Active ingredients: Denosumab
XGEVA 120 mg solution for injection
Indications Why is Xgeva used? What is it for?
XGEVA contains denosumab, a protein (monoclonal antibody) that works to decrease bone destruction caused by cancer spread to the bone (bone metastases) or giant cell cancer of bone.
XGEVA is used in adults with cancer to prevent serious complications caused by bone metastases (e.g. fracture, pressure on the bone marrow, or the need for radiation therapy or surgery). XGEVA is also used to treat giant cell cancer of bone, which cannot be treated by surgery or where surgery is not the best option, in adults and adolescents whose bones have stopped growing.
Contraindications When Xgeva should not be used
Do not use XGEVA
- if you are allergic to denosumab or any of the other ingredients of XGEVA.
Your healthcare professional will not give you XGEVA if you have a very low level of calcium in your blood which has not been treated.
Your healthcare professional will not give you XGEVA if you have any wounds that have not healed from dental or oral surgery.
Precautions for use What you need to know before you take Xgeva
Calcium and Vitamin D supplement
You must take calcium and vitamin D supplements while being treated with XGEVA, unless your blood calcium levels are high. Your doctor will discuss this with you. If your blood calcium level is low, your doctor may decide to give you calcium supplements before starting treatment with XGEVA.
Low levels of calcium in the blood
Tell your doctor immediately if you experience muscle spasms, twitching or cramps, and / or numbness or tingling in the fingers and toes or around the mouth and / or seizures, confusion or loss of consciousness while taking XGEVA. You may have low blood calcium levels.
Tell your doctor if you have or have ever suffered from severe kidney problems, kidney impairment or if you have been undergoing dialysis as it may increase the risk of having low blood calcium levels, especially if you do not take calcium supplements.
Problems with your mouth, teeth or jaw
A side effect called osteonecrosis of the jaw (severe bone degeneration of the jaw) has been reported commonly (may affect up to 1 in 10 people) in patients receiving XGEVA injections for cancer-related conditions.
Osteonecrosis of the jaw can also occur after stopping treatment.
It is important to try to prevent the development of osteonecrosis of the jaw as it is a painful condition which can be difficult to treat. In order to reduce the risk of developing osteonecrosis of the jaw you need to take certain precautions.
Before receiving treatment, tell your doctor / nurse (health care professional) if you have any problems with your mouth or teeth. Your doctor should delay the start of treatment if you have wounds in your mouth that have not healed from dental procedures or oral surgery. Your doctor may ask you to have a dental examination before starting treatment with XGEVA.
During the treatment it is necessary to maintain good oral hygiene and to undergo periodic dental check-ups. If you wear prostheses you need to make sure that they are inserted correctly.
If you are undergoing dental treatment or are planning to undergo dental surgery (e.g. tooth extractions), please inform your dental treatment doctor and inform your dentist that you are being treated with XGEVA.
Contact your doctor and dentist immediately if you notice any problems with your mouth or teeth, such as swinging of the teeth, pain or swelling, or if mouth sores or discharge do not heal, as these could be signs of osteonecrosis of the mandible / maxilla.
Patients who are undergoing chemotherapy and / or radiotherapy, who are taking steroids or anti-angiogenic medicines (used to treat cancer), who are undergoing dental surgery, who do not receive routine dental care or who suffer from gums, are smokers, may have a higher risk of developing osteonecrosis of the jaw.
Unusual fractures of the thigh bone
Some people have developed unusual fractures in the femur while being treated with XGEVA. Contact your doctor if you experience new or unusual pain in your hip, groin, or thigh.
Children and adolescents
XGEVA is not recommended for children and adolescents under the age of 18 except for adolescents with giant cell tumor of bone whose bones have stopped growing. The use of XGEVA in children and adolescents with other tumors that have invaded the bone has not been studied.
Interactions Which drugs or foods may change the effect of Xgeva
Tell your doctor or pharmacist if you are taking or have recently taken or might take any other medicines, including medicines obtained without a prescription. In particular, it is important that you tell your doctor if you are taking
- another medicine containing denosumab
- a bisphosphonate.
You should not take XGEVA together with other medicines containing denosumab or bisphosphonates
Warnings It is important to know that:
Pregnancy and breastfeeding
XGEVA has not been studied in pregnant women. It is important that you tell your doctor if you are pregnant, suspect or are planning to become pregnant. The use of XGEVA is not recommended if you are pregnant. Women of childbearing potential should use effective contraception while taking XGEVA and for at least 5 months after stopping XGEVA.
If you become pregnant during treatment with XGEVA or less than 5 months after stopping treatment with XGEVA, please inform your doctor. She is encouraged to enroll in Amgen's Pregnancy Surveillance Program. Details of the local Amgen representative are given in section 6 of this leaflet.
It is not known whether XGEVA is excreted in human milk. It is important that you tell your doctor if you are breast-feeding or planning to breast-feed. Your doctor will then help you decide whether to stop breast-feeding or to stop taking XGEVA, taking into account the benefit of breast-feeding for the child and the benefit of taking XGEVA for the mother.
If you are breast-feeding while taking XGEVA please tell your doctor. She is encouraged to enroll in Amgen's Lactation Surveillance Program.Details of the local Amgen representative are given in section 6 of this leaflet.
Ask your doctor or pharmacist for advice before using this medicine.
Driving and using machines
XGEVA has no or negligible influence on the ability to drive or use machines.
XGEVA contains sorbitol
If you have been told by your doctor that you have an "intolerance to some sugars, contact your doctor before taking this medicine, as it contains sorbitol (E420).
XGEVA contains sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per 120 mg, ie essentially "sodium free".
Dose, Method and Time of Administration How to use Xgeva: Posology
The recommended dose of XGEVA is 120 mg administered once every 4 weeks, as a single injection under the skin (subcutaneous). XGEVA will be injected into the thigh, abdomen or upper arm. If you are being treated for giant cell cancer of bone, you will receive an additional dose 1 week and 2 weeks after the first dose.
XGEVA must be administered under the responsibility of a healthcare professional.
Do not shake excessively.
You should also take calcium and vitamin D supplements while being treated with XGEVA. Your doctor will discuss this with you.
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.
Side Effects What are the side effects of Xgeva
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Tell your doctor immediately if you notice any of these symptoms while taking XGEVA:
- twitching, twitching, muscle cramps, numbness or tingling in the fingers and toes or around the mouth and / or seizures, confusion or loss of consciousness. These signs could indicate low blood calcium levels. Low blood calcium levels can also lead to a change in heart rhythm called QT prolongation, which is seen on electrocardiography (ECG).
Tell your doctor and dentist immediately if you experience any of these symptoms during treatment with XGEVA or after stopping treatment with XGEVA:
- pain in the mouth and / or jaw, swelling or non-healing sores in the mouth or jaw, discharge, numbness or a feeling of heaviness in the jaw, or wobbling of a tooth as these signs could indicate severe bone degeneration of the jaw (osteonecrosis).
Very common side effects (may affect more than 1 in 10 people):
- pain in the bones, joints and / or muscles sometimes severe,
- wheezing (dyspnoea),
- diarrhea.
Common side effects (may affect up to 1 in 10 people):
- low levels of calcium in the blood (hypocalcaemia),
- low levels of phosphate in the blood (hypophosphataemia),
- persistent pain and / or non-healing of sores in the mouth or jaw (osteonecrosis of the jaw),
- tooth extraction,
- excessive sweating.
Rare side effects (may affect up to 1 in 1,000 people):
- allergic reactions (e.g. wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin). In rare cases, allergic reactions can be severe.
- a new or unusual pain in the hip, groin or thigh (this could be an early sign of a possible thigh bone fracture).
Reporting of side effects
If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the label and carton after EXP. The expiry date refers to the last day of that month.
Store in a refrigerator (2 ° C - 8 ° C).
Do not freeze.
Store in the original package to protect the medicine from light.
The vial can be left out of the refrigerator to reach room temperature (up to 25 ° C) before injection. This will make the injection more comfortable. Once the vial has reached room temperature (up to 25 ° C), it must be used within 30 days.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Deadline "> Other information
What XGEVA contains
- The active ingredient is denosumab. Each vial contains 120 mg in 1.7 ml of solution (corresponding to 70 mg / ml).
- The other ingredients are glacial acetic acid, sodium hydroxide, sorbitol (E420), and water for injections.
Description of what XGEVA looks like and contents of the pack
XGEVA is a solution for injection in a vial.
Each pack contains one, three or four vials.
Not all pack sizes may be marketed.
XGEVA is a clear, colorless to slightly yellow solution. It may contain traces of clear to white particles.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT -
XGEVA 120 MG SOLUTION FOR INJECTION
▼ Medicinal product subject to additional monitoring. This will allow the rapid identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for information on how to report adverse reactions.
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -
Each vial contains 120 mg of denosumab in 1.7 ml of solution (70 mg / ml).
Denosumab is a human IgG2-type monoclonal antibody produced in a mammalian cell line (CHO) by recombinant DNA technology.
Excipient (s) with known effect
Each 1.7 ml of solution contains 78 mg of sorbitol (E420).
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM -
Solution for injection (injection).
Clear, colorless to slightly yellow solution which may contain traces of translucent to white protein particles.
04.0 CLINICAL INFORMATION -
04.1 Therapeutic indications -
Prevention of skeletal related events (pathological fractures, radiotherapy to bone, spinal cord compression or bone surgery) in adults with bone metastases from solid tumors.
Treatment of skeletally mature adults and adolescents with giant cell tumor of bone that is unresectable or for whom surgical resection could cause severe morbidity.
04.2 Posology and method of administration -
XGEVA must be administered under the responsibility of a healthcare professional.
Dosage
Supplementation of at least 500 mg of calcium and 400 IU of vitamin D per day is required in all patients except hypercalcaemia (see section 4.4).
Patients being treated with XGEVA should be given the package leaflet and patient reminder card.
Prevention of skeletal related events in adults with bone metastases from solid tumors
The recommended dose is 120 mg given as a single subcutaneous injection, once every 4 weeks in the thigh, abdomen or upper arm.
Giant cell tumor of bone
The recommended dose of XGEVA is 120 mg, given as a single subcutaneous injection, once every 4 weeks in the thigh, abdomen or upper arm, with additional doses of 120 mg on days 8 and 15 of treatment in the first month of therapy.
Patients in the phase II study who underwent complete resection of giant cell tumor of bone received an additional 6 months of treatment after surgery as per the study protocol.
Patients with giant cell cancer of bone should be evaluated at regular intervals to determine whether they continue to benefit from treatment. In patients whose disease is controlled by XGEVA, the effect of stopping or stopping treatment will not has been evaluated, however limited data in these patients do not indicate a rebound effect upon discontinuation of treatment.
Patients with renal impairment
No dose adjustment is required in patients with renal impairment (see sections 4.4 for recommendations on monitoring calcium levels, 4.8 and 5.2).
Patients with hepatic impairment
The safety and efficacy of denosumab have not been studied in patients with hepatic impairment (see section 5.2).
Elderly patients (age ≥ 65 years)
No dose adjustment is required in elderly patients (see section 5.2).
Pediatric population
The safety and efficacy of XGEVA have not been established in pediatric patients (age
XGEVA is not recommended in pediatric patients (age
Treatment of skeletally mature adolescents with unresectable giant cell tumor of bone or in whom surgical resection could cause severe morbidity: the posology is the same as for adults.
In animal studies, inhibition of RANK / RANK ligand (RANKL) has been associated with inhibition of bone growth and failure to erupt and these changes were partially reversible after discontinuation of RANKL inhibition (see paragraph 5.3).
Method of administration
For subcutaneous use.
For instructions on use, handling and disposal, see section 6.6.
04.3 Contraindications -
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Severe, untreated hypocalcaemia (see section 4.4).
Injuries not healed by dental or oral surgery.
04.4 Special warnings and appropriate precautions for use -
Calcium and Vitamin D supplement
It is important that all patients get an adequate intake of calcium and vitamin D, except in case of hypercalcaemia (see section 4.2).
Hypocalcemia
Pre-existing hypocalcaemia should be corrected prior to initiation of therapy with XGEVA.
Hypocalcaemia can occur at any time during therapy with XGEVA. Monitoring of calcium levels should be done before the initial dose of XGEVA, within two weeks following the initial dose, in case of suspected symptoms of hypocalcaemia (see section 4.8 for the list of symptoms). Additional monitoring of calcium levels should be considered during therapy in patients with risk factors for hypocalcaemia, or as otherwise indicated based on the patient's clinical condition.
Patients should be encouraged to report symptoms indicative of hypocalcaemia. If hypocalcaemia develops during administration of XGEVA, additional calcium supplementation and additional monitoring are required.
During post-marketing use, severe symptomatic hypocalcaemia (including fatal cases) has been reported (see section 4.8), with most cases occurring within the first weeks after initiation of therapy, but may occur later.
Renal impairment
Patients with severe renal impairment (creatinine clearance dialysis have an increased risk of developing hypocalcaemia. The risk of developing hypocalcaemia and consequent elevations in parathyroid hormone levels increases with increasing degree of renal impairment. Regular monitoring of levels of renal disease. calcium is especially important in these patients.
Osteonecrosis of the jaw (ONJ)
ONJ has been reported commonly in patients receiving XGEVA (see section 4.8).
Treatment initiation / new treatment should be postponed in patients with unhealed, open, soft tissue lesions in the mouth. A dental examination with dental prophylaxis and an individual benefit / risk assessment is recommended prior to treatment with XGEVA.
The following risk factors must be considered when evaluating a patient's risk of developing ONJ:
• the potency of the drug that inhibits bone resorption (the risk is higher with more potent drugs), route of administration (the risk is higher with parenteral administration) and the cumulative dose of bone resorption therapy.
• tumor, co-morbid conditions (eg anemia, coagulopathies, infection), smoking.
• concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy of the head and neck region.
• poor oral hygiene, periodontal disease, incorrectly inserted dental prostheses, pre-existing dental disease, invasive dental procedures (eg tooth extractions).
All patients should be encouraged to maintain good oral hygiene, have periodic dental check-ups, and immediately report any oral symptoms such as tooth mobility, pain or swelling or non-healing of mouth sores or the presence of secretions during treatment. treatment with XGEVA. During treatment, invasive dental procedures should only be performed after careful consideration and should be avoided in close proximity to the administration of XGEVA.
Management of patients who develop ONJ should be done in close collaboration between the treating physician and a dentist or maxillofacial surgeon experienced in the treatment of ONJ. Temporary interruption of treatment with XGEVA should be considered until the condition is resolved and, where possible, to mitigate the risk factors that contributed to its onset.
Atypical fractures of the femur
Cases of atypical femoral fractures have been reported in patients treated with XGEVA (see section 4.8). Atypical femoral fractures can occur with minimal or no trauma in the subtrochanteric and diaphyseal regions of the femur. These events are characterized by specific radiographic findings. Atypical femoral fractures have also been reported in patients with some comorbid conditions (e.g. vitamin D deficiency, rheumatoid arthritis, hypophosphatasia) and in the use of certain medications (e.g. bisphosphonates, glucocorticoids, proton pump inhibitors). These events also occurred in the absence of antiresorptive therapy. Similar fractures, reported in association with bisphosphonate use, are often bilateral; therefore the contralateral femur should be evaluated in denosumab-treated patients who have sustained a femoral shaft fracture. In patients with suspected atypical femoral fracture, termination should be considered. of therapy with XGEVA, pending evaluation of the patient based on an individual benefit / risk analysis. During treatment with XGEVA, patients should be advised to report new or unusual pain in the thigh, hip or at the groin. Patients presenting with such symptoms should be evaluated for an incomplete femoral fracture.
Patients with a growing skeletal system
XGEVA is not recommended in patients with growing skeletal systems (see section 4.2). Clinically significant hypercalcaemia has been reported in patients with growing skeletal systems treated with XGEVA after weeks to months of stopping treatment.
Others
Patients who are being treated with XGEVA should not be treated concomitantly with other denosumab-containing medicinal products (for indications of osteoporosis).
Patients who are being treated with XGEVA should not be treated concomitantly with bisphosphonates.
Giant cell tumor degeneration of bone to malignant disease or metastatic progression of the disease are infrequent events and represent a known risk in patients with giant cell tumor of bone. Patients should be monitored for radiological signs of malignancy, new radiolucency, or osteolysis. Available clinical data do not suggest an increased risk of malignancy in patients with giant cell tumor of bone treated with XGEVA.
Warnings for excipients
XGEVA contains sorbitol. Patients with rare hereditary conditions of fructose intolerance should not take XGEVA.
This medicinal product contains less than 1 mmol sodium (23 mg) per 120 mg, ie essentially "sodium free".
04.5 Interactions with other medicinal products and other forms of interaction -
No interaction studies have been performed.
In clinical studies, XGEVA was administered in combination with standard anti-tumor treatments and in patients previously treated with bisphosphonates. There were no clinically relevant alterations in the trough serum concentration and pharmacodynamics of denosumab (urinary creatinine-adjusted N-telopeptide, uNTx / Cr) due to hormone therapy and / or concomitant chemotherapy or previous intravenous administration of bisphosphonates.
04.6 Pregnancy and breastfeeding -
Pregnancy
No adequate data are available regarding the use of XGEVA in pregnant women. Reproductive toxicity was demonstrated in a study in cynomolgus monkeys with denosumab administration during pregnancy with AUC 12 times the human dose (see section 5.3. ).
The use of XGEVA is not recommended in pregnant women and in women of childbearing potential who are not using highly effective contraceptives. Women should be advised to avoid becoming pregnant during treatment with XGEVA and for at least 5 months after treatment. Treatment. Any effects of XGEVA are likely to be greatest during the second and third trimester of pregnancy, since monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the greatest amount being transferred during the third. trimester of pregnancy.
Feeding time
It is unknown whether denosumab is excreted in human breast milk. Studies in knockout mice suggest that the absence of RANKL during pregnancy could interfere with the maturation of the mammary gland, leading to impaired lactation after parturition (see section 5.3). A decision must be made whether to abstain from breast-feeding or from XGEVA therapy, taking into account the benefit of breast-feeding for the newborn / infant and the benefit of XGEVA therapy for the woman.
Fertility
There are no data on the effects of denosumab on human fertility. Animal studies do not indicate direct or indirect harmful effects on fertility (see section 5.3).
04.7 Effects on ability to drive and use machines -
XGEVA has no or negligible influence on the ability to drive and use machines.
04.8 Undesirable effects -
Summary of the safety profile
The overall safety profile is consistent across all approved indications.
Hypocalcaemia was commonly reported following administration of XGEVA mostly within the first 2 weeks. Hypocalcaemia can be severe and symptomatic (see section 4.8 - description of selected adverse reactions). Decreases in serum calcium concentrations are usually managed appropriately with calcium and vitamin D supplementation. The most common adverse reactions with XGEVA are musculoskeletal pain.
The safety of XGEVA has been evaluated on:
• 5,931 patients with advanced cancers involving bone in active controlled clinical trials evaluating the efficacy and safety of XGEVA versus zoledronic acid in the prevention of skeletal related events.
• 523 patients with giant cell tumor of bone in a single-arm clinical trial to evaluate the efficacy and safety of XGEVA.
Adverse reactions identified in these clinical trials and in the post-marketing setting are presented in Table 1.
Table of adverse reactions
For the classification of adverse reactions based on incidence rates in three phase III and two phase II clinical studies, the following convention was used (see table 1): very common (≥ 1/10), common (≥ 1 / 100,
Table 1: Adverse reactions reported in patients with advanced cancers involving bone or giant cell cancer of bone
¹ See section Description of selected adverse reactions
² See section Other special populations
Description of selected adverse reactions
Hypocalcemia
In three phase III active-controlled clinical trials in patients with advanced cancers involving bone, hypocalcaemia was reported in 9.6% of patients treated with XGEVA and 5.0% of patients treated with zoledronic acid. .
A grade 3 decrease in serum calcium levels was detected in 2.5% of patients treated with XGEVA and in 1.2% of patients treated with zoledronic acid. A grade 4 decrease in serum calcium levels was noted in 0.6% of patients treated with XGEVA and 0.2% of patients treated with zoledronic acid (see section 4.4).
In two single-arm phase II clinical trials in patients with giant cell tumor of bone, hypocalcaemia was reported in 5.7% of patients. None of the adverse events were considered serious.
Severe symptomatic hypocalcaemia (including fatal cases) has been reported during post-marketing use, with most cases occurring within the first few weeks of initiation of therapy. Examples of clinical manifestations of severe symptomatic hypocalcaemia included QT interval prolongation, tetany, seizures and altered mental status (including coma) (see section 4.4). Symptoms of hypocalcaemia in clinical trials included paraesthesia or muscle stiffness, twitching , muscle spasms and cramps.
Osteonecrosis of the jaw (ONJ)
In clinical trials, the incidence of ONJ was higher with a longer duration of exposure; ONJ was also diagnosed after the end of treatment with XGEVA with the majority of cases occurring within 5 months after the last dose. Patients with a history of ONJ or osteomyelitis of the jaw, with active dental or mandibular / maxillary inflammation requiring surgery, an outcome of unresolved dental / oral surgery, or patients for whom invasive dental procedures were planned , were excluded from clinical trials.
In the primary treatment phases of three phase III active-controlled clinical trials in patients with advanced cancers involving bone, ONJ was confirmed in 1.8% of patients treated with XGEVA (median exposure of 12, 0 months; range 0.1 - 40.5) and in 1.3% of patients treated with zoledronic acid. The clinical characteristics of these cases were similar between treatment groups. Among patients with confirmed ONJ, most (81% in both treatment groups) had a history of tooth extractions, poor oral hygiene, and / or use of braces Most of the subjects received or had received chemotherapy.
Clinical studies in patients with breast or prostate cancer included an extension phase of treatment with XGEVA (median overall exposure of 14.9 months; range 0.1 - 67.2). ONJ was confirmed in 6.9% of patients with breast cancer and prostate cancer during the extension phase of treatment.
The overall confirmed incidence of ONJ, adjusted for patient-year, was 1.1% during the first year of treatment, 3.7% during the second year, and 4.6% in subsequent years. The median time to "ONJ onset was 20.6 months (range: 4 - 53).
In two single-arm phase II clinical trials in patients with giant cell tumor of bone, ONJ occurred in 2.3% (12 of 523) of patients treated with XGEVA (median overall exposure of 20.3 months; range: 0-83.4). The incidence of ONJ, adjusted for patient year, was 0.2% during the first year of treatment and 1.7% during the second year. The median time to onset of ONJ was 19.4 months (range: 11-40). Based on the duration of exposure, there is insufficient data for patients with GCTB to assess the risk of ONJ beyond 2 years.
In a phase III clinical study, in patients with non-metastatic prostate cancer (a patient population for which XGEVA is not indicated), with a longer "exposure to treatment (up to 7 years), the incidence of ONJ confirmed, corrected per patient-year was 1.1% in the first year of treatment, 3.0% in the second year, and 7.1% in subsequent years.
Hypersensitivity reactions to the drug
Hypersensitivity events, including rare anaphylactic reactions, have been reported in patients receiving XGEVA during post-marketing use.
Atypical fractures of the femur
In the clinical development program, atypical femoral fractures have been reported rarely in patients treated with denosumab (see section 4.4).
Musculoskeletal pain
In the post-marketing setting, musculoskeletal pain, including severe cases, was reported in patients treated with XGEVA. In clinical trials, musculoskeletal pain was very common in both denosumab and zoledronic acid treatment groups. Musculoskeletal pain which led to treatment discontinuation was uncommon.
Pediatric population
XGEVA was studied in an open-label clinical study enrolling 18 skeletally mature adolescents with giant cell tumor of bone. Based on these limited data, the adverse event profile appears to be similar to that in adults.
Other special populations
Renal impairment
In a clinical study in patients with severe renal impairment (creatinine clearance calcium supplementation. The risk of developing hypocalcaemia during treatment with XGEVA is greater as the degree of renal impairment increases. In a clinical study in non-cancer patients. in advanced stage, 19% of patients with severe renal impairment (creatinine clearance
Subsequent elevations of parathyroid hormone levels have also been observed in patients with severe renal impairment or receiving dialysis treated with XGEVA. Monitoring of calcium levels and adequate calcium and vitamin D supplementation are particularly important in patients with impairment. renal (see section 4.4).
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system ( Italian Medicines Agency - Website: http // www.agenziafarmaco.gov.it / it / managers).
04.9 Overdose -
No cases of overdose have been reported in clinical studies. In clinical trials, XGEVA was administered at doses up to 180 mg every 4 weeks and 120 mg per week for 3 weeks.
05.0 PHARMACOLOGICAL PROPERTIES -
05.1 "Pharmacodynamic properties -
Pharmacotherapeutic group: Drugs for the treatment of bone diseases - Other drugs affecting bone structure and mineralization, ATC code: M05BX04
Mechanism of action
RANKL is a protein and comes in transmembrane or soluble form. RANKL is essential for the formation, function and survival of osteoclasts, the only cell type responsible for bone resorption. Increased osteoclastic activity, stimulated by RANKL, is a key mediator of bone destruction in metastatic bone disease. and in multiple myeloma. Denosumab is a human monoclonal antibody (IgG2) that targets and binds RANKL with high affinity and specificity, preventing the occurrence of the RANKL / RANK interaction, thus reducing the number and function of osteoclasts, resulting in decreased bone resorption and cancer-induced bone destruction.
Giant cell tumors of bone are characterized by neoplastic stromal cells that express the RANK ligand and osteoclast-like giant cells that express RANK. In patients with giant cell bone cancer, denosumab binds to the RANK ligand, reducing in significantly or by eliminating osteoclast-like giant cells. Consequently, osteolysis is reduced and the proliferative stroma of the tumor is replaced by new bone with a dense, non-proliferative, differentiated structure.
Pharmacodynamic effects
In phase II clinical studies in patients with advanced stage cancers involving bone, subcutaneous (sc) administration of XGEVA every 4 weeks or every 12 weeks resulted in a rapid reduction in bone resorption markers (uNTx / Cr, Serum CTx), with median decreases of approximately 80% for uNTx / Cr within one week, regardless of previous bisphosphonate therapy or baseline uNTx / Cr level. In phase III clinical trials, median reductions of approximately 80% in uNTx / Cr were maintained after 3 months of treatment in 2,075 patients with advanced cancer treated with XGEVA and naïve to IV bisphosphonate treatment.
Immunogenicity
In clinical studies, neutralizing antibodies directed against XGEVA were not observed. Based on the results of a sensitive immunoassay, less than 1% of patients treated with denosumab for up to 3 years tested positive for non-neutralizing antibodies with no evidence of altered pharmacokinetic, toxicological or clinical response profile.
Clinical efficacy in patients with bone metastases from solid tumors
Efficacy and safety of XGEVA 120 mg s.c., given every 4 weeks or of zoledronic acid 4 mg i.v. (with dose adjustment for reduced renal function), given every 4 weeks, were compared in three randomized, double-blind, active-controlled studies in patients naïve to IV bisphosphonate treatment and with advanced cancers with bone involvement: adult patients with breast cancer (study 1), other solid tumors or multiple myeloma (study 2) and castration-resistant prostate cancer (study 3). active dental or mandibular / maxillary requiring oral surgery, an unresolved dental / oral condition following surgery, or patients scheduled for invasive dental procedures were not eligible for enrollment in these studies. The primary and secondary endpoints assessed the occurrence of one or more skeletal-related events (SRE). In studies demonstrating superiority of XGEVA over zoledronic acid, patients were offered an extension phase. of pre-specified treatment, open label with XGEVA for 2 years.
XGEVA reduced the risk of developing SREs and of developing multiple (first and subsequent) SREs in patients with bone metastases of solid tumors (see Table 2).
Table 2: Efficacy results in patients with advanced cancers involving bone
NR = not reached; NA = not available; HCM = malignant hypercalcemia; SMR = skeletal morbidity rate; HR = hazard ratio; RRR = relative risk reduction † For Studies 1, 2 and 3 adjusted p-values are presented (endpoints: first SRE, and first and subsequent SREs); * Includes all skeletal events over time; only events that occurred ≥ 21 days after the previous event are considered.
** Including NSCLC, renal cell carcinoma, colorectal cancer, small cell lung cancer, bladder cancer, head and neck cancer, gastrointestinal / genitourinary cancer and other cancers except breast and prostate cancer
Disease progression and overall survival
Disease progression was similar between XGEVA and zoledronic acid in all three studies and in the combined pre-specified analysis of all three studies.
In all three studies, overall survival between XGEVA and zoledronic acid was balanced in patients with advanced cancers involving bone: breast cancer patients (hazard ratio and 95% CI: 0.95 [0.81- 1.11]), patients with prostate cancer (hazard ratio and 95% CI: 1.03 [0.91-1.17]) and patients with other solid tumors or multiple myeloma (hazard ratio and 95% CI : 0.95 [0.83- 1.08]). In a post-hoc analysis of study 2 (patients with other solid tumors or multiple myeloma) overall survival was examined for the three tumor types used for stratification (non-small cell lung cancer, multiple myeloma, and more). Overall survival was higher for XGEVA in non-small cell lung cancer (hazard ratio [95% CI] of 0.79 [0.65-0.95]; n = 702), higher for zoledronic acid in multiple myeloma (hazard ratio [95% CI] of 2.26 [1.13- 4.50]; n = 180) and similar for XGEVA and zoledronic acid in other tumor types (hazard ratio [95% CI] of 1.08 [0.90-1.30]; n = 894). Prognostic factors and antineoplastic treatments were not verified in this study. In a combined pre-specified analysis of studies 1, 2 and 3, overall survival was similar between XGEVA and zoledronic acid (hazard ratio and 95% CI: 0.99 [0.91-1.07]).
Effects on pain
The time to pain improvement (e.g., 2-point reduction from baseline, in BPI-SF worst pain score) was similar for denosumab and zoledronic acid in each study and integrated analyzes. In a "post-hoc analysis of the combined dataset, the median time to pain worsening (> 4 points in pain score of worst intensity) in patients with mild or no pain at baseline was delayed for XGEVA compared to" zoledronic acid (198 vs. 143 days) (p = 0.0002).
Clinical efficacy in skeletally mature adults and adolescents with giant cell tumor of bone
The safety and efficacy of XGEVA were studied in two open-label, single-arm phase II clinical trials (studies 4 and 5) in which 529 patients with either unresectable or unresectable giant cell tumor of bone were enrolled. which surgery would have constituted severe morbidity.
Study 4 enrolled 37 adult patients with histologically confirmed unresectable giant cell tumor of bone or recurrent giant cell tumor of bone. Response criteria included elimination of giant cells on a histopathological basis or absence of progression on radiographic basis.
Of the 35 patients included in the efficacy analysis, 85.7% (95% CI: 69.7-95.2) had a response to treatment with XGEVA. All 20 patients (100%) who underwent histological evaluation responded to treatment. In the remaining 15 patients, 10 (67%) radiological reports showed no progression of the target lesion.
Study 5 enrolled 507 skeletally mature adults or adolescents with giant cell tumor of bone and evidence of measurable active disease.
In Cohort 1 (patients with unresectable disease), the median time to disease progression was not reached, 21 of the 258 treated patients had disease progression. In Cohort 2 (patients with resectable disease, but for whom planned surgery was associated with severe morbidity), 209 of 228 evaluable patients treated with XGEVA did not undergo surgery at month 6. Overall, of 225 patients for whom it was Giant cell tumor bone surgery was scheduled (excluding lung metastases only), 109 underwent no surgery, and 84 underwent less invasive procedures than planned at baseline. Median time to surgery surgery was 261 days.
An independent retrospective review of the radiological imaging data was performed at enrollment of the 305 patients in Studies 4 and 5. One hundred and ninety had an evaluable response at least once and were included in the analysis (Table 3). Overall, XGEVA achieved objective responses in 71.6% of patients (95% CI: 64.6-77.9) (Table 3) assessed using different methodologies, with the majority of responses defined as reduction in the activity of the fluorodeoxyglucose PET or density increase measured in CT / HU, only 25.1% of patients had a response according to RECIST. Median time to response was 3.1 months (95% CI: 2.89-3 , 65) Median duration of response was not evaluable (four patients had disease progression following objective response.) In 190 subjects evaluable for objective tumor response, 55 subjects with GCTB underwent surgery, 40 of the which have undergone a complete resection.
Table 3: Objective Response to Treatment in Patients with Giant Cell Cancer of Bone
¹ CI = Exact confidence interval
² RECIST 1.1: modified criteria for evaluating the response in solid tumors to evaluate the tumor mass by means of computed axial tomography (CT) or magnetic resonance imaging (MRI).
³ EORTC: modified criteria of the European Organization for the Research and Treatment of Cancer to evaluate the metabolic response through the use of Positron Emission Tomography with Fluoridesoxyglucose (FDG-PET).
4Density / Size: Choi Inverse modified criteria to evaluate tumor size and density using Hounsfield units based on CT / MRI.
Effect on pain
At enrollment of 282 patients, in study 5 combined cohorts 1 and 2, a clinically significant reduction in worst pain (e.g. ≥ 2 points of decrease from baseline) was reported in 31.4% of patients at risk (eg, those who had a worst pain score of ≥ 2 at baseline) within one week of treatment and ≥ 50% at week 5. These pain improvements remained unchanged in subsequent assessments. Baseline use of pre-treatment analgesics in cohort 1 and cohort 2 was assessed using a seven-point scale, where 74.8% of patients reported moderate or non-use of analgesics (eg. analgesic score ≤ 2) and 25.2% of patients use strong opioids (e.g. analgesic score 3 to 7).
Pediatric population
The European Medicines Agency waived the obligation to submit the results of studies with XGEVA in all subsets of the pediatric population for the prevention of skeletal-related events in patients with bone metastases and in subsets of the pediatric population under 12 years for the treatment of giant cell cancer of bone (see section 4.2 for information on pediatric use).
In study 5, XGEVA was evaluated in a subgroup of 18 adolescent patients (13 to 17 years old) with giant cell tumor of bone who had reached skeletal maturity defined as at least one mature long bone (e.g. humerus with disc closed-closed epiphyseal growth plate of the humerus) and body weight ≥ 45 kg. An objective response was observed in four out of six evaluable adolescents in an "interim analysis of study 5." An investigator evaluation reported that all the 18 adolescent patients had the best stable or superior disease response (complete response in 2 patients, partial response in 8 patients, and disease stability in 8 patients). The European Medicines Agency has delayed the obligation to submit the final results of this study.
05.2 "Pharmacokinetic properties -
Absorption
Following subcutaneous administration, the bioavailability was 62%.
Biotransformation
Denosumab is composed solely of amino acids and carbohydrates such as native immunoglobulins and is unlikely to be eliminated by hepatic metabolic mechanisms. Drug metabolism and elimination are expected to follow the pathways of immunoglobulin clearance, ie degradation into small peptides and single amino acids.
Elimination
In subjects with advanced cancer, who received multiple doses of 120 mg every 4 weeks, an approximately 2-fold accumulation in serum denosumab concentrations was observed and steady-state was achieved within 6 months; this is consistent with time-independent pharmacokinetics. In subjects with giant cell tumor of bone who received 120 mg every 4 weeks with a loading dose on days 8 and 15, steady-state levels were achieved within the first month of treatment. Between weeks 9 and 49 , median levels varied by less than 9%. In subjects who stopped taking 120 mg every 4 weeks, the mean half-life was 28 days (range: 14-55 days).
A population pharmacokinetic analysis revealed no clinically significant changes in steady-state systemic denosumab exposure for age (18-87 years), race / ethnic group (Black, Hispanic, Asian and White subjects were studied. ), sex, or type of solid tumor. Weight gain was associated with reductions in systemic exposure and vice versa. The alterations were not considered clinically relevant, as the pharmacodynamic effects based on markers of bone turnover were constant over a wide range of body weights.
Linearity / non-linearity
Denosumab exhibited non-linear pharmacokinetics at various dose levels, but for doses of 60 mg (or 1 mg / kg) and above it exhibited approximately dose proportional increases in exposure. Non-linearity is likely due to an elimination mechanism. saturable mediated target, important at low concentrations.
Renal impairment
In studies with denosumab (60 mg, n = 55 and 120 mg, n = 32) in patients without advanced cancer but with varying degrees of renal function, including patients on dialysis, the degree of renal impairment was not no effect on denosumab pharmacokinetics; therefore no dose adjustment is required in case of renal impairment. Renal monitoring is not required when receiving XGEVA.
Hepatic impairment
No specific studies have been performed in patients with impaired liver function. In general, monoclonal antibodies are not eliminated by hepatic metabolism. Denosumab pharmacokinetics are expected to be unaffected by impaired hepatic function.
Senior citizens
Overall, no differences in safety and efficacy were observed between geriatric patients and younger patients. Controlled clinical trials of XGEVA in patients over 65 years of age with advanced malignancies with bone involvement have demonstrated similar efficacy and safety. in older and younger subjects No dose adjustment is required in elderly patients.
Pediatric population
The pharmacokinetic profile in the pediatric population has not been evaluated.
05.3 Preclinical safety data -
Since the biological activity of denosumab in animals is specific to non-human primates, evaluations of genetically modified (knockout) mice or the use of other biological inhibitors of the pathway were used to evaluate the pharmacodynamic properties of denosumab in rodent models. RANK / RANKL, such as OPG-Fc and RANK-Fc.
In mouse models of bone metastasis of human breast cancer, estrogen receptor positive and negative, prostate cancer, and non-small cell lung cancer, OPG-Fc reduced osteolytic, osteoblastic and osteolytic / osteoblastic lesions, delayed the formation of bone metastases de novo and reduced tumor growth of the skeletal system. In these models, when OPG-Fc was combined with hormonal therapy (tamoxifen) or chemotherapy (docetaxel), a "further inhibition of tumor growth of the skeletal system was found. , respectively, in breast cancer and in prostate or lung cancer. In a mouse model of breast cancer induction, RANK-Fc reduced hormone-induced proliferation in the mammary epithelium and delayed tumor formation.
No standard tests have been performed to investigate the potential genotoxicity of denosumab, as these tests are not relevant for this molecule. However, given its characteristics, denosumab is unlikely to have genotoxic potential.
The carcinogenic potential of denosumab has not been evaluated in long-term animal studies.
In single and repeated dose toxicity studies conducted in cynomolgus monkeys, doses of denosumab that resulted in "systemic exposure 2.7 to 15 times the recommended human dose had no impact on cardiovascular physiology, male fertility or female, or specific organ toxicity product.
In a multiple-dose denosumab study in cynomolgus monkeys during the period equivalent to the first trimester of pregnancy, doses of denosumab that resulted in a 9-fold systemic exposure of the recommended human dose did not induce maternal toxicity or harm to the fetus in a period equivalent to the first trimester; however, the fetal lymph nodes were not examined.
In another study of cynomolgus monkeys given denosumab during pregnancy, at a systemic exposure 12 times the human dose, there was an increase in stillbirth and postnatal mortality; abnormal growth bone resulting in reduced bone strength, reduced hematopoiesis and dental malalignment; absence of peripheral lymph nodes; and reduced neonatal growth. A dose level that may be negative for reproductive effects has not been established. Thereafter, at 6 months after birth, the bone changes showed a recovery and there was no effect on the tooth eruption. However, the effects on lymph nodes and dental malalignment persisted, and it was observed in one minimal to moderate mineralization in multiple tissues (treatment correlation uncertain). There was no evidence of maternal damage prior to labor. Maternal adverse effects occurred infrequently during labor. Maternal mammary gland development was normal.
In preclinical bone quality studies conducted in monkeys treated long-term with denosumab, decreased bone turnover was accompanied by improved bone strength and normal histology.
In male mice genetically engineered to express human RANKL (knock-in mice) and subjected to transcortical fracture, denosumab delayed cartilage removal and callus remodeling compared to the control group, but biomechanical strength was not adversely affected.
Absence of lactation due to inhibition of mammary gland maturation (development of the lobulo-alveolar structures of the mammary gland during pregnancy) was observed in knockout mice that did not express RANK or RANKL, as well as impaired formation RANK / RANKL knockout newborn mice exhibited weight loss, decreased bone growth, altered growth plates and lack of dental eruption. Reduced bone growth, altered growth plates and impaired dental eruption. were also observed in studies in neonatal rats given RANKL inhibitors; these changes were partially reversible following discontinuation of RANKL inhibitor administration. Adolescent primates treated with 2.7 and 15-fold doses of denosumab (doses of 10 and 50 mg / kg) showed anomalies of the ca growth lines. Therefore, denosumab treatment may impair bone growth in children with open growth plates and inhibit dental eruption.
06.0 PHARMACEUTICAL INFORMATION -
06.1 Excipients -
Glacial acetic acid *
Sodium hydroxide (for pH adjustment) *
Sorbitol (E420)
Water for injections
* Acetate buffer is obtained by mixing acetic acid and sodium hydroxide
06.2 Incompatibility "-
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
06.3 Period of validity "-
3 years.
XGEVA can be stored at room temperature (up to 25 ° C) for up to 30 days in the original packaging. Once removed from the refrigerator, XGEVA must be used within this 30 day period.
06.4 Special precautions for storage -
Store in a refrigerator (2 ° C - 8 ° C).
Do not freeze.
Keep the vial in the outer carton to protect the medicine from light.
06.5 Nature of the immediate packaging and contents of the package -
1.7 ml solution in a single use vial (type I glass) with a stopper (coated with elastomeric fluoropolymer) and a seal (aluminum) with a flip-off cap.
Pack size of one, three or four vials.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling -
Before administration, the XGEVA solution should be visually inspected. The solution may contain traces of translucent to white proteinaceous particles.Do not inject the solution if it is cloudy or discolored. Do not shake excessively. To avoid injection site problems, allow the vial to reach room temperature (up to 25 ° C) before injection and inject slowly. Inject the entire contents of the vial. A 27 gauge steel needle is recommended for administration of denosumab. Do not reuse the vial.
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -
Amgen Europe B.V.
Minervum 7061
NL-4817 ZK Breda
Netherlands
08.0 MARKETING AUTHORIZATION NUMBER -
EU / 1/11/703/001
EU / 1/11/703/002
EU / 1/11/703/003
041300017
041300029
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -
Date of first authorization: 13 July 2011
Date of last renewal: 4 April 2016
10.0 DATE OF REVISION OF THE TEXT -
December 2016
