Pharmacological properties

Pharmacodynamics. sodium diclofenac — npvp, having the expressed analgeziruyushchy and anti-inflammatory effect. it is prostaglandinsintetaza inhibitor (tsog).

Pharmacokinetics. Absorption. Fast absorption, but more slowly, than at application of tablets with an enterosoluble covering.

After application of suppositories of diclofenac of sodium in a dose of 50 mg the concentration on unit of a dose makes near ⅔ the concentration reached after application of tablets with an enterosoluble covering (1.95±0.8 mkg/ml (1.9 mkg/ml = 5.9 µmol/l)).

Bioavailability. As well as in case of application of oral dosage forms of medicine, AUC makes about a half from the value received at application of a parenteral dose. After repeated use of medicine its pharmacokinetics does not change. Cumulation of medicine is not observed on condition of observance of the recommended doses.

Distribution. Linking of diclofenac with proteins of blood plasma makes 99.7%, mainly with albumine — 99.4%.

Diclofenac gets into synovial fluid where its C _max is reached on 2–4 h later, than in blood plasma. The seeming T _½ makes 3–6 h of synovial fluid. In 2 h after achievement of the C _max in blood plasma the concentration of diclofenac in synovial fluid remains to higher, than in blood plasma, this phenomenon is observed during 12 h

Diclofenac was defined in low concentration (100 ng/ml) in breast milk at one woman. The expected amount of medicine getting into an organism of the baby with breast milk is equivalent to a dose of 0.03 mg/kg/days

Metabolism. Diclofenac is metabolized partially by a glyukuronization of not changed molecule, but mainly — by means of single and repeated hydroxylation and a metoksilirovaniye that leads to formation of several phenolic metabolites most of which part forms conjugates with glucuronic acid. Two of these phenolic metabolites are biologically active, but it is much less, than diclofenac.

Removal. The general system clearance of diclofenac is 263±56 ml/min. (average value ± SV). Final T _½ makes 1–2 h of blood plasma. The half-life period in blood of four metabolites, including two pharmacological active, is also short and is 1–3 h. About 60% of a dose of medicine are removed with urine in the form of conjugates with glucuronic acid of an intact molecule and in the form of metabolites, the majority of which also turns into glyukuronidny conjugates. In not changed look 1% of diclofenac is removed. Other doses of medicine are removed in the form of metabolites with a stake.

Pharmacokinetics at separate groups of patients. Influence of age of the patient on absorption, metabolism and removal of medicine was not noted, except the fact that at 5 patients of advanced age the 15-minute infusion brought to 50% above concentration of medicine in blood plasma, than it was expected at young healthy volunteers.

At the patients with a renal failure receiving therapeutic doses can not expect savings of not changed active agent, proceeding from medicine kinetics after single application. At patients with clearance of creatinine of 10 ml/min. the estimated equilibrium concentration of hydroxylated metabolites in blood plasma were about 4 times higher, than at healthy volunteers. However finally all metabolites were removed with bile.

Patients with an abnormal liver function. At patients with chronic hepatitis or the compensated cirrhosis the indicators of pharmacokinetics, metabolism of diclofenac are similar to that at patients without liver diseases.

Indication

Inflammatory and degenerative forms of rheumatism: a pseudorheumatism, the juvenile pseudorheumatism ankylosing a spondylitis, an osteoarthritis including a spondylarthritis.

Pain syndromes from a backbone.

Rheumatic diseases of extraarticular soft tissues.

Posttraumatic and postoperative pain syndromes which are followed by inflammation and hypostasis, especially after dental and orthopedic operations.

Gynecologic diseases which are followed by a pain syndrome and inflammation, for example primary dysmenorrhea and adnexitis.

migraine Attacks.

Bad attacks of gout.

As supportive application at a serious inflammatory illness of the ENT organs which are followed by painful feeling, for example at a pharyngotonsillitis, otitis.

According to the general therapeutic principles a basic disease should treat means of basic therapy. Fever in itself is not the indication to use of medicine.

Use

Should apply minimum effective dose during the short period, considering problems of treatment at each certain patient.

not to accept

inside, only for rectal administration.

Suppositories needs to be entered into a rectum as it is possible more deeply, it is desirable after purgation.

Initial dose usually makes 100–150 * mg/days. At not expressed symptoms and also at long therapy there is enough dose of 75*-100 mg/days

Daily dose to distribute on 2–3 receptions. In order to avoid night pain or morning constraint before administration of medicament to appoint sodium diclofenac in the form of rectal suppositories before going to bed in the afternoon (the daily dose should not exceed 150 * mg).

At primary dysmenorrhea a daily dose should be selected individually, usually it makes 50–150 * mg/days. The initial dose can be 50*–100 mg/days, but in need of it it is possible to raise during several menstrual cycles to maximum, making 200 mg/days

Use of medicine should be begun with

after emergence of the first painful symptoms and to continue several days, depending on dynamics of regression of symptoms.

a course to begin with

For treatment of attacks of migraine in a dose 100 mg at manifestation of the first signs of the beginning of an attack. In case of need on the same day it is possible to apply the second suppository (100 mg of diclofenac). In case of need in the next days the treatment can be continued (the daily dose should not exceed 150 * mg, to distribute a dose on 2–3 receptions).

* to Apply

in the corresponding dosage.

Patients of advanced age. Though at patients of advanced age the pharmacokinetics of diclofenac of sodium does not worsen to any clinically significant degree, NPVP needs to be applied with care to such patients as they, as a rule, are more inclined to development of undesirable reactions. In particular, the weakened patients of advanced age or patients with low body mass index are recommended to apply the lowest effective doses; also patients need to be examined concerning gastrointestinal bleedings during treatment of NPVP.

Route of administration of suppositories. Suppositories should be entered into a rectum as it is possible more deeply, it is desirable after purgation. Suppositories should not be divided into parts as similar change of a route of administration of medicine can lead to disturbance of distribution of active agent.

Contraindication

Hypersensitivity to active ingredient or any auxiliary component.

Bleeding or perforation of a GIT in the anamnesis connected with the previous treatment of NPVP.

Active form of an ulcer GIT/bleeding or a recurrent ulcer GIT/bleeding in the anamnesis (2 or more separate episodes of the established ulcer or bleeding).

III pregnancy trimester.

Inflammatory bowel diseases (for example Crohn's disease or ulcer colitis).

Liver failure.

Renal failure.

Stagnant heart failure (NYHA II–IV), an ischemic heart disease at patients with stenocardia, the postponed myocardial infarction.

Cerebrovascular diseases at the patients who had a stroke or with episodes of the passing ischemic attacks.

Disease of peripheral arteries.

Proctitis.

sodium Diclofenac, as well as other NPVP, is contraindicated to patients who in response to intake of acetylsalicylic acid or other NPVP have attacks OH, urticaria, a Quincke's disease or sharp rhinitis.

Side effects

from blood and lymphatic system: thrombocytopenia, leukopenia, anemia (hemolytic anemia, aplastic anemia), Agranulocytosis.

from the immune system: hypersensitivity, anaphylactic and anaphylactoid reactions (including hypotension and shock), a Quincke's disease (including a face edema).

Mental violations: disorientation, depression, insomnia, irritability, nightmares, psychotic violations.

from nervous system: headache, dizziness, drowsiness, increased fatigue, paresthesias, weakness, violation of memory, spasm, concern, tremor, aseptic meningitis, violations of taste, stroke, confusion of consciousness, hallucination, violation of sensitivity, general malaise.

from an organ of sight: visual violations, misting of sight, diplopia, optic neuritis.

from an organ of hearing and a labyrinth of an ear: vertigo, a ring in ears, disorders of hearing.

from a cardiovascular system: heartbeat, stethalgia, heart failure, myocardial infarction, AG, arterial hypotension, vasculitis.

from the respiratory system, bodies of a thorax and mediastinum: OH (including an asthma), a bronchospasm, a pneumonitis.

from digestive system: nausea, vomiting, diarrhea, dyspepsia, pain in epigastric area, the meteorism, gastritis, gastrointestinal bleeding, a hematemesis, a melena, hemorrhagic diarrhea, stomach ulcers and intestines which are followed or not followed by bleeding or perforation (sometimes lethal, especially at patients of advanced age), colitis (including hemorrhagic colitis and exacerbation of ulcer colitis or Crohn's disease), ischemic colitis, a lock, stomatitis (including a stomacace), a glossitis, dysfunction of a gullet, a diafragmopodobny intestinal stenosis, pancreatitis.

from a gepatobiliarny system: increase in level of Transaminases, hepatitis, jaundice, abnormal liver function, lightning hepatitis, liver necrosis, liver failure.

from skin and hypodermic cellulose: rash, urticaria, rashes in the form of bubbles, eczema, an erythema, a multiformny erythema, Stephens's syndrome — Johnson, a Lyell's disease (toxic epidermal necrolysis), exfoliative dermatitis, a hair loss, a photosensitization, purple, including allergic, an itch.

from kidneys and an urinary system: OPN, hamaturia, proteinuria, interstitial nephrite, nephrotic syndrome, papillary necrosis of a kidney.

General violations and violations in the injection site: irritation in the injection site, hypostasis, abscess in the place of an injection, exacerbation of hemorrhoids.

from a reproductive system and mammary glands: impotence.

Clinical trials and epidemiological data demonstrate the increased risk of the trombotichesky complications (for example a myocardial infarction or a stroke) connected with use of diclofenac, in particular in high therapeutic doses (150 mg/days) and at prolonged use.

Special instructions

General. to minimize side effects, it is necessary to apply a minimal effective dose during the short period.

Should avoid simultaneous application Diklosafe with system NPVP, such as selection TsOG-2 inhibitors, due to the lack of any proofs of synergy action and communication with potential additive side effects.

care at application for patients aged from 65 years Is necessary for

. In particular, it is recommended to apply the lowest effective dose at the weakened patients of advanced age with low body weight.

In rare instances, as well as at application of other NPVP, allergic reactions, including anaphylactic/anaphylactoid reactions, even without preliminary influence of diclofenac can be noted. Thanks to the pharmakodinamichesky properties the medicine Diklosafe, as well as other NPVP, can mask signs and symptoms of an infection.

Influence on a digestive tract. At application of all NPVP, including diclofenac, cases of gastrointestinal bleedings (vomiting blood, a melena), ulceration or perforation which can be lethal are registered and occur at any time in the course of treatment at existence or lack of precautionary symptoms or the previous anamnesis of the serious phenomena from a GIT. These phenomena usually have more serious consequences at patients of advanced age. If at the patients receiving sodium diclofenac the phenomena of gastrointestinal bleeding or ulceration are noted, use of medicine needs to be stopped.

As well as at application of other NPVP, including diclofenac, for patients with the symptoms demonstrating violations from a digestive tract (GIT) the medical observation and extra care are obligatory for

. The risk of developing of bleeding, ulcer or perforation increases in a GIT with increase in a dose of NPVP, including diclofenac, and at patients with an ulcer in the anamnesis, especially with a complication in the form of bleeding or perforation, and at patients of advanced age.

Patients of advanced age have the increased frequency of undesirable reactions to application of NPVP, especially concerning gastrointestinal bleeding and perforation which can be lethal.

to reduce risk of such toxic impact on a GIT, treatment it is necessary to begin and support by low effective doses.

For such patients and also those who need the combined use of the medicines containing low doses of acetylsalicylic acid (or other medicines which probably increase risk of undesirable impact on a GIT) it is necessary to consider a question of application of combination therapy using protective equipment (for example inhibitors of a proton pomp or mizoprostol). To patients with gastrointestinal toxicity in the anamnesis, especially advanced age, it is necessary to report about any unusual abdominal symptoms (especially bleedings in a GIT). Cautions are also necessary for the patients receiving at the same time medicines which can increase risk of developing of an ulcer or bleeding, such as system corticosteroids, anticoagulants (for example warfarin), antitrombotichesky means (for example acetylsalicylic acid) or selective serotonin reuptake inhibitors.

Influence on a liver. Careful medical observation is necessary if the medicine Diklosafe to appoint to patients with an abnormal liver function as their state can worsen.

As well as at treatment by other NPVP, including diclofenac, the level of one or several liver enzymes can increase. During prolonged use of diclofenac of sodium as a precautionary measure to appoint regular observation of functions of a liver. If abnormal liver functions remain or aggravated and if clinical signs or symptoms can be connected with the progressing liver diseases or if other manifestations are observed (for example an eosinophilia, rash), use of the medicine Diklosafe should be stopped. The course of diseases, such as hepatitis, can pass without the prodromal phenomena. Cautions are necessary if the medicament Diklosafe to use at patients with a hepatic porphyria because of the probability of provoking of attacks of a porphyria.

Influence on kidneys. As during treatment of NPVP, including diclofenac, liquid delay cases in an organism and hypostases are registered, special attention should be paid to patients with violations of functions of heart or kidneys, AG in the anamnesis, to the patients of advanced age, patients receiving the accompanying therapy by the diuretics or medicines significantly influencing function of kidneys and also to patients with considerable reduction of extracellular volume of liquid for any reason, for example to or after serious surgical intervention. In such cases as a precautionary measure the monitoring of function of kidneys is recommended. The therapy termination usually leads to return to the state preceding treatment.

Impact on skin. Due to the application of NPVP, including sodium diclofenac, serious reactions from skin (some of them were lethal) are seldom or never registered, including exfoliative dermatitis, Stephens's syndrome — Johnson and a toxic epidermal necrolysis. At patients the high risk of development of these reactions is observed at the beginning of a therapy course: emergence of reaction is noted in most cases within the first month of treatment. Use of the medicine Diklosafe needs to be stopped at the first appearance of skin rashes, damages of a mucous membrane or at emergence of any other signs of hypersensitivity.

System lupus erythematosus and the mixed diseases of connective tissue. At patients with a system lupus erythematosus and the mixed diseases of connective tissue the increased risk of developing aseptic meningitis can be observed.

Cardiovascular and cerebrovascular effects. The given clinical trials and epidemiological data demonstrate that use of diclofenac, especially in high doses (150 mg/days) and at long-term treatment, can be connected with slight increase of risk of development of arterial trombotichesky events (for example a myocardial infarction or a stroke).

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diclofenac to patients with considerable risk factors of the cardiovascular phenomena (for example AG, a lipidemia, diabetes, smoking) only after careful clinical assessment. As cardiovascular risks of diclofenac can increase with increase in a dose and duration of treatment, it is necessary to apply it shorter period and in a minimal effective dose. It is necessary to reconsider periodically need of the patient for use of diclofenac for reduction of expressiveness of symptoms and the response to therapy.

Patients needs to be informed on possibility of serious arterial trombotichesky cases (stethalgia, short wind, weakness, violation of the speech) which can occur at any time. In that case it is necessary to see a doctor immediately.

Influence on hematologic indicators. At prolonged use of diclofenac of sodium, as well as other NPVP, monitoring of complete analysis of blood is recommended.

Drug Diklosafe can oppress reversibly aggregation of platelets. It is necessary to observe carefully patients with violations of a hemostasis, hemorrhagic diathesis or hematologic violations.

OH in the anamnesis. Patients with OH, seasonal allergic rhinitis, a rhinedema (that is polyps), HOBL or persistent infections of airways (especially such which are connected with allergic similar to rhinitises symptoms) have reactions to NPVP, such as aggravation OH more often (so-called intolerance of analgetics / analgetic asthma), a Quincke's edema, urticaria. In this regard concerning such patients special measures (readiness for rendering emergency aid) are recommended. It also concerns patients with allergic reactions to other substances, such as rash, itch, urticaria.

As well as other medicines suppressing activity of a prostaglandinsintetaza, diclofenac of sodium and other NPVP can provoke development of a bronchospasm at application for patients with OH or patients with OH in the anamnesis.

Use during pregnancy and feeding by a breast. Pregnancy. In I and II trimester of pregnancy it is only possible to appoint diclofenac of sodium if the expected advantage for mother exceeds potential risk for a fruit, and only in a minimal effective dose, duration of treatment has to be so short as far as it is possible. As well as in case of application of other NPVP, medicine is contraindicated in the last 3 months of pregnancy (possibly suppression of sokratitelny ability of a uterus and premature closing of an arterial channel at a fruit). The inhibition of synthesis of prostaglandins can negatively affect pregnancy and/or development of an embryo/fruit. Data of epidemiological researches confirm the increased risk of development of warm defects and a gastroshizisa after use of inhibitor of synthesis of prostaglandins in the early stages of pregnancy. The absolute risk of emergence of cardiovascular defects was increased with less than 1 to 1.5%. It is possible that the risk increases with a dose and duration of treatment. It is established that at animals the introduction of inhibitor of synthesis of prostaglandins leads to increase pre- and post-implantation loss and lethality of an embryo/fruit.

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Besides, at the animals receiving inhibitor of synthesis of prostaglandins in the period of an organogenesis registered the increased frequency of various malformations, including from a cardiovascular system. If diclofenac of sodium is applied by the woman who aims to become pregnant, or in the I trimester of pregnancy, the dose has to be as low as possible, and treatment duration — as it is possible well.

In the III trimester of pregnancy at use of inhibitors of synthesis of prostaglandins the following side effects can arise:

• cardiopulmonary toxicity (with premature closing of an arterial channel and pulmonary hypertensia);
• a renal failure which can progress to a renal failure with oligogidramniony.

At mother and the newborn and also at the end of pregnancy:

lengthening of a bleeding time, antiagregantny effect which can arise even at very low doses are possible

• ;
• slowing down of reductions of a uterus which leads to a delay or lengthening of childbirth.

Thus, diclofenac of sodium is contraindicated in the III trimester of pregnancy.

Feeding by a breast. As well as other NPVP, diclofenac in insignificant quantity gets into breast milk. In this regard suppositories of diclofenac should not be applied at women during feeding by a breast to avoid undesirable influence on the baby.

Fertility of women. As well as other NPVP, diclofenac of sodium can have negative effect on female fertility therefore the women planning pregnancy are not recommended to appoint. At women who have problems with conception or undergo inspection concerning infertility, it is necessary to consider expediency of cancellation of diclofenac of sodium.

Ability to influence speed of response at control of vehicles or work with other mechanisms. To patients who during therapy by diclofenac of sodium have disorders of vision, dizziness, drowsiness, violations from central nervous system weakness or increased fatigue, it is not necessary to steer vehicles or to work with mechanisms.

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Interaction

specified the interactions observed at use of diclofenac in the form of enterosoluble tablets and/or in other dosage forms.

Lities. On condition of simultaneous application, diclofenac can increase concentration of lithium in blood plasma. Monitoring of level of lithium in blood plasma is recommended.

Digoksin. On condition of simultaneous application, diclofenac can increase concentration of digoxin in blood plasma. Monitoring of level of digoxin in blood plasma is recommended.

Diuretics and antihypertensive drugs. As well as reception of other NPVP, simultaneous use of diclofenac with diuretics and antihypertensive medicaments (for example blockers of β-adrenoceptors, APF inhibitors) can lead to decrease in their antihypertensive effect by inhibition of synthesis of vasodilating prostaglandins. Thus, the similar combination should be applied with the reservation, and patients, especially advanced age, have to be under careful observation concerning the ABP. Patients have to receive appropriate hydration, also monitoring of kidney function after the beginning of the accompanying therapy and on a regular basis after it, especially concerning diuretics and APF inhibitors, in connection with increase in risk of nephrotoxicity is recommended.

Drugs causing a hyperpotassemia. The accompanying treatment by kaliysberegayushchy diuretics, cyclosporine, takrolimusy or Trimethoprimum can be connected with increase in level of potassium in blood serum therefore monitoring of a condition of patients should be carried out more often.

Anticoagulants and antithrombocytic means. The combined application can increase risk of developing of bleeding therefore it is recommended to take precautionary measures. Though clinical trials do not demonstrate influence of diclofenac on activity of anticoagulants, there are separate data on increase in risk of bleeding at the patients accepting at the same time diclofenac and anticoagulants. Therefore for confidence that no changes in a dosage of anticoagulants are necessary, careful monitoring of such patients is recommended. As well as other NPVP, diclofenac in high doses can temporarily suppress aggregation of platelets.

Other NPVP, including selection TsOG-2 inhibitors and corticosteroids. Simultaneous use of diclofenac and other NPVP or GKS can increase risk of gastrointestinal bleeding or ulcer. It is necessary to avoid simultaneous application of two or more NPVP.

Selective serotonin reuptake inhibitors. Simultaneous application of NPVP and selection inhibitors of the return capture of a skerotonin can increase risk of gastrointestinal bleedings.

Antidiabetic medicines. Clinical trials showed that diclofenac can be applied together with oral hypoglycemic means that does not change their therapeutic effect. However there are some messages about development in such cases both a hypoglycemia, and a hyperglycemia that caused need of change of a dose of antidiabetic means at use of diclofenac. Therefore it is recommended to control at combination therapy glucose level in blood.

Methotrexate. Diclofenac can suppress clearance of a methotrexate in renal tubules that leads to increase in level of a methotrexate. It is necessary to be careful when assigning NPVP, including diclofenac, less than for 24 h before application of a methotrexate as in such cases can raise concentration of a methotrexate in blood and amplifies its toxic action. Cases of heavy toxicity when the interval between application of a methotrexate and NPVP, including diclofenac, was within 24 h are registered. This interaction is mediated because of accumulation of a methotrexate as a result of violation of kidney excretion in the presence of NPVP.

Cyclosporine. Diclofenac influence, as well as other NPVP, on synthesis of prostaglandins in kidneys can increase nephrotoxicity of cyclosporine, in this regard diclofenac should be applied in lower doses, than at the patients who are not applying cyclosporine.

Takrolimus. At application of NPVP with takrolimusy increase in risk of nephrotoxicity is possible that can is mediated to happen through renal antiprostaglandinovy effects of NPVP and inhibitor of a kaltsinevrin.

Antibacterial hinolona. There are separate data on development of spasms in the patients who are at the same time accepting derivatives of a hinolon and NPVP. It can be observed at patients as with epilepsy and spasms in the anamnesis, and without them. Thus, it is necessary to show care at the solution of a question of application of hinolon for the patients who are already receiving NPVP.

Phenytoinum. At use of Phenytoinum along with diclofenac it is recommended to carry out monitoring of concentration of Phenytoinum in blood plasma in connection with the expected increase in influence of Phenytoinum.

Kolestipol and Colestyraminum. These medicines can cause a delay or reduction of absorption of diclofenac. Thus, it is recommended to appoint diclofenac at least for 1 h to or in 4–6 h after application kolestipola / Colestyraminum.

Cardiac glycosides. Simultaneous use of cardiac glycosides and NPVP for patients can strengthen heart failure, reduce glomerular filtration rate and increase the level of cardiac glycosides in blood plasma.

Mifepristone. NPVP should not be applied within 8–12 days after use of mifepristone as NPVP can reduce effect of mifepristone.

Powerful CYP inhibitors 2C9. The care is recommended at the combined prescribing of diclofenac with powerful CYP inhibitors 2C9 (for example with vorikonazoly) that can lead to substantial increase of the C _max in blood plasma and exposure of diclofenac owing to diclofenac metabolism oppression.

Overdose

Symptoms. the typical clinical picture inherent to diclofenac overdose, does not exist. the overdose can cause such symptoms as a headache, nausea, vomiting, pain in epigastriums, gastrointestinal bleeding, diarrhea, dizziness, a disorientation, excitement, a coma, drowsiness, sonitus and spasms. opn and damage of a liver are possible in case of heavy intoxication.

Treatment. In case of need symptomatic treatment. During 1 h after use of potentially toxic amount of medicine it is necessary to consider the possibility of use of activated carbon. Besides, for adult patients it is necessary to consider the possibility of gastric lavage during 1 h after use of potentially toxic amount of medicine. In frequent or long spasms it is necessary in/in to enter diazepam. Taking into account a clinical condition of the patient other actions can be shown.

Storage conditions

In original packing at a temperature not above 25 °C.