Actonel 30 mg movie-covered drugs.
Each movie-covered pill consists of 30 mg risedronate sodium (equal to 27.8 mg risedronic acid).
Excipient with recognized effect
Each movie-covered pill incorporates 131.0 mg lactose monohydrate (equivalent to 124.45 mg lactose).
For a full listing of excipients, see phase 6.1.
Three. Pharmaceutical shape
Film-covered tablets.
Oval white movie-lined pill with RSN on one side and 30 mg on the alternative.
4. Clinical particulars
4.1 Therapeutic indicators
Treatment of Paget's disorder of the bone.
Four.2 Posology and approach of administration
Posology
The endorsed day by day dose in adults is one 30 mg tablet orally for two months. If re-treatment is considered necessary (at the least months post-remedy), a new treatment with the equal dose and length of therapy could be given.
SPECIAL POPULATIONS
Elderly:
No dosage adjustment is vital since bioavailability, distribution and removal had been similar in aged (>60 years of age) compared to more youthful subjects.
Renal Impairment:
No dosage adjustment is required for the ones patients with mild to mild renal impairment. The use of risedronate sodium is contraindicated in sufferers with severe renal impairment (creatinine clearance decrease than 30 ml/min) (see sections four.3 and five.2).
Paediatric population:
Risedronate sodium isn't recommended for use in youngsters beneath age 18 due to insufficient data on safety and efficacy (additionally see segment 5.1).
Method of management
The absorption of Actonel is laid low with food, as a consequence to ensure ok absorption patients should take Actonel:
• Before breakfast: At least 30 minutes before the primary food, different medicinal product or drink (other than plain water) of the day.
In the particular instance that before breakfast dosing isn't always realistic, Actonel may be taken among food or inside the nighttime on the equal time everyday, with strict adherence to the following commands, to ensure Actonel is taken on an empty stomach:
• Between meals: Actonel need to be taken at the least 2 hours earlier than and at the least 2 hours after any meals, medicinal product or drink (other than undeniable water).
• In the evening: Actonel need to be taken at the least 2 hours after the remaining meals, medicinal product or drink (apart from simple water) of the day. Actonel need to be taken at least half-hour earlier than going to mattress.
If an occasional dose is missed, Actonel can be taken earlier than breakfast, between meals, or within the evening according to the instructions above.
The tablet must be swallowed complete and not sucked or chewed. To resource shipping of the pill to the belly Actonel is to be taken even as in an upright role with a glass of plain water (>a hundred and twenty ml). Patients have to now not lie down for 30 minutes after taking the tablet (see phase 4.Four).
Physicians must don't forget the management of supplemental calcium and diet D if dietary consumption is inadequate, especially as bone turnover is substantially expanded in Paget's disease.
Four.Three Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Hypocalcaemia (see phase 4.Four).
Pregnancy and lactation.
Severe renal impairment (creatinine clearance <30ml/min).
Four.Four Special warnings and precautions for use
Foods, liquids (other than plain water) and medicinal products containing polyvalent cations (together with calcium, magnesium, iron and aluminium) intrude with the absorption of bisphosphonates and have to now not be taken on the identical time as Actonel (see section four.Five). In order to attain the supposed efficacy, strict adherence to dosing tips is vital (see section four.2).
Bisphosphonates have been associated with oesophagitis, gastritis, oesophageal ulcerations and gastroduodenal ulcerations. Thus, caution should be used:
• In sufferers who have a records of oesophageal disorders which postpone oesophageal transit or emptying e.G. Stricture or achalasia.
• In sufferers who are unable to live inside the upright position for at least 30 minutes after taking the tablet.
• If risedronate is given to sufferers with active or current oesophageal or upper gastrointestinal issues (which include regarded Barrett's oesophagus).
Prescribers should emphasise to sufferers the significance of taking note of the dosing instructions and be alert to any symptoms or signs of possible oesophageal response. The sufferers need to be instructed to are searching for timely medical attention in the event that they increase signs and symptoms of oesophageal inflammation which include dysphagia, pain on swallowing, retrosternal pain or new/worsened heartburn.
Hypocalcaemia must be dealt with earlier than beginning Actonel remedy. Other disturbances of bone and mineral metabolism (e.G. Parathyroid disorder, hypovitaminosis D) must be treated at the time of starting Actonel therapy.
Osteonecrosis of the jaw, typically associated with teeth extraction and/or neighborhood infection (consisting of osteomyelitis) has been suggested in patients with cancer receiving remedy regimens including primarily intravenously administered bisphosphonates. Many of those sufferers have been additionally receiving chemotherapy and corticosteroids. Osteonecrosis of the jaw has also been said in sufferers with osteoporosis receiving oral bisphosphonates.
A dental exam with suitable preventive dentistry should be taken into consideration prior to treatment with bisphosphonates in sufferers with concomitant danger elements (e.G. Most cancers, chemotherapy, radiotherapy, corticosteroids, bad oral hygiene).
While on remedy, those sufferers must avoid invasive dental approaches if possible. For patients who expand osteonecrosis of the jaw whilst on bisphosphonate remedy, dental surgical treatment can also exacerbate the condition. For patients requiring dental methods, there are not any data to be had to indicate whether discontinuation of bisphosphonate treatment reduces the hazard of osteonecrosis of the jaw.
Clinical judgment of the treating physician have to manual the management plan of each affected person based on individual advantage/risk evaluation.
Osteonecrosis of the outside auditory canal has been suggested with bisphosphonates, specifically in association with long-time period remedy. Possible chance factors for osteonecrosis of the outside auditory canal encompass steroid use and chemotherapy and/or neighborhood risk elements along with infection or trauma. The opportunity of osteonecrosis of the external auditory canal should be considered in sufferers receiving bisphosphonates who present with ear symptoms together with chronic ear infections.
Atypical fractures of the femur
Atypical subtrochanteric and diaphyseal femoral fractures had been mentioned with bisphosphonate remedy, typically in sufferers receiving lengthy-term remedy for osteoporosis. These transverse or quick oblique fractures can occur everywhere alongside the femur from simply underneath the lesser trochanter to just above the supracondylar flare. These fractures arise after minimal or no trauma and some patients experience thigh or groin pain, regularly related to imaging features of strain fractures, weeks to months before offering with a completed femoral fracture. Fractures are regularly bilateral; therefore the contralateral femur ought to be tested in bisphosphonate-handled sufferers who've sustained a femoral shaft fracture. Poor healing of these fractures has additionally been reported. Discontinuation of bisphosphonate therapy in sufferers suspected to have an ordinary femur fracture need to be taken into consideration pending assessment of the patient, based on an person benefit danger assessment.
During bisphosphonate remedy sufferers must be recommended to report any thigh, hip or groin pain and any affected person offering with such signs and symptoms should be evaluated for an incomplete femur fracture.
This medicinal product carries lactose. Patients with rare hereditary troubles of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption must now not take this medicinal product
Four.5 Interaction with different medicinal merchandise and different types of interplay
No formal interplay research had been executed, however no clinically applicable interactions with other medicinal merchandise had been located in the course of clinical research.
Concomitant ingestion of medicinal drugs containing polyvalent cations (e.G. Calcium, magnesium, iron and aluminium) will intrude with the absorption of risedronate sodium (see section 4.4).
Risedronate sodium isn't systemically metabolised, does no longer result in cytochrome P450 enzymes, and has low protein binding.
4.6 Fertility, pregnancy and lactation
There aren't any good enough statistics from the usage of risedronate sodium in pregnant girls. Studies in animals have proven reproductive toxicity (see segment 5.Three). The capability threat for people is unknown. Studies in animal imply that a small quantity of risedronate sodium skip into breast milk.
Risedronate sodium must now not be used in the course of being pregnant or by using breast-feeding girls.
Four.7 Effects on potential to drive and use machines
Actonal has no or negligible affect on the capacity to power and use machines.
4.Eight Undesirable consequences
Risedronate sodium has been studied in phase III medical studies regarding greater than 15,000 sufferers. The majority of unwanted results located in scientific studies turned into moderate to moderate in severity and generally did no longer require cessation of remedy.
Adverse reports reported in section III clinical studies in postmenopausal women with osteoporosis treated for as much as 36 months with risedronate 5mg/day (n=5020) or placebo (n=5048) and taken into consideration in all likelihood or probable associated with risedronate are indexed under the use of the subsequent convention (incidences versus placebo are proven in brackets): very commonplace (≥1/10); not unusual (≥1/100; <1/10); unusual (≥1/1,000; <1/one hundred); rare (≥1/10,000; <1/1,000); very uncommon (<1/10,000).
Nervous device issues:
Common: headache (1.8% vs. 1.Four%)
Eye issues:
Uncommon: iritis*
Gastrointestinal problems:
Common: constipation (five.Zero% vs. Four.8%), dyspepsia (4.5% vs. 4.1%), nausea (four.Three% vs. Four.0%), abdominal ache (3.5% vs. 3.Three%), diarrhoea (3.Zero% vs. 2.7%)
Uncommon: gastritis (0.Nine% vs. 0.7%), oesophagitis (0.Nine% vs. 0.Nine%), dysphagia (0.4% vs. 0.2%), duodenitis (0.2% vs. 0.1%), oesophageal ulcer (zero.2% vs. Zero.2%)
Rare: glossitis (<zero.1% vs. Zero.1%), oesophageal stricture (<zero.1% vs. Zero.Zero%),
Musculoskeletal and connective tissues problems:
Common: musculoskeletal ache (2.1% vs. 1.9%)
Very uncommon: Osteonecrosis of the external auditory canal (bisphosphonate elegance damaging reaction).
Investigations:
Rare: abnormal liver feature assessments*
* No relevant incidences from Phase III osteoporosis research; frequency based on unfavorable occasion/laboratory/rechallenge findings in earlier scientific studies.
In a phase III Paget's Disease medical trial evaluating risedronate vs. Etidronate (61 patients in each institution), the following additional detrimental reports considered possibly or possibly drug related by investigators had been said (occurrence more in risedronate than in etidronate): arthralgia (nine.8% vs. Eight.2%); amblyopia, apnoea, bronchitis, colitis, corneal lesion, cramps leg, dizziness, dry eye, flu syndrome, hypocalcaemia, myasthenia, neoplasm, nocturia, oedema peripheral, ache bone, pain chest, rash, sinusitis, tinnitus, and weight lower (all at 1.6% vs. Zero.Zero%).
Laboratory findings: Early, brief, asymptomatic and mild decreases in serum calcium and phosphate levels had been observed in a few sufferers.
The following extra destructive reactions had been mentioned in the course of submit-advertising use (frequency unknown):
Eye disorders:
Iritis, uveitis
Muskuloskeletal and connective tissues issues:
Osteonecrosis of the jaw
Skin and subcutaneous tissue disorders:
Hypersensitive reaction and pores and skin reactions, together with angioedema, generalised rash, urticaria and bullous pores and skin reactions, a few intense including remoted reviews of Stevens-Johnson syndrome, toxic epidermal necrolysis and leukocytoclastic vasculitis.
Hair loss.
Immune system disorders:
Anaphylactic reaction
Hepatobiliary problems:
Severe hepatic problems. In maximum of the mentioned cases the sufferers have been also handled with different merchandise recognised to cause hepatic issues.
During put up-marketing revel in the subsequent reactions had been reported (frequency uncommon):
Atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate magnificence adverse reaction).
Reporting of suspected unfavorable reactions
Reporting suspected negative reactions after authorisation of the medicinal product is essential. It lets in persisted monitoring of the advantage/chance stability of the medicinal product. Healthcare specialists are requested to record any suspected detrimental reactions via the Yellow Card Scheme at: www.Mhra.Gov.Uk/yellowcard.
4.Nine Overdose
No unique information is available at the treatment of overdose with risedronate sodium.
Decreases in serum calcium following significant overdose can be anticipated. Signs and signs and symptoms of hypocalcaemia might also arise in some of those patients.
Milk or antacids containing magnesium, calcium or aluminium need to take delivery of to bind risedronate and decrease absorption of risedronate sodium. In instances of tremendous overdose, gastric lavage can be taken into consideration to do away with unabsorbed risedronate sodium.
Five. Pharmacological residences
Five.1 Pharmacodynamic residences
Pharmaco-healing group: Bisphosphonates
ATC Code: M05 BA07
Mechanism of movement
Risedronate sodium is a pyridinyl bisphosphonate that binds to bone hydroxyapatite and inhibits osteoclast-mediated bone resorption. The bone turnover is reduced at the same time as the osteoblast hobby and bone mineralisation is preserved.
Clinical efficacy and safety
Paget's sickness of the bone: In the clinical programme Actonel was studied in patients with Paget's ailment. After remedy with Actonel 30 mg/day for 2 months the following became visible:
• serum alkaline phosphatase normalised in 77% of sufferers in comparison to 11% in the control institution (etidronate four hundred mg/day for 6 months). Significant reductions have been determined in urinary hydroxyproline/creatinine and urinary deoxypyridinoline/creatinine
• radiographs taken at baseline and after 6 months tested a decrease in the extent of osteolytic lesions in each the appendicular and axial skeleton. No new fractures have been observed.
The discovered response was comparable in pagetic patients regardless of whether or not that they had previously acquired different remedies for Paget's disease, or the severity of the disease.
53% of patients observed for 18 months after initiation of a single 2 month direction of Actonel remained in biochemical remission.
In a tribulation comparing before-breakfast dosing and dosing at other instances of the day in women with postmenopausal osteoporosis, lumbar backbone BMD gains were statistically better with before-breakfast dosing.
Paediatric populace:
The safety and efficacy of risedronate sodium has been investigated in a three-year observe (a randomized, double-blind, placebo-managed, multicenter, parallel group have a look at of 12 months length followed via 2 years of open-label treatment) in paediatric patients elderly four to less than 16 years with moderate to moderate osteogenesis imperfecta. In this study, sufferers weighing 10-30 kg obtained risedronate 2.5 mg day by day and sufferers weighing extra than 30 kg acquired risedronate five mg each day.
After final touch of its one-yr randomized, double-blind, placebo-managed section, a statistically huge boom in lumbar backbone BMD within the risedronate institution versus placebo organization turned into confirmed; but an expanded range of patients with as a minimum 1 new morphometric (identified by using x-ray) vertebral fracture was discovered within the risedronate group as compared to placebo. During the one-year double-blind duration, the proportion of sufferers who pronounced medical fractures turned into 30.Nine% within the risedronate institution and 49.Zero% inside the placebo group. In the open-label duration when all sufferers acquired risedronate (month 12 to month 36), scientific fractures had been reported via 65.Three% of sufferers to begin with randomized to the placebo group and by 52.Nine% of patients to start with randomized to the risedronate group. Overall, results do now not help using risedronate sodium in paediatric patients with moderate to slight osteogenesis imperfecta.
Five.2 Pharmacokinetic houses
Absorption:
Absorption after an oral dose is relatively speedy (tmax ~1 hour) and is impartial of dose over the range studied (2.5 to 30 mg). Mean oral bioavailability of the tablet is 0.Sixty three% and is decreased when risedronate sodium is administered with food. Bioavailability became similar in ladies and men.
Distribution:
The suggest regular country extent of distribution is 6.3 l/kg in human beings. Plasma protein binding is ready 24%.
Biotransformation
There is not any proof of systemic metabolism of risedronate sodium.
Elimination:
Approximately 1/2 of the absorbed dose is excreted in urine inside 24 hours, and eighty five% of an intravenous dose is recovered within the urine after 28 days. Mean renal clearance is one zero five ml/min and mean total clearance is 122 ml/min, with the difference in all likelihood attributed to clearance because of adsorption to bone. The renal clearance isn't attention structured, and there's a linear dating among renal clearance and creatinine clearance. Unabsorbed risedronate sodium is eliminated unchanged in faeces. After oral administration the attention-time profile shows 3 elimination phases with a terminal half of-life of 480 hours.
Special Populations:
Elderly:
No dosage adjustment is vital.
Five.Three Preclinical protection records
In toxicological research in rat and dog dose established liver poisonous consequences of risedronate sodium had been seen, by and large as enzyme will increase with histological adjustments in rat. The scientific relevance of those observations is unknown. Testicular toxicity took place in rat and dog at exposures considered in extra of the human therapeutic exposure. Dose associated incidences of upper airway irritation have been frequently cited in rodents. Similar effects had been seen with other bisphosphonates. Lower respiration tract results had been also visible in long run research in rodents, despite the fact that the medical importance of those findings is unclear. In duplicate toxicity studies at exposures near scientific publicity ossification changes had been visible in sternum and/or cranium of foetuses from treated rats and hypocalcemia and mortality in pregnant girls allowed to deliver. There was no proof of teratogenesis at three.2mg/kg/day in rat and 10mg/kg/day in rabbit, despite the fact that facts are handiest available on a small variety of rabbits. Maternal toxicity averted checking out of better doses. Studies on genotoxicity and carcinogenesis did no longer show any specific dangers for human beings.
6. Pharmaceutical particulars
6.1 List of excipients
Tablet middle:
Lactose monohydrate
Cellulose microcrystalline
Crospovidone
Magnesium stearate.
Film coating:
Hypromellose
Macrogol
Hydroxypropylcellulose
Colloidal anhydrous silica
Titanium dioxide E171.
6.2 Incompatibilities
Not relevant.
6.Three Shelf existence
Five years.
6.4 Special precautions for storage
This medicinal product does no longer require any unique garage conditions.
6.Five Nature and contents of field
Opaque PVC/aluminium foil blister playing cards of 14 tablets in cardboard carton, pill rely 28 (2 x 14) and tablet count number 14 (1 x 14).
Sample % – Opaque PVC/aluminium foil blister playing cards of three tablets in cardboard carton, tablet matter 3 (1 x 3).
Not all % sizes can be advertised.
6.6 Special precautions for disposal and different dealing with
No special necessities for disposal.
Any unused medicinal product or waste cloth have to be disposed of according with local necessities.
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