Natrium Salicylicum Biotika

SUMMARY OF PRODUCT CHARACTERISTICS 

1.  NAME OF THE MEDICINAL PRODUCT 

                                NATRIUM SALICYLICUM Biotika

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
Active substance:         Sodium salicylate 1 g in 10 ml.
 
For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM 
Solution for injection 
Fluid clear, colorless or light brown.

4. CLINICAL PARTICULARS
4. 1 Therapeutic indications 
Rheumatic fever, as a palliative medicine in other rheumatic diseases, root syndromes, usually mixed with 1% solution of procaine or mesocaine to extend treatment after discontinuation of glucocorticoids, in dermatology in exsudative erythema multiforme., in erythema nodosum, in acute skin eruptions, in psoriasis (not when treated with iodine) and in some torpid chronic eczema. 
 Do not administer sodium salicylate to children and to adolescents under 16 years during the feverish illness.
 
4.2 Posology and method of administration 
Dosage for adults and adolescents 
Individual, average daily dose is 3-5 g. The best intravenous administration is in infusion.  Rapid administration of undiluted solution may cause irritation of the vascular endothelium. 
 In rheumatic fever the drip infusion is the most appropriate route of administration, the usual dose in adults is up to 17 grams per day. 

4.3 Contraindications 
 Hypersensitivity to salicylates or to any of the excipients, allergic reaction (eg urticaria, bronchospasm, angioedema, asthma development) after previous administration of other nonsteroidal anti-inflammatory drugs.  Severe disturbances of liver function, bleeding conditions, ulcer disease, sodium and water retention, the period before surgery, eg before tonsillectomy. The third trimester of pregnancy. Under the age of 16 years and current febrile illness. When use of preparation containing acetylsalicylic acid in children and in adolescents during a feverish illness , the threat of Rey syndrome development is present.

4.4 Special warnings and precautions for use 
In chronic nephritis and in hyperuricemia, caution is required during administration.Salicylates may cause reversible reduced glomerular filtration in patients with existing kidney disease, but also in individuals with healthy kidneys.  Risk of side effects is increased in patients with hepatic impairment. Due to the sodium content special attention to patients with congestive heart failure should be given.  In people with asthma or nasal polyps ,hypersensitivity reaction with symptoms of bronchoconstriction and shock may arise.  When  acetylsalilcylic acid is administered in children and in adolescents under the age of 16 years during the feverish illness,  the risk of development of very rare, life-threatening Rey syndrome may arise.  Rey syndrome is characterized by noninfectious encephalopathy and by liver failure.  It typically appears when acute symptoms of feverish infectious diseases (varicella, flu-like illness) have resolved.  Clinical manifestations includes profused, protracted vomiting, headache, impaired consciousness. 
 There is evidence that drugs that inhibit cyclooxygenase / prostaglandin synthesis, affect ovulation and therefore could damage female fertility.  Damage is reversible and resolves after discontinuation of therapy. 

4.5 Interactions with other medicinal products and other forms of interaction
It potentiates the effect of anticoagulants, oral antidiabetic agents, barbiturates, phenytoin, and long-acting sulfonamides.  It reduces the effect of indomethacin, naproxen, spironolactone and saluretics. Concomitant administration with phenylbutazone increases urate retention.  Salicylates increase the plama concentration of methotrexate. Concomitant administration of NSAIDs and corticosteroids increases the risk of gastrointestinal bleeding.  Alcohol increases the toxicity of salicylates. 

4.6 Pregnancy and lactation 
 Dose of 100-500 mg / day 
 There is not enough clinical experience in the use of doses of 100-500 mg / day.  Therefore the information mentioned below  is valid for them. 
 Dose of 500mg/day and higher 
 Inhibition of prostaglandin synthesis may have adverse effect on pregnancy and on fetal / embryonic development.  Data from epidemiological studies suggest the increased risk of miscarriage, cardiac malformation and gastroschisis after use of prostaglandin synthesis inhibitors in early pregnancy.  The absolute risk of cardiovascular malformations has increased from less than 1% to about 1.5%.  It is assumed that the risk increases with dose and therapy duration. It has been proved in animals that administration of inhibitors of prostaglandin synthesis leads to an increase in pre-and post-implantation losses and to fetal / embryonic lethality.  Moreover, the increased incidence of various malformations, including cardiovascular after the administration of inhibitors of prostaglandin synthesis during the organogenetic period has been reported in animals.
 During the first and second trimester acetylsalicylic acid may not be administered unless absolutely necessary. 
 When acetylsalicylic acid is administered to women who want to conceive or in first and second trimester of pregnancy, the dose must be as low as possible and duration of treatment as short as possible. 
 During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose 
 fetus to: 
 -Cardiopulmonary toxicity (premature closure of the arterious duct and pulmonary hypertension) 
 -Renal dysfunction, which may progress to renal failure in oligohydroanmion 
 Mother and baby at the end of pregnancy: 
 antiaggregant effect and a potential extension of the bleeding that can occur even in small doses 
 inhibiting uterine contractions leading to a delay or extension of childbirth 
 Salicylates and their metabolites penetrate into breast milk in small amounts. In the short and small doses use in infants no adverse effects have been observed.  If a need of multiple high doses, breastfeeding should be interrupted. 

4.7 Effects on ability to drive and use machines 
No effect on attention. 

4.8 Undesirable effects 
 Increased bleeding. Dyspepsia, nausea, vomitus, erosion, ulceration, gastrointestinal bleeding.  Skin rashes.  Allergic reactions, which may manifest as urticaria, angioedema, bronchospasm, rhinitis, or orthostatic collapse (these types of reactions are more common in asthmatics patients and in patients with nasal polyps).  Due to the high sodium content, heart failure or worsening of existing heart failure may appear.  In children Rey Syndrome might develop. 

4.9. Overdose 
The first symptoms are dizziness, head buzzing and hearing loss.  Other overdose causes nausea, vomiting, sweating, diarrhea, drowsiness, headache, mental change, hallucinations, convulsions and coma.  Acid-base disturbances: respiratory alkalosis, metabolic acidosis and respiratory depression.  Metabolic acidosis is more common in young children, on the contrary in the elderly is the tendency to develop respiratory alkalosis.  Other manifestations of hypoglycaemia (at an early stage), hyperglycemia (in the later stages of intoxication), hypernatraemia, hypokalaemia, hypocalcaemia and blood clotting disorder. 
Treatment: Supportive therapy is pointed at the treatment of metabolic disorders.  It is necessary to correct the acid-base disturbances, disturbances in glycemia, in calcemia and in kalcemia. The appropriate examination shall be done more often, because it can be changed due to the treatment.  In convulsions calcemia and glycemia is necessary to be checked, or administer diazepam or phenobarbital. Excretion of salicylates can be accelerated by  urinary alkalinization or by administration of  bicarbonate infusion.  More effective than forced diuresis is hemodialysis. 

5. PHARMACOLOGICAL PROPERTIES 
5.1 Pharmacodynamic properties 
Pharmacotherapeutic group: Antirheumatic, antiflogistic. 
ATC code: N02BA04
Mechanism of effect 
  Sodium salicylate is a non-steroidal anti-inflammatory drug (NSAD), used in a form of injection.  Salicylates inhibit prostaglandin biosynthesis by irreversible blockade of the enzyme cyclooxygenase (prostaglandin-synthetase).  This enzyme catalyzes the conversion of arachidonic acid to endoperoxides. Except of reducing the production of prostaglandins the salicylates inhibit , depending on a dose, thromboxane A 2 synthesis, which  results in platelet aggregation inhibition. 
Reducing of the synthesis of inflammatory mediators, salicylates inhibit the adherence of granulocytes to the injured blood vessels, stabilise lysosomes and inhibit the migration of polymorphonuclear leukocytes and macrophages to sites of inflammation. 
 The analgesic effect is achieved due to peripheral effect to inflammation symptoms and suppression of painful stimuli in subcortical centers. 

5.2 Pharmacokinetic properties 
 It is passively distributed in the extracellular fluid of all tissues.  Crossing depends on the pH.  The active substance crosses the placenta.  It is metabolised in many tissues to salicyluric acid and glucuronides.  Small amount is oxidized to gentisic acid and digentisic acid  or to trihydroxybenzoic acid precisely. It is excreted in urine (10% as free salicylic acid, 75% as metabolites).  Excretion of fre salicylates is variable, depending on a dose and urinary pH.  In alkaline urine, about 30% of drug is excreted as a free salicylic acid and in acidic urine, only 2%.  The half-life in the low doses is 12 hours.  Efficacy of sodium salicylate is 50% of efficacy of aspirin. 

5.3 Preclinical safety data
The drug is not considered as toxic.  Toxicity is possible only in extreme dosage in some states, but this is hampered by a low volume of the product. 
Experimental results with acetylsalicylic acid have not shown mutagenic or carcinogenic potential of ASA, but in several animal species a teratogenic potential has been prooved.  For the teratogenic effect of sodium salicylate in mice are likely responsible higher doses per kilogram ased in animals, that are not used in humans.

6. PHARMACEUTICAL PARTICULARS 
6.1 List of excipients 
Excipients: lactose theophylline, disodium edetate, water for injection. 
 The sodium concentration: 14.378 mg / ml, which corresponds to 0.626 mmol / l. 

6.2 Incompatibilities 
 None known. 

6.3 Shelf life 
2 years

6.4 Special precautions for storage 
Store at 10-25 ° C.  Keep ampoules in the outer carton to protect from light.

6.5 Nature and contents of container 
Clear glass with a label, insert PVC box
Package size:  10 ampoules of 10 ml

6.6 Special precautions for disposal
Medicinal product subject to medical prescription. 
 Any unused product or waste material should be disposed of in accordance with local requirements. 

7. MARKETING AUTHORISATION HOLDER 
BB Pharma Pod Višňovkou 1662/21, 147 00 Prague 4, Czech Republic
8. MARKETING AUTHORISATION NUMBER(S) 
 29 / 779 / 92-S / C
9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION 
 December 14th, 1992 / Dec. 23rd, 1998
10. DATE OF REVISION OF THE TEXT
April 12th, 2006