Boniva 150mg Tablets

BONIVA 150 mg is indicated for the treatment of osteoporosis in postmenopausal women, in order to reduce the risk of vertebral fractures.

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.
BONIVA 150 mg 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 product or supplementation (including calcium).
In case a dose is missed, patients should be instructed to take one BONIVA 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.
Special populations
Renal impairment
No dosage adjustment is necessary for patients with mild or moderate renal impairment where creatinine clearance is equal to or greater than 30 mL/min. BONIVA 150 mg is not recommended for patients with a creatinine clearance below 30 mL/min due to limited clinical experience. See section 4.4 and section 4.5.
Hepatic impairment
No dosage adjustment is required, see section 5.2.
Elderly
No dosage adjustment is required, see section 5.2.
Children and adolescents
BONIVA 150 mg has not been tested in these age groups and should not be given to them.
Method of administration
For oral use. Tablets should be swallowed whole with a glass of plain water (180 u2013 240 mL) while the patient is sitting or standing in an upright position. Patients should not lie down for 1 hour after taking BONIVA 150 mg. Plain water is the only drink that should be taken with BONIVA 150 mg. Please note that some mineral waters may have a higher concentration of calcium and therefore, should not be used. Patients should not chew or suck the tablet because of a potential for oropharyngeal ulceration.

• Hypersensitivity to ibandronic acid or to any of the excipient listed in section 6.1.
• Hypocalcaemia, see section 4.4.
• Severe renal impairment (creatinine clearance < 30 mL/min).
• Abnormalities of the oesophagus which delay oesophageal emptying such as stricture or achalasia.
• Inability to stand or sit upright for at least 60 minutes.

Hypocalcaemia
Existing hypocalcaemia must be corrected before starting BONIVA 150 mg therapy. Other disturbances of bone and mineral metabolism should also be effectively treated before starting BONIVA 150 mg therapy. All patients must receive adequate supplemental calcium and vitamin D.
Gastrointestinal irritation
Orally administered bisphosphonates have been associated with dysphagia, oesophagitis and oesophageal or gastric ulcers. Therefore patients, especially those with a history of prolonged oesophageal transit time, should pay particular attention to and be able to comply with the dosing instructions. See section 4.2. Physicians should be alert to signs or symptoms signalling a possible oesophageal reaction during therapy, and patients should be instructed to discontinue BONIVA 150 mg and seek medical attention if they develop symptoms of oesophageal irritation such as new or worsening dysphagia, pain on swallowing, retrosternal pain or heartburn. Since NSAIDs and bisphosphonates are both associated with gastrointestinal irritation, caution should be taken during concomitant administration.
Osteonecrosis of the jaw
Osteonecrosis of the jaw (ONJ) has been reported in patients treated with bisphosphonates including BONIVA 150 mg. Most cases have been in cancer patients undergoing dental procedures, but some have occurred in patients with postmenopausal osteoporosis or other diagnoses. Known risk factors for ONJ include a diagnosis of cancer, concomitant therapies (e.g., chemotherapy, radiotherapy, corticosteroids), and co-morbid disorders (e.g., anaemia, coagulopathy, infection, pre-existing dental disease). Most reported cases have been in patients treated with bisphosphonates intravenously but some have been in patients treated orally. For patients who develop ONJ 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 ONJ. 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
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 (see section 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 patients receiving 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 completed fracture. In cases of ulna fracture, this may be associated with repetitive stress loading associated with the long-term use of walking aids (see section 4.8).
Renal impairment
Due to limited clinical experience, BONIVA 150 mg is not recommended for patients with a creatinine clearance below 30 mL/min. See section 4.2, 4.3 and 5.2.

Food interactions
Oral bioavailability of BONIVA 150 mg is generally reduced in the presence of food. In particular, products containing calcium and other multivalent cations (such as aluminium, magnesium, iron), including milk, are likely to interfere with absorption of BONIVA 150 mg, which is consistent with findings in animal studies. Therefore, patients should fast overnight (at least 6 hours) before taking BONIVA 150 mg and continue fasting for 1 hour following intake of BONIVA 150 mg.
Medicine interactions
Metabolic interactions are not considered likely, since BONIVA 150 mg does not inhibit the major human hepatic P450 isoenzymes and has been shown not to induce the hepatic cytochrome P450 system in rats. Furthermore, plasma protein binding is approximately 85 u2013 87 % (determined in vitro at therapeutic medicine concentrations), and thus there is a low potential for medicine-medicine interaction due to displacement. BONIVA 150 mg is eliminated by renal excretion only and does not undergo any biotransformation. The secretory pathway appears not to include known acidic or basic transport systems involved in the excretion of other active substances.
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 BONIVA 150 mg. Therefore, patients should not take other oral medicinal products for at least 6 hours before taking BONIVA 150 mg and for 1 hour following intake of BONIVA 150 mg.
Tamoxifen or hormone replacement therapy (estrogen)
Pharmacokinetic interaction studies in postmenopausal women have demonstrated the absence of any interaction potential with tamoxifen or hormone replacement therapy (estrogen). No interaction was observed when co-administered with melphalan/prednisolone in patients with multiple myeloma.
H2-antagonists or proton pump inhibitors
In healthy male volunteers and postmenopausal women, intravenous administration of ranitidine caused an increase in BONIVA 150 mg bioavailability of about 20 %, probably as a result of reduced gastric acidity. However, since this increase is within the normal variability of the bioavailability of BONIVA 150 mg, no dosage adjustment is considered necessary when BONIVA 150 mg is administered with H2-antagonists or other active substances which increase gastric pH.
Acetylsalicylic acid and NSAIDs
Since NSAIDs and bisphosphonates are associated with gastrointestinal irritation, caution should be taken during concomitant administration (see section 4.4).

BONIVA 150 mg should not be used during pregnancy and lactation.
Pregnancy
There are no adequate data from the use of BONIVA 150 mg in pregnant women. Studies in rats have shown some reproductive toxicity. The potential risk for humans is unknown.
Breastfeeding
It is not known whether BONIVA 150 mg is excreted in human milk. Studies in lactating rats have demonstrated the presence of low levels of BONIVA 150 mg in the milk following intravenous administration.
Fertility
There are no data on the effects of ibandronic acid from humans. In reproductive studies in rats by the oral route, BONIVA 150 mg decreased fertility. In studies in rats using the intravenous route, BONIVA 150 mg decreased fertility at high daily doses (see section 5.3).

On the basis of the pharmacodynamic and pharmacokinetic profile and reported adverse reactions, it is expected that BONIVA 150 mg has no or negligible influence on the ability to drive and use machines.

a. Summary of the safety profile
The most serious reported adverse reactions are anaphylactic reaction/shock, atypical fractures of the femur, osteonecrosis for the jaw and ocular inflammation (see paragraph u201cDescription of selected adverse reactionsu201d and section 4.4). The most frequently reported adverse reactions are 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 u201cInfluenza like illnessu201d).
b. Tabulated list of adverse reactions
In table 1 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 (BM16549) the overall proportion of patients who experienced a side effect, i.e. adverse event with a possible or probable relationship to trial medication, was 22,7 % for BONIVA 150 mg once monthly. The majority of side effects were mild to moderate in intensity. Most cases did not lead to cessation of 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 (u2265 1/100 to < 1/10), uncommon (u2265 1/1,000 to < 1/100), rare (u2265 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.

No specific information is available on the treatment of over dosage with BONIVA 150 mg. However, based on the knowledge of this class of compounds, oral over-dosage 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 BONIVA 150 mg 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.