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.

Treatment of osteoporosis in men at high risk of fracture.

Administration

The tablets must be swallowed whole with a glass of plain water and not 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.

The dose should be taken in the upright position, and the patient should not lie down for 30 minutes following administration.

Contraindications

Hypocalcaemia
Children under 18 years
Pregnancy - (see Pregnancy)
Breastfeeding - (see Lactation)
Severe renal impairment (creatinine clearance less than 30ml/min)
Galactosaemia

Precautions and Warnings

Bisphosphonates have been associated with oesophagitis, gastritis, oesophageal ulcerations and gastroduodenal ulcerations. Therefore, caution should be used in:
Patients who have a history of oesophageal disorders which delay oesophageal transit or emptying e.g. stricture or achalasia.
Patients who are unable to stay in the upright position for at least 30 minutes after taking the tablet.
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. 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.

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 risedronate therapy.

Supplemental calcium and vitamin D should be considered if the dietary intake is inadequate.

Foods, drinks (except plain water) and drugs containing polyvalent cations (such as calcium, magnesium, iron and aluminium) interfere with the absorption of risedronate and should not be taken at the same time.

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.

There is limited evidence to support the efficacy of bisphosphonates in elderly patients over 80 years.

Patient must remain upright for at least 30 minutes after dose.

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 or 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.

This product contains lactose and should be used with caution in patients with rare hereditary problems of galactose intolerance, glucose-galactose malabsorption syndrome or 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 new 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.

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 does not justify interruption of the pregnancy or additional diagnostic procedures.

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.

It is not known whether risedronate passes into human milk. Studies in animals indicate that a small amount of risedronate sodium passes into breast milk.

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

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

Side effects seen with all doses of risedronate are:
Dyspepsia
Abdominal pain
Constipation
Diarrhoea
Gastritis
Musculoskeletal pain
Headache
Rash
Nausea
Oesophagitis
Duodenitis
Dysphagia
Oesophageal ulceration
Oesophageal stricture
Glossitis
Iritis
Uveitis
Abnormal liver function tests
Skin reactions
Severe bullous lesions
Angioedema
Hypersensitivity reactions
Osteonecrosis (primarily of the jaw)
Stevens-Johnson syndrome
Toxic epidermal necrosis
Hair loss
Anaphylactic reaction
Hepatic disorders
Leukocytoclastic vasculitis
Decrease in plasma calcium
Decrease in serum phosphate
Urticaria
Atypical femoral fractures
Osteonecrosis of the external auditory canal

Additional side effects have been reported with these higher doses of risedronate sodium used for treatment of Paget's disease. These include:
Dizziness
Influenza-like symptoms
Weight loss
Myasthenia
Arthralgia
Apnoea
Bronchitis
Sinusitis
Nocturia
Corneal lesions
Dry eyes
Tinnitus
Chest pain
Amblyopia
Colitis
Leg cramps
Peripheral oedema
Hypocalcaemia
Bone pain
Neoplasm

Presentation

Tablets containing risedronate sodium 35mg.

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.

Treatment of osteoporosis in men at high risk of fracture.

Dosage

Dosage frequency is once weekly.

Adults

Elderly

Children

Patients with Renal Impairment

Additional Dosage Information

Administration

The tablets must be swallowed whole with a glass of plain water and not 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.

The dose should be taken in the upright position, and the patient should not lie down for 30 minutes following administration.

Contraindications

Hypocalcaemia
Children under 18 years
Pregnancy - (see Pregnancy)
Breastfeeding - (see Lactation)
Severe renal impairment (creatinine clearance less than 30ml/min)
Galactosaemia

Precautions and Warnings

Bisphosphonates have been associated with oesophagitis, gastritis, oesophageal ulcerations and gastroduodenal ulcerations. Therefore, caution should be used in:
Patients who have a history of oesophageal disorders which delay oesophageal transit or emptying e.g. stricture or achalasia.
Patients who are unable to stay in the upright position for at least 30 minutes after taking the tablet.
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. 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.

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 risedronate therapy.

Supplemental calcium and vitamin D should be considered if the dietary intake is inadequate.

Foods, drinks (except plain water) and drugs containing polyvalent cations (such as calcium, magnesium, iron and aluminium) interfere with the absorption of risedronate and should not be taken at the same time.

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.

There is limited evidence to support the efficacy of bisphosphonates in elderly patients over 80 years.

Patient must remain upright for at least 30 minutes after dose.

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 or 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.

This product contains lactose and should be used with caution in patients with rare hereditary problems of galactose intolerance, glucose-galactose malabsorption syndrome or 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 new 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.

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 does not justify interruption of the pregnancy or additional diagnostic procedures.

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.

It is not known whether risedronate passes into human milk. Studies in animals indicate that a small amount of risedronate sodium passes into breast milk.

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

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

No effects are known.

Counselling

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

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.

Patients should be instructed that if a dose is missed, one tablet should be taken on the day that the tablet is remembered. Patients should then return to taking the tablet once a week on the day the tablet is normally taken. Two tablets should not be taken on the same day.

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 to maintain adequate oral hygiene during and after treatment with bisphosphonates.

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

Side Effects

Side effects seen with all doses of risedronate are:
Dyspepsia
Abdominal pain
Constipation
Diarrhoea
Gastritis
Musculoskeletal pain
Headache
Rash
Nausea
Oesophagitis
Duodenitis
Dysphagia
Oesophageal ulceration
Oesophageal stricture
Glossitis
Iritis
Uveitis
Abnormal liver function tests
Skin reactions
Severe bullous lesions
Angioedema
Hypersensitivity reactions
Osteonecrosis (primarily of the jaw)
Stevens-Johnson syndrome
Toxic epidermal necrosis
Hair loss
Anaphylactic reaction
Hepatic disorders
Leukocytoclastic vasculitis
Decrease in plasma calcium
Decrease in serum phosphate
Urticaria
Atypical femoral fractures
Osteonecrosis of the external auditory canal

Additional side effects have been reported with these higher doses of risedronate sodium used for treatment of Paget's disease. These include:
Dizziness
Influenza-like symptoms
Weight loss
Myasthenia
Arthralgia
Apnoea
Bronchitis
Sinusitis
Nocturia
Corneal lesions
Dry eyes
Tinnitus
Chest pain
Amblyopia
Colitis
Leg cramps
Peripheral oedema
Hypocalcaemia
Bone pain
Neoplasm

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, 9th edition (2011) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.

Medications and Mother's Milk, 14th edition (2011) Hale, T.W. Hale Publishing, Amarillo, Texas.

Summary of Product Characteristics. Actonel Once a Week 35mg film-coated tablets. Warner Chilcott UK Ltd. Revised August 2011.

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