Velos

Package leaflet: Information for the user

VELOS 2.5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg and 30 mg
injectable solution in pre-filled syringe
Methotrexate
Please read all of this leaflet carefully before you start using this medicine, as it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others, even if they have the same symptoms as you, because it could be harmful.
• If you experience any side effects, including those not listed in this leaflet, consult your doctor or pharmacist. See section 4.

Contents of this leaflet:

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

1. What VELOS is and what it is used for

VELOS contains methotrexate as the active substance.
Methotrexate is a substance with the following properties:

• interferes with the growth of certain rapidly dividing cells in the body
• reduces the activity of the immune system (the body's defence mechanism)
• has anti-inflammatory effects.

VELOS is indicated for the treatment of:

• active rheumatoid arthritis in adult patients;
• severe, active polyarticular forms of juvenile idiopathic arthritis in children and adolescents who have responded inadequately to non-steroidal anti-inflammatory drugs (NSAIDs);
• severe, recurrent, disabling psoriasis that is inadequately responsive to other therapies such as phototherapy, PUVA, and retinoids, and severe psoriatic arthritis in adult patients;
• mild to moderate Crohn's disease in adult patients, in cases where adequate treatment with other medications is not possible.

Rheumatoid arthritis (RA) is a chronic connective tissue disease characterized by inflammation of the synovial membranes (joint membranes). These membranes produce a fluid that acts as a lubricant for many joints. Inflammation causes thickening of these membranes and joint swelling.
Juvenile idiopathic arthritis affects children and adolescents under 16 years of age. Polyarticular forms are those affecting five or more joints within the first six months after onset of the disease.
Psoriatic arthritis is a type of arthritis associated with psoriatic skin and nail lesions, particularly affecting the joints of the fingers and toes.
Psoriasis is a common chronic skin disease characterized by red patches covered with dry, thick, silvery scales that are difficult to remove.
VELOS has been shown to modify and slow the progression of these diseases.
Crohn's disease is a type of inflammatory bowel disease that can affect any part of the gastrointestinal tract, causing symptoms such as abdominal pain, diarrhoea, vomiting, or weight loss.

2. What you need to know before taking VELOS

Do not take VELOS

• if you are allergic to methotrexate or to any of the other ingredients of this medicine (listed in section 6).
• if you have severe liver or kidney disease or blood disorders.
• if you regularly consume large amounts of alcoholic beverages.
• if you have a serious infection, such as tuberculosis, HIV, or other immunodeficiency syndromes.
• if you have mouth ulcers or gastric or intestinal ulcers.
• if you are pregnant or breastfeeding (see section “Pregnancy, breastfeeding and fertility”).
• if you are receiving vaccinations with live vaccines simultaneously.

Warnings and precautions
Talk to your doctor or pharmacist before using VELOS if:

• you are elderly or generally feel unwell and weak.
• you have liver function problems.
• you suffer from dehydration (loss of body fluids).

Special precautions for treatment with Velos
Methotrexate temporarily affects sperm and egg production, an effect that in most cases is reversible.
Methotrexate may cause miscarriage and severe birth defects. While taking methotrexate and for at least six months after the end of treatment, you must avoid pregnancy. See also section “Pregnancy, breastfeeding and fertility”.

Follow-up examinations and recommended safety measures
Even when VELOS is administered at low doses, serious adverse effects may occur. To detect them early, your doctor must perform regular check-ups and laboratory tests.

Before starting therapy
Before beginning treatment, a blood sample should be taken to ensure adequate blood cell counts, and tests should be performed to assess liver and kidney function and serum albumin levels (a blood protein). Your doctor will also check for tuberculosis (an infectious disease associated with small nodules in affected tissues) by performing a chest X-ray.

During therapy
At least once a month for the first six months, and thereafter at least every three months, the following checks should be performed:

• Examination of the mouth and throat to detect any mucosal abnormalities
• Blood tests
• Liver function monitoring
• Kidney function monitoring
• Respiratory system monitoring, and if necessary, pulmonary function tests

Methotrexate may affect the immune system and vaccination outcomes. It may also interfere with immunological test results. Inactive chronic infections may reactivate (e.g. herpes zoster [shingles], tuberculosis, hepatitis B or C). Vaccination with live vaccines must not be performed during treatment with VELOS.
Radiation dermatitis and sunburn may reappear during methotrexate therapy (recall reaction). Psoriatic lesions may worsen with concomitant use of ultraviolet radiation and methotrexate.
Enlarged lymph nodes (lymphoma) may appear, in which case treatment should be discontinued.
Diarrhea may be a toxic effect of VELOS and requires interruption of therapy. If you experience diarrhea, discuss it with your doctor.
Encephalopathy (brain disease) and leukoencephalopathy (a specific disease of the brain's white matter) have occurred in cancer patients treated with methotrexate, and cannot be ruled out during methotrexate therapy for other conditions.

Children
VELOS is not recommended for children under 3 years of age due to limited experience with this age group.

Other medicines and VELOS
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
The treatment effect may be altered if VELOS is taken together with other medicines such as:

• Medicines harmful to the liver or blood cells, e.g. leflunomide
• Antibiotics (medicines to prevent/treat certain infections) such as: tetracyclines, chloramphenicol, non-absorbable broad-spectrum antibiotics, penicillins, glycopeptides, sulfonamides (sulphur-containing medicines that prevent/treat certain infections), ciprofloxacin and cephalothin
• Non-steroidal anti-inflammatory drugs or salicylates (medicines for pain and/or inflammation)
• Probenecid (a medicine for gout)
• Weak organic acids such as loop diuretics or certain medicines used to treat pain and inflammatory diseases (e.g. acetylsalicylic acid, diclofenac and ibuprofen) and pyrazolone derivatives (e.g. metamizole for pain treatment)
• Medicines that may have adverse effects on bone marrow, e.g. trimethoprim-sulfamethoxazole (an antibiotic) and pyrimethamine
• Sulfasalazine (a rheumatoid arthritis medicine)
• Azathioprine (an immunosuppressant sometimes used in severe rheumatoid arthritis)
• Mercaptopurine (a cytostatic agent)
• Retinoids (a medicine for psoriasis and other skin diseases)
• Theophylline (a medicine for bronchial asthma and other lung diseases)
• Proton pump inhibitors (medicines for stomach disorders)
• Hypoglycemics (medicines used to lower blood sugar)

Vitamin complexes containing folic acid may reduce the effectiveness of treatment and should only be taken under medical supervision.
Vaccinations with live vaccines must be avoided.

VELOS with food, drinks and alcohol
During treatment with VELOS, alcoholic beverages, large amounts of coffee, caffeine-containing drinks, and black tea should be avoided.

Pregnancy, breastfeeding and fertility
Pregnancy
Do not use VELOS during pregnancy or if you are trying to become pregnant. Methotrexate may cause birth defects, harm the fetus, or cause miscarriage. It is associated with malformations of the skull, face, heart and blood vessels, brain, and limbs. Therefore, it is very important that pregnant women or women planning pregnancy are not treated with methotrexate.
In women of childbearing age, pregnancy must be ruled out using appropriate measures, for example by performing a pregnancy test before starting treatment. During methotrexate treatment and for at least 6 months after treatment ends, you must avoid pregnancy by using reliable contraceptive methods throughout the entire period (see also section “Warnings and precautions”).
If you become pregnant during treatment or suspect you may be pregnant, consult your doctor as soon as possible. You will receive counseling regarding the risk of harmful effects on the baby due to the treatment.
If you plan to have a child, you should consult your doctor, who will refer you to a specialist before the planned start of treatment.

Breastfeeding
Breastfeeding must be discontinued before and during treatment with Velos.

Male fertility
Available evidence does not indicate an increased risk of birth defects or miscarriage if the father is taking a methotrexate dose below 30 mg/week. However, the risk cannot be completely excluded. Methotrexate may be genotoxic, meaning it may cause genetic mutations. Methotrexate may affect sperm production and potentially cause birth defects. Therefore, while taking methotrexate and for at least 6 months after treatment ends, you must avoid fathering a child or donating semen.

Driving and using machines
Treatment with VELOS may cause adverse reactions affecting the central nervous system, such as fatigue and dizziness. Therefore, the ability to drive a vehicle and/or operate machinery may, in some cases, be impaired. If you feel tired or drowsy, you must not drive or operate machinery.

VELOS contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per dose, i.e., it is practically “sodium-free”.

3. How to use VELOS

Your doctor will decide the dosage, which will be tailored to your individual needs. In general, the effects of treatment become noticeable after 4–8 weeks of therapy.
VELOS is administered by a doctor or under medical supervision, or by healthcare personnel, as an injection once weekly only. Together with your doctor, choose the day of the week on which to receive your weekly injection. VELOS must be injected subcutaneously (under the skin).
The appropriate dosage for children and adolescents with polyarticular juvenile idiopathic arthritis will be determined by the doctor.

Use in children
VELOS is not recommended for children under 3 years of age due to limited experience with this age group.

Method of administration and duration of treatment
VELOS is injected once a week!
The duration of treatment is determined by your treating physician. Treatments for rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis vulgaris, psoriatic arthritis, and Crohn's disease with VELOS are long-term therapies.
At the beginning of therapy, VELOS may be administered by medical staff. In some cases, your doctor may decide to instruct you on how to self-administer the subcutaneous injection of VELOS. In such cases, you will receive appropriate instructions.
Under no circumstances should you attempt to inject VELOS yourself without first receiving proper training.
Please refer to the instructions for use at the end of this leaflet.
Handling and disposal must be carried out as for other cytotoxic preparations, in accordance with local regulations. Healthcare personnel who are pregnant should avoid handling and/or administering VELOS.
Methotrexate must not come into contact with the skin surface or mucous membranes. In case of contamination, the affected area must be immediately rinsed thoroughly with abundant water.

If you use more VELOS than you should
Follow your doctor's dosing recommendations. Do not change the dose on your own initiative.
If you suspect that you have used too much VELOS, contact your doctor immediately. The appropriate treatment will be decided based on the severity of intoxication.

If you forget to use VELOS
Do not take a double dose to make up for a missed dose. Consult your doctor. Take the prescribed dose as soon as possible, and then continue weekly as directed.

If you stop treatment with VELOS
Do not interrupt or discontinue treatment with VELOS unless you have discussed it with your doctor. If you suspect serious adverse effects, contact your doctor immediately for advice.
If you feel that the effect of VELOS is too strong or too weak, inform your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
The frequency and severity of side effects depend on the dose and frequency of administration. Since serious side effects may occur even at low doses, it is important that your doctor carries out regular monitoring. Your doctor will therefore prescribe blood tests to detect possible abnormalities (e.g. reduced white blood cell count, reduced platelet count, lymphoma) and changes in kidney and liver function.

Contact your doctor immediately if you notice any of the following symptoms, which may indicate serious, potentially life-threatening side effects requiring urgent specific treatment:

• Persistent dry cough without phlegm, shortness of breath, and fever: these may be signs of lung inflammation (pneumonitis) [common – may affect up to 1 in 10 people];
• Signs of liver damage such as yellowing of the skin and whites of the eyes; methotrexate may cause chronic liver damage (hepatic cirrhosis), scarring of the liver (hepatic fibrosis), fatty degeneration of the liver [all uncommon – may affect up to 1 in 100 people], inflammation of the liver (acute hepatitis) [rare – may affect up to 1 in 1,000 people] and liver failure [very rare – may affect up to 1 in 10,000 people];
• Allergic symptoms such as skin rashes including red, itchy skin, swelling of hands, feet, ankles, face, lips, mouth or throat (which may cause difficulty swallowing or breathing), and feeling faint: these may be signs of severe allergic reactions or anaphylactic shock [rare – may affect up to 1 in 1,000 people];
• Signs of kidney damage such as swelling of hands, ankles, feet or changes in frequency of urination or reduced or absent urine output: these may be signs of kidney failure [rare – may affect up to 1 in 1,000 people];
• Signs of infection, e.g. fever, chills, aches, sore throat: methotrexate may increase susceptibility to infections. Severe infections may rarely occur [may affect up to 1 in 1,000 people], such as a specific type of pneumonia (Pneumocystis carinii pneumonia) or blood poisoning (sepsis);
• Severe diarrhoea, vomiting with blood, black or dark stools: these symptoms may indicate a rare but serious gastrointestinal complication caused by methotrexate, such as gastrointestinal ulcers;
• Symptoms associated with blockage (occlusion) of a blood vessel by a detached blood clot (thromboembolic event), such as weakness on one side of the body (stroke) or pain, swelling, redness and unusual warmth in one leg (deep vein thrombosis): methotrexate may cause thromboembolic events [rare – may affect up to 1 in 1,000 people];
• Fever and severe deterioration in general condition, or sudden fever accompanied by sore throat or mouth inflammation, or urinary problems: methotrexate may very rarely [may affect up to 1 in 10,000 people] cause a sudden drop in white blood cell count (agranulocytosis) and severe bone marrow suppression;
• Sudden bleeding, e.g. bleeding gums, blood in urine, vomiting blood or bruising: these may be signs of a severe drop in platelet count due to severe bone marrow suppression [very rare – may affect up to 1 in 10,000 people];
• Severe skin rash or skin blisters (may also appear in mouth, eyes and genitals): these may be signs of a very rare condition [may affect up to 1 in 10,000 people] called Stevens-Johnson syndrome or toxic epidermal necrolysis (burned skin syndrome).

Other side effects may also occur, listed below:

Very common: may affect more than 1 in 10 people

• Mouth inflammation, indigestion, nausea (feeling unwell), loss of appetite
• Increased liver enzymes

Common: may affect up to 1 in 10 people

• Mouth ulcers, diarrhoea
• Skin rash, skin redness, itching
• Headache, fatigue, drowsiness
• Reduced production of blood cells with decreased white and/or red blood cells and/or platelets (leucopenia, anaemia, thrombocytopenia)

Uncommon: may affect up to 1 in 100 people

• Sore throat, intestinal inflammation, vomiting
• Increased sensitivity to light, hair loss, increase in number of rheumatoid nodules, shingles (herpes zoster), inflammation of blood vessels, herpes-like skin rashes, urticaria
• Onset of diabetes mellitus
• Dizziness, confusion, depression
• Decreased serum albumin
• Reduced number of blood cells and platelets
• Inflammation and ulceration of the urinary bladder or vagina, reduced kidney function, urinary problems
• Joint pain, muscle pain, osteoporosis (reduced bone mass)

Rare: may affect up to 1 in 1,000 people

• Increased skin pigmentation, acne, bruising due to bleeding from blood vessels
• Allergic inflammation of blood vessels, fever, red eyes, infection, poor wound healing, reduced number of antibodies in the blood
• Visual disturbances
• Inflammation of the membrane surrounding the heart, fluid accumulation in the membrane surrounding the heart
• Low blood pressure
• Pulmonary fibrosis, shortness of breath and bronchial asthma, fluid accumulation in the membrane lining the lungs
• Electrolyte disturbances

Very rare: may affect up to 1 in 10,000 people

• Profuse bleeding, toxic megacolon (acute toxic dilation of the intestine)
• Increased nail pigmentation, inflammation around the nail folds, furunculosis (deep infection of hair follicles), visible enlargement of small blood vessels (capillaries)
• Local tissue damage (formation of sterile abscesses, changes in fatty tissue) at the injection site after intramuscular or subcutaneous administration
• Vision disorders, pain, loss of strength or numbness or tingling sensations in arms and legs, taste changes (metallic taste), seizures, paralysis, severe headache accompanied by fever
• Retinopathy (eye disorders of non-inflammatory origin)
• Loss of libido, impotence, enlargement of male breasts (gynaecomastia), abnormal sperm formation, menstrual disorders, vaginal discharge
• Enlargement of lymph nodes (lymphoma)
• Lymphoproliferative disorders (excessive growth of white blood cells)

Frequency not known: cannot be estimated from available data:

• Leukoencephalopathy (disease of the brain's white matter)
• Bone damage in the jaw/mandible (secondary to excessive growth of white blood cells)

Subcutaneous administration of methotrexate is well tolerated locally. Only mild local skin reactions have been observed, which decreased during treatment.

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 www.agenziafarmaco.gov.it/it/responsabili.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store VELOS

Keep this medicine out of the sight and reach of children.
Store below 25 °C.
Keep the pre-filled syringes in the outer carton to protect the medicine from light.
Do not use this medicine after the expiry date stated on the label and carton after EXP. The expiry date refers to the last day of that month.
For single use only. Any residual solution must be discarded.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Package contents and other information

What VELOS contains

• The active substance is methotrexate:
  VELOS 2.5 mg: Each 0.33 ml pre-filled syringe contains 2.5 mg of methotrexate.
  VELOS 7.5 mg: Each 0.30 ml pre-filled syringe contains 7.5 mg of methotrexate.
  VELOS 10 mg: Each 0.40 ml pre-filled syringe contains 10 mg of methotrexate.
  VELOS 12.5 mg: Each 0.31 ml pre-filled syringe contains 12.5 mg of methotrexate.
  VELOS 15 mg: Each 0.38 ml pre-filled syringe contains 15 mg of methotrexate.
  VELOS 17.5 mg: Each 0.44 ml pre-filled syringe contains 17.5 mg of methotrexate.
  VELOS 20 mg: Each 0.50 ml pre-filled syringe contains 20 mg of methotrexate.
  VELOS 22.5 mg: Each 0.56 ml pre-filled syringe contains 22.5 mg of methotrexate.
  VELOS 25 mg: Each 0.63 ml pre-filled syringe contains 25 mg of methotrexate.
  VELOS 27.5 mg: Each 0.69 ml pre-filled syringe contains 27.5 mg of methotrexate.
  VELOS 30 mg: Each 0.75 ml pre-filled syringe contains 30 mg of methotrexate.

• The other components are sodium chloride, sodium hydroxide for pH adjustment, water for injections.

Description of the appearance of VELOS and contents of the pack
VELOS syringes contain a clear, yellow-orange solution free from visible particles.
Pack sizes:
VELOS pre-filled syringes with fixed injection needle and rigid protective cap
impregnated with alcohol are available in packs of 1 and 4 syringes.
equipped with a safety system designed to help prevent needle-stick injuries.
Not all pack sizes may be marketed.

Marketing Authorization Holder
Difa Cooper S.p.A., 21042 Caronno Pertusella (VA), Italy

Manufacturer
Actavis Italy S.p.A., Via Pasteur 10, Nerviano (MI) 20014, Italy
S.C. Sindan-Pharma S.r.l., 11 Ion Mihalache Blvd, Bucharest – 011171, Romania

This medicinal product is authorized in the Member States of the European Economic Area under the following names:
VELOS

Instructions for use

Read these instructions carefully before starting the injection and always use the injection technique recommended by your doctor, pharmacist, or nurse.
For single use only. Any residual solution must be discarded.
The solution must be clear and free from particles.
For any problems or questions, contact your doctor, pharmacist, or nurse.

Preparation
Choose a clean, well-lit, flat working surface.
Before starting, gather everything you need:

• 1 pre-filled syringe of VELOS
• 1 antiseptic swab (alcohol swab) <(supplied in the package)>
  Wash your hands thoroughly. Before use, inspect the VELOS syringe for any visible defects (or cracks).

Injection site
The best injection sites are:

• upper thigh,
• abdomen, excluding the area around the navel.

• If you have assistance for the injection, it may also be administered on the back of the upper arm, just below the shoulder.
• Change the injection site with each injection. This way you can reduce the risk of developing irritation at the injection site.
• Never inject into areas of tender, bruised, red, hard, scarred, or stretch-marked skin. If you suffer from psoriasis, try to avoid injecting directly into lesions or areas of raised, thickened, red, flaky, or otherwise affected skin.

Injecting the solution

1. Remove the pre-filled syringe of methotrexate from its packaging and read the package leaflet carefully. Take the pre-filled syringe out of the packaging at room temperature.
2. Disinfection

Choose an injection site and disinfect it with an antiseptic swab
(e.g., using the alcohol swab included in the package).
Allow the antiseptic to dry for at least 60 seconds.

3. Remove the protective plastic cap
   Carefully remove the protective plastic cap by pulling it straight off the syringe. If the cap is difficult to remove, gently twist while pulling. Important: Do not touch the needle of the pre-filled syringe!

4. Needle insertion
   Using two fingers, pinch a fold of skin and quickly insert the needle into the skin at a 90-degree angle.

Note: It is normal for there to be a small air bubble in the syringe. Do not attempt to remove this air bubble before injecting – doing so may cause you to lose some of the medication.

< Pre-filled syringes without needle safety protection system: >
[5. Injection
Insert the needle completely into the skin fold. Inject the liquid subcutaneously by slowly pushing the plunger all the way down to the end of the syringe. Maintain a firm grip on the skin fold until the injection is complete.
Carefully remove the needle vertically.

To prevent injury, re-sheath the needle into the protective cap using one hand and gently press the cap back into place.

< Pre-filled syringes with needle safety protection system: >
[5. Injection
The VELOS pre-filled syringe is equipped with a safety system that helps prevent needle-stick injuries after use. The following instructions are specific to this safety system and may differ from instructions for other injection systems.
Insert the needle completely into the skin fold. Inject the liquid subcutaneously by slowly pushing the plunger all the way down to the end of the syringe. Maintain a firm grip on the skin fold until the injection is complete.
Carefully remove the needle vertically, keeping your finger on the plunger.

With the needle pointed away from yourself and others, activate the safety system by firmly pressing the plunger. The protective sleeve will automatically cover the needle, and you will hear a "click" confirming activation of the safety mechanism.

6. Immediately dispose of the syringe in a sharps container.

Methotrexate must not come into contact with the skin surface or mucous membranes. In case of contamination, the affected area must be immediately rinsed with abundant water.
If you or someone near you is injured by the needle, consult a doctor immediately and do not use the pre-filled syringe.

Disposal and other handling
Handling and disposal must be carried out as for other cytotoxic preparations, in accordance with local regulations. Healthcare personnel who are pregnant must refrain from handling and/or administering VELOS.