Cytarabine, the active substance in Alexan, inhibits cell division and therefore the growth of cancer cells.

Alexan is a medication used to treat various types of cancer (leukaemia, lymphomas).

Do not use Alexan

·                if you are allergic to cytarabine or any of the other ingredients of this medication listed under Section 6

·                in case of reduced production of blood cells in bone marrow (myelosuppression)

·                in case of severely reduced renal and/or hepatic function

·                in case of existing severe infections

·                in case of stomach and intestinal ulcers and recent operations

·                in case of anaemia (erythrocytopaenia), leukopaenia (white blood cell deficiency) and/or thrombocytopaenia (platelet deficiency)

·                if you are currently being treated or have received treatment for chickenpox or shingles (herpes zoster) with brivudine, sorivudine or their analogues in the last 4 weeks

·                during lactation

Warnings and Precautions

Speak to your doctor or pharmacist before using Alexan. If you take phenytoin against epileptic seizures, you should be examined regularly due to potentially elevated phenytoin plasma levels. Simultaneous use of phenytoin and Alexan can intensify the effect of phenytoin.

Alexan must only be used with caution in specialised facilities with appropriate possibilities for regular monitoring of the effects during and after administration.

Alexan inhibits the production of blood cells in bone marrow (myelosuppression). After discontinuing the medication, the number of blood cells may continue to decrease. The number of blood cells should be checked regularly, even after the end of therapy, and a bone marrow examination should be conducted if required.

Caution should be exercised with patients with drug-induced myelosuppression in their medical history.

Alexan can cause increased uric acid levels in the blood due to the destruction of cancer cells. The uric acid content in the blood should therefore be monitored. Your doctor will inform you about the need to take medications to control your uric acid level.

Special caution is required with mild reduction of hepatic and renal function.

Reduced liver and kidney function is considered a predisposing factor for increased CNS toxicity due to Alexan.

Since Alexan is mainly broken down in the liver, a stronger effect of the substance is possible in users with liver damage. An increase in efficacy also results in reduced renal function. In the case of reduced liver and/or kidney function, a corresponding dose reduction must be performed while blood levels are monitored. Regular monitoring of liver and kidney function as well as uric acid levels is necessary. In patients with preexisting reduced liver function, cytarabine should be administered with caution and after a strict risk-benefit assessment, particularly with high doses.

Ensure that you drink enough fluids.

Anaphylactic reactions may occur during treatment with Alexan, especially immediately after intravenous administration.

High-dose treatment with Alexan in patients over 60 years of age may only take place after a particularly careful risk-benefit assessment.

Birth Control Measures:

Alexan can change the genetic material. Men should therefore not father children during treatment and for up to six months after ending treatment. In addition, you should receive information before treatment regarding the option of sperm preservation, since there is the possibility of infertility (sterility) after Alexan therapy.

A genetic consultation is recommended if women wish to have children after the end of treatment.

Severe gastrointestinal side effects require antiemetic (for nausea) and other supportive measures.

High dosage treatments require regular monitoring of the central nervous system function and the lung function by a specialist.

In order to avoid eye problems, they must be rinsed regularly during high dosage treatment.

During therapy with Alexan, no vaccinations with live vaccines should be administered.

Treatment with Alexan involves the risk of bleeding complications and severe infections.

During high-dose therapy, disorders of the central nervous system, the gastrointestinal tract, the liver, as well as skin reactions and eye symptoms may occur.

Contact with the skin, mucous membranes and eyes must be avoided.

Simultaneous use of Alexan with other medications may cause acute inflammation of the pancreas.

Cases of severe neurological side effects that range from headache to paralysis, coma, and stroke-like episodes have been mainly observed in children and adolescents who received intravenous Alexan in combination with intrathecal methotrexate.

Cytarabine, the active substance of Alexan, is a substance that can harm your unborn child and change the genetic material.

Use of Alexan with Other Medications

Inform your doctor or pharmacist if you are taking/using other medications, have recently taken/used other medications or intend to take/use any other medications.

Concomitant use of certain antiviral (used to treat viruses) medications such as sorivudine, brivudine, or their derivatives, may significantly intensify the side effects of Alexan (see the Section “Do Not Use Alexan”).

You must exercise particular caution if you take medications against epileptic seizures (phenytoin). Simultaneous use of phenytoin and Alexan can intensify the effect of phenytoin. Your doctor will regularly monitor your phenytoin plasma level.

Simultaneous or prior therapy with cell-damaging substances or radiation therapy may intensify the myelosuppression caused by Alexan.

Alexan may cause acute pancreatitis in case of previous treatment with L-asparaginase (medication used to treat blood cancer).

Interactions are to be expected when combining different cytostatics (medication used to treat cancer).

5-fluorocytosin should not be administered with Alexan, as it has been shown that the effect of 5-fluorocytosin (medication to treat fungal infections) can be inhibited by Alexan.

In patients who also receive digoxin (medication used to treat heart failure), digoxin levels in the blood must be monitored during Alexan therapy since a reduction in blood levels and therefore an impaired effect of digoxin may occur. Since this is not the case with digitoxin, a switch from digoxin to digitoxin is advisable for patients receiving cytarabine therapy.

In laboratory studies, Alexan appears to reduce the susceptibility of some bacteria (K. pneumoniae) to the antibiotic gentamicin. If there is no response to gentamicin, your doctor will switch antibiotics if necessary.

Pregnancy, Breastfeeding and Fertility

If you are pregnant or breastfeeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medication.

Pregnancy

In some animal species, malformations occurred in the use of cytarabine on the foetus. The use of cytarabine in women who are pregnant or could become pregnant may only be carried out after careful consideration of the possible risks and benefits.

If you become pregnant during treatment with Alexan, please notify your doctor immediately.

Breastfeeding

Do not breastfeed during treatment with Alexan. Breastfeeding must be stopped before the start of treatment with Alexan.

Fertility

Alexan may be mutagenic. This means that the medication may cause genetic mutations. Alexan may impair sperm and egg production, which is associated with the possibility of birth defects.

During treatment with Alexan and at least during the first 6 months after the end of treatment, you must avoid conceiving a child. Since treatment with Alexan can lead to infertility, it may be advisable for male patients to consider sperm preservation before the start of treatment (see also the Section “Warnings and Precautions”).

Driving and Operating Machinery

    Caution: This medication may affect the ability to react and impair the ability to   drive.

Alexan contains sodium

This medication contains less than 1 mmol (23 mg) of sodium per ml, i.e. it is virtually “sodium-free”.

Alexan therapy may only be used by doctors with special training and experience in the field of cancer therapy. This therapy should be initiated in hospital.

For intravenous (in a vein) and intrathecal (in the cerebrospinal fluid) or subcutaneous (in the subcutaneous fatty tissue) administration.

You will receive Alexan either as an infusion into a vein (intravenous), as an injection into the cerebrospinal fluid or occasionally as an injection into the subcutaneous fatty tissue (subcutaneous).

Information for the Physician: For information on dosage, see the prescribing information or treatment protocols in the specialist literature.

If you receive more Alexan than you should

Your doctor will ensure that you receive the correct dose for your disease. In the event of an overdose, increased side effects may occur. Your doctor will then discontinue the therapy and, if required, treat any side effect symptoms and initiate supportive measures.

If you have any further questions on the use of this medication, contact your doctor or pharmacist.

Like all medications, this medication can cause adverse reactions, though they will not occur in every person being treated with Alexan.

The side effects caused by Alexan depend on the dosage, method of administration and treatment duration.

Local tolerance is generally high. Sometimes inflammation may occur at the injection site.

The evaluation of adverse reactions is based on the following frequencies:

Very common (may affect more than 1 in 10 persons treated)

Common (may affect up to 1 in 10 persons treated)

Uncommon (may affect up to 1 in 100 persons treated)

Rare (may affect up to 1 in 1,000 persons treated)

Very rare (may affect up to 1 in 10,000 persons treated)

Unknown (frequency cannot be estimated from the available data)

Very common (may affect more than 1 in 10 persons treated)

·         Blood poisoning (sepsis)

·         Inflammation of the lungs (pneumonia)

·         Infection

·         Bone marrow failure disorders, changes in blood count (e.g. white or red blood cell or platelet deficiency, abnormal blood cells); are dosage-dependent

·         Rash

·         Conjunctivitis (in case of high dosage therapy)

·         Reduced liver function, hyperbilirubinaemia (increased levels of the bile pigment bilirubin) have been observed in 25–50% of patients receiving high dosage treatment.

Common (may affect up to 1 in 10 persons treated)

·         Loss of appetite, increased uric acid levels in the blood. Hypocalcaemia may also occur (calcium deficiency in the blood).

·         Abdominal pain

·         Swallowing difficulties

·         Inflammation or ulcers in the mouth or anus

·         Severe diarrhoea, nausea and vomiting (especially after rapid intravenous injection)

·         Skin reactions (redness, ulceration, skin rash, hives), vascular inflammation, mottled skin, itching. After high doses, exfoliative dermatitis (inflammation of the skin with blistering and peeling skin) and hair loss may occur.

·         Cerebral disorders (eye tremor, speech disorders, movement disorders, confusion and personality changes), thought and movement disorders, dizziness, impaired consciousness with increased stimulation threshold, coma, trembling, seizures and loss of appetite

·         Conjunctivitis, inflammation of the cornea, light sensitivity, burning eyes, severe lacrimation and vision disorders are dosage-dependent and were observed in 25–80% of patients undergoing high dosage therapy. (The symptoms may be prevented or mitigated with frequent eye rinses or prophylactic use of corticosteroid eye drops.)

·         Urinary disorders, renal impairment. An increase in plasma creatinine (metabolite) has been observed in 5 to 20% of patients receiving high-dose cytarabine therapy, but a confirmed causal connection with cytarabine has not been proven. Measures to prevent uric acid nephropathy should be taken in the case of massive cell degeneration.

·         Throat inflammation, allergic oedema (water accumulation), disordered production of sex hormones, sperm and ovum cells, pain in the chest area, ascites (water accumulation in the abdominal cavity), weakened immune system, sepsis (blood poisoning), thrombophlebitis (inflammation and occlusion of the veins) and bleeding. Fever occurs in 20–50% of patients undergoing high dosage therapy.

Uncommon (may affect up to 1 in 100 persons treated)

·         Inflammation or ulcers in the oesophagus, severe mucous membrane changes in the gastrointestinal tract with ulceration, destruction and perforation of the intestinal wall (necrosis), intestinal obstruction, peritonitis

·         Brown/black pigment spots on the skin (lentigo), ulcers on the skin, itching, burning pain on the palms and soles of the feet

·         Disease of the peripheral nerves (peripheral neuropathy)

·         Muscle pain and/or joint pain were observed after high doses of Alexan.

·         Breathing problems, shortness of breath, sore throat, pulmonary oedema (fluid accumulation in the lungs, can be cured in most cases), pneumonia (diffuse interstitial pneumonia)

·         Acute pericardial inflammation

Rare (may affect up to 1 in 1,000 persons treated)

·         Intrathecal (injection into the cerebrospinal fluid) use of Alexan may cause nausea, vomiting and fever

Very rare (may affect up to 1 in 10,000 persons treated)

·         Inflammation of the pancreas

·         Inflammation of the perspiratory glands

·         Isolated cases of pathological changes in white brain matter (necrotising leucoencephalopathy), damage to the spinal cord with symptoms of paralysis that affect the limbs (para- and quadriplegia) and blindness have been described after administration of Alexan into the cerebrospinal fluid.

·         Occurrence of rhabdomyolysis (breakdown of muscle fibres) has been described.

·         Enlargement of the liver. There are individual reports of the occlusion of blood vessels that drain the liver (Budd-Chiari syndrome).

·         Heart muscle damage, temporary cardiac arrhythmia

·         Allergic reactions (hives, allergic shock)

·         The syndrome of inadequate antidiuretic hormone secretion has been observed in individual cases in patients receiving high dosage treatment with Alexan.

Unknown (frequency cannot be estimated from the available data)

·         Cellulitis (inflammation of the deep layers of skin) at the injection site, liver abscess

·         Hand-foot syndrome

·         Dizziness, headache, inflammation of the nerves and, after high doses, individual cases of peripheral nerve damage have been described, as well as cases of paralysis, meningitis and encephalitis.

·         Jaundice

·         Slow heart rate

Alexan (Ara-C) syndrome

This syndrome described in the literature is characterised by fever, muscle pain, bone pain, occasionally chest pain, skin rash with blistering, conjunctivitis and nausea. It generally occurs 6–12 hours after administration. Corticosteroids (anti-inflammatory agent) have been proved to be successful in the treatment or prevention of the syndrome. If corticosteroids are effective in this regard, continuation of treatment with Alexan may be considered.

With a high dosage prolonged infusion, the side effects are more pronounced than in standard therapy.

Cases of early death were reported as a result of myelosuppression.

Store below 25°C.

Store in the original packaging in order to protect from light.

Keep this medication out of the sight and reach of children.

Do not use this medication past the expiry date indicated on the outer packaging or on the label after “Use by”. The expiry date refers to the last day of the month specified.

For single use only. Dispose of any unused product.

Solution for infusion after dilution

The chemical and physical stability of the ready-for-use preparation when diluted with 0.9% sodium chloride has been demonstrated at 2°C to 8°C for 28 days.

From a microbiological point of view, the reconstituted preparation should be used immediately. If the reconstituted preparation is not used immediately, the user is responsible for the duration and conditions of storage. If the ready-to-use solution is not prepared under controlled and validated aseptic conditions, it should not be stored for longer than 24 hours at 2°C to 8°C.

After use, dispose of the bottle and injection materials (including gloves) according to the regulations for cytostatics. Any unused product as well as the primary packaging must be disposed of as hazardous waste.