Ibandronic acid - farmex

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT IBANDRONIC ACID-PHARMEX (IBANDRONIC ACID-PHARMEX)

Composition:

Active substance: ibandronic acid;

1 ml of solution contains ibandronic acid (as sodium ibandronate monohydrate) 1 mg;

Excipients: sodium chloride, glacial acetic acid, sodium acetate trihydrate, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless liquid.

Pharmacotherapeutic group.

Drugs affecting bone structure and mineralization. Bisphosphonates. ATC code M05B A06.

Pharmacological properties.

Pharmacodynamics.

Ibandronic acid is a highly active nitrogen-containing bisphosphonate that selectively acts on bone tissue and specifically inhibits osteoclast activity without having a direct effect on bone formation. The drug does not affect the process of replenishing the osteoclast pool. In postmenopausal women, it reduces the elevated rate of bone turnover to premenopausal levels, leading to progressive increases in bone mass and a reduction in fracture frequency.

Ibandronic acid inhibits bone resorption. In vivo, ibandronic acid prevents bone destruction induced by experimental suppression of gonadal function, retinoids, tumors, and tumor extracts. In young (rapidly growing) rats, increased bone resorption was observed, resulting in greater normal bone mass compared to untreated animals.

Animal models confirm that ibandronic acid is a highly potent inhibitor of osteoclast activity. In growing rats, no signs of impaired mineralization were observed even at doses exceeding more than 5000 times the dose required for osteoporosis treatment.

Long-term daily administration and intermittent administration (with long intervals) over prolonged periods in rats, dogs, and monkeys were associated with formation of new bone of normal quality, with preserved or increased mechanical strength, even at toxic dose ranges. The efficacy of both daily and intermittent dosing of ibandronic acid with dosing intervals of 9–10 weeks has been confirmed in clinical studies in humans, during which ibandronic acid demonstrated effectiveness in preventing fractures.

In animal models, ibandronic acid induces biochemical changes indicating dose-dependent inhibition of bone tissue resorption, including reduced levels of urinary biochemical markers of bone collagen degradation (such as deoxypyridinoline and cross-linked N-telopeptide of type I collagen).

Daily and intermittent administration (with dosing intervals of 9–10 weeks, quarterly) of ibandronic acid, either orally or intravenously, in postmenopausal women leads to biochemical changes indicating dose-dependent inhibition of bone resorption.

Intravenous administration of ibandronic acid results in a reduction of serum C-telopeptide of the alpha chain of type I collagen within 3–7 days after initiation of treatment and a reduction in osteocalcin levels within 3 months.

After discontinuation of treatment, a return to the pathological level of increased bone resorption associated with postmenopausal osteoporosis, observed prior to treatment initiation, occurs.

Histological analysis of bone biopsy samples obtained after 2 and 3 years of treatment in postmenopausal women receiving oral ibandronic acid at a daily dose of 2.5 mg and intermittent intravenous administration at a dose of up to 1 mg every 3 months showed normal bone tissue status. Furthermore, no evidence of mineralization deficiency was detected. After 2 years of treatment with 3 mg injections of ibandronic acid, the expected reduction in bone metabolism was observed, along with normal bone tissue quality and absence of mineralization defects.

Pharmacokinetics.

The primary pharmacological effect of ibandronic acid on bone is not directly related to the actual plasma concentration of ibandronic acid.

Plasma concentration of ibandronic acid increases proportionally to the dose after intravenous administration of 0.5–6 mg.

Distribution. After initial systemic exposure, ibandronic acid rapidly binds to bone tissue or is excreted via urine. The apparent volume of distribution is at least 90 L; approximately 40–50% of the drug circulating in the blood penetrates into and accumulates in bone tissue. About 85–87% binds to plasma proteins (determined in vitro at therapeutic concentrations of ibandronic acid); therefore, due to displacement, the potential for interaction with other medicinal products is low.

Metabolism. There are no data on the metabolism of ibandronic acid in animals or humans.

Elimination. Ibandronic acid is eliminated from the bloodstream via bone uptake (40–50% in postmenopausal women), with the remainder excreted unchanged by the kidneys.

The range of apparent elimination half-life is broad, varying between 10 and 72 hours. Since calculated values depend significantly on study duration, administered dose, and assay sensitivity, the terminal half-life is likely considerably longer, as seen with other bisphosphonates. Initial plasma levels of the drug decrease rapidly, reaching 10% of peak values within 3 hours and 8 hours after intravenous and oral administration, respectively.

Total clearance of ibandronic acid is low, averaging 84–160 mL/min. Renal clearance (approximately 60 mL/min in healthy postmenopausal women) accounts for 50–60% of total clearance and depends on creatinine clearance. The difference between apparent total and renal clearance reflects uptake by bone tissue.

Secretion pathways likely do not involve known acidic or basic transport systems involved in the excretion of other active substances (see section "Interaction with other medicinal products and other forms of interaction"). Additionally, ibandronic acid does not inhibit major human hepatic P450 isoenzymes and does not induce the cytochrome P450 system in rats.

Pharmacokinetics in special populations

Gender. Pharmacokinetic parameters of ibandronic acid are not dependent on gender.

Race. There are no data indicating clinically significant ethnic differences between Mongoloid and Caucasian patients regarding the distribution of ibandronic acid. Data on Negroid patients are insufficient.

Patients with renal impairment. Renal clearance of ibandronic acid in patients with various stages of renal impairment is linearly dependent on creatinine clearance. Dose adjustment is not required in patients with mild to moderate renal impairment (creatinine clearance ≥ 30 mL/min).

In individuals with severe renal impairment (creatinine clearance ≤ 30 mL/min) receiving oral ibandronic acid at a dose of 10 mg for 21 days, plasma concentrations were 2–3 times higher than in individuals with normal renal function, and total clearance of ibandronic acid was 44 mL/min. After intravenous administration of 0.5 mg ibandronic acid, total, renal, and non-renal clearance decreased by 67%, 77%, and 50%, respectively, in individuals with severe renal impairment, but no reduction in drug tolerability due to increased exposure was observed. Due to limited clinical experience, ibandronic acid is not recommended for patients with severe renal impairment (see sections "Special precautions for use" and "Method of administration and dosage"). Pharmacokinetics of ibandronic acid in patients with end-stage renal disease has been evaluated only in a small number of patients undergoing hemodialysis; pharmacokinetics in non-dialyzed patients is unknown. Due to limited data, ibandronic acid should not be used in patients with end-stage renal disease.

Patients with hepatic impairment (see section "Method of administration and dosage"). There are no data on the pharmacokinetics of ibandronic acid in patients with hepatic impairment. The liver does not play a significant role in the clearance of ibandronic acid, which is not metabolized but excreted by the kidneys and through uptake by bone tissue. Therefore, dose adjustment is not required in patients with hepatic impairment.

Elderly patients (see section "Method of administration and dosage"). Pharmacokinetic parameters evaluated in multivariate analysis do not depend on age. Since renal function declines with age, this is the only factor to consider (see section "Patients with renal impairment").

Children (see section "Method of administration and dosage")

There are no data on the use of ibandronic acid in children.

Clinical characteristics.

Indications.

Treatment of osteoporosis in postmenopausal women with increased risk of fractures. Reduction in the risk of vertebral fractures has been demonstrated; efficacy in preventing hip fractures has not been established.

Contraindications.

Hypersensitivity to ibandronic acid or to any other component of the medicinal product (see section "Composition"). Hypocalcemia.

Interaction with other medicinal products and other forms of interaction.

Metabolic interactions are considered unlikely, since ibandronic acid does not inhibit major human hepatic CYP450 isoenzymes and does not induce the hepatic cytochrome P450 system in rats (see section "Pharmacokinetics"). Ibandronic acid is excreted via the kidneys and is not subject to biotransformation.

Special precautions for use.

Administration errors

The drug should be administered intravenously only. Care must be taken to avoid intra-arterial or perivenous injection of ibandronic acid, as this may cause tissue damage.

Hypocalcemia

Administration of ibandronic acid, as with other intravenously administered bisphosphonates, may lead to a temporary decrease in serum calcium levels. Hypocalcemia and other disturbances of bone metabolism and electrolyte balance should be corrected prior to initiating treatment with ibandronic acid. All patients should receive adequate intake of calcium and vitamin D.

Anaphylactic reaction/shock

Cases of anaphylactic reaction/shock, including fatal outcomes, have been observed in patients receiving intravenous ibandronic acid.

Appropriate medical support and monitoring equipment should be readily available during intravenous administration of the drug. If an anaphylactic or other severe hypersensitivity/allergic reaction occurs, the infusion must be stopped immediately and appropriate treatment initiated.

Renal impairment

Patients with concomitant diseases or those taking medications that may adversely affect the kidneys should undergo regular monitoring during treatment, in accordance with standard medical practice.

Due to limited clinical experience, ibandronic acid injections are not recommended for patients with serum creatinine levels exceeding 200 µmol/L (2.3 mg/dL) or creatinine clearance below 30 mL/min (see sections "Dosage and administration" and "Pharmacokinetics in special situations").

Heart failure

Patients at risk of developing heart failure should avoid excessive hydration.

Osteonecrosis of the jaw

Osteonecrosis of the jaw has been reported very rarely during post-marketing use in patients receiving ibandronic acid for oncological indications (see section "Adverse reactions").

Initiation or re-initiation of treatment should be delayed in patients with non-healing open soft tissue lesions in the oral cavity. Prior to starting treatment with ibandronic acid, patients with concomitant risk factors should undergo a dental examination with appropriate preventive interventions and individual benefit-risk assessment.

When assessing the risk of developing osteonecrosis of the jaw, the following risk factors should be considered:

• Potency of the bone resorption-inhibiting drug (higher risk with highly potent compounds), route of administration (higher risk with parenteral administration), and cumulative dose of bone resorption therapy.
• Malignant neoplasms, concomitant medical conditions (e.g., anemia, coagulopathy, infection), and tobacco smoking.
• Concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, and radiotherapy to the head and neck region.
• Poor oral hygiene, periodontal disease, ill-fitting dentures, dental disease history, and invasive dental procedures such as tooth extractions.

All patients receiving this medicinal product should be advised to maintain good oral hygiene, undergo regular dental check-ups, and promptly report any oral symptoms such as loose teeth, pain, swelling, or non-healing ulcers or discharge. Invasive dental procedures should only be performed after careful consideration and should be avoided during and for some time after treatment with ibandronic acid. Management of patients who develop osteonecrosis of the jaw should be planned in close collaboration with a dentist or an oral and maxillofacial surgeon experienced in managing this condition. Temporary discontinuation of treatment should be considered until improvement occurs and, if possible, until concomitant risk factors are reduced.

Osteonecrosis of the external auditory canal

Osteonecrosis of the external auditory canal has been reported with bisphosphonate use, primarily in association with long-term therapy. Risk factors for osteonecrosis of the external auditory canal include steroid and chemotherapy use 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 femoral fractures

Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, particularly in patients receiving long-term treatment for osteoporosis. These transverse or short oblique fractures may occur anywhere along the femur, from slightly below the lesser trochanter to slightly above the condyles. These fractures occur after minimal trauma or in the absence of trauma, and some patients experience thigh or groin pain, often associated with characteristic features of stress fractures, for several weeks to months before the fracture becomes a complete femoral fracture. Fractures are often bilateral; therefore, the contralateral femur should also be evaluated in patients receiving bisphosphonate therapy who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. The question of discontinuing bisphosphonate therapy in patients with suspected atypical femoral fractures should be considered pending full assessment of the patient, taking into account individual benefit-risk evaluation.

Patients undergoing bisphosphonate therapy should be advised to report new thigh, hip, or groin pain; all patients with such symptoms should be evaluated for incomplete femoral fracture.

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 bisphosphonate therapy. As with atypical femoral fractures, these fractures occur after minimal or no trauma, and some patients experience prodromal pain before the complete fracture occurs. In cases of ulnar fracture, this may be associated with repetitive stress from prolonged use of walking aids (see section "Adverse reactions").

The medicinal product contains less than 1 mmol sodium (23 mg) per 3 mL pre-filled syringe, i.e., essentially "sodium-free".

Disposal of unused medicine and expired products

Any unused injectable solution, syringe, and injection needles must be disposed of in accordance with local requirements. Environmental contamination should be minimized. The product must not be disposed of via wastewater or household waste. A designated "waste collection system" should be used for disposal, if available.

Use during pregnancy or breastfeeding

Pregnancy

Ibandronic acid is indicated only for postmenopausal women. The drug should not be administered to women of reproductive age.

There is no clinical experience with the use of ibandronic acid in pregnant women.

The drug should not be used during pregnancy.

Breastfeeding

It is unknown whether ibandronic acid passes into human breast milk. Studies have demonstrated low levels of ibandronic acid in the milk of lactating rats after intravenous administration. Ibandronic acid-Farmex should not be used during breastfeeding.

Fertility

There are no data on the effect of ibandronic acid on human fertility. Reproductive studies in rats showed that ibandronic acid reduced fertility at high daily oral doses.

Ability to affect reaction speed when driving or operating machinery

Considering the pharmacodynamic characteristics, pharmacokinetic profile, and reported adverse reactions, ibandronic acid is expected to have no effect or a negligible effect on the ability to drive or operate machinery.

Dosage and Administration

Dosage

The recommended dose for the treatment of osteoporosis is 3 mg of ibandronic acid administered as an intravenous injection over 15–30 seconds every 3 months. The drug is intended for intravenous use only (see section "Special Warnings and Precautions for Use").

Patients should receive additional calcium and vitamin D supplementation (see sections "Interaction with Other Medicinal Products and Other Forms of Interaction" and "Special Warnings and Precautions for Use").

If a scheduled dose is missed, the injection should be administered as soon as possible. Subsequent injections should then be given every 3 months from the date of the last dose.

The optimal duration of bisphosphonate treatment for osteoporosis has not been established. The need for continued treatment with ibandronic acid should be periodically reassessed on an individual basis, taking into account the benefit-risk balance, particularly after 5 or more years of treatment.

Special Patient Groups

Patients with renal impairment

Dose adjustment is not required in patients with mild or moderate renal impairment with serum creatinine levels ≤200 µmol/L (2.3 mg/dL) or creatinine clearance (measured or calculated) ≥30 mL/min.

Ibandronic acid injections are not recommended in patients with serum creatinine levels >200 µmol/L (2.3 mg/dL) or creatinine clearance (measured or calculated) <30 mL/min, due to limited clinical data in this patient group (see sections "Special Warnings and Precautions for Use" and "Pharmacokinetics in Special Situations").

Patients with hepatic impairment

Dose adjustment is not required (see section "Pharmacokinetics in Special Situations").

Elderly patients (>65 years of age)

Dose adjustment is not required (see section "Pharmacokinetics in Special Situations").

Children

There is insufficient experience with the use of ibandronic acid in children (under 18 years of age). The use of ibandronic acid in children (under 18 years of age) has not been studied (see sections "Pharmacodynamics" and "Pharmacokinetics").

Special Instructions for Use

If the medicinal product is administered via an existing intravenous infusion system, the infusion fluid must be either isotonic saline or 5% glucose solution (50 mg/mL). This also applies to solutions used for flushing the catheter and other devices.

Any unused injection solution, syringes, and injection needles must be disposed of in accordance with local requirements. Environmental contamination with the medicinal product should be minimized.

The following recommendations for the use and disposal of syringes and other sharp instruments must be strictly observed:

• Needles and syringes should never be reused.
• All used needles and syringes must be placed in a sharps container (puncture-resistant, single-use container).
• This container must be kept out of the reach of children.
• The sharps container must not be disposed of in household waste.
• A full container must be disposed of in accordance with local regulations or as instructed by a physician.

Children

The safety and efficacy of ibandronic acid in patients under 18 years of age have not been established; therefore, the drug is not used in children.

Overdose

There is no specific information on overdose with ibandronic acid. Based on current knowledge of bisphosphonates, overdose following intravenous administration may lead to hypocalcemia, hypophosphatemia, and hypomagnesemia. Clinically significant reductions in serum calcium, phosphate, and magnesium levels should be corrected by intravenous administration of calcium gluconate, potassium or sodium phosphate, and magnesium sulfate, respectively.

Adverse Reactions

The most serious adverse reactions reported include anaphylactic reaction/shock, atypical femoral fractures, osteonecrosis of the jaw, and ocular inflammation (see "Description of selected adverse reactions" and section "Special precautions for use").

The most commonly reported adverse reactions were arthralgia and influenza-like symptoms. These symptoms were usually associated with the first dose, were generally transient, mild to moderate in severity, and typically resolved with continued treatment without requiring medical intervention (see "Description of selected adverse reactions").

Adverse reactions listed below are presented according to the Medical Dictionary for Regulatory Activities (MedDRA) system organ class and frequency categories. Adverse reactions are categorized by frequency as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), and frequency not known (cannot be estimated from the available data). Within each category, adverse reactions are listed in decreasing order of severity.

Immune system disorders:
uncommon – asthma exacerbation;
rare – hypersensitivity reactions;
very rare – anaphylactic reaction/shock.

Nervous system disorders:
common – headache.

Eye disorders:
rare – ocular inflammation.

Vascular disorders:
uncommon – phlebitis/thrombophlebitis.

Gastrointestinal disorders:
common – gastritis, dyspepsia, diarrhea, abdominal pain, nausea, constipation.

Skin and subcutaneous tissue disorders:
common – rash;
rare – angioedema, facial swelling/edema, urticaria;
very rare – Stevens-Johnson syndrome, erythema multiforme, bullous dermatitis.

Musculoskeletal and connective tissue disorders:
common – arthralgia, myalgia, musculoskeletal pain, back pain;
uncommon – bone pain;
rare – atypical subtrochanteric and diaphyseal femoral fractures;
very rare – osteonecrosis of the jaw;
frequency not known – atypical fractures of other long bones. Osteonecrosis of the external auditory canal (an adverse reaction characteristic of bisphosphonates as a class). Osteoarthritis, joint function disorders.

General disorders and administration site conditions:
common – influenza-like illness, fatigue;
uncommon – injection site reactions, asthenia.

Description of selected adverse reactions

Influenza-like illness

Influenza-like illness included acute phase reactions or symptoms such as myalgia, arthralgia, fever, chills, fatigue, nausea, loss of appetite, and bone pain.

Osteonecrosis of the jaw

Osteonecrosis of the jaw has been reported in patients receiving bisphosphonates. Most reports have been in cancer patients, but cases have also been reported in patients receiving treatment for osteoporosis. Osteonecrosis of the jaw is usually associated with tooth extraction and/or local infection (including osteomyelitis). Malignant disease, chemotherapy, radiotherapy, corticosteroid use, and poor oral hygiene are also considered risk factors (see section "Special precautions for use").

Atypical subtrochanteric and diaphyseal femoral fractures

Although the pathophysiology is not fully understood, epidemiological data suggest an increased risk of atypical subtrochanteric and diaphyseal femoral fractures with long-term bisphosphonate therapy for postmenopausal osteoporosis, particularly after three to five years of treatment. The absolute risk of atypical subtrochanteric and diaphyseal fractures of long bones (a class effect of bisphosphonates) remains very low.

Eye disorders

Inflammatory ocular events such as uveitis, episkleritis, and scleritis have been reported during treatment with bisphosphonates, including ibandronic acid. In some cases, these inflammatory conditions resolved only after discontinuation of bisphosphonates.

Anaphylactic reaction/shock

Cases of anaphylactic reaction/shock, including fatal outcomes, have been observed in patients receiving intravenous ibandronic acid.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Incompatibilities.

Ibandronic acid must not be mixed with calcium-containing solutions or with other medicinal products for intravenous administration.

Packaging.

3 ml in a pre-filled syringe, 1 pre-filled syringe with needle in a blister pack, 1 blister pack in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

TOV "FARMEKS GROUP".

Manufacturer's address and place of business.

100 Shevchenka St., Boryspil, Kyiv region, 08301, Ukraine.