Safotsid

Сафоцид Drug photo

The description is actual on 01.04.2016

  • Latin name: Safocid
  • ATH code: J01FA10
  • Active ingredient: Azithromycin + Seknidazol + Flukonazol
  • Producer: Lyka Labs (India)

Structure

1 tablet includes 1000 mg of azithromycin.

In addition: 2 mg of colloid silicon of dioxide, 12 mg of sodium lauryl sulfate; 37,24 mg of croscarmellose sodium; 40 mg of K30 povidone; 16 mg of magnesium stearate.

Cover: 24,5 mg of a gipromelloza; 6 mg of titanium dioxide; 3,8 mg of diethyl phthalate; 5,2 mg of talc; 4,2 mg of a macrogoal 4000; 1,06 mg of crimson dye (Ponso 4R).

1 tablet includes 150 mg of a flukonazol.

In addition: 153 mg of microcrystallic cellulose; 14,5 mg of calcium hydrophosphate; 5 mg of croscarmellose sodium; 4 mg of magnesium stearate; 1 mg of colloid silicon of dioxide; 2,5 mg of crimson dye (Ponso 4R).

1 tablet includes 1000 mg of a seknidazol.

In addition: 6 mg of colloid silicon of dioxide; 95 mg of corn starch; 130 mg of microcrystallic cellulose; 20 mg of carboxymethylstarch of sodium; 2,5 mg of povidone (PVPK-30); 10 mg of magnesium stearate; 11,5 mg of talc.

Cover: 27,1 mg of a gipromelloza; 5,7 mg of talc; 4 mg of diethyl phthalate; 11,2 mg of titanium dioxide; 4,6 mg of a macrogoal 4000.

Release form

The remedy Safotsid is made in the form of a set of 4 tablets (azithromycin No. 1; flukonazol No. 1; seknidazol No. 2) in the blisters No. 1 or No. 3 placed in a cardboard pack.

Pharmacological action

Antiprotozoan, antimicrobic, antifungal.

Pharmacodynamics and pharmacokinetics

Safotsid is the set of the tableted dosage forms including an antibiotic azithromycin, antifungal means flukonazol and antiprotozoan means seknidazol from what tablets at their concomitant use possess very extensive, directed to destruction of various microorganisms, an action spectrum.

Azithromycin

Antibacterial drug the azalead which is characterized quite extensive bacteriostatic (in therapeutic doses) and bactericidal (in high concentration) the range of overwhelming action directed to elimination of both intracellular, and vneshnekletochny activators. Efficiency of drug is shown thanks to its ability to communicate with 50S in subunit of ribosomes owing to what there is a suppression of a stage of broadcast of a peptidtranslokaza, oppression of proteinaceous synthesis, braking of a reproduction and growth of bacteria.

The range of microorganisms sensitive to influence of azithromycin mentions: gram-positive aerobes (metitsillinchuvstvitelny strains of Staphylococcus aureus penitsillinchuvstvitelny strains of Streptococcus pneumoniae, and also Streptococcus pyogenes); gram-negative aerobes (Pasteurella multocida, Haemophilus influenzae, Neisseria gonorrhoeae, Legionella pneumophila, Haemophilus parainfluenzae, Moraxella catarrhalis); anaerobe bacterias (Porphyromonas spp., Clostridium perfringens, Prevotella spp., Fusobacterium spp.); other microorganisms (Borrelia burgdorferi, Chlamydia trachomatis, Mycoplasma hominis, Chlamydia pneumoniae, Mycoplasma pneumoniae, Chlamydia psittaci, Mycoplasma hominis).

The acquired resistance to azithromycin is observed at gram-positive aerobes: penitsillinrezistentny strains of Streptococcus pneumoniae, and also strains possessing average sensitivity to penicillin influence.

Natural resistance to azithromycin is noted at gram-positive aerobes: Enterococcus faecalis, metitsillinrezistentny strains of Staphylococcus epidermidis, metitsillinrezistentny strains of Staphylococcus aureus, and also at anaerobe bacterias: Bacteroides fragilis.

There are data on the cross resistance developing between Enterococcus faecalis, Streptococcus pyogenes, Streptococcus pneumoniae and Staphylococcus aureus together with its metitsillinrezistentny strains to azithromycin, erythromycin, linkozamida and macroleads.

Thanks to the lipophilicity and stability in acid medium azithromycin is quickly enough soaked up from bodies of a gastrointestinal tract. After one-time oral administration of 500 mg of drug its bioavailability equals 37% (owing to "the first passing" through a liver), Tmax varies within 2,5-2,9 hours, and Cmax makes 0,4 mg/l.

Concentration of azithromycin in cells and fabrics at 10-50 times exceeds its serumal contents. Vd is at the level of 31,1 l/kg. Drug with ease passes gistogematichesky barriers, is characterized by good penetration into respiratory tracts, a prostate, urinogenital fabrics and bodies, soft tissues and integuments. Accumulation of azithromycin in the environment with a low rn, and also in lysosomes is observed (this feature is important for an eradikation of the disease-producing activators located in intracellular space).

Transport of azithromycin is carried out by phagocytes, macrophages and polymorphonuclear leukocytes (without exerting significant impact on their functionality). Azithromycin gets through cellular membranes and creates in them high concentration. Content of drug in the infectious centers is reliable above (on average, for 24-34%) rather healthy fabrics and is connected with weight of puffiness. In the inflammation center effective concentration of azithromycin remains for 5-7 days after the end of its reception. Communication with plasma proteins fluctuates in borders of 7-50% (it is inversely proportional to drug level in blood).

Azithromycin demetilirutsya in a liver with allocation of inactive products of the metabolism. The plasma clearance equals 630 ml/min. Excretion from serum is carried out in 2 stages. In the beginning – in the range of time of 8-24 hours after reception with T1/2 around 14-20 hours, after – in the range of time of 24-72 hours with T1/2 about 41 hour. Removal of azithromycin happens to bile in not changed form (about 50%) and to urine (about 6%).

Parallel meal influences pharmacokinetics of orally accepted azithromycin, increasing its Cmax by 31%, but not changing AUC indicator. At men at advanced age (65-85 years) of deviations in pharmacokinetic parameters it is not observed, at women increase of Cmax is noted (for 30-50%).

Flukonazol

The antimycotic (antifungal means) differing in the high-specific influence directed to suppression of enzymatic activity of the mushroom strains dependent on functionality of their system of P450 cytochrome. Action of a flukonazol blocks transformation of a lanosterol to ergosterol in cells of mushrooms, increases membrane cellular permeability, breaks replication and development of the most mushroom cell. Flukonazol, being high-selective concerning P450 cytochrome of a mushroom cell, this fermental complex in a human body, in comparison with Ketokonazol, Tstrakonazol, Ekonazol and Clotrimazolum actually does not oppress, and also in a smaller measure suppresses the oxidizing processes subordinated to P450 cytochrome in microsomes of a human liver. Does not show anti-androgenic activity.

Flukonazol is effective at treatment of opportunistic mycoses, including formed under the influence of Candida spp. (including, the generalized candidosis forms which developed against an immunosuppression); Coccidioides immitis and Cryptococcus neoformans (including, intracranial forms); Trichophyton spp. and Microsporum spp.; Blastomyces dermatidis causing local mycoses; Histoplasma capsulation (including, in the presence of an immunosuppression).

Flukonazol possesses high extent of absorption and bioavailability at the level of 90%. The combined oral administration of drug with food does not influence its absorption. After internal reception of 150 mg of a flukonazol on an empty stomach its Tmax varies within 0,5-1,5 hours, and plasma Cmax equals 90% in comparison with this indicator observed at in introduction of a similar dose.

flukonazol contacts plasma proteins for 11-12%. Serumal concentration of drug dozozavisimy. Flukonazol is characterized by good penetration into all biological liquids of a human body. Content of active ingredient in peritoneal liquid, breast milk, saliva, joint liquid and a phlegm corresponds to plasma indicators. At fungal meningitis in cerebrospinal fluid the concentration of drug making about 85% of its plasma level are found. In epidermis, stalemate liquid and a corneous layer the maintenance of a flukonazol exceeds serumal. Observed Vd is similar to the cumulative content of water in a human body.

T1/2 of drug of about 30 hours. Flukonazol inhibits a hepatic isoenzyme of CYP2C9. It is excreted by the most part kidneys (80% — in not changed form, 11% — in the form of metabolism products). The clearance corresponds to clearance of creatinine.

Pharmacokinetic parameters of a flukonazol in many respects depend on renal functionality, at the same time inverse relation among T1/2 and KK is noted. When holding a 3-hour session of a hemodialysis plasma concentration of a flukonazol goes down twice.

Seknidazol

The bactericidal germicide which is to synthetic derivatives of a nitroimidazole. Interacting with DNA of cells of microorganisms, provokes a rupture of threads of DNA and disturbance of its helical structure, suppresses processes of production of nucleic acids, thereby leading to death of a microbic cell. Is the reason of a sensitization to alcohol (has teturamopodobny effects).

It is pernicious for strict anaerobes, both spore-forming, and asporous, and also for some causative agents of protozoan infections: Entamoeba histolytica, Giardia lamblia, Trichomonas spp. Does not show activity in relation to aerobes.

Seknidazol differs in high absorption and bioavailability about 80%. At single oral administration of 2000 mg of drug of its Tmax makes 4 hours. Seknidazol gets through a placental barrier and it is found in milk of the nursing mother.

Metabolic transformations happen in a liver. Removal is carried out with urine for 72 hours (about 16% of a dose).

Indications to use

Safotsid is shown to appointment at the combined infections of urinogenital system (sexually transmitted infections), sexually transmitted:

Contraindications

Before accepting Safotsid, it is necessary to be convinced of absence at the patient of the absolute contraindications to his appointment including:

  • parallel reception of Erythromycin, Digidroergotamina, Astemizola, Pimozidum, Tsizaprid, Quinidine, Ergotamine;
  • organic pathologies of TsNS;
  • pregnancy;
  • the combined reception of the other drugs increasing a QT-interval;
  • heavy insufficiency of hepatic function;
  • blood diseases (including observed in the anamnesis);
  • feeding by a breast;
  • insufficiency of renal function (KK is less than 40 ml/min.);
  • high personal sensitivity to any of active and/or additional ingredients of each of tablets, and also to macroleads, azolny connections, nitroimidazoles;
  • age till 18 years.

The below-stated situations are connected with risk of formation of the negative phenomena or complications in case of combined use of drug with them Safotsid for what it is appointed with extra care at:

  • parallel treatment by Rifabutin or the other remedies which are metabolized thanks to system of P450 cytochrome;
  • potentially proaritmogenny painful states at patients with numerous risk factors (disturbances of balance of electrolytes, organic heart diseases);
  • the combined reception with Terfenadin, Digoxin, Warfarin;
  • carrying out therapy by the drugs increasing a QT interval (IA and the III class of antiarrhytmic drugs);
  • pathologies of function of livers/kidneys of moderate weight;
  • arrhythmias (possibility of ventricular arrhythmias and increase in a QT interval);
  • myasthenias.

Side effects

Azithromycin

Reproductive system:

  • vaginitis;
  • vaginal candidiasis.

Alimentary system:

  • fulminantny hepatitis;
  • meteorism;
  • liver dysfunction;
  • nausea/vomiting;
  • cholestatic jaundice;
  • lock/diarrhea;
  • color changes of language;
  • abdominal pain;
  • pancreatitis;
  • loss of appetite;
  • increase of level of bilirubin;
  • gastritis;
  • pseudomembranous colitis;
  • hepatitis;
  • digestive disturbance;
  • melena;
  • increase in activity of transaminases of a liver;
  • liver failure;
  • candidiasis mucous oral cavity;
  • liver necrosis (with potentially death).

Hemopoietic system:

  • lymphopenia;
  • neutropenia;
  • leukopenia;
  • thrombocytopenia;
  • neutrophilia;
  • hemolitic anemia.

Urinary system:

  • acute insufficiency of renal function;
  • intersticial nephrite;
  • increase of plasma levels of urea and creatinine.

Nervous system:

Cardiovascular system:

  • increase in a QT interval;
  • heart consciousness;
  • ventricular bidirectional tachycardia;
  • stethalgias;
  • arrhythmia;
  • ventricular tachycardia;
  • decrease in the ABP.

Sense bodys:

  • disturbance flavoring and olfactory perception;
  • sonitus;
  • disturbance of acoustical function up to deafness (reversible).

Allergic manifestations:

Others:

  • adynamy;
  • change of level of potassium;
  • photosensitization;
  • indisposition;
  • conjunctivitis;
  • peripheral hypostases;
  • visual acuity disturbance;
  • myasthenia;
  • eosinophilia;
  • arthralgia.

Flukonazol

Nervous system:

Alimentary system:

  • dryness mucous oral cavity;
  • abdominal pain;
  • dispepsichesky phenomena;
  • diarrhea;
  • taste change;
  • meteorism;
  • nausea/vomiting;
  • disturbances of hepatic function (hyperbilirubinemia, jaundice, increase in level of an alkaline phosphatase, hepatitis, increase of activity of enzymes of a liver, cholestasia, hepatocellular necrosis) with potentially lethal outcome.

Cardiovascular system:

  • trembling/ventricular fibrillation;
  • increase in a QT interval;
  • ventricular tachycardia.

Hemopoietic system:

  • leukopenia;
  • agranulocytosis;
  • neutropenia;
  • thrombocytopenia.

Allergic manifestations:

Others:

  • hypercholesterolemia;
  • disturbances of renal function;
  • fever;
  • alopecia;
  • weakness;
  • gipertriglitseridemiya;
  • adynamy;
  • hypopotassemia;
  • hyperhidrosis;
  • mialgiya.

Seknidazol

Hemopoietic system:

  • leukopenia.

Alimentary system:

  • glossitis;
  • nausea/vomiting;
  • metal smack;
  • abdominal pain;
  • stomatitis.

Nervous system:

Allergic manifestations:

  • small tortoiseshell.

Application instruction of Safotsid

All tableted drug set (all 3 tablets: azithromycin; flukonazol; seknidazol) it is necessary to accept orally (inside) once.

The application instruction of Safotsid assumes a single dose of all of the drugs included in it taking into account meal time. Because of influence of parallel meal on azithromycin absorption, the tableted set recommend to accept in 60 minutes prior to food or after 120 minutes after it.

Overdose

Overdose episodes when passing treatment with use of the tableted set Safotsid are not described. At accidental reception of the dosages of drug exceeding recommended the patient needs to ask for the qualified help immediately.

Azithromycin

The negative symptomatology of overdose is considered azithromycin: nausea/vomiting, the passing hearing loss, diarrhea.

These manifestations are subject to the symptomatic treatment including reception of sorbents and control over the vital functions of an organism.

Flukonazol

Characteristic symptoms of reception of overdoses of a flukonazol are: paranoid behavior and hallucinations.

In this case symptomatic therapy with cleaning of a gastrointestinal tract and an artificial diuresis is also shown. Holding a 3-hour session of a hemodialysis reduces plasma concentration of a flukonazol approximately twice.

Seknidazol

At suspicion on overdose seknidazoly, in turn, recommend to carry out the symptomatic and supporting treatment with cleaning of a gastrointestinal tract and reception of sorbents.

Interaction

Azithromycin

Parallel meal, magniysoderzhashchy and aluminum-bearing antiacid means, and also ethanol promotes decrease and delay of absorption of azithromycin.

In case of the combined use of Warfarin and Azithromycin (in therapeutic dosages) deviations of a prothrombin time were not revealed. However, in view of possible increase in anti-coagulative effect at interaction of Warfarin and macroleads, at the patients taking such complex of medicine it is necessary to watch an indicator of a prothrombin time constantly.

At combined use significant influence of azithromycin on serumal concentration in Rifabutin's blood, Carbamazepine, Methylprednisolonum, Cimetidinum, Atorvastatin, Trimethoprimum/sulfamethoxazole, Didanozin, Sildenafila, Efavirenz, Tsetirizin is not revealed. It is the antiallergic (antihistaminic) drug II of generation possessing quick start of action and its big duration. Use of drug is justified in cases when prolonged treatment of allergic diseases is necessary: chronic small tortoiseshell, year-round rhinitis, Flukonazola, Triazolam, Indinavir, Theophylline, Midazolam.

The combined purpose of azithromycin and Terfenadin demands care as simultaneous use of Terfenadin with various antibiotics led to developing of arrhythmia and increase in a QT interval. Relying on these supervision, it is impossible to exclude emergence of the above-stated negative complications when carrying out complex therapy with use of azithromycin and Terfenadin.

Joint treatment by Ergotamine or Digidroergotamin can strengthen toxic actions (including a dizesteziya and a vasospasm).

Medicines from group of macroleads increase plasma concentration, slow down removal and increase Felodipin's toxicity, indirect anticoagulants, Cycloserinum, Methylprednisolonum, and also drugs undergoing a microsomal oxidation (peroral hypoglycemic HP, Carbamazepine, Phenytoinum, Terfenadin, Bromocriptinum, Cyclosporine, ergot alkaloids, Hexobarbital, Valproic acid, Disopyramidum). However in case of a combination of the above-stated drugs with azaleads (including azithromycin) such negative interaction was not observed.

Chloramphenicol and Tetracycline strengthen, and linkozamida reduce efficiency of azithromycin.

Parallel reception of azithromycin and Digoxin demands a constant control of plasma contents of the last because many macroleads increase intestinal absorption of digoxin, thereby increasing its serumal concentration.

In case of need the combined use of Cyclosporine recommend to trace its plasma level, because of substantial increase of AUC.

At combined use of azithromycin and the Zidovudine changes of pharmacokinetic parameters of the last in a blood plasma, and also renal excretion of the drug and its glyukuronirovanny metabolite are not observed. However in monocytes increase in concentration of a fosforilirovanny zidovudine (an active metabolite) is noted. At the moment clinical value of this fact is not found out.

Simultaneous therapy using Nelfinavir can lead to increase of serumal content of azithromycin which is not followed by significant strengthening of by-effects and does not demand correction of the dosing mode.

Flukonazol

In case of simultaneous treatment with Astemizol lowering of its clearance and increase in plasma concentration is possible that can lead to lengthening of a QT interval and developing of ventricular tachycardia.

At the combined use of a flukonazol and Pimozidum the inhibition of metabolic transformations of the last can be observed. Increase in serumal maintenance of Pimozidum can provoke lengthening of a QT interval and development of ventricular tachycardia.

Parallel therapy using a flukonazol and Quinidine can lead to inhibition of a metabolism of the last. Carrying out treatment by quinidine is associated with increase in a QT interval and rare episodes of developing of ventricular tachycardia.

At a combination with erythromycin increase of risk of forming of cardiotoxicity (including lengthening of a QT interval and development of ventricular tachycardia) with a possible sudden cardiac standstill is noted.

Joint reception of a flukonazol and Tsizaprid sometimes led to heavy disturbances of cordial function, including episodes paroxysms of ventricular tachycardia. In case of concomitant daily use of 200 mg of a flukonazol and 80 mg (in 4 receptions a day) Tsizaprida essential increase of plasma concentration of Tsizaprid and increase in a QT interval was observed.

At parallel use of a flukonazol with benzodiazepines of short action were noted: increase of content of Midazolam after its oral administration that can lead to increase in risk of the psychomotor phenomena; increase of T1/2 and AUC of Triazolam after his oral administration owing to what there can be an increase of its efficiency and duration of action. For this reason carrying out simultaneous treatment flukonazoly and benzodiazepines of short action can demand correction of dosages of the last (towards their decrease) and careful control over the general condition of the patient.

Effects of Rifampicin increase a metabolism of a flukonazol that leads to lowering of its plasma concentration for 25% and to reduction of T1/2 by 20% and can demand review of dosages of a flukonazol (towards their increase).

Flukonazol is capable to increase plasma keeping of Takrolimus accepted inside, because of inhibition an isoenzyme of CYP3A4 of an intestinal metabolism of the last. At in introduction of a takrolimus of significant changes of its pharmacokinetics did not arise. High serumal levels of a takrolimus increase risk of nephrotoxic effects. In case of such combination of drugs it is necessary to control plasma concentration of a takrolimus and at need to adjust its dosages.

Flukonazol can raise zidovudine AUC for 74% and its Cmax for 84%, owing to reduction of clearance of this drug approximately for 45%. In this regard the risk of forming of collateral manifestations of a zidovudine increases that demands careful supervision over patients regarding development of such negative states and their timely stopping.

Purpose of some azoles in a combination with Terfenadin were associated with forming of heavy disturbances of a cordial rhythm, including strengthening of ventricular tachycardia because of increase in a QT interval. The conducted researches of interactions of a flukonazol showed that its reception in a daily dose to 200 mg inclusive did not lead to lengthening of a QT interval. Reception of dosages of a flukonazol of 400 mg or 800 mg became the reason of significant increase of plasma level of a terfenadin, in communication than it is contraindicated to combine Terfenadin and flukonazol (in a daily dose more than 400 mg). At parallel reception of a terfenadin and daily dosages of a flukonazol less than 400 mg it is necessary to watch a condition of the patient carefully.

The combined reception of a hydrochlorothiazide increases serumal concentration of a flukonazol by 40%, however with the improbable clinical importance.

Flukonazol can increase plasma concentration and T1/2 of the hypoglycemic medical drugs for oral administration relating to sulfonilmochevina derivatives (Tolbutamidum, Chlorproramidum, Glipizid, Glibenclamidum). At a combination of these medicines it is necessary to investigate periodically the patient's blood on concentration of glucose (risk of a hypoglycemia) and, in case of need, to adjust dosages of peroral hypoglycemic HP.

At purpose of a flukonazol during therapy by Coumarin derivatives (including warfarin) noted increase of a prothrombin time in this connection simultaneous treatment by such set of drugs demands careful tracking of a prothrombin time.

Combined use of a flukonazol and Rifabutin can become the reason of increase in serumal contents of the last (at such combination uveitis cases were sometimes observed).

Action of a flukonazol leads to lowering of clearance of Theophylline and increase in its plasma concentration. The patients receiving high doses of theophylline or patients with high probability of developing of teofillinovy intoxication, are obliged to be under continuous medical supervision for early identification of symptomatology of overdose by theophylline and its timely prevention.

Reception of a flukonazol significantly increases the serumal level of Phenytoinum that at parallel reception of these drugs demands tracking of this indicator and, if necessary, carrying out correction of doses of Phenytoinum.

Flukonazol increases AUC Cyclosporine. Co-administration of 200 mg of a flukonazol and 2,7 mg/kg of Cyclosporine a day to patients with the transplanted kidney led to increase of AUC cyclosporine by 1,8 times.

The combined use of oral contraceptives and 50 mg of a flukonazol did not lead at 24 o'clock to significant changes of serumal content of Levonorgestrel and Ethinylestradiol. Reception of 200 mg of a flukonazol a day raised AUC Levonorgestrel for 24%, and Ethinylestradiol for 40%. In this regard influence of a flukonazol on efficiency of the combined oral contraceptives is not expected.

Seknidazol

Seknidazol increases hypoglycemic efficiency in parallel of the accepted peroral hypoglycemic drugs and insulin.

The combined use with indirect anticoagulants strengthens their action.

It is not recommended to combine seknidazol with not depolarizing muscle relaxants (including a vekuroniya bromide).

Joint purpose of a seknidazol with drugs of lithium leads to increase of plasma concentration of lithium.

Seknidazol, similar to Disulfiramum, possesses the action causing intolerance of ethanol.

Terms of sale

Safotsid treats the prescription list of medical drugs.

Storage conditions

The maximum temperature indicator of storage of the tableted set is equal to 30 °C.

Period of validity

3 years from the moment of production.

Special instructions

In case of need parallel use of antiacid drugs, it is necessary to appoint them in 120 minutes prior to azithromycin reception.

Seknidazol can lead to an immobilization of treponemas that can become the reason of a false positive test result of Nelson – RIPT (reaction of an immobilization of pale treponemas).

Safotsid's analogs

Safotsid's analogs are provided by the following medical drugs:

Zdravzona

  • Safotsid set No. 4 tabletkiskopinsky pharmaceutical plant of closed joint stock company
  • Safotsid set No. 12 tabletkikhemofarm A.D. (SERBIA)

Drugstore of IFC

  • Safotsid tbl set No. 12, Lyka Labsindiya
  • Safotsid tbl set No. 4, Ooorossiya's Makiz-Pharma
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Section: Antibiotics Antifungal Antimicrobic
in more detail

Education: Graduated from the Vinnytsia national medical university of N. I. Pirogov, pharmaceutical faculty, the higher pharmaceutical education – the specialty "Pharmacist".

Experience: Work in Koneks and Bios-Media pharmacy chains as "Druggist". Work as "Pharmacist" in Avicenna pharmacy chain of the city of Vinnytsia.

PAY ATTENTION! Information on drugs on the website is help generalizing, collected from public sources and can form the basis for making decision on use of medicines it is not aware of treatment. Before medicine use Safotsid surely consult with the attending physician.