Active ingredients: alendronic acid, cholecalciferol
ADROVANCE 70 mg / 2,800 IU tablets
ADROVANCE 70 mg / 5,600 IU tablets
Why is Adrovance used? What is it for?
What is ADROVANCE?
ADROVANCE is a tablet that contains two active substances, alendronic acid (commonly called alendronate) and colecalciferol, known as vitamin D3.
What is alendronate?
Alendronate belongs to a group of non-hormonal medicines called bisphosphonates. Alendronate prevents the loss of bone that occurs in postmenopausal women and helps rebuild bone. Alendronate reduces the risk of vertebral and spine fractures. "hip.
What is Vitamin D?
Vitamin D is an essential nutrient needed for calcium absorption and bone health. The body can only adequately absorb calcium from food if it has enough vitamin D. Foods that contain vitamin D are very few. The main supply of vitamin D occurs in the summer through exposure to sunlight, which produces vitamin D in the skin. As we age, the skin produces less vitamin D. Too low amounts of vitamin D can cause bone loss and osteoporosis. Severe vitamin D deficiency can cause muscle weakness which can lead to falls and an increased risk of fractures. .
What is ADROVANCE used for?
Your doctor has prescribed ADROVANCE to treat osteoporosis and to reduce the risk of vitamin D insufficiency. This medicine reduces the risk of spine and hip fractures in women after menopause.
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 everyday activities such as lifting weights, or with minor injuries that would generally 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 deformities and disabilities, such as bowing of the back (hump) and limitations in movement.
How can osteoporosis be treated?
Along with treatment with ADROVANCE, 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 The doctor will be able to give information on the diet or on the possible need to take food supplements.
Contraindications When Adrovance should not be used
Do not take ADROVANCE
- if you are allergic to alendronic acid, cholecalciferol or any of the other ingredients of this medicine
- if you have certain problems with your esophagus (the tube that connects your mouth with your stomach), such as narrowing or difficulty swallowing,
- if you cannot 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 tablets. Consult your doctor and follow the instructions given.
Precautions for use What you need to know before you take Adrovance
Talk to your doctor or pharmacist before taking ADROVANCE if:
- suffer from kidney problems,
- have, or have recently had, difficulty swallowing or problems with the digestive system,
- your doctor told you that you have Barrett's esophagus (a disease associated with changes in the cells that line the lower part of the esophagus),
- your doctor has told you that you have a problem with the absorption of minerals in the stomach or intestines (malabsorption syndrome),
- have poor dental health, have gum disease, are planning to have a tooth extraction or do not have regular dental check-ups,
- has cancer,
- are undergoing chemotherapy or radiotherapy,
- you are taking angiogenesis inhibitors (such as bevacizumab or thalidomide) which are used in the treatment of cancer,
- are taking corticosteroids (such as prednisone or dexamethasone) which are used to treat conditions such as asthma, rheumatoid arthritis and severe allergies,
- 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 ADROVANCE.
It is important to maintain good oral hygiene during treatment with ADROVANCE. You should have periodic check-ups at your dentist 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, difficulty or pain in swallowing, especially if patients do not drink a full glass. of tap water and / or stretch during the first 30 minutes after taking ADROVANCE These side effects may get worse if patients continue to take ADROVANCE after experiencing these symptoms.
Children and adolescents
ADROVANCE should not be given to children and adolescents under the age of 18.
Interactions Which drugs or foods may change the effect of Adrovance
Other medicines and ADROVANCE
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
Calcium supplements, antacids and some orally administered medicines are likely to interfere with the absorption of ADROVANCE if taken at the same time. It is therefore important to wait at least 30 minutes before taking any other orally administered medicines or supplements.
Some long-term pain or rheumatism medicines called NSAIDs (e.g. acetylsalicylic acid or ibuprofen) may cause digestive problems. Therefore, caution should be used when these medicinal products are taken concomitantly with ADROVANCE.
It is likely that some medicines or food additives can prevent the vitamin D contained in ADROVANCE from entering your body, including artificial fat substitutes, mineral oils, weight loss medicines, orlistat, and cholesterol-lowering medicines cholestyramine and cholestipol. for seizures (epilepsy) (such as phenytoin or phenobarbital) they may decrease the effectiveness of vitamin D. Addition of other vitamin D supplements on an individual basis may be considered.
ADROVANCE with food and drink
Food and drinks (including mineral water) are likely to make ADROVANCE less effective if taken at the same time. You must wait at least 30 minutes before taking any food and drink other than tap water.
Warnings It is important to know that:
Pregnancy and breastfeeding
ADROVANCE is only indicated for postmenopausal women. Do not take ADROVANCE if you are pregnant or pregnant or if you are breastfeeding.
Driving or using machines
Side effects (eg blurred vision, dizziness and severe bone, muscle or joint pain) have been reported with ADROVANCE that may affect the ability to drive or use machines. If any of these side effects occur you should not drive until it feels good.
ADROVANCE contains lactose and sucrose
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.
Dose, Method and Time of Administration How to use Adrovance: Posology
Always take ADROVANCE exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.
Take one ADROVANCE tablet once a week.
Follow the instructions below carefully:
- Choose the day of the week that best fits your activities. Take one ADROVANCE tablet once a 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 ADROVANCE tablet into your stomach and to help reduce the possibility of irritating the esophagus (the tube that connects your mouth to the stomach).
- After getting out of bed to start the day, and before taking any food, drink or other medicine, swallow the ADROVANCE tablet whole with a full glass of tap water (not mineral water) (not less than 200 ml), so that ADROVANCE is adequately absorbed. 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 crush or chew or let the tablet dissolve in the mouth due to the possible formation of ulcers in the oral cavity.
- Do not lie down - keep your torso upright (while sitting, standing or walking) - for at least 30 minutes after swallowing the tablet. Do not relax until you have eaten something.
- ADROVANCE should not be taken at bedtime or before getting out of bed at the beginning of the day. 5) If you experience difficulty or pain when swallowing, chest pain or a burning sensation in your upper stomach, stop taking it. of ADROVANCE and contact your doctor.
- After swallowing the ADROVANCE tablet, wait at least 30 minutes before eating, drinking or taking any other medicines of the day, including antacids, calcium supplements and vitamins. ADROVANCE is only effective when taken on an empty stomach.
If you forget to take ADROVANCE
If you forget to take your tablet, simply take one ADROVANCE tablet the next morning. Do not take two tablets on the same day. Thereafter, resume taking the tablet on your chosen day of the week.
If you stop taking ADROVANCE
It is important that you take ADROVANCE for as long as your doctor prescribes it. Since it is not known how long you should take ADROVANCE, you should periodically check with your doctor the need to continue taking this medicine to determine if ADROVANCE is still right for you.
An instruction card for use is included in the carton of ADROVANCE. It contains important information reminding you how to take ADROVANCE correctly.
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 Adrovance
If you take too many tablets by mistake, 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 Adrovance
Like all medicines, this medicine can cause side effects, although not everybody gets them.
See your doctor right away if you notice any of the following side effects, which can be serious and for which you may need urgent medical treatment:
Common (may affect up to 1 in 10 people):
- heartburn in the upper stomach; difficulty swallowing; pain when swallowing; ulcers in the esophagus (the tube that connects your mouth to your stomach) which may cause chest pain, heartburn or difficulty or pain in swallowing.
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 or swallowing; 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 these 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,
- bone, muscle and / or joint pain which is severe.
Other side effects include
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):
- joint swelling,
- abdominal pain; feeling of stomach discomfort or belching after meals; constipation; feeling of fullness or bloating in the stomach; diarrhea, intestinal gas,
- hair loss; itch,
- headache; dizziness,
- tiredness; swelling of the hands or legs.
Uncommon (may affect up to 1 in 100 people):
- nausea; He retched,
- irritation or inflammation of the esophagus (the tube that connects your mouth to your stomach) or stomach,
- black or dark stools,
- blurred vision; eye pain or redness,
- 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):
- symptoms of low blood calcium levels including muscle cramps or spasms and / or tingling in the fingers or around the mouth,
- peptic or stomach ulcers (sometimes severe or with bleeding),
- narrowing of the esophagus (the tube that connects your mouth to your stomach),
- rash made worse by exposure to sunlight,
- mouth ulcers.
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.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.
You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The expiry date refers to the last day of that month.
Store in the original blister in order to protect from moisture and light.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Other Information
What ADROVANCE
The active ingredients are alendronic acid and cholecalciferol (vitamin D3). Each ADROVANCE 70 mg / 2,800 IU tablet contains 70 mg of alendronic acid (as sodium trihydrate) and 70 micrograms (2,800 IU) of colecalciferol (vitamin D3). Each ADROVANCE 70 mg / 5,600 IU tablet contains 70 mg of alendronic acid (as sodium trihydrate) and 140 micrograms (5,600 IU) of colecalciferol (vitamin D3).
The other ingredients are microcrystalline cellulose (E460), anhydrous lactose (see section 2), medium chain triglycerides, gelatin, croscarmellose sodium, sucrose (see section 2), colloidal silica dioxide, magnesium stearate (E572), butylhydroxytoluene (E321) , modified starch (maize) and sodium aluminum silicate (E554).
Description of what ADROVANCE looks like and contents of the pack
ADROVANCE 70 mg / 2,800 IU tablets are available as white to off-white, modified capsule-shaped tablets, engraved with an outline of a bone image on one side and "710" on the other. ADROVANCE 70 mg / 2,800 IU tablets are available in packs containing 2, 4, 6 or 12 tablets.
ADROVANCE 70 mg / 5,600 IU tablets are available as modified rectangle-shaped, white to off-white tablets engraved with an outline of a bone image on one side and "270" on the other. ADROVANCE 70 mg / 5,600 IU tablets are available in packs containing 2, 4 or 12 tablets.
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
ADROVANCE
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
ADROVANCE 70 mg / 2,800 IU tablets
Each tablet contains 70 mg of alendronic acid (as sodium trihydrate) and 70 mcg (2,800 IU) of cholecalciferol (vitamin D3).
Excipients with known effects
Each tablet contains 62 mg of lactose (as anhydrous lactose) and 8 mg of sucrose.
ADROVANCE 70 mg / 5,600 IU tablets
Each tablet contains 70 mg of alendronic acid (as sodium trihydrate) and 140 mcg (5,600 IU) of cholecalciferol (vitamin D3).
Excipients with known effects
Each tablet contains 63 mg of lactose (as anhydrous lactose) and 16 mg of sucrose.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Tablet.
ADROVANCE 70 mg / 2,800 IU tablets
Modified capsule-shaped, white to off-white tablets embossed with an outline of a bone image on one side and "710" on the other.
ADROVANCE 70 mg / 5,600 IU tablets
White to off-white, modified rectangle-shaped tablets embossed with an outline of a bone image on one side and "270" on the other.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
ADROVANCE is indicated for the treatment of postmenopausal osteoporosis in women at risk of vitamin D insufficiency. It reduces the risk of vertebral and hip fractures.
04.2 Posology and method of administration
Dosage
The recommended dose is one tablet once a week.
Patients should be advised that if they have forgotten to take their dose of ADROVANCE, they should take one tablet on the morning following the day they notice. They should not take two tablets on the same day but should restart taking one tablet once a week, on the chosen day as previously stated.
Due to the nature of the disease process of osteoporosis, ADROVANCE should be used as a long-term therapy.
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 ADROVANCE, particularly after 5 or more years of use. .
Patients should take calcium supplements if dietary calcium intake is inadequate (see section 4.4). On an individual basis, additional vitamin D supplementation taking into account all daily vitamin intake should be considered. D taken with vitamin and dietary supplements.
ADROVANCE 70 mg / 2,800 IU tablets
The equivalence of intakes of ADROVANCE 2,800 IU of vitamin D3 once weekly and 400 IU of vitamin D once daily has not been studied.
ADROVANCE 70 mg / 5,600 IU tablets
The equivalence of intakes of ADROVANCE 5,600 IU vitamin D3 once weekly and 800 IU vitamin D once daily has not been studied.
Senior citizens
In clinical studies, no age-related difference in the efficacy or safety profiles of alendronate was demonstrated. Therefore, no dose adjustment is necessary in the elderly.
Renal impairment
ADROVANCE is not recommended in patients with renal impairment when creatinine clearance is less than 35 ml / min, as there is no experience in this regard. No dose adjustment is necessary in patients with creatinine clearance greater than 35 ml / min.
Pediatric population
The safety and efficacy of ADROVANCE have not been established in children under the age of 18. This medicine should not be used in children under the age of 18 as there are no data available for the combination of alendronic acid / colecalciferol. Currently available data for alendronic acid in the pediatric population are described in section 5.1.
Method of administration
Oral use.
To obtain adequate absorption of alendronate:
ADROVANCE should only be taken with tap water (not mineral water) at least 30 minutes before any food, drink or medicine (including antacids, calcium supplements and vitamins) of the day. Other beverages (including mineral water), food and some medicinal products are likely to reduce the absorption of alendronate (see sections 4.5 and 4.8).
The following instructions must be followed exactly to minimize the risk of oesophageal irritation and related adverse reactions (see section 4.4):
• ADROVANCE should only be swallowed after getting out of bed to start the day with a full glass of water (not less than 200 ml).
• The patient should only swallow ADROVANCE whole. The patient should not crush or chew or dissolve the tablet in the mouth due to the potential risk of oropharyngeal ulceration.
• The patient should not lie down for at least 30 minutes after taking ADROVANCE and as long as they have not eaten anything.
• ADROVANCE should not be taken at bedtime or before getting out of bed at the beginning of the day.
04.3 Contraindications
- Hypersensitivity to the active substances 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.
04.4 Special warnings and appropriate precautions for use
Alendronate
Adverse reactions of the upper gastrointestinal tract
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, esophageal, gastritis, duodenitis, ulcers or with a recent (within the previous year) history of major gastrointestinal disorders such as peptic ulcer or active gastrointestinal bleeding or upper gastrointestinal surgery excluding pyloroplasty (see section 4.3). In patients with Barrett's esophagus already known, the physician should evaluate the potential benefits and risks of alendronate on an individual basis.
Esophageal reactions (some severe and requiring hospitalization) such as esophagitis, esophageal ulcers and esophageal erosions, rarely followed by esophageal strictures, have been reported in patients receiving alendronate. any signs or symptoms that indicate a possible oesophageal reaction and advise the patient to discontinue alendronate and seek medical attention if symptoms of oesophageal irritation such as dysphagia, odynophagia or retrosternal pain or development or worsening of heartburn occur (see section 4.8).
The risk of severe esophageal adverse reactions 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, rare (post-marketing) cases of gastric and duodenal ulcers, some severe and associated with complications, have been reported (see section 4.8). .
Osteonecrosis of the mandible / maxilla
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 (maximum for zoledronic acid), route of administration (see above) and cumulative dose
• cancer, chemotherapy, radiotherapy, corticosteroids, angiogenesis inhibitors, smoking
• a history of dental disease, poor oral hygiene, periodontal disease, invasive dental procedures and poorly fitting dentures.
Before initiating treatment with oral bisphosphonates 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. 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.
Osteonecrosis of the external auditory canal
Osteonecrosis of the external auditory canal has been reported in conjunction with the use of bisphosphonates, predominantly in association with long-term therapies. 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 bisphosphonate-treated patients who present with ear symptoms such as pain or discharge, or chronic ear infections.
Musculoskeletal pain
Bone, joint and / or muscle pain has been reported in patients receiving bisphosphonates. In post-marketing experience these symptoms have rarely been severe and / or have caused disability (see section 4.8). The timing of symptom onset ranged from one day to several months after initiation of treatment. Discontinuation of treatment resulted in symptom relief in most patients. Following re-administration of the same medicine or another bisphosphonate, a subgroup of patients experienced a relapse of symptoms.
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 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, discontinuation of bisphosphonate therapy should be considered pending an assessment of the patient based on individual benefit risk.
During bisphosphonate treatment, patients should be advised to report any pain in the thigh, hip or groin and any patient exhibiting such symptoms should be evaluated for the presence of an incomplete femur fracture.
Renal impairment
The use of ADROVANCE in patients with renal impairment is not recommended when creatinine clearance is less than 35 ml / min (see section 4.2).
Bone and mineral metabolism
Causes of osteoporosis other than estrogen deficiency and age must be carefully considered.
Hypocalcaemia must be corrected before initiating therapy with ADROVANCE (see section 4.3). Other disorders of mineral metabolism (such as vitamin D deficiency and hypoparathyroidism) should also be adequately treated before initiating therapy with this medicinal product. The vitamin D content in ADROVANCE is not suitable for correcting vitamin D deficiency. Patients with these clinical conditions should be monitored for serum calcium levels and symptoms of hypocalcaemia during treatment with ADROVANCE.
Due to the positive effect of alendronate on increased bone mineralization, decreases in serum calcium and phosphate levels may occur especially in patients taking glucocorticoids in whom calcium absorption may be reduced. Such decreases are usually However, there have been rare reports of symptomatic hypocalcaemia, occasionally severe and often in patients with predisposing conditions (eg, hypoparathyroidism, vitamin D deficiency and calcium malabsorption) (see section 4.8).
Cholecalciferol
Vitamin D3 may increase the extent of hypercalcaemia and / or hypercalciuria when administered to patients with diseases associated with irregular overproduction of calcitriol (eg. Leukemia, lymphoma, sarcoidosis). In these patients, serum and serum calcium should be monitored. urinary.
Patients with malabsorption may not adequately absorb vitamin D3.
Excipients
This medicinal product contains lactose and sucrose. Patients with rare hereditary problems of fructose intolerance, galactose intolerance, the Lapp lactase deficiency, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
04.5 Interactions with other medicinal products and other forms of interaction
Alendronate
Food and beverages (including mineral water), calcium supplements, antacids and other oral medicines, 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 to elapse after taking alendronate before taking any other medicinal product orally (see sections 4.2 and 5.2).
Since the use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) is associated with gastrointestinal irritation, caution should be exercised during concomitant treatment with alendronate.
Cholecalciferol
Olestra, mineral oils, orlistat, and bile sequestering agents (eg cholestyramine, colestipol) can hinder the absorption of vitamin D. The anticonvulsants, cimetidine and thiazides can increase the catabolism of vitamin D. Additional vitamin D supplements can be considered on an individual basis.
04.6 Pregnancy and breastfeeding
ADROVANCE is for use in postmenopausal women only and therefore should not be used during pregnancy or breastfeeding.
Pregnancy
There are no or limited data from the use of alendronate in pregnant women. Animal studies have shown reproductive toxicity. Alendronate caused dystocia due to hypocalcaemia in pregnant rats (see section 5.3). Hypercalcaemia and reproductive toxicity have been observed with high doses of vitamin D in animal studies (see section 5.3) ADROVANCE should not be used during pregnancy.
Feeding time
It is unknown whether alendronate / metabolites are excreted in human milk. A risk to the newborns / infants cannot be excluded. Cholecalciferol and some of its active metabolites pass into breast milk. ADROVANCE should not be used during breastfeeding.
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
ADROVANCE has no or negligible influence on the ability to drive and use machines. Patients may experience some adverse reactions (e.g. blurred vision, dizziness and severe bone, muscle or joint pain (see section 4.8)) which may affect the ability to drive and use machines.
04.8 Undesirable effects
Summary of the safety profile
The most commonly reported adverse reactions are upper gastrointestinal adverse reactions including abdominal pain, dyspepsia, oesophageal ulcer, dysphagia, abdominal distension and acid regurgitation (> 1%).
Table of adverse reactions
The following adverse reactions come from clinical studies and / or from the use of alendronate after its marketing.
No further adverse reactions were identified with the combination of alendronate and cholecalciferol.
Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to
Reporting of suspected adverse reactions
The reporting of suspected adverse reactions that occur after the authorization of the medicinal product is important, as it allows continuous monitoring of the benefit / risk ratio of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Italian Medicines Agency. , website: www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
Alendronate
Symptoms
Hypocalcaemia, hypophosphataemia and upper gastrointestinal adverse reactions, such as gastric disturbance, heartburn, esophagitis, gastritis or ulcer, may be the consequence of oral overdose.
Management
No specific information is available on the treatment of overdose with alendronate. In case of overdose with ADROVANCE, give milk or antacids that bind to alendronate. Due to the risk of oesophageal irritation, do not induce vomiting and keep the patient strictly erect.
Cholecalciferol
Vitamin D toxicity has not been documented during chronic therapy in generally healthy adults at a dose below 10,000 IU / day. In a clinical study of healthy adults, a daily dose of 4,000 IU of vitamin D3 for up to five months was not associated with hypercalciuria or hypercalcemia.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: drugs for the treatment of bone diseases, bisphosphonates, combinations.
ATC code: M05BB03.
Mechanism of action
Alendronate
Alendronate sodium is a bisphosphonate which acts as a specific inhibitor of osteoclast-mediated bone resorption 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.
Cholecalciferol (vitamin D3)
Vitamin D3 is produced in the skin through the conversion of 7-dehydrocholesterol to vitamin D3 by ultraviolet light. In the absence of adequate exposure to sunlight, vitamin D3 is an essential nutrient. Vitamin D3 is converted to 25-hydroxyvitamin D3 in the liver and stored for the needs of the organism. Conversion in the kidney to 1,25-dihydroxyvitamin D3 (calcitriol), the active form of the hormone that mobilizes calcium, is subjected to careful adjustment. The main activity of 1,25-dihydroxyvitamin D3 is to increase the absorption of both calcium and phosphate in the intestine and to regulate serum calcium, the renal excretion of calcium and phosphate, the formation of bone and bone resorption.
Vitamin D3 is needed for normal bone formation. Vitamin D insufficiency occurs when both exposure to sunlight and dietary intake are inadequate. Insufficiency is associated with a negative calcium balance, bone loss, and increased risk of skeletal fracture. In severe cases, the deficiency results in secondary hyperparathyroidism, hypophosphataemia, proximal muscle weakness and osteomalacia, thus increasing the risk of falls and fractures in people with osteoporosis Vitamin D supplements reduce these risks and their consequences.
Osteoporosis is defined as bone mineral density (BMD) of the spine or hip that is 2.5 standard deviations (SD) less than the mean value in a normal young population or as a history of fragility fracture, regardless of BMD .
Clinical efficacy and safety
Studies on ADROVANCE
The effect of the lower dose of ADROVANCE (alendronate 70 mg / vitamin D3 2,800 IU) on vitamin D parameters was demonstrated in a 15-week multinational study enrolling 682 postmenopausal women with osteoporosis (25- Baseline serum hydroxyvitamin D: mean 56 nmol / L [22.3 ng / mL]; range 22.5-225 nmol / L [9-90 ng / mL]). Patients were treated with the lower dose formulation (70 mg / 2,800 IU) of ADROVANCE (n = 350) or with FOSAMAX (alendronate) 70 mg (n = 332) once weekly; further vitamin D supplements were prohibited. Serum 25-hydroxyvitamin D was significantly higher (26%) in the ADROVANCE group (70 mg / 2,800 IU) (56 nmol / l [23 ng / ml]) compared to the group treated with alendronate alone (46 nmol / l [18 , 2 ng / ml]). The percentage of patients with vitamin D insufficiency (serum 25-hydroxyvitamin D
In a 24-week extension study in which 619 postmenopausal women with osteoporosis were enrolled, the effect of the lower dose of ADROVANCE (alendronate 70 mg / vitamin D3 2,800 IU) plus an additional 2,800 IU of vitamin D3 was demonstrated. for a total of 5,600 IU (corresponding to the amount of vitamin D3 in the highest dose of ADROVANCE) once weekly. Patients in the vitamin D3 2,800 group were treated with ADROVANCE (70 mg / 2,800 IU) (n = 299) and patients in the vitamin D3 group 5,600 were treated with ADROVANCE (70 mg / 2,800 IU) plus an additional 2,800 IU of vitamin D3 (n = 309) once weekly; use of additional vitamin D supplements was allowed. After 24 weeks of treatment, mean serum 25-hydroxyvitamin D levels were significantly higher in the vitamin D3 5,600 (69 nmol / l [27.6 ng / ml]) group compared to the vitamin D3 2,800 (64 nmol / l [25, 5 ng / ml]). The percentage of patients with vitamin D insufficiency was 5.4% in the vitamin D3 group 2,800 vs. 3.2% in the vitamin D3 5,600 group throughout the extension to 24 weeks. The percentage of patients with vitamin D deficiency was 0.3% in the vitamin D3 group 2,800 vs zero in the vitamin D 35,600 group. there were differences in mean serum calcium and phosphate levels or 24-hour urinary calcium between treatment groups. The percentage of patients with hypercalciuria at the end of the 24-week extension period was not statistically different between treatment groups .
Studies on alendronate
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 increases in BMD from baseline in the lumbar spine at one year was 5.1% (95% Confidence Interval -IC- 4.8, 5.4%) in the 70 mg once weekly 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 examined 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, the mean increases in BMD with alendronate 10 mg / day compared with placebo at three years were 8.8%, 5.9%, and 7.8% at the spine, neck of the femur and trochanter. Also the organism's DMO 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. In 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. 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 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 trials, asymptomatic, mild and transient decreases in serum calcium and phosphate were reported 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
Pediatric population
Alendronate sodium 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 sodium in pediatric patients with osteogenesis imperfecta.
05.2 Pharmacokinetic properties
Alendronate
Absorption
Compared to an intravenous reference dose, the mean oral bioavailability of alendronate in women was 0.64% for doses ranging from 5 mg to 70 mg administered after an overnight fast and 2 hours before a standardized breakfast. Likewise, bioavailability decreased to approximately 0.46% and 0.39% when alendronate was administered an "hour or half" before a standardized breakfast. In osteoporosis studies, alendronate was effective when it was given at least 30 minutes before the first food or drink of the day.
The alendronate contained in the ADROVANCE combination tablet (70 mg / 2,800 IU) and the ADROVANCE combination tablet (70 mg / 5,600 IU) is bioequivalent to one alendronate 70 mg tablet.
Bioavailability was negligible when alendronate was administered with or within two hours of a standardized breakfast. Concomitant administration of coffee or orange juice with alendronate reduced its bioavailability by approximately 60%.
In healthy subjects, prednisone administered orally (20 mg three times daily for five days) did not produce clinically relevant changes in the oral bioavailability of alendronate (a mean increase of 20% to 44%).
Distribution
Studies in rats show that following intravenous administration of 1 mg / kg l "alendronate, initially distributed in soft tissues, is rapidly redistributed to bone or excreted in the urine. In humans, the mean volume of distribution at steady state, exclusive of bone, is at least 28 liters. Plasma concentrations of alendronate following therapeutic oral doses are too low to be analytically detected (plasma protein is approximately 78%.
Biotransformation
In both humans and animals, there is no evidence that alendronate is metabolised.
Elimination
Following a single intravenous dose of 14C-labeled alendronate, approximately 50% of the radioactivity was excreted in the urine within 72 hours and little or no radioactivity was recovered in the faeces. After single intravenous administration of 10 mg, the clearance renal of alendronate was 71 ml / min and the clearance systemic did not exceed 200 ml / min. Plasma concentrations fell by more than 95% within 6 hours of intravenous administration. The terminal half-life in humans has been estimated to exceed ten years, reflecting the release of alendronate from the skeleton. "man interferes at this level with the excretion of other medicines."
Cholecalciferol
Absorption
In healthy adults (of both sexes) following administration of ADROVANCE 70 mg / 2,800 IU tablets in the morning on an empty stomach and two hours before a meal, the mean area under the serum concentration-time curve (AUC0-120 h) for vitamin D3 (not adjusted for endogenous vitamin D3 levels) was 296.4 ng • h / ml. The mean maximum serum concentration (Cmax) of vitamin D3 was 5.9 ng / ml, and the time median required to reach maximum serum concentration (Tmax) was 12 hours The bioavailability of the 2,800 IU vitamin D3 in ADROVANCE is similar to the 2,800 IU vitamin D3 given alone.
In healthy adults (of both sexes), following administration of ADROVANCE 70 mg / 5,600 IU tablets in the morning on an empty stomach and two hours before a meal, the mean area under the serum concentration-time curve (AUC0-80 h ) for vitamin D3 (not adjusted for endogenous vitamin D3 levels) was 490.2 ng • h / ml. The mean maximum serum concentration (Cmax) of vitamin D3 was 12.2 ng / ml and time median required to reach the maximum serum concentration (Tmax) was 10.6 hours The bioavailability of the 5,600 IU of vitamin D3 in ADROVANCE is similar to the 5,600 IU of vitamin D3 given alone.
Distribution
After absorption, vitamin D3 enters the bloodstream carried by chylomicrons. Vitamin D3 is rapidly distributed mostly in the liver where it is metabolized to 25-hydroxyvitamin D3, the main reserve form. More negligible quantities are distributed to adipose tissues. and muscle and stored at these sites as vitamin D3 for later release into the circulation.Circulating vitamin D3 is bound to vitamin D binding protein.
Biotransformation
Vitamin D3 is rapidly metabolized by hydroxylation in the liver to 25-hydroxyvitamin D3, and subsequently metabolized in the kidney to 1,25-dihydroxyvitamin D3, which is the biologically active form. Further hydroxylation takes place prior to elimination. A small percentage of vitamin D3 undergoes glucuronidation before being eliminated.
Elimination
When radioactive vitamin D3 was administered to healthy people, the mean urinary excretion of radioactivity after 48 hours was 2.4%, and the mean faecal excretion of radioactivity after 4 days was 4.9%. In both cases, the excreted radioactivity was found to derive almost exclusively from the metaboltites of the original molecule. The mean half-life of serum vitamin D3 following an oral dose of ADROVANCE (70 mg / 2,800 IU) is approximately 24 hours.
Renal impairment
Preclinical studies show that alendronate which does not settle in bone is rapidly excreted in the urine. There was no evidence of saturation of bone uptake following chronic administration of cumulative intravenous doses up to 35 mg / kg in animals.
Although no clinical information is available, it is likely that, as in animals, renal elimination of alendronate will be reduced in patients with impaired renal function. As a result, slightly greater accumulation of alendronate in bone might be expected in patients. with impaired renal function (see section 4.2).
05.3 Preclinical safety data
Non-clinical studies have not been conducted with the combination of alendronate and cholecalciferol.
Alendronate
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 alendronate treatment during pregnancy is associated with dystocia linked to hypocalcaemia in mothers during parturition. In studies, rats given the highest doses showed a higher incidence of incomplete fetal ossification. The relevance of these finds to man is not known.
Cholecalciferol
At doses well above the therapeutic range, reproductive toxicity has been observed in animal studies.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Microcrystalline cellulose (E460)
Anhydrous lactose
Medium-chain triglycerides
Jelly
Croscarmellose sodium
Sucrose
Colloidal silicon dioxide
Magnesium stearate (E572)
Butylated hydroxytoluene (E321)
Modified starch (corn)
Sodium aluminum silicate (E554)
06.2 Incompatibility
Not relevant.
06.3 Period of validity
18 months.
06.4 Special precautions for storage
Store in the original blister in order to protect from moisture and light.
06.5 Nature of the immediate packaging and contents of the package
ADROVANCE 70 mg / 2,800 IU tablets
Aluminum / aluminum blisters, in packs of 2, 4, 6 or 12 tablets.
ADROVANCE 70 mg / 5,600 IU tablets
Aluminum / aluminum blisters, in packs of 2, 4 or 12 tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
UK
08.0 MARKETING AUTHORIZATION NUMBER
ADROVANCE 70 mg / 2,800 IU tablets
EU / 1/06/364/001 - 2 tablets
037603014
EU / 1/06/364/002 - 4 tablets
037603026
EU / 1/06/364/003 - 6 tablets
037603038
EU / 1/06/364/004 - 12 tablets
037603040
ADROVANCE 70 mg / 5,600 IU tablets
EU / 1/06/364/006 - 2 tablets
037603065
EU / 1/06/364/007 - 4 tablets
037603077
EU / 1/06/364/008 - 12 tablets
037603089
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 4 January 2007
Date of most recent renewal: November 21, 2011
10.0 DATE OF REVISION OF THE TEXT
19 September 2016
