Ibandronic Acid Mylan 150mg Film-coated Tablets

4.4 Special warnings and precautions for use

Osteonecrosis of the jaw
Osteonecrosis of the jaw (ONJ, generally associated with tooth extraction and/or local infection (including osteomyelitis) has been reported very rarely in the post marketing setting in patients with cancer receiving ibandronic acid for osteoporosis (see section 4.8)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.

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

A dental examination with appropriate preventive dentistry and an individual benefit-risk assessment is recommended should be considered prior to treatment with Ibandronic Acid Mylan bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, radiotherapy, corticosteroids, poor oral hygiene).

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 potent compounds), route of administration (higher risk for parenteral administration) and cumulative dose of bone resorption therapy
• Cancer, co-morbid conditions (e.g. anaemia, coagulopathies, infection), smoking
• Concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy to head 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 of sores or discharge during treatment with Ibandronic Acid Mylan. While on treatment, invasive dental procedures should be performed only after careful consideration and be avoided in close proximity to Ibandronic Acid Mylan administration.

The management plan of the patients who develop ONJ should be set up in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ. Temporary interruption of Ibandronic Acid Mylan treatment should be considered until the condition resolves and contributing risk factors are mitigated where possible.

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 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.

4.8 Undesirable effects

4.8 Undesirable effects

Osteonecrosis of jaw
Cases of Osteonecrosis osteonecrosis of the jaw has been reported, predominantly in cancer patients treated with medicinal products that inhibit bone resorption, such as ibandronic acid by bisphosphonates. The majority of the reports refer to cancer patients, but such cases have also been reported in patients treated for osteoporosis. Osteonecrosis of the jaw is generally associated with tooth extraction and / or local infection (including osteomyelitis). Diagnosis of cancer, chemotherapy, radiotherapy, corticosteroids and poor oral hygiene are also deemed as risk factors (see section 4.4). Cases of ONJ have been reported in the post marketing setting for ibandronic acid.

Ocular inflammation

1. NAME OF THE MEDICINAL PRODUCT

Ibandronic Acid Mylan 150mg Film-coated TabletTablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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

Excipients with known effect:
Contains 171.78 mg lactose monohydrate.
For the full list of excipients, see section 6.1.

4.2 Posology and method of administration

Posology

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

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

In case a dose is missed, patients should be instructed to take one Ibandronic Acid Mylan 150 mg tablet the 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 the next scheduled dose is within 7 days, patients should wait until their next dose and then continue taking one tablet once a month as originally scheduled.

Patients should not take two tablets within the same week.

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

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

Special populations
Patients with renal impairment
Ibandronic Acid Mylan acid is not recommended for patients with a creatinine clearance below 30 ml/min due to limited clinical experience (see section 4.4 and section 5.2).

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

Paediatric population
There is no relevant use of Ibandronic Acid Mylan in children below 18 years, and Ibandronic Acid Mylan ibandronic acid was not studied in this population (see section 5.1 and section 5.2).

4.4 Special warnings and precautions for use

Hypocalcaemia
Existing hypocalcaemia must be corrected before starting Ibandronic Acid Mylanibandronic acid therapy. Other disturbances of bone and mineral metabolism should also be effectively treated. Adequate intake of calcium 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 ibandronic acid is given to patients with active upper gastrointestinal 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 cases severe and requiring hospitalisation, rarely with bleeding or followed by oesophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates. The risk of severe oesophageal adverse experiences appears to be greater in patients who do not comply with the dosing instruction and/or who continue to take oral bisphosphonates after developing symptoms suggestive of oesophageal irritation. Patients should pay particular attention to and be able to comply with the dosing instructions (see section 4.2).

Osteonecrosis of the external auditory canal
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.

Galactose intolerance
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

4.5 Interaction with other medicinal products and other forms of interaction

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 Mylan ibandronic acid, which is consistent with findings in animal studies. Therefore, patients should fast overnight (at least 6 hours) before taking ibandronic acid Ibandronic Acid Mylan and continue fasting for 1 hour following intake of ibandronic acid Ibandronic Acid Mylan (see section 4.2).

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

Calcium supplements, antacids and some oral medicinal products containing multivalent cations (such as aluminium, magnesium, iron) are likely to interfere with the absorption of ibandronic acid Ibandronic Acid Mylan. Therefore, patients should not take other oral medicinal products for at least 6 hours before taking Ibandronic Acid Mylan and for 1 hour following intake of ibandronic acid Ibandronic Acid Mylan.

Acetylsalicylic acid and NSAIDs
In a two-year study in postmenopausal women with osteoporosis (BM 16549), the incidence of upper gastrointestinal events in patients concomitantly taking acetylsalicylic acid or NSAIDs was similar in patients taking ibandronic acid 2.5 mg daily or 150 mg once monthly after one and two years.
Since Acetylsalicylic acid, Nonsteroidal Anti-Inflammatory medicinal products (NSAIDs) and bisphosphonates are associated with gastrointestinal irritation, caution should be taken during concomitant administration (see section 4.4).

4.6 Fertility, pregnancy and lactation

Pregnancy
Ibandronic Acid Mylan is only for use in postmenopausal women and must not be taken by women of childbearing potential.

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

Ibandronic Acid Mylan should not be used during pregnancy.

4.7 Effects on ability to drive and use machines

On the basis of the pharmacodynamic and pharmacokinetic profile and reported adverse reactions, it is expected that Ibandronic ibandronic acid has no or negligible influence on the ability to drive and use machines.


4.8 Undesirable effects

Summary of the safety profile

The most serious reported adverse reactions are anaphylactic reaction/shock, atypical fractures of the femur, osteonecrosis of the jaw, gastrointestinal irritation, and ocular inflammation, (see paragraph “Description of selected adverse reactions” and section 4.4). The safety profile of Ibandronic acid is derived from controlled clinical trials and post-marketing experience.

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

Tabulated list of adverse reactions
In table 1 an overview a complete list of known adverse reactions is presented. The safety of oral treatment with ibandronic acid 2.5 mg daily was evaluated in 1251 patients treated in 4 placebo-controlled clinical studies, with the large majority of patients coming from the pivotal three-year fracture study (MF 4411).

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


Table 1: Adverse reactions occurring in postmenopausal women receiving Ibandronic acid 150 mg once monthly or ibandronic acid 2.5 mg daily in the phase III studies BM16549 and MF4411 and in 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 frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1: Adverse reactions occurring in postmenopausal women receiving ibandronic acid 150 mg once monthly or ibandronic acid 2.5 mg daily in the phase III studies BM16549 and MF4411 and in post-marketing experience.

System Organ Class	Common			Uncommon		Rare			Very rare
Immune system disorders		Asthma exacerbation			Hypersensitivity reaction			Anaphylactic reaction/shock* †
Nervous system disorders			Headache				Dizziness
Eye disorders					Ocular inflammation*†
Gastrointestinal disorders*		Oesophagitis, Gastritis, Gastro oesophageal reflux disease, Dyspepsia, Diarrhoea, Abdominal pain, Nausea			Oesophagitis including oesophageal ulcerations or strictures and dysphagia, Vomiting, Flatulence			Duodenitis
Skin and subcutaneous tissues disorders		Rash			Angioedema, Face oedema, Urticaria			Stevens-Johnson Syndrome†, Erythema Multiforme†, Dermatitis Bullous†
Musculoskeletal and connective tissue disorders	Arthralgia, Myalgia, Musculoskeletal pain, Muscle cramp, Musculoskeletal stiffness			Back pain		Atypical subtrochanteric and diaphyseal femoral fractures†			Osteonecrosis of jaw*†, Oesteonecrosis of the external auditory canal (bisphosphate class adverse reaction).
General disorders and administration site conditions

*See further information below

†Identified in post-marketing experience.

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 preferably through the online reporting option accessible from the IMB homepage. A downloadable report form is also accessible from the IMB website, which may be completed manually and submitted to the IMB via ‘freepost’. Alternatively, the traditional post-paid ‘yellow card’ option may also continue to be used.
FREEPOST
Pharmacovigilance Section
Irish Medicines Board
Kevin O’Malley House
Earlsfort Centre
Earlsfort Terrace
Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.imb.ie
e-mail: imbpharmacovigilance@imb.ie
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 Ibandronic Acid Mylan ibandronic acid.

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

5.2 Pharmacokinetic properties

Patients with renal impairment
Renal clearance of ibandronic acid in patients with various degrees of renal impairment is linearly related to creatinine clearance.
No dose adjustment is necessary for patients with mild or moderate renal impairment (CLcr equal or greater than 30 ml/min), as shown in study BM 16549 where the majority of patients had mild to moderate renal impairment.
Subjects with severe renal failure (CLcr less than 30 ml/min) receiving daily oral administration of 10 mg ibandronic acid for 21 days, had 2-3 fold higher plasma concentrations than subjects with normal renal function and total clearance of ibandronic acid was 44 ml/min. After intravenous administration 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 associated with the increase in exposure. Due to the limited clinical experience, Ibandronic Acid Mylan ibandronic acid is not recommended in patients with severe renal impairment (see section 4.2 and section 4.4). The pharmacokinetics of ibandronic acid was not assessed in patients with end-stage renal disease managed by other than hemodialysis. The pharmacokinetics of ibandronic acid in these patients is unknown, and ibandronic acid should not be used under these circumstances.

Paediatric population (see section 4.2 and section 5.1)
There are no data on the use of Ibandronic Acid Mylan ibandronic acid in these age groups.

6.6 Special precautions for disposal and other handling

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

8. MARKETING AUTHORISATION NUMBER

PA0577/111/001

Section 6.3, the shelf-life has been changed from 2 years to 3 years.

Extensive updates to the SPC in line with the BL and QRD.

None provided