Bonviva, 3 mg/3 ml 3 ml syringe-tubes

Pharmacodynamics

Ibandronic acid is a highly active nitrogen-containing bisphosphonate, an inhibitor of bone resorption and osteoclast activity. Ibandronic acid prevents bone destruction caused by blockade of glandular function, retinoids, tumors and tumor extracts in vivo. Inhibits endogenous resorption in young (fast-growing) rats, which is manifested by higher bone mass compared to intact animals.

Does not impair bone mineralization when administered at doses more than 5000 times higher than doses for the treatment of osteoporosis and does not affect the process of osteoclast pool replenishment. The selective effect of ibandronic acid on bone tissue is due to its high affinity for hydroxyapatite, which constitutes the mineral matrix of bone.

Ibandronic acid inhibits bone resorption in a dose-dependent manner and has no direct effect on bone formation. In menopausal women it decreases increased rate of bone renewal to the level of reproductive age resulting in overall progressive increase of bone mass, decrease of bone collagen breakdown indices (concentration of deoxypyridinoline and cross-linked C- and N-telopeptides of type I collagen) in urine and serum, fracture rate and increase of BMD.

The high activity and therapeutic range allow for flexible dosing and intermittent administration of the drug with long periods of no treatment at relatively low doses.

Effectiveness

The administration of Bonviva 150 mg once a month for one year increases mean lumbar spine, femur, femoral neck, and trochanteric spine BMD by 4.9, 3.1, 2.2, and 4.6%; Boneviva 3 mg once every 3 months for 1 year increased mean BMD of the femur, femoral neck and trochanter by 2.4, 2.3 and 3.8%, respectively.

Independent of the duration of menopause and the degree of baseline bone mass loss, Bonviva leads to significantly more pronounced BMD changes than placebo. One-year benefit, defined as an increase in BMD, was seen in 83.9% (with coated tablets) and 92.1% (intravenous injection) of patients.

Biochemical markers of bone resorption

Shell tablets, 2.5 mg. Biochemical markers of bone resorption (concentration of C-terminal procollagen peptide type I in urine (CTX) and osteocalcin in blood serum) decrease to their levels in reproductive age; the maximum decrease is observed after 3-6 months of treatment. One month after the use of the drug Bonviva 2.5 mg daily and 20 mg in the intermittent mode, a clinically significant reduction of biochemical markers of bone resorption by 50 and 78% was achieved, respectively; moreover, some decrease in these figures was observed after one week of treatment. A clinically significant reduction in biochemical markers of bone resorption (CTX concentration in urine) was observed one month after the start of treatment.

Daily use of 2.5 mg of Bonviva for prevention of postmenopausal osteoporosis (study MF4499) increased mean lumbar spinal BMD by 1.9% over baseline. Regardless of the duration of menopause and the degree of baseline loss of basic bone substance, the use of Bonviva leads to significantly more pronounced changes in lumbar vertebral BMD. Benefit of Bonviva, defined as an increase in BMD over baseline, was seen in 70% of patients.

The coated tablets are 150 mg and the solution for intravenous injection. A 28% reduction in serum concentration of CTC was observed as early as 24 hours after the first administration of 150 mg of Bonviva, the maximum reduction was 68% after 6 days. After the third and fourth doses of Bonviva 150 mg, a maximum decrease in serum CTC of 74% was observed after 6 days. After 28 days of the fourth dose, a decrease in suppression of biochemical markers of bone resorption was observed up to 56%.

A clinically significant reduction in serum CBC was obtained after 3, 6 and 12 months of therapy. After one year of therapy with Bonviva 150 mg, the reduction was 76%; compared with the baseline value, when 3 mg was used intravenously, it was 58.6%.

A CTX reduction greater than 50% from baseline was seen in 83.5% of patients who received Bonviva 150 mg once every 28 days.

Pharmacokinetics

There is no direct correlation between the effectiveness of ibandronic acid and the plasma concentration of the substance. Plasma concentrations increase dose-dependently with increasing doses of intravenous solution from 0.5 to 6 mg. Similar efficacy of ibandronic acid has been confirmed with daily and intermittent regimens, provided that the total dose administered during the treatment period is the same.

Absorption

After oral administration ibandronic acid is rapidly absorbed in the upper gastrointestinal tract. Plasma concentrations increase dose-dependently with increasing doses up to 50 mg and significantly more with further increasing doses. Time of reaching Cmax (TCmax) is 0.5-2 hours (median – 1 hour) after an empty stomach, absolute bioavailability – 0.6%. Absorption is impaired when taking the drug with food or drinks (except pure water). Simultaneous intake of food or drinks (except pure water) reduces bioavailability of ibandronic acid by 90%. When taking ibandronic acid 60 min before a meal there is no significant decrease in bioavailability. Intake of food or liquid less than 60 min after ibandronic acid reduces its bioavailability and the induced increase in bone mineral density (BMD).

Distribution

After entering the systemic bloodstream, ibandronic acid is rapidly bound in the bone tissue or excreted in the urine. 40-50% of the drug circulating in the blood penetrates well into bone tissue and accumulates there. Apparent final volume of distribution is 90 l. Blood plasma protein binding is 85% when administered orally and 85-87% when administered intravenously.

Metabolism

There is no evidence that ibandronic acid is metabolized. Ibandronate does not inhibit the 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4 enzymes of the cytochrome P450 system.

40-50% of the absorbed in the bloodstream dose taken orally or injected intravenously is bound in the bone, and the rest is excreted unchanged by the kidneys.

The unabsorbed drug is excreted unchanged in the feces.

The terminal T1/2 for 2.5 mg tablets is 10-60 hours; for 150 mg tablets and intravenous solution it is 10-72 hours. The blood concentration of the drug decreases rapidly and is 10% of the maximum after 8 hours after oral administration and 3 hours after intravenous administration.

The total clearance of ibandronic acid is 84-160 ml/min. Renal clearance (60 ml/min in healthy menopausal women) is 50-60% of total clearance and depends on creatinine clearance. The difference between total and renal clearance reflects bone uptake of the substance.

Pharmacokinetics in Special Patient Groups

The pharmacokinetics of ibandronic acid is independent of gender.

There are no clinically significant interracial differences in the distribution of ibandronic acid in persons of Southern European and Asian race. There is insufficient data regarding the Negro race.

Patients with impaired renal function. In patients with impaired renal function, the renal clearance of ibandronic acid is linearly related to creatinine clearance (creatinine Cl). No dose adjustment is required in patients with mild to moderate renal dysfunction (creatinine Cl ≥30 ml/min).

In patients with severe renal impairment (creatinine Cl

Patients with impaired liver function. 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 through the kidneys and by capture in the bone tissue. Therefore, no dose adjustment is required for patients with impaired liver function.

Since when administered orally in therapeutic concentrations ibandronic acid weakly binds to plasma proteins (85%), it is likely that hypoproteinemia in severe liver disease does not lead to clinically significant increase in blood concentrations of free substance.

Elderly age. The studied pharmacokinetic parameters are independent of age. Possible decreased renal function in elderly patients should be considered.

Children. There are no data on the use of Bonviva in persons younger than 18 years of age.

Indications

Postmenopausal osteoporosis to prevent fractures.

Active ingredient

Ibandronic acid

Composition

1 syringe-tube (3 ml) with solution for intravenous administration contains:

the active ingredient:

ibandronic acid 3 mg (in the form of ibandronate monohydrate sodium 3.375 mg),

auxiliary substances:

Sodium chloride;

Sodium acetate trihydrate;

glacial acetic acid;

water for injection

How to take, the dosage

Intravenously. The drug is for intravenous use only!

Injection only by a specialist. Intra-arterial administration or ingestion into the surrounding tissue should be avoided.

The solution should be inspected before administration to make sure there is no foreign matter or discoloration.

The needles in the syringe tube kit should be used.

The syringe tube is for single administration only.

The standard dosing regimen

3 mg intravenously bolus (for 15-30 seconds) once every 3 months.

The patient should take additional calcium and vitamin D.

If a scheduled injection is missed, the injection should be given as soon as possible. Then continue injections every 3 months after the last injection.

The drug should not be given more than once every 3 months.

Key kidney function, serum calcium, phosphorus and magnesium should be monitored during treatment.

Dosage in special groups of patients

Hepatic impairment. No dose adjustment is necessary.

Dose adjustment is not required in mild to moderately significant renal dysfunction (creatinine Cl ≥30 ml/min). If creatinine Cl

Elderly age. No dose adjustment is required.

Children. Safety and effectiveness in persons under 18 years of age has not been established.

Interaction

Bonviva is incompatible with calcium-containing solutions and other solutions for intravenous administration.

Ibandronic acid has no effect on the activity of the main isoenzymes of the cytochrome P450 system.

In therapeutic concentrations ibandronic acid weakly binds to plasma proteins, and therefore it is unlikely to displace other drugs from binding sites with proteins.

Ibandronic acid is excreted only through the kidneys and does not undergo any biotransformation. The ibandronic acid excretion pathway does not appear to include any transport systems involved in the excretion of other drugs.

Special Instructions

Risk factors for postmenopausal osteoporosis and fractures include hereditary history, history of bone fractures, early menopause, active bone metabolism, low BMD (at least 1.0 SD less than average BMD in reproductive age), frail build, and Southern European and Asian races, smoking. These factors are important in deciding whether to prescribe Bonviva 2.5 mg film-coated tablets to prevent osteoporosis.

Osteoporosis may be confirmed if low BMD (T index)

Hypocalcemia and other bone and electrolyte metabolic disorders should be corrected before initiating the use of Bonviva. Patients should consume adequate amounts of calcium and vitamin D.

If a patient does not get enough calcium and vitamin D in her diet, additional calcium and vitamin D supplements should be taken.

When taken orally, the side effects of the drug are usually mild to moderate. Transient flu-like syndrome is noted after the first dose and resolves on its own without correction of therapy. No increase in the incidence of upper gastrointestinal adverse effects in patients with gastrointestinal diseases (including peptic ulcer without bleeding and hospitalization, dyspepsia or reflux disease) has been noted.

The use of oral bisphosphonates is often accompanied with impaired swallowing, esophagitis, and formation of esophageal and gastric ulcers, so special attention should be paid to compliance with the drug recommendations (sitting or standing position for 60 minutes after intake).

In case of signs and symptoms of possible esophageal involvement (appearance or increase of swallowing disorders, pain while swallowing, pain in the chest, heartburn), stop taking Bonviva and consult a physician.

Postmarketing experience with Bonviva is limited.

Serum creatinine should be determined before each injection.

Osteonecrosis of the jaw has been reported with bisphosphonates. Most cases have been reported in female patients with cancer during dental procedures, with a few cases in female patients with postmenopausal osteoporosis or other diseases. Risk factors for osteonecrosis of the jaw include an established cancer diagnosis, concomitant therapy (chemotherapy, radiation therapy, corticosteroids) and other disorders (anemia, coagulopathy, infection, gum disease). Most cases were seen with bisphosphonates administered by injection, but isolated cases were seen in those receiving oral medications.

Dental surgery during therapy with bisphosphonates may increase the manifestations of osteonecrosis of the jaw. It is not known whether withdrawal of bisphosphonates reduces the risk of osteonecrosis. The decision to treat must be made for each patient individually after assessing the risk/benefit ratio.

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Contraindications

• high sensitivity to ibandronic acid or other drug components
• hypocalcemia (hypocalcemia should be corrected before starting Bonviva, as with all bisphosphonates used to treat osteoporosis).
• pregnancy
• breastfeeding
• severe renal impairment (serum creatinine >200 μmol/L (2.3 mg/dL) or creatinine Cl

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Side effects

Gastrointestinal disorders: dyspepsia, diarrhea, gastritis.

Muscular system disorders: arthralgia, myalgia.

Nervous system disorders: headache, dizziness.

The body in general: flu-like syndrome.

Skin and its appendages: rash.

Hypersensitivity reactions: angioedema, urticaria.

Very rarely osteonecrosis of the jaw has been reported when administering ibandronic acid.

Bonviva, like other bisphosphonates, may cause a transient decrease in serum calcium levels when administered intravenously.

Gastrointestinal disorders: constipation, gastroenteritis.

Muscular system disorders: pain in the limbs and bones, osteoarthritis.

Nervous system and mental disorders: insomnia, depression.

The body in general: weakness, reactions at the injection site, phlebitis, thrombophlebitis, nasopharyngitis, cystitis, urinary tract infections, bronchitis, upper respiratory tract infections, arterial hypertension, hypercholesterolemia, uveitis, scleritis.

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Overdose

Symptoms: hypocalcemia, hypophosphatemia, hypomagnesemia.

Treatment: no specific information available. Clinically significant decrease in serum calcium, phosphate and magnesium can be corrected by intravenous administration of calcium gluconate, potassium or sodium phosphate and magnesium sulfate, respectively. Dialysis is ineffective if administered 2 hours after drug administration.

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Pregnancy use

Pregnancy. No evidence of direct embryotoxic or teratogenic effects was found during preclinical studies; no adverse effects on offspring development were found in F1 rats at doses at least 35-fold higher than the human dose. Adverse effects of ibandronic acid in reproductive toxicity studies in animals were the same as those of all bisphosphonates: reduction in the number of embryos, impaired childbirth, increased frequency of visceral anomalies (pelvic-ureteric segment narrowing syndrome).

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

Breast-feeding period. It is excreted with milk in animals. After 24 hours, the concentration of ibandronic acid in plasma and milk is the same and corresponds to 5% of the maximum.

It is not known whether ibandronic acid is excreted with breast milk in women.