ACID IBANDRONIC TEVA 150mg tablets medication leaflet

Ibandronic Acid Teva 150 mg film-coated tablets

Each film-coated tablet contains 150 mg ibandronic acid (as sodium monohydrate).

For the full list of excipients, see section 6.1.

Film-coated tablet.

White, biconvex, capsule-shaped film-coated tablets, engraved “I150” on one side and plain on theother.

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

A reduction in the risk of vertebral fractures has been demonstrated, efficacy on femoral neck fractureshas not been established.

The recommended dose is one 150 mg film-coated tablet once a month. The tablet should preferablybe taken on the same date each month.

Ibandronic Acid Teva should be taken after an overnight fast (at least 6 hours) and 1 hour before thefirst food or drink (other than water) of the day (see section 4.5) or any other oral medicinal productsor supplementation (including calcium).

In case a dose is missed, patients should be instructed to take one Ibandronic Acid Teva 150 mg tabletthe morning after the tablet is remembered, unless the time to the next scheduled dose is within 7 days.

Patients should then return to taking their dose once a month on their originally scheduled date. If thenext scheduled dose is within 7 days, patients should wait until their next dose and then continuetaking one tablet once a month as originally scheduled. Patients should not take two tablets within thesame week.

Patients should receive supplemental calcium and/or vitamin D if dietary intake is inadequate (seesections 4.4 and 4.5).

The optimal duration of bisphosphonate treatment for osteoporosis has not been established. The needfor continued treatment should be re-evaluated periodically based on the benefits and potential risks of

Ibandronic Acid Teva on an individual patient basis, particularly after 5 or more years of use.

Ibandronic Acid Teva is not recommended for patients with a creatinine clearance below 30 ml/mindue to limited clinical experience (see sections 4.4 and 5.2).

No dose adjustment is necessary for patients with mild or moderate renal impairment where creatinineclearance is equal or greater than 30 ml/min.

No dose adjustment is required (see section 5.2).

Elderly population (>65 years)

No dose adjustment is required (see section 5.2).

There is no relevant use of Ibandronic Acid Teva in children below 18 years, and Ibandronic Acid

Teva was not studied in this population (see section 5.1 and section 5.2).

For oral use.

- Tablets should be swallowed whole with a glass of water (180 to 240 ml) while the patient issitting or standing in an upright position. Water with a high concentration of calcium should not beused. If there is a concern regarding potentially high levels of calcium in the tap water (hardwater), it is advised to use bottled water with a low mineral content.

- Patients should not lie down for 1 hour after taking Ibandronic Acid Teva.

- Water is the only drink that should be taken with Ibandronic Acid Teva.

- Patients should not chew or suck the tablet, because of a potential for oropharyngeal ulceration.

- Hypersensitivity to ibandronic acid or to any of the excipients listed in section 6.1

- Hypocalcaemia

- Abnormalities of the oesophagus which delay oesophageal emptying such as stricture orachalasia

- Inability to stand or sit upright for at least 60 minutes

Existing hypocalcaemia must be corrected before starting Ibandronic Acid Teva therapy. Otherdisturbances of bone and mineral metabolism should also be effectively treated. Adequate intake ofcalcium and vitamin D is important in all patients.

Gastrointestinal irritation

Orally administered bisphosphonates may cause local irritation of the upper gastrointestinal mucosa.

Because of these possible irritant effects and a potential for worsening of the underlying disease,caution should be used when Ibandronic Acid Teva is given to patients with active uppergastrointestinal problems (e.g. known Barrett’s oesophagus, dysphagia, other oesophageal diseases,gastritis, duodenitis or ulcers).

Adverse reactions such as oesophagitis, oesophageal ulcers and oesophageal erosions, in some casessevere and requiring hospitalisation, rarely with bleeding or followed by oesophageal stricture orperforation, have been reported in patients receiving treatment with oral bisphosphonates. The risk ofsevere oesophageal adverse experiences appears to be greater in patients who do not comply with thedosing instruction and/or who continue to take oral bisphosphonates after developing symptomssuggestive of oesophageal irritation. Patients should pay particular attention to and be able to complywith the dosing instructions (see section 4.2).

Physicians should be alert to any signs or symptoms signaling a possible oesophageal reaction andpatients should be instructed to discontinue Ibandronic Acid Teva and seek medical attention if theydevelop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn.

While no increased risk was observed in controlled clinical trials there have been post-marketingreports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and withcomplications.

Since Nonsteroidal Anti-Inflammatory medicinal products and bisphosphonates are both associatedwith gastrointestinal irritation, caution should be taken during concomitant administration.

Osteonecrosis of the jaw (ONJ) has been reported very rarely in the post-marketing setting in patientsreceiving Ibandronic Acid Teva for osteoporosis (see section 4.8).

The start of treatment or of a new course of treatment should be delayed in patients with unhealedopen soft tissue lesions in the mouth.

A dental examination with preventive dentistry and an individual benefit-risk assessment isrecommended prior to treatment with Ibandronic Acid Teva in patients with concomitant risk factors.

The following risk factors should be considered when evaluating a patient’s risk of developing ONJ:

- Potency of the medicinal product that inhibit bone resorption (higher risk for highly potentcompounds), route of administration (higher risk for parenteral administration) and cumulativedose of bone resorption therapy.

- Cancer, co-morbid conditions (e.g. anaemia, coagulopathies, infection), smoking.

- Concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy tohead and neck.

- Poor oral hygiene, periodontal disease, poorly fitting dentures, history of dental disease,invasive dental procedures e.g. tooth extractions.

All patients should be encouraged to maintain good oral hygiene, undergo routine dental check-ups,and immediately report any oral symptoms such as dental mobility, pain or swelling, or non-healing ofsores or discharge during treatment with Ibandronic Acid Teva. While on treatment, invasive dentalprocedures should be performed only after careful consideration and be avoided in close proximity to

Ibandronic Acid Teva administration.

The management plan of the patients who develop ONJ should be set up in close collaborationbetween the treating physician and a dentist or oral surgeon with expertise in ONJ. Temporaryinterruption of Ibandronic Acid Teva treatment should be considered until the condition resolves andcontributing risk factors are mitigated where possible.

Osteonecrosis of the external auditory canal

Osteonecrosis of the external auditory canal has been reported with bisphosphonates, mainly inassociation with long-term therapy. Possible risk factors for osteonecrosis of the external auditorycanal include steroid use and chemotherapy and/or local risk factors such as infection or trauma. Thepossibility of osteonecrosis of the external auditory canal should be considered in patients receivingbisphosphonates who present with ear symptoms including chronic ear infections.

Atypical fractures of the femur

Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonatetherapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or shortoblique fractures can occur anywhere along the femur from just below the lesser trochanter to justabove the supracondylar flare. These fractures occur after minimal or no trauma and some patientsexperience thigh or groin pain, often associated with imaging features of stress fractures, weeks tomonths before presenting with a completed femoral fracture. Fractures are often bilateral; therefore thecontralateral femur should be examined in bisphosphonate-treated patients who have sustained afemoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation ofbisphosphonate therapy in patients suspected to have an atypical femur fracture should be consideredpending 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 andany patient presenting with such symptoms should be evaluated for an incomplete femur fracture (seesection 4.8).

Atypical fractures of other long bones

Atypical fractures of other long bones, such as the ulna and tibia have also been reported in patientsreceiving long-term treatment. As with atypical femoral fractures, these fractures occur after minimal,or no trauma and some patients experience prodromal pain prior to presenting with a completedfracture. In cases of ulna fracture, this may be associated with repetitive stress loading associated withthe long-term use of walking aids (see section 4.8).

Due to limited clinical experience, Ibandronic Acid Teva is not recommended for patients with acreatinine clearance below 30 ml/min (see section 5.2).

Excipient(s)

This medicine contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to sayessentially ‘sodium-free’.

Medicinal product-Food Interaction

Oral bioavailability of ibandronic acid is generally reduced in the presence of food. In particular,products containing calcium, including milk and other multivalent cations (such as aluminium,magnesium, iron), are likely to interfere with absorption of Ibandronic Acid Teva, which is consistentwith findings in animal studies. Therefore, patients should fast overnight (at least 6 hours) beforetaking Ibandronic Acid Teva and continue fasting for 1 hour following intake of Ibandronic Acid Teva(see section 4.2).

Metabolic interactions are not considered likely, since ibandronic acid does not inhibit the majorhuman hepatic P450 isoenzymes and has been shown not to induce the hepatic cytochrome P450system in rats (see section 5.2). Ibandronic acid is eliminated by renal excretion only and does notundergo any biotransformation.

Calcium supplements, antacids and some oral medicinal products containing multivalent cations

Calcium supplements, antacids and some oral medicinal products containing multivalent cations (suchas aluminium, magnesium, iron) are likely to interfere with the absorption of Ibandronic Acid Teva.

Therefore, patients should not take other oral medicinal products for at least 6 hours before taking

Ibandronic Acid Teva and for 1 hour following intake of Ibandronic Acid Teva.

Acetylsalicylic acid and NSAIDs

Since Acetylsalicylic acid, Nonsteroidal Anti-Inflammatory medicinal products (NSAIDs) andbisphosphonates are associated with gastrointestinal irritation, caution should be taken duringconcomitant administration (see section 4.4).

H2 blockers or proton pump inhibitors

Of over 1500 patients enrolled in study BM 16549 comparing monthly with daily dosing regimens ofibandronic acid, 14% and 18% of patients used histamine (H2) blockers or proton pump inhibitorsafter one and two years, respectively. Among these patients, the incidence of upper gastrointestinalevents in the patients treated with ibandronic acid 150 mg once monthly was similar to that in patientstreated with ibandronic acid 2.5 mg daily.

In healthy male volunteers and postmenopausal women, intravenous administration of ranitidinecaused an increase in ibandronic acid bioavailability of about 20%, probably as a result of reducedgastric acidity. However, since this increase is within the normal variability of the bioavailability ofibandronic acid, no dose adjustment is considered necessary when Ibandronic Acid Teva isadministered with H2-antagonists or other active substances which increase gastric pH.

Ibandronic Acid Teva is only for use in postmenopausal women and must not be taken by women ofchildbearing potential.

There are no adequate data from the use of ibandronic acid in pregnant women. Studies in rats haveshown some reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Ibandronic Acid Teva should not be used during pregnancy.

It is not known whether ibandronic acid is excreted in human milk. Studies in lactating rats havedemonstrated the presence of low levels of ibandronic acid in the milk following intravenousadministration. Ibandronic Acid Teva should not be used during breast-feeding.

There are no data on the effects of ibandronic acid from humans. In reproductive studies in rats by theoral route, ibandronic acid decreased fertility. In studies in rats using the intravenous route, ibandronicacid decreased fertility at high daily doses (see section 5.3).

On the basis of the pharmacodynamic and pharmacokinetic profile and reported adverse reactions, it isexpected that Ibandronic Acid Teva has no or negligible influence on the ability to drive and usemachines.

The most serious reported adverse reactions are anaphylactic reaction/shock, atypical fractures of thefemur, osteonecrosis of the jaw, gastrointestinal irritation, ocular inflammation, (see paragraph“Description of selected adverse reactions” and section 4.4).

The most frequently reported adverse reactions are arthralgia and influenza-like symptoms. Thesesymptoms are typically in association with the first dose, generally of short duration, mild or moderatein intensity, and usually resolve during continuing treatment without requiring remedial measures (seeparagraph “Influenza like illness”).

In table 1 a complete list of known adverse reactions is presented. The safety of oral treatment withibandronic acid 2.5 mg daily was evaluated in 1251 patients treated in 4 placebo-controlled clinicalstudies, with the large majority of patients coming from the pivotal three year fracture study (MF4411).

In a two-year study in postmenopausal women with osteoporosis (BM 16549) the overall safety ofibandronic acid 150 mg once monthly and ibandronic acid 2.5 mg daily was similar. The overallproportion of patients who experienced an adverse reaction, was 22.7 % and 25.0 % for ibandronicacid 150 mg once monthly after one and two years, respectively. Most cases did not lead to cessationof therapy.

Adverse reactions are listed according to MedDRA system organ class and frequency category.

Frequency categories are defined using the following convention: very common (>1/10), common(≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare(<1/10,000), not known (cannot be estimated from the available data). Within each frequencygrouping, adverse reactions are presented in order of decreasing seriousness.

Table 1: Adverse reactions occurring in postmenopausal women receiving ibandronic acid 150 mgonce monthly or ibandronic acid 2.5 mg daily in the phase III studies BM 16549 and MF 4411 and inpost-marketing experience.

System Organ Common Uncommon Rare Very rare Not known

Class

Immune Asthma Hypersensitivity Anaphylacticsystem exacerbation reaction reaction/shock*†disorders

Metabolism Hypocalcaemia†and nutritiondisorders

Nervous Headache Dizzinesssystemdisorders

Eye disorders Ocularinflammation*†

Gastrointestina Oesophagit Oesophagitis Duodenitisl disorders* is, Gastritis, including

Gastro oesophagealoesophagea ulcerations orl reflux strictures anddisease, dysphagia,

Dyspepsia, Vomiting,

Diarrhoea, Flatulence

Abdominalpain,

Nausea

Skin and Rash Angioedema, Stevens-Johnsonsubcutaneous Face oedema, syndrome†,tissues Urticaria Erythemadisorders multiforme†,

Dermatitisbullous†

Musculoskelet Arthralgia, Back pain Atypical Osteonecrosis of Atypicalal and Myalgia, subtrochanteric jaw*†, fractures ofconnective Musculosk and diaphyseal Osteonecrosis of long bonestissue eletal pain, femoral the external other thandisorders Muscle fractures† auditory canal the femurcramp, (bisphosphonate

Musculosk class adverseeletal reaction)†stiffness

General Influenza Fatiguedisorders and like illness*administrationsite conditions

*See further information below†Identified in post-marketing experience.

Patients with a previous history of gastrointestinal disease including patients with peptic ulcer withoutrecent bleeding or hospitalisation, and patients with dyspepsia or reflux controlled by medication wereincluded in the once monthly treatment study. For these patients, there was no difference in theincidence of upper gastrointestinal adverse events with the 150 mg once monthly regimen compared tothe 2.5 mg daily regimen.

Influenza-like illness

Influenza-like illness includes events reported as acute phase reaction or symptoms including myalgia,arthralgia, fever, chills, fatigue, nausea, loss of appetite, or bone pain.

Osteonecrosis of jaw

Cases of osteonecrosis of the jaw have been reported, predominantly in cancer patients treated withmedicinal products that inhibit bone resorption, such as ibandronic acid (see section 4.4.) Cases of

ONJ have been reported in the post-marketing setting for ibandronic acid.

Atypical subtrochanteric and diaphyseal femoral fractures

Although the pathophysiology is uncertain, evidence from epidemiological studies suggests anincreased risk of atypical subtrochanteric and diaphyseal femoral fractures with long-termbisphosphonate therapy for postmenopausal osteoporosis, particularly beyond three to five years ofuse. The absolute risk of atypical subtrochanteric and diaphyseal long bone fractures (bisphosphonateclass adverse reaction) remains very low.

Ocular inflammation

Ocular inflammation events such as uveitis, episcleritis and scleritis have been reported withibandronic acid. In some cases, these events did not resolve until the ibandronic acid was discontinued.

Anaphylactic reaction/shock

Cases of anaphylactic reaction/shock, including fatal events, have been reported in patients treatedwith intravenous ibandronic acid.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No specific information is available on the treatment of overdose with Ibandronic Acid Teva.

However, based on a knowledge of this class of compounds, oral overdose may result in uppergastrointestinal adverse reactions (such as upset stomach, dyspepsia, oesophagitis, gastritis, or ulcer)or hypocalcaemia. Milk or antacids should be given to bind Ibandronic Acid Teva, and any adversereactions treated symptomatically. Owing to the risk of oesophageal irritation, vomiting should not beinduced and the patient should remain fully upright.

Pharmacotherapeutic group: Medicinal products for treatment of bone diseases, bisphosphonates, ATCcode: M05-BA06

Ibandronic acid is a highly potent bisphosphonate belonging to the nitrogen-containing group ofbisphosphonates, which act selectively on bone tissue and specifically inhibit osteoclast activitywithout directly affecting bone formation. It does not interfere with osteoclast recruitment. Ibandronicacid leads to progressive net gains in bone mass and a decreased incidence of fractures through thereduction of elevated bone turnover towards premenopausal levels in postmenopausal women.

The pharmacodynamic action of ibandronic acid is inhibition of bone resorption. In vivo, ibandronicacid prevents experimentally induced bone destruction caused by cessation of gonadal function,retinoids, tumours or tumour extracts. In young (fast growing) rats, the endogenous bone resorption isalso inhibited, leading to increased normal bone mass compared with untreated animals. Animalmodels confirm that ibandronic acid is a highly potent inhibitor of osteoclastic activity. In growingrats, there was no evidence of impaired mineralization even at doses greater than 5,000 times the doserequired for osteoporosis treatment.

Both daily and intermittent (with prolonged dose-free intervals) long-term administration in rats, dogsand monkeys was associated with formation of new bone of normal quality and maintained orincreased mechanical strength even at doses in the toxic range. In humans, the efficacy of both dailyand intermittent administration with a dose-free interval of 9-10 weeks of ibandronic acid wasconfirmed in a clinical trial (MF 4411), in which ibandronic acid demonstrated anti-fracture efficacy.

In animal models ibandronic acid produced biochemical changes indicative of dose-dependentinhibition of bone resorption, including suppression of urinary biochemical markers of bone collagendegradation (such as deoxypyridinoline, and cross-linked N-telopeptides of type I collagen (NTX)).

In a Phase 1 bioequivalence study conducted in 72 postmenopausal women receiving 150 mg orallyevery 28 days for a total of four doses, inhibition in serum CTX following the first dose was seen asearly as 24 hours post-dose (median inhibition 28 %), with median maximal inhibition (69 %) seen6 days later. Following the third and fourth dose, the median maximum inhibition 6 days post dosewas 74 % with reduction to a median inhibition of 56 % seen 28 days following the fourth dose. Withno further dosing, there is a loss of suppression of biochemical markers of bone resorption.

Independent risk factors, for example, low BMD, age, the existence of previous fractures, a familyhistory of fractures, high bone turnover and low body mass index should be considered in order toidentify women at increased risk of osteoporotic fractures.

Ibandronic acid 150 mg once monthly

Bone mineral density (BMD)

Ibandronic acid 150 mg once monthly was shown to be at least as effective as ibandronic acid 2.5 mgdaily at increasing BMD in a two year, double-blind, multicentre study (BM 16549) ofpostmenopausal women with osteoporosis (lumbar spine BMD T score below -2.5 SD at baseline).

This was demonstrated in both the primary analysis at one year and in the confirmatory analysis at twoyears endpoint (Table 2).

Table 2: Mean relative change from baseline of lumbar spine, total hip, femoral neck and trochanter

BMD after one year (primary analysis) and two years of treatment (Per-Protocol Population) in study

BM 16549.

One year data in study BM 16549 Two year data in study BM

Mean relative changes Ibandronic acid Ibandronic acid Ibandronic Ibandronicfrom baseline % [95 % 2.5 mg daily 150 mg once acid 2.5 mg acid 150 mg

CI] (N=318) monthly daily (N=294) once monthly(N=320) (N=291)

Lumbar spine L2-L4 3.9 [3.4, pct. 4.3] 4.9 [4.4, 5.3] 5.0 [4.4, 5.5] 6.6 [6.0, 7.1]

BMD

Total hip BMD 2.0 [1.7, 2.3] 3.1 [2.8, 3.4] 2.5 [2.1, 2.9] 4.2 [3.8, 4.5]

Femoral neck BMD 1.7 [1.3, 2.1] 2.2 [1.9, 2.6] 1.9 [1.4, 2.4] 3.1 [2.7, 3.6]

Trochanter BMD 3.2 [2.8, 3.7] 4.6 [4.2, 5.1] 4.0 [3.5, 4.5] 6.2 [5.7, 6.7]

Furthermore, ibandronic acid 150 mg once monthly was proven superior to ibandronic acid 2.5 mgdaily for increases in lumbar spine BMD in a prospectively planned analysis at one year, p=0.002, andat two years, p<0.001.

At one year (primary analysis), 91.3 % (p=0.005) of patients receiving ibandronic acid 150 mg oncemonthly had a lumbar spine BMD increase above or equal to baseline (BMD responders), comparedwith 84.0 % of patients receiving ibandronic acid 2.5 mg daily. At two years, 93.5 % (p=0.004) and86.4 % of patients receiving ibandronic acid 150 mg once monthly or ibandronic acid 2.5 mg daily,respectively, were responders.

For total hip BMD, 90.0 % (p<0.001) of patients receiving ibandronic acid 150 mg once monthly and76.7 % of patients receiving ibandronic acid 2.5 mg daily had total hip BMD increases above or equalto baseline at one year. At two years 93.4 % (p<0.001) of patients receiving ibandronic acid 150 mgonce monthly and 78.4 %, of patients receiving ibandronic acid 2.5 mg daily had total hip BMDincreases above or equal to baseline.

When a more stringent criterion is considered, which combines both lumbar spine and total hip BMD,83.9 % (p<0.001) and 65.7 % of patients receiving ibandronic acid 150 mg once monthly oribandronic acid 2.5 mg daily, respectively, were responders at one year. At two years, 87.1 %(p<0.001) and 70.5 %,of patients met this criterion in the 150 mg monthly and 2.5 mg daily armsrespectively.

Biochemical markers of bone turn-over

Clinically meaningful reductions in serum CTX levels were observed at all time points measured, i.e.months 3, 6, 12 and 24. After one year (primary analysis) the median relative change from baselinewas -76 % for ibandronic acid 150 mg once monthly and -67 % for ibandronic acid 2.5 mg daily. Attwo years the median relative change was -68 % and -62 %, in the 150 mg monthly and 2.5 mg dailyarms respectively.

At one year, 83.5 % (p= 0.006) of patients receiving ibandronic acid 150 mg once monthly and 73.9 %of patients receiving ibandronic acid 2.5 mg daily were identified as responders (defined as a decrease≥50% from baseline). At two years 78.7 % (p=0.002) and 65.6 % of patients were identified asresponders in the 150 mg monthly and 2.5 mg daily arms respectively.

Based on the results of study BM 16549, ibandronic acid 150 mg once monthly is expected to be atleast as effective in preventing fractures as ibandronic acid 2.5 mg daily.

Ibandronic acid 2.5 mg daily

In the initial three-year, randomised, double-blind, placebo-controlled, fracture study (MF 4411), astatistically significant and medically relevant decrease in the incidence of new radiographicmorphometric and clinical vertebral fractures was demonstrated (table 3). In this study, ibandronicacid was evaluated at oral doses of 2.5 mg daily and 20 mg intermittently as an exploratory regimen.

Ibandronic acid was taken 60 minutes before the first food or drink of the day (post-dose fastingperiod). The study enrolled women aged 55 to 80 years, who were at least 5 years postmenopausal,who had a BMD at lumbar spine of 2 to 5 SD below the premenopausal mean (T-score) in at least onevertebra [L1-L4], and who had one to four prevalent vertebral fractures. All patients received 500 mgcalcium and 400 IU vitamin D daily. Efficacy was evaluated in 2,928 patients. Ibandronic acid 2.5 mgadministered daily, showed a statistically significant and medically relevant reduction in the incidenceof new vertebral fractures. This regimen reduced the occurrence of new radiographic vertebralfractures by 62 % (p=0.0001) over the three year duration of the study. A relative risk reduction of61 % was observed after 2 years (p=0.0006). No statistically significant difference was attained after1 year of treatment (p=0.056). The anti-fracture effect was consistent over the duration of the study.

There was no indication of a waning of the effect over time. The incidence of clinical vertebralfractures was also significantly reduced by 49 % (p=0.011). The strong effect on vertebral fractureswas furthermore reflected by a statistically significant reduction of height loss compared to placebo(p<0.0001).

Table 3: Results from 3 years fracture study MF 4411 (%, 95 % CI)

Placebo Ibandronic acid 2.5 mg daily(N=974) (N=977)

Relative Risk Reduction 62 % (40.9, 75.1)

New morphometric vertebralfractures

Incidence of new morphometric 9.56 % (7.5, 11.7) 4.68 % (3.2,6.2)vertebral fractures

Relative risk reduction of clinical 49 % (14.03, 69.49)vertebral fracture

Incidence of clinical vertebral 5.33 % (3.73, 6.92) 2.75 % (1.61, 3.89)fracture

BMD - mean change relative to 1.26 % (0.8, 1.7) 6.54 % (6.1, 7.0)baseline lumbar spine at year 3

BMD - mean change relative to -0.69 % (-1.0, -0.4) 3.36 % (3.0, 3.7)baseline total hip at year 3

The treatment effect of ibandronic acid was further assessed in an analysis of the subpopulation ofpatients who at baseline had a lumbar spine BMD T-score below -2.5. The vertebral fracture riskreduction was very consistent with that seen in the overall population.

Table 4: Results from 3 years fracture study MF 4411 (%, 95 % CI) for patients with lumbar spine

BMD T-score below -2.5 at baseline

Placebo (N=587) Ibandronic acid 2.5 mg daily(N=575)

Relative Risk Reduction New 59 % (34.5, 74.3)morphometric vertebral fractures

Incidence of new morphometric 12.54 % (9.53, 15.55) 5.36 % (3.31, 7.41)vertebral fractures

Relative risk reduction of clinical 50 % (9.49, 71.91)vertebral fracture

Incidence of clinical vertebral fracture 6.97 % (4.67, 9.27) 3.57 % (1.89, pct. 5.24)

BMD - mean change relative to 1.13 % (0.6, 1.7) 7.01 % (6.5, 7.6)baseline lumbar spine at year 3

BMD - mean change relative to -0.70 % (-1.1, -0.2) 3.59 % (3.1, 4.1)baseline total hip at year 3

In the overall patient population of the study MF 4411, no reduction was observed for non-vertebralfractures, however daily ibandronic acid appeared to be effective in a high-risk subpopulation (femoralneck BMD T-score < -3.0), where a non-vertebral fracture risk reduction of 69 % was observed.

Daily treatment with 2.5 mg resulted in progressive increases in BMD at vertebral and nonvertebralsites of the skeleton.

Three-year lumbar spine BMD increase compared to placebo was 5.3 % and 6.5 % compared tobaseline. Increases at the hip compared to baseline were 2.8 % at the femoral neck, 3.4 % at the totalhip, and 5.5 % at the trochanter. Biochemical markers of bone turnover (such as urinary CTX andserum Osteocalcin) showed the expected pattern of suppression to premenopausal levels and reachedmaximum suppression within a period of 3-6 months. A clinically meaningful reduction of 50 % ofbiochemical markers of bone resorption was observed as early as one month after start of treatmentwith ibandronic acid 2.5 mg. Following treatment discontinuation, there is a reversion to thepathological pre-treatment rates of elevated bone resorption associated with postmenopausalosteoporosis. The histological analysis of bone biopsies after two and three years of treatment ofpostmenopausal women showed bone of normal quality and no indication of a mineralization defect.

Paediatric population (see section 4.2 and section 5.2)

Ibandronic acid was not studied in the paediatric population, therefore no efficacy or safety data areavailable for this patient population.

The primary pharmacological effects of ibandronic acid on bone are not directly related to actualplasma concentrations, as demonstrated by various studies in animals and humans.

The absorption of ibandronic acid in the upper gastrointestinal tract is rapid after oral administrationand plasma concentrations increase in a dose-proportional manner up to 50 mg oral intake, withgreater than dose-proportional increases seen above this dose. Maximum observed plasmaconcentrations were reached within 0.5 to 2 hours (median 1 hour) in the fasted state and absolutebioavailability was about 0.6 %. The extent of absorption is impaired when taken together with food orbeverages (other than water). Bioavailability is reduced by about 90 % when ibandronic acid isadministered with a standard breakfast in comparison with bioavailability seen in fasted subjects.

There is no meaningful reduction in bioavailability provided ibandronic acid is taken 60 minutesbefore the first food of the day. Both bioavailability and BMD gains are reduced when food orbeverage is taken less than 60 minutes after ibandronic acid is ingested.

After initial systemic exposure, ibandronic acid rapidly binds to bone or is excreted into urine. Inhumans, the apparent terminal volume of distribution is at least 90 l and the amount of dose reachingthe bone is estimated to be 40-50 % of the circulating dose. Protein binding in human plasma isapproximately 85 %-87 % (determined in vitro at therapeutic concentrations), and thus there is a lowpotential for interaction with other medicinal products due to displacement.

There is no evidence that ibandronic acid is metabolised in animals or humans.

The absorbed fraction of ibandronic acid is removed from the circulation via bone absorption(estimated to be 40-50% in postmenopausal women) and the remainder is eliminated unchanged by thekidney. The unabsorbed fraction of ibandronic acid is eliminated unchanged in the faeces.

The range of observed apparent half-lives is broad, the apparent terminal half-life is generally in therange of 10-72 hours. As the values calculated are largely a function of the duration of study, the doseused, and assay sensitivity, the true terminal half-life is likely to be substantially longer, in commonwith other bisphosphonates. Early plasma levels fall quickly reaching 10 % of peak values within 3and 8 hours after intravenous or oral administration respectively.

Total clearance of ibandronic acid is low with average values in the range 84-160 ml/min. Renalclearance (about 60 ml/min in healthy postmenopausal females) accounts for 50-60 % of totalclearance and is related to creatinine clearance. The difference between the apparent total and renalclearances is considered to reflect the uptake by bone.

The secretory pathway appears not to include known acidic or basic transport systems involved in theexcretion of other active substances. In addition, ibandronic acid does not inhibit the major humanhepatic P450 isoenzymes and does not induce the hepatic cytochrome P450 system in rats.

Pharmacokinetics in special clinical situations

Bioavailability and pharmacokinetics of ibandronic acid are similar in men and women.

There is no evidence for any clinically relevant inter-ethnic differences between Asians and

Caucasians in ibandronic acid disposition. There are few data available on patients of African origin.

Renal clearance of ibandronic acid in patients with various degrees of renal impairment is linearlyrelated to creatinine clearance.

No dose adjustment is necessary for patients with mild or moderate renal impairment (CLcr equal orgreater than 30 ml/min), as shown in study BM 16549 where the majority of patients had mild tomoderate renal impairment.

Subjects with severe renal failure (CLcr less than 30 ml/min) receiving daily oral administration of10 mg ibandronic acid for 21 days, had 2-3 fold higher plasma concentrations than subjects withnormal renal function and total clearance of ibandronic acid was 44 ml/min. After intravenousadministration of 0.5 mg, total, renal, and non-renal clearances decreased by 67 %, 77 % and 50 %,respectively, in subjects with severe renal failure but there was no reduction in tolerability associatedwith the increase in exposure. Due to the limited clinical experience, ibandronic acid is notrecommended in patients with severe renal impairment (see sections 4.2 and 4.4). Thepharmacokinetics of ibandronic acid was not assessed in patients with end-stage renal diseasemanaged by other than hemodialysis. The pharmacokinetics of ibandronic acid in these patients isunknown, and ibandronic acid should not be used under these circumstances.

Patients with hepatic impairment (see section 4.2)

There are no pharmacokinetic data for ibandronic acid in patients who have hepatic impairment. Theliver has no significant role in the clearance of ibandronic acid which is not metabolised but is clearedby renal excretion and by uptake into bone. Therefore dose adjustment is not necessary in patientswith hepatic impairment.

Elderly population (see section 4.2)

In a multivariate analysis, age was not found to be an independent factor of any of thepharmacokinetic parameters studied. As renal function decreases with age this is the only factor totake into consideration (see renal impairment section).

Paediatric population (see section 4.2 and section 5.1)

There are no data on the use of ibandronic acid in these age groups.

Toxic effects, e.g signs of renal damage, were observed in dogs only at exposures consideredsufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

Mutagenicity/Carcinogenicity

No indication of carcinogenic potential was observed. Tests for genotoxicity revealed no evidence ofgenetic activity for ibandronic acid.

There was no evidence for a direct foetal toxic or teratogenic effect of ibandronic acid in orally treatedrats and rabbits and there were no adverse effects on the development in F1 offspring in rats at anextrapolated exposure of at least 35 times above human exposure. In reproductive studies in rats by theoral route effects on fertility consisted of increased preimplantation losses at dose levels of 1mg/kg/day and higher. In reproductive studies in rats by the intravenous route, ibandronic aciddecreased sperm counts at doses of 0.3 and 1 mg/kg/day and decreased fertility in males at 1mg/kg/day and in females at 1.2 mg/kg/day. Adverse effects of ibandronic acid in reproductivetoxicity studies in the rat were those observed with bisphosphonates as a class. They include adecreased number of implantation sites, interference with natural delivery (dystocia), and an increasein visceral variations (renal pelvis ureter syndrome).

Cellulose microcrystalline

Povidone K-30

Crospovidone (type A)

Silica colloidal anhydrous

Stearic acid

Opadry white YS-1-7003:

Titanium dioxide (E 171)

Hypromellose

Macrogol 400

Polysorbate 80

Not applicable.

2 years

This medicinal product does not require any special storage conditions.

PVC/Aclar/PVC - Aluminium blisters in cardboard boxes of 1 or 3 tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements. The release of pharmaceuticals in the environment should be minimized.

Teva B.V.

Swensweg 52031 GA Haarlem

The Netherlands

EU/1/10/642/003 1 film-coated tablet in PVC/Aclar/PVC - Aluminium blister in cardboardboxes

EU/1/10/642/004 3 film-coated tablets in PVC/Aclar/PVC - Aluminium blisters incardboard boxes

Date of first authorisation: 17 September 2010

Date of latest renewal: 25 June 2015

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu/