Mebyphon®

INSTRUCTIONS FOR MEDICAL USE OF MEDICINAL PRODUCT MEBIFON® (MEBIFON®)

Composition:

Active substance: mebifon;

1 ml of solution contains mebifon 15 mg;

Excipients: sodium chloride, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical characteristics: clear colorless liquid.

Pharmacotherapeutic group.

Antineoplastic agents. ATC code L01X X.

Agents affecting bone structure and mineralization. ATC code M05B A.

Pharmacological Properties

Pharmacodynamics

A drug from the bisphosphonate group, a structural analogue of natural pyrophosphate. Mibifon® effectively inhibits bone destruction and exerts an antitumor effect, pronounced analgesic action (bone pain decreases or disappears), improves the general condition and physical activity of patients. Mibifon® normalizes the level of ionized calcium in blood serum of patients with breast cancer and other localizations – kidneys, lungs, prostate gland, melanoma with bone metastases, and lymphoproliferative disorders with bone involvement.

Mibifon**®** does not suppress the hematopoietic system, immunogenesis, or immune response. In some patients, stimulation of hematopoiesis may occur. It may slightly alter parameters of the blood coagulation and anticoagulation systems. During treatment, minor diffuse changes in the myocardium may occur. Mibifon**®** does not affect the condition of respiratory organs or liver function.

Pharmacokinetics

The drug is not metabolized in the body. It is excreted almost unchanged in urine and feces and has the ability to accumulate in immunocompetent tissues (thymus, spleen). The half-life period is 6 hours.

Clinical characteristics.

Indications.

Malignant tumors of the breast, prostate gland, and lungs with bone metastases; hypercalcemia associated with malignant tumors; melanoma, lymphoproliferative disorders with bone involvement.

Contraindications.

Individual hypersensitivity to bisphosphonates and other components of the drug; history of stroke or myocardial infarction (less than 6 months prior to initiation of therapy); decompensated heart failure; active tuberculosis; severe hepatic and renal dysfunction; thrombocyte count below 100×10⁹/l.

Interaction with other medicinal products and other forms of interaction.

Mebiphon**®** must not be used concomitantly with other bisphosphonates.

When used in combination regimens with platinum derivatives, monitoring of renal function (serum creatinine levels, etc.) is required due to the potential for enhanced nephrotoxic effects.

Special precautions for use

Before administering Mefon® it is necessary to ensure adequate hydration of all patients, including those with mild to moderate renal impairment. Hyperhydration should be avoided in patients at risk of heart failure. Standard metabolic parameters associated with hypercalcemia, such as calcium, phosphate, and magnesium levels, should be carefully monitored after initiation of therapy.

Patients receiving Mefon® should not simultaneously take other bisphosphonates.

Due to the potential effects of bisphosphonates on kidney function and in the absence of comprehensive clinical safety data in patients with severe renal impairment, administration of Mefon® is not recommended in such patients.

Renal function impairment

When considering the use of Mefon in patients with malignancy-associated hypercalcemia and concomitant renal impairment, the patient's condition should be evaluated to determine whether the potential benefit of treatment outweighs the possible risk.

Renal function deterioration has been reported during bisphosphonate therapy.

Factors that may increase the risk of renal impairment include: dehydration, pre-existing renal dysfunction, multiple cycles of bisphosphonate therapy, concomitant use of nephrotoxic agents, or infusion administered over a shorter duration than recommended.

Serum creatinine levels should be assessed before initiating treatment.

Osteonecrosis of the jaw

Cases of osteonecrosis of the jaw have been reported in patients with cancer receiving bisphosphonates as part of their treatment. Most of these patients were also receiving chemotherapy and corticosteroids.

The majority of reported cases were associated with dental procedures such as tooth extraction. Most of these patients showed signs of local infection, including osteomyelitis.

Post-marketing experience with bisphosphonates and published literature indicate that the incidence of osteonecrosis of the jaw depends on tumor type (e.g., advanced breast cancer, multiple myeloma) and dental status (e.g., tooth extractions, periodontal disease, local trauma including trauma from ill-fitting dentures).

A dental examination with appropriate preventive dental measures should be performed prior to bisphosphonate therapy in patients with relevant risk factors (e.g., cancer, chemotherapy, corticosteroid therapy, poor oral hygiene).

During bisphosphonate therapy, these patients should, if possible, avoid invasive dental procedures. Dental surgery may worsen the condition in patients who have developed osteonecrosis of the jaw while on bisphosphonate therapy.

Atypical femoral fracture

Atypical subtrochanteric and diaphyseal femoral fractures have been reported during bisphosphonate therapy, particularly in patients receiving long-term treatment for osteoporosis. These transverse or short oblique fractures may occur anywhere along the femur between the lesser trochanter and the supracondylar region. Such fractures may occur following minimal or no trauma, and some patients experience thigh or groin pain, often associated with radiological signs of stress fracture, several weeks or months before complete femoral fracture occurs. These fractures are often bilateral; therefore, the contralateral femur should be evaluated in patients on bisphosphonate therapy who have sustained a femoral shaft fracture. Delayed healing of these fractures has also been reported. Based on individual assessment of benefit and risk, consideration should be given to discontinuing bisphosphonate therapy in patients suspected of having atypical femoral fractures.

During bisphosphonate therapy, patients should be advised to report any new or unusual pain in the hip, groin, or thigh. Any patient presenting with such symptoms should be evaluated for the presence of an incomplete femoral fracture.

Musculoskeletal pain

In post-marketing surveillance, severe and occasionally incapacitating bone, joint, and/or muscle pain have been reported in patients taking bisphosphonates. These reports have been infrequent. The onset of such pain may vary from one day to several months after initiation of treatment. In most patients, symptoms improved after discontinuation of therapy. Recurrence of symptoms has been observed in this group of patients when treatment was resumed with the same or another bisphosphonate.

Mefon® administered in the postoperative period as an adjuvant does not impair the patient's general condition and reduces the hematotoxicity of chemotherapy.

This medicinal product contains 5.42 mmol (or 124.6 mg)/dose of sodium. Caution should be exercised when prescribing to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding

The drug should not be used during pregnancy or breastfeeding.

Ability to affect reaction speed when driving or operating machinery

No studies on the effect of the drug on the ability to drive or operate machinery have been conducted. Given the possible adverse reactions, patients should refrain from driving or operating machinery.

Administration and Dosage

Depending on the indications, Mebifon® can be prescribed as monotherapy or as part of antitumor chemotherapy regimens for malignant tumors; in either case, the single and total course doses of Mebifon® remain unchanged.

Mebifon® should be administered intravenously by drip infusion to adults at a dose of 300 mg (1 ampoule) in 200 mL of 0.9% sodium chloride solution once daily. This solution should be infused over 30–40 minutes.

The treatment course is 5 days, with a total course dose of 1.5 g. The number of courses ranges from 1 to 6, depending on the course of the disease, treatment regimen, and therapeutic response. The interval between courses should be at least 3 weeks.

Children. There is no experience with the use of the drug in children.

Overdose.

Intravenous administration of doses exceeding the recommended ones, especially with rapid infusion, may lead to acute renal failure and hypocalcemia. In such cases, administer 10–40 mL of 10% calcium gluconate or calcium chloride solution (depending on the severity of overdose) and implement measures to support respiration and hemodynamics, along with symptomatic therapy. In cases of severe poisoning, if the aforementioned measures are insufficiently effective, hemodialysis should be performed.

Side effects.

In isolated cases – rhythm disturbances (atrial fibrillation and atrial flutter), increased blood coagulation, decreased platelet count within 24 hours after the first administration of the drug, in some cases – slight increase in serum creatinine levels. Allergic reactions, itching.

The adverse reactions listed below occur with the use of bisphosphonate-class drugs; therefore, the possibility of these adverse reactions occurring with the use of Mebifon® cannot be excluded.

Blood and lymphatic system disorders: anemia, thrombocytopenia, leukopenia.

Nervous system disorders: headache, dizziness, paresthesia.

Psychiatric disorders: restlessness, confusion.

Eye disorders: conjunctivitis, uveitis, scleritis, episcleritis.

Gastrointestinal disorders: nausea, vomiting, anorexia, diarrhea, constipation, abdominal pain, dyspepsia.

Respiratory, thoracic and mediastinal disorders: dyspnea, bronchospasm.

Skin and subcutaneous tissue disorders: itching, rash.

Musculoskeletal and connective tissue disorders: bone pain, myalgia, arthralgia, generalized pain, muscle spasms, osteonecrosis of the jaw, atypical femoral fracture.

Cardiovascular disorders: arterial hypertension, arterial hypotension, rhythm disturbances (atrial fibrillation and atrial flutter).

Renal and urinary disorders: acute renal failure, hematuria.

Immune system disorders: hypersensitivity reactions, angioneurotic edema.

General disorders and administration site conditions: fever, flu-like symptoms (including increased fatigue, chills, malaise, hot flushes).

Laboratory findings: hypophosphatemia, increased creatinine and urea levels in blood, hypocalcemia, hypomagnesemia, hypokalemia, rarely – hyperkalemia, hypernatremia.

Shelf life. 3 years.

Do not use the drug after the expiry date stated on the packaging.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

20 ml in an ampoule. 5 or 10 ampoules per pack.

Prescription category. Prescription only.

Manufacturer.

JSC "Farmak".

Manufacturer's location and address of place of business.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.