Drugs List

Therapeutic Indications

Uses

Treatment of postmenopausal osteoporosis, to reduce the risk of vertebral fractures.
Treatment of established postmenopausal osteoporosis, to reduce the risk of hip fractures.

Administration

The tablets must be swallowed whole with a full glass of plain water (at least 120ml) in the upright position. The patient should not lie down for 30 minutes following administration.

The tablet should not be sucked or chewed.

The absorption of risedronate is affected by food and medicines containing polyvalent ions (such as calcium, magnesium, iron and aluminium), thus to ensure adequate absorption patients should take the dose at least 30 minutes before the first food, drink (other than water) or other medicinal product of the day.

Sachets of granules should be added to a glass of plain water, stirred and drunk as soon as the fizzing has subsided.

Contraindications

Hypocalcaemia
Hypercalcaemia
Hypercalciuria
Prolonged immobilisation
Nephrolithiasis
Renal impairment - creatinine clearance less than 30ml/minute
Hypervitaminosis D
Pregnancy ( see Pregnancy section )
Breastfeeding ( see Lactation section )
Hereditary fructose intolerance
Galactosaemia
Hypersensitivity to arachis oil (peanuts)
Children under 18 years

Precautions and Warnings

The absorption of risedronate is affected by food and medicines containing polyvalent ions (such as calcium, magnesium, iron and aluminium), thus to ensure adequate absorption patients should take the dose at least 30 minutes before the first food, drink (other than water) or other medicinal product of the day.

Patient must remain upright for at least 30 minutes after taking risedronate to aid delivery of the tablet to the stomach.

There is limited clinical experience in the use of risedronate in patients with oesophageal disease. Patients with a history of oesophageal disorders which delay oesophageal transit or emptying e.g. stricture or achalasia, or who are unable to stay in an upright position for at least 30 minutes after taking risedronate, should be treated with caution. Prescribers should emphasise the importance of the dosing instructions to these patients and advise patients to seek medical attention upon signs of oesophageal irritation, such as; dysphagia, pain on swallowing or retrosternal pain.

Treatment of osteoporosis should only be initiated in the presence of low bone mineral density (BMD) (T-score at hip or lumbar spine equal or less than -2.5 SD) and/or prevalent fracture.)

Evidence to support efficacy of bisphosphonate therapy for the treatment of osteoporosis in elderly patients over 80 is limited.

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

Osteonecrosis of the jaw has been reported in cancer patients taking bisphosphonate regimens often with concurrent chemotherapy and corticosteroids. These cases have mainly been associated with dental procedures such as tooth extraction and many have shown signs of local infection including osteomyelitis.

Perform dental examination with appropriate preventative procedures prior to risedronate sodium therapy in patients with risk factors (cancer chemotherapy, corticosteroids, poor oral hygiene).

Invasive dental procedures should be avoided in patients taking bisphosphonates. Advise patients to inform their dentist that they are taking bisphosphonates and should not undergo invasive dental procedures. There is no data available to suggest discontinuation of bisphosphonate treatment prior to dentistry reduces the risk of osteonecrosis of the jaw. Recovery from such procedures is likely to be prolonged.

Adequate oral hygiene should be maintained during and after treatment with bisphosphonates.

Osteonecrosis of the external auditory canal has been reported very rarely with bisphosphonates, mainly in association with long term therapy (2 years or longer). Risk factors include steroid use and chemotherapy and/or local risk factors as infection or trauma. The possibility of osteonecrosis of the external auditory canal should be considered in patients receiving bisphosphonates who present with ear symptoms including chronic ear infections.

Atypical stress fractures of the proximal femoral shaft with poor healing have been reported for treatment with another bisphosphonate, alendronic acid. Limited data exists regarding a relationship for other bisphosphonates and atypical stress fractures. However, the possibility of atypical stress fractures cannot be excluded. Patients who develop atypical stress fractures should discontinue treatment and receive no further bisphosphonate treatment.

Regular monitoring of renal function, serum and urinary calcium and phosphate is recommended in patients with the following conditions:
-mild to moderate renal impairment
-history of absorptive or renal hypercalciuria
-nephrocalcinosis
-kidney stone formation
-hypophosphataemia

Colecalciferol (vitamin D3) should be used with caution in patients with renal impairment and the effects on calcium and phosphate levels monitored. The risk of soft tissue calcification should be considered. Vitamin D in the form of colecalciferol is not metabolised normally in patients with severe renal impairment. An alternative form of vitamin D is recommended in these patients.

Use with caution in patients with sarcoidosis due to the risk of increased metabolism of vitamin D to its active metabolite. Serum calcium levels and urinary calcium excretion must be monitored in these patients.

Monitor serum calcium levels and urinary calcium levels regularly, especially in elderly patients, patients receiving concurrent treatment with diuretics, cardiac glycosides or in patients with a high tendency to calculus formation. Where treatment is long term, renal function and urinary calcium excretion must be monitored and treatment must be reduced or suspended if renal function becomes impaired or if urinary calcium exceeds 7.5mmol/24 hours (300mg/24 hours).

Discontinue treatment if hypercalcaemia or signs of renal impairment occur.

When used concurrently with other drugs containing vitamin D, serum and urinary calcium levels should be monitored regularly.

Caution is recommended when treating immobilised patients with osteoporosis due to the increased risk of hypercalcaemia. Treatment with calcium/vitamin D3 may be discontinued during prolonged immobilisation and should only be resumed when the patient is mobile again.

This product contains lactose, sucrose and sorbitol. Prescribe with caution to patients with glucose-galactose malabsorption syndrome, lactose intolerance.

CSM Warnings

The CHM recommends the following:

Atypical stress fractures of the proximal femoral shaft with poor healing have been reported rarely with long-term bisphosphonate treatment;

Patients should be re-evaluated periodically based on an assessment of the benefits and risks of the bisphosphonate treatment, especially after 5 years or more of treatment;

Patients should report any thigh, hip or groin pain during treatment with a bisphosphonate;

Discontinuation of bisphosphonate treatment in patients suspected to have an atypical femoral fracture should be considered after an assessment of the benefits and risks of continued treatment.

Pregnancy and Lactation

Pregnancy

Contraindicated during pregnancy.

Animal studies have shown reproduction toxicological effects and although the significance to humans is unknown, risedronate should not be used in human pregnancy. If treatment has been discontinued before pregnancy, the very long elimination half life from bone indicates that women treated with risedronate will have detectable concentrations of the drug for a prolonged interval. If exposure occurs during gestation, detailed ultrasound examination of the foetal skeleton appears to be warranted (Briggs, 2011) although Schaeffer (2007) states that accidental use of a single dose in the first trimester does not justify interruption of the pregnancy or additional diagnostic procedures.

During pregnancy the daily intake of calcium should not exceed 1500mg and 600IU of colecalciferol. Overdose of calcium and vitamin D should be avoided as hypercalcaemia has been associated with adverse effects on the developing foetus. There is no evidence that vitamin D at therapeutic doses is teratogenic in humans. Animal studies have shown reproductive toxicity with high doses of vitamin D.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14-17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Contraindicated during breastfeeding.

Animal studies have shown that small quantities of risedronate sodium passed into breast milk. With no published experience of risedronate use during breastfeeding an alternative drug may be preferred.

However, the extremely low oral bioavailability of bisphosphonates in the non-fasting state implies that systemic levels in the nursing infant should be negligible.

Both calcium and vitamin D3 are excreted in breast milk.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Headache
Iritis
Constipation
Dyspepsia
Nausea
Abdominal pain
Diarrhoea
Gastritis
Oesophagitis
Dysphagia
Duodenitis
Oesophageal ulceration
Oesophageal stricture
Musculoskeletal pain
Abnormal liver function tests
Decrease in plasma calcium
Decrease in serum phosphate
Uveitis
Osteonecrosis (primarily of the jaw)
Hypersensitivity reactions
Angioedema
Rash
Bullous reactions
Hypercalcaemia
Hypercalciuria
Flatulence
Pruritus
Urticaria
Glossitis
Stevens-Johnson syndrome
Toxic epidermal necrolysis
Hair loss
Hepatic disorders
Leukocytoclastic vasculitis
Skin reactions
Gastrointestinal disorder
Pain
Anaphylactic reaction
Atypical femoral fractures
Osteonecrosis of the external auditory canal

Presentation

Tablets containing risedronate sodium 35mg (equivalent to 32.5mg risedronic acid) and sachets of effervescent granules containing calcium carbonate 2500mg (equivalent to 1000mg of calcium) and 22micrograms (880 units) colecalciferol (vitamin D3).

Drugs List

Therapeutic Indications

Uses

Treatment of postmenopausal osteoporosis, to reduce the risk of vertebral fractures.
Treatment of established postmenopausal osteoporosis, to reduce the risk of hip fractures.

Dosage

Treatment with this product should only be initiated in patients with established osteoporosis where the quantity of calcium and vitamin D3 included is considered to provide adequate supplementation.

Adults

Elderly

Children

Patients with Renal Impairment

Additional Dosage Information

Administration

The tablets must be swallowed whole with a full glass of plain water (at least 120ml) in the upright position. The patient should not lie down for 30 minutes following administration.

The tablet should not be sucked or chewed.

The absorption of risedronate is affected by food and medicines containing polyvalent ions (such as calcium, magnesium, iron and aluminium), thus to ensure adequate absorption patients should take the dose at least 30 minutes before the first food, drink (other than water) or other medicinal product of the day.

Sachets of granules should be added to a glass of plain water, stirred and drunk as soon as the fizzing has subsided.

Contraindications

Hypocalcaemia
Hypercalcaemia
Hypercalciuria
Prolonged immobilisation
Nephrolithiasis
Renal impairment - creatinine clearance less than 30ml/minute
Hypervitaminosis D
Pregnancy ( see Pregnancy section )
Breastfeeding ( see Lactation section )
Hereditary fructose intolerance
Galactosaemia
Hypersensitivity to arachis oil (peanuts)
Children under 18 years

Precautions and Warnings

The absorption of risedronate is affected by food and medicines containing polyvalent ions (such as calcium, magnesium, iron and aluminium), thus to ensure adequate absorption patients should take the dose at least 30 minutes before the first food, drink (other than water) or other medicinal product of the day.

Patient must remain upright for at least 30 minutes after taking risedronate to aid delivery of the tablet to the stomach.

There is limited clinical experience in the use of risedronate in patients with oesophageal disease. Patients with a history of oesophageal disorders which delay oesophageal transit or emptying e.g. stricture or achalasia, or who are unable to stay in an upright position for at least 30 minutes after taking risedronate, should be treated with caution. Prescribers should emphasise the importance of the dosing instructions to these patients and advise patients to seek medical attention upon signs of oesophageal irritation, such as; dysphagia, pain on swallowing or retrosternal pain.

Treatment of osteoporosis should only be initiated in the presence of low bone mineral density (BMD) (T-score at hip or lumbar spine equal or less than -2.5 SD) and/or prevalent fracture.)

Evidence to support efficacy of bisphosphonate therapy for the treatment of osteoporosis in elderly patients over 80 is limited.

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

Osteonecrosis of the jaw has been reported in cancer patients taking bisphosphonate regimens often with concurrent chemotherapy and corticosteroids. These cases have mainly been associated with dental procedures such as tooth extraction and many have shown signs of local infection including osteomyelitis.

Perform dental examination with appropriate preventative procedures prior to risedronate sodium therapy in patients with risk factors (cancer chemotherapy, corticosteroids, poor oral hygiene).

Invasive dental procedures should be avoided in patients taking bisphosphonates. Advise patients to inform their dentist that they are taking bisphosphonates and should not undergo invasive dental procedures. There is no data available to suggest discontinuation of bisphosphonate treatment prior to dentistry reduces the risk of osteonecrosis of the jaw. Recovery from such procedures is likely to be prolonged.

Adequate oral hygiene should be maintained during and after treatment with bisphosphonates.

Osteonecrosis of the external auditory canal has been reported very rarely with bisphosphonates, mainly in association with long term therapy (2 years or longer). Risk factors include steroid use and chemotherapy and/or local risk factors as infection or trauma. The possibility of osteonecrosis of the external auditory canal should be considered in patients receiving bisphosphonates who present with ear symptoms including chronic ear infections.

Atypical stress fractures of the proximal femoral shaft with poor healing have been reported for treatment with another bisphosphonate, alendronic acid. Limited data exists regarding a relationship for other bisphosphonates and atypical stress fractures. However, the possibility of atypical stress fractures cannot be excluded. Patients who develop atypical stress fractures should discontinue treatment and receive no further bisphosphonate treatment.

Regular monitoring of renal function, serum and urinary calcium and phosphate is recommended in patients with the following conditions:
-mild to moderate renal impairment
-history of absorptive or renal hypercalciuria
-nephrocalcinosis
-kidney stone formation
-hypophosphataemia

Colecalciferol (vitamin D3) should be used with caution in patients with renal impairment and the effects on calcium and phosphate levels monitored. The risk of soft tissue calcification should be considered. Vitamin D in the form of colecalciferol is not metabolised normally in patients with severe renal impairment. An alternative form of vitamin D is recommended in these patients.

Use with caution in patients with sarcoidosis due to the risk of increased metabolism of vitamin D to its active metabolite. Serum calcium levels and urinary calcium excretion must be monitored in these patients.

Monitor serum calcium levels and urinary calcium levels regularly, especially in elderly patients, patients receiving concurrent treatment with diuretics, cardiac glycosides or in patients with a high tendency to calculus formation. Where treatment is long term, renal function and urinary calcium excretion must be monitored and treatment must be reduced or suspended if renal function becomes impaired or if urinary calcium exceeds 7.5mmol/24 hours (300mg/24 hours).

Discontinue treatment if hypercalcaemia or signs of renal impairment occur.

When used concurrently with other drugs containing vitamin D, serum and urinary calcium levels should be monitored regularly.

Caution is recommended when treating immobilised patients with osteoporosis due to the increased risk of hypercalcaemia. Treatment with calcium/vitamin D3 may be discontinued during prolonged immobilisation and should only be resumed when the patient is mobile again.

This product contains lactose, sucrose and sorbitol. Prescribe with caution to patients with glucose-galactose malabsorption syndrome, lactose intolerance.

CSM Warnings

The CHM recommends the following:

Atypical stress fractures of the proximal femoral shaft with poor healing have been reported rarely with long-term bisphosphonate treatment;

Patients should be re-evaluated periodically based on an assessment of the benefits and risks of the bisphosphonate treatment, especially after 5 years or more of treatment;

Patients should report any thigh, hip or groin pain during treatment with a bisphosphonate;

Discontinuation of bisphosphonate treatment in patients suspected to have an atypical femoral fracture should be considered after an assessment of the benefits and risks of continued treatment.

Pregnancy and Lactation

Pregnancy

Contraindicated during pregnancy.

Animal studies have shown reproduction toxicological effects and although the significance to humans is unknown, risedronate should not be used in human pregnancy. If treatment has been discontinued before pregnancy, the very long elimination half life from bone indicates that women treated with risedronate will have detectable concentrations of the drug for a prolonged interval. If exposure occurs during gestation, detailed ultrasound examination of the foetal skeleton appears to be warranted (Briggs, 2011) although Schaeffer (2007) states that accidental use of a single dose in the first trimester does not justify interruption of the pregnancy or additional diagnostic procedures.

During pregnancy the daily intake of calcium should not exceed 1500mg and 600IU of colecalciferol. Overdose of calcium and vitamin D should be avoided as hypercalcaemia has been associated with adverse effects on the developing foetus. There is no evidence that vitamin D at therapeutic doses is teratogenic in humans. Animal studies have shown reproductive toxicity with high doses of vitamin D.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14-17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Contraindicated during breastfeeding.

Animal studies have shown that small quantities of risedronate sodium passed into breast milk. With no published experience of risedronate use during breastfeeding an alternative drug may be preferred.

However, the extremely low oral bioavailability of bisphosphonates in the non-fasting state implies that systemic levels in the nursing infant should be negligible.

Both calcium and vitamin D3 are excreted in breast milk.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Effects on Ability to Drive and Operate Machinery

None known.

Counselling

Advise patients that the tablets should be swallowed whole and not crushed or chewed, and taken with a full glass of water in the upright position.

Patients should be advised to take the dose at least 30 minutes before the first food, drink (other than water) or other medicinal product of the day.

Patients should be advised to remain in an upright position and not to lie down for 30 minutes after taking the tablet, and not to take the tablet at bedtime or before rising.

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.

Instruct patients to seek timely medical attention if they develop symptoms of oesophageal irritation such as dysphagia, pain on swallowing, retrosternal pain or new/worsened heartburn.

Patients should report any new thigh, hip or groin pain during treatment with a bisphosphonate.

Advise patients to inform their dentist that they are taking bisphosphonates and should not undergo invasive dental procedures.

Advise patients of the need to maintain high standards of oral hygiene during and after treatment.

If a tablet is missed, the dose should be taken in the morning of the next day according to the dosage information above. Sachets of calcium/vitamin D3 should be taken on the next day. Tablets and sachets should NOT be taken on the same day.

If a sachet of calcium/vitamin D3 is missed, the next sachet should be taken on the day the missed dose is remembered. Patients should be advised that two sachets should NOT be taken on the same day. Any remaining sachets at the end of a weekly cycle should be discarded.

Advise patient to report any ear pain, discharge or infection.

Side Effects

Headache
Iritis
Constipation
Dyspepsia
Nausea
Abdominal pain
Diarrhoea
Gastritis
Oesophagitis
Dysphagia
Duodenitis
Oesophageal ulceration
Oesophageal stricture
Musculoskeletal pain
Abnormal liver function tests
Decrease in plasma calcium
Decrease in serum phosphate
Uveitis
Osteonecrosis (primarily of the jaw)
Hypersensitivity reactions
Angioedema
Rash
Bullous reactions
Hypercalcaemia
Hypercalciuria
Flatulence
Pruritus
Urticaria
Glossitis
Stevens-Johnson syndrome
Toxic epidermal necrolysis
Hair loss
Hepatic disorders
Leukocytoclastic vasculitis
Skin reactions
Gastrointestinal disorder
Pain
Anaphylactic reaction
Atypical femoral fractures
Osteonecrosis of the external auditory canal

Overdosage

It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

The following number will direct the caller to the relevant local centre (0844) 892 0111

Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Shelf Life and Storage

No special requirements.

Further Information

Last Full Review Date: February 2012

Reference Sources

British National Formulary, 62nd Edition (2011) Pharmaceutical Press, London.

Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 2nd edition (2007) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.

Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 8th edition (2008) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.

Martindale: The Complete Drug Reference, 37th edition (2011) ed. Sweetman, S. Pharmaceutical Press, London.

Medications and Mothers' Milk, 14th Edition (2010) Hale, T. Hale Publishing, Amarillo, Texas

Summary of Product Characteristics: Actonel Combi D 35mg film-coated tablets + 100mg / 880 IU effervescent granules. Warner Chilcott UK Limited. Revised january 2016.

The Renal Drug Handbook. 3rd edition. (2009) ed. Ashley, C and Currie, Radcliffe Publishing Ltd, Abingdon.

MHRA Drug Safety Update: Bisphosphonates: atypical stress fractures. Dated: March 2009.
https://www.mhra.gov.uk/Publications/Safetyguidance/DrugSafetyUpdate/CON041211
Last accessed: February 3, 2012

MHRA Drug Safety Update: Bisphosphonates-osteonecrosis of the jaw. Dated: November 2009.
https://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON087832
Last accessed: February 3, 2012

MHRA Drug Safety Update December 2015
Available at: https://www.mhra.gov.uk
Last accessed: 13 January 2016

US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
Available at: https://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
Risedronate. Last revised: January 4, 2011
Last accessed: February 3, 2012