Ibandronic Acid

Ibandronic acid is a bisphosphonate, a compound that acts specifically on bone because of its high affinity for bone mineral. By inhibiting osteoclast activity it reduces the excessive bone resorption of malignant disease, which is not balanced by new bone formation, and so lowers skeletal complications and, in hypercalcaemia of malignancy, serum calcium.

Mechanism of Action

• Bone targeting: after entering the circulation, ibandronic acid binds rapidly to bone or is excreted in the urine.
• Osteoclast inhibition: bisphosphonates inhibit osteoclast activity, although the SmPC notes that the precise mechanism is not clear. In animals, ibandronic acid prevented bone destruction caused by loss of gonadal function, retinoids, tumours or tumour extracts.
• Osteoclast uptake and mevalonate pathway: bisphosphonates are released from bone during resorption and taken up by osteoclasts, where they disrupt the ring structures (podosomes) that attach the cell to bone, so it detaches. Nitrogen-containing bisphosphonates such as ibandronic acid also inhibit enzymes of the mevalonate pathway (farnesyl diphosphate synthase), which blocks prenylation of small GTP-binding proteins such as Rap1 and can lead to apoptosis.
• Hypercalcaemia of malignancy: the inhibition of tumour-induced bone breakdown shows as a fall in serum calcium and in urinary calcium excretion.
• Bone mineralisation: at doses far above the effective ones, ibandronic acid had no effect on mineralisation.

Pharmacokinetics

• Intravenous dosing: after a 2-hour infusion of 2, 4 and 6 mg, pharmacokinetic parameters are dose proportional.
• Absorption (oral): very low, with a bioavailability of about 0.6%, and reduced further by food and by calcium and other multivalent cations, hence the strict fasting rules.
• Distribution: rapidly binds to bone or is excreted into urine. The apparent terminal volume of distribution is at least 90 L, and an estimated 40–50% of the circulating dose reaches bone. Plasma protein binding is about 87% at therapeutic concentrations, so displacement interactions are unlikely.
• Metabolism: there is no evidence that ibandronic acid is metabolised in animals or humans. It does not inhibit the major human hepatic cytochrome P450 enzymes.
• Elimination: the apparent terminal half-life is generally 10–60 hours, depending on dose and assay. Early plasma levels fall quickly, to 10% of peak within 3 hours (intravenous) or 8 hours (oral). Total clearance is low (84–160 mL/min); renal clearance, about 60 mL/min in healthy postmenopausal women, accounts for 50–60% of it and follows creatinine clearance. There was no systemic accumulation with intravenous dosing every 4 weeks for 48 weeks.
• Special populations: pharmacokinetics are similar in men and women, and no clinically relevant differences between Asians and Caucasians were found. In severe renal impairment (mean creatinine clearance 21.2 mL/min) the dose-adjusted AUC rose by 110% compared with healthy volunteers.

Bondronat concentrate for solution for infusion (2 mg and 6 mg vials), in adults:

• Prevention of skeletal events (pathological fractures, bone complications requiring radiotherapy or surgery) in patients with breast cancer and bone metastases.
• Treatment of tumour-induced hypercalcaemia, with or without metastases.

Bondronat 50 mg film-coated tablets, in adults:

• Prevention of skeletal events (pathological fractures, bone complications requiring radiotherapy or surgery) in patients with breast cancer and bone metastases.

Osteoporosis: Bonviva 150 mg film-coated tablets and nationally authorised 150 mg generics

• Treatment of osteoporosis in postmenopausal women at increased risk of fracture. A reduction in the risk of vertebral fractures has been demonstrated; efficacy on femoral neck fractures has not been established.

Bondronat concentrate for solution for infusion

• Hypersensitivity to ibandronic acid or to any excipient.
• Hypocalcaemia.

Tablets (Bondronat 50 mg, Bonviva and 150 mg generics)

• Hypersensitivity to ibandronic acid or to any excipient.
• Hypocalcaemia.
• Abnormalities of the oesophagus that delay oesophageal emptying, such as stricture or achalasia.
• Inability to stand or sit upright for at least 60 minutes.

The most serious reactions are anaphylactic reaction/shock, atypical femoral fractures, osteonecrosis of the jaw and ocular inflammation. When the intravenous form is used for tumour-induced hypercalcaemia, a rise in body temperature is the most frequent effect and a fall in serum calcium below normal is less frequent; in prevention of skeletal events, asthenia is most frequent, followed by a rise in body temperature and headache.

Common (≥1/100 to <1/10): infection; parathyroid disorder; hypocalcaemia; headache, dizziness and taste disturbance; cataract; bundle branch block; pharyngitis; diarrhoea, vomiting, dyspepsia, gastrointestinal pain and tooth disorder; skin disorder and ecchymosis; osteoarthritis, myalgia, arthralgia, joint disorder and bone pain; pyrexia, influenza-like illness, peripheral oedema, asthenia and thirst; raised gamma-GT and creatinine.

Uncommon (≥1/1,000 to <1/100): cystitis, vaginitis and oral candidiasis; benign skin neoplasm; anaemia and blood dyscrasia; hypophosphataemia; sleep disorder, anxiety and affect lability; cerebrovascular disorder, nerve root lesion, amnesia, migraine, neuralgia, hypertonia, hyperaesthesia, circumoral paraesthesia and parosmia; deafness; myocardial ischaemia, cardiovascular disorder and palpitations; lung oedema and stridor; gastroenteritis, gastritis, mouth ulceration, dysphagia and cheilitis; cholelithiasis; rash and alopecia; urinary retention and renal cyst; pelvic pain; hypothermia; raised alkaline phosphatase and weight loss; injury and injection site pain.

Rare (≥1/10,000 to <1/1,000): ocular inflammation (uveitis, episcleritis, scleritis); atypical subtrochanteric and diaphyseal femoral fractures.

Very rare (<1/10,000): hypersensitivity, bronchospasm, angioedema and anaphylactic reaction/shock; Stevens-Johnson syndrome, erythema multiforme and bullous dermatitis; osteonecrosis of the jaw and of the external auditory canal.

Not known: asthma exacerbation; atypical fractures of long bones other than the femur.

Anaphylactic reactions, including fatal events, have been reported with intravenous use. Flu-like symptoms (fever, chills, bone and muscle pain) usually settled within hours or days without treatment. In some patients ocular inflammation did not resolve until ibandronic acid was stopped.

Oral osteoporosis tablets: with Bonviva the most frequent reactions are arthralgia and influenza-like symptoms, typically with the first dose, short-lived and mild to moderate; the serious ones are as above plus gastrointestinal irritation. The Spanish SmPC of the 150 mg tablets lists as common headache, oesophagitis, gastritis, reflux, dyspepsia, diarrhoea, abdominal pain, nausea, rash, arthralgia, myalgia, musculoskeletal pain, muscle cramps and stiffness, and influenza-like illness; as uncommon dizziness, oesophagitis with ulcers or strictures, dysphagia, vomiting, flatulence, back pain, fatigue and hypocalcaemia; and as rare hypersensitivity reactions, duodenitis, angioedema, facial oedema and urticaria. The 50 mg tablet has its own table in the Bondronat SmPC.

• Aminoglycosides: caution, because both can lower serum calcium for prolonged periods. Attention should also be paid to possible simultaneous hypomagnesaemia.
• Metabolic interactions are considered unlikely: ibandronic acid does not inhibit or induce the main hepatic cytochrome P450 enzymes, is eliminated by renal excretion only and does not undergo biotransformation.
• Food, calcium and other cations (tablets): food lowers oral bioavailability, and calcium-containing products, including milk, and other multivalent cations (aluminium, magnesium, iron) interfere with absorption. Calcium supplements, antacids and other oral medicines containing such cations are likely to interfere, so no other oral medicine is taken from at least 6 hours before to 1 hour after the 150 mg tablet. Only plain water is taken with the tablet.
• Non-steroidal anti-inflammatory medicines (tablets): caution, because both they and oral bisphosphonates irritate the gastrointestinal tract.

Bondronat treatment is started only by physicians experienced in the treatment of cancer. Patients are given the package leaflet and the patient reminder card.

Bondronat Concentrate for Infusion

• Prevention of skeletal events (breast cancer with bone metastases): 6 mg intravenously every 3–4 weeks, added to 100 mL isotonic sodium chloride or 100 mL 5% dextrose and infused over at least 15 minutes. The 15-minute infusion is for normal renal function or mild renal impairment only; there are no data for creatinine clearance below 50 mL/min.
• Tumour-induced hypercalcaemia: rehydrate first with 0.9% sodium chloride. The dose depends on severity and tumour type: in most patients with severe hypercalcaemia 4 mg is an adequate single dose, and in moderate hypercalcaemia (albumin-corrected serum calcium below 3 mmol/L) 2 mg is effective. 6 mg added no further benefit. Patients with osteolytic bone metastases generally need lower doses than those with humoral hypercalcaemia. The dose is added to 500 mL isotonic sodium chloride or 5% dextrose and infused over 2 hours. Serum calcium usually returns to normal within 7 days; the median time to relapse was 18–19 days with 2 mg and 4 mg and 26 days with 6 mg. Repeat treatment may be considered for recurrent hypercalcaemia or insufficient efficacy.
• Method: intravenous only, single use, clear solution without particles. Avoid intra-arterial or paravenous administration, which could damage tissue.

Renal Impairment (Skeletal Events, Intravenous)

• Creatinine clearance 50 to below 80 mL/min: 6 mg in 100 mL over 15 minutes (no adjustment).
• Creatinine clearance 30 to below 50 mL/min: 4 mg in 500 mL over 1 hour.
• Creatinine clearance below 30 mL/min: 2 mg in 500 mL over 1 hour.
• Each is given every 3–4 weeks in 0.9% sodium chloride or 5% glucose. A 15-minute infusion has not been studied in cancer patients with creatinine clearance below 50 mL/min. Hepatic impairment (section 4.4 notes that there are no clinical data in severe hepatic insufficiency) and age over 65 years need no adjustment. Safety and efficacy below 18 years have not been established.

Bondronat 50 mg Tablets

• Dose: one 50 mg tablet daily. In moderate renal impairment (creatinine clearance 30 to below 50 mL/min) one tablet every second day; in severe impairment (below 30 mL/min) one tablet once weekly; no adjustment in mild impairment, hepatic impairment or the elderly.
• How to take: after an overnight fast of at least 6 hours and before the first food or drink of the day; avoid other medicines and supplements (including calcium) beforehand and keep fasting for at least 30 minutes afterwards. Swallow whole with a full glass (180–240 mL) of plain water, sitting or standing upright, and do not lie down for 60 minutes. Do not chew, suck or crush the tablet, because of the risk of oropharyngeal ulceration. Avoid water with a high calcium content.

Bonviva 150 mg Tablets (Osteoporosis)

• Dose: one 150 mg tablet once a month, preferably on the same date, after an overnight fast of at least 6 hours and 1 hour before the first food or drink (other than water) or any other oral medicine or supplement, including calcium.
• Missed dose: take one tablet the morning after remembering, unless the next dose is due within 7 days; then wait for the next dose. Never take two tablets in the same week.
• Other points: swallow whole with 180–240 mL of water, upright, and do not lie down for 1 hour. Give calcium and/or vitamin D if dietary intake is inadequate, and reassess the need for treatment periodically, particularly after 5 or more years. Not recommended below a creatinine clearance of 30 mL/min; no adjustment otherwise, in hepatic impairment or in the elderly. There is no relevant use in children below 18 years.

Hypocalcaemia and Mineral Metabolism

Hypocalcaemia and other disturbances of bone and mineral metabolism must be treated effectively before starting therapy for metastatic bone disease. Adequate calcium and vitamin D intake is important for all patients, with supplements if the diet is inadequate. Renal function, serum calcium, phosphate and magnesium should be monitored as clinically appropriate.

Anaphylactic Reactions

Anaphylactic reaction/shock, including fatal events, has been reported with intravenous ibandronic acid. Medical support and monitoring should be readily available during intravenous administration; if an anaphylactic or other severe allergic reaction occurs, stop the injection immediately and start treatment. Use caution in patients with known hypersensitivity to other bisphosphonates.

Osteonecrosis of the Jaw

Osteonecrosis of the jaw has been reported very rarely after marketing in patients receiving Bondronat for oncology indications.

• Delay starting treatment, or a new course, in patients with unhealed open soft tissue lesions in the mouth.
• A dental examination with preventive dentistry and an individual benefit-risk assessment are recommended before treatment in patients with risk factors: potent, parenteral and high cumulative-dose bone resorption therapy; cancer, anaemia, coagulopathy, infection or smoking; corticosteroids, chemotherapy, angiogenesis inhibitors or head and neck radiotherapy; poor oral hygiene, periodontal disease, ill-fitting dentures, dental disease or invasive dental procedures.
• Patients should keep good oral hygiene, attend routine dental check-ups and report oral symptoms such as loose teeth, pain, swelling, non-healing sores or discharge. Invasive dental procedures during treatment need careful consideration and should be avoided close to an administration.
• If it develops, a dentist or oral surgeon experienced in the condition should help plan management, and a temporary interruption of treatment should be considered.

Osteonecrosis of the External Auditory Canal and Atypical Fractures

• Osteonecrosis of the external auditory canal has been reported with bisphosphonates, mainly after long-term therapy; steroid use, chemotherapy, infection and trauma are possible risk factors. Consider it in patients with ear symptoms, including chronic ear infections.
• Atypical subtrochanteric and diaphyseal femoral fractures occur after minimal or no trauma, mostly in long-term osteoporosis treatment, and are often bilateral; thigh or groin pain may precede them by weeks to months. Patients should report thigh, hip or groin pain; evaluate for an incomplete femoral fracture, examine the other femur and consider stopping the bisphosphonate pending assessment. Atypical fractures of other long bones, such as the ulna and tibia, have also been reported.

Kidney, Liver and Heart

• Clinical studies showed no deterioration in renal function with long-term Bondronat; monitor renal function, calcium, phosphate and magnesium as clinically indicated.
• No dose recommendations can be given in severe hepatic insufficiency, for lack of clinical data.
• Avoid overhydration in patients at risk of cardiac failure.

Oral Tablets: Oesophagus and Stomach

Oral bisphosphonates can irritate the upper gastrointestinal mucosa, so the 150 mg tablets are used with caution in active upper gastrointestinal disease (for example Barrett’s oesophagus, dysphagia, other oesophageal disease, gastritis, duodenitis or ulcers). Oesophagitis, oesophageal ulcers and erosions have been reported, sometimes severe enough to need hospital care; the risk appears higher when dosing instructions are not followed or treatment continues after symptoms appear. Patients should stop the tablets and seek medical advice if they develop difficulty or pain on swallowing, retrosternal pain, or new or worsening heartburn. Gastric and duodenal ulcers have also been reported.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: there are no adequate data in pregnant women and animal studies showed reproductive toxicity, so Bondronat should not be used during pregnancy.
• Breastfeeding: it is not known whether ibandronic acid enters human milk (low levels were found in lactating rats), so Bondronat should not be used during breastfeeding.
• Fertility: there are no human data; fertility was reduced in rats, orally and at high intravenous daily doses.

Excipients and Driving

The 50 mg tablet contains lactose (88.1 mg); the concentrate is essentially sodium free. Bondronat is expected to have no or negligible influence on the ability to drive and use machines.

• Concentrate for infusion: no special storage conditions before dilution. After dilution, store at 2–8 °C and use immediately; if not used immediately, in-use times and conditions are the user’s responsibility and would normally not exceed 24 hours at 2–8 °C, unless dilution was done under controlled and validated aseptic conditions. Supplied as one 2 mL type I glass vial with a bromobutyl rubber stopper per pack.
• Tablets: Bondronat 50 mg tablets are stored in the original package to protect from moisture; Bonviva and the 150 mg generics need no special storage conditions.
• No cold chain is needed for the unopened products.

5 years for the concentrate and the tablets. After dilution, 24 hours at 2–8 °C.

Prescription only (Rx). Bondronat is started by physicians experienced in the treatment of cancer. The concentrate is given by intravenous infusion with medical support available, so it is supplied to the hospital or clinic that administers it. The tablets (Bondronat 50 mg; Bonviva and the 150 mg generics) are taken at home and supplied to the patient or the treating clinic on prescription.