Instructions for use Ibandronic acid-Vista 150 mg film-coated tablets 150 mg No. 3
Composition
active ingredient: ibandronic acid;
1 film-coated tablet contains 150 mg of ibandronic acid in the form of 168.75 mg of ibandronate sodium monohydrate;
Excipients: lactose monohydrate; microcrystalline cellulose; crospovidone (type A); colloidal anhydrous silica, sodium stearyl fumarate;
film coating (Opadry II white): polyvinyl alcohol, titanium dioxide (E 171), talc, macrogol 3350.
Dosage form
Film-coated tablets.
Main physicochemical properties: oblong tablets, white to almost white in color, engraved with “I9ВЕ” on one side and “150” on the other.
Pharmacotherapeutic group
Drugs used to treat bone disease. Drugs that affect bone structure and mineralization. Bisphosphonates. Ibandronic acid.
ATX code M05V A06.
Pharmacological properties
Pharmacodynamics
Mechanism of action
Ibandronic acid is a highly active nitrogen-containing bisphosphonate that selectively acts on bone tissue and specifically inhibits osteoclast activity and has no direct effect on bone formation. The drug does not affect the process of osteoclast pool replenishment. In women during menopause, it 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
Ibandronic acid inhibits bone resorption. In vivo, ibandronic acid prevents bone destruction induced experimentally by gonadal blockade, retinoids, tumors and tumor extracts. In young (rapidly growing) rats, 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 exceeding more than 5000 times the dose required for the treatment of osteoporosis.
Daily long-term use and intermittent use (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 used 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 human clinical trial (MF 4411), in which ibandronic acid demonstrated efficacy in preventing fractures.
In animal models, ibandronic acid produces biochemical changes indicative of a dose-dependent inhibition of bone resorption, including a decrease in urinary biochemical markers of bone collagen degradation (such as deoxypyridinoline and cross-linked N-telopeptide of type I collagen).
Pharmacokinetics
The primary pharmacological effects of ibandronic acid on bone are not directly related to the actual plasma concentrations of ibandronic acid, as demonstrated in various animal and human studies.
Absorption.
After oral administration, ibandronic acid is rapidly absorbed from the upper gastrointestinal tract. Plasma concentrations increase proportionally with increasing doses up to 50 mg orally and significantly more with further increases in dose. Peak plasma concentrations are reached within 30 minutes to 2 hours (mean 1 hour) under fasting conditions, with absolute bioavailability of 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 standard breakfast compared to when taken on an empty stomach. There is no significant reduction in bioavailability when ibandronic acid is taken 60 minutes before the first meal. When food or drink is taken less than 60 minutes after ibandronic acid intake, bioavailability and bone mineral density gains are reduced.
Distribution.
After first systemic distribution, ibandronic acid is rapidly bound to bone or excreted in the urine. In humans, the apparent final 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 85-87% (determined in vitro at therapeutic concentrations of ibandronic acid), therefore, due to displacement, there is a low potential for drug interactions.
Metabolism.
There is no evidence that ibandronic acid is metabolized in animals or humans.
Breeding.
The apparent half-life range is wide and varies between 10 and 72 hours. Since the calculated values are largely dependent on the duration of the study, the dose used, and the sensitivity of the assay, the terminal half-life is likely to be significantly longer, as with other bisphosphonates. Initial plasma levels of the drug decline rapidly and reach 10% of the maximum value 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 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 the known acid and base 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.
Patients with renal failure.
Renal clearance of ibandronic acid in patients with varying degrees of renal impairment is linearly related to creatinine clearance. No dose adjustment is required in patients with mild to moderate renal impairment (creatinine clearance ≥ 30 ml/min).
In subjects with severe renal impairment (creatinine clearance < 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 subjects with normal renal function, and the total clearance of ibandronic acid was 44 ml/min. After intravenous administration of 0.5 mg ibandronic acid, total, renal and non-renal clearance were reduced by 67%, 77% and 50%, respectively, in subjects with severe renal impairment, but no reduction in tolerability due to increased exposure was observed. Due to limited clinical experience, the use of the drug is not recommended in 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 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 for patients with hepatic impairment.
Elderly patients (see sections “Method of administration and dosage”).
Multivariate analysis showed that the pharmacokinetic parameters studied were independent of age. Since renal function decreases with age, this is the only factor to be considered (see section “Patients with renal impairment”).
Children (see section "Method of administration and dosage").
There are no data on the use of the drug 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 other component of the medicinal product (see section "Composition").
Hypocalcemia.
Esophageal disease with delayed esophageal emptying, such as 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-food interaction.
The oral bioavailability of ibandronic acid is generally reduced in the presence of food. In particular, calcium-containing foods, including milk, and other polyvalent cations (aluminum, magnesium, iron) may impair absorption of the drug, which is consistent with the results obtained in animal studies. Therefore, the drug should be taken after an overnight fast (at least 6 hours) and food should not be consumed for 1 hour after taking the drug (see section "Method of administration and dosage").
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.
Calcium preparations (supplements), antacids and some other drugs containing polyvalent cations.
Calcium supplements, antacids, and some other oral medications containing polyvalent cations (aluminum, magnesium, iron) may interfere with the absorption of the drug. Therefore, patients should not take other oral medications for at least 6 hours before and 1 hour after taking the drug.
Acetylsalicylic acid and NSAIDs.
Since acetylsalicylic acid, nonsteroidal anti-inflammatory drugs (NSAIDs) and bisphosphonates can cause gastrointestinal irritation, NSAIDs should be used with caution simultaneously with the drug (see section "Special warnings and precautions for use").
H2 blockers and proton pump inhibitors.
Study BM16549 compared ibandronic acid dosing regimens (daily and once monthly) in 1500 patients, with 14% and 18% of patients also receiving H2-receptor blockers or proton pump inhibitors after 1 and 2 years, respectively. The incidence of upper gastrointestinal events in patients receiving ibandronic acid 150 mg once monthly was similar to that in patients receiving ibandronic acid 2.5 mg daily.
In a study in healthy male and postmenopausal women, intravenous ranitidine increased the bioavailability of ibandronic acid by approximately 20%, possibly by reducing gastric acidity. However, since this increase is within the normal range of ibandronic acid bioavailability, no dose adjustment is required when co-administered with H2-receptor blockers or other drugs that increase gastric pH.
Application features
Hypocalcemia.
Hypocalcemia should be corrected before starting the drug. All other disorders of bone and mineral metabolism should also be effectively treated. Adequate calcium and vitamin D intake should be ensured, as this is important for all patients.
Gastrointestinal tract irritation.
Oral bisphosphonates may cause local irritation of the upper gastrointestinal mucosa.
Due to these possible effects and the possibility of worsening of the underlying disease, caution should be exercised when using the drug in patients with active upper gastrointestinal diseases (Barrett's esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis or ulcers). Adverse reactions such as esophagitis, esophageal ulcers, esophageal erosions, which in some cases were severe and required hospitalization, rarely with bleeding or with subsequent development of esophageal stricture or perforation, have been reported with the use of oral bisphosphonates. The risk of developing serious esophageal adverse reactions is higher in patients who do not comply with the dosage recommendations and/or in those who continue to take oral bisphosphonates after developing symptoms suggestive of esophageal irritation. Therefore, patients should pay special attention to compliance with the dosage recommendations (see section "Method and dosage"). Physicians should be alert to symptoms suggestive of a possible esophageal reaction and advise patients to discontinue the drug and seek medical attention if dysphagia, pain on swallowing, chest pain, new or worsening heartburn occurs. Although no increased risk was observed in controlled clinical trials, cases of gastric and duodenal ulcers have been reported with oral bisphosphonates in the postmarketing setting. Some of these were severe and complicated. Since NSAIDs and bisphosphonates can cause gastrointestinal irritation, caution should be exercised when NSAIDs are used concomitantly. Osteonecrosis of the jaw
Osteonecrosis of the jaw has been observed very rarely during post-marketing use in patients receiving ibandronic acid for oncological indications (see section 4.8).
The start of treatment or a new course of treatment should be delayed in patients with unhealed open soft tissue lesions of the oral cavity. Before starting treatment with ibandronic acid, patients with concomitant risk factors are recommended to undergo a dental examination with appropriate preventive intervention and an individual benefit/risk assessment.
- The potency of the drug that inhibits bone resorption (the risk is higher with highly potent compounds), the route of administration (the risk is higher with parenteral administration), and the cumulative dose of bone resorption therapy.
- Malignant neoplasms, concomitant pathological conditions (including 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 ibandronic acid, 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 undertaken after careful consideration and should be avoided during and shortly after treatment with ibandronic acid. The management of patients who develop osteonecrosis of the jaw should be planned in close collaboration with a dentist or maxillofacial surgeon experienced in the management of osteonecrosis of the jaw. Temporary interruption of ibandronic acid treatment should be considered until the condition improves and associated risk factors are reduced.
Osteonecrosis of the external auditory canal.
Osteonecrosis of the external auditory canal has been reported with bisphosphonates, mainly with long-term therapy. Possible risk factors for osteonecrosis of the external auditory canal include steroid use and chemotherapy and/or local risk factors such as infection or trauma. The possibility of osteonecrosis of the external auditory canal should be considered in patients taking bisphosphonates who have ear symptoms, including chronic ear infections.
Atypical hip fractures.
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 short oblique fractures can occur anywhere along the femur, from just below the lesser trochanter to just above the supracondylar eminence. 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. Poor healing of these fractures has also been reported. Until the patient's condition is evaluated, including an individual benefit-risk assessment, consideration should be given to discontinuing bisphosphonates in patients with suspected atypical femoral 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. Renal failure.
Due to limited clinical experience, the drug is not recommended for use in patients with creatinine clearance less than 30 ml/min (see section "Pharmacokinetics").
Important information about excipients.
Galactose intolerance.
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
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.
The medicinal product is intended for use in postmenopausal women only. The medicinal product should not be used in women of childbearing potential. 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 to humans is unknown. The medicinal product should not be used during pregnancy.
Breastfeeding period.
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. The drug 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 when administered orally.
Ability to influence reaction speed when driving vehicles or other mechanisms
Based on the pharmacodynamic properties, pharmacokinetic profile and reported adverse reactions, ibandronic acid is expected to have no or negligible influence on the ability to drive and use machines.
Method of administration and doses
Dosage.
For the treatment of osteoporosis, the recommended dose is 1 tablet of 150 mg orally once a month. The tablets should be taken on the same day each month. The medicine should be taken after an overnight fast (at least 6 hours) and 60 minutes before the first food or liquid (other than water) of the day (see section “Interaction with other medicines and other types of interactions”) or other oral medicines or supplements (including calcium).
The patient should be informed that if a monthly dose is missed, the patient should take 1 150 mg tablet the next morning as soon as they remember, unless the next scheduled dose is within the next 7 days. The patient should take the next dose on the day of the month that is scheduled. If the next scheduled dose is within the next 7 days, the dose should be missed and the next dose should be taken on the day of the month that is scheduled and the patient should continue taking 1 tablet per month on the day of the month that is scheduled. 2 tablets should not be taken within one week. Patients should take calcium and/or vitamin D supplements if dietary intake is inadequate (see sections 4.4 and 4.5). The optimal duration of bisphosphonate treatment for osteoporosis has not been established. The need for continued treatment should be reviewed periodically for each patient individually, taking into account the benefits and potential risks of using the drug, particularly after 5 or more years of use. Special patient groups.
Patients with renal failure.
Due to limited clinical experience, the drug is not recommended for patients with creatinine clearance below 30 ml/min (see sections "Pharmacokinetics" and "Special warnings and precautions for use").
No dose adjustment is required for patients with mild or moderate renal impairment if creatinine clearance is equal to or greater than 30 ml/min.
Patients with liver failure.
No dose adjustment is required (see section "Pharmacokinetics").
Elderly patients (>65 years).
No dose adjustment is required (see section "Pharmacokinetics").
Method of application.
– The tablets should be swallowed whole with 1 glass of plain water (180-240 ml) while sitting or standing upright. Water with a high calcium concentration should not be consumed. If there is concern about potentially high calcium levels in drinking water (hard water), it is recommended to consume bottled water with a low mineral content.
– Patients should not lie down for 60 minutes after taking the medication.
– The medicine should be taken with plain water only.
– Patients should not chew or suck the tablet due to the possibility of ulceration of the oropharyngeal mucosa.
Children
There is no relevant experience with the use of the drug in children under 18 years of age. The use of the drug has not been studied in children under 18 years of age (see sections “Pharmacodynamics” and “Pharmacokinetics”).
Overdose
There is no specific information on the treatment of overdose with ibandronic acid. Symptoms: However, based on current knowledge of bisphosphonates, upper gastrointestinal adverse reactions such as gastric upset, dyspepsia, oesophagitis, gastritis, ulcer or hypocalcaemia may occur.
Treatment: Milk or antacids should be administered to bind ibandronic acid, and any adverse reactions should be treated symptomatically. Vomiting should not be induced due to the risk of esophageal irritation. Patients should be kept in an upright position.
Adverse reactions
Security profile summary.
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 frequently reported adverse reactions were arthralgia and flu-like symptoms. These symptoms were usually associated with the first dose, were generally short-lived, mild to moderate in severity, resolved most often with continued treatment, and did not require medical intervention (see “Description of selected adverse reactions”).
Below is a complete list of known side effects.
Adverse reactions are listed below according to the MedDRA terminology by system organ class and frequency category. Adverse reactions are classified according to frequency as 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 frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Immune system disorders: uncommon – exacerbation of bronchial asthma; rare – hypersensitivity reactions; very rare – anaphylactic reaction/shock*†.
Nervous system disorders: common – headache; uncommon – dizziness.
On the part of the organs of vision: rarely - eye inflammation*†.
From the digestive system: common - esophagitis, gastritis, gastroesophageal reflux disease, dyspepsia, diarrhea, abdominal pain, nausea; uncommon - esophagitis, including esophageal ulceration or strictures and dysphagia, vomiting, flatulence; rare - duodenitis.
Skin and subcutaneous tissue disorders: common - rash; rare - angioedema, facial edema, urticaria; very rare - Stevens-Johnson syndrome, erythema multiforme, bullous dermatitis.
Musculoskeletal and connective tissue disorders: common: arthralgia, myalgia, musculoskeletal pain, muscle cramps, musculoskeletal rigidity; uncommon: back pain; rare: atypical subacromial and diaphyseal femoral fractures; very rare: osteonecrosis of the jaw; osteonecrosis of the external auditory canal (a class adverse reaction of bisphosphonates)†. General disorders: common: influenza-like illness*; uncommon: weakness.
*See below.
†Identified during post-marketing use.
Description of selected adverse reactions.
Adverse reactions from the digestive system.
Patients with a prior history of gastrointestinal disease, including patients with peptic ulcer disease without recent bleeding or hospitalization and patients with dyspepsia or reflux controlled by medical treatment, were included in the once-monthly study. In these patients, there was no difference in the incidence of upper gastrointestinal adverse events with the 150 mg once-monthly dose compared with the 2.5 mg/day dose.
Flu-like illness.
Influenza-like illness included symptoms such as acute phase reactions or symptoms such as myalgia, arthralgia, fever, chills, fatigue, nausea, loss of appetite, and bone pain.
Osteonecrosis of the jaw bones.
Cases of osteonecrosis of the jaw have been reported, predominantly in patients with malignancies, who have been treated with medicinal products 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.
Ophthalmia.
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 ibandronic acid.
Anaphylactic reaction/shock.
Cases of anaphylactic reaction/shock, including fatal cases, have been reported in patients treated with intravenous ibandronic acid. Report suspected adverse reactions.
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
3 years.
Storage conditions
Store in original packaging at a temperature not exceeding 25 ° C. Keep out of the reach of children.
Packaging
3 tablets in a blister. 1 blister in a cardboard box.
Vacation category
According to the recipe.
Producer
Sinton Hispania, S. L.
Location of the manufacturer and address of its place of business
Calle C/Castello, no. 1, Sant Boi de Llobregat, Barcelona, 08830, Spain.
