Active ingredients: Risedronic acid (risedronate sodium)
Actonel 5 mg film-coated tablets
Why is Actonel used? What is it for?
So is Actonel
Actonel belongs to a group of non-hormonal medicines called bisphosphonates, which are used to treat bone diseases. It acts directly on the bones, strengthening them and thus reducing the risk of fractures.
Bone is living tissue. Old bone matter is constantly being removed and replaced with new bone.
Postmenopausal osteoporosis is a disease that develops in women after the menopause, whereby women's bones become more fragile and more prone to fractures from falls or strain.
Osteoporosis occurs more easily in women who have reached early menopause and also in patients treated for prolonged periods with cortisone therapies.
The bones most prone to fracture are those of the spine, hip and wrist, although all bones in the body can fracture. Fractures associated with osteoporosis can also cause back pain, loss of height and back curvature (hump ). Many patients with osteoporosis do not have any symptoms and do not even know they have them.
What Actonel is suitable for
For the treatment of osteoporosis
- In postmenopausal women
For the prevention of osteoporosis
- In women at high risk of osteoporosis (including low bone density, early menopause, or family history of osteoporosis)
- In postmenopausal women undergoing systemic cortisone therapy for prolonged periods. Actonel maintains or increases bone mass.
Contraindications When Actonel should not be used
Do not take Actonel:
- If you are allergic to risedronate sodium or any of the other ingredients of this medicine
- If your doctor has told you that you have hypocalcaemia (low level of calcium in the blood);
- If you are pregnant, if you may be pregnant, or if you are planning to become pregnant anyway;
- If you are breast-feeding
- If you have severe kidney problems.
Precautions for use What you need to know before taking Actonel
Talk to your doctor or pharmacist before taking Actonel:
- If you are unable to keep your torso erect (sitting or standing) for at least thirty minutes;
- If you have an abnormal bone and mineral metabolism (such as vitamin D deficiency, parathyroid hormone abnormalities, both of which cause low blood calcium levels);
- If you have or have had problems with your esophagus (the tube that connects your mouth to your stomach) in the past. For example, you may have had pain or difficulty in swallowing food or you have previously been told that you have Barrett's esophagus (a condition associated with changes in the cells that line the lower esophagus);
- If you have been told by your doctor that you have an intolerance to some sugars (such as lactose)
- If you have or have had pain, swelling or numbness in the jaw, or a feeling of "heavy jaw and / or jaw" or loosening of a tooth;
- If you are undergoing dental treatment or are due to undergo dental surgery, please inform your dentist that you are being treated with Actonel.
If you have any of these problems, your doctor will tell you what to do to take Actonel.
Children and adolescents
The use of risedronate sodium is not recommended in children below 18 years due to insufficient data on safety and efficacy.
Interactions Which drugs or foods can modify the effect of Actonel
Medicines that contain any of the following reduce the effect of Actonel when taken at the same time:
- football
- magnesium
- aluminum (for example some preparations for digestive problems)
- iron
These medicines should be taken at least thirty minutes after the Actonel tablet.
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
Actonel with food and drink
It is very important NOT to take the Actonel tablet with food or drink (except tap water) as this may make the medicine less effective.
In particular, do not take this medicine together with dairy products (including milk), as they contain calcium (see section "Other medicines and Actonel").
Food and drinks (except tap water) should be taken at least 30 minutes after the Actonel tablet.
Warnings It is important to know that:
Pregnancy and breastfeeding
DO NOT take Actonel if you are or may be pregnant, or if you are planning to become pregnant (see section "Do not take Actonel"). The potential risks associated with the use of 'risedronate sodium (the active substance in Actonel) in pregnant women are unknown. DO NOT take Actonel if you are breast-feeding (see section' Do not take Actonel ').
Driving and using machines
Actonel has no known effects that interfere with the ability to drive or use machines.
Actonel contains a small amount of lactose (see section "Warnings and precautions").
Dose, Method and Time of Administration How to use Actonel: Posology
Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.
Recommended dose:
Take ONE Actonel tablet (5 mg risedronate sodium) once a day.
For your convenience, the days of the week are printed on the back of the blister to help you remember to take your tablet.
WHEN to take your Actonel tablet
It is very IMPORTANT that you take Actonel at least 30 minutes before food or drink (except tap water) or other medicine to be taken during the day.
In the particular case where administration before breakfast is not possible, Actonel can be taken at the same time each day, on an empty stomach, in one of the following ways:
- between meals: at least 2 hours after the last intake of food, drink (except tap water) or other medicine. Do not eat or drink (except tap water) for 2 hours after taking the Actonel tablet.
Or
- in the evening: Actonel should be taken at least 2 hours after the last intake of food, drink (except for tap water) or medicinal product of the day. Actonel should be taken at least 30 minutes before bedtime.
HOW to take the Actonel tablet
- The tablet should be taken while keeping the torso upright (standing or sitting) to avoid heartburn.
- The tablet should be swallowed with at least one glass (120 ml) of tap water.
- The tablet should be swallowed whole and not dissolved or chewed.
- Once you have swallowed the tablet, avoid lying down for 30 minutes.
Your doctor will tell you if you need calcium and vitamin supplements if you have insufficient intake of these substances in your diet.
Overdose What to do if you have taken too much Actonel
If you take more Actonel than you should
In case you or anyone else has accidentally swallowed more Actonel tablets than prescribed, drink a full glass of milk and consult a doctor.
If you forget to take Actonel
If you have forgotten to take your tablet at the scheduled time, take it as soon as possible following the instructions above (eg before breakfast, between meals, or in the evening).
DO NOT take two tablets on the same day to make up for a forgotten tablet.
If you stop taking Actonel
If you stop, you may start to lose bone mass. It is therefore recommended that you consult your doctor before stopping therapy.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Actonel
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Stop taking Actonel and see your doctor immediately if you experience any of the following side effects:
- Symptoms of a severe allergic reaction such as:
- Swelling of the face, tongue or throat
- Difficulty swallowing
- Hives and difficulty in breathing
- Severe skin reactions which may include blistering skin reactions
Consult your doctor promptly if the following side effects occur:
- Eye inflammation, usually with pain, redness and sensitivity to light
- Bone necrosis of the jaw (osteonecrosis) associated with delayed healing and infection often after tooth extraction (see section "Warnings and precautions")
- Symptoms of the esophagus, such as pain when swallowing, difficulty swallowing, chest pain or the onset / aggravation of heartburn
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.
However, the other undesirable effects observed in clinical trials were generally mild in severity and did not require treatment discontinuation.
Common side effects (may affect up to 1 in 10 people)
- Indigestion, nausea, stomach pain, stomach cramps or upset, constipation, feeling full, bloating, diarrhea.
- Pain in the bones, muscles or joints.
- Headache.
Uncommon side effects (may affect up to 1 in 100 people)
- Inflammation or ulcer of the esophagus (the tube that connects the mouth to the stomach) which causes difficulty and pain in swallowing (see also the section "Warnings and precautions"), inflammation of the stomach and duodenum (the first part of the intestine where passes digested food from the stomach).
- Inflammation of the colored part of the eye (iris) (red and painful eyes with possible changes in vision).
Rare side effects (may affect up to 1 in 1,000 people)
- Inflammation of the tongue (red, swollen, possibly painful), narrowing of the esophagus (the tube that connects the mouth to the stomach).
- Abnormalities in liver function tests have been reported. This can only be diagnosed after a blood test.
The following undesirable effects have been reported during marketing (frequency not known):
- Hair and / or hair loss
- Liver disorders, in some severe cases.
Rarely, at the start of treatment, the patient's plasma levels of calcium and phosphate may fall; these changes are usually small and cause no symptoms.
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.
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.
This medicine does not require any special storage conditions.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
What Actonel contains
The active ingredient is risedronate sodium. Each tablet contains 5 mg of risedronate sodium, equivalent to 4.64 mg of risedronic acid.
The other ingredients are:
Core of the tablet: lactose monohydrate (see section 2), crospovidone, magnesium stearate and microcrystalline cellulose.
Coating: hypromellose, macrogol, hydroxypropylcellulose, silicon dioxide, titanium dioxide [E171], yellow iron oxide [E172].
What Actonel looks like and contents of the pack
Actonel 5 mg film-coated tablets are oval shaped and yellow in color with the letters "RSN" on one side and "5 mg" on the other. They are available in pack sizes of 14, 28 (2x14) , 84 (6x14), 140 (10x14) 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
ACTONEL 5 MG TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 5 mg of risedronate sodium (equivalent to 4.64 mg of risedronic acid).
Excipients with known effects:
Each film-coated tablet contains 156.0 mg of lactose monohydrate (equivalent to 148.2 mg of lactose).
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated tablets.
Yellow, oval, film-coated tablets debossed with RSN on one side and 5 mg on the other.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Treatment of postmenopausal osteoporosis to reduce the risk of vertebral fractures.
Treatment of manifest postmenopausal osteoporosis to reduce the risk of hip fractures. Prevention of postmenopausal osteoporosis in women at increased risk of osteoporosis (see section 5.1).
Maintenance or increase in bone mass in postmenopausal women on systemic corticosteroid therapy for prolonged periods (over three months) with a dose equal to or greater than 7.5 mg / day of prednisone or equivalent compounds.
04.2 Posology and method of administration
Dosage
The recommended daily dose for adults is one 5 mg tablet orally.
Method of administration
The absorption of Actonel is affected by food, therefore, to ensure adequate absorption, patients should take Actonel:
• In the morning, before breakfast: at least 30 minutes before ingesting the first food, other medicinal products or drinks of the day (except for tap water).
In the particular case that administration before breakfast is not possible, Actonel can be taken at the same time each day, between meals or in the evening strictly adhering to the following instructions, to ensure that Actonel is taken on an empty stomach:
• Between meals: Actonel should be taken at least 2 hours before or at least 2 hours after any food, medicinal product or drink (except tap water)
• In the evening: Actonel should be taken at least 2 hours after the last food, medicine or drink of the day (except for tap water). Actonel should be taken at least 30 minutes before bedtime.
If a dose is missed occasionally, Actonel can be taken in the morning before breakfast, between meals or in the evening as described in the instructions above.
The tablet should be swallowed whole and not dissolved or chewed. To facilitate the esophageal transit of the tablet, take Actonel with a glass of tap water (≥120 ml), keeping the torso upright. Once the tablet has been ingested, patients should avoid bedtime for 30 minutes (see section 4.4).
The supplementation of calcium and vitamin D should be considered in case of inadequate dietary intake.
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, particularly after 5 or more years of use.
Special populations
Elderly patients
No dosage adjustment is required as bioavailability, distribution and elimination in elderly subjects (> 60 years) were found to be similar to those in younger subjects.
Impaired renal function
No dosage adjustment is necessary in patients with mild to moderate renal impairment. The use of risedronate sodium is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 ml / min) (see sections 4.3 and 5.2).
Pediatric population
The use of risedronate sodium is not recommended in children below 18 years of age due to insufficient data on safety and efficacy (see also section 5.1).
04.3 Contraindications
- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
- Hypocalcaemia (see section 4.4).
- Pregnancy and breastfeeding.
- Severe impairment of renal function (creatinine clearance
04.4 Special warnings and appropriate precautions for use
Food, drinks (except for tap water) and medicinal products containing polyvalent cations (such as calcium, magnesium, iron and aluminum) interfere with the absorption of bisphosphonates and should not be taken at the same time as Actonel (see section 4.5). . To achieve the desired efficacy, the administration instructions must be strictly adhered to (see section 4.2).
The efficacy of bisphosphonates in the treatment of postmenopausal osteoporosis is related to the presence of decreased bone mineral density calculated with Bone Mineral Density (T-score of the BMD for the hip or lumbar spine ≤-2.5 SD) and / or prevalence of fractures.
Older age or clinical risk factors for fractures alone do not justify initiating osteoporosis treatment with a bisphosphonate.
There is limited evidence to support the efficacy of bisphosphonates including Actonel in very elderly women (over 80 years) (see section 5.1).
Bisphosphonates have been associated with esophagitis, gastritis, esophageal ulcers and gastroduodenal ulcers. Therefore, caution should be exercised:
• in patients with a history of esophageal disorders causing delayed esophageal transit or gastric emptying, such as narrowing or achalasia
• in patients unable to keep their torso erect for at least 30 minutes after taking the tablet
• if risedronate is given to patients with current or recent problems with the upper gastrointestinal tract or the esophagus (including diagnosed Barrett's esophagus).
Physicians should emphasize to patients the importance of paying attention to the administration instructions and paying attention to the appearance of any signs or symptoms that indicate a possible oesophageal reaction. Patients should be advised that if they develop symptoms of oesophageal irritation such as dysphagia, pain swallowing, retrosternal pain or the onset / aggravation of heartburn, should seek immediate medical attention.
Hypocalcaemia must be corrected prior to initiation of Actonel therapy. It is also necessary to correct other disorders of the bones and mineral metabolism (eg parathyroid dysfunction, hypovitaminosis D) when initiating therapy with Actonel.
Osteonecrosis of the jaw, usually associated with tooth extraction and / or local infection (including osteomyelitis), has been reported in cancer patients treated with regimens including bisphosphonates administered primarily intravenously. Many of these patients they were also treated with chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been reported in patients with osteoporosis being treated with oral bisphosphonates.
Before starting treatment with bisphosphonates in patients with concomitant risk factors (such as cancer, chemotherapy, radiotherapy, corticosteroids, poor oral hygiene) 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 and / or jaw during bisphosphonate therapy, dental surgery can exacerbate the condition. For patients requiring dental surgery, there are no data available to suggest that discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw and / or 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.
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, discontinuation of bisphosphonate therapy should be considered pending evaluation of the patient based on individual benefit / risk.
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.
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
04.5 Interactions with other medicinal products and other forms of interaction
No interaction studies have been conducted with other treatments, however clinically relevant interactions with other medicinal products have not been observed in clinical studies.
The concomitant use of medicinal products containing polyvalent cations (eg calcium, magnesium, iron and aluminum) interferes with the absorption of risedronate sodium (see section 4.4).
Risedronate sodium is not systemically metabolised, does not induce cytochrome P-450 enzymes and is low in protein binding.
In the phase III studies of risedronate sodium in the treatment of osteoporosis, 33% and 45% of patients received acetylsalicylic acid or other non-steroidal anti-inflammatory drugs (NSAIDs), respectively.
If deemed appropriate, risedronate sodium can be used concomitantly with estrogen replacement therapy.
04.6 Pregnancy and lactation
There are insufficient data regarding the treatment of pregnant women with risedronate sodium. Studies in animals have shown toxic effects on reproduction (see section 5.3). The potential risk to humans is unknown. Animal studies indicate that a small amount of risedronate sodium passes into breast milk.
Risedronate sodium should not be administered in pregnant or breastfeeding women.
04.7 Effects on ability to drive and use machines
Actonel has no or negligible influence on the ability to drive and use machines.
04.8 Undesirable effects
Risedronate sodium has been studied in phase III clinical trials involving more than 15,000 patients. The majority of undesirable effects seen in clinical trials were mild or moderate in severity and usually did not require discontinuation of therapy.
Undesirable effects that occurred during phase III clinical trials in women with postmenopausal osteoporosis treated for up to 36 months with risedronate 5 mg / day (n = 5,020) or placebo (n = 5,048), and considered possibly or probably related to risedronate, are listed using the following definition (the incidence versus placebo is indicated in brackets): very common (≥1 / 10); common (≥1 / 100;
Nervous system disorders.
Common: headache (1.8% vs. 1.4%)
Eye disorders.
Uncommon: iritis *
Gastrointestinal disorders.
Common: constipation (5.0% vs. 4.8%), dyspepsia (4.5% vs. 4.1%), nausea (4.3% vs. 4.0%), abdominal pain (3.5 % vs. 3.3%), diarrhea (3.0% vs. 2.7%)
Uncommon: gastritis (0.9% vs. 0.7%), oesophagitis (0.9% vs. 0.9%), dysphagia (0.4% vs. 0.2%), duodenitis (0.2 % vs. 0.1%), oesophageal ulcer (0.2% vs. 0.2%)
Rare: glossitis (esophageal stricture (
Musculoskeletal and connective tissue disorders.
Common: musculoskeletal pain (2.1% vs. 1.9%)
Diagnostic tests.
Rare: abnormal liver function tests *
* No relevant incidence from Phase III clinical trials in osteoporosis; frequency is based on adverse event / laboratory / rechallenge data from previous clinical trials.
Laboratory parameters.
Initial mild, transient and asymptomatic decreases in serum calcium and phosphate have been observed in some patients.
The following additional adverse reactions have been reported from marketing (frequency not known)
Eye disorders.
Iritis, uveitis
Musculoskeletal and connective tissue disorders.
Osteonecrosis of the mandible and / or maxilla
Skin and subcutaneous tissue disorders.
Skin and hypersensitivity reactions, including angioedema, generalized rash, urticaria and bullous skin reactions, some severe including isolated cases of Stevens Johnson syndrome, toxic epidermal necrolysis and leukocytoclastic vasculitis.
Hair loss and / or dander.
Disorders of the immune system.
Anaphylactic reactions
Hepatobiliary disorders.
Severe liver disease. In most of the reported cases, patients were also being treated with other products known to induce liver disease.
The following reactions have been reported during post-marketing experience (frequency rare):
Atypical subtrochanteric and diaphyseal fractures of the femur (bisphosphonate class adverse reaction).
04.9 Overdose
No specific data are available on the treatment of cases of overdose with risedronate sodium.
In the event of an overdose, decreases in serum calcium can be expected. Some of these patients may also have signs and symptoms of hypocalcemia.
Milk or antacids containing magnesium, calcium or aluminum should be given to bind risedronate sodium and reduce its absorption. In cases of overdose, gastric lavage may be considered to remove unabsorbed risedronate sodium.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmaco-therapeutic category: bisphosphonates.
ATC code M05BA07.
Mechanism of action
Risedronate sodium is a pyridinyl bisphosphonate which attaches to the hydroxyapatite of the bone and inhibits bone resorption by osteoclasts. Bone turnover is reduced while osteoblastic activity and bone mineralization are maintained.
Pharmacodynamic effects
In preclinical studies, risedronate sodium has shown a potent anti-osteoclastic and anti-resorption action resulting in a dose-dependent increase in bone mass and biomechanical bone strength. The activity of risedronate sodium was confirmed by measurements of biochemical indexes of bone turnover. during pharmacodynamic and clinical studies. Decreases in biochemical indices of bone turnover were observed within the first month and peaked within 3-6 months.
Clinical efficacy and safety
Therapy and Prevention of Postmenopausal Osteoporosis
Many risk factors are associated with postmenopausal osteoporosis including low bone mass, low bone mineral density, early menopause, smoking, and a family history of osteoporosis. The clinical consequence of osteoporosis is an increased incidence of fractures. The risk of fractures increases with increasing risk factors.
The clinical development program evaluated the effects of risedronate sodium on the risk of hip and vertebral fractures and included postmenopausal women, both early and late, with or without fractures.Doses of 2.5 mg and 5 mg per day were evaluated and all groups, including controls, received calcium and vitamin D (if baseline levels were decreased).
The absolute and relative risk of new vertebral and hip fractures was calculated using an "analysis"time to first event'.
• Two placebo-controlled studies (n = 3,661) enrolled postmenopausal women less than 85 years of age with baseline vertebral fractures. Risedronate sodium 5 mg daily given for 3 years resulted in a reduction in the risk of new vertebral fractures compared with to the control group.
In women with at least 2 vertebral fractures or 1 vertebral fracture, the relative risk reduction of new fractures was 49% and 41%, respectively (the incidence of new vertebral fractures with risedronate sodium was 18.1% and 11 , 3% respectively, while with placebo 29% and 16.3% respectively). The treatment effect was observed already from the end of the first year of therapy. The benefits have also been demonstrated in women with multiple fractures at baseline. Risedronate sodium 5 mg per day reduced the annual loss of weight compared to the control group.
• Two additional placebo-controlled studies enrolled postmenopausal women over 70 years of age with or without baseline vertebral fractures. Women aged 70-79 years with a skeletal femoral neck BMD T-score were enrolled for hip fracture or on the basis of decreased bone mineral density of the femoral neck. Statistically, the efficacy of risedronate sodium versus placebo was only achieved when the two groups treated with 2.5 mg and 5 mg were combined. The following results are based only on post-post analysis of subgroups of patients chosen from clinical cases or on the current definition of osteoporosis:
° In a subgroup of patients with femoral neck BMD T-score ≤-2.5 SD (NHANES III) and at least one baseline vertebral fracture, risedronate sodium administered for three years reduced the risk of hip fracture. in 46% of cases compared to the control group (the incidence of hip fractures in the groups treated with risedronate sodium 2.5 mg and 5 mg was 3.8%, with placebo 7.4%).
° Data suggest that more limited protection is evident in older patients (≥80 years). This may be a consequence of the increased importance of non-skeletal risk factors for hip fracture over the years.
° In these studies, the secondary endpoint analysis highlighted the decreased risk of new vertebral fractures in patients with decreased femoral neck BMD without vertebral fractures and in patients with decreased femoral neck BMD with or without fractures. vertebral.
Risedronate sodium 5 mg daily given for 3 years increased bone mineral density (BMD) of the lumbar spine, femoral neck, trochanter and wrist compared to the control group and prevented bone loss in the distal third of the radius. .
• A rapid reduction in the suppressive effects of risedronate sodium on bone turnover rate was observed in the "year following discontinuation of therapy after three years of treatment with risedronate sodium 5 mg daily."
• In postmenopausal women on estrogen replacement therapy, risedronate sodium 5 mg daily increased bone mineral density (BMD) to a limited extent in the femoral neck and distal third of the radius compared to estrogen-only patients.
• Bone biopsies performed on postmenopausal women treated with Actonel 5 mg daily for 2-3 years showed an expected moderate decrease in bone turnover. Bone tissue during risedronate sodium treatment was found to have a normal lamellar structure and bone mineralization rate. These data, together with the decreased incidence of osteoporotic vertebral fractures in women with osteoporosis, seem to indicate the absence of harmful effects on bone quality.
• Endoscopic measurements carried out on a number of patients, both treated with risedronate sodium and belonging to the control group, suffering from various moderate to severe gastrointestinal disorders, did not reveal esophageal, gastric or duodenal ulcers related to the therapy, although cases of duodenitis were observed uncommonly in the risedronate sodium group.
• In a comparative clinical study in women with postmenopausal osteoporosis treated with one dose before breakfast or with a dose at other times of the day, the increase in lumbar spine bone mineral density was statistically higher with the dose taken. before breakfast.
• In osteopenic postmenopausal women, risedronate sodium showed superiority over placebo in increasing lumbar spine BMD at 12 and 24 months.
Corticosteroid-induced osteoporosis
The risedronate sodium clinical development program included patients who had initiated corticosteroid therapy (≥ 7.5 mg / day prednisone or equivalent) within 3 months prior to starting the studies or patients who had taken corticosteroids for more than 6 months. The results of these studies showed the following:
- Risedronate sodium 5 mg daily for one year maintains or increases bone mineral density compared to the control group at the level of the lumbar spine, femoral neck and trochanter.
- Risedronate sodium 5 mg daily reduces the incidence of vertebral fractures at 1 year compared to the control group, assessed for safety reasons with a cumulative study analysis.
- the histological examination of the bone biopsies of patients receiving corticosteroid therapy and treated with sodium risedronate 5 mg per day showed no signs of alteration of the mineralization process.
Pediatric population
The safety and efficacy of risedronate sodium are being evaluated in an ongoing study in pediatric patients aged 4 to less than 16 years with osteogenesis imperfecta. Following completion of its randomized, double-blind, placebo-controlled phase, lasting one year, a statistically significant increase in lumbar spine BMD was demonstrated in the risedronate group versus the placebo group; however an increase in the number, of at least 1 new morphometric vertebral fracture (assessed radiographically), was found in the risedronate group compared to placebo. Overall, the results do not support the use of risedronate sodium in pediatric patients with osteogenesis imperfecta.
05.2 "Pharmacokinetic properties
Absorption
Absorption from an oral dose is relatively rapid (tmax ≥1 hour) and is dose independent over the doses studied (2.5 to 30 mg). The oral bioavailability of the tablet averages 0.63% and decreases when risedronate sodium is administered with food. Bioavailability was similar in men and women.
Distribution
The mean steady state volume of distribution in humans is 6.3 L / kg. The plasma protein bound fraction of the drug is approximately 24%.
Biotransformation
There is no evidence that risedronate sodium is metabolised systemically.
Elimination
Approximately half of the absorbed dose is eliminated in the urine within 24 hours, while 85% of an intravenous dose is eliminated in the urine after 28 days. Mean renal clearance is 105 ml / min and total clearance is 122 ml. / min: The difference is likely attributable to clearance due to "adsorption to bone". Renal clearance is not concentration dependent and there is a linear relationship between renal clearance and creatinine clearance. Unabsorbed risedronate sodium is eliminated unchanged via the faeces After oral administration the concentration-time curve shows three elimination phases with a terminal half-life of 480 hours.
Special populations
Elderly patients
No dosage adjustment is necessary.
Patients treated with acetylsalicylic acid or other non-steroidal anti-inflammatory drugs (NSAIDs)
Among patients treated regularly (three or more days a week) with acetylsalicylic acid or other NSAIDs, the incidence of adverse events in the upper gastrointestinal tract in the Actonel treated was similar to that in the control group.
05.3 Preclinical safety data
Dose dependent hepatotoxic effects of risedronate sodium, mainly as an increase in enzymes, with histological changes in rats, were observed in toxicological studies in rats and dogs. The clinical relevance of these observations is unknown. Testicular toxicity appeared in rats and dogs at exposures considered in excess of the therapeutic exposure in humans. In rodents, dose-dependent irritation of the upper airways has often been noted.
Similar effects have been reported with other bisphosphonates. Effects on the lower respiratory tract have been observed in long-term rodent studies, however the clinical relevance of these findings is unclear. In reproductive toxicity studies for exposures close to clinical exposures, changes in ossification at the sternal and / or cranial level were observed in fetuses of treated rats and hypocalcaemia and mortality in treated females who gave birth. There is no evidence of teratogenesis at delivery. dose of 3.2 mg / kg / day in rats and 10 mg / kg / day in rabbits, although data are only available on a limited number of rabbits. Maternal toxicity prevented the study of higher doses. on genotoxicity and carcinogenesis have not shown any particular risk for humans.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Core of the tablet: Lactose monohydrate,
microcrystalline cellulose,
crospovidone,
magnesium stearate.
Coating: Yellow iron oxide E 172,
hypromellose,
macrogol,
hydroxypropylcellulose,
silicon dioxide,
titanium dioxide E171.
06.2 Incompatibility
Not relevant.
06.3 Period of validity
5 years.
06.4 Special precautions for storage
This medicine does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package
Opaque PVC / Aluminum blister of 14 tablets in a cardboard box, number of tablets 14, 28 (2 x 14), 84 (6 x 14) or 10 x 14 (for hospital use).
2 perforated blister strips of 10 tablets (packaging for hospital use).
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions for disposal.
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Warner Chilcott Italy S.r.l.
Via dei Pratoni, 16
50018 Scandicci (FI) - Italy
08.0 MARKETING AUTHORIZATION NUMBER
5 mg film-coated tablets 14 tablets in blister - AIC 034568016 / M
5 mg film-coated tablets 20 (2 x 10) tablets in blister - AIC 034568028 / M
5 mg film-coated tablets 28 (2 x 14) tablets in blister - AIC 034568030 / M
5 mg film-coated tablets 84 (6 x 14) tablets in blister - AIC. 034568042 / M
5 mg film-coated tablets 140 (10 x 14) tablets in blister - AIC 034568055 / M
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: July 2000
Date of most recent renewal: August 2009
10.0 DATE OF REVISION OF THE TEXT
March 2013
