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Drug Details

ACTONEL Combi

• Drug Class Description
  Bisphosphonates
• Generic Name
  Risedronate sodium
• Presentation
  Film-coated tablet: Risedronate tablets: Oval, light-orange, film-coated tablet with RSN on one side and 35 mg on the other. Effervescent granules: Calcium carbonate/colecalciferol, white effervescent granules
• Description
  Actonel Combi 35 mg + 1000 mg / 880 IU film-coated tablets + effervescent granules
• Indications
  Treatment of postmenopausal osteoporosis, to reduce the risk of vertebral fractures. Treatment of established postmenopausal osteoporosis, to reduce the risk of hip fractures. Actonel Combi is only intended for use in assessed patients for whom the amount of calcium and vitamin D3 included is considered to provide adequate supplementation
• Adult Dosage
  

  A weekly unit of Actonel Combi consists of 1 Actonel 35 mg film-coated tablet and 6 calcium/vitamin D₃ sachets in a box.
  
  The recommended dose in adults is 1 Actonel 35 mg tablet on the first day followed on the next day by 1 calcium/vitamin D₃ sachet daily for 6 days. This 7-day sequence is then repeated each week starting with Actonel 35 mg tablet.

  Actonel 35 mg (light-orange tablet):

  The Actonel 35 mg tablet should be taken orally on the same day each week.

  The absorption of risedronate sodium is affected by food, thus to ensure adequate absorption, patients should take the Actonel 35 mg tablet

  • breakfast: at least 30 minutes before the first food, other medicinal product or drink (other than plain water) of the day.

  The tablet must be swallowed whole and not sucked or chewed. To aid delivery of the tablet to the stomach the Actonel 35 mg tablet is to be taken while in an upright position with a glass of plain water (>120 ml). Patients should not lie down for 30 minutes after taking the tablet (see section 4.4).

  Calcium/vitamin D₃ (sachet):

  Calcium/vitamin D₃ sachet should be taken each day for 6 days per week starting on the day after the Actonel 35 mg tablet is taken. The contents of the sachet should be poured into a glass of plain water, stirred and drunk immediately once the fizzing has subsided.

  In case the Actonel 35 mg tablet dose is missed, patients should be instructed that the Actonel 35 mg tablet should be taken on the next day in the morning according to the dosing instructions. In this particular instance, patients should then take their calcium/vitamin D₃ sachet on the following day. Patients should be instructed that they should never take the tablet and the sachet the same day.

  If the calcium/vitamin D₃ sachet dose is missed, the patient should be instructed to continue taking one sachet each day beginning on the day the missed dose is remembered. Patient should be instructed that they should not take two sachets on the same day. Any remaining calcium/vitamin D₃ sachet at the end of the weekly cycle should be discarded.

  Renal Impairment: No dosage adjustment is required for those patients with mild to moderate renal impairment. The use of risedronate sodium and calcium/vitamin D₃ is contraindicated in patients with severe renal impairment (creatinine clearance lower than 30ml/min) (see sections 4.3 and 5.2).

• Child Dosage
  

  Safety and efficacy of Actonel Combi has not been established in children and adolescents.

• Elderly Dosage
  

  No dosage adjustment is necessary since bioavailability, distribution and elimination were similar in elderly (>60 years of age) compared to younger subjects. This has also been shown in the very elderly, 75 years old and above in postmenopausal population.

• Contra Indications
  
  • Hypersensitivity to risedronate sodium, calcium carbonate, colecalciferol or to any of the excipients (in particular soya-bean oil).
  • Hypocalcaemia
  • Hypercalcaemia.
  • Hypercalciuria
  • Diseases and/or conditions (such as prolonged immobilization) associated with hypercalcaemia and/or hypercalciuria
  • Nephrolithiasis
  • Pregnancy and lactation.
  • Severe renal impairment (creatinine clearance <30ml/min).
  • Hypervitaminosis D
• Special Precautions
  

  Risedronate sodium:

  Foods, drinks (other than plain water) and medicinal products containing polyvalent cations (such as calcium, magnesium, iron and aluminium) may interfere with the absorption of risedronate sodium and should not be taken at the same time. Therefore the risedronate sodium tablet (light-orange tablet) should be taken at least 30 minutes before the first food, other medicinal product or drink of the day.

  Efficacy of bisphosphonates in the treatment of postmenopausal osteoporosis is related to the presence of low bone mineral density (BMD) [T-score at hip or lumbar spine -2.5 standard deviations (SD)] and/or prevalent fracture.

  High age or clinical risk factors for fracture alone are not sufficient reasons to initiate treatment of osteoporosis with a bisphosphonate. The evidence to support efficacy of bisphosphonates including risedronate sodium in very elderly women (>80 years) is limited.

  Bisphosphonates have been associated with oesophagitis, gastritis, oesophageal ulcerations and gastroduodenal ulcerations. Thus, caution should be used:

  • In patients who have a history of oesophageal disorders which delay oesophageal transit or emptying e.g. stricture or achalasia.
  • In patients who are unable to stay in the upright position for at least 30 minutes after taking the tablet.
  • If risedronate is given to patients with active or recent oesophageal or upper gastrointestinal problems.

  Prescribers should emphasise to patients the importance of paying attention to the dosing instructions and be alert to any signs and symptoms of possible oesophageal reaction. The patients should be instructed to seek timely medical attention if they develop symptoms of oesophageal irritation such as dysphagia, pain on swallowing, retrosternal pain or new/worsened heartburn.

  Hypocalcaemia should be treated before starting Actonel Combi therapy. Other disturbances of bone and mineral metabolism (i.e. parathyroid dysfunction, hypovitaminosis D) should be treated at the time of starting Actonel Combi therapy.

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

  A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, radiotherapy, corticosteroids, poor oral hygiene).

  While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

  In patients with mild to moderate renal impairment or a history of absorptive or renal hypercalciuria, nephrocalcinosis, kidney stone formation, or hypophosphataemia, renal function, serum and urinary calcium and phosphate should be monitored regularly.

  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.

  Calcium carbonate/vitamin D₃:

  Vitamin D₃ should be used with caution in patients with impairment of renal function and the effect on calcium and phosphate levels should be monitored. The risk of soft tissue calcification should be taken into account. In patients with severe renal insufficiency, vitamin D in the form of colecalciferol is not metabolised normally and another form of vitamin D should be used.

  During long-term treatment, serum and urinary calcium levels should be followed and renal function should be monitored through measurement of serum creatinine. Monitoring is especially important in elderly patients on concomitant treatment with cardiac glycosides or diuretics and in patients with a high tendency to calculus formation. Treatment must be reduced or suspended if urinary calcium exceeds 7.5 mmol/24 hour (300 mg/24 hour). In case of hypercalcaemia or signs of impaired renal function, treatment with calcium/vitamin D₃ sachets should be discontinued.

  The dose of vitamin D₃ in the sachets should be considered when prescribing other drugs containing vitamin D. Additional doses of calcium or vitamin D should be taken under close medical supervision. In such cases it is necessary to monitor serum calcium levels and urinary calcium excretion frequently.

  Calcium/vitamin D₃ sachets should be used with caution in patients suffering from sarcoidosis because of the risk of increased metabolism of vitamin D to its active metabolite. In these patients, serum calcium levels and urinary calcium excretion must be monitored.

  Calcium/vitamin D₃ sachets should be used with caution in immobilised patients with osteoporosis due to the increased risk of hypercalcaemia. The calcium/vitamin D₃ treatment might be discontinued in prolonged immobilization and should only be resumed once the patient becomes mobile again.

  This medicinal product contains sorbitol and sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicinal product.

• Interactions
  

  Risedronate sodium:

  No formal interaction studies have been performed with risedronate sodium, however no clinically relevant interactions with other medicinal products were found during clinical trials. In the risedronate sodium Phase III osteoporosis studies with daily dosing, acetyl salicylic acid or non-steroidal anti-inflammatory drug (NSAID) use was reported by 33% and 45% of patients respectively. In the Phase III once a week study, acetyl salicylic acid or NSAID use was reported by 57% and 40% of patients respectively. Among regular acetyl salicylic acid or NSAID users (3 or more days per week) the incidence of upper gastrointestinal adverse events in risedronate sodium treated patients was similar to that in control patients.

  If considered appropriate risedronate sodium may be used concomitantly with oestrogen supplementation.

  Concomitant ingestion of medications containing polyvalent cations (e.g. calcium, magnesium, iron and aluminium) will interfere with the absorption of risedronate sodium (see section 4.4).

  Risedronate sodium is not systemically metabolised, does not induce cytochrome P450 enzymes, and has low protein binding.

  Calcium carbonate/vitamin D₃:

  Thiazide diuretics reduce the urinary excretion of calcium. Due to increased risk of hypercalcemia serum calcium should be regularly monitored during concomitant use of thiazide diuretics.

  Systemic corticosteroids reduce calcium absorption. During concomitant use, it may be necessary to increase the dose of calcium.

  Calcium carbonate may interfere with the absorption of concomitant administered tetracycline preparations. For this reason, tetracycline preparations should be administered at least two hours before or four to six hours after oral intake of calcium carbonate/vitamin D₃.

  Hypercalcaemia may increase the toxicity of digitalis and other cardiac glycosides (risk of dysrhythmia) during treatment with calcium combined with vitamin D₃. Such patients should be monitored with regard to electrocardiogram (ECG) and serum calcium levels.

  If sodium fluoride is used concomitantly, this preparation should be administered at least three hours before intake of calcium carbonate/vitamin D₃ since gastrointestinal absorption may be reduced.

  Oxalic acid (found in spinach and rhubarb) and phytic acid (found in whole cereals) may inhibit calcium absorption through formation of insoluble compounds with calcium ions. The patient should not take calcium products within two hours of eating foods with high concentration of oxalic acid and phytic acid.

  Simultaneous treatment with ion exchange resins such as cholestyramine or laxatives such as paraffin oil may reduce the gastrointestinal absorption of vitamin D.

• Adverse Drug Reactions
  

  Risedronate sodium:

  Risedronate sodium has been studied in phase III clinical trials involving more than 15,000 patients. The majority of undesirable effects observed in clinical trials were mild to moderate in severity and usually did not require cessation of therapy.

  Adverse experiences reported in phase III clinical trials in postmenopausal women with osteoporosis treated for up to 36 months with risedronate sodium 5mg/day (n=5020) or placebo (n=5048) and considered possibly or probably related to risedronate sodium are listed below using the following convention (incidences versus placebo are shown in brackets): very common (1/10); common (1/100; <1/10); uncommon (1/1,000; <1/100); rare (1/10,000; <1/1,000); very rare (<1/10,000).

  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%), diarrhoea (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 (<0.1% vs. 0.1%), oesophageal stricture (<0.1% vs. 0.0%),

  Musculoskeletal and connective tissues disorders:

  Common: musculoskeletal pain (2.1% vs. 1.9%)

  Investigations:

  Rare: abnormal liver function tests*

  * No relevant incidences from Phase III osteoporosis studies; frequency based on adverse event/laboratory/rechallenge findings in earlier clinical trials.

  In a one-year, double-blind, multicentre study comparing risedronate 5 mg daily (n= 480) and risedronate sodium 35 mg weekly (n=485) in postmenopausal women with osteoporosis, the overall safety and tolerability profiles were similar. The following additional adverse experiences considered possibly or probably drug related by investigators have been reported (incidence greater in risedronate 35 mg than in risedronate sodium 5 mg group): gastrointestinal disorder (1.6% vs. 1.0%) and pain (1.2% vs. 0.8%).

  Laboratory findings: Early, transient, asymptomatic and mild decreases in serum calcium and phosphate levels have been observed in some patients.

  The following additional adverse reactions have been reported during post-marketing use (frequency unknown):

  Eye disorders:

  iritis, uveitis

  Muskuloskeletal and connective tissues disorders:

  osteonecrosis of the jaw

  Skin and subcutaneous tissue disorders:

  hypersensitivity and skin reactions, including angioedema, generalised rash, urticaria and bullous skin reactions, some severe including isolated reports of Stevens-Johnson syndrome and toxic epidermal necrolysis.

  hair loss.

  Immune system disorders:

  anaphylactic reaction

  Hepatobiliary disorders :

  serious hepatic disorders. In most of the reported cases the patients were also treated with other products known to cause hepatic disorders.

  Calcium carbonate/vitamin D₃

  Adverse reactions are listed below, by system organ class and frequency following convention: very common (1/10); common (1/100; <1/10); uncommon (1/1,000; <1/100); rare (1/10,000; <1/1,000); very rare (<1/10,000).

  Metabolism and nutrition disorders

  Uncommon: Hypercalcaemia and hypercalciuria.

  Gastrointestinal disorders

  Rare: Constipation, flatulence, nausea, abdominal pain and diarrhoea.

  Skin and subcutaneous disorders

  Rare: Pruritus, rash and urticaria.