Index of drugs

Intrathecal treatment of lymphomatous meningitis. In most patients, such treatment will be part of the relief of disease symptoms.

1 vial (5 ml) contains 50 mg of cytarabine.

A drug with long-term release of cytarabine, intended for direct administration to the cerebrospinal fluid. Cytarabine is an anticancer drug that works on cells only in the S phase of cell division. In the cell cytarabine is metabolized to the active metabolite - 5'-cytarabine triphosphate (ara-CTP). The mechanism of action has not been fully understood, but it seems that ara-CTP acts mainly blocking DNA synthesis. The incorporation in DNA and RNA may also contribute to cytarabine toxicity. Cytarabine is cytotoxic to a wide variety of mammalian proliferating cell cultures. Pharmacokinetic data analysis showed that after intrathecal medication with long-term release of cytarabine, both by lumbar puncture and intraventricular reservoir, the maximum concentration of cytarabine was observed within 5 h, both in the ventricles of the brain and in the epidural space. A two-phase elimination profile consisting of an initial acute concentration reduction followed a slower phase followed by a terminal half-life ranging from 100 to 263 h for doses from 12.5 mg to 75 mg followed by peaks. In contrast, for intrathecal administration of 30 mg of free cytarabine, the biphasic CSF profile with the terminal phase of half-life was approximately 3.5 hours. Exposure to cytarabine in the brain and epidural spaces is similar regardless of the route of administration (intraventricular or intraventricular). through a lumbar puncture). In addition, compared to free cytarabine, a drug with long-term release of cytarabine increases the biological half-life by a factor of 27 to 71 depending on the route of administration and the compartment being tested. The concentration of cytarabine in capsules and the titre of fat molecules, when administered in the form of cytarabine capsules, were similarly distributed. The AUC of free cytarabine and intraventricular encapsulated capsule administration seemed to increase linearly with increasing dose, indicating that release of cytarabine from the formulation and cytarabine pharmacokinetics are linear in the human cerebrospinal fluid. The main route of elimination of cytarabine is metabolism to the inactive compound ara-U (1-β-D-arabinofuranosyluracil or arabinoside uridine), followed by the excretion of ara-U in the urine. In contrast to systemically administered cytarabine, which is rapidly metabolised to ara-U, transformation in ara-U in the cerebrospinal fluid is negligible after intrathecal administration, due to the significantly lower activity of cytidine deaminase in the CNS tissues and cerebrospinal fluid. The cytarabine clearance in the cerebrospinal fluid is approximately 0.24 ml / min. More than 90% of cytarabine was excreted by day 4, and an additional 2.7% after 21 days. The lipid components undergo hydrolysis and are mostly incorporated into tissues after breakdown in the inter-epidermal space.

Hypersensitivity to cytarabine or any of the excipients. Active infection of the meninges.

Patients receiving the medicine should also take corticosteroids (eg dexamethasone) to relieve symptoms of arachnoiditis (untreated arachnoiditis may lead to death). Patients should be monitored closely to detect neurotoxicity; early signs of neurotoxicity may include headache, nausea, vomiting and fever. Intrathecal cytarabine is associated with severe CNS toxicity that may lead to permanent failure, including blindness, bone marrow dysfunction, and other symptoms of neurotoxicity. Administration of the drug in combination with other neurotoxic chemotherapeutics or cranial and spinal irradiation increases the risk of neurotoxicity. If neurotoxicity occurs, the dose should be reduced; if the symptoms persist, treatment should be discontinued.Intrathecal administration of drugs may be associated with meningitis as a result of infection. There have also been reports of hydrocephalus, probably due to arachnoiditis. Stopping or reducing cerebrospinal fluid flow may lead to increased concentrations of free cytarabine in the cerebrospinal fluid, which increases the risk of neurotoxicity. Therefore, a need to assess cerebrospinal fluid flow should be considered before starting treatment. The systemic effects of intrathecal cytarabine should not be expected, but cytarabine can not be excluded for bone marrow function. Monitoring of the hematopoietic system is recommended. Because the drug molecules have a similar size and appearance as white blood cells, caution should be exercised when interpreting the results of cerebrospinal fluid analysis after drug administration. It is not recommended for children and adolescents, as the safety and efficacy in children have not been adequately proven.

Cytarabine administered systemically during pregnancy, mainly in the first trimester, can damage the fetus. However, since systemic exposure to cytarabine following intrathecal administration is negligible, fetal failure concerns are unjustified. Although the risk seems low, women of childbearing age should not be treated until the likelihood of pregnancy is ruled out and effective contraception is not implemented. Since cytarabine is a drug with mutagenic properties and can damage chromosomes in human reproductive cells, men and women taking the drug should use effective contraception. It is not known whether intrathecal cytarabine is excreted in breast milk. Systemic exposure to free cytarabine following intrathecal administration is negligible. Because cytarabine is likely to pass into breast milk and because it can cause serious side effects in breastfed babies, it should not be used during breast-feeding.

Severe toxicity may occur after administration of single and cumulative doses. The highest probability of side effects is within the first 5 days of administration. Adverse reactions occurring in more than 10% of cycles: headache, arachnoiditis, confusion, nausea, vomiting, diarrhea, weakness, fever, fatigue, thrombocytopenia. In addition, irritation of the meninges can be manifested by: back pain, convulsions, neck pain, stiff neck, acquired hydrocephalus, mycocyte pleocytosis, meningitis. There have been reports of: severe central nervous system toxicity, including persistent extreme drowsiness, confusion, hemiplegia, visual disturbances (including blindness), deafness and cranial nerve palsies; periodically increase the protein concentration in the m-r fluid. and the number of white blood cells and the occurrence of symptoms of peripheral nervous system neuropathy, such as pain, numbness, paresthesia, hypoaesthesia, weakness, difficulty in maintaining urine and faeces. A horse tail syndrome was also reported. Intrathecal administration of cytarabine may cause myelopathy and have other neurotoxic effects, sometimes leading to permanent neurological dysfunction. In phase 1-4 trials, seizure frequency was higher in the medication group than in the cytarabine group.

The drug should only be administered under the supervision of a physician experienced in the use of anti-cancer chemotherapeutic drugs. Adults (including the elderly): induction therapy - 2 doses of 50 mg administered every 14 days (weeks 1 and 3); consolidation treatment - 3 doses of 50 mg administered every 14 days (weeks 5, 7 and 9) followed by an additional dose of 50 mg at week 13; maintenance treatment - 4 doses of 50 mg administered every 28 days (week 17, 21, 25 and 29). If neurotoxicity occurs, the dose should be reduced to 25 mg. If symptoms persist, treatment should be discontinued. On the day of administration, all patients should start receiving oral or intravenous 4 mg Dexamethasone twice daily for 5 days.Way of giving. The drug should be administered as a slow infusion over a period of 1-5 minutes directly into the cerebrospinal fluid through the intraventricular reservoir or a direct injection through the spinal tap. After administration in a lumbar puncture, the patient should remain in the prone position for an hour after administration of the drug.