Active ingredients: Denosumab
Prolia 60 mg solution for injection in pre-filled syringe
Prolia package inserts are available for pack sizes:- Prolia 60 mg solution for injection in pre-filled syringe
- Prolia 60 mg solution for injection
Why is Prolia used? What is it for?
What is Prolia and how it works
Prolia contains denosumab, a protein (monoclonal antibody) that interferes with the action of another protein, for the treatment of bone loss and osteoporosis. Treatment with Prolia makes bones stronger and less prone to fractures.
Bone is a living tissue that is constantly renewing. Estrogen helps to keep bones healthy. After menopause, the reduction in estrogen levels can make bones thin and brittle, which can lead to the development of a condition called osteoporosis. Osteoporosis can also occur in men for various causes including aging and / or a low level of the male hormone, testosterone. Many patients with osteoporosis have no symptoms but are still at risk of bone fractures, especially in the spine, femur and wrists.
Surgery or drugs that stop the production of estrogen or testosterone used to treat patients with breast or prostate cancer can also cause bone loss. The bones become more fragile and fracture more easily.
What kind of treatment is Prolia used for
Prolia is used to treat:
- osteoporosis in women after menopause (postmenopausal osteoporosis) and in men who have an increased risk of fractures (broken bones), to reduce the risk of vertebral, non-vertebral and hip fractures.
- bone loss in men resulting from decreased hormone (testosterone) levels due to surgery or drug therapy in patients with prostate cancer.
Contraindications When Prolia should not be used
Do not use Prolia
- if you have low blood calcium levels (hypocalcaemia).
- if you are allergic to denosumab or any of the other ingredients of this medicine
Precautions for use What you need to know before taking Prolia
Talk to your doctor or pharmacist before using Prolia.
During treatment with Prolia you may notice redness and swelling of the skin, most commonly in the lower leg, with a feeling of heat and pain (cellulite) and possibly with feverish symptoms. Tell your doctor immediately if you get any of these symptoms.
Tell your doctor if you have a latex allergy (the needle cap of the pre-filled syringe contains a derivative of latex).
You should also take calcium and vitamin D supplements while being treated with Prolia. Your doctor will discuss this with you.
You may have low blood calcium levels while being treated with Prolia. Tell your doctor immediately if you notice any of the following symptoms: spasms, twitching or cramps in the muscles, and / or numbness or tingling in the fingers, toes or around the mouth, and / or seizures, confusion or loss of consciousness.
Tell your doctor if you have or have ever suffered from severe kidney problems, kidney impairment or if you have had dialysis, which may increase your risk of having low blood calcium levels if you do not take calcium supplements.
An undesirable effect called osteonecrosis of the jaw (severe bone degeneration of the jaw) has been reported rarely (may affect up to 1 in 1,000 people) in patients receiving Prolia for osteoporosis. Osteonecrosis of the jaw. it 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 or nurse (healthcare professional) if you:
- have any problems with your mouth or teeth, such as poor dental hygiene, gum disease, or are planning to have a tooth extraction;
- do not have regular dental care or have not had a dental check-up for a long time;
- you are a smoker (as this may increase the risk of dental problems);
- have previously been treated with a bisphosphonate (used to treat or prevent bone disorders);
- you are taking medicines called corticosteroids (such as prednisolone or dexamethasone);
- has cancer.
Your doctor may ask you to have a dental examination (at the dentist) before starting treatment with Prolia.
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 Prolia.
Contact your doctor and dentist immediately if you notice any problems with your mouth or teeth such as falling teeth, pain or swelling or non-healing of mouth sores or discharge, as these could be signs of a side effect called osteonecrosis of the mandible / maxilla (ONJ).
Children and adolescents
Prolia is not recommended for children and adolescents under the age of 18. The use of Prolia in children and adolescents has not been studied.
Interactions Which drugs or foods can modify the effect of Prolia
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. It is especially important that you tell your doctor if you are taking any other medications that contain denosumab.
You should not take Prolia together with other medicines that contain denosumab
Warnings It is important to know that:
Prolia has not been studied in pregnant women. It is important that you tell your doctor if you are pregnant; if you think you may be pregnant; or if you are planning a pregnancy.
The use of Prolia is not recommended if you are pregnant. If you become pregnant while taking Prolia, please tell your doctor. You may be encouraged to participate in Amgen's pregnancy surveillance program. Local contact details are given. in paragraph 6 of this leaflet.
It is not known if Prolia passes into breast milk. It is important that you tell your doctor if you are breastfeeding or planning to breastfeed. Your doctor will then help you decide whether to stop breast-feeding or to stop taking Prolia, considering the benefit of breast-feeding for the baby and the benefit of taking Prolia for the mother.
If you are breastfeeding while taking Prolia, please inform your doctor. You may be encouraged to participate in Amgen's breastfeeding surveillance program. Local contact details are provided in section 6 of this leaflet. Ask your doctor or pharmacist for advice before using this medicine.
Driving and using machines
Prolia has no or negligible influence on the ability to drive or use machines.
Prolia contains sorbitol (E420)
If you have been told by your doctor that you have an "intolerance to some sugars (sorbitol E420), contact your doctor before taking this medicine.
If you are on a low sodium diet
This medicinal product contains less than 1 mmol sodium (23 mg) per 60 mg, ie essentially "sodium free".
Dose, Method and Time of Administration How to use Prolia: Posology
The recommended dose is a 60 mg pre-filled syringe administered once every 6 months as a single injection under the skin (subcutaneous). The most suitable places for injection are the upper thighs and abdomen. If someone is assisting you to give you the injection, they can also use the outer upper arm. Each Prolia package contains a reminder card with removable stickers, which can be removed from the box. Use the removable stickers to mark on your calendar the date of the next injection and / or use the reminder card to keep track of the date of the next injection.
You should also take calcium and vitamin D supplements while being treated with Prolia. Your doctor will discuss this with you.
Your doctor can decide whether it is best for you or the caregiver to inject with Prolia. Your doctor or nurse will show you or your caregiver how to take Prolia.
Before using a Prolia pre-filled syringe with automatic needle guard, please read this important information:
- It is important that you do not try to give the injection unless you have received proper instructions from your doctor or healthcare professional.
- Prolia is given as an injection into the tissue just under the skin (subcutaneous injection).
- Tell your doctor if you are allergic to latex (the needle cap on the pre-filled syringe contains a latex derivative). Do not remove the gray needle cap from the pre-filled syringe until you are ready to inject.
- Do not use the pre-filled syringe if it has been dropped on a hard surface. Use a new pre-filled syringe and contact your doctor or healthcare professional.
- Do not try to activate the pre-filled syringe before the injection.
- Do not try to remove the clear safety shield from the pre-filled syringe.
Contact your doctor or healthcare professional with any questions.
Step 1: Preparation
A) Remove the pre-filled syringe wrapper from the package and prepare the materials needed for injection: alcohol wipes, a cotton ball or gauze pad, a patch and a sharps disposal container (not included).
For a more comfortable injection, leave the pre-filled syringe at room temperature for about 30 minutes before injecting. Wash your hands thoroughly with soap and water.
Place the new pre-filled syringe and other necessary materials on a clean, well-lit work surface.
- Do not try to warm the syringe using a heat source such as hot water or a microwave.
- Do not leave the pre-filled syringe exposed to direct sunlight. No.
- Do not shake the pre-filled syringe excessively.
- Keep the pre-filled syringe out of the sight and reach of children.
B) Open the pouch, tearing off the cover. Grasp the safety guard on the pre-filled syringe to remove the pre-filled syringe from the pouch.
For security reasons:
- Don't grab the plunger.
- Don't grab the gray needle cap.
C) Check the medicine and the pre-filled syringe.
- Do not use the pre-filled syringe if:
- The medicine is cloudy or there are particles in it. It should be a clear, colorless to slightly yellow solution.
- Some parts appear cracked or broken.
- The gray needle cap is missing or not securely attached.
- The expiration date printed on the label has passed the last day of the month indicated.
In all cases, contact your doctor or healthcare professional.
Step 2: Preparation
A) Wash your hands thoroughly. Prepare and clean the injection site.
Can use:
- The upper part of the thigh.
- The belly, except for an area of 5 centimeters just around the navel.
- The outer upper arm (only if someone else is giving you the injection).
- Clean the injection site with an alcohol wipe. Leave the skin dry.
- Do not touch the injection site before injecting.
- Do not inject into areas where the skin is sensitive, wounded, red, or hard. Avoid injecting into areas with scars or stretch marks.
B) Carefully pull the gray needle cap out and away from your body
C) Lift the injection site to create a stable surface.
- It is important to keep the skin pinched during the injection
Step 3: Injection
A) Keep the skin pinched. INSERT the needle into the skin
- Do not touch the clean area of the skin
B) PUSH the plunger with slow and steady pressure until you feel or hear a "click". Push all the way in until it clicks
- It is important to push all the way down to the "tac" to inject the full dose.
C) RELEASE your thumb. Then MOVE the syringe away from your skin
After the plunger is released, the safety shield of the pre-filled syringe will cover the injection needle securely.
- Do not put the gray needle cap back on used pre-filled syringes.
Step 4: Finish
A Throw away the used pre-filled syringe and other materials in a sharps disposal container.
Medicines must be disposed of in accordance with local regulations. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.
Keep the syringe and sharps disposal container out of the sight and reach of children.
- Do not reuse the pre-filled syringe.
- Do not recycle pre-filled syringes or dispose of them in household waste.
B) Examine the injection site.
If you notice blood, press a cotton ball or gauze over the injection site. Do not rub the injection site. If necessary, apply a patch.
Overdose What to do if you have taken too much Prolia
If you forget to take Prolia
If you have missed a dose of Prolia, the injection should be given as soon as possible. Thereafter, the injections should be given every 6 months from the date of the last injection.
If you stop taking Prolia
To get the most benefit from your treatment, it is important that you take Prolia for as long as your doctor prescribes. Consult your doctor before considering stopping treatment.
Side Effects What are the side effects of Prolia
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Uncommonly, patients being treated with Prolia may develop skin infections (mainly cellulitis). Tell your doctor immediately if you get any of these symptoms while you are taking Prolia: redness and swelling of the skin, most commonly in the lower leg, with a feeling of heat and pain and possibly feverish symptoms.
Rarely, patients being treated with Prolia may develop pain in the mouth and / or jaw, swelling or non-healing lesions in the mouth or jaw, discharge, numbness or a feeling of heaviness in the jaw / jaw, or wobbling of a tooth. These could be signs of severe bone degeneration of the jaw (osteonecrosis). Tell your doctor and dentist immediately if you experience such symptoms during treatment with Prolia or after stopping treatment.
Rarely, patients being treated with Prolia may have low blood calcium levels (hypocalcaemia). Symptoms include muscle spasms, twitching or cramps, and / or numbness or tingling in the fingers, toes or around the mouth and / or seizures, confusion, or loss of consciousness. Contact your doctor immediately if any of these symptoms appear. Low blood calcium levels can also lead to a change in the heart's rhythm called QT interval prolongation, which is seen on electrocardiography (ECG).
Very common side effects (may affect more than 1 in 10 people):
- pain in the bones, joints and / or muscles sometimes severe,
- pain in the arms or legs (pain in extremities).
Common side effects (may affect up to 1 in 10 people):
- frequent and painful need to pass urine, blood in the urine, urinary incontinence,
- upper respiratory infections,
- pain, tingling or numbness radiating to the lower limbs (sciatica),
- clouding of the lens (cataract),
- constipation,
- abdominal discomfort,
- rash,
- itching, redness and / or dryness of the skin (eczema).
Uncommon side effects (may affect up to 1 in 100 people):
- fever, vomiting and abdominal pain or abdominal discomfort (diverticulitis),
- ear infections.
Rare side effects (may affect up to 1 in 1,000 people):
- allergic reactions (e.g. swelling of the face, lips, tongue, throat or other parts of the body; rash, itching, hives, wheezing or difficulty in breathing).
Uncommon fractures of the femur may rarely occur.
Contact your doctor if you experience new or unusual pain in your hip, groin or thigh during treatment with Prolia, as this could be an early sign of a possible fracture of the femur.
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. 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.
Do not shake excessively.
The pre-filled syringe can be left out of the refrigerator to reach room temperature (up to 25 ° C) before injecting. This will make the injection more comfortable. Once the syringe 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.
6. Contents of the pack and other information
What Prolia contains
- The active ingredient is denosumab. Each 1 ml pre-filled syringe contains 60 mg of denosumab (60 mg / ml).
- The other ingredients are glacial acetic acid, sodium hydroxide, sorbitol (E420), polysorbate 20 and water for injections.
What Prolia looks like and contents of the pack
Prolia is a clear, colorless to slightly yellow solution for injection in a ready-to-use pre-filled syringe.
Each pack contains one pre-filled syringe with needle shield. Each pack contains one pre-filled syringe.
Important
Before using a Prolia pre-filled syringe with automatic needle guard, please read this important information:
- It is important that you do not try to give the injection unless you have received proper instructions from your doctor or healthcare professional.
- Prolia is given as an injection into the tissue just under the skin (subcutaneous injection).
- Tell your doctor if you are allergic to latex (the needle cap on the pre-filled syringe contains a derivative of latex).
- Do not remove the gray needle cap from the pre-filled syringe until you are ready to inject.
- Do not use the pre-filled syringe if it has been dropped on a hard surface. Use a new pre-filled syringe and contact your doctor or healthcare professional.
- Do not try to activate the pre-filled syringe before the injection.
- Do not try to remove the clear safety shield from the pre-filled syringe.
Contact your doctor or healthcare professional with any questions.
Step 1: Preparation
A Remove the pre-filled syringe wrapper from the package and prepare the materials needed for injection: alcohol wipes, a cotton swab or gauze pad, a patch, and a sharps disposal container (not included).
For a more comfortable injection, leave the pre-filled syringe at room temperature for about 30 minutes before injecting. Wash your hands thoroughly with soap and water.
Place the new pre-filled syringe and other necessary materials on a clean, well-lit work surface.
- Do not try to warm the syringe using a heat source such as hot water or a microwave.
- Do not leave the pre-filled syringe exposed to direct sunlight.
- Do not shake the pre-filled syringe excessively.
- Keep the pre-filled syringe out of the sight and reach of children.
B Open the wrapping, tearing off the cover. Grasp the safety shield of the pre-filled syringe to remove the pre-filled syringe from the wrapping
For security reasons:
- Don't grab the plunger.
- Don't grab the gray needle cap.
C Check the medicine and the pre-filled syringe.
Do not use the pre-filled syringe if:
- The medicine is cloudy or there are particles in it. It should be a clear, colorless to slightly yellow solution.
- Some parts appear cracked or broken.
- The gray needle cap is missing or not securely attached.
- The expiration date printed on the label has passed the last day of the month indicated.
In all cases, contact your doctor or healthcare professional.
Step 2: Preparation
A Wash your hands thoroughly. Prepare and clean the injection site.Can use:
- The upper part of the thigh. Upper arm Belly Upper thigh
- The belly, except for an area of 5 centimeters just around the navel.
- The outer upper arm (only if someone else is giving you the injection).
Clean the injection site with an alcohol wipe. Leave the skin dry.
- Do not touch the injection site before injecting.
- Do not inject into areas where the skin is sensitive, wounded, red, or hard. Avoid injecting into areas with scars or stretch marks.
B Carefully pull off the gray needle cap outward and away from your body.
C Lift the injection site to create a stable surface.
It is important to keep the skin pinched during the injection
Step 3: Injection
A Keep the skin lifted. INSERT the needle into the skin.
- Do not touch the clean area of the skin
B PUSH the plunger with slow, steady pressure until you feel or hear a "click". Push all the way in until it clicks.
- It is important to push all the way down to the "tac" to inject the full dose.
C RELEASE your thumb. Then MOVE the syringe away from your skin
After the plunger is released, the safety shield of the pre-filled syringe will cover the injection needle securely.
- Do not put the gray needle cap back on used pre-filled syringes.
Step 4: Finish
A Throw away the used pre-filled syringe and other materials in a sharps disposal container.
Medicines must be disposed of in accordance with local regulations. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.
Keep the syringe and sharps disposal container out of the sight and reach of children.
- Do not reuse the pre-filled syringe.
- Do not recycle pre-filled syringes or dispose of them in household waste.
B Examine the injection site.
If you notice blood, press a cotton ball or gauze over the injection site. Do not rub the injection site. If necessary, apply a patch.
Instructions for injecting Prolia using a pre-filled syringe
This section contains information on how to use the Prolia pre-filled syringe. It is important that you or your caregiver do not inject before you have received proper instructions from your doctor or nurse. Wash your hands before each injection. If you have any questions about the injection, ask your doctor or nurse. nursing staff to get help
Before starting
Read all the instructions carefully before using the pre-filled syringe.
Do not use the pre-filled syringe if the needle cap has been removed.
How is the Prolia pre-filled syringe used?
Your doctor has prescribed a pre-filled syringe for injecting Prolia under the skin (subcutaneously). You must inject the entire contents (1 ml) of the Prolia pre-filled syringe, which must be injected once every 6 months according to the prescriptions of the doctor.
What is needed:
To give yourself the injection, you will need:
- A new Prolia pre-filled syringe; And
- Alcohol-soaked cotton balls or similar disinfectants.
What you must do before the subcutaneous injection of Prolia
- Remove the pre-filled syringe from the refrigerator. DO NOT pick up the pre-filled syringe by the plunger or cap side of the needle, as this may damage it.
- Leave the pre-filled syringe out of the refrigerator until it reaches room temperature. This will make the injection more comfortable. DO NOT heat the syringe in any other way (for example, in a microwave oven or hot water). DO NOT expose the syringe to direct sunlight.
- DO NOT shake the pre-filled syringe excessively.
- DO NOT remove the needle cap from the pre-filled syringe until you are ready to inject.
- Check the expiry date on the pre-filled syringe label (EXP). DO NOT use it if this is after the last day of the month shown.
- Check the appearance of Prolia. It must be a clear, colorless to slightly yellow liquid. Do not inject the solution if it contains particles or if it appears cloudy or discolored.
- Find a comfortable, well-lit and clean surface and keep everything you need close at hand.
- Wash your hands thoroughly.
Where to inject?
The most suitable places for injection are the upper thighs and abdomen.
If someone who is assisting you injecting you, they can also use the outer upper arm.
How to inject?
- Disinfect the skin using an alcohol wipe.
- To avoid bending the needle, gently pull the cap off the needle horizontally without turning it. DO NOT touch the needle or push the plunger.
- You may notice a small air bubble in the pre-filled syringe. You must not remove the air bubble before injecting. Injecting the solution with the air bubble is harmless.
- Lift the skin between your thumb and forefinger (without squeezing it). Push the needle completely into your skin as shown by your doctor or nurse.
- Push the plunger with slow, steady pressure, always keeping the skin pinched. Push the plunger all the way in until all of the solution has been injected.
- Pull out the needle and release the skin.
- If you notice a drop of blood, you can gently remove it with a cotton ball or gauze. Do not rub the injection site. If necessary, you can cover the injection site with a patch
- Use each pre-filled syringe for one injection only. DO NOT reuse Prolia that is left in the syringe.
Remember: if you have any problems, don't hesitate to consult your doctor or nurse for help or advice.
Disposal of used syringes
- DO NOT put the cap back on used needles.
- Keep used syringes out of the reach and sight of children.
- Used syringes should be disposed of in accordance with local requirements. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
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
PROLIA 60 MG SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each pre-filled syringe contains 60 mg of denosumab in 1 ml of solution (60 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 ml of solution contains 47 mg of sorbitol (E420) (see section 4.4).
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Solution for injection (injection).
Clear, colorless to slightly yellow solution.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Treatment of osteoporosis in postmenopausal women and in men at increased risk of fractures.
In postmenopausal women, Prolia significantly reduces the risk of vertebral, non-vertebral and hip fractures.
Treatment of bone loss associated with hormone ablative therapy in men with prostate cancer at increased risk of fractures (see section 5.1). In men with prostate cancer being treated with hormone ablative therapy, Prolia significantly reduces the risk of vertebral fractures.
04.2 Posology and method of administration
Dosage
The recommended dose of Prolia is 60 mg given as a single subcutaneous injection once every 6 months in the thigh, abdomen or upper arm.
Patients should receive adequate calcium and vitamin D supplementation (see section 4.4).
Patients being treated with Prolia should be given the package leaflet and the patient reminder card.
Patients with renal impairment
No dose adjustment is required in patients with renal impairment (see section 4.4 for recommendations on calcium monitoring).
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)
No dose adjustment is required in elderly patients.
Pediatric population
Prolia is not recommended in pediatric patients (age
Method of administration
For subcutaneous use.
Administration should be performed by a person adequately trained in injection techniques.
For instructions on use, handling and disposal, see section 6.6.
04.3 Contraindications
• Hypocalcaemia (see section 4.4).
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
04.4 Special warnings and appropriate precautions for use
Intake of Calcium and Vitamin D
It is important that all patients get an adequate intake of calcium and vitamin D.
Precautions for use
Hypocalcemia
It is important to identify patients at risk for hypocalcemia. Hypocalcaemia should be corrected by adequate calcium and vitamin D intake prior to initiation of therapy. Clinical monitoring of calcium levels is recommended before each dose and, in patients predisposed to developing hypocalcaemia, within two weeks of the dose. If some patients experience suspected symptoms of hypocalcaemia during treatment (see section 4.8 for list of symptoms) calcium levels should be measured. Patients should be encouraged to report symptoms indicative of hypocalcaemia.
Severe symptomatic hypocalcaemia has been reported in the post-marketing setting (see section 4.8) which occurred in the majority of cases in the first weeks after initiation of therapy, but which may also occur later.
Skin infections
Patients treated with Prolia may develop skin infections (mainly cellulitis) requiring hospitalization (see section 4.8). Patients should be told to seek immediate medical attention if they develop signs or symptoms of cellulitis.
Osteonecrosis of the jaw (ONJ)
ONJ has been reported rarely in patients treated with Prolia for the treatment of osteoporosis (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 Prolia treatment in patients. with concomitant risk factors.
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 such as tooth extractions.
All patients should be encouraged to maintain good oral hygiene, have regular dental checkups, 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 Prolia. During treatment, invasive dental procedures should only be performed after careful consideration and should be avoided in close proximity to Prolia administration.
The management plan for patients developing ONJ should be defined in close cooperation between the treating physician and a dentist or oral surgeon experienced with ONJ. Temporary interruption of treatment should be considered until the condition is resolved and, where possible, to mitigate the risk factors that contributed to its occurrence.
Atypical fractures of the femur
Cases of atypical femoral fractures have been reported in patients treated with Prolia (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
he in patients with some comorbid conditions (e.g. vitamin D deficiency, rheumatoid arthritis, hypophosphatasia) and in case of use of certain medicines (e.g. bisphosphonates, glucocorticoids, proton pump inhibitors). These events also occurred in the absence of antiresorptive therapy. Similar fractures, reported in association with the use of bisphosphonates, are often bilateral; therefore the contralateral femur should be evaluated in Prolia-treated patients who have sustained a femoral shaft fracture. In patients with suspected atypical femoral fracture, L should be considered. discontinuation of Prolia therapy pending patient assessment based on individual benefit / risk analysis. During treatment with Prolia, patients should be advised to report new or unusual pain in thigh, hip or to the groin. Patients presenting with such symptoms should be evaluated for an incomplete femoral fracture.
Concomitant treatment with other denosumab-containing medicinal products
Patients being treated with Prolia should not be treated concomitantly with other denosumab-containing medicines (for the prevention of skeletal events in adults with bone metastases from solid tumors).
Renal impairment
Patients with severe renal impairment (creatinine clearance dialysis have an increased risk of developing hypocalcaemia. The risk of developing hypocalcaemia and consequent elevation of parathyroid hormone levels increases with increasing degree of renal impairment. Adequate calcium intake, Vitamin D and regular calcium monitoring are particularly important in these patients, as noted above.
Dry natural rubber
The needle cap of the pre-filled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions.
Warnings for excipients
This medicine contains sorbitol. Patients with rare hereditary conditions of fructose intolerance should not take Prolia.
This medicinal product contains less than 1 mmol sodium (23 mg) per 60 mg, ie essentially "sodium free".
04.5 Interactions with other medicinal products and other forms of interaction
In an interaction study, Prolia did not affect the pharmacokinetics of midazolam, which is metabolised by cytochrome P450 3A4 (CYP3A4). This indicates that Prolia is not expected to alter the pharmacokinetics of medicinal products metabolised by CYP3A4.
No clinical data are available regarding concomitant administration of denosumab and hormone replacement therapy (estrogen), however a potential risk of pharmacodynamic interaction is considered low.
In a transitional clinical study (alendronate to denosumab) in postmenopausal women with osteoporosis, the pharmacokinetics and pharmacodynamics of denosumab were not altered by previous alendronate therapy.
04.6 Pregnancy and lactation
Pregnancy
No adequate data are available regarding the use of Prolia in pregnant women. Reproductive toxicity was demonstrated in a study conducted in cynomolgus monkeys treated during pregnancy with denosumab dosages resulting in 119-fold systemic exposure in terms of AUC. higher than the dose used in humans (see section 5.3).
The use of Prolia is not recommended in pregnant women.
Women who become pregnant while being treated with Prolia are encouraged to enroll in Amgen's pregnancy surveillance program.Contact details are given in section 6 of the package leaflet - Information for the user.
Feeding time
It is unknown whether denosumab is excreted in human breast milk. Studies conducted in genetically modified mice in which the gene encoding RANKL has been removed (knockout mice) suggest that the absence of RANKL (the target of denosumab - see section 5.1) during pregnancy could interfere with the maturation of the mammary gland. , causing alterations in lactation after delivery (see section 5.3). A decision must be made whether to abstain from breastfeeding or from Prolia therapy, taking into account the benefit of breastfeeding for the newborn / infant and the benefit of Prolia therapy for the woman.
Women who are breastfeeding during treatment with Prolia are encouraged to enroll in Amgen's breastfeeding surveillance program. Contact details are provided in section 6 of the package leaflet - Information for the user.
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
Prolia has no or negligible influence on the ability to drive or use machines.
04.8 Undesirable effects
Summary of the safety profile
The overall safety profile of Prolia was similar in patients with osteoporosis and in patients with breast or prostate cancer treated with hormone ablative therapy in five placebo-controlled Phase III clinical trials.
The most common side effects with Prolia (seen in more than one in ten patients) are musculoskeletal pain and pain in the extremities. Cases of cellulite have been observed uncommonly in patients treated with Prolia; rare cases of hypocalcaemia, hypersensitivity, osteonecrosis of the jaw and atypical femoral fractures (see section 4.4 and section 4.8 - Description of selected adverse reactions).
Table of adverse reactions
The data shown in Table 1 describe adverse reactions reported in Phase II and III clinical studies in patients with osteoporosis and in patients with breast or prostate cancer who received ablative hormone therapy and / or from spontaneous reports.
The following convention has been used for the classification of adverse reactions (see table 1): very common (≥ 1/10), common (≥ 1/100,
Table 1 Adverse reactions reported in patients with osteoporosis and breast or prostate cancer patients treated with hormone ablative therapy
1 See section Description of selected adverse reactions
In a "pooled analysis of data from all Phase II and III placebo-controlled clinical trials, influenza-like syndrome was reported with a crude incidence rate of 1.2% in denosumab-treated subjects and 0.7%" in subjects treated with placebo. Although this difference emerged in a "pooled analysis of the different studies, it was not observed in a" stratified analysis.
Description of selected adverse reactions
Hypocalcemia
In two placebo-controlled phase III clinical trials in women with postmenopausal osteoporosis, approximately 0.05% (2 out of 4,050) of patients reported decreases in serum calcium levels (less than 1.88 mmol / l) in following the administration of Prolia. On the other hand, decreases in serum calcium levels (less than 1.88 mmol / l) were not reported in either the two phase III placebo-controlled clinical trials in patients treated with hormone ablative therapy or in the phase III placebo-controlled clinical trial in men with osteoporosis.
In the post-marketing setting, rare cases of symptomatic severe hypocalcaemia have been reported mainly in patients treated with Prolia at increased risk of hypocalcaemia, which occurred in the majority of cases within the first weeks after initiation of therapy. Examples of clinical manifestations of severe symptomatic hypocalcaemia, including QT interval prolongation, tetany, seizures and altered mental status (see section 4.4). Symptoms of hypocalcaemia in clinical trials with denosumab included muscle numbness or stiffness, muscle twitching, spasms and cramps.
Skin infections
In placebo-controlled phase III clinical trials in women with postmenopausal osteoporosis, the overall incidence of skin infections was similar in the placebo and Prolia groups (placebo [1.2%, 50 out of 4,041] vs. Prolia [1.5%, 59 of 4,050]); in men with osteoporosis (placebo [0.8%, 1 of 120] vs. Prolia [0%, 0 of 120]. Similar evidence was also observed in clinical studies Phase III placebo-controlled trials in breast or prostate cancer patients treated with hormone ablative therapy (placebo [1.7%, 14 out of 845] vs. Prolia [1.4%, 12 out of 860]). that required hospitalization were reported in 0.1% (3 of 4,041) of women with postmenopausal osteoporosis treated with placebo, compared to 0.4% (16 of 4,050) of women receiving Prolia. Mostly these were cases of cellulite In studies conducted on patients with breast and prostate cancer, l and skin infections reported as serious adverse reactions were similar in the placebo (0.6%, 5 of 845) and Prolia (0.6%, 5 of 860) groups.
Osteonecrosis of the mandible / maxilla
In clinical trials in osteoporosis and in breast or prostate cancer patients receiving hormone ablative therapy in a total of 19,521 patients, ONJ was reported rarely in 14 patients (see section 4.4).
Atypical fractures of the femur
In the osteoporosis clinical development program, atypical femoral fractures have been reported rarely in patients treated with Prolia (see section 4.4).
Cataract
In a single placebo-controlled phase III clinical trial in prostate cancer patients receiving androgen deprivation therapy (ADT), a difference in the incidence of cataracts was observed (4.7% denosumab, 1.2% placebo). No difference was observed in women with postmenopausal osteoporosis or in men with osteoporosis or in women treated with aromatase inhibitors for non-metastatic breast cancer.
Diverticulitis
A difference in the incidence of diverticulitis (1.2% denosumab, 0% placebo) was observed in a single, placebo-controlled phase III clinical trial in prostate cancer patients on androgen deprivation therapy (ADT). L Incidence of diverticulitis was comparable between treatment groups in women with postmenopausal osteoporosis or men with osteoporosis and in women treated with aromatase inhibitors for non-metastatic breast cancer.
Hypersensitivity reactions to the drug
Rare events of hypersensitivity to the drug including rash, urticaria, facial swelling, erythema and anaphylactic reactions have been reported in post-marketing reports in patients receiving Prolia.
Musculoskeletal pain
Musculoskeletal pain, including severe cases, has been reported in Prolia-treated patients in the post-marketing setting. In clinical trials, musculoskeletal pain was very common in both denosumab and placebo groups. Musculoskeletal pain which resulted. discontinuation in studies was uncommon.
Other special populations
In clinical trials, patients with severe renal impairment (creatinine clearance
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: https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse).
04.9 Overdose
No cases of overdose have been reported in clinical studies. In clinical trials, denosumab was administered at doses up to 180 mg every 4 weeks (cumulative doses up to 1,080 mg over 6 months) and no further adverse reactions were observed.
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
Denosumab is a human monoclonal antibody (IgG2) directed against RANKL, to which it binds with high affinity and specificity, preventing the activation of its RANK receptor, present on the surface of osteoclasts and their precursors. Blocking the interaction between RANKL and RANK inhibits the formation, function and survival of osteoclasts, thereby reducing bone resorption, both at the cortical and trabecular level.
Pharmacodynamic effects
Treatment with Prolia rapidly reduced bone turnover, reaching the nadir for the serum marker of bone resorption C-terminal telopeptide type I collagen (CTX) (85% reduction) in 3 days. maintained throughout the dosing interval. At the end of each dosing interval, reductions in CTX were partially attenuated from a maximum reduction of ≥ 87% to approximately ≥ 45% (range 45-80%), reflecting the reversibility of Prolia's effects on bone remodeling once levels serum decreases. These effects were maintained by continuing treatment with Prolia. Markers of bone turnover typically reached pre-treatment levels within 9 months of the last dose. Upon resumption of treatment, denosumab-induced reductions in CTX were similar to those seen in naïve patients starting denosumab treatment.
Immunogenicity
In clinical studies, neutralizing antibodies directed against Prolia were not observed. Based on the results of a sensitive immunoassay, less than 1% of denosumab-treated patients for up to 5 years tested positive for non-neutralizing antibodies with no evidence of altered pharmacokinetic, toxicological or clinical response profile.
Treatment of postmenopausal osteoporosis
The efficacy and safety of Prolia administered every 6 months for 3 years were evaluated in postmenopausal women (7,808 women aged between 60 and 91 years of which 23.6% had prevalent vertebral fractures) with values baseline BMD (bone mineral density) expressed in lumbar spine or total femur T-scores ranging from -2.5 to -4.0 and with a 10-year mean absolute probability of fracture of 18.60% ( deciles: 7.9-32.4%) for major osteoporotic fractures and 7.22% (deciles: 1.4-14.9%) for hip fractures. influencing bone metabolism were excluded from the study Patients received daily calcium (at least 1,000 mg) and vitamin D (at least 400 IU) supplementation.
Effects on vertebral fractures
Prolia significantly reduced the risk of new vertebral fractures at 1, 2, and 3 years (p
Table 2 Effects of Prolia on the risk of new vertebral fractures
* p
Effects on hip fractures
Prolia demonstrated a 40% relative reduction (0.5% absolute risk reduction) in the 3-year risk of hip fractures (p
In a post-hoc analysis in women over 75 years of age, Prolia demonstrated a relative risk reduction of 62% (absolute risk reduction of 1.4%, p
Effects on all clinical fractures
Prolia significantly reduced all fracture types / groups (see table 3).
Table 3 Effects of Prolia on 3-year clinical fracture risk
* p ≤ 0.05; ** p = 0.0106 (secondary endpoint after multiplicity correction), *** p ≤ 0.0001
+ Incidence of events based on 3-year Kaplan-Meier estimates.
1 Including clinical vertebral and non-vertebral fractures.
2 Excluding those affecting the vertebrae, skull, face, mandible, metacarpus and phalanges of the fingers and toes.
3 Includes pelvis, distal femur, proximal tibia, ribs, proximal humerus, forearm and femur.
4 Including clinical vertebral, femur, forearm and humerus fractures as defined by the WHO.
In women with baseline BMD values expressed in femoral neck T-score ≤-2.5 Prolia reduced the risk of non-vertebral fractures (relative risk reduction of 35%, absolute risk reduction of 4.1%, p
Prolia's 3-year reduction in the incidence of new vertebral fractures, hip fractures and non-vertebral fractures remained constant, regardless of baseline fracture risk at 10 years.
Effects on bone mineral density
Compared to placebo treatment, Prolia significantly increased BMD at all skeletal sites measured at 1, 2 and 3 years. Prolia increased BMD by 9.2% in the lumbar spine, by 6.0% in the total femur, by 4.8% in the femoral neck, by 7.9% in the trochanter, by 3. , 5% at the level of the distal third of the radius and 4.1% at the level of the total body over 3 years (all p
In clinical trials evaluating the effects of discontinuing Prolia, BMD returned to approximately pre-treatment levels within 18 months of the last dose and remained above placebo. These data indicate that continued treatment with Prolia is necessary to maintain the effect of therapy. Resumption of Prolia therapy resulted in increases in BMD similar to those seen when Prolia was first administered.
Open-label extension study for the treatment of postmenopausal osteoporosis
A total of 4,550 women (2,343 Prolia and 2,207 placebo) who did not miss more than one drug administration in the pivotal study described above and who completed the visit at month 36 of the study, gave consent to be enrolled in a study of Multinational, multicenter, open-label, single-arm extension lasting 7 years to evaluate the long-term safety and efficacy of Prolia. All women in the extension study received Prolia at a dose of 60 mg every 6 months, as well as received daily calcium (at least 1 g) and vitamin D (at least 400 IU). At month 60 of the extension study, after 8 years of treatment with Prolia, in the long-term group (n = 1,542) the BMD increased by 18 , 4% at the lumbar spine, 8.3% at the total femur, 7.8% at the femoral neck, and 11.6% at the trochanter from baseline in the original pivotal study.
The incidence of fractures was evaluated as a safety endpoint.
From the 4th to the 8th year the incidence of new vertebral and non-vertebral fractures did not increase over time; the incidence on an annual basis was approximately 1.1% and 1.3% respectively.
Eight confirmed cases of osteonecrosis of the jaw (ONJ) and two atypical fractures of the femur occurred during the extension study.
Treatment of osteoporosis in men
The efficacy and safety of Prolia, administered once every 6 months for 1 year, were evaluated in 242 men aged 31 to 84 years. Subjects with an estimated glomerular filtration rate (eGFR) 2 were all men received daily calcium (at least 1,000 mg) and vitamin D (at least 800 IU) supplementation.
The primary efficacy variable was the percent change in lumbar spine BMD; anti-fracture efficacy was not evaluated. Prolia significantly increased BMD in all skeletal sites measured compared to placebo at 12 months: 4.8% at lumbar spine, 2.0% at total femur , 2.2% at the level of the femoral neck, 2.3% at the level of the trochanter, and 0.9% at the level of the distal third of the radius (all p
Bone histology
Bone histology was evaluated after 1-3 years of treatment with Prolia in 62 women with postmenopausal osteoporosis or low bone mass who had not received osteoporosis therapy or who had previously been treated with alendronate. Forty-one women participated in the bone biopsy sub-study at month 24 of the extension study. Bone histology was also evaluated in 17 men with osteoporosis after 1 year of treatment with Prolia. Bone biopsy results showed bone of normal architecture and quality with no evidence of mineralization defects, non-lamellar bone or medullary fibrosis.
Treatment of bone loss associated with androgen deprivation therapy
The efficacy and safety of Prolia, administered once every 6 months for 3 years, was evaluated in men with histologically confirmed, non-metastatic prostate cancer treated with ADT (1,468 men aged 48 to 97 years ) with increased risk of fracture (defined as age> 70 years or
Compared to placebo treatment, Prolia significantly increased BMD in all skeletal sites measured at 3 years by 7.9% at the lumbar spine level, by 5.7% at the total femur level, by 4.9% at the femoral neck, 6.9% at the trochanter level, 6.9% at the distal third of the radius and 4.7% at the total body level (all p
Prolia demonstrated a significant reduction in the relative risk of new vertebral fractures: 85% (absolute risk reduction of 1.6%) at 1 year, 69% (absolute risk reduction of 2.2%) at 2 years and 62 % (2.4% absolute risk reduction) at 3 years (all p
Treatment of bone loss associated with adjuvant aromatase inhibitor therapy
The efficacy and safety of Prolia administered once every 6 months for 2 years were evaluated in women with non-metastatic breast cancer (252 women aged 35 to 84 years) with baseline BMD values expressed in T-scores. between -1.0 and -2.5 at the level of the lumbar spine, total femur or femoral neck.All women received daily supplementation of calcium (at least 1,000 mg) and vitamin D (at least 400 IU).
The primary efficacy endpoint of the study was percent change in lumbar spine BMD, while fracture efficacy was not evaluated. Compared to 2-year placebo treatment, Prolia significantly increased BMD at all measured skeletal sites of the 7.6% at the level of the lumbar spine, 4.7% at the level of the total femur, 3.6% at the level of the femoral neck, 5.9% at the level of the trochanter, 6.1% at the level of the distal third of the radius and 4.2% at the total body level (all p
Pediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with Prolia in all subsets of the pediatric population for the treatment of bone loss associated with hormone ablative therapy, and in subsets of the younger pediatric population. 2 years for the treatment of osteoporosis. See section 4.2 for information on pediatric use.
05.2 Pharmacokinetic properties
Absorption
Following subcutaneous administration of a dose of 1.0 mg / kg, equivalent to approximately the approved dose of 60 mg, exposure based on AUC was 78% compared to intravenous administration of the same dose. For a subcutaneous dose of 60 mg, the maximum serum concentration (Cmax) of denosumab of 6 mcg / ml (range 1-17 mcg / ml) was reached in 10 days (range 2-28 days).
Biotransformation
Denosumab is composed solely of amino acids and carbohydrates such as native immunoglobulins and is unlikely to be eliminated by hepatic metabolism. The metabolism and elimination of the drug can be expected to follow the pathways of immunoglobulin clearance, which occur with degradation into small peptides and single amino acids.
Elimination
After reaching Cmax, serum levels decreased with a "half-life of 26 days (range 6-52 days) over a period of 3 months (range 1.5-4.5 months). 53% of patients had no quantity measurable denosumab detectable at 6 months after dose administration.
No accumulation or change in denosumab pharmacokinetics over time was observed following multiple subcutaneous dosing of 60 mg once every 6 months. Denosumab pharmacokinetics were unaffected by drug-binding antibody formation and were similar in men and women. Age (28-87 years), race and disease status (reduced bone mass or osteoporosis; prostate or breast cancer) do not appear to have significant effects on denosumab pharmacokinetics.
A trend between higher body weight and lower drug exposure was observed based on AUC and Cmax. However, this trend was not considered clinically relevant, as pharmacodynamic effects based on bone turnover markers and increases in BMDs were constant over a wide range of body weights.
Linearity / Non-linearity
In dose ranging studies, denosumab exhibited non-linear, dose-dependent pharmacokinetics, with lower clearance at higher doses or concentrations, but with approximately dose-proportional increases in exposure for doses equal to or greater. to 60 mg.
Renal impairment
In a study of 55 patients with varying degrees of renal function, including patients on dialysis, the degree of renal impairment had no effect on denosumab pharmacokinetics.
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.
Pediatric population
The pharmacokinetic profile in the pediatric population has not been evaluated.
05.3 Preclinical safety data
In single and repeated dose toxicity studies conducted in cynomolgus monkeys, dosages of denosumab resulting in systemic exposure up to 100-150 times the recommended human dose had no impact on cardiovascular physiology, male or female fertility. or specific organ toxicity product.
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 preclinical studies conducted in knockout mice that did not express RANK or RANKL, impaired fetal lymph node formation was observed. Absence of lactation due to inhibition of mammary gland maturation (development of the lobulo-alveolar structures of the gland during pregnancy) was also observed in knockout mice that did not express RANK or RANKL.
In a study conducted in cynomolgus monkeys treated during the period equivalent to the first trimester of pregnancy with denosumab dosages resulting in systemic exposure in terms of AUC up to 99 times the human dose (60 mg every 6 months), no harm to the mother or fetus has been reported. Fetal lymph nodes were not examined in this study.
In another study in cynomolgus monkeys treated during pregnancy with denosumab dosages resulting in a systemic exposure in terms of AUC 119 times higher than the dose used in humans (60 mg every 6 months), an increase in fetuses was observed. stillbirths and postnatal mortality; abnormal bone growth with reduced bone strength, reduced hematopoiesis and dental misalignment; absence of peripheral lymph nodes and reduced neonatal growth. A level has not been established at which no harmful effects on reproduction are observed. Six months after birth, bone abnormalities observed regressed and there was no effect on dental eruption. However, the effects on lymph nodes and dental misalignment persisted, and mild to moderate mineralization in various tissues (of uncertain correlation with treatment) was observed in one animal. Prior to labor, there was no evidence of damage to the mother; adverse maternal events were rarely reported 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. Calcium levels were transiently decreased, while parathyroid hormone levels were temporarily increased in denosumab-treated ovariectomized monkeys.
In male mice genetically engineered to express human RANKL (knockin 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.
Knockout mice (see section 4.6) that did not express RANK or RANKL exhibited weight loss, reduced bone growth, and lack of tooth eruption. In neonatal rats, inhibition of RANKL (target of denosumab therapy) with high doses of Fc-linked osteoprotegerin (OPG-Fc) was associated with inhibition of bone growth and dental eruption. In this model, these changes were partially reversible upon discontinuation of the RANKL inhibitor administration. Adolescent primates treated with denosumab doses 27 and 150 times (doses 10 and 50 mg / kg) higher than the doses used in the clinic presented abnormalities. growth plates. Therefore, denosumab treatment may impair bone growth in children with open growth plates and inhibit tooth eruption.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Glacial acetic acid *
Sodium hydroxide (for pH adjustment) *
Sorbitol (E420)
Polysorbate 20
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.
Prolia can be stored at room temperature (up to 25 ° C) for up to 30 days in the original packaging. Once removed from the refrigerator, Prolia 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 pre-filled syringe in the outer carton to protect the medicine from light.
06.5 Nature of the immediate packaging and contents of the package
A 1 ml solution in a single use type I glass pre-filled syringe with a stainless steel 27 gauge needle, with or without needle shield.
The needle cap of the pre-filled syringe contains dry natural rubber, which is a derivative of latex (see section 4.4).
Pack size of one syringe, with blister (pre-filled syringe with or without needle shield) or without blister (pre-filled syringe only).
06.6 Instructions for use and handling
Before administration, the solution should be inspected. Do not inject the solution if it contains visible particles or if it appears cloudy or discolored. Do not shake excessively. To avoid injection site reactions, allow the pre-filled syringe to reach room temperature (up to 25 ° C) before injection and inject slowly. Inject the entire contents of the pre-filled syringe. Discard any remnants of medicine left inside the pre-filled syringe.
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Amgen Europe B.V.
Minervum 7061
NL-4817 ZK Breda
Netherlands
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/10/618/001
EU / 1/10/618/002
EU / 1/10/618/003
040108019
040108033
040108021
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 26 May 2010
Date of most recent renewal: January 15, 2015
10.0 DATE OF REVISION OF THE TEXT
June 2015
