Bonablast film-coated tablets 50 mg blister No. 28

Instructions Bonablast film-coated tablets 50 mg blister No. 28

Composition

active ingredient: ibandronic acid;

1 film-coated tablet contains 50 mg of ibandronic acid, equivalent to 56.25 mg of ibandronate sodium monohydrate;

excipients: povidone, microcrystalline cellulose, pregelatinized starch, crospovidone, colloidal anhydrous silica, glycerol dibehenate; film coating: Opadry II white OY-LS-28908: (titanium dioxide (E 171), lactose monohydrate; hypromellose 15 CP, polyethylene glycol, hypromellose 3 CP, hypromellose 50 CP).

Dosage form

Film-coated tablets.

Main physicochemical properties: round, biconvex tablets of white color.

Pharmacotherapeutic group

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

Pharmacological properties

Pharmacodynamics.

Ibandronic acid is a bisphosphonate that specifically acts on bone tissue. It has a selective effect on bone tissue due to its high affinity for the mineral components of bone tissue. It inhibits osteoclast activity, although the exact mechanism is still unknown.

In vivo, ibandronic acid prevents bone destruction caused by experimentally induced gonadal blockade, retinoids, tumors and tumor extracts. Inhibition of endogenous bone resorption has also been documented in 45Ca kinetic studies - by the release of radioactive tetracycline, which was previously introduced into the bone tissue. Ibandronic acid does not affect bone mineralization when administered at doses significantly exceeding the pharmacologically effective.

Bone resorption due to malignancy is characterised by excessive bone resorption that is not balanced by adequate bone formation. Ibandronic acid selectively inhibits osteoclast activity, reducing bone resorption and thus reducing the skeletal complications of malignancy.

In clinical studies in patients with breast cancer and bone metastases, a dose-dependent inhibitory effect on bone osteolysis, as determined by bone resorption markers, and a dose-dependent effect on skeletal damage were demonstrated.

Clinical trials in the treatment of tumor-induced hypercalcemia.

Clinical studies in hypercalcaemia of malignancy have shown that the inhibitory effect of ibandronic acid on tumour-induced osteolysis, and in particular on tumour-induced hypercalcaemia, is characterised by a reduction in serum calcium levels and urinary calcium excretion.

Within the dose range recommended for treatment, the following response rates with corresponding confidence intervals have been shown in clinical trials for patients with corrected serum albumin and serum calcium ≥ 3.0 mmol/L after adequate rehydration.

For these patients and dosages, the median time to normocalcemia was 4-7 days. The median time to relapse (return of albumin-corrected serum calcium above 3.0 mmol/L) was 18-26 days.

Clinical trials on the prevention of skeletal injuries in patients with breast cancer and bone metastases.

Clinical studies in patients with breast cancer and bone metastases have shown that there is a dose-dependent inhibitory effect on bone osteolysis, as expressed by markers of bone resorption, and a dose-dependent effect on skeletal damage.

Prevention of skeletal events in patients with breast cancer and bone metastases using intravenous ibandronic acid 6 mg was evaluated in one randomised, placebo-controlled phase III study of 96 weeks duration. Patients with breast cancer and radiologically confirmed bone metastases were randomised to receive placebo (158 patients) or ibandronic acid 6 mg (154 patients). The results of this trial are summarised below. Primary efficacy endpoints.

The primary endpoint of the trial was the cutaneous morbidity rate (SMPR). This was a composite endpoint that had the following skeletal-related events (SREs) as subcomponents:

- radiation therapy to bones to treat fractures/future fractures;

- bone surgery to treat fractures;

- vertebral fractures;

- non-vertebral fractures.

The SMPR analysis was time-adjusted and considered that one or more events occurring within a single 12-week period could be potentially related. Therefore, multiple events were counted only once for the purposes of the analysis. The data from this study demonstrated a significant advantage for ibandronic acid 6 mg intravenous over placebo in reducing SREs as measured by time-adjusted SMPR (p = 0.004). The number of SREs was also significantly reduced with ibandronic acid 6 mg, and the risk of SREs was reduced by 40% compared with placebo (relative risk 0.6, p = 0.003).

A statistically significant improvement in bone pain score was demonstrated for ibandronic acid 6 mg intravenously compared with placebo. The reduction in pain was consistently below baseline throughout the study and was accompanied by a significant reduction in analgesic use. The deterioration in quality of life was significantly less in patients receiving ibandronic acid compared with placebo.

Patients treated with ibandronic acid showed a significant reduction in urinary markers of bone resorption (pyridinoline and deoxypyridinoline), which was statistically significant compared to placebo.

A study of 130 patients with metastatic breast cancer compared the safety of ibandronic acid administered over 1 hour or 15 minutes. No differences in renal function were observed. The overall adverse event profile of ibandronic acid following a 15-minute infusion was consistent with the known safety profile over longer infusion times, and no new safety concerns were identified for use over a 15-minute infusion.

The 15-minute infusion time has not been studied in cancer patients with creatinine clearance < 50 mL/min. Pediatric patients.

The safety and efficacy of ibandronic acid in children and adolescents under 18 years of age have not been established. Data are not available.

Pharmacokinetics.

Absorption.

After oral administration, ibandronic acid is rapidly absorbed from the upper gastrointestinal tract. The time to reach maximum plasma concentrations is 0.5-2 hours (median 1 hour) after administration in the fasted state, and the absolute bioavailability is approximately 0.6%. Absorption is impaired when taken with food or drink (other than plain water). Bioavailability is reduced by approximately 90% when taken with a normal breakfast compared to when taken in the fasted state. When ibandronic acid is taken 30 minutes before a meal, bioavailability is reduced by approximately 30%. When ibandronic acid is taken 60 minutes before a meal, there is no significant reduction in bioavailability.

Bioavailability is reduced by approximately 75% when Bonablast tablets are taken 2 hours after a standard meal. Therefore, Bonablast tablets should be taken in the morning (after a fast of at least 6 hours) and continued on an empty stomach for at least 30 minutes after taking Bonablast (see section 4.2).

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 drug penetrates and accumulates in bone. Plasma protein binding is approximately 87% at therapeutic concentrations, suggesting a low potential for drug interactions due to displacement.

Metabolism.

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

Breeding.

The absorbed portion of ibandronic acid is eliminated from the bloodstream by bone resorption (approximately 40-50%), the remainder is excreted unchanged by the kidneys. The unabsorbed portion of ibandronic acid is excreted unchanged in the faeces. The apparent half-life is wide and depends on the dose used and the sensitivity of the assay, but the apparent terminal half-life is in the range of 10-60 hours. However, initial plasma levels of the drug decline rapidly and reach 10% of peak levels within 3 hours and 8 hours after intravenous and oral administration, respectively.

Total clearance of ibandronic acid is low and averages 84-160 ml/min. Renal clearance (approximately 60 ml/min in healthy postmenopausal women) accounts for 50-60% of total 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 do not appear to involve the known acidic and basic transport systems involved in the excretion of other active substances. Furthermore, ibandronic acid does not inhibit the major hepatic P450 isoenzymes in humans and does not induce the cytochrome P450 system in rats.

Pharmacokinetics in special cases.

Sex.

The bioavailability and pharmacokinetics of ibandronic acid are independent of gender. Race.

There are no data on clinically significant inter-ethnic differences between patients of Mongoloid and Caucasian race in the distribution of ibandronic acid. There are insufficient data on patients of Negroid race.

Renal clearance of ibandronic acid in patients with varying degrees of renal impairment is related to creatinine clearance. In subjects with severe renal impairment (creatinine clearance ≤30 ml/min) given 10 mg ibandronic acid orally for 21 days, plasma concentrations were 2-3 times higher than in subjects with normal renal function (creatinine clearance ≥80 ml/min). Total clearance of ibandronic acid was reduced to 44 ml/min in subjects with severe renal impairment compared to 129 ml/min in subjects with normal renal function. No dose adjustment is required in patients with mild renal impairment (creatinine clearance ≥50 ml and <80 ml/min). For subjects with moderate renal impairment (creatinine clearance ≥30 and <50 mL/min) and severe renal impairment (creatinine clearance <30 mL/min), dose adjustment is recommended (see section 4.2).

Patients with hepatic impairment (see section 4.2). 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 metabolised but is excreted by the kidneys and by absorption into bone tissue. Therefore, no dose adjustment is required in patients with hepatic impairment. Since the binding of ibandronic acid to plasma proteins at therapeutic concentrations is negligible (approximately 87%), it is unlikely that hypoproteinaemia in severe liver disease will lead to a clinically significant increase in free drug concentrations.

Age (see section "Method of administration and dosage").

The pharmacokinetic parameters studied 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 Bonablast in children under 18 years of age.

Indication

The drug is indicated in adult patients for: prevention of skeletal injuries (pathological fractures, bone lesions requiring radiation therapy or surgical treatment) in patients with breast cancer and metastatic bone lesions.

Contraindication

Hypersensitivity to ibandronic acid or to any of the other ingredients of the drug. Hypocalcemia. Disease of the esophagus with delayed esophageal emptying, e.g. stricture, achalasia. Inability to remain upright (standing or sitting) for at least 60 minutes.

Interaction with other medicinal products and other types of interactions

Drug interaction with food.

Calcium-containing foods, including milk, and other polyvalent cations (aluminum, magnesium, iron) may interfere with the absorption of Bonablast. Therefore, these foods, including food, should be taken at least 30 minutes after oral administration of Bonablast. Bioavailability was reduced by approximately 75% when Bonablast tablets were administered 2 hours after a standard meal. Therefore, Bonablast should be taken in the morning (after a minimum of 6 hours of fasting) and continued on an empty stomach for 30 minutes after administration (see section 4.2).

Interaction with other drugs.

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 by renal excretion and is not subject to biotransformation.

H2 antagonists and other drugs that increase gastric pH.

In a study in healthy male and postmenopausal women, intravenous ranitidine increased the bioavailability of ibandronic acid by approximately 20% (which is within the normal variability of ibandronic acid bioavailability), possibly by reducing gastric acidity. However, no dose adjustment of Bonablast is required when administered concomitantly with H2-antagonists or other drugs that increase gastric acidity.

Acetylsalicylic acid and non-steroidal anti-inflammatory drugs (NSAIDs). Since acetylsalicylic acid, NSAIDs and bisphosphonates can cause gastrointestinal irritation, NSAIDs should be used with caution simultaneously with Bonablast (see section "Special instructions").

Aminoglycosides.

Bisphosphonates should be used with caution with aminoglycosides, as both substances may lower serum calcium levels over a prolonged period of time.

Also, when using these drugs simultaneously, attention should be paid to hypomagnesemia.

Application features

Hypocalcemia and other disorders of bone and mineral metabolism should be corrected before starting treatment with Bonablast. Patients should consume adequate amounts of calcium and vitamin D. If the patient does not receive enough calcium and/or vitamin D from food, they should be supplemented with these nutrients.

Gastrointestinal tract irritation.

Oral bisphosphonates may cause local irritation of the upper gastrointestinal mucosa. Due to these potential effects and the potential for worsening of the underlying disease, caution should be exercised when using Bonablast in patients with active upper gastrointestinal disease (Barrett's esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis, ulcers). Adverse reactions such as esophagitis, esophageal ulcers, and esophageal erosions, some of which were severe and required hospitalization, and rarely with bleeding or subsequent stricture or perforation, have been reported with oral bisphosphonates. The risk of severe esophageal adverse reactions is higher in patients who do not follow dosing recommendations and/or who continue to take oral bisphosphonates after developing symptoms suggestive of esophageal irritation. Therefore, patients should strictly follow the dosage recommendations (see section “Method of administration and dosage”).

Physicians should be alert to any signs and symptoms suggestive of a possible esophageal reaction or esophageal irritation and inform patients to discontinue Bonablast and seek medical attention if dysphagia, pain upon swallowing, chest pain, or new or worsening heartburn occur.

Although no increased risk was observed in controlled clinical trials, cases of gastric and duodenal ulcers, some of which were severe and complicated, have been reported during post-marketing use of oral bisphosphonates.

Acetylsalicylic acid and non-steroidal anti-inflammatory drugs (NSAIDs): Since acetylsalicylic acid, NSAIDs and bisphosphonates may cause gastrointestinal irritation, caution should be exercised when these medicinal products are used concomitantly with Bonablast.

Osteonecrosis of the jaw bones.

Osteonecrosis of the jaw (ONJ) has been reported very rarely in post-marketing experience in patients receiving ibandronic acid for oncological indications (see section 4.8).

The start of treatment or a new course of treatment should be postponed in patients with unhealed open soft tissue lesions in the oral cavity. Before starting treatment with Bonablast, patients with concomitant risk factors are recommended to undergo a dental examination with appropriate preventive intervention and an individual benefit-risk assessment. When assessing the risk of osteonecrosis of the jaw in a patient, the following risk factors should be taken into account:

- the potency of the drug that inhibits bone resorption (the risk is higher for compounds with high potency), the route of administration (the risk is higher with parenteral administration), and the cumulative dose of bone resorption therapy;

- malignant neoplasms, concomitant pathological conditions (in particular, anemia, coagulopathy, infection), smoking;

- concomitant treatment: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy 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 Bonablast, all patients should be advised to maintain good oral hygiene, have regular dental check-ups and promptly report any oral symptoms such as tooth mobility, pain or swelling, or non-healing ulcers or discharge. During treatment, invasive dental procedures should only be undertaken after careful consideration and should be avoided in the immediate post-treatment period after Bonablast administration. The management plan for patients who develop osteonecrosis of the jaw should be developed in close collaboration with a dentist or maxillofacial surgeon experienced in the management of osteonecrosis of the jaw. Temporary interruption of Bonablast treatment should be considered until the condition improves and, if possible, associated 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 therapy. 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 subtrochanteric and diaphyseal fractures of the femur have been reported with bisphosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or oblique fractures can occur anywhere along the femur, from just below the lesser trochanter to just above the epicondyle. These fractures occur after minimal or no trauma, and some patients experience hip or groin pain, often associated with the features of a stress fracture, for several weeks to months before the fracture manifests as a complete femoral fracture. The fractures are often bilateral, so the other hip should also be examined in patients receiving bisphosphonate therapy who develop a diaphyseal femoral fracture. Nonunion of these fractures has also been reported. Discontinuation of bisphosphonates in patients with suspected atypical femoral fractures should be considered pending a complete evaluation of the patient, taking into account the individual benefit-risk assessment. Patients should be advised to report thigh, hip, or groin pain during bisphosphonate treatment; all patients with such symptoms should be evaluated for an incomplete femoral fracture.

Kidney failure.

In clinical studies, no signs of renal dysfunction were observed during long-term treatment with ibandronic acid. According to the clinical assessment of each patient, it is recommended to monitor renal function, serum calcium, phosphorus and magnesium during treatment.

Patients with hypersensitivity to other bisphosphonates.

Caution should be exercised in patients with hypersensitivity to other bisphosphonates. Hereditary problems. The drug Bonablast contains lactose and is not recommended for patients with hereditary problems (rarely occurring) associated with galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

Disposal of unused or expired medicinal products: Release of medicinal products into the environment should be minimised. The medicinal product should not be disposed of via wastewater or household waste. For disposal, use a so-called “waste collection system” if available.

Important information about excipients.

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

Use during pregnancy or breastfeeding

Pregnancy.

There are no adequate data from the use of ibandronic acid in pregnant women. Studies in rats have shown reproductive toxicity. The potential risk to humans is unknown. Bonablast should not be used during pregnancy. Breast-feeding.

It is not known whether ibandronic acid is excreted in human milk. Studies in lactating rats have shown low levels of ibandronic acid in milk after intravenous administration. Bonablast 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 and intravenous doses.

Ability to influence reaction speed when driving vehicles or other mechanisms

Given the specific pharmacodynamic and pharmacokinetic profile, as well as the reported adverse reactions, Bonablast is expected to have no or negligible influence on the ability to drive or use machines.

Method of administration and doses

Treatment with Bonablast should only be prescribed by a physician experienced in the treatment of malignant neoplasms.

Dosage. It is recommended to take 1 tablet (50 mg) once a day. The tablets should be taken orally in the morning (after at least 6 hours without food) and before the first food or liquid of the day. Similarly, other medicines and food supplements (including calcium) should be avoided before taking Bonablast tablets. Food should also be avoided for at least 30 minutes after taking Bonablast tablets. Plain water can be consumed at any time during the course of Bonablast therapy (see section “Interaction with other medicinal products and other types of interactions”). Water with a high calcium concentration should not be consumed. If there are concerns about potentially high levels of calcium in drinking water (hard water), it is recommended to use bottled water with a low mineral content.

The tablets should be swallowed whole, not chewed, with a glass of plain water (180-240 ml), in an upright position (sitting or standing).

Patients should not lie down for 60 minutes after taking Bonablast.

Do not chew, dissolve, or crush tablets due to the possibility of ulceration of the oropharyngeal mucosa.

Bonablast should be taken with plain water only.

Patients with hepatic insufficiency: No dose adjustment is required (see section "Pharmacokinetics in special cases").

Patients with renal insufficiency. For patients with mild renal impairment (creatinine clearance ≥50 ml and <80 ml/min), no dose adjustment is required. For patients with moderate renal impairment (creatinine clearance ≥30 and <50 ml/min), a dose reduction to 1 tablet of 50 mg every other day is recommended (see section "Pharmacokinetics in special cases"). For patients with severe renal impairment (creatinine clearance <30 ml/min), the recommended dose is 1 tablet of 50 mg once a week.

Elderly patients: No dose adjustment is required for the elderly (see section “Pharmacokinetics in special cases”).

Children.

The safety and efficacy of Bonablast have not been established in children under the age of 18. No data are available.

Overdose

Symptoms: In case of oral overdose, gastrointestinal reactions such as stomach upset, heartburn, esophagitis, gastritis or ulcer may occur.

Treatment. There is no specific information on the treatment of overdose with ibandronic acid. Milk or antacids should be administered to bind Bonablast. Vomiting should not be induced due to the risk of esophageal irritation. Patients should be kept in an upright position.

Adverse reactions

Summary of the safety profile. The most serious adverse reactions reported are anaphylactic reaction/shock, atypical hip fractures, osteonecrosis of the jaw, gastrointestinal irritation, eye inflammation (see “Description of selected adverse reactions” and section “Special warnings and precautions for use”). The most common adverse reaction associated with treatment was a decrease in serum calcium levels below normal (hypocalcaemia). The next most common adverse reaction was dyspepsia. The adverse reactions observed in the 2 pivotal phase III studies (prevention of skeletal events in patients with breast cancer and bone metastases: 286 patients treated with ibandronic acid 50 mg orally) and those observed during post-marketing use are listed below. Adverse reactions are listed below according to the MedDRA regulatory medical dictionary terminology by system organ class and frequency category. Adverse reactions are classified according to frequency as follows: 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), very rare (<1/10,000), not known (cannot be estimated from the available data). Within each group, adverse reactions are presented in order of decreasing incidence.

Blood and lymphatic system disorders: uncommon – anemia.

Immune system disorders: very rare: hypersensitivity†, bronchospasm†, angioedema†, anaphylactic reaction/shock**†; frequency unknown: exacerbation of asthma.

Metabolic disorders: common – hypocalcemia**.

Nervous system: uncommon – paresthesia (taste distortion).

On the part of the organs of vision: rarely - eye inflammation†**.

Gastrointestinal: common - esophagitis, abdominal pain, dyspepsia, nausea; uncommon - bleeding, duodenal ulcer, gastritis, dysphagia, dry mouth.

Skin and subcutaneous tissue disorders: uncommon - pruritus; very rare - Stevens-Johnson syndrome†, erythema multiforme†, bullous dermatitis†. Musculoskeletal and connective tissue disorders: uncommon - atypical subtrochanteric and diaphyseal fractures of the femur†; very rare - osteonecrosis of the jaw†**. Osteonecrosis of the external auditory canal (a class adverse reaction of bisphosphonates)†.

From the urinary system: uncommon - azotemia (uremia).

General disorders and administration site conditions: common - asthenia; uncommon - chest pain, influenza-like illness, malaise, pain.

Investigations: uncommon – increased serum parathyroid hormone levels. ** See below for details.

† Identified during post-marketing use.

Description of selected adverse reactions.

Hypocalcemia: Decreased renal calcium excretion may be accompanied by a decrease in serum phosphate levels that does not require therapeutic intervention. Serum calcium levels may fall to levels consistent with hypocalcemia.

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

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

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

Reporting suspected adverse reactions after the marketing authorisation of a medicinal product is an important procedure. It allows for continued monitoring of the benefit-risk balance of the medicinal product in question. Healthcare professionals should report any suspected adverse reactions via the national reporting system.

Expiration date

5 years.

Storage conditions

This medicinal product does not require any special storage conditions. Keep out of the reach of children.

Packaging

7 tablets in a blister, 4 blisters in a cardboard pack.

Vacation category

According to the recipe.

Producer

PHARMATEN SA

Location of the manufacturer and address of its place of business

Dervenakion 6, Pallini Attica, 15351, Greece.