Nebid

Procedure: Transfer of Marketing Authorization from Bayer to Grunenthal Srl
Date of AIFA Approval/Silent Approval: Official Journal No. XX of dd/mm/yyyy

Package leaflet: Information for the user

NEBID 1000 mg/4 ml solution for injection

Testosterone undecanoate
Please read this entire leaflet carefully before taking this medicine, as it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, consult your doctor.
• This medicine has been prescribed for you personally. Do not give it to others, even if their symptoms are similar to yours, as it could be harmful.
• If you experience any adverse reactions, including those not listed in this leaflet, consult your doctor. See section 4.

Contents of this leaflet

1. What Nebid is and what it is used for
2. What you need to know before using Nebid
3. How to use Nebid
4. Possible side effects
5. How to store Nebid
6. Contents of the pack and other information

1. What Nebid is and what it is used for

Nebid contains testosterone as the active substance, a male hormone. Nebid is injected into a muscle, where it accumulates and is gradually released over a period of time. Nebid is used to replace testosterone in adult men for the treatment of various health problems caused by testosterone deficiency (male hypogonadism). This condition must be confirmed by two separate measurements of testosterone in the blood and must include clinical symptoms such as:

• impotence
• infertility
• low sexual desire
• fatigue
• depressed mood
• loss of bone tissue due to low hormone levels

2. What you need to know before using Nebid

Do not use Nebid:

• if you are allergic to testosterone undecanoate or to any of the other ingredients of this medicine (listed in section 6).
• if you have androgen-dependent cancer, or suspected cancer, of the prostate or breast gland.
• if you have or have had a liver tumour.

Nebid is not intended for use in women.
Warnings and precautions
Talk to your doctor before using Nebid if you suffer or have previously suffered from:

• epilepsy
• heart, kidney or liver problems
• migraine
• temporary interruptions of breathing during sleep (apnoea), as these may worsen
• cancer, because regular monitoring of calcium levels in the blood may be necessary
• high blood pressure or if you are being treated for high blood pressure, since testosterone may cause an increase in blood pressure
• blood clotting disorders
• bleeding disorders (i.e. haemophilia)
• thrombophilia (a blood clotting disorder that increases the risk of thrombosis – blood clots in veins)
• factors that increase the risk of blood clots in a vein: previous blood clots in a vein; smoking; obesity; cancer; immobility; if one of your close relatives has had a blood clot in a leg, lung or other organ at a young age (e.g. under approximately 50 years of age); or with ageing.

How to recognize a blood clot: painful swelling of one leg or sudden change in skin colour, for example becoming pale, red or blue; sudden shortness of breath; sudden unexplained cough, possibly producing blood; or sudden chest pain, severe dizziness or vertigo, severe stomach pain, sudden loss of vision. Seek immediate medical attention if you experience any of these symptoms.
If you suffer from severe heart, liver or kidney disease, treatment with Nebid may cause serious complications in the form of fluid retention in the body, sometimes accompanied by congestive heart failure.
Before and during treatment, your doctor must perform the following blood tests: blood testosterone levels, complete blood count.
If you have liver problems
Formal studies have not been conducted in patients with impaired liver function. Nebid will not be prescribed to you if you have had liver cancer (see "Do not use Nebid").
Children and adolescents
Nebid must not be used in children and adolescents. There are no data available on the use of Nebid in males under 18 years of age.
Elderly patients (65 years or older)
If you are over 65 years old, your doctor does not need to adjust your dosage (see "Medical examinations/monitoring").
Muscle development and anti-doping
Nebid is not indicated to promote muscle development in healthy individuals or to enhance physical performance.
Misuse of the medicine and dependence
Always take this medicine exactly as prescribed by your doctor or pharmacist.
Abuse of testosterone, especially when taken in excess or combined with other anabolic androgenic steroids, may cause serious health problems affecting the heart and blood vessels (which may be fatal), mental health and/or the liver.
Individuals who have abused testosterone may develop dependence and may experience withdrawal symptoms when dosage is significantly changed or abruptly discontinued. Do not misuse this medicine alone or in combination with other anabolic androgenic steroids, as this may lead to serious health risks. (See "Possible side effects").
Doping
For individuals engaged in sports: using this medicine without therapeutic need constitutes doping and may result in a positive anti-doping test.
Medical examinations/monitoring
Male hormones may promote the growth of prostate cancer and enlargement of the prostate gland (benign prostatic hyperplasia). Before administering Nebid, your doctor will examine you to ensure you do not have prostate cancer.
Your doctor will perform regular checks of your prostate and breast glands, especially if you are elderly. You will also undergo regular blood tests.
Benign (non-cancerous) and malignant (cancerous) liver tumours have been observed following the use of hormonal substances such as androgenic compounds.
Other medicines and Nebid
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicine, including those without a prescription.
Your doctor may need to adjust your dosage if you are taking any of the following medicines:

• ACTH hormone or corticosteroids (used to treat various conditions such as rheumatism, arthritis, allergies and asthma): Nebid may increase the risk of fluid retention, especially if heart or liver function is impaired
• blood-thinning tablets (coumarin derivatives, oral anticoagulants), as this may increase the risk of bleeding. Your doctor will monitor your dosage.
• Medicines used to treat diabetes. It may be necessary to adjust your blood sugar-lowering medication. Like other androgens, testosterone may enhance the effect of insulin.

Please make sure to inform your doctor if you have a blood clotting disorder, as it is important that your doctor knows this before deciding to administer Nebid.
Nebid may also affect the results of certain laboratory tests (e.g. thyroid function tests). Inform your doctor or laboratory staff that you are using Nebid.
Pregnancy and breastfeeding
The use of Nebid is not indicated in women and the medicine must not be used during pregnancy or breastfeeding.
Fertility
Treatment with high doses of testosterone-containing preparations usually causes reversible suppression or reduction of sperm production (see also "Possible side effects").
Driving and using machines
Nebid has no known effect on the ability to drive vehicles or operate machinery.
Nebid contains benzyl benzoate
This medicine contains 2000 mg of benzyl benzoate in each 4 ml vial/bottle, equivalent to 500 mg/ml.

3. How to use Nebid

Your doctor will inject Nebid (1 vial/bottle) very slowly into a muscle. You will receive an injection every 10–14 weeks. This frequency allows sufficient testosterone levels to be maintained without causing an accumulation of testosterone in the blood.
Nebid must be administered strictly by intramuscular injection.
Particular care will be taken to avoid injecting the medicine into a blood vessel (see “Administration”).

Starting treatment
Before starting treatment and during its early stages, your doctor will measure your testosterone levels in the blood. Your doctor may administer the second injection after only six weeks in order to rapidly achieve the required testosterone level. This will depend on your symptoms and initial testosterone levels.

Maintaining Nebid levels during treatment
The interval between injections must always remain between 10 and 14 weeks, as recommended.
Your doctor will regularly measure your testosterone levels at the end of an injection interval to ensure they are appropriate. If the measured values are too low, your doctor may decide to increase the frequency of injections. Conversely, if the values are high, your doctor may decide to reduce the frequency of injections. Do not miss your injection appointments, otherwise optimal testosterone levels cannot be maintained.
If you think that the effect of Nebid is too strong or too weak, discuss this with your doctor.

If you use more Nebid than you should
Symptoms of an overdose of Nebid include:

• irritability
• nervousness
• weight gain
• prolonged or frequent erections

Inform your doctor if you experience any of these symptoms. Your doctor will space out the injections or discontinue treatment.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody will experience them.
The most common side effects are acne and pain at the injection site.

Common side effects (may affect up to 1 in 10 patients):

• abnormally high levels of red blood cells
• weight gain
• hot flushes
• acne
• enlarged prostate and associated disorders
• various reactions at the injection site (e.g. pain, bruising or irritation)

Uncommon side effects (may affect up to 1 in 100 patients):

• allergic reaction
• increased appetite, changes in certain blood tests (e.g. increased blood sugar or blood fats)
• depression, emotional disturbances, insomnia, restlessness, aggression, irritability
• headache, migraine, tremor
• cardiovascular disorders, high blood pressure, dizziness
• bronchitis, sinusitis, cough, breathlessness, snoring, voice changes
• diarrhoea, nausea
• changes in liver function tests
• hair loss, various skin reactions (e.g. itching, redness or dry skin)
• joint pain, limb pain, muscle problems (e.g. spasm, pain or stiffness), or an increase in creatine phosphokinase in the blood
• urinary disorders (e.g. reduced urinary flow, urinary retention, need to urinate at night)
• prostate disorders (e.g. prostate dysplasia, hardening or inflammation of the prostate), changes in sexual desire, testicular pain, pain, hardening or enlargement of the breasts, increased levels of male and female hormones
• fatigue, general feeling of weakness, excessive sweating, night sweats

Rare side effects (may affect up to 1 in 1000 patients):

• Nebid, which is an oily liquid, may reach the lungs (pulmonary microembolism of oily solutions), and this, in rare cases, may lead to signs and symptoms such as cough, dyspnoea, general malaise, excessive sweating, chest pain, dizziness, tingling or fainting. These reactions may occur during or immediately after the injection and are reversible.

Cases of suspected anaphylactic reaction have been reported after Nebid injection.
In addition to those listed above, the following side effects have been reported with testosterone-containing preparations: nervousness, hostility, brief interruptions of breathing during sleep, various skin reactions including dandruff and oily skin, increased body hair, more frequent erections, and very rare cases of yellowing of the skin and eyes (jaundice).
Commonly, treatment with high-dose testosterone preparations suppresses or reduces sperm production, although this usually returns to normal after treatment is stopped. Testosterone replacement therapy for reduced testicular function (hypogonadism) may, in rare cases, cause persistent and painful erections (priapism). Administration of testosterone at high doses or for prolonged periods may occasionally lead to more frequent manifestations of fluid retention and oedema (swelling due to fluid accumulation).
For testosterone-containing products in general, a common risk of increased red blood cell count, haematocrit (percentage of red blood cells in the blood), and haemoglobin (the component of red blood cells that carries oxygen) has been observed through periodic blood tests.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Nebid

Keep this medicine out of the sight and reach of children.
This medicine does not require any special storage conditions.
Do not use this medicine after the expiry date stated on the carton and label following
“Exp”. The expiry date refers to the last day of that month.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer in use. This will help protect the environment.

6. Package contents and other information

What Nebid contains
The active substance is testosterone undecanoate 250 mg/ml (equivalent to 157.9 mg of testosterone).
One vial/bottle contains 1000 mg of testosterone undecanoate (equivalent to 631.5 mg of
testosterone).
The other components are benzyl benzoate and refined castor oil.

Description of the appearance of Nebid and contents of the pack
Nebid is a clear oily liquid, colourless to yellowish-brown. The pack contains:
1 brown glass vial / 1 brown glass bottle containing 4 ml of injectable solution.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
GRÜNENTHAL ITALIA S.r.l.
Via Vittor Pisani 16 - 20124 Milan, Italy
Manufacturer
Bayer AG
13342 Berlin, Germany

This medicinal product is authorised in the EEA Member States under the following names:

• Cyprus, Czech Republic, Greece, Denmark, Estonia, Latvia, Luxembourg, Malta, Poland and Portugal: Nebido
• Austria: Nebido 1000 mg/4 ml Injektionslösung
• Belgium: Nebido 1000 mg/4 ml, oplossing voor injectie
• Bulgaria: Небидо 250 mg/ml инжекционен разтвор
• Croatia: Nebido 1000 mg/4 ml otopina za injekciju
• Finland: Nebido 1000 mg/4 ml injektioneste, liuos
• France: Nebido 1000 mg/4 ml, solution injectable
• Germany: Nebido 1000 mg Injektionslösung
• Hungary: Nebido 250 mg/ml oldatos injekció
• Iceland: Nebido 1000 mg/4 ml stungulyf, lausn
• Italy: NEBID 1000 mg/4ml soluzione iniettabile
• Lithuania: Nebido 1000 mg/4 ml injekcinis tirpalas
• Netherlands: Nebido 1000 mg/4 ml
• Norway: Nebido 1000 mg/4 ml injeksjonsvæske, oppløsning
• Romania: Nebido 1000 mg/ 4 ml soluţie injectabilă
• Slovakia: Nebido 1000 mg/4 ml injekčný roztok
• Slovenia: Nebido 1000 mg/4 ml raztopina za injiciranje
• Spain: REANDRON 1000 MG/ 4 ML SOLUCIÓN INYECTABLE
• Sweden: Nebido, 1000 mg/4 ml injektionsvätska, lösning
• United Kingdom and Ireland: Nebido 1000mg/4ml, solution for injection

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The following information is intended exclusively for healthcare professionals:
Under conditions of storage at low temperatures, the properties of this oil-based solution may temporarily change (e.g. increased viscosity, turbidity). If stored at low temperature, the product must be brought to room or body temperature before use.
The injectable solution for intramuscular use must be visually inspected before administration; only clear solutions free from suspended particles should be used.
The contents of one vial/bottle must be administered intramuscularly immediately after opening.
The medicine is for single use only; any unused solution must be discarded.

Administration:
Particular care must be taken to avoid intravascular injection.
Like all oily solutions, Nebid must be administered strictly by intramuscular injection and very slowly.
The formation of pulmonary microemboli from oily solutions may, in rare cases, lead to signs and symptoms such as cough, dyspnoea, malaise, hyperhidrosis, chest pain, feeling of instability, paraesthesia or syncope. These reactions may occur during or immediately after injection and are reversible. Treatment is usually supportive, for example, administration of oxygen.
Cases of suspected anaphylactic reactions have been reported after administration of Nebid.

Warning:
Patients undergoing testosterone therapy must be carefully and regularly monitored for prostate gland (digital rectal examination and serum PSA determination) and breast conditions, according to recommended methods, at least once a year, and twice a year for elderly patients and those at risk (patients with clinical or familial risk factors).
In patients undergoing long-term androgen therapy, in addition to laboratory tests for testosterone concentration, the following laboratory parameters should be monitored periodically: haemoglobin, haematocrit, liver function tests and lipid profile.
In patients with severe heart, liver or renal failure or ischaemic heart disease, treatment with testosterone may induce serious complications, characterised by oedema with or without congestive heart failure. In such cases, treatment must be immediately discontinued.

Instructions for handling the OPC (One-Point Cut) vial:
Below the coloured dot, the vial has a pre-scored line, eliminating the need for a file to open it. Before opening, ensure that any solution present in the upper part of the vial has flowed down into the lower part. Use both hands to open: hold the lower part of the vial with one hand and break off the upper part with the other hand, in the direction opposite to the coloured dot.

Instructions for handling the bottle:
The bottle is for single use only. The contents of the bottle must be injected intramuscularly immediately after aspiration into the syringe. After removing the plastic cap (A), do not remove the metal ring (B) or the screw cap (C).