Bonablast

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BONABLAST (BONABLAST)

Composition:

Active substance: ibandronic acid;

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

Excipients: povidone, microcrystalline cellulose, pregelatinized starch, crospovidone, colloidal anhydrous silicon dioxide, 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).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, biconvex tablets.

Pharmacotherapeutic group.

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

Pharmacological properties.

Pharmacodynamics.

Ibandronic acid is a bisphosphonate that acts specifically on bone tissue. It exerts a selective effect on bone tissue due to its high affinity for the mineral components of bone. It inhibits osteoclast activity, although the precise mechanism is not yet known.

In vivo, ibandronic acid prevents bone destruction caused by experimentally induced suppression of gonadal function, retinoids, tumors, and tumor extracts. Inhibition of endogenous bone resorption has also been documented in kinetic studies using 45Ca and by measuring the release of radiolabeled tetracycline previously incorporated into bone tissue. Ibandronic acid does not affect bone mineralization when administered at doses significantly exceeding pharmacologically effective levels.

Bone resorption associated with malignancy is characterized by excessive bone resorption that is not balanced by adequate bone formation. Ibandronic acid selectively inhibits osteoclast activity, thereby reducing bone resorption and consequently decreasing skeletal complications of malignancy.

In clinical studies in patients with breast cancer and bone metastases, a dose-dependent inhibitory effect on bone osteolysis has been demonstrated, as assessed by markers of bone resorption, along with a dose-dependent effect on skeletal events.

Clinical studies in the treatment of tumor-induced hypercalcemia.

Clinical studies in malignancy-associated hypercalcemia have shown that the inhibitory effect of ibandronic acid on tumor-induced osteolysis, and particularly on tumor-induced hypercalcemia, is characterized by a reduction in serum calcium levels and urinary calcium excretion.

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

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

Clinical studies on prevention of skeletal events in patients with breast cancer and bone metastases.

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

Prevention of skeletal events in patients with breast cancer and bone metastases using intravenous administration of 6 mg of ibandronic acid was evaluated in one randomized, placebo-controlled, Phase III study lasting 96 weeks. Patients with breast cancer and radiologically confirmed bone metastases were randomized to receive either placebo (158 patients) or 6 mg of ibandronic acid (154 patients). Results of this trial are summarized below. Primary efficacy endpoints.

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

• Radiation therapy to bone for treatment of fractures/future fractures;
• Bone surgery for treatment of fractures;
• Vertebral fractures;
• Non-vertebral fractures.

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

Secondary efficacy endpoints.

A statistically significant improvement in bone pain score was demonstrated for intravenous 6 mg ibandronic acid compared to placebo. Pain reduction remained consistently below baseline levels throughout the study and was accompanied by significantly reduced analgesic use. Worsening of quality of life was significantly less in patients receiving ibandronic acid compared to placebo.

In patients receiving ibandronic acid, a marked reduction in urinary markers of bone resorption (pyridinoline and deoxypyridinoline) was observed, which was statistically significant compared to placebo.

In a study of 130 patients with metastatic breast cancer, the safety of ibandronic acid administered over 1 hour versus 15 minutes was compared. No differences in renal function parameters were observed. The overall safety profile of ibandronic acid after 15-minute infusion was consistent with the known safety profile during longer infusion times, and no new safety concerns were identified with the 15-minute infusion.

The 15-minute infusion duration 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 lacking.

Pharmacokinetics.

Absorption.

After oral administration, ibandronic acid is rapidly absorbed in the upper gastrointestinal tract. Time to maximum plasma concentration is 0.5–2 hours (median 1 hour) when administered fasting, with absolute bioavailability of approximately 0.6%. Absorption is impaired when administered with food or beverages (other than plain water). Bioavailability is reduced by approximately 90% when taken with a standard breakfast compared to administration on an empty stomach. When ibandronic acid is taken 30 minutes before food intake, bioavailability is reduced by approximately 30%. When ibandronic acid is taken 60 minutes before food intake, no significant reduction in bioavailability is observed.

Bioavailability is reduced by approximately 75% when Bonablast tablets are administered 2 hours after a standard meal. Therefore, Bonablast tablets should be taken in the morning (after at least 6 hours without food) and patients should remain fasting for at least 30 minutes after taking Bonablast (see section "Dosage and administration").

Distribution.

After initial systemic exposure, ibandronic acid rapidly binds to bone tissue or is excreted in urine. In humans, the apparent volume of distribution is at least 90 L, and approximately 40–50% of the drug circulating in blood penetrates and accumulates in bone tissue. At therapeutic concentrations, approximately 87% is bound to plasma proteins, thus indicating a low potential for interactions with other drugs due to displacement.

Metabolism.

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

Elimination.

The absorbed portion of ibandronic acid is removed from the bloodstream either by bone uptake (approximately 40–50%) or excreted unchanged by the kidneys. The portion not absorbed is excreted unchanged in feces. The range of apparent elimination half-life is broad and depends on the dose and analytical method sensitivity; however, the apparent terminal half-life ranges from 10 to 60 hours. However, initial plasma drug levels decline rapidly, reaching 10% of peak values within 3 hours and 8 hours after intravenous administration or 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 depends on creatinine clearance. The difference between apparent total and renal clearance reflects drug uptake by bone tissue.

Secretion pathways do not appear to involve known acidic or basic transport systems involved in the excretion of other active substances. Furthermore, ibandronic acid does not inhibit major human hepatic P450 isoenzymes and does not induce the cytochrome P450 system in rats.

Pharmacokinetics in special populations.

Gender.

Bioavailability and pharmacokinetic parameters of ibandronic acid are not influenced by gender. Race.

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

Patients with renal impairment.

Renal clearance of ibandronic acid in patients with varying degrees of renal impairment is correlated with creatinine clearance. In individuals with severe renal impairment (creatinine clearance ≤30 ml/min) receiving 10 mg oral ibandronic acid for 21 days, plasma concentrations were 2–3 times higher than in individuals with normal renal function (creatinine clearance ≥80 ml/min). Total clearance of ibandronic acid was reduced to 44 ml/min in individuals with severe renal impairment compared to 129 ml/min in those with normal renal function. For patients with mild renal impairment (creatinine clearance ≥50 ml/min and <80 ml/min), dose adjustment is not required. For individuals with moderate renal impairment (creatinine clearance ≥30 to <50 ml/min) and severe renal impairment (creatinine clearance <30 ml/min), dose adjustment is recommended (see section "Dosage and administration").

Patients with hepatic impairment (see section "Dosage and administration"). There are no data on the pharmacokinetics of ibandronic acid in patients with hepatic impairment. The liver does not play a significant role in the clearance of ibandronic acid, which is not metabolized but excreted by the kidneys and via uptake into bone tissue. Therefore, dose adjustment is not required in patients with hepatic impairment. Since plasma protein binding of ibandronic acid at therapeutic concentrations is low (approximately 87%), it is unlikely that hypoalbuminemia in severe liver disease would lead to a clinically significant increase in free drug concentration.

Age (see section "Dosage and administration").

Studied pharmacokinetic parameters are not influenced by age. Since renal function declines with age, this is the only factor to consider (see section "Patients with renal impairment").

Children (see section "Dosage and administration").

There are no data on the use of Bonablast in children under 18 years of age.

Clinical characteristics.

Indications.

The medicinal product is indicated for adult patients for: prevention of skeletal-related events (pathological fractures, bone complications requiring radiation therapy or surgical intervention) in patients with breast cancer and metastatic bone involvement.

Contraindications.

Hypersensitivity to ibandronic acid or to any other component of the medicinal product. Hypocalcemia. Esophageal disorders with delayed esophageal emptying, such as stricture or achalasia. Inability to remain in an upright position (standing or sitting) for at least 60 minutes.

Interaction with other medicinal products and other forms of interaction.

Interaction of the medicinal product with food.

Food products containing calcium, including milk, and other polyvalent cations (aluminum, magnesium, iron) may interfere with the absorption of the medicinal product Bonablast. Therefore, such products, including food, should be consumed no earlier than 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 at least 6 hours without food intake) and fasting should be maintained for 30 minutes after administration of the medicinal product (see section "Dosage and administration").

Interaction with other medicinal products.

Metabolic interactions are considered unlikely, as ibandronic acid does not inhibit major human hepatic CYP450 isoenzymes and does not induce the hepatic cytochrome P450 system in rats (see section "Pharmacokinetics"). Ibandronic acid is eliminated via renal excretion and does not undergo biotransformation.

H2-receptor antagonists and other medicinal products that increase gastric pH.

In a study involving healthy male volunteers and postmenopausal women, intravenous ranitidine increased the bioavailability of ibandronic acid by approximately 20% (within the normal variability range of ibandronic acid bioavailability), possibly due to reduced gastric acidity. However, dose adjustment of Bonablast is not required when co-administered with H2-receptor antagonists or other medicinal products that increase gastric pH.

Acetylsalicylic acid and nonsteroidal anti-inflammatory drugs (NSAIDs). Since acetylsalicylic acid, NSAIDs, and bisphosphonates may cause gastrointestinal irritation, caution is required when using NSAIDs concomitantly with the medicinal product Bonablast (see section "Special precautions for use").

Aminoglycosides.

Bisphosphonates should be used with caution together with aminoglycosides, as both substances may reduce serum calcium levels for a prolonged period.

Additionally, hypomagnesemia should be monitored when these medicinal products are used concomitantly.

Special precautions for use.

Patients with impaired bone and mineral metabolism.

Hypocalcemia and other disturbances of bone tissue and mineral metabolism should be corrected before initiating treatment with Bonablast. Patients should receive adequate intake of calcium and vitamin D. If dietary intake of calcium and/or vitamin D is insufficient, supplementation with these agents should be considered.

Gastrointestinal irritation.

Oral bisphosphonates may cause local irritation of the upper gastrointestinal mucosa. Due to these potential effects and the possibility of worsening underlying conditions, caution should be exercised when using Bonablast in patients with active upper gastrointestinal disorders (Barrett’s esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis, peptic ulcers). Cases of adverse reactions such as esophagitis, esophageal ulcers, and esophageal erosions have been reported with oral bisphosphonates, some of which were severe and required hospitalization, and rarely resulted in bleeding or subsequent development of strictures or perforation. The risk of developing severe esophageal adverse reactions is higher in patients who do not follow dosing instructions and/or in individuals who continue taking oral bisphosphonates after developing symptoms indicative of esophageal irritation. Therefore, patients must strictly adhere to dosing recommendations (see section "Dosage and administration").

Physicians should be vigilant for any signs or symptoms suggesting possible esophageal reactions or esophageal irritation and should inform patients of the necessity to discontinue Bonablast and contact their physician if they experience dysphagia, pain upon swallowing, retrosternal pain, new or worsening heartburn.

Although an increased risk was not observed in controlled clinical trials, cases of gastric and duodenal ulcers have been reported during post-marketing use of oral bisphosphonates. Some of these cases were severe and associated with complications.

Acetylsalicylic acid and nonsteroidal anti-inflammatory drugs (NSAIDs). Since acetylsalicylic acid, NSAIDs, and bisphosphonates may cause gastrointestinal irritation, concomitant use of these medicinal products with Bonablast should be done with caution.

Osteonecrosis of the jaw (ONJ).

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

Initiation or re-initiation of treatment should be delayed in patients with unhealed open soft tissue lesions in the oral cavity. Prior to starting treatment with Bonablast, patients with concomitant risk factors are recommended to undergo a dental examination with appropriate preventive interventions and individual benefit-risk assessment. When assessing the risk of developing ONJ, the following risk factors should be considered:

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

During treatment with Bonablast, all patients should be advised to maintain proper oral hygiene, undergo regular dental check-ups, and promptly report any oral symptoms such as tooth mobility, pain, swelling, or non-healing ulcers or discharge. Invasive dental procedures during treatment should only be performed after careful consideration and should be avoided shortly after administration of Bonablast. The management plan for patients who develop ONJ should be developed in close collaboration between the physician and a dentist or oral and maxillofacial surgeon experienced in managing ONJ. Consideration should be given to temporarily interrupting treatment with Bonablast until improvement in condition and, if possible, reduction of concomitant risk factors.

Osteonecrosis of the external auditory canal.

Osteonecrosis of the external auditory canal has been reported with bisphosphonate use, primarily in association with long-term therapy. Potential risk factors for osteonecrosis of the external auditory canal include steroid hormone use, 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 present with ear symptoms, including chronic ear infections.

Atypical femoral fractures.

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

Atypical fractures of other long bones.

Atypical fractures of other long bones, such as the ulna and tibia, have been reported in patients receiving long-term bisphosphonate therapy. As with atypical femoral fractures, these fractures may occur after minor trauma or without trauma, and some patients experience prodromal pain before the fracture manifests as a complete fracture. In cases of ulnar fracture, this may be associated with repetitive stress due to prolonged use of walking aids (see section "Adverse reactions").

Renal impairment.

No signs of renal function impairment have been observed in clinical studies with long-term therapy using ibandronic acid. Based on clinical assessment of each patient, monitoring of renal function, and serum levels of calcium, phosphorus, and magnesium is recommended during treatment.

Patients with hypersensitivity to other bisphosphonates.

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

Disposal of unused or expired medicinal product: Environmental contamination should be minimized. The medicinal product should not be disposed of via wastewater or household waste. Disposal should be carried out via a "waste collection system" if available.

Important information on excipients.

If you have been diagnosed with intolerance to certain sugars, consult your doctor before taking this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy.

There are no adequate data on the use of ibandronic acid in pregnant women. Reproductive toxicity was observed in rat studies. The potential risk to humans is unknown. Bonablast should not be used during pregnancy.

Breastfeeding.

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

Fertility.

There are no data on the effect of ibandronic acid in humans. In reproductive studies in rats, ibandronic acid reduced fertility at high daily doses administered orally or intravenously.

Effect on ability to drive and use machines.

Given the pharmacodynamic and pharmacokinetic profile and the reported adverse reactions, Bonablast is expected to have no or negligible effect on the ability to drive or operate machinery.

Method of Administration and Dosage

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

Dosage. The recommended dose is 1 tablet (50 mg) once daily. The tablet should be taken orally in the morning (after at least 6 hours of fasting) and before the first intake of food or liquids of the day. Similarly, other medicinal products and dietary supplements (including calcium) should be avoided until after taking Bonablast tablets. Food should also be avoided for at least 30 minutes after taking Bonablast tablets. Plain water may be consumed at any time during Bonablast therapy (see section "Interaction with other medicinal products and other forms of interaction"). Water with a high calcium concentration should not be consumed. If there is concern regarding potentially high calcium levels in drinking water (hard water), it is recommended to use bottled water with low mineral content.

Tablets should be swallowed whole, not chewed, and taken with a glass of plain water (180–240 mL) while in an upright position (sitting or standing).

Patients should remain upright for at least 60 minutes after taking Bonablast.

Tablets should not be chewed, sucked, or crushed due to the risk of developing mucosal lesions in the oropharynx.

Bonablast should only be taken with plain water.

Special Dosage Recommendations.

Patients with hepatic impairment. Dose adjustment is not required (see section "Pharmacokinetics in Special Situations").

Patients with renal impairment. For patients with mild renal impairment (creatinine clearance ≥50 mL/min and <80 mL/min), no dose adjustment is necessary. For patients with moderate renal impairment (creatinine clearance ≥30 to <50 mL/min), the recommended dose is reduced to 1 tablet (50 mg) every other day (see section "Pharmacokinetics in Special Situations"). For patients with severe renal impairment (creatinine clearance <30 mL/min), the recommended dose is 1 tablet (50 mg) once weekly.

Elderly patients. Dose adjustment is not required for elderly patients (see section "Pharmacokinetics in Special Situations").

Children.

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

Overdose.

Symptoms. In cases of oral overdose, gastrointestinal reactions may occur, such as gastrointestinal disturbances, heartburn, esophagitis, gastritis, or ulceration.

Treatment. There is no specific information on the treatment of ibandronic acid overdose. To bind Bonablast, milk or antacids should be administered. Due to the risk of esophageal irritation, vomiting should not be induced. Patients should remain in an upright position.

Side effects.

Summary of safety profile.

The most serious adverse reactions reported are anaphylactic reaction/shock, atypical femoral fractures, osteonecrosis of the jaw, gastrointestinal irritation, and ocular 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 the normal range (hypocalcemia). The next most frequent adverse reaction was dyspepsia. The adverse reactions listed below were observed in two phase III pivotal studies (prevention of skeletal events in patients with breast cancer and bone metastases: 286 patients treated with 50 mg oral ibandronic acid), as well as those reported during post-marketing use. Adverse reactions are listed below according to the Medical Dictionary for Regulatory Activities (MedDRA) system organ class and frequency categories. Frequency categories are defined 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), and not known (cannot be estimated from available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.

Blood and lymphatic system disorders: uncommon – anaemia.

Immune system disorders: very rare – hypersensitivity†, bronchospasm†, angioedema†, anaphylactic reaction/shock**†; not known – asthma exacerbation.

Metabolism and nutrition disorders: common – hypocalcemia**.

Nervous system disorders: uncommon – paraesthesia, dysgeusia (taste disturbance).

Eye disorders: rare – eye inflammation†**.

Gastrointestinal disorders: common – oesophagitis, abdominal pain, dyspepsia, nausea; uncommon – gastrointestinal haemorrhage, 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: rare – atypical subtrochanteric and diaphyseal femoral fractures†; very rare – osteonecrosis of the jaw†**. Osteonecrosis of the external auditory canal (an adverse reaction characteristic of bisphosphonates as a class)†; not known – atypical fractures of long bones other than femur.

Renal and urinary disorders: uncommon – azotemia (uraemia).

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

Investigations: uncommon – increased serum parathyroid hormone level. ** See below for detailed information.

† Identified during post-marketing use.

Description of selected adverse reactions.

Hypocalcemia.

Reduced renal excretion of calcium may be accompanied by decreased serum phosphate levels, which does not require therapeutic intervention. Serum calcium levels may decrease to levels consistent with hypocalcemia.

Osteonecrosis of the jaw.

Cases of osteonecrosis of the jaw have been reported, primarily in patients with malignancies receiving treatment with bone resorption inhibitors, including ibandronic acid (see section "Special warnings and precautions for use"). Cases of osteonecrosis of the jaw have also been reported during post-marketing use of ibandronic acid.

Atypical subtrochanteric and diaphyseal femoral fractures.

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

Ocular inflammation.

Inflammatory eye disorders such as uveitis, episkleritis, and scleritis have been reported with the use of ibandronic acid. In some cases, these inflammatory conditions resolved only after discontinuation of bisphosphonates.

Anaphylactic reaction/shock.

Anaphylactic reactions/shock, including fatal cases, have been observed in patients receiving intravenous ibandronic acid.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals are required to report any suspected adverse reactions via the national reporting system.

Shelf life.

5 years.

Storage conditions.

No special storage conditions required. Keep out of the reach of children.

Packaging.

7 tablets per blister, 4 blisters per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

FARMATEN S.A.

Manufacturer's address and place of business.
Derivenakion 6, Pallini Attica, 15351, Greece.