Manual Xavron

INSTRUCTIONS
for use of the medicinal product XAVRON

Composition:
active substance: edaravone;
1 ml of solution contains 1.5 mg of edaravone;
excipients: sodium metabisulfite (E 223), sodium chloride, sodium hydroxide, phosphoric acid, water for injection.

Pharmaceutical form. Solution for injection.
Basic physical and chemical properties: clear, colorless or slightly yellowish solution.

Pharmacotherapeutic group. Other drugs for the treatment of the central nervous system diseases. ATC code: N07 XX.

Pharmacological properties.
Pharmacodynamics.
Free radicals, such as hydroxyl radicals (OH), are one of the main factors of vascular disorders in the brain associated with ischemia; in ischemia or hemorrhage, at the time of patency restoration through an abnormal increase in arachidonic acid production, the number of free radicals produced increases. These free radicals peroxidize unsaturated fatty acid of cell membrane lipids, which leads to cell membrane injury and ultimately to cerebral dysfunction.

This product protects the brain in case of acute ischaemic stroke by exerting its inhibitory effects against the development and progression (exacerbation) of ischaemic cerebral vascular disorder such as cerebral oedema, neurological deficits, and delayed neuronal death.

The etiology of development and progress of amyotrophic lateral sclerosis (ALS) is unknown. However, a possible involvement of oxidative stress caused by free radicals is suggested. Edaravon, due to its inhibitory effect on lipid peroxidation by binding free radicals, demonstrates inhibition of the disease progression by reducing oxidative damage to brain cells (vascular endothelial cells/nerve cells).

Pharmacokinetics.
Pharmacokinetics of the medicinal product was studied in five healthy male volunteers and five elderly healthy male volunteers in 30 minutes after multiple intravenous dosing (0.5 mg/kg) twice a day for 2 days. The plasma unchanged drug concentration decreased in both groups in the almost same way without any signs of accumulation.

Pharmacokinetic parameters
Healthy male volunteers (n = 5)
Elderly healthy male volunteers (n = 5)
С max (нг/мл)
888±171
1041±106
t ½ α (г)
0,27±0,11
0,17±0,03
t ½ β (г)
2,27±0,80
1,84±0,17

The binding rates of edaravone to human serum protein and human serum albumin were 92 % and 89-91 %, respectively (in vitro).

The major metabolite was sulfate conjugate in plasma, and glucuronide conjugate was also detected in plasma. Glucuronides and, to a lesser extent, sulfates were mainly detected in the urine.

12 hours after injection, 0.7–0.9% of the medicinal product is excreted in the urine unchanged, and 71.0–79.9% in the form of metabolites.

Clinical particulars.
Indications.
Relief of neurological symptoms, manifested disorders of activities of daily living and functional disorders associated with acute ischemic stroke.
Inhibition of progression of functional disorder in patients with amyotrophic lateral sclerosis.

Contraindications.
Severe renal failure.
Hypersensitivity to the components of the product.

Interaction with other medicinal products and other forms of interactions.
The patients should be carefully monitored and renal function tests should be performed frequently in the concomitant use of the antibiotics with renal excretion (cefazolin sodium, cefotiam hydrochloride, piperacillin sodium, etc.), since renal impairment may be aggravated.
Before injection Xavron should be dissolved in 100 ml of physiological saline solution. Mixing the product with other intravenous solutions containing various sugars may result in decreased concentration of edaravone.
The product should not be mixed with solutions for parenteral nutrition and/or solutions containing amino acids, and administered through the same infusion system.
The product should not be mixed with anticonvulsants, including diazepam, sodium phenytoin, etc., because of the possibility of turbidity formation. Do not mix with potassium canrenoate.

Special warnings and precautions for use.
The product should be used under the close supervision of physicians experienced in the use of this medicinal product.
During therapy, there may be deterioration in acute renal failure or impaired renal function, severe hepatic dysfunction and/or disseminated intravascular clotting (DIC), which may result in lethal outcome.
The efficacy and safety of this product in patients with ALS severity classification of grade 4 or above and patients with forced vital capacity less than 70% of theoretical normal value have not been established, since there is little clinical experience in such patients. Careful decision about prescription of Xavron to such patients should be based on the risk and benefit assessment.
Cases of recurrence of cerebral embolism or cerebral hemorrhage during or after administration of the product have been reported.
Laboratory tests for renal function and platelet count, blood urea nitrogen (BUN), creatinine, AST, ALT, LDH, CK, red blood cell count should be performed before the therapy.
During the administration of edaravone, tests for renal, hepatic function and blood cell counts should be performed, and if abnormal changes in test results or oliguria are detected, the product should be immediately discontinued and appropriate measures should be taken. In addition, careful monitoring of the patient’s condition after the end of injections should be continued.
Patients with amyotrophic lateral sclerosis (ALS) progression may likely show decreased serum creatinine due to muscular atrophy; therefore, time course of serum creatinine level should be monitored to detect deteriorating tendency, instead of comparing serum creatinine value at single point in time with the reference value.
In addition, since BUN level may fluctuate according to water amount in the body, time course of BUN level should be monitored to detect deteriorating tendency, instead of comparing BUN value at single point in time with the reference value.
In patients with muscle atrophy, renal function evaluation not affected by muscle mass should be performed before and during injection, such as estimated glomerular filtration rate (eGFR) based on serum cystatin C level, calculation of creatinine clearance by urine collection, in addition to measurement of serum creatinine and BUN.
If renal dysfunction occurs during injection, the product should be discontinued immediately and appropriate measures should be taken in cooperation with physicians who have sufficient knowledge and experience in the treatment of renal dysfunction.
If complications, such as infection, occurred during injection and the need for concurrent administration of antibiotics arouse, carefully consider the need to continue the product injections, and if injections are continued, laboratory parameters should be carefully monitored. In addition, even after the end of the product injection, the patient’s condition should be carefully checked and monitored (see section “Interaction with other medicinal products and other forms of interactions” for details).
Since fever, cough, shortness of breath and acute lung dysfunction may occur during treatment with the product, accompanied by abnormal chest X-rays results, the patient should be carefully monitored, and if such symptoms appear, the product should be discontinued and appropriate measures taken, such as administration of adrenal corticosteroids.
The elderly patients should be monitored carefully, since many fatal outcomes have been reported in these patients.

Xavron should be carefully administered to the following categories of patients:

  • with impaired renal function and/or dehydration due to a high risk of acute renal failure;
  • with infection (renal failure may be aggravated due to deterioration of the general condition of the patient);
  • with hepatic dysfunction (possible aggravation of hepatic failure);
  • with heart diseases (possible disease aggravation as well as development of renal failure);
  • with severe disturbance of consciousness (patients do not respond to external stimulation);
  • elderly patients (reported deaths in this category of patients).

Pregnancy and breastfeeding.
The safety of the product in pregnant women has not been established. It is preferable to avoid the use of the product during pregnancy.
Lactation should be avoided during administration of this product as the product is excreted in breast milk.

Effects on ability to drive and use machinery.
The product is intended for use in a hospital, therefore, such data are not available.

Posology and method of administration.
Neurological symptoms associated with acute ischemic stroke, manifested disorders of activities of daily living, relief of various kinds of dysfunction: 30 mg edaravone (1 ampoule) twice a day, in the morning and in the evening, administered as an intravenous infusion over 30 minutes. Before administration, the contents of an ampoule should be dissolved in 100 ml of sodium chloride 0.9 %. Therapy should be initiated within 24 hours after the onset of symptoms, the duration of treatment is not less than 14 days.

Inhibitory effect on the progression of dysfunction in amyotrophic lateral sclerosis (ALS): 60 mg edaravone (2 ampoules) administered as an intravenous infusion over 60 minutes, once daily. Before administration, the contents of an ampoule should be dissolved in a sufficient amount of sodium chloride 0.9 %. Usually, the duration of administration and cessation of this product are combined in one cycle of treatment for 28 days and the cycle should be repeated. This product is consecutively infused for 14 days in the duration of administration followed by cessation for 14 days in the 1st cycle, and from the 2nd cycle, this product is infused for 10 of 14 days in the duration of administration followed by cessation for 14 days.

In patients with acute ischemic stroke, the duration of therapy may be reduced depending on the clinical condition of the patient.

Elderly patients.
Since elderly patients often have reduced physiological function, this product should be discontinued and appropriate therapeutic measures taken when any adverse reactions are found. Many cases of death in elderly patients have been published, therefore, such patients should be monitored carefully.

Pediatric population.
Safety of this product in pediatric patients has not been established.
Acute ischaemic stroke: little clinical experience; ALS: no clinical experience in children.

Overdose.
Cases of overdose are not described.

Adverse reactions.
Urinary system disorders: acute renal failure, nephrotic syndrome.
Skin disorders: rash, redness, swelling, itching, erythema.
Hepatobiliary disorders: hepatic dysfunction, hepatic failure, fulminant hepatitis, jaundice.
Nervous system disorders: insomnia, headache.
Cardiovascular disorders: increased blood pressure.
Blood disorders: agranulocytosis, DIC syndrome, decreased red blood cell count, leukocytosis, leukopenia, decreased hematocrit, decreased hemoglobin, thrombocytosis, thrombocytopenia.
Respiratory disorders: acute lung injury syndrome with pyrexia, cough, dyspnoea, chest X-ray abnormalities.
Gastrointestinal disorders: nausea, vomiting.
Musculoskeletal disorders: rhabdomyolysis.
Immune system disorders: shock, anaphylaxis (urticaria, lower blood pressure, shortness of breath, etc.).
Changes in laboratory findings: increased ALT, AST, LDH, ɣ-glutamyltranspeptidase, ALP, bilirubin, creatinine, uric acid in serum, glucosuria, hematuria, proteinuria.
Changes at the injection site: redness at the injection site, swelling at the injection site.
General disorders: hyperthermia.

Shelf life. 2 years.

Storage conditions.
Store in the original package at temperatures below 25°C.
Keep out of reach of children.

Incompatibility.
Do not mix with other drugs, except for the drugs specified in the section “Posology and method of administration”.

 Packaging.
20 ml in glass ampoules;
2 ampoules in a blister; 1 blister in a carton box;
5 ampoules in a blister; 1 blister in a carton box;
5 ampoules in a blister; 2 blisters in a carton box.

 Prescription status. Prescription drug.

 Manufacturer.
Yuria-Pharm LLC.

 Manufacturer’s location and business address.
Ukraine, 18030, Cherkaska region, the city of Cherkasy, 108, Verbovetskoho Street. Tel. (044) 281-01-01.