Ostivea

Ibandronic acid.

OSTIVEA 3 mg/3ml Solution for IV Injection is clear, colorless, sterile and ready-to-use solution for intravenous injection.
Each syringe contains active ingredients 3.375 mg Ibrandronate Sodium Monohydrate equivalence to 3 mg Ibandronic Acid.
Each 3 ml sterile pre-filled syringes with tip cap and closed with stopper contains 3 mg (1 mg/ml) of Ibandronic Acid as the active ingredients.
Excipients/Inactive Ingredients: Each syringe contains: Glacial Acetic Acid, Sodium Acetate Trihydrate, Sodium Chloride, Water for Injection.

Pharmacology: Pharmacodynamics: The pharmacodynamic action of ibandronic acid is inhibition of bone resorption. In vivo, ibandronic acid prevents experimentally induced bone destruction caused by cessation of gonadal function, retinoids, tumors or tumor extracts. In young (fast growing) rats, the endogenous bone resorption is also inhibited, leading to increased bone mass compared with untreated animals. The high potency and therapeutic margin of ibandronic acid allows for more flexible dosing regimens and intermittent treatment with long drug-free intervals at comparatively low doses. Both daily and intermittent (with prolonged dose-free intervals) long-term administration in rats, dogs and monkeys were associated with formation of new bone of normal quality and/or increased mechanical strength even in doses in excess of any pharmacologically intended dose, including the toxic range. In humans, the efficacy of both daily and intermittent administration with a dose-free interval of 9-10 weeks of ibandronic acid was confirmed, in which ibandronic acid demonstrated anti-fracture efficacy. Both daily and intermittent (with a drug-free interval of 9-10 weeks per quarter) oral doses as well as intravenous doses of (product name) in postmenopausal women produced biochemical changes indicative of dose-dependent inhibition of bone resorption. (product name) intravenous injection decreased levels of serum CTX within 3-7 days of starting treatment and decreased levels of osteocalcin within 3 months. Following treatment discontinuation, there is a reversion to the pathological pre-treatment rates of elevated bone resorption associated with postmenopausal osteoporosis. The histological analysis of bone biopsies after two and three years of treatment of postmenopausal women with doses of (product name) 2.5 mg daily and intermittent i.v. doses of up to 1 mg every 3 months showed bone of normal quality and no indication of a mineralisation defect.
Mechanism of Action: Ibandronic acid is a highly potent bisphosphonate belonging to the nitrogen-containing group of bisphosphonates, which act on bone tissue and specifically inhibit osteoclast activity. It does not interfere with osteoclast recruitment. The selective action of ibandronic acid on bone tissue is based on the high affinity of this compound for hydroxyapatite, which represents the mineral matrix of the bone. Ibandronic acid reduces bone resorption, with no direct effect on bone formation. In postmenopausal women, it reduces the elevated rate of bone turnover towards premenopausal levels, leading to a progressive net gain in bone mass. Daily or intermittent administration of ibandronic acid results in reduced bone resorption as reflected in reduced levels of serum and urinary biochemical markers of bone turnover, increased BMD and a decreased incidence of fractures.
Pharmacokinetics: The primary pharmacological effects of Ibandronic acid on bone are not directly related to actual plasma concentrations.
Plasma concentrations of Ibandronic acid increase in a dose-proportional manner after intravenous administration of 0.5 mg to 6 mg.
Absorption: Not applicable.
Distribution: After initial systemic exposure, Ibandronic acid rapidly binds to bone or is excreted into urine.
Biotransformation: There is no evidence that Ibandronic acid is metabolised in animals or humans.
Elimination: Ibandronic acid is removed from the circulation via bone and the remainder is eliminated unchanged by the kidney.
The range of observed apparent half-lives is broad, the apparent terminal half-life is generally in the range of 10-72 hours.
Total clearance of Ibandronic acid is low with average values in the range 84-160 ml/min. Renal clearance accounts for 50-60% of total clearance and is related to creatinine clearance. The difference between the apparent total and renal clearances is considered to reflect the uptake by bone.
The secretory pathway appears not to include known acidic or basic transport systems involved in the excretion of other active substances.
Pharmacokinetics in special clinical situations: Gender: Pharmacokinetics of ibandronic acid are similar in men and women.
Race: There is no evidence for any clinically relevant inter-ethnic differences between Asians and Caucasians in ibandronic acid disposition.
Patients with renal impairment: Renal clearance of ibandronic acid in patients with various degrees of renal impairment is linearly related to creatinine clearance (CLcr).
No dose adjustment is necessary for patients with mild or moderate renal impairment.
The pharmacokinetics of ibandronic acid in patients with end-stage renal disease was only assessed in a small number of patients managed by haemodialysis, therefore, the pharmacokinetics of ibandronic acid in the patients not undergoing haemodialysis is unknown.
Ibandronic acid is not recommended in patients with severe renal impairment after intravenous administration of 0.5 mg of ibandronic acid, total, renal, and non-renal clearances decreased by 67%, 77% and 50% respectively, in those with severe renal failure, but there was no reduction in tolerability associated with the increase in exposure.
Due to the limited data available, ibandronic acid should not be used in all patients with end-stage renal disease. The pharmacokinetics of ibandronic acid in patients with end-stage renal disease was only assessed in a small number of patients managed by haemodialysis, therefore, the pharmacokinetics of ibandronic acid in the patients not undergoing haemodialysis is unknown.
Patients with hepatic impairment: There are no pharmacokinetic data for ibandronic acid in patients who have hepatic impairment. The liver has no significant role in the clearance of ibandronic acid, which is not metabolised but is cleared by renal excretion and by uptake into bone. Therefore dose adjustment is not necessary in patients with hepatic impairment.
Elderly population: As renal function decreases with age, renal function is the only factor to take into consideration.
Paediatric population: There are no data on the use of ibandronic acid in patients less than 18 years old.

Therapeutic Indication(s): Ostivea 3 mg/3ml Solution for IV Injection in Pre-filled Syringe is indicated for the treatment of postmenopausal osteoporosis, to reduce the risk of fractures. Efficacy on femoral neck fractures has not been established.
Treatment of Osteoporosis: Osteoporosis may be confirmed by the finding of low bone mass (T score < -2.0 SD) and the presence or history of osteoporotic fracture, or a low bone mass (T-score < -2.5 SD) in the absence of documented pre-existing osteoporotic fracture.

Posology: The recommended dose of Ibandronic acid is 3 mg, administered as an intravenous injection over 15-30 seconds, every three months.
Patients must receive supplemental calcium and vitamin D (see Precautions and Interactions).
If a dose is missed, the injection should be administered as soon as convenient. Thereafter, injections should be scheduled every 3 months from the date of the last injection.
The optimal duration of bisphosphonate treatment for osteoporosis has not been established. The need for continued treatment should be reevaluated periodically based on the benefits and potential risks of Ostivea on an individual patient basis, particularly after 5 or more years of use.
Special populations: Patients with renal impairment: OSTIVEA injection is not recommended for use in patients who have a serum creatinine above 200 μmol/l (2.3 mg/dl) or who have a creatinine clearance (measured or estimated) below 30 ml/min, because of limited clinical data available from studies including such patients (see Precautions and Interactions).
No dose adjustment is necessary for patients with mild or moderate renal impairment where serum creatinine is equal or below 200 μmol/l (2.3 mg/dl) or where creatinine clearance (measured or estimated) is equal or greater than 30 ml/min.
Patients with hepatic impairment: No dose adjustment is required (see Pharmacology: Pharmacokinetics under Actions).
Elderly population (>65 years): No dose adjustment is required.
Paediatric population: There is no relevant use of Ostivea in children below 18 years, and Ostivea was not studied in this population.
Method of administration: For intravenous use over 15-30 seconds, every three months.
Strict adherence to the intravenous administration route is required (see Precautions).

No specific information is available on the treatment of overdosage with ibandronic acid.
Based on knowledge of this class of compounds, intravenous overdosage may result in hypocalcaemia, hypophosphataemia, and hypomagnesaemia. Clinically relevant reductions in serum levels of calcium, phosphorus, and magnesium should be corrected by intravenous administration of calcium gluconate, potassium or sodium phosphate, and magnesium sulfate, respectively.

Ibandronate sodium is contraindicated in patients with the following conditions: Hypocalcemia; Known hypersensitivity to Ostivea 3 mg/3 mL Solution for IV Injection or to any of its excipients.

Administration failures: Care must be taken not to administer Ostivea injection via intra-arterial or paravenous administration as this could lead to tissue damage.
Hypocalcemia: Ostivea, like other bisphosphonates administered intravenously, may cause a transient decrease in serum calcium values.
Existing hypocalcaemia must be corrected before starting Ostivea injection therapy. Other disturbances of bone and mineral metabolism should also be effectively treated before starting Ostivea injection therapy.
All patients must receive adequate supplemental calcium and vitamin D.
Anaphylactic reaction/shock: Cases of anaphylactic reaction/shock, including fatal events, have been reported in patients treated with intravenous ibandronic acid.
Appropriate medical support and monitoring measures should be readily available when Ostivea intravenous injection is administered. If anaphylactic or other severe hypersensitivity/allergic reactions occur, immediately discontinue the injection and initiate appropriate treatment.
Patients with cardiac impairment: Overhydration should be avoided in patients at risk of cardiac failure.
Osteonecrosis of the jaw: Osteonecrosis of the jaw (ONJ) has been reported very rarely in the post marketing setting in patients receiving Ostivea for osteoporosis.
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 preventive dentistry and an individual benefit-risk assessment is recommended prior to treatment with Ostivea 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 potent compounds), route of administration (higher risk for parenteral administration) and cumulative dose of bone resorption therapy.
Cancer, co-morbid conditions (e.g. anemia, 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 Ostivea. While on treatment, invasive dental procedures should be performed only after careful consideration and be avoided in close proximity to Ostivea 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 Ostivea treatment should be considered until the condition resolves and contributing risk factors are mitigated where possible.
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.
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 acid has no or negligible influence on the ability to drive and use machines.
Renal impairment: Patients with concomitant diseases, or who use medicinal products which have potential for undesirable effects on the kidney, should be reviewed regularly in line with good medical practice during treatment.
Due to limited clinical experience, Ostivea injection is not recommended for patients with a serum creatinine above 200 μmol/l (2.3 mg/dl) or with a creatinine clearance below 30 ml/min.

Pregnancy: Ibandronic acid is only for use in postmenopausal women and must not be taken by women of child bearing potential. There are no adequate data from the use of ibandronic acid in pregnant women. The potential risk for humans is unknown. Ibandronic acid should not be used during pregnancy.
Breastfeeding: It is not known whether ibandronic acid is excreted in human milk.
Ibandronic acid should not be used during breast-feeding.
Fertility: There are no data on the effects of ibandronic acid from humans.

Summary of the safety profile: The most serious reported adverse reactions are anaphylactic reaction/shock, atypical fractures of the femur, osteonecrosis of the jaw, ocular inflammation, (see Description of selected adverse reactions as follows & Precautions).
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 (see Influenza like-illness under Description of selected adverse reactions as follows).
Tabulated list of adverse reactions: In the table as follows a complete list of known adverse reactions is presented.
In postmenopausal women with osteoporosis, the overall safety of intravenous injection of ibandronic acid 3 mg every 3 months and oral ibandronic acid 2.5 mg daily were shown to be similar. The overall proportion of patients who experienced an adverse reaction was 26.0% and 28.6% for ibandronic acid 3 mg injection every 3 months after one year and two years, respectively. Most cases of adverse reactions 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, common, uncommon, rare, very rare, not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. (See table.)

Click on icon to see table/diagram/image

Description of selected adverse reactions: 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, and bone pain.
Osteonecrosis of the jaw: Cases of osteonecrosis of the jaw have been reported, predominantly in cancer patients treated with medicinal products that inhibit bone resorption, such as ibandronic acid (see Precautions). 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 with ibandronic 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 treated with intravenous ibandronic acid.

Metabolic interactions are not considered likely. Ibandronic acid is eliminated by renal excretion only and does not undergo any biotransformation.

Incompatibility: Ibandronic acid solution for injection must not be mixed with calcium-containing solutions or other intravenously administered medicinal products.
Instruction for Use: This injection is for single use only. Only syringes containing a clear solution without particles should be used.
Strict adherence to the intravenous route of administration is recommended.
Where the medicinal product is administered into an existing intravenous infusion line, the infusate should be restricted to either isotonic saline or 50 mg/ml (5%) glucose solution. This also applies to solutions used to flush butterfly and other devices.
Any unused solution for injection, syringe and injection needle should be disposed of in accordance with local requirements. The release of pharmaceuticals in the environment should be minimized.
The following points should be strictly adhered to regarding the use and disposal of syringes and other medicinal sharps: Needles and syringes should never be reused.
Place all used needles and syringes into a sharps container (puncture-proof disposable container).
Placing used sharps containers in the household waste should be avoided.
Dispose of the full container according to local requirements or as instructed by a healthcare professional.

Store at or below 30°C. Protect from light.
Shelf-Life: Shelf life of the product as packaged for sale: 36 months.

Agents Affecting Bone Metabolism

M05BA06 - ibandronic acid ; Belongs to the class of bisphosphonates. Used in the treatment of bone diseases.

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