RISOFOS Kit (Risedronate sodium + Calcium citrate malate + Vitamin D3)

Table of Content

Composition

Each kit contains:
A) 1 Risedronate Sodium tablet
Each film-coated tablet contains:
Risedronate Sodium Pentahydrate equivalent to
Risedronate Sodium ….................... 35 mg

B) 12 Calcium Citrate Malate and Vitamin D3 tablets
Each film-coated tablet contains:
Elementary Calcium …........................... 250 mg
Vitamin D, IP …................................... 400 IU

Dosage Form

Tablet for oral use.

Pharmacology

Pharmacodynamics

Risedronate
Risedronate is a pyridinyl bisphosphonate that inhibits osteoclast-mediated bone resorption and modulates bone metabolism. Risedronate has an affinity for hydroxyapatite crystals in bone and acts as an anti-resorptive agent. At the cellular level, risedronate inhibits osteoclasts. The osteoclasts adhere normally to the bone surface, but show evidence of reduced active resorption (e.g. lack of ruffled border).

Vitamin D3
Cholecalciferol also called as vitamin D3, is produced naturally by ultraviolet irradiation of the provitamin, 7-dehydrocholesterol (a precursor of vitamin D) in the skin. Absorbed cholecalciferol requires metabolic activation. The circulating vitamin undergoes hydroxylation in the liver with the help of the enzyme, vitamin D 25-hydroxylase to form 25-hydroxycholecalciferol (calcidiol), which is the predominant circulating metabolite. Further hydroxylation of this metabolite in the kidneys (in response to the need for phosphorus and calcium) forms 1,25-dihydroxycholecalciferol (calcitriol), with the help of 1alpha-hydroxylase. Calcidiol possesses some intrinsic activity, but calcitriol is the most active vitamin D metabolite with respect to initiating intestinal transport of calcium and phosphate and mobilizing calcium from bone. Calcitriol may prevent phosphaturia by inhibiting parathyroid hormone (PTH) secretion. Conversion to calcitriol is stimulated by PTH, as well as decreases in serum inorganic phosphate levels. Reduced renal conversion of calcidiol to calcitriol contributes to altered calcium haemostasis and osteodystrophy in uraemia.

Calcium
Calcium plays a critical role in the body. It is essential for normal functioning of nerves, cells, muscle and bone. Calcium prevents bone loss and is associated with a modest reduction in fracture risk. Calcium and vitamin D preparations are used to prevent or to treat calcium deficiency. A vitamin D-resistant state may exist in uraemic patients because of the failure of the kidneys to adequately produce calcitriol.

Pharmacokinetics

Risedronate
Absorption
Absorption after an oral dose is relatively rapid (tmax ~ 1 hour) and occurs throughout the upper gastrointestinal tract. The fraction of the dose absorbed is independent of dose over the range studied (single dose, 2.5 to 30 mg; multiple dose, 2.5 to 5 mg). Steady-state conditions in the serum are observed within 57 days of daily dosing. Mean absolute oral bioavailability of the 30 mg tablet is 0.63% (90% CI: 0.54% to 0.75%) and is comparable to a solution. The extent of absorption of a 30 mg dose (three 10 mg tablets) when administered 0.5 hours before breakfast is reduced by 55% compared to dosing in the fasting state (no food or drink for 10 hours prior to or 4 hours after dosing). Dosing 1 hour prior to breakfast reduces the extent of absorption by 30% compared to dosing in the fasting state. Dosing either 0.5 hours prior to breakfast or 2 hours after dinner (evening meal) results in a similar extent of absorption. Risedronate is effective when administered at least 30 minutes before breakfast.

Distribution
The mean steady-state volume of distribution is 13.8 L/kg in humans. Human plasma protein binding of drug is about 24%.

Metabolism
There is no evidence of systemic metabolism of risedronate.

Elimination
In young healthy subjects, approximately half of the absorbed dose is excreted in urine within 24 hours, and 85% of an intravenous dose is recovered in the urine over 28 days. Mean renal clearance is 105 mL/min (CV = 34%) and mean total clearance is 122 mL/min (CV = 19%), with the difference primarily reflecting non-renal clearance or clearance due to adsorption to bone. The renal clearance is not concentration-dependent, and there is a linear relationship between renal clearance and creatinine clearance. Unabsorbed drug is eliminated unchanged in faeces. Unabsorbed drug is eliminated unchanged in faeces. In osteopenic postmenopausal women, the terminal exponential half-life was 561 hours, mean renal clearance was 52 mL/min (CV = 25%), and mean total clearance was 73 mL/min (CV = 15%).

Vitamin D3
Absorption
Vitamin D substances are well absorbed from the gastrointestinal tract. The presence of bile is essential for adequate intestinal absorption; absorption may be decreased in patients with decreased fat absorption.

Distribution
Vitamin D and its metabolites circulate in the blood bound to a specific alpha-globulin. Vitamin D can be stored in adipose and muscle tissue for long periods of time. It is slowly released from such storage sites and from the skin where it is formed in the presence of sunlight or ultraviolet light. Cholecalciferol has a slow onset and a long duration of action.

Metabolism
Cholecalciferol is converted in the liver by hydroxylation to the active form 25-hydroxycholecalciferol. It is then further converted in the kidneys to 1,25- dihydroxycholecalciferol. 1,25-dihydroxycholecalciferol (calcitriol) is the metabolite responsible for increasing calcium absorption. Vitamin D that is not metabolized is stored in adipose and muscle tissues.

Excretion
Vitamin D compounds and their metabolites are excreted mainly in the bile and faeces, with only small amounts appearing in urine. There is some enterohepatic recycling but it is considered to have a negligible contribution to vitamin D status. Certain vitamin D substances may be distributed into breast milk.

Calcium
Absorption
Calcium citrate malate salt comprises 23.7% elemental calcium. In a study conducted to calculate percent absorption of a test dose in humans, it was seen that calcium citrate malate had a mean percent absorption of 37.3%.

Distribution and Metabolism
In the body, 99% of calcium is concentrated in the hard structure of bones and teeth. The remaining 1% is present in the intra- and extracellular fluids. About 50% of the total blood calcium content is in a physiologically active ionized form, with approximately 10% being complexed to citrate, phosphate or other anions, and the remaining 40% being bound to proteins, principally albumin.

Elimination
Calcium is eliminated through the faeces, urine and sweat. Renal excretion depends on glomerular filtration and calcium tubular reabsorption.

Indications

Postmenopausal Osteoporosis

RISOFOS KIT is indicated for the treatment and prevention of osteoporosis in postmenopausal women. In postmenopausal women with osteoporosis, risedronate reduces the incidence of vertebral fractures and a composite endpoint of non-vertebral osteoporosis-related fractures.

Osteoporosis in Men

RISOFOS KIT is indicated for treatment to increase bone mass in men with osteoporosis.

Glucocorticoid-Induced Osteoporosis

RISOFOS KIT is indicated for the treatment and prevention of glucocorticoid-induced osteoporosis in men and women who are either initiating or continuing systemic glucocorticoid treatment (daily dosage of ≥7.5 mg prednisone or equivalent) for chronic diseases. Patients treated with glucocorticoids should receive adequate amounts of calcium and vitamin D.

Paget's Disease

RISOFOS KIT is indicated for treatment of Paget's disease of the bone in men and women. Treatment is indicated to induce remission (normalization of serum alkaline phosphatase) in patients with Paget's disease of the bone as follows: (1) In those who have a level of serum alkaline phosphatase at least two times the upper limit of normal; or (2) who are symptomatic; or (3) who are at risk for future complications from their disease.

RISOFOS KIT is only intended for use in assessed patients for whom the amount of calcium and vitamin D3 included is considered to provide adequate supplementation.

Important Limitations of Use

The safety and effectiveness of risedronate with calcium for the treatment of osteoporosis are based on clinical data of 3 years duration. The optimal duration of use has not been determined. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis.

Dosage and Administration

A weekly unit of RISOFOS KIT consists of 1 tablet of risedronate 35 mg and 12 tablets of calcium citrate malate and vitamin D3.

The recommended dose in adults is 1 tablet of risedronate on the first day followed on the next day by 1 tablet of calcium/vitamin D3 twice daily for 6 days. This 7-day sequence is then repeated each week, starting with the risedronate tablet.

Risedronate Tablet

The risedronate 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 risedronate tablet with a glass of plain water 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 risedronate tablet is to be taken while in an upright position with a glass of plain water. Patients should not lie down for 30 minutes after taking the tablet.

Calcium/Vitamin D3 Tablets 

Calcium/vitamin D3 tablets should be taken twice daily each day for 6 days per week, starting on the day after the risedronate tablet is taken.

RISOFOS kit is not recommended for use in patients with severe renal impairment (creatinine clearance

Missed Dose

Risedronate
In case the risedronate tablet dosage is missed, patients should be instructed that the risedronate 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 tablet on the following day. Patients should be instructed that they should never take the risedronate tablet and the calcium/vitamin D3 tablets the same day.

Calcium/Vitamin D3
If the calcium/vitamin D3 dose is missed, the patient should be instructed to take the tablets as soon as remembered and then continue taking calcium/vitamin D3 tablets twice daily as scheduled.

Contraindications

  • Hypersensitivity to risedronate sodium, calcium citrate malate, vitamin D3 or to any of the excipients.
  • Inability to stand or sit upright for at least 30 minutes.
  • Abnormalities of the oesophagus, which delay oesophageal emptying, such as stricture or achalasia.
  • Severe renal impairment.
  • Malabsorption syndrome.
  • 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
  • Hypervitaminosis D
  • Renal osteodystrophy with hyperphosphataemia (risk of metastatic calcification; however, vitamin D therapy can begin once serum phosphate levels have stabilized).

Warnings and Precautions

General

Risedronate

Upper Gastrointestinal Adverse Reactions
Risedronate, like other bisphosphonates administered orally, may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for worsening of the underlying disease, caution should be used when risedronate is given to patients with active upper gastrointestinal problems (such as known Barrett's oesophagus, dysphagia, other oesophageal diseases, gastritis, duodenitis or ulcers). Oesophageal adverse experiences, such as oesophagitis, oesophageal ulcers and oesophageal erosions, occasionally with bleeding and rarely followed by oesophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates. In some cases, these have been severe and required hospitalization. Physicians should therefore be alert to any signs or symptoms signalling a possible oesophageal reaction and patients should be instructed to discontinue risedronate and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn. The risk of severe oesophageal adverse experiences appears to be greater in patients who lie down after taking oral bisphosphonates and/or who fail to swallow it with the recommended full glass (6 to 8 oz.) of water, and/or who continue to take oral bisphosphonates after developing symptoms suggestive of oesophageal irritation. Therefore, it is very important that the full dosing instructions are provided to, and understood by, the patient. In patients who cannot comply with dosing instructions due to mental disability, therapy with risedronate should be used under appropriate supervision. There have been postmarketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications, although no increased risk was observed in controlled clinical trials.

Mineral Metabolism
Hypocalcaemia and other disturbances of bone and mineral metabolism should be effectively treated before starting therapy. Adequate intake of calcium and vitamin D is important in all patients, especially in patients with Paget`s disease in whom bone turnover is significantly elevated.

Osteonecrosis of the Jaw
Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing, and has been reported in patients taking bisphosphonates, including risedronate. Known risk factors for ONJ include invasive dental procedures (e.g. tooth extraction, dental implants, bone surgery), diagnosis of cancer, concomitant therapies (e.g. chemotherapy, corticosteroids), poor oral hygiene, and co-morbid disorders (e.g. periodontal and/or other pre-existing dental disease, anaemia, coagulopathy, infection, ill-fitting dentures).

For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk for ONJ. Clinical judgement of the treating physician and/or oral surgeon should guide the management plan of each patient, based on individual benefit/risk assessment.

Patients who develop ONJ while on bisphosphonate therapy should receive care by an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of bisphosphonate therapy should be considered, based on individual benefit/risk assessment.

Musculoskeletal Pain
In postmarketing experience, there have been infrequent reports of severe and, occasionally, incapacitating bone, joint and/or muscle pain in patients taking bisphosphonates. The time to onset of symptoms varied from 1 day to several months after starting the drug. Most patients had relief of symptoms after stopping medication. A subset had recurrence of symptoms when re-challenged with the same drug or another bisphosphonate. Consider discontinuing use if severe symptoms develop.

Atypical Subtrochanteric and Diaphyseal Femoral Fractures
Atypical, low-energy or low trauma fractures of the femoral shaft have been reported in bisphosphonate-treated patients. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short-oblique in orientation without evidence of comminution. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with bisphosphonates. Atypical femur fractures most commonly occur with minimal or no impact to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture. Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out a femur fracture. Subjects presenting with an atypical fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of bisphosphonate therapy should be considered, pending a risk/benefit assessment, on an individual basis.

Glucocorticoid-Induced Osteoporosis
The risk versus benefit of risedronate for the prevention and treatment of glucocorticoid-induced osteoporosis at daily doses of glucocorticoids

Laboratory Test Interactions
Bisphosphonates are known to interfere with the use of bone-imaging agents. Specific studies with risedronate have not been performed.

Geriatric Use
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. Efficacy of bisphosphonates in the treatment of postmenopausal osteoporosis is related to the presence of low bone mineral density (BMD) and/or prevalent fracture.

Calcium/Vitamin D3
Risk-benefit should be considered when the following medical problems exist: 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 impairment, vitamin D in the form of cholecalciferol is not metabolized 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 hours (300 mg/24 hours). In case of hypercalcaemia or signs of impaired renal function, treatment with calcium/vitamin D3 should be discontinued. Chronic or acute administration of excessive doses may lead to hypervitaminosis D, manifested by hypercalcemia and its sequelae.

The dose of vitamin D3 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 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 should be used with caution in immobilized 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.

Conditions like arteriosclerosis or cardiac function impairment may be exacerbated due to possibility of hypercalcaemia and elevated serum cholesterol conentrations.

Impaired calcium absorption has been observed in achlorhydria which is common in elderly. Caution should observed in hypoparathyroid patients on high doses of vitamin D, as calcium/vitamin D3 supplement may increase the risk of hypercalcaemia and hypercalciuria. Calcium/vitamin D3 supplement should be given with caution in patients with history of kidney stones or renal failure.

Cholecalciferol (vitamin D3) should be administered with caution in patients with hyperlipidaemia as it could potentially exacerbate LDL elevation. Administration of cholecalciferol in patients with hyperphosphataemia may put the patient at risk of metastatic calcification; normalization of phosphate levels is indicated prior to therapy. Liver disease may, in turn, impair the absorption of cholecalciferol.

Drug Interactions

Risedronate
No specific drug-drug interaction studies were performed. Risedronate is not metabolized and does not induce or inhibit hepatic microsomal drug-metabolizing enzymes (cytochrome P450).

Calcium Supplements/Antacids
Co-administration of risedronate and calcium, antacids, or oral medications containing divalent cations will interfere with the absorption of risedronate.

Hormone Replacement Therapy
One study of about 500 early postmenopausal women has been conducted to date in which treatment with risedronate (5 mg daily) plus oestrogen replacement therapy was compared to oestrogen replacement therapy alone. Exposure to the study drugs was approximately 12 to 18 months and the primary endpoint was change in bone mineral density (BMD). If considered appropriate, risedronate may be used concomitantly with hormone replacement therapy.

Aspirin/Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Of over 5,700 patients enrolled in the risedronate Phase 3 osteoporosis studies, aspirin use was reported by 31% of patients, 24% of who were regular users (3 or more days per week). NSAID use was reported by 48% of patients, 21% of whom were regular users. Among regular aspirin or NSAID users, the incidence of upper gastrointestinal adverse experiences in risedronate-treated patients (24.5%) was similar to that in placebo-treated patients (24.8%).

H2-Blockers and Proton-Pump Inhibitors (PPIs)
Of over 5,700 patients enrolled in the risedronate Phase 3 osteoporosis studies, 21% used H2-blockers and/or PPIs. Among these patients, the incidence of upper gastrointestinal adverse experiences in the risedronate-treated patients was similar to that in placebo-treated patients.

Vitamin D3
Cholestyramine
Simultaneous treatment with ion-exchange resins such as cholestyramine or laxatives such as paraffin oil may reduce the gastrointestinal absorption of vitamin D.

Rifampicin, Phenytoin or Barbiturates
The co-administration of phenytoin or phenobarbital or barbiturates will not affect plasma concentrations of vitamin D, but may reduce endogenous plasma levels of calcitriol by accelerating metabolism. Since blood level of calcitriol will be reduced, higher doses of cholecalciferol may be necessary if these drugs are administered simultaneously.

Thiazides
Thiazides are known to induce hypercalcaemia by the reduction of calcium excretion in urine. Some reports have shown that the concomitant administration of thiazides with vitamin D causes hypercalcaemia. Therefore, precaution should be taken when co-administration is necessary.

Digitalis
Vitamin D dosage must be determined with care in patients undergoing treatment with digitalis, as hypercalcaemia in such patients may precipitate cardiac arrhythmias.

Ketoconazole
Ketoconazole may inhibit both synthetic and catabolic enzymes of vitamin D. Reductions in serum endogenous vitamin D concentrations have been observed following the administration of 300 mg/day to 1,200 mg/day ketoconazole for a week to healthy men. However, in vivo drug interaction studies of ketoconazole with vitamin D have not been investigated.

Corticosteroids
A relationship of functional antagonism exists between vitamin D analogues, which promote calcium absorption, and corticosteroids, which inhibit calcium absorption.

Phosphate-Binding Agents
Since vitamin D also has an effect on phosphate transport in the intestine, kidneys and bones, the dosage of phosphate-binding agents must be adjusted in accordance with the serum phosphate concentration.

Calcium Supplements
Uncontrolled intake of additional calcium-containing preparations should be avoided.

Magnesium
Magnesium-containing preparations (e.g. antacids) may cause hypermagnesaemia and should, therefore, not be taken during therapy with vitamin D by patients on long-term renal dialysis.

Calcium
Thiazide diuretics reduce the urinary excretion of calcium. Due to increased risk of hypercalcaemia, serum calcium should be regularly monitored during concomitant use of thiazide diuretics. Hypercalcaemia must be avoided in digitalized patients.

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

Calcium carbonate may interfere with the absorption of concomitantly administered tetracycline preparations. For this reason, tetracycline preparations should be administered at least 2 hours before, or 4 to 6 hours after oral intake of calcium.

Hypercalcaemia may increase the toxicity of cardiac glycosides during treatment with calcium and vitamin D. Patients should be monitored with regard to electrocardiogram (ECG) and serum calcium levels.

If a bisphosphonate or sodium fluoride is used concomitantly, these products should be administered at least 3 hours before the intake of calcium/vitamin D3 since gastrointestinal absorption may be reduced.

Calcium salts may decrease the absorption of iron, zinc or strontium. Consequently, the iron, zinc or strontium preparation should be taken at a distance of 2 hours from the calcium preparation.

Calcium salts may reduce the absorption of the estramustine or thyroid hormones.

Oxalic acid (found in spinach, sorrel and rhubarb) and phytic acid (found in whole cereals) may inhibit calcium absorption through the formation of insoluble compounds with calcium ions. The patient should not take calcium products within 2 hours of eating foods high in oxalic acid and phytic acid.

Renal Impairment

Risedronate is not recommended for use in patients with severe renal impairment (creatinine clearance <30 mL/min) because of lack of clinical experience. No dosage adjustment is necessary in patients with a creatinine clearance >30 mL/min.

Hepatic Impairment

No studies have been performed to assess risedronate's safety or efficacy in patients with hepatic impairment. Risedronate is not metabolized in human liver preparations. Dosage adjustment is unlikely to be needed in patients with hepatic impairment.

Pregnancy

Pregnancy Category C
Risedronate
There are no adequate data from use of risedronate sodium in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk to humans is unknown. Risedronate should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and foetus.

Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over periods of weeks to years. The amount of bisphosphonate incorporation into adult bone and, hence, the amount available for release back into the systemic circulation, is directly related to the dose and duration of bisphosphonate use. There are no data on foetal risk in humans. However, there is a theoretical risk of foetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been studied.

Calcium/Vitamin D3
During pregnancy, the daily intake should not exceed 1,500 mg calcium and 600 IU cholecalciferol (15 µg vitamin D3). There are no indications that vitamin D at therapeutic doses is teratogenic in humans. Studies in animals have shown reproductive toxicity with high doses of vitamin D. In pregnant women, overdoses of calcium and vitamin D should be avoided as permanent hypercalcaemia has been related to adverse effects on the developing foetus and, therefore, must not be used during pregnancy.

Lactation

It is not known whether risedronate is excreted in human milk. Calcium and vitamin D3 pass in to human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from bisphosphonates, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother

Pediatric Use

Safety and effectiveness in paediatric patients have not been established.

Geriatric Use

Risedronate
No overall differences in safety between geriatric and younger patients were observed in the risedronate trials, but the greater sensitivity of some older individuals cannot be ruled out.

Vitamin D3
Studies have shown that the elderly may have an increased need for vitamin D due to a possible decrease in the capacity of the skin to produce provitamin D3, or a decrease in exposure to the sun or impaired renal function or impaired vitamin D absorption.

Calcium
The dose selection for an elderly patient should be cautious, usually starting at the lower end of the dose range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy.

Undesirable Effects

Risedronate

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 5 mg/day (n=5,020) or placebo (n=5,048) and considered possibly or probably related to risedronate are listed below using the 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).

Body as a Whole
Common: Infection, back pain, accidental injury, pain, abdominal pain, flu syndrome, headache, asthenia, neck pain, chest pain, allergic reaction.

Cardiovascular System
Common: Hypertension.

Metabolic and Nutritional Disorders
Common: Peripheral oedema.

Musculoskeletal System
Common: Arthralgia, arthritis, traumatic bone fracture, joint disorder, myalgia, bone pain.

Respiratory System
Common: Bronchitis, sinusitis, rhinitis, pharyngitis, increased cough.

Special Senses
Common: Cataract.

Urogenital System
Common: Urinary tract infection.

Nervous System Disorders
Common: Headache, dizziness, depression, insomnia.

Eye Disorders
Uncommon: Iritis.

Gastrointestinal Disorders
Common: Constipation, dyspepsia, nausea, abdominal pain, diarrhoea.
Uncommon: Gastritis, oesophagitis, dysphagia, duodenitis, oesophageal ulcer.br />
Rare: Glossitis, oesophageal stricture.

Laboratory Investigations
Rare: Abnormal liver function tests, early, transient, asymptomatic and mild decreases in serum calcium and phosphate levels.

Vitamin D3

Vitamin D at normal doses usually has no side effects. Too much vitamin D can cause harmful high calcium levels. Some of the associated symptoms are: nausea/vomiting, constipation, loss of appetite, increased thirst, increased urination, mental/mood changes, and unusual tiredness.

A very serious allergic reaction to this drug is rare. However, medical help may be needed in case of a serious allergic reaction, including rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, and trouble breathing. This is not a complete list of possible side effects.

Toxicity is much more likely to occur from high intakes of dietary supplements containing vitamin D. Vitamin D toxicity can cause non-specific symptoms such as anorexia, weight loss, polyuria, and heart arrhythmias. More seriously, it can also raise blood levels of calcium which leads to vascular and tissue calcification, with subsequent damage to the heart, blood vessels and kidneys. The use of supplements of both calcium (1,000 mg/day) and vitamin D (400 IU) by postmenopausal women was associated with a 17% increase in the risk of kidney stones over 7 years in the Women's Health Initiative. A serum calcidiol concentration consistently >500 nmol/L (>200 ng/mL) is considered to be potentially toxic.

Vitamin D toxicity, including nephrocalcinosis/renal failure, hypertension, and psychosis, can occur with prolonged use of cholecalciferol; relatively low doses can produce toxicity in hypersensitive infants and children. Hypervitaminosis D is reversible upon discontinuation of treatment unless renal damage is severe. Chronic excessive dosing can also lead to impairment of renal function with polyuria, nocturia, polydipsia, hypercalciuria, reversible azotaemia, hypertension, nephrocalcinosis, generalized vascular calcification, or irreversible renal insufficiency which may result in death. Other problems associated with long-term overdosage include mental retardation, widespread calcification of the soft tissues, including the heart, blood vessels, renal tubules, and lungs and bone demineralization (osteoporosis) in adults occurs concomitantly. It could cause decline in the average rate of linear growth, increased mineralization of bones in infants and children (dwarfism), vague aches, stiffness, and weakness, nausea, anorexia, constipation, mild acidosis, anaemia, and weight loss.

Most reports suggest a toxicity threshold for vitamin D of 10,000 to 40,000 IU/day and serum calcidiol levels of 500 to 600 nmol/L (200 to 240 ng/mL). While symptoms of toxicity are unlikely at daily intakes below 10,000 IU/day, the FNB pointed to emerging science from national survey data, observational studies and clinical trials, suggesting that even lower vitamin D intakes and serum calcidiol levels might have adverse health effects over time. The FNB concluded that serum calcidiol levels above approximately 125 to 150 nmol/L (50 to 60 ng/mL) should be avoided, as even lower serum levels (approximately 75 to 120 nmol/L or 30 to 48 ng/mL) are associated with increases in all-cause mortality, greater risk of cancer at some sites like the pancreas, greater risk of cardiovascular events, and more falls and fractures among the elderly.

Vitamin D toxicity associated with hypercalcemia is a well-recognized complication of acute or long-term administration of cholecalciferol. Hypercalcemia is solely related to circulating levels of calcidiol. Initial symptoms related to hypercalcemia include diarrhoea, constipation (primarily in children/adolescents), nausea, vomiting, anorexia, polyuria, polydipsia, nocturia, weakness/fatigue, headache, and mental changes. More chronic manifestations include proteinuria and renal impairment; soft-tissue calcification in kidneys (with nephrolithiasis and/or nephrocalcinosis), heart, vessels, and skin; hypertension and possibly arrhythmias; worsening of GI symptoms; pancreatitis; and psychotic symptomatology. Renal failure and death may occur after prolonged use of high doses.

Calcium

Adverse effects are in general similar to those encountered with excessive vitamin D intake. Some uncommon disorders are hypercalcaemia and hypercalciuria. Rare incidences of constipation, flatulence, nausea, abdominal pain, diarrhoea, pruritus, rash and urticaria have also been reported.

The early symptoms of vitamin D intoxication associated with hypercalcaemia include weakness, headache, somnolence, nausea, vomiting, dry mouth, constipation, flatulence, diarrhoea, urticarial, muscle pain and weakness, mental disturbances, abdominal pain, thirst, nephrocalcinosis, renal calculi, bone pain and metallic taste.

Late signs include polyuria, polydipsia, anorexia, weight loss, nocturia, conjunctivitis (calcific), pancreatitis, photophobia, rhinorrhoea, pruritus, hyperthermia, decreased libido, elevated BUN, albuminuria, hypercholesterolaemia, elevated SGOT and SGPT, ectopic calcification, hypertension, cardiac arrhythmias, dystrophy, sensory disturbances, apathy, arrested growth, urinary tract infections and, rarely, overt psychosis. Extreme hypercalcaemia may result in coma and death. Persistently high calcium levels may lead to irreversible renal damage and soft-tissue calcification.

Postmarketing Experience

Because these adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:

Skin and Subcutaneous Disorders
Hypersensitivity and skin reactions, including angio-oedema, generalized rash, urticaria, bullous skin reactions and leucocytoclastic vasculitis, some severe, including isolated reports of Stevens-Johnson syndrome and toxic epidermal necrolysis. Hair loss

Gastrointestinal Adverse Events
Events involving upper gastrointestinal irritation, such as oesophagitis and oesophageal or gastric ulcers, have been reported.

Musculoskeletal Pain
Bone, joint or muscle pain, described as severe or incapacitating, has been reported rarely.

Eye Inflammation
Reactions of eye inflammation, including iritis and uveitis, have been reported rarely.

ONJ
ONJ has been reported rarely.

Pulmonary
Asthma exacerbations.

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.

Atypical Subtrochanteric and Diaphyseal Femoral Fractures
Unusual fracture of the femur, particularly in patients on long-term treatment for osteoporosis, may occur rarely.

Overdosage

Risedronate

Decreases in serum calcium and phosphorus following substantial overdose may be expected in some patients. Signs and symptoms of hypocalcaemia may also occur in some of these patients. Milk or antacids containing calcium should be given to bind risedronate and reduce absorption of the drug.

In cases of substantial overdose, gastric lavage may be considered to remove unabsorbed drug. Standard procedures that are effective for treating hypocalcaemia, including the administration of calcium intravenously, would be expected to restore physiologic amounts of ionized calcium and to relieve signs and symptoms of hypocalcaemia.

Calcium/Vitamin D3

Overdose can lead to hypervitaminosis, hypercalciuria and hypercalcaemia. Symptoms of hypercalcaemia may include anorexia, thirst, nausea, vomiting, constipation, abdominal pain, muscle weakness, fatigue, mental disturbances, polydipsia, polyuria, bone pain, nephrocalcinosis, renal calculi and, in severe cases, cardiac arrhythmias. Extreme hypercalcaemia may result in coma and death. Persistently high calcium levels may lead to irreversible renal damage and soft- tissue calcification.

Treatment of Hypercalcaemia
The treatment with calcium must be discontinued. Treatment with thiazide diuretics, lithium, vitamin A, vitamin D3 and cardiac glycosides must also be discontinued. Emptying of the stomach should be done in patients with impaired consciousness. Rehydration and, according to severity, isolated or combined treatment with loop diuretics, bisphosphonates, calcitonin and corticosteroids should be performed. Serum electrolytes, renal function and diuresis must be monitored. In severe cases, ECG and central venous pressure should be undertaken.

Storage and Handling Instructions

Store in a cool and dry place.

Packaging Information

Each pack of RISOFOS KIT contains 1 tablet of Risedronate Sodium and 12 tablets of Calcium Citrate Malate and Vitamin D3.