Pemetrexed Sandoz B.V.

Package leaflet: Information for the user

Pemetrexed Sandoz BV 25 mg/ml concentrate for solution for infusion

Generic medicine
Please read all of this leaflet carefully before you start using this medicine because 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 other people, even if their symptoms are the same as yours, as it may be harmful.
• If you experience any adverse reactions, including those not listed in this leaflet, contact your doctor or pharmacist. See section 4.

Contents of this leaflet:

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

1. What Pemetrexed Sandoz BV is and what it is used for

Pemetrexed Sandoz BV is a medicine used in the treatment of tumours.
Pemetrexed Sandoz BV is administered in combination with cisplatin, another anticancer drug,
as treatment for malignant pleural mesothelioma, a type of tumour affecting the lining of the lungs,
in patients who have not previously received chemotherapy.
Additionally, Pemetrexed Sandoz BV in combination with cisplatin is administered as first-line therapy
in patients with advanced-stage lung cancer.
Pemetrexed Sandoz BV may be prescribed for advanced-stage lung cancer if the disease has responded to treatment or if it remains mostly unchanged after initial chemotherapy.
Furthermore, Pemetrexed Sandoz BV is a treatment for patients with advanced-stage lung cancer whose disease has progressed after prior initial chemotherapy treatment.
This medicine is intended for use in adults only.

2. What you should know before using Pemetrexed Sandoz BV

Do not use Pemetrexed Sandoz BV:

• if you are allergic to pemetrexed or to any of the other ingredients of this medicine (listed in section 6).
• if you are breastfeeding; you must stop breastfeeding during treatment with Pemetrexed Sandoz BV.
• if you have recently received or are about to receive the yellow fever vaccine.

Warnings and precautions
Talk to your doctor or hospital pharmacist before receiving Pemetrexed Sandoz BV.
If you have or have previously had kidney problems, inform your doctor or hospital pharmacist, as you may not be able to receive Pemetrexed Sandoz BV.
Before each infusion, blood tests will be performed to assess whether you have adequate kidney and liver function and to check that you have enough blood cells to receive Pemetrexed Sandoz BV. Your doctor may decide to adjust the dose or delay treatment depending on your general condition and if your blood cell count is too low. Additionally, if you are receiving cisplatin, your doctor will ensure that you are adequately hydrated and receive appropriate treatment before and after receiving cisplatin to prevent vomiting.
If you have undergone or will undergo radiotherapy, inform your doctor, as you may experience an early or delayed reaction due to radiotherapy when using Pemetrexed Sandoz BV.
If you have recently been vaccinated, inform your doctor, as this could cause harmful effects when using Pemetrexed Sandoz BV.
If you have heart disease or a history of heart disease, inform your doctor.
If you have fluid accumulation around the lungs, your doctor may decide to remove the fluid before administering Pemetrexed Sandoz BV.

Children and adolescents
This medicine must not be used in children and adolescents, as there is no experience with use in individuals under 18 years of age.

Other medicines and Pemetrexed Sandoz BV
Inform your doctor if you are taking any medicine for pain or inflammation (swelling), such as medicines called "non-steroidal anti-inflammatory drugs" (NSAIDs), including medicines purchased without a prescription (such as ibuprofen). There are many types of NSAIDs with different durations of action. Depending on the scheduled date for your Pemetrexed Sandoz BV infusion and/or your kidney function, your doctor will advise you on which medicines you can take and when you can take them. If you are unsure, ask your doctor or pharmacist whether any of your medicines are NSAIDs.
Inform your doctor or hospital pharmacist if you are taking or have recently taken any other medicines, including medicines purchased without a prescription.

Pregnancy, breastfeeding and fertility
Pregnancy
If you are pregnant, suspect you may be pregnant, or are planning a pregnancy, inform your doctor.
Use of Pemetrexed Sandoz BV during pregnancy should be avoided. Your doctor will discuss with you the potential risks of taking Pemetrexed Sandoz BV during pregnancy.
Women must use an effective method of contraception during treatment with Pemetrexed Sandoz BV.

Breastfeeding
If you are breastfeeding, inform your doctor.
Breastfeeding must be discontinued during treatment with Pemetrexed Sandoz BV.

Fertility
Men are advised not to father a child during treatment with Pemetrexed Sandoz BV and for up to 6 months after treatment, and should therefore use an effective contraceptive during treatment with Pemetrexed Sandoz BV and for 6 months afterwards. If you wish to father a child during treatment or within 6 months afterwards, consult your doctor or pharmacist. It is recommended to seek information on sperm preservation methods before starting therapy.

Driving and using machines
Pemetrexed Sandoz BV may cause fatigue. Exercise caution when driving a vehicle or operating machinery.

Pemetrexed Sandoz BV contains sodium and propylene glycol
Pemetrexed Sandoz BV 100 mg (4 ml vial):
This medicine contains less than 1 mmol of sodium (23 mg) per vial, i.e. essentially "sodium-free". This medicine contains 200 mg of propylene glycol in each vial.

Pemetrexed Sandoz BV 500 mg (20 ml vial):
This medicine contains 55.6 mg of sodium (a main component of table salt) per vial. This corresponds to 3% of the maximum daily recommended dietary intake for an adult. This medicine contains 1000 mg of propylene glycol in each vial.

Pemetrexed Sandoz BV 1000 mg (40 ml vial):
This medicine contains 111.2 mg of sodium (a main component of table salt) per vial. This corresponds to 6% of the maximum daily recommended dietary intake for an adult. This medicine contains 2000 mg of propylene glycol in each vial.

3. How to use Pemetrexed Sandoz BV

Pemetrexed Sandoz BV must only be administered under the supervision of a qualified physician experienced in the use of antitumor chemotherapeutic agents.
The dose of Pemetrexed Sandoz BV is 500 mg per square meter of body surface area. Your height and weight will be measured to calculate your body surface area. Your doctor will use this body surface area to determine the correct dose for you. This dosage may be adjusted or the treatment may be delayed depending on blood test results and your general condition. A hospital pharmacist, nurse, or doctor will have mixed the Pemetrexed Sandoz BV solution with an injectable solution of sodium chloride 9 mg/ml (0.9%) or glucose 50 mg/ml (5%) before administration.
You will receive Pemetrexed Sandoz BV by intravenous infusion only. The infusion will last approximately 10 minutes.
When Pemetrexed Sandoz BV is used in combination with cisplatin:
Your doctor or hospital pharmacist will calculate the dose you require based on your height and weight. Cisplatin is also administered by intravenous infusion, approximately 30 minutes after completion of the Pemetrexed Sandoz BV infusion. The cisplatin infusion will last about 2 hours.
Typically, you should receive the infusion once every 3 weeks.
Additional medications:
Corticosteroids: Your doctor will prescribe steroid tablets (equivalent to 4 milligrams of dexamethasone twice daily) to be taken the day before, on the day of, and the day after treatment with Pemetrexed Sandoz BV. This medication is given to reduce the frequency and severity of skin reactions that may occur during antitumor therapy.
Vitamin supplement: Your doctor will prescribe folic acid (vitamin) or a multivitamin product containing folic acid (350–1000 micrograms) to be taken orally once daily during treatment with Pemetrexed Sandoz BV. You must take at least five doses during the seven days before your first dose of Pemetrexed Sandoz BV. You must continue taking folic acid for 21 days after your last dose of Pemetrexed Sandoz BV. You will also receive an injection of vitamin B({12}) (1000 micrograms) during the week before administration of Pemetrexed Sandoz BV, and then approximately every 9 weeks (corresponding to 3 treatment cycles with Pemetrexed Sandoz BV). Vitamin B({12}) and folic acid are administered to reduce the potential toxic effects of antitumor therapy.
If you have any doubts about how to use this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
You must contact your doctor immediately if you notice any of the following side effects:

• Fever or infection (respectively, common or very common): if you have a body temperature of 38°C or higher, sweating, or other signs of infection (because you may have fewer white blood cells than normal, which is very common). Infection (sepsis) can be severe and may lead to death.
• If you start experiencing chest pain (common) or have an increased heart rate (uncommon).
• If you have pain, redness, swelling or sores in the mouth (very common).
• Allergic reaction: if you develop a rash (very common)/ burning sensation or tingling (common), or fever (common). Rarely, skin reactions can be severe and may lead to death. Contact your doctor if a severe rash appears, or if you have itching or blisters form (Stevens-Johnson syndrome or toxic epidermal necrolysis).
• If you feel tired, feel faint, feel short of breath or are pale (because you may have lower than normal haemoglobin levels, which is very common).
• If you have bleeding from the gums, nose or mouth, or any bleeding that does not stop, red or slightly pink urine, or unexpected bruising (because you may have fewer platelets than normal, which is common).
• If you suddenly feel short of breath, have severe chest pain or have a cough with blood in the sputum (uncommon) (this may indicate a blood clot in the blood vessels of the lungs).

Side effects with Pemetrexed Sandoz BV may include:
Very common (may affect more than 1 in 10 people)
Infection
Pharyngitis (sore throat)
Low neutrophil granulocyte count (a type of white blood cell)
Low white blood cell count
Low haemoglobin levels
Pain, redness, swelling or ulcers in the mouth
Loss of appetite
Vomiting
Diarrhoea
Nausea
Skin redness
Skin peeling
Abnormal blood tests showing reduced kidney function
Fatigue (tiredness)
Common (may affect up to 1 in 10 people)
Blood infection
Fever with low neutrophil granulocyte count (a type of white blood cell)
Low platelet count
Allergic reactions
Loss of body fluids
Altered taste
Nerve damage that may cause stiffness and muscle atrophy, leading to muscle weakness and atrophy (wasting) primarily in the arms and legs
Sensory nerve damage that may cause loss of sensation, burning sensations, and unsteady gait
Dizziness
Inflammation or swelling of the conjunctiva (the membrane lining the eyelids and covering the white part of the eye)
Dry eyes
Excessive tearing
Dryness of the conjunctiva (the membrane lining the eyelids and covering the white part of the eye) and cornea (the transparent layer in front of the iris and pupil)
Swollen eyelids
Eye disorders with dryness, tearing, irritation and/or pain
Heart failure (a condition affecting the heart muscle's pumping ability)
Irregular heartbeat
Indigestion
Constipation
Abdominal pain
Liver: increased blood levels of chemicals produced by the liver
Increased skin pigmentation
Itchy skin
Widespread red spots
Hair loss
Hives
Kidney failure
Reduced kidney function
Fever
Pain
Excess fluid in body tissues, causing swelling
Chest pain
Inflammation and ulceration of the mucous membranes lining the digestive tract
Uncommon (may affect up to 1 in 100 people)
Reduction in the number of white and red blood cells and platelets in the blood
Stroke
Type of stroke when an artery in the neck is blocked
Bleeding in the skull
Angina (chest pain caused by reduced blood flow to the heart)
Heart attack
Narrowing or blockage of the coronary arteries
Increased heart rate
Inadequate blood supply to the limbs
Blockage in the lungs of one of the pulmonary arteries
Inflammation and scarring of the lining of the lungs causing breathing problems
Bleeding of bright red blood from the anus
Gastrointestinal tract bleeding
Intestinal rupture
Inflammation of the oesophageal lining
Inflammation of the lining of the large intestine, which may be accompanied by intestinal or rectal bleeding (seen only in combination with cisplatin)
Inflammation, oedema, erythema and erosion of the oesophageal mucosal surface caused by radiation therapy
Lung inflammation caused by radiation therapy
Rare (may affect up to 1 in 1,000 people)
Destruction of red blood cells
Anaphylactic shock (severe allergic reaction)
Inflammatory liver condition
Skin redness
Sudden skin redness developing in a previously irradiated area
Very rare (may affect up to 1 in 10,000 people)
Infection of the skin and soft tissues
Stevens-Johnson syndrome (a type of severe skin and mucous membrane reaction that could be life-threatening)
Toxic epidermal necrolysis (a type of severe skin reaction that could be life-threatening)
Autoimmune disorders resulting in sudden skin redness and blisters on the legs, arms and abdomen
Skin inflammation characterized by the presence of fluid-filled blisters
Skin fragility, blistering, erosion and scarring of the skin
Redness, pain and swelling, mainly in the lower limbs
Inflammation of the skin and underlying fat (pseudocellulitis)
Skin inflammation (dermatitis)
Skin becoming inflamed, itchy, red, cracked and rough
Intensely itchy spots
Not known: frequency cannot be estimated from the available data
A form of diabetes primarily due to kidney disease
Kidney disorders leading to death of tubular epithelial cells forming the kidney tubules

You may experience one or more of these symptoms and/or conditions. You must inform your doctor as soon as possible if you start experiencing any of these side effects.
If you have any concerns about any side effect, discuss them with your doctor.
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.aifa.gov.it/content/come-segnalare-una-sospetta-reazione-avversa.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Pemetrexed Sandoz BV

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton and label after
Exp. The expiry date refers to the last day of that month.

Closed vial
Do not store above 25°C. Keep in the original packaging to protect the medicine from light.

After first opening
The product must be used immediately. Any unused portions of the product must be discarded.

After dilution
100 mg vial
The stability of the prepared infusion solution has been demonstrated for 3 days when stored refrigerated at 2–8°C, protected from light.

500 mg and 1000 mg vials
The stability of the prepared infusion solution has been demonstrated for 7 days at room temperature protected from light and for 14 days when stored refrigerated at 2°C–8°C, protected from light.

From a microbiological standpoint, the product should be used immediately. If not used immediately, the storage times and conditions prior to use are the responsibility of the user and should normally not exceed 24 hours at 2°C–8°C, unless the dilution was carried out under controlled and validated aseptic conditions.

Do not dispose of any medicine 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 Pemetrexed Sandoz BV contains
The active substance is pemetrexed (as pemetrexed disodium hemipentahydrate).
Each ml of concentrate for infusion solution contains 25 mg of pemetrexed (as pemetrexed
disodium hemipentahydrate).
Each 4 ml vial contains 100 mg of pemetrexed (as pemetrexed disodium hemipentahydrate).
Each 20 ml vial contains 500 mg of pemetrexed (as pemetrexed disodium
hemipentahydrate).
Each 40 ml vial contains 1000 mg of pemetrexed (as pemetrexed disodium
hemipentahydrate).
The other components are sodium thiosulfate pentahydrate (E539), propylene glycol (E1520),
hydrochloric acid (for pH adjustment), sodium hydroxide (E524) (for pH adjustment), water for
injection.

Description of the appearance of Pemetrexed Sandoz BV and package contents
Pemetrexed Sandoz BV is a concentrate for infusion solution. It is a clear, colourless to yellow or yellow-green solution, practically free from particles.
Pemetrexed Sandoz BV is supplied in a type I glass vial, with a bromobutyl rubber stopper, an aluminium screw cap and a blue plastic flip-off seal.
Each vial contains 4 ml, 20 ml or 40 ml of concentrate for infusion solution.
Each package contains 1 vial (with or without overwrap).

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Sandoz BV
Veluwezoom 22
1327 AH Almere
The Netherlands
Local representative for Italy: Sandoz S.p.A., L.go U. Boccioni 1, 21040 Origgio (VA), Italy
Manufacturer
Ebewe Pharma Ges.m.b.H. Nfg.KG
Mondseestrasse 11,
4866 Unterach am Attersee,
Austria

This medicinal product is authorised in the European Economic Area Member States under the following names:
Austria Pemetrexed Sandoz 25 mg/ml – Konzentrat zur Herstellung einer
Infusionslösung
Belgium Pemetrexed Sandoz 25 mg/ml concentraat voor oplossing voor infusie
Bulgaria Пеметрексед Сандоз 25 mg/ml концентрат за инфузионен разтвор
Denmark Pemetrexed Hexal
Finland Pemetrexed Hexal 25 mg/ml
Infuusiokonsentraatti, liuosta varten
France Pemetrexed GNR 25 mg/ml, solution à
diluer pour perfusion
Germany Pemetrexed HEXAL 25 mg/ml Konzentrat zur Herstellung einer Infusionslösung
Greece Pemetrexed/EBEWE 25mg/ml πυκνό διάλυμα για παρασκευή διαλύματος
προς έγχυση
Ireland Pemetrexed Rowex 25 mg/ml concentrate for solution for Infusion
Iceland Pemetrexed Hexal 25 mg/ml Koncentrat til infusionsvæske, opløsning
Italy Pemetrexed Sandoz BV
Lithuania Pemetrexed Ebewe 25mg/ml koncentratas infuziniam tirpalui
Norway Pemetrexed Hexal
The Netherlands Pemetrexed Sandoz 25 mg/ml, concentraat voor oplossing voor infusie
Poland Pemetrexed Sandoz
Portugal Pemetrexed Sandoz
Slovenia Pemetreksed Sandoz 25 mg/ml koncentrat za raztopino za infundiranje
Spain Pemetrexed Ebewe 25mg/ml concentrado para solución para perfusión
Sweden Pemetrexed Hexal 25 mg/ml Koncentrat till infusionsvätska, lösning

The following information is intended exclusively for healthcare professionals:
Special precautions for use and handling
Pemetrexed solutions are for single use only. Unused medicine and waste derived from it must be disposed of in accordance with local regulations for cytotoxic agents.

1. Use aseptic techniques when diluting pemetrexed for intravenous infusion administration.
2. Calculate the required dose and number of Pemetrexed Sandoz BV vials needed. Each vial contains an excess of concentrated pemetrexed to facilitate delivery of the amount stated on the label.
3. The appropriate volume of concentrated pemetrexed must be further diluted to 100 ml with an injection solution (without preservatives) of sodium chloride 9 mg/ml (0.9%) or glucose 50 mg/ml (5%) and administered by intravenous infusion over 10 minutes.
4. Pemetrexed infusion solutions prepared as described above are compatible with infusion bags and administration sets coated with polyolefins.
5. Prior to administration, parenteral medicines should be inspected visually for particulate matter and discoloration. Do not administer if particulate matter is observed.

Precautions for preparation and administration: As with other potentially toxic antineoplastic agents, caution should be exercised when handling and preparing pemetrexed infusion solutions. Wearing gloves is recommended. If a pemetrexed solution comes into contact with the skin, wash immediately and thoroughly with water and soap. If pemetrexed solutions contact mucous membranes, rinse thoroughly with water. Pemetrexed is not a vesicant. There is no specific antidote for pemetrexed extravasation. Cases of pemetrexed extravasation have been reported, which were not considered severe by the investigator. Extravasation should be managed according to standard procedures for non-vesicant agents.

Monitoring
Patients receiving pemetrexed must be monitored before each administration with a complete blood count, including white blood cell count with differential (WCC) and platelet count. Before each chemotherapy administration, blood chemistry tests must be performed to assess renal and liver function. Prior to starting a chemotherapy cycle, patients must meet the following criteria:

• Absolute neutrophil count (ANC) must be ≥ 1,500 cells/mm³
• Platelet count must be ≥ 100,000 cells/mm³
• Creatinine clearance must be ≥ 45 ml/min
• Total bilirubin must be ≤ 1.5 times the upper limit of normal
• Alkaline phosphatase (AP), aspartate aminotransferase (AST or SGOT), and alanine aminotransferase (ALT or SGPT) must be ≤ 3 times the upper limit of normal.
  Levels of alkaline phosphatase, AST, and ALT ≤ 5 times the upper limit of normal are acceptable if the liver is the site of metastases.

Dose adjustments
Dose adjustments at the beginning of a subsequent cycle must be based on the nadir blood count or the maximum non-haematological toxicity observed during the previous treatment cycle. Treatment may be delayed to allow sufficient recovery time. Once patients have recovered, treatment should be resumed according to the guidelines provided in Tables 1, 2, and 3, which apply to Pemetrexed Sandoz BV used either as monotherapy or in combination with cisplatin.

Bleeding ≥ Grade 2 according to the National Cancer Institute Common Toxicity Criteria (CTC) (v2.0; NCI 1998)
If patients develop non-hematological toxicity ≥ Grade 3 (excluding neurotoxicity), Pemetrexed Sandoz BV must be withheld until the value returns to less than or equal to that present prior to therapy. Treatment should be restarted according to the guidelines indicated in Table 2.

National Cancer Institute Common Toxicity Criteria (CTC v2.0; NCI 1998)
Neurotoxicity excluded
In case of neurotoxicity, the recommended dose adjustment for Pemetrexed Sandoz BV and
cisplatin is described in Table 3. Patients must discontinue treatment if grade 3 or 4
neurotoxicity is observed.

National Cancer Institute Common Toxicity Criteria (CTC v2.0; NCI 1998)
Treatment with Pemetrexed Sandoz BV must be discontinued if a patient develops any grade 3 or 4 hematological or non-hematological toxicity after two dose reductions, or immediately if grade 3 or 4 neurotoxicity is observed.

Elderly patients
In clinical studies, there was no evidence that patients aged 65 years or older were at increased risk for adverse reactions compared to patients younger than 65 years. Dose reductions beyond those recommended for all patients are not required.

Patients with renal impairment (Standard Cockcroft and Gault formula or Method for calculating glomerular filtration rate measured with Tc99m-DPTA)
Pemetrexed is primarily eliminated unchanged via renal excretion. In clinical studies, patients with creatinine clearance ≥ 45 ml/min did not require dosage adjustments beyond those recommended for all patients. There are insufficient data on the use of pemetrexed in patients with creatinine clearance below 45 ml/min; therefore, the use of pemetrexed is not recommended (see section 4.4).

Patients with hepatic impairment
No relationships between AST (SGOT), ALT (SGPT), or total bilirubin and the pharmacokinetics of pemetrexed have been identified. However, patients with hepatic impairment, such as those with bilirubin > 1.5 times the upper limit of normal and/or aminotransferases > 3.0 times the upper limit of normal (in the absence of liver metastases) or > 5.0 times the upper limit of normal (in the presence of liver metastases), have not been specifically studied.