Leaflet ACID IBANDRONIC SANDOZ 50mg film-coated tablets
Indicated for: osteoporosis
Route of administration: oral
Substance: ibandronic acid (bisphosphonate)
ATC: M05BA06 (Musculo-skeletal system | Drugs affecting bone structure and mineralization | Bisphosphonates)
Take this medicine on an empty stomach.
Do not take with milk, calcium, iron, magnesium, or antacids if separation is recommended.
Ibandronic acid is a medication from the bisphosphonate class used for the prevention and treatment of osteoporosis, particularly in postmenopausal women, to reduce the risk of bone fractures, especially in the spine. It is also used to treat hypercalcemia associated with bone metastases in certain types of cancer.
Ibandronic acid works by inhibiting the activity of osteoclasts, the cells responsible for bone resorption, helping to maintain bone density and prevent bone loss. It is available in tablet or injection form, with administration being periodic (monthly or quarterly, depending on the indication).
Side effects may include muscle or joint pain, gastrointestinal irritation (such as heartburn or nausea), and, in rare cases, osteonecrosis of the jaw. It is important to take the medication as directed by a doctor, and patients should remain upright for at least 30-60 minutes after oral administration to reduce the risk of esophageal irritation.
General data about ACID IBANDRONIC SANDOZ 50mg
- Substance: ibandronic acid
- Date of latest medicines list: 01-06-2016
- Product code: W57730004
- Concentration: 50mg
- Pharmaceutical form: film-coated tablets
- Quantity: 28
- Product type: Generic medicine
- Prescription status: P-RF - Medicines dispensed with a medical prescription that is retained by the pharmacy and cannot be renewed.
Pharmaceutical forms available for ibandronic acid
Concentrations available for ibandronic acid
- 150mg
- 1mg/1ml
- 2.5mg
- 2mg
- 2mg/2ml
- 3mg
- 3mg/3ml
- 50mg
- 6mg
- 6mg/6ml
Leaflet ACID IBANDRONIC SANDOZ 50mg
Contents of the package leaflet for the medicine ACID IBANDRONIC SANDOZ 50mg film-coated tablets
1. NAME OF THE MEDICINAL PRODUCT
Ibandronic acid Sandoz 50 mg film-coated tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 50 mg of ibandronic acid (as ibandronate sodium monohydrate).
Excipient with known effectEach film-coated tablet contains 0.86 mg lactose (as monohydrate).
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
White round biconvex tablets
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Ibandronic acid Sandoz is indicated in adults for the prevention of skeletal events (pathologicalfractures, bone complications requiring radiotherapy or surgery) in patients with breast cancer andbone metastases.
4.2 Posology and method of administration
Ibandronic acid Sandoz therapy should only be initiated by physicians experienced in the treatment ofcancer.
PosologyThe recommended dose is one 50 mg film-coated tablet daily.
Special populationsHepatic impairment
No dose adjustment is required (see section 5.2).
Renal impairmentNo dose adjustment is necessary for patients with mild renal impairment (CLcr ≥50 and <80 mL/min).
For patients with moderate renal impairment (CLcr ≥30 and <50 mL/min) a dosage adjustment to one50 mg film-coated tablet every second day is recommended (see section 5.2).
For patients with severe renal impairment (CLcr <30 mL/min) the recommended dose is one 50 mgfilm-coated tablet once weekly. See dosing instructions, above.
ElderlyNo dose adjustment is necessary (see section 5.2).
Paediatric populationThe safety and efficacy of ibandronic acid in children and adolescents below the age of 18 years havenot been established. No data are available (see section 5.1 and 5.2).
Method of administrationFor oral use.
Ibandronic acid Sandoz tablets should be taken after an overnight fast (at least 6 hours) and before thefirst food or drink of the day. Medicinal products and supplements (including calcium) shouldsimilarly be avoided prior to taking Ibandronic acid Sandoz tablets. Fasting should be continued for atleast 30 minutes after taking the tablet. Water may be taken at any time during the course of
Ibandronic acid Sandoz treatment (see section 4.5). Water with a high concentration of calcium shouldnot be used. If there is concern regarding potentially high levels of calcium in the tap water (hardwater), it is advised to use bottled water with a low mineral content.
- The tablets should be swallowed whole with a full glass of water (180 to 240 ml) while thepatient is standing or sitting in an upright position.
- Patients should not lie down for 60 minutes after taking Ibandronic acid Sandoz.
- Patients should not chew, suck or crush the tablet because of a potential for oropharyngealulceration.
- Water is the only drink that should be taken with Ibandronic acid Sandoz.
4.3 Contraindications
- Abnormalities of the oesophagus which delay oesophageal emptying such as stricture orachalasia
- Inability to stand or sit upright for at least 60 minutes
- Hypocalcaemia
- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
Patients with disturbances of bone and mineral metabolism
Hypocalcaemia and other disturbances of bone and mineral metabolism should be effectively treatedbefore starting Ibandronic acid Sandoz therapy. Adequate intake of calcium and vitamin D isimportant in all patients. Patients should receive supplemental calcium and/or vitamin D if dietaryintake is inadequate.
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 Sandoz is given to patients with active uppergastrointestinal problems (e.g. known Barrett’s oesophagus, dysphagia, other oesophageal diseases,gastritis, duodenitis or ulcers).
Adverse experiences such as oesophagitis, oesophageal ulcers and oesophageal erosions, in somecases severe and requiring hospitalization, 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 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 Sandoz 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.
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.
Osteonecrosis of the jawOsteonecrosis of the jaw (ONJ) has been reported very rarely in the post marketing setting in patientsreceiving ibandronic acid for oncology indications (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 Sandoz 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 Sandoz. While on treatment, invasive dentalprocedures should be performed only after careful consideration and be avoided in close proximity to
Ibandronic acid Sandoz 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 Sandoz 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 of bisphosphonate therapy in patients suspected to have an atypical femur fractureshould 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 andany patient presenting with such symptoms should be evaluated for an incomplete femur fracture.
Renal functionClinical studies have not shown any evidence of deterioration in renal function with long termibandronic acid therapy. Nevertheless, according to clinical assessment of the individual patient, it isrecommended that renal function, serum calcium, phosphate and magnesium should be monitored inpatients treated with ibandronic acid.
Patients with known hypersensitivity to other bisphosphonates
Caution is to be taken in patients with known hypersensitivity to other bisphosphonates.
Ibandronic acid Sandoz contains lactose and sodium
This medicinal product contains lactose. Patients with rare hereditary problems of galactoseintolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinalproduct.
This medicinal product contains less than 1mmol (23 mg) sodium per film-coated tablet, that is to sayessentially sodium free.
4.5 Interaction with other medicinal products and other forms of interaction
Medicinal product-Food Interactions
Products containing calcium and other multivalent cations (such as aluminium, magnesium, iron),including milk and food, are likely to interfere with absorption of Ibandronic acid Sandoz tablets.
Therefore, with such products, including food, intake must be delayed at least 30 minutes followingoral administration.
Bioavailability was reduced by approximately 75% when ibandronic acid tablets were administered 2hours after a standard meal. Therefore, it is recommended that the tablets should be taken after anovernight fast (at least 6 hours) and fasting should continue for at least 30 minutes after the dose hasbeen taken (see section 4.2).
Interactions with other medicinal productsMetabolic 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.
H2-antagonists or other medicinal products that increase gastric pH.
In healthy male volunteers and postmenopausal women, intravenous ranitidine caused an increase inibandronic acid bioavailability of about 20% (which is within the normal variability of thebioavailability of ibandronic acid), probably as a result of reduced gastric acidity. However, no dosageadjustment is required when ibandronic acid is administered with H2-antagonists or medicinal productsthat increase gastric pH.
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).
Aminoglycosides
Caution is advised when bisphosphonates are administered with aminoglycosides, since bothsubstances can lower serum calcium levels for prolonged periods. Attention should also be paid to thepossible existence of simultaneous hypomagnesaemia.
4.6 Fertility, pregnancy and lactation
There are no adequate data from the use of ibandronic acid in pregnant women. Studies in rats haveshown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Therefore,ibandronic acid should not be used during pregnancy.
Breast-feedingIt 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 should not be used during lactation.
FertilityThere are no data on the effects of ibandronic acid in 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).
4.7 Effects on ability to drive and use machines
On the basis of the pharmacodynamic and pharmacokinetic profile and reported adverse reactions, it isexpected that ibandronic acid has no or negligible influence on the ability to drive and use machines.
4.8 Undesirable effects
The most serious reported adverse reactions are anaphylactic reaction/shock, atypical fractures of thefemur, osteonecrosis of the jaw, gastrointestinal irritation, and ocular inflammation (see paragraph“Description of selected adverse reactions” and section 4.4).Treatment was most frequently associatedwith a decrease in serum calcium to below normal range (hypocalcaemia), followed by dyspepsia.
Tabulated list of adverse reactionsTable 1 lists adverse reactions from 2 pivotal phase III studies (Prevention of skeletal events inpatients with breast cancer and bone metastases: 286 patients treated with Ibandronic acid Sandoz50 mg administered orally), and from post-marketing experience.
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 Drug Reactions Reported for Oral Administration of Ibandronic acid
System Organ Common Uncommon Rare Very rare Not known
Class
Blood and Anaemialymphaticsystemdisorders
Immune system Hypersensitivity†, Asthmadisorders bronchospasm†, exacerbationangioedema†,
Anaphylacticreaction/shock†**
Metabolism and Hypocalcaemia**nutritiondisorders
System Organ Common Uncommon Rare Very rare Not known
Class
Nervous system Paraesthesia,disorders dysgeusia(tasteperversion)
Eye disorders Ocularinflammation†**
Gastrointestinal Oesophagitis, Haemorrhage,disorders abdominal pain, duodenaldyspepsia, nausea ulcer, gastritis,dysphagia, drymouth
Skin and Pruritus Stevens-Johnsonsubcutaneous Syndrome†,tissue disorders Erythema
Multiforme†,
Dermatitis
Bullous†
Musculoskeletal Atypical Osteonecrosis ofand connective subtrochanteric jaw†**,tissue disorders and diaphyseal osteonecrosis offemoral the externalfractures† auditory canal(bisphosphonateclass adversereaction) †
Renal and Azotaemiaurinary (uraemia)disorders
General Asthenia Chest pain,disorders and influenza-likeadministration illness,site conditions malaise, pain
Investigations Bloodparathyroidhormoneincreased
**See further information below†Identified in post-marketing experience.
Description of selected adverse reactionsHypocalcaemia
Decreased renal calcium excretion may be accompanied by a fall in serum phosphate levels notrequiring therapeutic measures. The serum calcium level may fall to hypocalcaemic values.
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.
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 of suspected adverse reactionsReporting 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.
4.9 Overdose
No specific information is available on the treatment of overdosage with ibandronic acid. However,oral overdosage may result in upper gastrointestinal events, such as upset stomach, heartburn,oesophagitis, gastritis or ulcer. Milk or antacids should be given to bind ibandronic acid. Due to therisk of oesophageal irritation, vomiting should not be induced and the patient should remain fullyupright.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Medicinal products for treatment of bone diseases, Bisphosphonates,
ATC Code: M05BA06.
Ibandronic acid belongs to the bisphosphonate group of compounds which act specifically on bone.
Their selective action on bone tissue is based on the high affinity of bisphosphonates for bone mineral.
Bisphosphonates act by inhibiting osteoclast activity, although the precise mechanism is still not clear.
In vivo, ibandronic acid prevents experimentally-induced bone destruction caused by cessation ofgonadal function, retinoids, tumours or tumour extracts. The inhibition of endogenous bone resorptionhas also been documented by 45Ca kinetic studies and by the release of radioactive tetracyclinepreviously incorporated into the skeleton.
At doses that were considerably higher than the pharmacologically effective doses, ibandronic acid didnot have any effect on bone mineralisation.
Bone resorption due to malignant disease is characterized by excessive bone resorption that is notbalanced with appropriate bone formation. Ibandronic acid selectively inhibits osteoclast activity,reducing bone resorption and thereby reducing skeletal complications of the malignant disease.
Clinical studies in patients with breast cancer and bone metastases have shown that there is a dosedependent inhibitory effect on bone osteolysis, expressed by markers of bone resorption, and a dosedependent effect on skeletal events.
Prevention of skeletal events in patients with breast cancer and bone metastases with ibandronic acid50 mg tablets was assessed in two randomized placebo controlled phase III trials with a duration of 96weeks. Female patients with breast cancer and radiologically confirmed bone metastases wererandomised to receive placebo (277 patients) or 50 mg ibandronic acid (287 patients). The results fromthese trials are summarised below.
Primary Efficacy Endpoints
The primary endpoint of the trials was the skeletal morbidity period rate (SMPR). This was acomposite endpoint which had the following skeletal related events (SREs) as sub-components:
- radiotherapy to bone for treatment of fractures/impending fractures
- surgery to bone for treatment of fractures
- vertebral fractures
- non-vertebral fractures
The analysis of the SMPR was time-adjusted and considered that one or more events occurring in asingle 12 week period could be potentially related. Multiple events were therefore, counted only oncein any given 12 week period for the purposes of the analysis. Pooled data from these studiesdemonstrated a significant advantage for ibandronic acid 50 mg p.o. over placebo in the reduction in
SREs measured by the SMPR (p=0.041). There was also a 38% reduction in the risk of developing an
SRE for ibandronic acid treated patients when compared with placebo (relative risk 0.62, p=0.003).
Efficacy results are summarised in Table 2.
Table 2 Efficacy Results (Breast Cancer Patients with Metastatic Bone Disease)
All Skeletal Related Events (SREs)
Placebo Ibandronic acid p-valuen=277 50 mgn=287
SMPR (per patient year) 1.15 0.99 p=0.041
SRE relative risk - 0.62 p=0.003
Secondary Efficacy Endpoints
A statistically significant improvement in bone pain score was shown for ibandronic acid 50 mgcompared to placebo. The pain reduction was consistently below baseline throughout the entire studyand accompanied by a significantly reduced use of analgesics compared to placebo. The deteriorationin Quality of Life and WHO performance status was significantly less in ibandronic acid treatedpatients compared with placebo. Urinary concentrations of the bone resorption marker CTx (C-terminal telopeptide released from Type I collagen) were significantly reduced in the ibandronic acidgroup compared to placebo. This reduction in urinary CTx levels was significantly correlated with theprimary efficacy endpoint SMPR (Kendall-tau-b (p<0.001)). A tabular summary of the secondaryefficacy results is presented in Table 3.
Table 3 Secondary Efficacy Results (Breast Cancer Patients with Metastatic Bone Disease)
Placebo Ibandronic acid p-valuen=277 50 mgn=287
Bone pain * 0.20 -0.10 p=0.001
Analgesic use * 0.85 0.60 p=0.019
Quality of Life * -26.8 -8.3 p=0.032
WHO performance score * 0.54 0.33 p=0.008
Urinary CTx ** 10.95 -77.32 p=0.001
* Mean change from baseline to last assessment.
** Median change from baseline to last assessment
Paediatric population (see section 4.2 and section 5.2)
The safety and efficacy of ibandronic acid in children and adolescents below the age of 18 years havenot been established. No data are available.
5.2 Pharmacokinetic properties
The absorption of ibandronic acid in the upper gastrointestinal tract is rapid after oral administration.
Maximum observed plasma concentrations were reached within 0.5 to 2 hours (median 1 hour) in thefasted state and absolute bioavailability was about 0.6%. The extent of absorption is impaired whentaken together with food or beverages (other than water). Bioavailability is reduced by about 90%when ibandronic acid is administered with a standard breakfast in comparison with bioavailabilityseen in fasted subjects. When taken 30 minutes before a meal, the reduction in bioavailability isapproximately 30%. There is no meaningful reduction in bioavailability provided ibandronic acid istaken 60 minutes before a meal.
Bioavailability was reduced by approximately 75% when ibandronic acid tablets were administered 2hours after a standard meal. Therefore, it is recommended that the tablets should be taken after anovernight fast (minimum 6 hours) and fasting should continue for at least 30 minutes after the dose hasbeen taken (see section 4.2).
DistributionAfter 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 87% at therapeutic concentrations, and thus interaction with other medicinal productsdue to displacement is unlikely.
BiotransformationThere is no evidence that ibandronic acid is metabolized in animals or humans.
EliminationThe absorbed fraction of ibandronic acid is removed from the circulation via bone absorption(estimated to be 40-50%) and the remainder is eliminated unchanged by the kidney. The unabsorbedfraction of ibandronic acid is eliminated unchanged in the faeces.
The range of observed apparent half-lives is broad and dependent on dose and assay sensitivity, butthe apparent terminal half-life is generally in the range of 10-60 hours. However, early plasma levelsfall quickly, reaching 10% of peak values within 3 and 8 hours after intravenous or oral administrationrespectively.
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 of renal elimination does not appear to include known acidic or basic transportsystems involved in the excretion of other active substances In addition, ibandronic acid does notinhibit the major human hepatic P450 isoenzymes and does not induce the hepatic cytochrome P450system in rats.
Pharmacokinetics in special populationsGender
Bioavailability and pharmacokinetics of ibandronic acid are similar in both men and women.
RaceThere is no evidence for clinically relevant interethnic differences between Asians and Caucasians inibandronic acid disposition. There are only very few data available on patients with African origin.
Renal impairmentExposure to ibandronic acid in patients with various degree of renal impairment is related to creatinineclearance (CLcr). Subjects with severe renal impairment (CLcr 30 mL/min) receiving oraladministration of 10 mg ibandronic acid daily for 21 days, had 2-3 fold higher plasma concentrationsthan subjects with normal renal function (CLcr ≥80 mL/min). Total clearance of ibandronic acid wasreduced to 44 ml/min in the subjects with severe renal impairment compared with 129 mL/min insubjects with normal renal function. No dosage adjustment is necessary for patients with mild renalimpairment (CLcr ≥50 and <80 mL/min). For patients with moderate renal impairment (CLcr ≥30 and<50 mL/min) or severe renal impairment (CLcr <30 mL/min) an adjustment in the dose isrecommended (see section 4.2).
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 since it is not metabolized but iscleared by renal excretion and by uptake into bone. Therefore dosage adjustment is not necessary inpatients with hepatic impairment. Further, as protein binding of ibandronic acid is approximately 87%at therapeutic concentrations, hypoproteinaemia in severe liver disease is unlikely to lead to clinicallysignificant increases in free plasma concentration.
Elderly (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 Sandoz in patients less than 18 years old.
5.3 Preclinical safety data
Effects in non-clinical studies were observed only at exposures sufficiently in excess of the maximumhuman exposure indicating little relevance to clinical use. As with other bisphosphonates, the kidneywas identified to be the primary target organ of systemic toxicity.
Mutagenicity/Carcinogenicity:
No indication of carcinogenic potential was observed. Tests for genotoxicity revealed no evidence ofgenetic activity for ibandronic acid.
Reproductive toxicity:No evidence of direct foetal toxicity or teratogenic effects was observed for ibandronic acid inintravenously or orally treated rats and rabbits. In reproductive studies in rats by the oral route effects onfertility consisted of increased preimplantation losses at dose levels of 1 mg/kg/day and higher. Inreproductive studies in rats by the intravenous route, ibandronic acid decreased sperm counts at doses of0.3 and 1 mg/kg/day and decreased fertility in males at 1 mg/kg/day and in females at 1.2 mg/kg/day.
Adverse effects of ibandronic acid in reproductive toxicity studies in the rat were those expected for thisclass of medicinal products (bisphosphonates). They include a decreased number of implantation sites,interference with natural delivery (dystocia), an increase in visceral variations (renal pelvis uretersyndrome) and teeth abnormalities in F1 offspring in rats.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Povidone
Cellulose, microcrystalline
Crospovidone
Maize starch pregelatinised
Glycerol dibehenate
Silica, anhydrous colloidal
Tablet coat:Lactose monohydrate
Macrogol 4000
Hypromellose
Titanium dioxide
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
6.4 Special precautions for storage
Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
Ibandronic acid Sandoz 50 mg film-coated tablets are supplied in Polyamide/Al/PVC - Aluminium foilblister with 3, 6, 9, 28 or 84 tablets, packaged in a cardboard box.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
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.
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu/