ACTONEL 75 Milligram Film Coated Tablet

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
RISEDRONATE SODIUM
Available from:
Warner Chilcott UK Limited
ATC code:
M05BA07
INN (International Name):
RISEDRONATE SODIUM
Dosage:
75 Milligram
Pharmaceutical form:
Film Coated Tablet
Prescription type:
Product subject to prescription which may be renewed (B)
Therapeutic area:
Bisphosphonates
Authorization status:
Authorised
Authorization number:
PA1635/001/004
Authorization date:
2010-04-30

Package leaflet: Information for the patient

Actonel 75 mg film-coated tablets

risedronate sodium

Read all of this leaflet carefully before you start taking this medicine because it contains

important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,

even if their signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side

effects not listed in this leaflet. See section 4.

What is in this leaflet

What Actonel is and what it is used for

What you need to know before you take Actonel

How to take Actonel

Possible side effects

How to store Actonel

Contents of the pack and other information

1.

What Actonel is and what it is used for

What Actonel is

Actonel belongs to a group of non-hormonal medicines called bisphosphonates which are used to treat

bone diseases. It works directly on your bones to make them stronger and therefore less likely to

break.

Bone is a living tissue. Old bone is constantly removed from your skeleton and replaced with new

bone.

Postmenopausal osteoporosis is a condition occurring in women after the menopause where the bones

become weaker, more fragile and more likely to break after a fall or strain.

The spine, hip and wrist are the most likely bones to break, although this can happen to any bone in

your body. Osteoporosis-related fractures can also cause back pain, height loss and a curved back.

Many patients with osteoporosis have no symptoms and you may not even have known that you had it.

What Actonel is used for

The treatment of osteoporosis in postmenopausal women.

2.

What you need to know before you take Actonel

Do not take Actonel

If you are allergic to risedronate sodium or any of the other ingredients of this medicine (listed

in section 6)

If your doctor has told you that you have a condition called hypocalcaemia (a low blood

calcium level)

If you may be pregnant, are pregnant or planning to become pregnant

If you are breast-feeding

If you have severe kidney problems.

Warnings and precautions

Talk to your doctor or pharmacist before taking Actonel:

If you are unable to stay in an upright position (sitting or standing) for at least 30 minutes.

If you have abnormal bone and mineral metabolism (for example lack of vitamin D, parathyroid

hormone abnormalities, both leading to a low blood calcium level).

If you have or have had problems in the past with your oesophagus (the tube that connects your

mouth with your stomach). For instance you may have or have had pain or difficulty in

swallowing food or you have previously been told that you have Barrett's oesophagus (a

condition associated with changes in the cells that line the lower oesophagus).

If you have had or have pain, swelling or numbness of the jaw or a “heavy jaw feeling” or

loosening of a tooth.

If you are under dental treatment or will undergo dental surgery, tell your dentist that you are

being treated with Actonel.

Your doctor will advise you on what to do when taking Actonel if you have any of the above.

Children and adolescents

Risedronate sodium is not recommended for use in children below age 18 due to insufficient data on

safety and efficacy.

Other medicines and Actonel

Medicines containing one of the following lessen the effect of Actonel if taken at the same time:

calcium

magnesium

aluminium (for example some indigestion mixtures)

iron.

Take these medicines at least 30 minutes after your Actonel tablet.

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other

medicines.

Actonel with food and drink

It is very important that you do NOT take your Actonel tablet with food or drinks (other than plain

water) so that it can work properly. In particular do not take this medicine at the same time as dairy

products (such as milk) as they contain calcium (see section 2, “Other medicines and Actonel”).

Take food and drinks (other than plain water) at least 30 minutes after your Actonel tablet.

Pregnancy and breast-feeding

Do NOT take Actonel if you may be pregnant, are pregnant or planning to become pregnant (see

section 2, “Do not take Actonel”). The potential risk associated with the use of risedronate sodium

(active substance in Actonel) in pregnant women is unknown.

Do NOT take Actonel if you are breast-feeding (see section 2, “Do not take Actonel”).

Actonel should only be used to treat postmenopausal women.

Driving and using machines

Actonel is not known to affect your ability to drive and use machines.

3.

How to take Actonel

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor

or pharmacist if you are not sure.

Recommended dose:

Actonel tablets should be taken on the SAME two consecutive dates each month, e.g. on the 1

and 2

of the month, or the 15

and 16

Choose TWO dates in a row that best fit your schedule to take your Actonel. Take ONE Actonel tablet

in the morning of your first chosen date. Take the SECOND tablet in the morning of the following

day.

Repeat every month keeping the same two consecutive dates. To help you remember when to take

your tablets next, you can mark your calendar ahead of time with a pen or stickers.

WHEN to take the Actonel tablet

Take your Actonel tablet at least 30 minutes before the first food, drink (other than plain water) or

other medicine of the day.

HOW to take the Actonel tablet

Take the tablet whilst you are in an upright position (you may sit or stand) to avoid heartburn.

Swallow it with at least one glass (120 ml) of plain water. Do not take your tablet with mineral

water or drinks other than plain water.

Swallow it whole. Do not suck or chew it.

Do not lie down for 30 minutes after taking your tablet.

Your doctor will tell you if you need calcium and vitamin supplements, if you are not taking enough

from your diet.

If you take more Actonel than you should

If you or somebody else has accidentally taken more Actonel tablets than prescribed, drink one full

glass of milk and seek medical attention.

If you forget to take Actonel

You forgot

When

What to do

and 2

tablets

Next monthly dose is

more than 7 days ahead

Take 1

tablet the next morning

and 2

tablet the morning of the

following day

Next monthly dose is

within 7 days

Do not take the tablets you have

forgotten

tablet only

Next monthly dose is

more than 7 days ahead

Take 2

tablet the next morning

Next monthly dose is

within 7 days

Do not take the tablet you have

forgotten

The next month, take your tablets again as usual.

In any case:

If you miss your dose of Actonel in the morning, do NOT take it later in the day.

Do NOT take three tablets within the same week.

If you stop taking Actonel

If you stop treatment you may begin to lose bone mass. Please talk to your doctor before you consider

stopping treatment.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Stop taking Actonel and contact a doctor immediately if you experience any of the following:

Symptoms of a severe allergic reaction such as:

Swelling of face, tongue or throat

Difficulties in swallowing

Hives and difficulties in breathing

Severe skin reactions that can include blistering of the skin.

Tell your doctor promptly if you experience the following side effects:

Eye inflammation, usually with pain, redness and light sensitivity.

Bone necrosis of the jaw (osteonecrosis) associated with delayed healing and infection, often

following tooth extraction (see section 2, “Warnings and precautions”).

Symptoms from oesophagus such as pain when you swallow, difficulties in swallowing, chest

pain or new or worsened heartburn.

Unusual fracture of the thigh bone particularly in patients on long-term treatment for osteoporosis may

occur rarely. Contact your doctor if you experience pain, weakness or discomfort in your thigh, hip or

groin as this may be an early indication of a possible fracture of the thigh bone.

However in clinical studies the other side effects that were observed were usually mild and did not

cause the patient to stop taking their tablets.

Common side effects (may affect up to 1 in 10 people)

Indigestion, feeling sick, vomiting, stomach ache, stomach cramps or discomfort, constipation,

feelings of fullness, bloating, diarrhoea.

Pain in your bones, muscles or joints.

Headache.

Uncommon side effects (may affect up to 1 in 100 people)

Inflammation or ulcer of the oesophagus (the tube that connects your mouth with your stomach)

causing difficulty and pain in swallowing (see also section 2, “Warnings and Precautions”),

inflammation of the stomach and duodenum (bowel draining the stomach).

Inflammation of the coloured part of the eye (iris) (red painful eyes with a possible change in

vision).

Fever and/or Flu like symptoms

Rare side effects (may affect up to 1 in 1,000 people)

Inflammation of the tongue (red, swollen, possibly painful), narrowing of the oesophagus (the

tube that connects your mouth with your stomach).

Abnormal liver tests have been reported. These can only be diagnosed from a blood test.

During post-marketing experience, the following have been reported

Very rare

Talk to your doctor if you have ear pain, discharge from the ear, and/or an ear

infection. These could be signs of bone damage in the ear.

Unknown frequency:

Hair loss

Liver disorders, some cases were severe.

Rarely, at the beginning of treatment, a patient’s blood calcium and phosphate levels may fall. These

changes are usually small and cause no symptoms.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects

not listed in this leaflet. You can also report side effects directly via HPRA Pharmacovigilance,

Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website:

www.hpra.ie; E-mail: medsafety@hpra.ie. By reporting side effects you can help provide more

information on the safety of this medicine.

5.

How to store Actonel

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The

expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to

throw away medicines you no longer use. These measures will help protect the environment.

6.

Contents of the pack and other information

What Actonel contains

The active substance is risedronate sodium. Each tablet contains 75 mg risedronate sodium, equivalent

to 69.6 mg risedronic acid.

The other ingredients are:

Tablet core: cellulose microcrystalline, crospovidone A and magnesium stearate.

Film coating: hypromellose, macrogol 400, macrogol 8000, hydroxypropylcellulose, colloidal

anhydrous silica, titanium dioxide [E171], iron oxide red [E172].

What Actonel looks like and contents of the pack

Actonel 75 mg film-coated tablets are oval pink 11.7 x 5.8 mm tablets with the letters “RSN” on one

side and “75 mg” on the other side. The tablets are supplied in blister packs of 2, 4, 6 or 8 tablets. Not

all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder:

Warner Chilcott UK Limited

Old Belfast Road

Millbrook

Larne

County Antrim

BT40 2SH

United Kingdom

Manufacturer:

Warner Chilcott Deutschland GmbH,

Dr.-Otto-Röhm-Str. 2-4,

64331 Weiterstadt, Germany

Balkanpharma-Dupnitsa AD

3, Samokovsko Shosse Str.

2600 Dupnitsa

Bulgaria

This medicinal product is authorised in the Member States of the EEA under the following

names:

Belgium: Actonel 75 mg filmomhulde tabletten,

Actonel 75 mg comprimé pelliculé,

Actonel 75 mg Filmtabletten

Cyprus: Actonel / ''2 συνεχόμενες ημέρες το μήνα'' 75 mg επικαλυμμένα με λεπτό υμένιο δισκία

France: Actonel 75 mg comprimé pelliculé

Germany: Actonel 75 mg Filmtabletten

Greece: Actonel / ''2 συνεχόμενες ημέρες το μήνα'' 75 mg επικαλυμμένα με λεπτό υμένιο δισκία

Ireland: Actonel 75 mg film-coated tablets

Italy: Actonel 75 mg compresse rivestite con film

Luxembourg: Actonel 75 mg comprimé pelliculé,

The Netherlands: Actonel 75 mg, filmomhulde tabletten

Romania: Actonel 75 mg comprimate filmate

Slovenia: Actonel 75 mg filmsko obložene tablete

Spain: Actonel 75 mg comprimidos recubiertos con película

Sweden: Actonel 75 mg filmdragerade tabletter

This leaflet was last revised in March 2017

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Actonel 75 mg Film Coated Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each Film-coated tablet contains 75 mg risedronate sodium, (equivalent to 69.6 mg risedronic acid).

For the list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet.

Oval pink 11.7 x 5.8 mm film-coated tablet engraved with RSN on one side and 75 mg on the other.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Treatment of osteoporosis in postmenopausal women at increased risk of fractures (see section 5.1).

4.2 Posology and method of administration

Posology

The recommended dose in adults is one 75 mg tablet orally on two consecutive days a month. The first tablet should be taken on

the same day each month, followed by the second tablet the next day.

Special populations

Elderly

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, postmenopausal population.

Renal Impairment

No dosage adjustment is required for those patients with mild to moderate renal impairment. The use of risedronate

sodium is contraindicated in patients with severe renal impairment (creatinine clearance lower than 30 ml/min) (see

sections 4.3 and 5.2).

Paediatric population

Risedronate sodium is not recommended for use in children below age 18 due to insufficient data on safety and efficacy

(see section 5.1).

Method of administration

The absorption of risedronate sodium is affected by food and polyvalent cations (see section 4.5), thus to ensure adequate

absorption patients should take Optinate 75 mg before breakfast: at least 30 minutes before the first food, other medicinal

product or drink (other than plain water) of the day. Plain water is the only drink that should be taken with Optinate 75 mg

tablet. Please note that some mineral water may have a higher concentration of calcium and therefore should not be used

(see section 5.2).

Patients who miss a dose of Optinate 75 mg should be instructed to take one Optinate 75 mg tablet the morning after the day

it is remembered, unless the time to the next month’s scheduled doses are within 7 days. Patients should then return to

taking Optinate 75 mg tablet on two consecutive days a month on the day the tablet is normally taken.

If the next month’s scheduled doses Optinate 75 mg are within 7 days, patients should wait until their next month’s

scheduled doses and then continue taking Optinate 75 mg on two consecutive days each month as originally scheduled.

Three tablets should not be taken in the same week.

The tablet must be swallowed whole and not sucked or chewed. To aid delivery of the tablet to the stomach Optinate 75 mg 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

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taking the tablet (see section 4.4).

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

The optimal duration of bisphosphonate treatment for osteoporosis has not been established. The need for continued treatment

should be re-evaluated periodically based on the benefits and potential risks of risedronate on an individual patient basis,

particularly after 5 or more years of use.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Hypocalcaemia (see section 4.4).

Pregnancy and lactation.

Severe renal impairment (creatinine clearance <30 ml/min).

4.4 Special warnings and precautions for use

Foods, drinks (other than plain water) and medicinal products containing polyvalent cations (such as calcium,

magnesium, iron and aluminium) interfere with the absorption of bisphosphonates and should not be taken at the same

time as Actonel 75 mg (see section 4.5). In order to achieve the intended efficacy, strict adherence to dosing

recommendations is necessary (see section 4.2).

Efficacy of bisphosphonates in the treatment of osteoporosis is related to the presence of low bone mineral density

and/or prevalent fracture.

High age or clinical risk factors for fracture alone are not reasons to initiate treatment of osteoporosis with a

bisphosphonate.

The evidence to support efficacy of bisphosphonates including risedronate sodium in the very elderly (>80 years) is

limited (see section 5.1).

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

(including known Barrett’s oesophagus).

Prescribers should emphasise to patients the importance of paying attention to the dosing instructions and be alert to

any signs or 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 75 mg therapy. Other disturbances of bone and mineral

metabolism (i.e. parathyroid dysfunction, hypovitaminosis D) should be treated at the time of starting Actonel 75 mg

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

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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.

Osteonecrosis of the external auditory canal has been reported with bisphosphonates, mainly in association with long-

term therapy. Possible risk factors for osteonecrosis of the external auditory canal include steroid use and

chemotherapy and/or local risk factors such 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 fractures of the femur

Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, primarily

in patients receiving long

term treatment for osteoporosis. These transverse or short oblique fractures can occur

anywhere along the femur from just below the lesser trochanter to just above the supracondylar flare. These fractures

occur after minimal or no trauma and some patients experience thigh or groin pain, often associated with imaging

features of stress fractures, weeks to months before presenting with a completed femoral fracture. Fractures are often

bilateral; therefore the contralateral femur should be examined in bisphosphonate

treated patients who have sustained a

femoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation of bisphosphonate

therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient,

based on an individual benefit/risk assessment.

During bisphosphonate treatment patients should be advised to report any thigh, hip or groin pain and any patient

presenting with such symptoms should be evaluated for an incomplete femur fracture.

4.5 Interaction with other medicinal products and other forms of interaction

No formal interaction studies have been performed, however no clinically relevant interactions with other medicinal

products were found during clinical studies.

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.

In the risedronate sodium Phase III osteoporosis studies with daily dosing, acetyl salicylic acid or NSAID use was

reported by 33% and 45% of patients respectively. In the Phase III study comparing 75mg on 2 consecutive days a

month and 5 mg daily in postmenopausal women, acetyl salicylic acid/NSAID use was reported by 54.8% of patients.

Similar percentages of patients experienced upper gastrointestinal adverse events regardless of NSAIDs and aspirin

use.

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

4.6 Fertility, pregnancy and lactation

There are no adequate data from the use of risedronate sodium in pregnant women. Studies in animals have shown

reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Studies in animals indicate that a

small amount of risedronate sodium pass into breast milk.

Risedronate sodium must not be used during pregnancy or by breast-feeding women.

4.7 Effects on ability to drive and use machines

Actonel has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Risedronate sodium has been studied in phase III clinical studies involving more than 15,000 patients. The majority of

undesirable effects observed in clinical studies was mild to moderate in severity and usually did not require cessation of

therapy.

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Adverse experiences reported in phase III clinical studies in postmenopausal women with osteoporosis treated for up to

36 months with risedronate sodium 5 mg/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 studies.

In a 2

year, double

blind, multicentre study comparing risedronate sodium 5 mg daily (n=613) and risedronate sodium

75 mg tablets on two consecutive days a month (n=616) in postmenopausal women with osteoporosis, the overall safety

profiles were similar. The following additional adverse experiences considered possibly or probably drug related by

investigators have been reported (incidence greater in risedronate sodium 75 mg than in risedronate sodium 5 mg

group)

Gastrointestinal disorders

Common: gastritis erosive (1.5% vs 0.8%), vomiting (1.3% vs 1.1%)

Musculoskeletal and connective tissues disorders

Common: arthralgia (1.5% vs. 1.0%) bone pain (1.1% vs 0.5%) and pain in extremity (1.1% vs 0.5%).

General disorders

Uncommon: acute phase reactions, such as fever and/or influenza-like illness (within 5 days of the first dose) (0.6% vs.

0.0%)

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

Musculoskeletal and connective tissues disorders

osteonecrosis of the jaw

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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 toxic epidermal necrolysis, and leukocytoclastic

vasculitis.

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.

During post

marketing experience the following reactions have been reported:

Rare: Atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction).

Very rare: Osteonecrosis of the external auditory canal (bisphosphonate class adverse reaction).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of

the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via

HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie;

E-mail: medsafety@hpra.ie.

4.9 Overdose

No specific information is available on the treatment of overdose with risedronate sodium.

Decreases in serum calcium following substantial overdose may be expected. Signs and symptoms of hypocalcaemia

may also occur in some of these patients.

Milk or antacids containing magnesium, calcium or aluminium should be given to bind risedronate and reduce

absorption of risedronate sodium. In cases of substantial overdose, gastric lavage may be considered to remove

unabsorbed risedronate sodium.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Bisphosphonates, ATC Code: M05BA07.

Mechanism of action

Risedronate sodium is a pyridinyl bisphosphonate that binds to bone hydroxyapatite and inhibits osteoclast

mediated

bone resorption. The bone turnover is reduced while the osteoblast activity and bone mineralisation is preserved.

Pharmacodynamic effects

In preclinical studies risedronate sodium demonstrated potent anti-osteoclast and anti

resorptive activity, and dose

dependently increased bone mass and biomechanical skeletal strength. The activity of risedronate sodium was

confirmed by measuring biochemical markers for bone turnover during pharmacodynamic and clinical studies. In

studies of postmenopausal women, decreases in biochemical markers of bone turnover were observed within 1 month

and reached a maximum in 3

6 months. In a 2

year study, decreases in biochemical markers of bone turnover (urinary

collagen cross-linked N telopeptide and serum bone specific alkaline phosphatase) were similar between risedronate

sodium 75 mg tablets on two consecutive days a month and risedronate sodium 5 mg tablets daily at 24 months.

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Clinical efficacy and safety

Treatment of Postmenopausal Osteoporosis

A number of risk factors are associated with postmenopausal osteoporosis including low bone mass, low bone mineral

density, existence of previous fractures, early menopause, a history of smoking, alcohol consumption and a family

history of osteoporosis. The clinical consequence of osteoporosis is fractures. The risk of fractures is increased with the

number of risk factors.Based on effects on mean percent change in lumbar spine BMD, risedronate sodium 75 mg

(n=524) on two consecutive days a month was shown to be equivalent to risedronate sodium 5 mg (n=527) daily in a

year, double

blind, multicentre study of postmenopausal women with osteoporosis. Both groups had statistically

significant mean percent increases from baseline to Month 6, 12, 24 and endpoint in lumbar spine BMD.

The clinical programme for risedronate sodium administered once daily studied the effect of risedronate sodium on the

risk of hip and vertebral fractures and contained early and late postmenopausal women with and without fracture. Daily

doses of 2.5 mg and 5 mg were studied and all groups, including the control groups, received calcium and vitamin D (if

baseline levels were low). The absolute and relative risk of new vertebral and hip fractures was estimated by use of a

time-to-first event analysis.

Two placebo

controlled studies (n=3.661) enrolled postmenopausal women under 85 years with vertebral fractures

at baseline. Risedronate sodium 5 mg daily given for 3 years reduced the risk of new vertebral fractures relative to the

control group. In women with respectively at least 2 or at least 1 vertebral fractures, the relative risk reduction was 49%

and 41% respectively (incidence of new vertebral fractures with risedronate sodium 18.1% and 11.3%, with placebo

29.0% and 16.3%, respectively). The effect of treatment was seen as early as the end of the first year of treatment.

Benefits were also demonstrated in women with multiple fractures at baseline. Risedronate sodium 5 mg daily also

reduced the yearly height loss compared to the control group.

Two further placebo controlled studies enrolled postmenopausal women above 70 years with or without vertebral

fractures at baseline. Women 70

79 years were enrolled with femoral neck BMD T

score <-3 SD (manufacturer’s

range, i.e. -2.5 SD using NHANES III (National Health and Nutrition Examination Survey)) and at least one additional

risk factor. Women >80 years could be enrolled on the basis of at least one non

skeletal risk factor for hip fracture or

low bone mineral density at the femoral neck. Statistical significance of the efficacy of risedronate versus placebo is

only reached when the two treatment groups 2.5 mg and 5 mg are pooled. The following results are only based on a-

posteriori analysis of subgroups defined by clinical practise and current definitions of osteoporosis:

In the subgroup of patients with femoral neck BMD T

score <-2.5 SD (NHANES III) and at least one vertebral

fracture at baseline, risedronate sodium given for 3 years reduced the risk of hip fractures by 46% relative to the control

group (incidence of hip fractures in combined risedronate sodium 2.5 mg and 5 mg groups 3.8%, placebo 7.4%);

Data suggest that a more limited protection than this may be observed in the very elderly (>80 years). This may be

due to the increasing importance of non-skeletal factors for hip fracture with increasing age.

In these studies, data analysed as a secondary endpoint indicated a decrease in the risk of new vertebral fractures in

patients with low femoral neck BMD without vertebral fracture and in patients with low femoral neck BMD with or

without vertebral fracture.

Risedronate sodium 5 mg daily given for 3 years increased bone mineral density (BMD) relative to control at the

lumbar spine, femoral neck, trochanter and wrist and maintained bone density at the mid

shaft radius.

In a one

year follow-up off therapy after three years treatment with risedronate sodium 5 mg daily there was rapid

reversibility of the suppressing effect of risedronate sodium on bone turnover rate.

Bone biopsy samples from postmenopausal women treated with risedronate sodium 5 mg daily for 2 to 3 years,

showed an expected moderate decrease in bone turnover. Bone formed during risedronate sodium treatment was of

normal lamellar structure and bone mineralisation. These data together with the decreased incidence of osteoporosis

related fractures at vertebral sites in women with osteoporosis appear to indicate no detrimental effect on bone quality.

Endoscopic findings from a number of patients with a number of moderate to severe gastrointestinal complaints in both

risedronate sodium and control patients indicated no evidence of treatment related gastric, duodenal or oesophageal

ulcers in either group, although duodenitis was uncommonly observed in the risedronate sodium group.

Paediatric population

The safety and efficacy of risedronate sodium has been investigated in a 3-year study (a randomized, double-blind,

placebo-controlled, multicenter, parallel group study of one year duration followed by 2 years of open-label treatment)

in paediatric patients aged 4 to less than 16 years with mild to moderate osteogenesis imperfecta. In this study, patients

weighing 10-30 kg received risedronate 2.5 mg daily and patients weighing more than 30 kg received risedronate 5 mg

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daily.

After completion of its one-year randomized, double-blind, placebo-controlled phase, a statistically significant increase

in lumbar spine BMD in the risedronate group versus placebo group was demonstrated; however an increased number

of patients with at least 1 new morphometric (identified by x-ray) vertebral fracture was found in the risedronate group

compared to placebo. During the one-year double-blind period, the percentage of patients who reported clinical

fractures was 30.9% in the risedronate group and 49.0% in the placebo group. In the open-label period when all patients

received risedronate (month 12 to month 36), clinical fractures were reported by 65.3% of patients initially randomized

to the placebo group and by 52.9% of patients initially randomized to the risedronate group. Overall, results do not

support the use of risedronate sodium in paediatric patients with mild to moderate osteogenesis imperfecta.

5.2 Pharmacokinetic properties

Absorption

Absorption after an oral dose is relatively rapid (t

~1 hour) and is independent of dose over the range studied (single

dose study, from 2.5 to 30 mg; multiple dose studies, from 2.5 to 5 mg daily and up to 75 mg on two consecutive days a

month). Mean oral bioavailability of the tablet is 0.63% and is decreased when risedronate sodium is administered with

food. Compared with a 4

hour fast after dose, bioavailability decreased by about 50% and 30%, respectively, when

breakfast was eaten 30 minutes or 1 hour after administration of a risedronate tablet. Swallowing the 75 mg tablet with

hard water was shown to decrease bioavailability by about 60% compared with soft water. Bioavailability was similar

in men and women.

Distribution

The mean steady state volume of distribution is 6.3 l/kg in humans. Plasma protein binding is about 24%.

Biotransformation

There is no evidence of systemic metabolism of risedronate sodium.

Elimination

Approximately half of the absorbed dose is excreted in urine within 24 hours, and 85% of an intravenous dose is

recovered in the urine after 28 days. Mean renal clearance is 105 ml/min and mean total clearance is 122 ml/min, with

the difference probably attributed to 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 risedronate

sodium is eliminated unchanged in faeces. After oral administration the concentration

time profile shows three

elimination phases with a terminal half-life of 480 hours.

Special Populations

Elderly

No dosage adjustment is necessary.

Acetyl salicylic acid/NSAID users

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 (see section 4.5).

5.3 Preclinical safety data

In toxicological studies in rat and dog dose dependent liver toxic effects of risedronate sodium were seen, primarily as

enzyme increases with histological changes in rat. The clinical relevance of these observations is unknown. Testicular

toxicity occurred in rat and dog at exposures considered in excess of the human therapeutic exposure. Dose related

incidences of upper airway irritation were frequently noted in rodents. Similar effects have been seen with other

bisphosphonates. Lower respiratory tract effects were also seen in longer term studies in rodents, although the clinical

significance of these findings is unclear. In reproduction toxicity studies at exposures close to clinical exposure

ossification changes were seen in sternum and/or skull of foetuses from treated rats and hypocalcemia and mortality in

pregnant females allowed to deliver. There was no evidence of teratogenesis at 3.2mg/kg/day in rat and 10mg/kg/day in

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rabbit, although data are only available on a small number of rabbits. Maternal toxicity prevented testing of higher

doses. Studies on genotoxicity and carcinogenesis did not show any particular risks for humans.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

cellulose microcrystalline,

crospovidone A,

magnesium stearate.

Film coating:

hypromellose,

macrogol 400, macrogol 8000,

hydroxypropylcellulose,

Colloidal anhydrous silica

titanium dioxide (E171),

iron oxide red (E172).

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

5 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Clear PVC/aluminium foil blisters in a cardboard carton.

Blisters in packs containing 2, 4, 6 or 8 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.

Any usused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Warner Chilcott UK Limited

Old Belfast Road

Millbrook

Larne

County Antrim

BT40 2SH

United Kingdom

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8 MARKETING AUTHORISATION NUMBER

PA1635/001/004

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 24th October 2008

Date of last renewal: 19th July 2012

10 DATE OF REVISION OF THE TEXT

May 2017

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