Forsedeno^® (Solution) Instructions for Use

ATC Code

M05BX04 (Denosumab)

Active Substance

Denosumab (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Bone resorption inhibitor. Monoclonal antibody

Pharmacotherapeutic Group

Means for the treatment of bone diseases; agents affecting bone structure and mineralization; other agents affecting bone structure and mineralization

Pharmacological Action

Denosumab is a human monoclonal antibody (IgG2) with high affinity and specificity for RANKL (Receptor Activator of Nuclear Factor Kappa-B Ligand), thereby preventing the activation of RANK receptors on the surface of osteoclasts and their precursors.

Preventing the binding of the RANKL ligand to the RANK receptor inhibits the maturation, function, and survival of osteoclasts, which reduces bone resorption in the cortical and trabecular bone layers.

Pharmacokinetics

After subcutaneous administration at a dose of 1.0 mg/kg, approximately corresponding to the registered dose of 60 mg, the AUC values were 78% compared to intravenous administration of denosumab at the same dose.

After subcutaneous administration of denosumab at a dose of 60 mg, the C_max was 6 µg/ml (range: 1-17 µg/ml) and was achieved within 10 days (range: 2-28 days).

Denosumab consists only of amino acids and carbohydrates, like a natural immunoglobulin, and therefore its elimination via hepatic metabolic pathways is unlikely.

Therefore, it is assumed that the elimination of the drug occurs through standard pathways of immunoglobulin degradation, resulting in breakdown into small peptides and individual amino acids.

After reaching C_max, the concentration in serum decreases with a T_1/2 of 26 days (range: 6-52 days) over 3 months (range: 1.5-4.5 months).

In 53% of patients, 6 months after the last dose of denosumab, its concentration in the blood was below the quantifiable limit.

No accumulation or change in pharmacokinetic parameters over time was observed with repeated subcutaneous administration of denosumab at a dose of 60 mg over 6 months.

The production of binding antibodies to denosumab, similar in both men and women, did not affect the pharmacokinetics of denosumab.

A trend towards decreased exposure (AUC and C_max) with increasing body weight was observed.

However, this trend was not considered clinically significant, as the pharmacodynamic effects (assessed by bone metabolism marker concentrations and increases in BMD) were similar across a wide range of body weight values.

Indications

Treatment of postmenopausal osteoporosis and osteoporosis in men at increased risk of fractures.

Treatment of bone loss in men with prostate cancer receiving hormone-deprivation therapy, at increased risk of fractures.

Treatment of bone loss associated with long-term systemic glucocorticoid therapy in adult patients at increased risk of fractures.

ICD codes

Dosage Regimen

Solution

For subcutaneous administration.

The recommended dose of denosumab is 60 mg once every 6 months in the thigh, abdomen, or upper arm.

During the course of treatment, it is necessary to take calcium and vitamin D supplements in adequate doses.

The optimal duration of osteoporosis therapy with antiresorptive drugs (both denosumab and bisphosphonates) has not been established.

The need to continue therapy should be periodically re-evaluated, taking into account the benefits and potential risks of using denosumab in each specific patient, in particular, after 5 years or more from the start of denosumab use.

Adverse Reactions

Infections and infestations Common – urinary tract infections, upper respiratory tract infections; Uncommon – diverticulitis, panniculitis, ear infections.

Immune system disorders Rare – hypersensitivity reactions, anaphylactic reaction.

Metabolism and nutrition disorders Rare – hypocalcemia.

Nervous system disorders Common – sciatica.

Gastrointestinal disorders Common – constipation, abdominal discomfort.

Skin and subcutaneous tissue disorders: Common – rash, eczema, alopecia; Uncommon – lichenoid drug eruption; Very rare – hypersensitivity vasculitis.

Musculoskeletal and connective tissue disorders Very common – pain in extremity; Rare – osteonecrosis of the jaw, atypical femoral fracture; Uncommon – multiple vertebral fractures due to denosumab treatment discontinuation; Frequency unknown – osteonecrosis of the external auditory canal.

Contraindications

Hypersensitivity to denosumab; hypocalcemia; pregnancy, breastfeeding period; age under 18 years.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Women are advised to avoid pregnancy during the therapy period and for at least 5 months after completion of denosumab therapy.

Reproductive toxicity has been found in animal studies.

Should not be used in women of childbearing potential not using contraception.

Any effects of denosumab are likely to be more pronounced during the second and third trimesters of pregnancy, as monoclonal antibodies cross the placental barrier, and the extent of their transfer increases linearly with gestational age, with the highest levels noted during the third trimester.

Use in Hepatic Impairment

The safety and efficacy of denosumab in patients with hepatic impairment have not been established.

Use in Renal Impairment

No dose adjustment is required in patients with renal impairment.

There are no data on the use of denosumab in patients with severe renal impairment (GFR < 30 ml/min) receiving long-term systemic glucocorticoid therapy.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

No dose adjustment of the drug is required in elderly patients.

Special Precautions

All patients are recommended to take calcium and vitamin D supplements in adequate doses during denosumab therapy.

It is important to identify patients at risk of developing hypocalcemia.

Hypocalcemia should be corrected with adequate doses of calcium and vitamin D supplements before starting therapy.

Clinical monitoring of calcium concentration is recommended before each dose of denosumab in patients predisposed to developing hypocalcemia, and for 2 weeks after the first dose.

If symptoms of hypocalcemia develop during the course of therapy, blood calcium levels should be assessed.

Patients should be warned to report the occurrence of symptoms indicating hypocalcemia.

Post-marketing cases of severe symptomatic hypocalcemia (including fatal outcomes) have been reported, most commonly during the first weeks after starting therapy, but development is also possible at later times.

Concomitant therapy with glucocorticoids is an additional risk factor for hypocalcemia.

In patients with severe renal impairment (CrCl < 30 ml/min) or on dialysis, there is an increased risk of developing hypocalcemia.

The risk of developing hypocalcemia and concomitant increase in parathyroid hormone levels increases with the severity of renal impairment.

It is especially important for these patients to take adequate doses of calcium and vitamin D supplements and to regularly monitor blood calcium levels.

Patients should be informed to seek immediate medical attention if signs or symptoms of panniculitis appear.

The initiation of therapy/a new course of therapy should be postponed in patients with unhealed open soft tissue lesions of the oral cavity.

Before starting denosumab therapy in patients with concomitant risk factors, a dental examination and preventive dental measures should be performed, and an individual benefit-risk assessment of denosumab therapy should be conducted.

When assessing the individual risk of developing osteonecrosis of the jaw in a patient, the following risk factors should be considered: potency of the bone resorption-inhibiting drug (increased risk for more potent drugs), route of administration (increased risk with parenteral administration) and cumulative dose of antiresorptive therapy; malignancies, concomitant pathology (e.g., anemia, coagulopathies, infections), smoking; concomitant therapy (glucocorticoids, chemotherapy, angiogenesis inhibitors, head and neck radiation); poor oral hygiene, periodontal disease, ill-fitting dentures, history of dental disease, invasive dental procedures (e.g., tooth extractions).

During denosumab treatment, all patients should maintain good oral hygiene, undergo regular dental check-ups, and immediately report any oral adverse symptoms, such as loose teeth, pain, swelling, non-healing mucosal lesions, or discharge.

During therapy, invasive dental procedures should be performed only after careful assessment; these procedures should be avoided immediately before and/or immediately after denosumab administration.

A treatment plan for patients with osteonecrosis of the jaw should be developed in conjunction with the attending physician and a dentist or oral and maxillofacial surgeon experienced in managing this condition.

Temporary discontinuation of therapy until resolution of the condition and elimination of risk factors should be considered in all cases where possible.

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 developing osteonecrosis of the external auditory canal should be considered in patients taking Denosumab who have ear symptoms, including chronic ear infections.

Atypical femoral fractures may occur with minimal or no trauma in the subtrochanteric or diaphyseal proximal femur.

On radiographs, these fractures usually have a characteristic appearance.

Atypical femoral fractures have also been reported in patients with certain comorbidities and conditions (e.g., vitamin D deficiency, rheumatoid arthritis, hypophosphatasia) and in patients taking certain medications (e.g., bisphosphonates, glucocorticoids, proton pump inhibitors).

These cases have also been observed in the absence of antiresorptive therapy.

Such fractures associated with bisphosphonate use are often bilateral; therefore, in patients receiving denosumab therapy, if a femoral fracture is identified, the contralateral hip should be examined.

Discontinuation of denosumab therapy should be considered in patients with suspected atypical hip fracture, taking into account an individual benefit-risk assessment.

During denosumab treatment, patients should be advised to report new or unusual pain in the thigh, hip, or groin area.

Patients who develop such symptoms should be evaluated for an incomplete femoral fracture.

Patients should be warned not to discontinue denosumab therapy without consulting their doctor.

Before discontinuing denosumab treatment, an individual benefit-risk assessment should be performed.

In case of denosumab treatment discontinuation, switching to alternative antiresorptive therapy should be considered.

Long-term antiresorptive therapy (both with denosumab and bisphosphonates) may contribute to an increased risk of complications such as osteonecrosis of the jaw and atypical hip fractures due to profound suppression of bone remodeling.

Patients receiving denosumab therapy should not receive concomitant therapy with other medicinal products containing Denosumab (for the prevention of skeletal-related events in adults with bone metastases from solid tumors).

Drug Interactions

In a drug interaction study, Denosumab did not affect the pharmacokinetics of midazolam, which is metabolized by the CYP3A4 isoenzyme.

This means that Denosumab should not affect the pharmacokinetics of drugs metabolized by CYP3A4.

There are no clinical data on the concomitant use of denosumab and hormone replacement therapy (estrogens); the likelihood of this pharmacodynamic interaction is considered low.

In women with postmenopausal osteoporosis, prior therapy with alendronic acid did not affect the pharmacokinetics and pharmacodynamics of denosumab according to a transition study (from alendronic acid to Denosumab).

Storage Conditions

Store at 2°C (36°F) to 8°C (46°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.