Oral Solution when taken at the same time.

Therefore, it is important to follow the instructions given in section 3. HOW TO TAKE BONASOL ORAL SOLUTION.

Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

Taking Bonasol oral solution with food and drink

Food and drinks (including mineral water) are likely to affect the effectiveness of Bonasol oral solution when taken concomitantly with the medicine.Therefore, it is important to follow the instructions given in section 3. HOW TO TAKE BONASOL ORAL SOLUTION.

Warnings It is important to know that:

Use in children and adolescents

Bonasol oral solution should not be given to children and adolescents.

Pregnancy and breastfeeding

Bonasol oral solution is only intended for use by postmenopausal women.

You should not take Bonasol oral solution if you think you are pregnant or if you are breast-feeding.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

Side effects (including blurred vision, dizziness and bone, muscle or joint pain, even severe), which may affect your ability to drive or use machines, have been reported with the use of alendronate. Individual responses to alendronate are variable (see paragraph 4. POSSIBLE SIDE EFFECTS).

Important information about some of the ingredients of Bonasol oral solution

This medicine contains 0.15 vol% ethanol (alcohol), i.e. up to 115 mg per dose, equivalent to 3 ml of beer and 1.3 ml of wine per dose.

It also contains Sunset Yellow (E110), methyl- and propyl-parahydroxybenzoates (E218, E216) which may cause allergic reactions (sometimes delayed). Allergy is more common in the case of people allergic to aspirin. If in doubt, you should check with your doctor or pharmacist.

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

Always take Bonasol oral solution exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.

The usual dose is one 70mg dose unit (100ml) once a week.

To make sure you get the most benefit from Bonasol oral solution, please follow these instructions carefully.

Choose the day of the week that suits you best according to your schedules. Take Bonasol oral solution once a week on your chosen day.

It is very important to follow the instructions below to make Bonasol oral solution reach your stomach as quickly as possible and to minimize the possibility of irritating the esophagus (the channel between your mouth and your stomach).

  • In the morning, after getting up, take Bonasol Oral Solution, before taking any food or drink or any other medicine.
  • Take the entire contents of one bottle, followed by at least 30 ml (one sixth of a glass) of tap water. You may drink more tap water.
  • Do not take with mineral water (still or carbonated), coffee, tea, fruit juice or milk.
  • Do not lie down, but keep your torso upright (sitting, standing or walking) for at least 30 minutes after taking the solution. Do not lie down until you have taken your first food of the day.
  • Do not take Bonasol oral solution at bedtime or before getting up in the morning.
  • If you develop difficulty or pain when swallowing, new onset chest pain or heartburn, or an aggravation of a pre-existing heartburn, talk to your doctor.
  • After taking Bonasol oral solution, wait at least 30 minutes before taking your first food, drink or first medicine of the day, including antacids, calcium supplements and vitamins. Bonasol oral solution is only effective on an empty stomach.

If you forget to take Bonasol oral solution

If you forget to take a dose, take it in the morning of the day after you miss it. Do not take two doses on the same day. Resume taking a weekly dose on your chosen day according to your starting schedule.

If you stop taking Bonasol oral solution

It is important that you continue to take Bonasol oral solution for as long as your doctor tells you. Bonasol oral solution can only treat your osteoporosis if you keep taking the medicine.

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

Overdose What to do if you have taken too much Bonasol

If, by mistake, you take too much Solution, drink a 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 Bonasol

Like all medicines, Bonasol oral solution can cause side effects, although not everybody gets them.

The following terms are used to describe the frequencies of reported undesirable effects:

Very common (occurring in at least 1 in 10 patients treated)

  • Common (occurring in more than 1 in 100 and less than 1 in 10 treated patients)
  • Uncommon (occurring in more than 1 in 1000 and less than 1 in 100 treated patients)
  • Rare (occurring in more than 1 in 10,000 and less than 1 in 1000 patients treated)
  • Very rare (occurring in less than 10,0000 patients treated)

Common:

  • heartburn; difficulty or pain in swallowing; ulcers of the esophagus (channel between the mouth and stomach) which may cause chest pain, burning or difficulty or pain in swallowing
  • bone, muscle and / or joint pain
  • abdominal pain; stomach discomfort or belching after meals; constipation; feeling of fullness or bloating in the stomach; diarrhea; flatulence;
  • headache
  • dysgeusia

Uncommon:

  • nausea; He retched
  • irritation or inflammation of the esophagus (channel between the mouth and stomach)
  • dark or tarry-looking stools
  • rash; itch; skin redness
  • alopecia

Rare:

  • allergic reactions such as hives; swelling of the face, lips, tongue and / or throat, which may cause difficulty in breathing or swallowing
  • symptoms of low serum calcium levels, such as muscle cramps or spasms and / or tingling in the fingers or around the mouth
  • stomach or peptic ulcers (sometimes severe or accompanied by bleeding)
  • narrowing of the esophagus (channel between the mouth and stomach)
  • jaw problems associated with delayed healing and infection, often following tooth extraction
  • visual blurring, eye pain or redness
  • rash aggravated by light
  • severe bone, muscle and / or joint pain
  • ulcerations in the mouth after chewing or sucking tablets
  • transient flu-like symptoms, such as muscle pain, general malaise, sometimes accompanied by fever, especially at the start of therapy

Very rare:

  • severe skin reactions

The following undesirable effects have been reported in post-marketing experience (frequency not known):

  • dizziness
  • joint swelling, hip fracture in patients treated with alendronate for prolonged periods. Hip pain, weakness or a feeling of discomfort may be an early indication of a possible hip fracture.
  • tiredness, swelling of the hands or legs

Laboratory investigations:

Very common: Mild and transient decreases in serum calcium and phosphate levels, usually within a normal range.

Rarely, an unusual fracture of the femur may 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.

Report these or any other unusual symptoms to your doctor or pharmacist immediately. It may be useful to take note of the manifested symptom, when it occurred and its duration.

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.

Expiry and Retention

Keep out of the reach and sight of children.

Do not use Bonasol oral solution after the expiry date (exp.) Which is stated on the carton and bottle. The expiry date refers to the last day of the month.

Store below 25 ° C

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Deadline "> Other information

What Bonasol oral solution contains

Active principle

The active ingredient is alendronate sodium trihydrate: Each 100 ml of solution contains 70 mg of alendronic acid in the form of alendronate sodium trihydrate.

Excipients

  • Xanthan gum (E415),
  • Sodium cyclamate (E952),
  • Sucralose (E955),
  • Sunset Yellow FCF (E110),
  • Methyl parahydroxybenzoate (E218),
  • Propyl parahydroxybenzoate (E216)
  • Orange flavor containing ethanol and butylated hydroxyanisole,
  • Purified water.

What Bonasol oral solution looks like and contents of the pack

Bonasol 70mg Oral Solution is an orange colored solution.

It comes in clear polyethylene terephthalate (PET) bottles with a tamper evident closure in packs of 1, 2, 4, and 12 bottles.

Each bottle contains 100ml of solution and is for single use only.

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 Bonasol 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 -

BONASOL 70 MG WEEKLY ORAL SOLUTION

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -

Each single dose of 100 ml contains 70 mg of alendronate (as 91.35 mg of alendronate sodium trihydrate).

Excipients:

Each dose (100 ml) contains 80 mg of methyl parahydroxybenzoate (E218), 20 mg of propyl parahydroxybenzoate (E216) and 6 mg of Sunset Yellow (E110).

For the full list of excipients, see section 6.1

03.0 PHARMACEUTICAL FORM -

Oral solution.

Orange opalescent solution.

04.0 CLINICAL INFORMATION -

04.1 Therapeutic indications -

Treatment of osteoporosis in postmenopausal women.

Alendronate reduces the risk of fractures of the vertebrae and hip.

04.2 Posology and method of administration -

Dosage

For oral administration.

The recommended dosage is one unit dose of 70 mg (100 ml) once weekly.

The optimal duration of bisphosphonate treatment for osteoporosis has not been established. The need for continued treatment should be reassessed periodically in each individual patient based on the potential benefits and risks of Bonasol 70 mg Oral Solution weekly, particularly after 5 or more years of use.

Method of administration

To allow for adequate absorption of alendronate.

Bonasol 70 mg weekly oral solution it must be taken at least 30 minutes before ingesting any food, drink or medicine of the day, accompanied only by tap water. Other beverages (including mineral water), foods and medicines are likely to reduce the absorption of alendronate (see section 4.5).

To facilitate transit in the stomach, thus reducing the possibility of local and esophageal irritation and any undesirable effects (see section 4.4)

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

• Patients should not lie down for at least 30 minutes after taking Bonasol 70 mg weekly oral solution.

Bonasol 70 mg weekly oral solution it should only be swallowed in the morning when getting out of bed, as a single dose of 100 ml (full contents of the vial) followed by at least 30 ml of tap water. It is allowed to take more tap water.

Bonasol 70 mg weekly oral solution it should not be taken at bedtime or before getting up in the morning.

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

Use in elderly patients: Clinical studies did not reveal any age-related difference in the efficacy or safety profiles of alendronate. Therefore no dosage adjustment is necessary in elderly patients.

Use in the presence of kidney damage: No dosage adjustment is necessary in patients with glomerular filtration rate (GFR) greater than 35 mL / min. Administration of alendronate is not recommended in patients with renal impairment when the GFR is less than 35 ml / min due to lack of experience in this regard.

Use in children and adolescents: The use of alendronate is not recommended in children and adolescents below 18 years of age due to insufficient data on safety and efficacy in conditions associated with pediatric osteoporosis (see also section 5.1).

Alendronate has not been studied in relation to the treatment of glucocorticoid-induced osteoporosis.

04.3 Contraindications -

• Diseases of the esophagus and other factors that delay the emptying of the esophagus such as stricture and achalasia

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

• Hypersensitivity to alendronate or to any of its excipients

• Hypocalcemia

• Patients who have difficulty swallowing fluids

• Patients at risk of aspiration

See also section 4.4 "Special warnings and precautions for use".

04.4 Special warnings and appropriate precautions for use -

Adverse reactions affecting the upper gastrointestinal tract

Bonasol weekly oral solution can cause local irritation of the upper gastrointestinal mucosa. As the potential for aggravation of the underlying disease exists, caution should be exercised when administering Bonasol weekly to patients with upper digestive tract problems such as dysphagia, esophageal disease, gastritis, duodenitis or ulcers, or to patients with a recent "medical history" (within the last year) of major digestive disease such as peptic ulcer, or active gastrointestinal bleeding, or who have undergone upper digestive tract surgery (except for pyloroplasty) (see section 4.3). For patients with Barrett's esophagus, prescribers should weigh the potential benefits and risks of alendronate on an individual basis.

Esophageal reactions (sometimes severe and requiring hospitalization) such as esophagitis, ulcers and esophageal erosions, rarely followed by esophageal stricture, have been reported in patients taking alendronate. Therefore, the physician should pay particular attention to the appearance of any signs or symptoms that indicate a possible esophageal reaction and advise the patient to discontinue treatment with alendronate and to seek medical attention if symptoms of esophageal irritation such as dysphagia occur. pain when swallowing or retrosternal pain, or new or worsening heartburn.

The risk of serious oesophageal adverse events is 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 is well acquainted with and understands how to take the medicinal product (see section 4.2 "Posology and method of administration"). Patients should be advised that failure to follow these instructions may increase the risk of oesophageal problems.

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

Osteonecrosis of the mandible / maxilla

Cases of osteonecrosis of the jaw, usually associated with tooth extraction and / or local infection (including osteomyelitis), have been observed in cancer patients treated with therapeutic regimens that included bisphosphonates administered mainly 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.

The following risk factors should be considered when assessing the individual risk of developing osteonecrosis of the jaw:

• potency of the bisphosphonate (maximum for zoledronic acid), route of administration (see above) and cumulative dose

• cancer, chemotherapy, radiotherapy, corticosteroids, smoking

• history of dental disease, poor oral hygiene, periodontal disease, invasive dental procedures and poorly fitting dentures

Before initiating treatment with oral bisphosphonates in patients in poor dental health the need for a dental examination with appropriate preventive dental procedures should be considered.

During treatment, these patients should avoid invasive dental procedures as much as possible. In patients who develop osteonecrosis of the jaw during bisphosphonate therapy, dental surgery can aggravate their condition. For patients requiring dental surgery, there are no data to suggest that discontinuation of bisphosphonate treatment may reduce the risk of osteonecrosis of the jaw. Clinical judgment of the physician should guide each patient's management program. on the basis of the individual assessment of the risk / benefit ratio.

During bisphosphonate treatment 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 mobility, pain or dental swelling.

Musculoskeletal pain

Pain in the bones, joints and muscles has been reported in patients treated with bisphosphonates. In post-marketing experience these symptoms have rarely been severe and / or disabling (see section "4.8). The time to onset of symptoms ranged from one day to several months after initiation of treatment. Most patients reported symptom relief after discontinuation of the drug. A subset of patients experienced relapse of symptoms after stopping the drug. the same medicine or a different bisphosphonate again.

Atypical fractures of the femur

Atypical subtrochanteric and shaft 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 findings and radiographic evidence of stress fractures, weeks or months before the onset of stress fractures. a complete femoral fracture. Fractures are often bilateral; therefore in bisphosphonate-treated patients who have sustained a femoral shaft fracture, 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 fracture of the femur.

Skin reactions

Rare cases of severe skin reactions, including Stevens Johnson syndrome and toxic epidermal necrolysis, have been reported in post-marketing experience.

Missed dose

Patients should be advised that if they miss a dose of Bonasol 70 mg Oral Solution, they should take a single unit dose (100 ml) the morning after the day they realize they have forgotten. They should not take two doses on the same day but should resume taking a single unit dose per week, as originally scheduled on the chosen day.

Kidney damage

The use of alendronate is not recommended in patients with renal impairment with a GFR below 35 ml / min (see section 4.2).

Bone and mineral metabolism

Other causes of osteoporosis need to be considered besides estrogen deficiency and age.

Hypocalcaemia should 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 effectively treated. Patients with these clinical conditions should be monitored. serum calcium and symptoms of hypocalcaemia during weekly Bonasol treatment.

Due to the positive effects of alendronate on increasing bone mineralization, a decrease in serum calcium and phosphate levels may occur, especially in patients taking glucocorticoids in whom calcium absorption may be reduced. Usually, these reductions are modest and asymptomatic. However, there have been some rare reports of symptomatic hypocalcaemia, sometimes severe, which have occurred in individuals with predisposing conditions (such as hypoparathyroidism, vitamin D deficiency and calcium malabsorption). It is particularly important to ensure adequate calcium and vitamin D intake in patients on glucocorticoid therapy.

Excipients

This medicinal product contains 0.15% by volume in ethanol (alcohol), i.e. up to 115 mg per dose, equivalent to 3 ml of beer or 1.3 ml of wine per dose. It is harmful to alcoholics. This must be kept in mind for high risk groups such as patients suffering from liver disease or epilepsy.

Bonasol 70 mg weekly oral solution contains the dye Sunset Yellow (E110), methyl parahydroxybenzoate (E218) and propyl parahydroxybenzoate (E216) which can cause allergic reactions.

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

When taken at the same time, food and beverages (including mineral water), calcium supplements, antacids and other oral medications are likely to interfere with the absorption of alendronate. Therefore, patients should allow at least 30 minutes to elapse after taking taken alendronate before oral intake of any other medicinal product (see sections 4.2 and 5.2).

No other interactions with medicinal products of clinical importance are foreseeable. In clinical studies, some patients were treated with estrogen (intravaginally, transdermally or orally) while receiving alendronate. No undesirable effects attributable to the concomitant use of these medicines have been observed.

Since the use of NSAIDs is associated with gastrointestinal irritation, special care should be taken when these medicinal products are taken concomitantly with alendronate.

Although specific interaction studies have not been performed, alendronate has been used in clinical studies in combination with a wide range of commonly used medicinal products without giving rise to evidence of clinically relevant adverse effects.

04.6 Pregnancy and breastfeeding -

Pregnancy

There are no or limited data from the use of alendronate in pregnant women. Animal studies have shown reproductive toxicity. Alendronate administered to pregnant rats caused dystocia associated with hypocalcaemia in the dams (see section 5.3).

Bonasol 70mg Weekly Oral Solution should not be used during pregnancy.

Feeding time

It is not known whether alendronate is excreted in human milk in humans. A risk to the newborn / infant cannot be excluded. Alendronate should not be used in 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 -

Alendronate has no or negligible influence on the ability to drive or use machines. However, some adverse reactions that have been reported with alendronate may affect the ability of some patients to drive and use machines. Individual reactions to Bonasol weekly oral solution may be different (see section 4.8).

04.8 Undesirable effects -

In a one-year study involving postmenopausal women with osteoporosis, the overall safety profiles of alendronate tablets given weekly (n = 519) and alendronate 10 mg / day (n = 370) were found to be similar.

In two three-year studies, with virtually identical scheme, performed in postmenopausal women (alendronate 10 mg: n = 196; placebo: n = 397), the general safety profiles for alendronate 10 mg / day and for placebo they were similar.

Adverse events reported by investigators as possibly, probably or definitely drug related are shown in the table below when, in the one-year study, they occurred in ≥ 1% in either treatment group, or when , in the three-year studies, occurred in ≥ 1% in patients treated with alendronate 10 mg / day and at a higher frequency than observed for patients treated with placebo:

Study lasted a year Studies lasted three years Alendronate weekly tablet (n = 519) % Alendronate 10 mg / day(n = 370) % Alendronate 10 mg / day (n = 196) % Placebo(n = 397) % Gastrointestinal effects 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 effects 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 effects Headache 0,4 0,3 2,6 1,5

The following undesirable effects have also been reported during clinical trials and / or post marketing use:

Frequencies are defined as follows: [Very common (≥1 / 10), Common (≥1 / 100,

Immune system disorders:

Rare: hypersensitivity reactions including urticaria and angioedema

Metabolism and nutrition disorders:

Rare: symptomatic hypocalcaemia, often associated with predisposing conditions (see section 4.4)

Nervous system disorders:

Common: headache, dizziness †

Uncommon: dysgeusia †

Eye disorders:

Uncommon: eye inflammation (uveitis, scleritis, episcleritis)

Ear and labyrinth disorders:

Common: dizziness †

Gastrointestinal disorders:

Common: abdominal pain, dyspepsia, constipation, diarrhea, flatulence, oesophageal ulcer *, dysphagia *, abdominal distension, acid regurgitation

Uncommon: nausea, vomiting, gastritis, oesophagitis *, oesophageal erosions *, melaena †

Rare: oesophageal stricture *, oropharyngeal ulceration *, perforation, ulceration, upper gastrointestinal bleeding (see section 4.4)

Skin and subcutaneous tissue disorders:

Common: Alopecia †, pruritus †

Uncommon: rash, erythema

Rare: Rash with photosensitivity, severe skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis ‡

Musculoskeletal system disorders:

Very common: musculoskeletal pain (bone, muscle or joint) † (see section 4.4)

Common: joint swelling †

Rare: Cases of osteonecrosis of the jaw have been reported in patients treated with bisphosphonates. Most of these reports concern cancer patients, but cases have also occurred in patients treated for osteoporosis. Usually, osteonecrosis of the jaw is associated with tooth extraction and / or local infection (including osteomyelitis). Diagnosis of cancer, chemotherapy, radiotherapy, corticosteroid therapy, and poor oral hygiene are also considered risk factors; severe musculoskeletal pain (bone, muscle or joint) (see section 4.4); Atypical subtrochanteric and diaphyseal fractures of the femur (bisphosphonate class adverse reaction) || and stress fractures of the proximal femoral shaft (see section 4.4).

General disorders and administration site conditions:

Common: asthenia †, peripheral edema †

Uncommon: transient symptoms as in acute phase response (myalgia, malaise and rarely, fever), typically in association with initiation of therapy †.

† Frequency in clinical trials was similar in both 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.

|| Reported during the post-marketing experience.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address: www.agenziafarmaco.gov.it/it/responsabili.

04.9 Overdose -

Symptoms

Oral overdose can lead to hypocalcaemia, hypophosphataemia and upper gastrointestinal side effects such as gastric upset, heartburn, oesophagitis, gastritis or ulcers.

Treatment

No specific data are available on the treatment of overdose with alendronate. In case of overdose, give milk or antacids that bind to alendronate. Due to the risk of irritation of the esophagus, vomiting should not be induced and the patient should be kept upright.

05.0 PHARMACOLOGICAL PROPERTIES -

05.1 "Pharmacodynamic properties -

Pharmacotherapeutic group: Medicinal products for the treatment of bone diseases, bisphosphonates.

ATC code: M05B A04.

Mechanism of action

The active substance in Bonasol weekly oral solution, alendronate (in the form of alendronate trihydrate), is an anti-osteoclastic bisphosphonate that has no direct effect on bone formation. Preclinical studies have shown that alendronate is preferentially localized to sites of active resorption. The activity is inhibited, but recruitment and adhesion of osteoclasts are not altered. The bone tissue formed during treatment with alendronate is qualitatively normal.

Clinical efficacy and safety

Treatment of postmenopausal osteoporosis

Osteoporosis is defined as a BMD of the spine or hip that is 2.5 SD less than the mean value in a normal young population, or as a history of a previous fragility fracture, regardless of BMD.

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. After one year, mean increases in lumbar spine BMD from baseline were 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 in the 70 mg once weekly and 10 mg once daily groups, respectively. The two groups were also similar with regard to increases in DMO values ​​in other bone districts.

The effects of alendronate on bone mass and fracture incidence in postmenopausal women were studied 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) following administration of alendronate 10 mg / day compared with placebo at three years were 8.8%, 5.9% and 7.8%. % in the spine, femoral neck and trochanter, respectively. BMD of the whole organism also increased significantly. A 48% reduction (alendronate 3.2% vs placebo 6.2%) was observed in the number of patients treated with alendronate, with one or more vertebral fractures compared with to those who received placebo.

Over the two-year extension of these studies, BMD continued to increase in the spine and trochanter and remained stable in the femoral neck and body as a whole.

The FIT consisted of two placebo-controlled studies using alendronate (5 mg per day for two years and 10 mg per day for an additional year or two):

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

• FIT 2: A four-year study of 4,432 patients with low bone mass but no 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 hip fractures (alendronate 1.0% vs placebo 2.2%, a reduction of 56%) and in the incidence of ≥ 1 vertebral fracture (2.9% vs. 5.8%, a reduction of 50%).

Laboratory data

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

Pediatric population

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

05.2 "Pharmacokinetic properties -

Absorption

Compared to an intravenous reference dose, the mean oral bioavailability of alendronate in women was 0.64% for doses ranging from 5 to 70 mg administered after an overnight fast and two hours before a standardized breakfast. Likewise, bioavailability decreased to approximately 0.46% and 0.39% after administration of alendronate one "hour or half" before a standardized breakfast. 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 administered with or within two hours of a standardized breakfast. Concomitant administration of alendronate and coffee or orange juice reduced its bioavailability by approximately 60%.

In healthy subjects, prednisone administered orally (20 mg 3 times daily for five days) did not produce clinically important changes in the oral bioavailability of alendronate (a mean increase of 20% to 44%).

Distribution

Studies in rats have shown that after intravenous administration of 1 mg / kg, alendronate initially distributed into soft tissues, is rapidly redistributed to bone or excreted in the urine. In humans, the mean steady-state volume of distribution, exclusive to "bone, is at least 28 liters.

The plasma concentrations of the medicinal product, after administration of therapeutic oral doses, are too low to be detected analytically (plasma protein is approximately 78%.

Biotransformation

In both humans and animals, there is no evidence that alendronate is metabolised.

Elimination

After a single intravenous dose of [14C] -labelled alendronate, approximately 50% of the absorbed radioactivity was eliminated in the urine within 72 hours, and little or no radioactivity was found in the faeces. Following administration of a single 10 mg intravenous dose, the renal clearance of alendronate was 71 ml / min, and the systemic clearance did not exceed 200 ml / min. Plasma concentrations fell by more than 95% within six hours of intravenous administration. The terminal half-life in humans was estimated to be greater than ten years, reflecting the release of alendronate from the skeleton.

In rats, renal excretion of alendronate does not occur via acid-base transport systems, and therefore it is not expected in humans to interfere at this level with the elimination of other medicinal products.

Kidney damage

Preclinical studies show that the medicinal product which does not settle in bone is rapidly eliminated in the urine. In animals, after chronic administration of cumulative doses up to 35 mg / kg, there was no evidence of saturation of uptake by Although no clinical information is available, it is likely that, as in animals, elimination of alendronate via the kidney is likely to be reduced in patients with renal impairment. Therefore, slightly more bone accumulation of alendronate could be expected. at the bone level in patients with renal impairment (see section 4.2 "Posology and method of administration").

05.3 Preclinical safety data -

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. Studies in rats have shown that treatment with alendronate during pregnancy is associated with dystocia linked to hypocalcaemia in mothers during parturition. In studies, rats given the highest doses had a higher incidence of incomplete fetal ossification. The relevance of these observations to humans is unknown.

06.0 PHARMACEUTICAL INFORMATION -

06.1 Excipients -

Xanthan gum (E415),

sodium cyclamate (E952),

sucralose (E955),

sunset yellow FCF (E110),

methyl parahydroxybenzoate (E218),

propyl parahydroxybenzoate (E216),

orange flavoring containing ethanol and butylated hydroxyanisole,

purified water.

06.2 Incompatibility "-

Not relevant.

06.3 Period of validity "-

2 years.

06.4 Special precautions for storage -

Store below 25 ° C.

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

Clear polyethylene terephthalate (PET) bottle with tamper evident closure, with low density polyethylene liner, in packs of 1,2, 4, and 12 bottles. Each bottle contains 100 ml of solution.

Not all pack sizes may be marketed.

06.6 Instructions for use and handling -

For single use only.

No special instructions for disposal.

07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -

Bruno Farmaceutici S.p.A.

Via delle Ande, 15

00144 Rome

08.0 MARKETING AUTHORIZATION NUMBER -

BONASOL 70 mg oral solution - 1 PET bottle: 040622019

BONASOL 70 mg oral solution - 2 PET bottles: 040622021

BONASOL 70 mg oral solution - 4 PET bottles: 040622033

BONASOL 70 mg oral solution - 12 PET bottles: 040622045

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -

26 August 2011

10.0 DATE OF REVISION OF THE TEXT -

July 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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