Cytarabine Hikma

Italy
Brand name Cytarabine Hikma
Form solution for injection
Active substance / Dosage
CYTARABINE
Prescription type Prescription only – non-repeatable
ATC code
L01BC01
Registration number 034164
Manufacturer HIKMA FARMACEUTICA (PORTUGAL) S.A.
Cytarabine Hikma solution for injection

Table of Contents

Package leaflet: Information for the user

Cytarabine Hikma 100 mg/ml solution for injection, 500 mg/5 ml solution for injection, 1 g/10 ml solution for injection, 2 g/20 ml solution for injection, 100 mg/5 ml solution for injection, 1 g/50 ml solution for injection

Cytarabine
Generic medicine
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 nurse.
  • If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of this leaflet:

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

1. What CITARABINA HIKMA is and what it is used for

CITARABINA HIKMA contains the active substance cytarabine, which belongs to a group of
medicinal products called antineoplastics, used in the treatment of tumours.
This medicine is indicated for the treatment of a particular type of blood cell cancer called acute myeloid leukaemia (characterized by a high number of white blood cells), in both adults and children.
Specifically, this medicine is indicated to induce remission of acute myeloid leukaemia, that is, to attempt to restore a more normal balance of blood cells, thereby improving the patient's health condition.
This medicine is also indicated for the treatment of other diseases (proliferative disorders of the white cell series) in which an increase in white blood cells (leukocytes) in the blood occurs.

2. What you should know before using CITARABINE HIKMA

Do not use CITARABINE HIKMA

  • if you are allergic to cytarabine or to any of the other ingredients of this medicine (listed in section 6);
  • if your blood cell count (red blood cells, white blood cells, and platelets) is very low, either due to cancer or other causes such as reduced bone marrow function (bone marrow aplasia, drug-induced bone marrow suppression), unless otherwise decided by your doctor;
  • if you have memory loss or difficulty concentrating, as these may be signs of serious brain problems (degenerative or toxic encephalopathies), particularly after radiation therapy or treatment with other anticancer medicines such as methotrexate;
  • if you suspect you are pregnant or are actually pregnant (See section “Pregnancy and breastfeeding”).

Warnings and precautions
Please speak with your doctor or nurse before receiving CITARABINE HIKMA.
Do not forget to inform your doctor if you have undergone radiation therapy.
CITARABINE HIKMA will only be administered by specialized and experienced medical staff
in this type of therapy (antineoplastic chemotherapy) and in a specialized facility capable of
managing emergency situations.
During administration of CITARABINE HIKMA, the following will be closely monitored:

  • daily white blood cell and platelet counts; treatment may be immediately suspended if these blood cell levels drop too low, as this may increase your susceptibility to infections or bleeding;
  • bone marrow activity, because cytarabine may reduce its function (myeloinhibitory activity);
  • liver and kidney function;
  • blood uric acid levels (uricemia), as cytarabine may cause an increase in these levels (hyperuricemia). During administration of CITARABINE HIKMA, especially in combination with other medicines, the following may occur:
  • abdominal pain (peritonitis) or intestinal pain (colitis);
  • reduced number of certain types of white blood cells in the blood (neutropenia) or of platelets (thrombocytopenia);
  • generalized paralysis, potentially fatal (delayed progressive ascending paralysis), particularly after intravenous (endovenous) or direct administration into the brain (intrathecal);
  • severe inflammation of the pancreas (acute pancreatitis).
    When CITARABINE HIKMA is administered in combination with methotrexate directly into the brain (intrathecal route), the following may occur:
  • headache, coma, paralysis, and stroke-like episodes, especially in younger patients.
    Approximately 6–12 hours after cytarabine administration, a condition known as cytarabine syndrome usually develops, with symptoms such as fever, muscle pain (myalgia), bone and chest pain, skin rash (maculopapular rash), eye problems (conjunctivitis), nausea, and general malaise. Your doctor may prescribe corticosteroids (anti-inflammatory drugs) to prevent or treat these symptoms. If effective, cytarabine treatment may continue.

If CITARABINE HIKMA therapy requires high doses, the following problems may occur
(see section “Possible side effects”):

  • neurological problems (cerebral and cerebellar dysfunction, usually reversible), including personality changes, drowsiness, seizures, and coma, particularly if you have previously received anticancer drugs administered directly into the brain (intrathecal chemotherapy) or radiation therapy. In such cases, transfusion of certain blood cells (granulocytes) should be avoided, as serious respiratory problems (respiratory failure) may occur;
  • eye problems (reversible corneal toxicity and hemorrhagic conjunctivitis);
  • heart problems (cardiomyopathy, cardiomegaly) after high-dose cytarabine, especially when combined with cyclophosphamide;
  • respiratory problems (respiratory failure, pulmonary edema, adult respiratory distress syndrome);
  • gastrointestinal problems (severe gastrointestinal ulceration, including intestinal pneumatosis leading to peritonitis, intestinal necrosis, necrotizing colitis);
  • liver problems (sepsis and abscesses, liver damage with increased bilirubinemia);
  • skin disorders (cutaneous rash);
  • hair loss (alopecia).
    The administration of certain vaccines (live vaccines) should be avoided, while other types of vaccines (killed or inactivated vaccines) may be given.

Other medicines and CITARABINE HIKMA
Inform your doctor or nurse if you are currently taking, have recently taken, or might take any other medicines.
This medicine will be administered with caution if you are taking the following medicines:

  • digoxin, a medicine used to increase heart activity;
  • gentamicin, an antibiotic used to treat bacterial infections;
  • flucytosine, an antifungal medicine used to treat fungal infections;
  • methotrexate, a medicine used to treat certain cancers and other conditions such as rheumatoid arthritis, particularly when methotrexate is administered directly into the brain (intrathecal route);
  • immunosuppressive agents, medicines used to suppress harmful immune responses in other diseases, as serious infections may occur.

Pregnancy, breastfeeding, and fertility
If you are pregnant, suspect you may be pregnant, plan to become pregnant, or are breastfeeding, consult your doctor or nurse before receiving this medicine.
Pregnancy
No studies on the use of cytarabine in pregnant women have been conducted. This medicine should be used during pregnancy or in women of childbearing potential only after careful consideration of the potential benefit versus the potential risk to both mother and fetus.
CITARABINE HIKMA, especially during the first trimester of pregnancy, may cause birth defects such as:

  • malformations of arms, legs, and ears;
  • serious blood disorders (pancytopenia, leukopenia, anemia, thrombocytopenia, electrolyte imbalances, transient eosinophilia, elevated IgM levels);
  • enlargement of the spleen (splenomegaly);
  • genetic abnormalities (trisomy of a chromosome from group C in chorionic tissue);
  • high fever, widespread infection (sepsis), and death.
    For these reasons, avoid pregnancy while you or your partner are undergoing treatment with cytarabine. If you are of childbearing potential, you are advised to use an effective contraceptive method during treatment and for six months after treatment, regardless of gender. Cytarabine may cause birth defects; therefore, it is important to inform your doctor if you think you may be pregnant.
    Breastfeeding
    You must stop breastfeeding before starting treatment with cytarabine, as this medicine may be harmful to breastfed infants.
    Fertility
    CITARABINE HIKMA may cause cessation of the menstrual cycle in women (amenorrhea) and may suppress sperm production in male patients (azoospermia), especially when combined with other anticancer medicines known as alkylating agents. Men undergoing treatment with cytarabine should use a reliable contraceptive method. Consult your doctor before using this medicine.

Driving and using machines
This medicine does not impair the ability to drive or operate machinery. However, cancer treatment in general may affect this ability in some patients. If this applies to you, avoid driving or operating machinery.
Cytarabine Hikma 100 mg/5 ml solution for injection and Cytarabine Hikma 1 g/50 ml solution for injection contain sodium
Cytarabine Hikma 100 mg/5 mL Solution for Injection contains less than 1 mmol (23 mg) of sodium per 5 mL vial, i.e., essentially ‘sodium-free’.
Cytarabine Hikma 1 g/50 mL Solution for Injection contains 131 mg of sodium (main component of table salt) per 50 mL vial. This corresponds to 6.7% of the maximum daily dietary intake recommended for an adult.

3. How to use CYTARABINE HIKMA

This medicine will be administered to you by specialized healthcare personnel. If you have any doubts, consult your doctor or nurse.
Your doctor will determine the dose according to your condition. The recommended dose for the treatment of acute non-lymphocytic leukaemia is 100 mg of cytarabine per square metre (m²) daily, administered by continuous intravenous infusion for a period of 1 to 7 days, or 100 mg per m² given by intravenous infusion every 24 hours for a period of 1 to 7 days; in combination with other anticancer medicines (cytostatic agents).
For use in other types of leukaemia, such as acute lymphocytic leukaemia, your doctor will determine the appropriate dose depending on the type of tumour and your condition.

Children
The safety of CYTARABINE HIKMA in infants has not been established.

CYTARABINE HIKMA may be administered to you via:

  • an intravenous injection (rapid intravenous injection or slow intravenous infusion); administration of the medicine by rapid infusion may cause nausea and sometimes vomiting, which may last for several hours;
  • subcutaneous injection (under the skin);
  • intrathecal route (into the central nervous system), but only if using Cytarabine Hikma 100 mg/5 ml injectable solution or Cytarabine Hikma 1 g/50 ml injectable solution. All other CYTARABINE HIKMA dosage forms will not be administered via this route.

If you use more CYTARABINE HIKMA than you should
This medicine will be administered by specialized personnel, so it is unlikely that you will receive an excessive dose. However, in case of overdose, treatment will be discontinued and appropriate management initiated for the resulting decrease in white blood cell and platelet counts, including blood transfusion or administration of antibiotics, if necessary.
If you have any doubts about the use of this medicine, consult your doctor or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

The following side effects may occur:

Very common (may affect more than 1 in 10 people)

  • inflammation of the lungs (pneumonitis), severe widespread infection (sepsis), infections (caused by viruses, bacteria, fungi, parasites or saprophytes) in any part of the body;
  • various blood disorders such as reduced levels of a substance called haemoglobin in the blood (anaemia, megaloblastic anaemia), decreased white blood cells (leucopenia) and other blood cells (reticulocytopenia), reduced platelet count (thrombocytopenia), reduced bone marrow function (bone marrow failure);
  • inflammation and/or sores (ulceration) inside the mouth (stomatitis), abdominal pain, nausea, vomiting, diarrhoea, inflammation and/or sores (ulceration) around the anus;
  • abnormal liver function (abnormal liver function tests);
  • progressive hair loss (alopecia), skin irritation (skin rash);
  • a condition called cytarabine syndrome, which presents with symptoms such as fever, muscle pain (myalgia), bone and chest pain, skin rash (maculopapular rash), eye problems (conjunctivitis), and nausea (see section “Warnings and precautions”). Your doctor may prescribe corticosteroids (anti-inflammatory medicines) to prevent or treat these symptoms. If effective, cytarabine treatment may continue;
  • fever (pyrexia);
  • abnormal blood tests (abnormal bone marrow biopsy, abnormal peripheral blood test).

Common (may affect up to 1 in 10 people)

  • severe loss of appetite (anorexia);
  • high levels of uric acid in the blood (hyperuricaemia);
  • difficulty speaking (dysarthria);
  • eye disorders such as uncontrolled eye movements (nystagmus) or inflammation of the cornea (keratitis);
  • difficulty swallowing (dysphagia);
  • increased levels of certain substances (elevated enzyme levels) produced by the liver, which return to normal later;
  • skin disorders such as skin sores (cutaneous ulceration), skin irritation (urticaria), skin redness (erythema), skin inflammation with blistering (bullous dermatitis);
  • inflammation of blood vessels (vasculitis) or superficial inflammation of veins at the injection site (thrombophlebitis);
  • kidney function disorders (renal dysfunction).

Uncommon (may affect up to 1 in 100 people)

  • intestinal problems such as intestinal cysts (intestinal cystic pneumatosis), peritonitis, severe damage to intestinal walls (necrotizing colitis);
  • nervous system disorders (peripheral neuropathy);
  • itching, burning sensation in the palms of the hands and soles of the feet, appearance of freckles;
  • muscle pain (myalgia) or joint pain (arthralgia).

Rare (may affect up to 1 in 10,000 people)

  • heart rhythm disorders (arrhythmias);
  • inflammatory disease of the sweat glands (neutrophilic eccrine hidradenitis).

Frequency not known (cannot be estimated from the available data):

  • slowed heart rate (sinus bradycardia);
  • cellulitis at the injection site;
  • changes in the shape of bone marrow cells, reduced bone marrow function and consequent reduction in all blood cells (pancytopenia, which may last 15–25 days); neutropenia and febrile neutropenia;
  • allergic reactions, including severe ones (anaphylaxis leading to acute cardiopulmonary arrest requiring resuscitation, allergic oedema);
  • decreased appetite;
  • nervous system disorders (neurotoxicity, neuritis), dizziness, headache (cephalalgia);
  • eye disorders (conjunctivitis), excessive sensitivity to light (photophobia), burning eyes, increased tear production, and vision disturbances;
  • heart problems (pericarditis);
  • vein problems (thrombophlebitis);
  • lung inflammation (pneumonitis), difficulty breathing (dyspnoea), pain in the mouth and pharynx (oropharyngeal pain);
  • inflammation of the pancreas (pancreatitis), sores or inflammation of the oesophagus (oesophageal ulceration or oesophagitis);
  • liver problems (hepatic dysfunction, jaundice);
  • tingling and burning in the palms of the hands and soles of the feet, followed by swelling and redness (palmar-plantar erythrodysesthesia syndrome), skin discolouration (pigmentation), appearance of specific dark spots (freckles);
  • kidney problems (kidney damage, urinary retention);
  • chest pain, infusion site reactions (pain and skin inflammation);
  • menstrual cycle disturbances (amenorrhoea) and male fertility problems (azoospermia) (see section “Pregnancy, breastfeeding and fertility”).

Possible side effects associated with intrathecal administration

Frequency not known (cannot be estimated from the available data):

  • systemic reactions (systemic toxicity);
  • nausea, vomiting, fever, and headache;
  • meningism (symptoms similar to meningitis such as headache, neck stiffness, altered mental status, intolerance to light and sound);
  • tingling in arms and legs (paraesthesia), leg paralysis (paraplegia), and uncontrolled muscle movements (convulsions);
  • nervous system problems (neurotoxicity) due to preservatives contained in other medicines injected intrathecally together with cytarabine.

Possible side effects due to high-dose therapy not authorised:

Very common (may affect up to 1 in 10 people)

  • nervous system problems (cerebral and cerebellar disorders, drowsiness);
  • damage to the cornea (the central transparent part of the eye) and inflammation of the conjunctiva (the white part of the eye), sometimes with bleeding. To prevent these effects, you may be given corticosteroid eye drops;
  • increased fluid in the lungs (pulmonary oedema), difficulty breathing (adult respiratory distress syndrome, respiratory failure).

Common (may affect up to 1 in 100 people)

  • severe damage to intestinal walls (necrotizing colitis);
  • skin irritation (skin exfoliation).

Frequency not known (cannot be estimated from the available data):

  • liver problems such as widespread infection of the organ (hepatic abscesses), increased bilirubin levels in the blood (bilirubinaemia), liver damage (ulceration), increased liver size (hepatomegaly), a condition characterised by jaundice and enlarged liver and/or spleen (Budd-Chiari syndrome);
  • inflammation of the pancreas (pancreatitis);
  • nervous system disorders with personality changes, altered consciousness, speech difficulties (dysarthria), difficulty in muscle coordination (ataxia), tremors, eye problems (nystagmus), confusion, headache (cephalalgia), drowsiness, involuntary muscle contractions (convulsions), coma, various nervous system disorders (neuropathies) affecting both motor coordination and sensory organs. This is particularly likely if you are elderly, have liver or kidney damage, have had or previously received radiation therapy, or have a history of alcohol abuse. For these reasons, you will be closely monitored to prevent such nervous system changes, which may not be reversible;
  • heart function disorders (cardiomyopathy);
  • slowed heart rate (sinus bradycardia);
  • intestinal problems such as severe sores (ulceration), increased intestinal gas content (intestinal pneumatosis), severe damage to intestinal walls (intestinal necrosis), peritonitis, intestinal perforation;
  • increased fluid in the lungs (pulmonary oedema);
  • heart problems due to enlargement of the heart (cardiomegaly) or impaired heart function (cardiomyopathy), especially if you are also receiving another anticancer medicine called cyclophosphamide;
  • severe skin irritation (skin rash with desquamation);
  • breakdown of skeletal muscle cells with release of muscle contents into the blood (rhabdomyolysis).

Reporting of side effects

If you experience any side effects, 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: http://www.agenziafarmaco.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 CYTARABINE HIKMA

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the packaging after "Exp".
The expiry date refers to the last day of that month and applies to the product in its original
intact packaging and properly stored.
Medical personnel are aware of the appropriate storage conditions for this medicine.
Store the medicine at a temperature not exceeding 25°C and protect it from light.
The product does not contain preservatives; therefore, it must be discarded immediately after use.
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 CITARABINA HIKMA 100mg/ml Injectable Solution contains

  • The active substance is cytarabine. Each ml of solution contains 100 mg of cytarabine.
  • The other components are: NaOH and/or HCl to adjust pH, water for injections.

What CITARABINA HIKMA 500mg/5 ml Injectable Solution contains

  • The active substance is cytarabine. Each ml of solution contains 100 mg of cytarabine.
  • The other components are: NaOH and/or HCl to adjust pH, water for injections.

What CITARABINA HIKMA 1g/10 ml Injectable Solution contains

  • The active substance is cytarabine. Each ml of solution contains 100 mg of cytarabine.
  • The other components are: NaOH and/or HCl to adjust pH, water for injections.

What CITARABINA HIKMA 2g/20 ml Injectable Solution contains

  • The active substance is cytarabine. Each ml of solution contains 100 mg of cytarabine.
  • The other components are: NaOH and/or HCl to adjust pH, water for injections.

What CITARABINA HIKMA 100mg/5 ml Injectable Solution contains

  • The active substance is cytarabine. Each ml of solution contains 20 mg of cytarabine.
  • The other components are: sodium chloride, NaOH and/or HCl to adjust pH, water for injections.

What CITARABINA HIKMA 1g/50 ml Injectable Solution contains

  • The active substance is cytarabine. Each ml of solution contains 20 mg of cytarabine.
  • The other components are: sodium chloride, NaOH and/or HCl to adjust pH, water for injections.

Description of the appearance of CITARABINA HIKMA and package contents
CITARABINA HIKMA 100mg/ml injectable solution: pack containing one 1 ml glass vial or a pack containing five 1 ml glass vials.
CITARABINA HIKMA 500mg/5ml injectable solution: pack containing one 5 ml glass vial or a pack containing five 5 ml glass vials.
CITARABINA HIKMA 1 g/10ml injectable solution: pack containing one 10 ml glass vial.
CITARABINA HIKMA 2 g/20ml injectable solution: pack containing one 20 ml glass vial.
CITARABINA HIKMA 100mg/5ml injectable solution: pack containing one 5 ml glass vial or a pack containing five 5 ml glass vials.
CITARABINA HIKMA 1 g/50ml injectable solution: pack containing one 50 ml glass vial.
Not all pack sizes may be marketed.

Marketing Authorization Holder
Hikma Farmacêutica (Portugal), S.A.
Estrada do Rio da Mó n.º 8, 8A and 8B, Fervença
2705-906 Terrugem SNT
Portugal

Manufacturer
Hospira UK Limited,
Horizon, Honey Lane,
Hurley, Maidenhead, SL6 6RJ
United Kingdom
Hospira Enterprises B.V.
Randstad 22-11
1316 BN Almere
The Netherlands
Thymoorgan Pharmazie GmbH
Schiffgraben 23
D-38690 Goslar
Germany

Marketing Company
Hikma Italia SpA
Viale Certosa 10
27100 Pavia

Package leaflet: information for healthcare professionals
The following information is intended exclusively for physicians or healthcare professionals

Dosage and method of administration:
CITARABINA HIKMA 100 mg/ml injectable solution only:
Prior to use, if crystallization is observed as a result of exposure to low temperatures, vials of cytarabine at a concentration of 100 mg/ml should be heated at 55°C for 30 minutes with adequate agitation and then allowed to cool to room temperature.
CITARABINA HIKMA may be diluted with sterile water for injections, glucose solutions, or physiological saline. Infusions prepared under aseptic conditions should be used immediately or, alternatively, may be stored for up to 24 hours between 2°C and 8°C, protected from light.

Incompatibilities
Cytarabine is incompatible in solution with various drugs; incompatibilities depend on several factors such as drug concentration, diluents used, solution pH, and temperature.
CITARABINA HIKMA is incompatible with heparin, insulin, methotrexate, 5-fluorouracil, nafcillin, oxacillin, penicillin G, methylprednisolone sodium succinate, vitamin B complex, carbenicillin sodium, cephalothin sodium, gentamicin sulfate, and hydrocortisone sodium succinate.

Stability after first opening
The medicinal product does not contain preservatives. After use, any unused portion must be discarded, even if only partially used.

Instructions for use
Guidelines for handling cytotoxic drugs

Administration
Must be administered only under the direct supervision of a physician experienced in the use of cytostatic agents.

Preparation (guidelines):

  1. Chemotherapeutic agents should be prepared only by professionals experienced in their handling.
  2. Procedures such as reconstitution of powder and transfer into syringes must be performed only in suitable, specially designated areas (preferably under a laminar flow hood appropriate for handling cytotoxic compounds).
  3. Personnel performing these operations must wear protective gowns, gloves, and safety goggles.
  4. Pregnant female personnel must not handle these substances.

Contamination
a) In case of accidental contact with skin or eyes, the affected area should be thoroughly rinsed with water or normal saline. A mild cream may be used to treat transient skin irritation. Consult a specialist in case of accidental eye contact.
b) In case of spillage, personnel should wear gloves and absorb the solution using a sponge kept in the designated work area for this purpose. Wash the surface twice with water. Place the solution, sponge, and contaminated materials into a plastic bag and seal it.

Disposal
Syringes, containers, absorbent materials, solution, and any other contaminated materials should be placed in a double plastic bag or other impermeable containers and incinerated at 1000°C.

Overdose
There is no antidote for overdose with CITARABINA HIKMA. Management recommendations for overdose include: discontinuation of therapy followed by treatment of resulting bone marrow suppression, including transfusion of whole blood or platelets and antibiotics, if necessary. A dosage of 4.5 g/m² administered over 1 hour every 12 hours for 12 doses by intravenous infusion has resulted in unacceptable increases in irreversible toxic effects on the central nervous system and cases of death. Cytarabine can be removed by hemodialysis.

For further information, please refer to the Summary of Product Characteristics.