Vivanat Rompharm solution for injection 0.1% pre-filled syringe 3 ml No. 1

Instructions Vivanat Rompharm solution for injection 0.1% pre-filled syringe 3 ml No. 1

Composition

active ingredient: ibandronic acid;

1 pre-filled syringe (3 ml) contains 3 mg of ibandronic acid in the form of 3.375 mg of ibandronate sodium monohydrate;

Excipients: sodium acetate trihydrate; glacial acetic acid; sodium chloride; acetic acid solution 1%; water for injections.

Dosage form

Solution for injection.

Main physicochemical properties: transparent colorless solution.

Pharmacotherapeutic group

Agents affecting bone structure and mineralization. Bisphosphonates. Ibandronic acid. ATC code M05B A06.

Pharmacological properties

Pharmacodynamics.

Mechanism of action

Ibandronic acid is a highly active bisphosphonate belonging to the group of nitrogen-containing bisphosphonates and selectively acts on bone tissue and specifically inhibits the activity of osteoclasts, has no direct effect on bone formation. The drug does not affect the process of replenishing the osteoclast pool. In postmenopausal women, ibandronic acid reduces the increased rate of bone turnover to premenopausal levels, which leads to a progressive increase in bone mass and a decrease in the frequency of fractures.

Pharmacodynamic effects

The pharmacodynamic action of ibandronic acid is inhibition of bone resorption. In vivo, ibandronic acid prevents bone destruction induced experimentally by blockade of gonadal function with retinoids, tumors and tumor extracts. In young (rapidly growing) rats, inhibition of endogenous bone resorption was also observed, resulting in an increase in normal bone mass compared with 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 more than 5000 times the dose required for the treatment of osteoporosis.

Long-term daily and intermittent administration (at long intervals) over a long period of time in rats, dogs and monkeys was associated with the formation of new bone of normal quality with maintained or increased mechanical strength, even when administered in the toxic range. The efficacy of daily and intermittent administration of ibandronic acid with a dosing interval of 9–10 weeks was confirmed in a clinical study in humans. Ibandronic acid has been shown to be effective in preventing fractures.

In animal models, ibandronic acid produced biochemical changes indicative of a dose-dependent inhibition of bone resorption, including decreases in urinary biochemical markers of bone collagen degradation (such as deoxypyridinoline and cross-linked N-telopeptide of type I collagen (NTX)).

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

Intravenous administration of ibandronate resulted in a decrease in serum C-telopeptide of the alpha chain of type I collagen (CTX) within 3–7 days of treatment initiation and in a decrease in osteocalcin levels within 3 months.

After discontinuation of treatment, there is a return to the pathological level of increased bone resorption observed before the start of treatment, associated with postmenopausal osteoporosis.

Histological analysis of bone biopsy specimens obtained after 2 and 3 years of treatment of postmenopausal women with ibandronic acid orally at a dose of 2.5 mg daily and intravenously intermittently at a dose of up to 1 mg every 3 months showed normal bone tissue with no signs of impaired mineralization. After 2 years of treatment with ibandronic acid injections at a dose of 3 mg, the expected decrease in bone metabolism was observed, as well as normal bone quality and no impaired mineralization.

Pharmacokinetics.

As demonstrated in various animal and human studies, the primary pharmacological effects of ibandronic acid on bone are not directly related to the actual plasma concentration.

The concentration of ibandronic acid in the blood plasma increases proportionally to the dose after intravenous administration of 0.5-6 mg.

Distribution

After initial systemic exposure, ibandronic acid is rapidly bound to bone or excreted in the urine. In humans, the apparent terminal volume of distribution is at least 90 l and approximately 40-50% of the circulating dose penetrates bone. Plasma protein binding is approximately 85-87% (determined in vitro at therapeutic concentrations of ibandronic acid), therefore, due to displacement, the potential for interactions with other medicinal products is low.

Biotransformation

There is no evidence that ibandronic acid is metabolized in humans or animals.

Ibandronic acid is removed from the bloodstream by bone absorption (approximately 40-50% in postmenopausal women), the remainder is excreted unchanged by the kidneys.

The apparent half-life range is wide and is usually 10–72 hours. Since the calculated values depend largely on the duration of the study, the dose used, and the sensitivity of the assay, the terminal half-life is likely to be considerably longer, as with other bisphosphonates. Initial plasma levels decline rapidly and reach 10% of peak values within 3 and 8 hours after intravenous or oral administration, respectively.

The total clearance of ibandronic acid is low and averages 84–160 ml/min. Renal clearance (60 ml/min in healthy postmenopausal women) accounts for 50–60% of total clearance and is dependent on creatinine clearance. The difference between apparent, total and renal clearance reflects the uptake of the drug by bone tissue.

The secretory pathways are unlikely to involve known acid-base transport systems involved in the excretion of other active substances (see section 4.5). Furthermore, ibandronic acid does not inhibit the major hepatic P450 isoenzymes in humans and does not induce the hepatic cytochrome P450 system in rats.

Pharmacokinetics in special cases

Sex

The pharmacokinetics of ibandronic acid in men and women are similar.

Race

There are no clinically significant ethnic differences in the disposition of ibandronic acid between Caucasian and Mongoloid patients. Data on Negroid patients are limited.

Patients with renal impairment

Renal clearance of ibandronic acid in patients with varying degrees of renal impairment is linearly related to creatinine clearance (ClCr).

No dose adjustment is required for patients with mild to moderate renal impairment (ClCr ≥ 30 mL/min).

In patients with severe renal impairment (ClCr < 30 ml/min) given ibandronic acid orally at a dose of 10 mg for 21 days, plasma concentrations were 2-3 times higher than in patients with normal renal function; total clearance of ibandronic acid was 44 ml/min. After intravenous administration of 0.5 mg ibandronic acid to patients with severe renal impairment, total, renal and non-renal clearances were reduced by 67%, 77% and 50%, respectively, but no reduction in tolerability due to increased exposure was observed. Due to limited clinical experience, Vivanat Rompharm is not recommended for patients with severe renal impairment (see sections 4.4 and 2.2). The pharmacokinetics of ibandronic acid in patients with end-stage renal disease have only been evaluated in a small number of patients undergoing haemodialysis, therefore the pharmacokinetics of ibandronic acid in patients not undergoing dialysis are unknown. Due to limited data, ibandronic acid should not be used in patients with end-stage renal disease.

Patients with hepatic insufficiency (see section "Method of administration and dosage")

There are no data on the pharmacokinetics of ibandronic acid in patients with hepatic insufficiency. The liver does not play a significant role in the clearance of ibandronic acid, which is not metabolized but is excreted by the kidneys and by absorption into bone tissue. Therefore, no dose adjustment is required in patients with hepatic insufficiency.

Elderly patients (see section "Method of administration and dosage")

The pharmacokinetic parameters studied in multivariate analysis are not age-dependent. Since renal function decreases with age, this is the only factor to be taken into account (see section "Patients with renal insufficiency").

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

There are no data on the use of Vivanat Rompharm in children.

Indication

Treatment of osteoporosis in postmenopausal women at increased risk of fractures. A reduction in the risk of vertebral fractures has been demonstrated, but efficacy in preventing hip fractures has not been established.

Contraindication

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

Hypocalcemia.

Interaction with other medicinal products and other types of interactions

Metabolic interactions are not considered likely as ibandronic acid does not inhibit the major hepatic P450 isoenzymes in humans and does not induce the hepatic cytochrome P450 system in rats (see section 5.2). Ibandronic acid is eliminated only by renal excretion and is not subject to biotransformation.

Application features

Input errors

Caution should be exercised and avoid administering Vivanat Rompharm intraarterially or into the perivenous space, as this may cause tissue damage.

Hypocalcemia

Pre-existing hypocalcemia should be corrected before initiating therapy with Vivanat Rompharm. Other disorders of bone and mineral metabolism should also be effectively treated.

All patients should receive adequate calcium and vitamin D.

Anaphylactic reaction/shock

Cases of anaphylactic reaction/shock, including fatal cases, have been reported in patients treated with intravenous ibandronic acid.

Appropriate medical attention and monitoring facilities should be readily available during the intravenous administration of Vivanat Rompharm. If anaphylactic or other severe hypersensitivity/allergic reactions occur, the injection should be discontinued immediately and appropriate treatment should be initiated.

Kidney dysfunction

Patients with concomitant diseases or those taking medications that may adversely affect the kidneys should be monitored regularly during treatment in accordance with good medical practice.

Due to limited clinical experience, Vivanate Rompharm 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 “Pharmacokinetics” and “Dosage and administration”).

Heart failure

Patients at risk of developing heart failure should avoid overhydration.

Osteonecrosis of the jaw bones

During post-marketing use, osteonecrosis of the jaw (ONJ) has been reported very rarely in patients treated with ibandronate for osteoporosis (see section 4.8). In patients with unhealed open soft tissue lesions of the oral cavity, the start of treatment or a new course of treatment should be postponed. Before starting treatment with Vivanat Rompharm, a dental examination with appropriate preventive intervention and an individual benefit-risk assessment are recommended in patients with concomitant risk factors.

When assessing a patient's risk of developing OSCC, the following risk factors should be taken into account:

the potency of the drug that inhibits bone resorption (risk is higher with highly potent compounds); the route of administration (risk is higher with parenteral administration) and the cumulative dose of bone resorption therapy;

malignant neoplasms, concomitant pathological conditions (e.g., anemia, coagulopathy, infection), smoking;

concomitant treatment: corticosteroids, chemotherapy, angiogenesis inhibitors, radiation therapy to the head and neck area;

poor oral hygiene, periodontal disease, poorly fitting dentures, history of dental disease, invasive dental procedures, such as tooth extraction.

During treatment with Vivanat Rompharm, all patients should maintain good oral hygiene, have regular dental check-ups, and promptly report any oral symptoms such as tooth mobility, pain or swelling, non-healing ulcers, or discharge. During treatment, invasive dental procedures should only be performed after careful consideration: they should be avoided during and immediately after treatment with Vivanat Rompharm.

The management plan for patients who develop OTC should be developed in close collaboration with a dentist or maxillofacial surgeon experienced in the treatment of OTC. Temporary interruption of Vivanat Rompharm treatment should be considered until the condition improves and risk factors are reduced.

Osteonecrosis of the external auditory canal

Osteonecrosis of the external auditory canal has been reported with bisphosphonates, mostly in association with long-term treatment. Possible risk factors for osteonecrosis of the external auditory canal include steroid hormone 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 have ear symptoms, including chronic ear infections.

Atypical hip fractures

During bisphosphonate treatment, patients should be advised to report hip, hip, or groin pain; all patients with such symptoms should be evaluated for an incomplete femoral fracture.

Vivanat Rompharm does not contain sodium.

Disposal of unused and expired medication

The release of the medicinal product into the environment should be minimised. The medicinal product should not be disposed of in wastewater or household waste. For disposal, use a so-called waste collection system, if available.

Use during pregnancy or breastfeeding

Pregnancy

Vivanate Rompharm is intended for use in postmenopausal women only. It should not be used in women of reproductive age.

There are no adequate data from the use of ibandronic acid in pregnant women. Some reproductive toxicity was observed in studies in rats. The potential risk for humans is unknown. Vivanat Rompharm should not be used during pregnancy.

Breastfeeding period

It is not known whether ibandronic acid is excreted in human milk. Studies have shown low levels of ibandronic acid in the milk of lactating rats after intravenous administration. Vivanate Rompharm should not be used during breast-feeding.

Fertility

There are no data on the effects of ibandronic acid in humans. In reproductive studies in rats, ibandronic acid reduced fertility at high daily oral doses. In studies in rats, ibandronic acid reduced fertility at high daily intravenous doses.

Ability to influence reaction speed when driving vehicles or other mechanisms

Given the pharmacodynamic characteristics, pharmacokinetic profile and reported adverse reactions, it is expected that Vivanat Rompharm has no or negligible influence on the ability to drive or use machines.

Method of administration and doses

Dosage

The recommended dose of ibandronic acid is 3 mg as an intravenous injection over 15-30 seconds, every 3 months.

The intravenous route of administration should be strictly adhered to (see section "Special precautions for use").

Patients should take additional calcium and vitamin D (see sections “Interaction with other medicinal products and other types of interactions” and “Special instructions for use”).

If a dose is missed, the injection should be given as soon as possible. Subsequent injections should be given 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 reviewed periodically, taking into account the expected benefits and potential risks of Vivanat Rompharm for each individual patient, especially after 5 or more years of use.

Special patient groups

Patients with renal impairment

Vivanate Rompharm injections are not recommended for patients with serum creatinine levels greater than 200 μmol/L (2.3 mg/dL) or creatinine clearance (determined or estimated) less than 30 mL/min, as clinical trial data, including in this group of patients, are limited.

No dose adjustment is required for patients with mild or moderate renal impairment whose serum creatinine level is equal to or below 200 μmol/L (2.3 mg/dL) or whose creatinine clearance (determined or calculated) is equal to or above 30 mL/min.

Patients with liver dysfunction

No dose adjustment is required (see section "Pharmacokinetics").

Elderly patients (> 65 years)

No dose adjustment is required (see section "Pharmacokinetics").

Special instructions for use

If the drug is administered into an existing intravenous infusion system, the infusate should be only isotonic saline or 5% glucose solution (50 mg/ml). This also applies to solutions used to flush the catheter and other devices.

Any unused solution for injection, syringe and injection needle should be disposed of in accordance with local requirements. Release of medicinal products into the environment should be minimised.

The following recommendations for the use and disposal of syringes and other sharps and cutting instruments should be strictly followed:

Needles and syringes should never be reused.

Place all used needles and syringes in a sharps container (a puncture-resistant container for single use).

This container should be kept out of the reach of children.

Do not throw away the sharps container in household waste.

The filled container should be disposed of in accordance with local requirements or as directed by your doctor.

Children.

There is no relevant experience with the use of Vivanat Rompharm in children (under 18 years of age). The use of the drug in this patient population has not been studied (see sections "Pharmacodynamics" and "Pharmacokinetics").

Overdose

There is no specific information on the treatment of overdose with ibandronic acid.

Given the current knowledge of this class of compounds, overdose by intravenous administration may result in hypocalcemia, hypophosphatemia, and hypomagnesemia. Clinically significant decreases in serum calcium, phosphorus, and magnesium should be corrected by intravenous administration of calcium gluconate, potassium or sodium phosphate, and magnesium sulfate, respectively.

Side effects

Summary of safety profile

The most serious adverse reactions reported are anaphylactic reaction/shock, atypical hip fractures, osteonecrosis of the jaw, and eye inflammation (see “Description of selected adverse reactions” and section “Special warnings and precautions for use”).

The most frequently reported adverse reactions were arthralgia and flu-like symptoms. These symptoms were usually associated with the first dose, were in most cases short-lived, mild to moderate in severity, and usually resolved with continued treatment without requiring medical intervention (see “Description of selected adverse reactions”).

Below is a complete list of known adverse reactions.

The safety of treatment with ibandronic acid 2.5 mg/day orally was studied in 1,251 patients who participated in 4 placebo-controlled clinical trials, with the majority of patients participating in a pivotal three-year fracture study (MF 4411).

In a pivotal two-year study in postmenopausal women with osteoporosis (BM16550), the overall safety profile was similar for ibandronic acid 3 mg intravenous injection every 3 months and ibandronic acid 2.5 mg orally daily. The overall number of patients experiencing an adverse reaction was 26.0% and 28.6% after one and two years of ibandronic acid 3 mg intravenous injection every 3 months, respectively. In most cases, adverse reactions did not lead to discontinuation of treatment.

Tabulated list of adverse reactions

The table provides a complete list of known adverse reactions.

Adverse reactions are presented according to MedDRA system organ class and frequency. The frequency was estimated using the following conventional categories: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); rare (<1/10,000), frequency unknown (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Adverse reactions reported during the phase III studies VM16550 and MF4411 in postmenopausal women receiving the drug as an intravenous injection of 3 mg every 3 months or ibandronic acid at a dose of 2.5 mg orally daily and during postmarketing use:

* See below for additional information.

† Identified during post-marketing use.

Description of selected adverse reactions

Flu-like illness

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

Osteonecrosis of the jaw (ONJ)

Cases of OAB have been reported, predominantly in patients with malignancies treated with drugs that inhibit bone resorption, including ibandronic acid (see section 4.4). Cases of OAB have been reported during post-marketing use of ibandronic acid.

Inflammatory ocular disorders, such as uveitis, episcleritis, and scleritis, have been reported with ibandronic acid. In some cases, these disorders resolved only after discontinuation of ibandronic acid.

Anaphylactic reaction/shock

Cases of anaphylactic reaction/shock, including fatal cases, have been observed in patients treated with intravenous ibandronic acid.

Reporting of suspected adverse reactions

Reporting adverse reactions after the registration of a medicinal product is important. This allows monitoring of the benefit/risk ratio of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua

Expiration date

2 years.

Storage conditions

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

Incompatibility

Vivanat Rompharm, solution for injection, should not be mixed with solutions containing calcium or with other drugs for intravenous use.

Packaging

3 ml in a pre-filled syringe with a capacity of 5.0 ml; 1 or 4 pre-filled syringes in a blister together with 1 or 4 needles in a cardboard box.

Vacation category

According to the recipe.

Producer

K.T. ROMPHARM COMPANY SRL

Location of the manufacturer and address of its place of business.

Eroilor St. No. 1A, Otopeni, 075100, Ilfov County, Romania – Romfarm 1 and Romfarm 2 buildings.