Diclofenac - instructions for use, dose, side effects, contraindications

Excipients: propylene glycol 200 mg, benzyl alcohol 40 mg, mannitol 6 mg, sodium metabisulphite sodium disulfite 3 mg, sodium hydroxide solution 1 M to pH 8.0 9.0, water for injection 1.0 ml.

Description:Transparent or slightly opalescent liquid colorless or slightly yellowish with a faint smell of benzyl alcohol.

Pharmacotherapeutic group:Non-steroidal anti-inflammatory drug (NSAID).

ATX: & nbsp

S.01.B.C.03 Diclofenac

M.01.A.B.05 Diclofenac

Pharmacodynamics:

The active component of the drug diclofenac - non-steroidal anti-inflammatory drug (NSAID), which has pronounced analgesic, antipyretic and anti-inflammatory properties. Non-selective inhibitor of cyclooxygenases 1 and 2 type (COX-1 and COX-2).It disrupts the metabolism of arachidonic acid and the synthesis of prostaglandins, which are the main link in the development of inflammation.

In rheumatic diseases, the drug contributes to a significant reduction in pain, morning stiffness, swelling of the joints, which contributes to the improvement of the functional state of the joint. With injuries, in the postoperative period diclofenac reduces pain and inflammatory swelling.

Pharmacokinetics:

Suction

After intramuscular injection of diclofenac, its absorption begins immediately. The maximum concentration in the plasma (Cms), the average value of which is about 2.5 μg / ml (8 μmol / L), is reached after about 20 minutes. The amount of absorbing active substance is in linear dependence on the amount of the drug.

The area under the "concentration-time" curve (AUC) after intramuscular administration of diclofenac is approximately 2 times greater than after its oral or rectal administration, since in the latter cases about half the amount of diclofenac is metabolized by "first passage" through the liver.With subsequent administration of the drug, pharmacokinetic parameters do not change. Provided that the recommended intervals between injections of the drug cumulation is not noted.

Distribution

The connection with serum proteins is 99.7%, mainly with albumins (99.4%). The apparent volume of distribution is 0.12-0.17 l / kg.

Diclofenac penetrates into the synovial fluid, where its maximum concentration is reached 2-4 hours later than in the blood plasma. Apparent half-life (T ¹L) from the synovial fluid is 3-6 hours. Two hours after reaching the maximum concentration in the blood plasma, the concentration of diclofenac in the synovial fluid is higher than in the plasma, and its values remain higher for a period of time, up to 12 hours. Metabolism

The metabolism of diclofenac is partly due to the glucuronization of the unmodified molecule, but mainly through single and multiple hydroxylation and methoxylation, which leads to the formation of several phenolic metabolites (3'-hydroxy-, 4'-hydroxy-, 5'-hydroxy-, 4 ' 5-dihydroxy and 3'-hydroxy-4'-methoxydiclofenac), most of which are converted to glucuronide conjugates.Two phenolic metabolites are biologically active, but to a much lesser extent than diclofenac. In the metabolism of the drug takes part isoenzyme CYP2C9.

Excretion

The total systemic plasma clearance of diclofenac is 263 ± 56 ml / min. The final T 1/2 is 1-2 hours. T 1/2 4 metabolites, including two pharmacologically active, also short-lived and is 1-3 hours. One of the metabolites,

3 '-hydroxy-4' -methoxy-diclofenac, has a longer T _1/2, however this metabolite

completely inactive.

About 60% of the dose is excreted through the kidneys in the form of glucuronic conjugates of unchanged active substance, as well as in the form of metabolites, most of which are also glucuronic conjugates. Unchanged, less than 1% of diclofenac is excreted. The rest of the dose is excreted as metabolites with bile.

Pharmacokinetics in selected patient groups

The pharmacokinetic parameters of diclofenac in elderly patients do not change.

In patients with impaired renal function, cumulation of the unchanged active substance is not observed when the recommended dosage regimen is observed.When creatinine clearance (CK) is less than 10 ml / min, the calculated equilibrium concentrations of diclofenac hydroxy metabolites are approximately 4 times higher than in healthy volunteers, with the metabolites being excreted exclusively with bile. In patients with chronic hepatitis or compensated cirrhosis, the pharmacokinetics of diclofenac are similar to those in patients without liver disease.

Diclofenac penetrates into breast milk.

Indications:

Inflammatory and degenerative forms of rheumatic diseases:

- rheumatoid arthritis;

- ankylosing spondylitis;

- osteoarthritis;

- spondyloarthritis.

Pain syndromes from the side of the spine.

Rheumatic diseases of extraarticular soft tissues. Acute attack of gout.

Post-traumatic and postoperative pain syndrome, accompanied by inflammation.

Severe attacks of migraine.

The drug is intended for symptomatic therapy, reducing pain and inflammation at the time of use, the progression of the disease is not affected.

Contraindications:

- Hypersensitivity to diclofenac (in t. Components of the drug.

- Complete or incomplete combination of bronchial asthma, recurrent nasal polyposis or paranasal sinuses and intolerance to acetylsalicylic acid and other NSAIDs (including in the anamnesis).

- Exacerbation of peptic ulcer of the stomach and duodenum, ulcerous bleeding of the gastrointestinal tract, perforation.

- Severe hepatic, renal (creatinine clearance (CK) less than 30 ml / min) and heart failure.

- Conditions accompanied by a risk of bleeding (eg, cerebrovascular vascular bleeding, etc.), hemophilia and other bleeding disorders.

- Confirmed hyperkalemia.

- Early postoperative period after aortocoronary bypass surgery.

- Inflammatory bowel disease (Crohn's disease, ulcerative colitis) in the phase of exacerbation.

- Active liver disease.

- Pregnancy III trimester, the period of breastfeeding.

- Children under 18 years.

Carefully:When diclofenac or other NSAIDs, careful medical supervision of patients having ulcerative lesion of the stomach or bowel, infection of Helicobacter pylori, ulcerative colitis, Crohn's disease, impaired liver function or a history of the patients complained, pointing to the gastro-intestinal tract. The risk of gastrointestinal bleeding increases with increasing doses of NSAIDs or in the presence of ulcer history, especially bleeding and perforation of ulcers in elderly patients.Care should be taken when using in patients with seasonal allergic rhinitis, edema of the nasal mucosa (including those with nasal polyps), chronic obstructive pulmonary disease, chronic respiratory infections (especially associated with allergic rhinitis-like symptoms).

Special care should be taken when using diclofenac in patients,

receiving drugs that increase the risk of gastrointestinal

bleeding:

systemic glucocorticosteroids (incl. prednisolone), anticoagulants (incl. warfarin), antiplatelet agents (including clopidogrel, acetylsalicylic acid) or selective serotonin reuptake inhibitors (including citalopram, fluoxetine, paroxetine, sertraline).

Caution is necessary for the administration of diclofenac to patients with hepatic porphyria, since the drug may provoke porphyria attacks. Since prostaglandins play an important role in maintaining renal blood flow, special care is required in the treatment of patients with cardiovascular diseases (including coronary heart disease,cerebrovascular diseases, compensated heart failure, peripheral vascular disease), with defects in the hemostasis system, with a risk of cardiovascular thrombosis (including myocardial infarction and strokes), impaired renal function, including chronic renal failure (KK 30-60 ml / min), dyslipidemia / hyperlipidemia, diabetes mellitus, hypertension, in the treatment of smokers or alcohol abusers in the treatment of elderly patients receiving diuretics or other drugs, guides on renal function as well as patients with significant; a decrease in the volume of circulating blood of any etiology, for example, in periods before and after massive surgical interventions.

Caution should be exercised when using diclofenac in elderly patients. This is especially true in weakened or low-weight elderly people; they are recommended to prescribe the drug at the lowest effective dose. Particular care should be taken when intramuscular diclofenac is administered to patients with bronchial asthma due to the risk of exacerbation of the disease.

Pregnancy and lactation:The safety of diclofenac in pregnant women has not been studied. Assign diclofenac in the I and II trimesters of pregnancy should only be in cases where the expected benefit to the mother exceeds the potential risk to the fetus. Diclofenac, like other inhibitors of prostaglandin synthesis, is contraindicated in the last 3 months of pregnancy (possibly suppressing the uterine contractility and premature closure of the arterial duct in the fetus). In studies on animals, no negative effect of diclofenac on the course of pregnancy, embryonic and postnatal development has been established.

Although diclofenac, like other NSAIDs, penetrates into breast milk in small quantities, the drug should not be given to nursing women to avoid undesirable effects on the child. If it is necessary to prescribe diclofenac in a nursing woman, breastfeeding is discontinued. Because the diclofenac, like other NSAIDs, can have a negative effect on fertility, women planning a pregnancy are not recommended to take the drug. In patients undergoing examination and treatment for infertility, the drug should be canceled.

Dosing and Administration:

Diclofenac, a solution for intramuscular injection, should be administered individually, at the lowest effective dose for the shortest possible time. Diclofenac in ampoules is especially suitable for the initial treatment of inflammatory and degenerative rheumatic diseases, as well as with pain due to inflammation of non-rheumatic origin. The drug is injected by deep injection into the gluteus muscle. Do not inject diclofenac more than 2 consecutive days. If necessary, treatment can be continued with diclofenac in tablets or rectal suppositories.

When carrying out intramuscular injection in order to avoid damage to the nerve or other tissues, it is recommended that the following rules be adhered to. The drug should be injected deeply intramuscularly into the upper outer quadrant of the gluteal region. The dose is usually 75 mg (the contents of 1 ampoule) once a day. In severe cases, as an exception, 2 injections of 75 mg can be given, with an interval of at least 12 hours (the second injection should be performed in the opposite gluteal region). As an alternative,one injection per day (75 mg) can be combined with the administration of other dosage forms of diclofenac (tablets, rectal suppositories), while the total daily dose should not exceed 150 mg.

In migraine attacks, the best result is achieved if diclofenac as soon as possible after the onset of the attack, intramuscularly at a dose of 75 mg (1 ampoule), followed by the use of suppositories in a dose of up to 100 mg on the same day, if required. The total daily dose should not exceed 175 mg on the first day, then not more than 150 mg.

The drug solution should be clear. Do not use a solution with a crystalline or other precipitate.

The ampoule of the drug should be used only once. The solution must be entered

immediately after opening the ampoule. After a single use, the unused diclofenac solution remains unused for treatment.

Do not mix the diclofenac solution contained in the ampoules with solutions of other drugs for injection.

Diclofenac, a solution for intramuscular injection, should not be used in children and adolescents under 18 due to the difficulty of dosing the drug; if necessary, treatment in this category of patients diclofenac can be given in tablets or suppositories.

Side effects:

To assess the incidence of adverse reactions of diclofenac (various dosage forms), the following grades are used:

"very often"> 1/10, "often" from> 1/100 to <1/10, "infrequently" from> 1/1000 to <1/100, "rarely" from> 1/10000 to <1/1000 , "very rarely" from <1/10000, including individual messages.

Infectious and parasitic diseases: very rarely - an abscess at the injection site.

Disorders from the digestive system: often - abdominal pain, nausea, vomiting, diarrhea, dyspepsia, flatulence, anorexia. Rarely - gastritis, gastrointestinal bleeding, vomiting of blood, melena, diarrhea with a trace of blood, proctitis, ulcers of the stomach and intestines (with or without bleeding or perforation). Very rarely - stomatitis, glossitis, esophagitis, damage to the esophagus, the appearance of diaphragm-like structures in the intestine, colitis (nonspecific hemorrhagic colitis, exacerbation of ulcerative colitis or Crohn's disease), constipation, pancreatitis, exacerbation of hemorrhoids.

Disorders from the liver and bile ducts: often - increased activity of aminotransferases in blood serum. Rarely - hepatitis, jaundice, liver function disorders. Very rarely - liver necrosis, hepatic insufficiency, hepatorenal syndrome.

Impaired nervous system: often - headache, dizziness. Rarely, drowsiness. Very rarely - disorders of sensitivity, including paresthesia, memory disorders, tremors, convulsions, anxiety, acute disorders of cerebral circulation, aseptic meningitis, taste disorders.

Disorders of the psyche: very rarely - disorientation, depression, insomnia, nightmares, irritability, mental disorders.

Disorders from the side of the organ of vision: very rarely - blurred vision (fogging

view, diplopia).

Hearing disorders and labyrinthine disturbances: often - vertigo; highly

rarely - hearing impairment, tinnitus.

Disturbances from the skin and subcutaneous tissues: often - skin rash; rarely - hives; very rarely - bullous eruptions, eczema, erythema, erythema multiforme, Stevens-Johnson syndrome, Lyell syndrome (toxic epidermal necrolysis), exfoliative dermatitis, itching, hair loss, photosensitivity reactions; purpura, incl. allergic.

Disorders from the kidneys and urinary tract: very rarely - acute renal failure, hematuria, proteinuria, interstitial nephritis; nephrotic syndrome; papillary necrosis.

Violations from the blood and lymphatic system: very rarely thrombocytopenia, leukopenia, hemolytic anemia, aplastic anemia, agranulocytosis, eosinophilia.

Immune system disorders: rarely - hypersensitivity, anaphylactic / anaphylactoid reactions, including lowering blood pressure and shock; very rarely - angioedema.

Heart Disease: very rarely - a feeling of palpitation, chest pain, heart failure, myocardial infarction.

Vascular disorders: very rarely - increased blood pressure (BP), vasculitis.

Disturbances from the respiratory system, chest and mediastinal organs: rarely - bronchial asthma (including dyspnea), cough, laryngeal edema; very rarely - pneumonitis.

General disorders and reactions at the site of administration: often - pain, compaction at the injection site; rarely - swelling, necrosis at the injection site.

Overdose:There are no typical clinical manifestations of an overdose of diclofenac. In case of an overdose of the drug, vomiting, bleeding from the gastrointestinal tract (GIT), diarrhea, dizziness, tinnitus or cramps, shortness of breath, respiratory depression, coma may be observed.In the event of a significant overdose, acute renal failure and liver damage can occur.

Treatment: Symptoms of an overdose of NSAIDs, including diclofenac, include supportive and symptomatic therapy. Supportive and symptomatic treatment is indicated in such complications as lowering of arterial pressure, renal failure, convulsions, gastrointestinal disturbances and respiratory depression. The effectiveness of forced diuresis, hemodialysis or hemoperfusion is unlikely, since NSAIDs, including diclofenac, largely bind to plasma proteins and undergo intensive metabolism.

Interaction:

The following drug interactions were noted with the use of various dosage forms of diclofenac.

Lithium, digoxin. Because the diclofenac can increase the concentration of lithium and digoxin in blood plasma, it is recommended to measure the concentration of lithium and digoxin in the blood with simultaneous application with diclofenac for intramuscular injection.

Diuretic and antihypertensives. When applied simultaneously with diuretic and antihypertensive drugs (e.g., beta-blockers, ACE inhibitors) diclofenac, like other NSAIDs, can reduce their hypotensive effect. Therefore, in patients, especially the elderly, with the simultaneous administration of diclofenac and diuretics or antihypertensive agents, blood pressure, kidney function and hydration should be regularly monitored (especially when combined with diuretics and ACE inhibitors due to increased risk of nephrotoxicity). The simultaneous use of potassium-sparing diuretics may lead to an increase in the potassium concentration in blood serum (in the case of this combination of drugs often, the indicator should monitor).

NSAIDs and glucocorticosteroids. Simultaneous systemic administration of diclofenac and other systemic NSAIDs or corticosteroids may increase the incidence of adverse effects from the gastrointestinal tract.

Anticoagulants and antiaggregants. Although clinical studies have not been found to influence the action of anticoagulants diclofenac,there are some reports of an increased risk of bleeding in patients taking this combination of drugs. Therefore, in the case of such a combination of drugs, careful monitoring of patients is recommended.

Selective serotonin reuptake inhibitors. The simultaneous use of NSAIDs, including diclofenac with selective serotonin reuptake inhibitors increases the risk of developing gastrointestinal bleeding.

Hypoglycemic drugs. In clinical studies, it has been established that when diclofenac is used together with hypoglycemic drugs for oral administration, diclofenac does not affect the effectiveness of the latter. However, separate reports on the development of both hypoglycemic and hyperglycemic conditions are known on the background of the use of diclofenac, requiring a change in the dose of hypoglycemic drugs. In patients receiving simultaneous treatment with hypoglycemic drugs and diclofenac, the blood glucose concentration should be measured regularly.

Methotrexate. Care should be taken when prescribing NSAIDs, including diclofenac, less than 24 hours before or after taking methotrexate, since in such cases, the concentration of methotrexate in the blood may increase and its toxic effect may be increased.

Cyclosporine. Changing the activity of prostaglandins in the kidneys, diclofenac, like other NSAIDs, can enhance the nephrotoxicity of cyclosporine. When administered simultaneously with cyclosporine, the dose of diclofenac should be lower than in patients not using ciclosporin.

Antibacterial agents derived from quinolone. There are separate reports on the development of seizures in patients receiving concurrently derivatives of quinolone and NSAIDs.

Strong inhibitors CYP2C9. Caution should be exercised when co-administration of diclofenac and strong inhibitors CYP2C9 (such as sulfinpyrazone and voriconazole) because of a possible increase in diclofenac concentration in the serum and an increase in systemic action caused by inhibition of diclofenac metabolism.

Phenytoin. With the simultaneous use of phenytoin and diclofenac, it is necessary to monitor the concentration of phenytoin in the blood plasma because of the possible increase in its systemic effect.

Cyclosporine and preparations of gold. Changing the activity of prostaglandins in the kidneys, diclofenac, like other NSAIDs, can enhance the nephrotoxicity of cyclosporine and gold preparations. With simultaneous use with cyclosporine, gold preparations, the dose of diclofenac should be lower than in patients not using ciclosporin or preparations of gold.

Cefamandol, cefoperazone, cefotetan, valproic acid and plikamycin increase the frequency of hypoprothrombinemia.

Simultaneous application with ethanol, colchicine, corticotropin, preparations of St. John's wort perfumed increases the risk of bleeding in the gastrointestinal tract.

Medicines that cause photosensitivity, increase the sensitizing effect of diclofenac to UV irradiation.

Drugs that block the tubular secretion, increase the concentration in the plasma of diclofenac, thereby increasing its effectiveness and toxicity.

Acetylsalicylic acid reduces the concentration of diclofenac in the blood.

Special instructions:

When using NSAIDs, including diclofenac, such phenomena as bleeding or ulceration / perforation of the gastrointestinal tract, in some cases with a fatal outcome, were noted.These phenomena can occur at any time with the use of drugs in patients with the presence or absence of previous symptoms and serious gastrointestinal diseases in or without anamnesis. In elderly patients, such complications can have serious consequences. When developing in patients receiving the drug diclofenac, bleeding or ulceration of the gastrointestinal tract, the drug should be discontinued. To reduce the risk of toxic effects on the gastrointestinal tract, patients with ulcerative gastrointestinal lesions, especially complicated bleeding or perforating history, and elderly patients, the drug should be given at the lowest effective dose.

Patients with an increased risk of developing gastrointestinal complications, as well as patients receiving low-dose acetylsalicylic acid therapy, or other drugs that can increase the risk of gastrointestinal damage, should take gastroprotectors (for example, proton pump inhibitors or misoprostol). Patients with a history of gastrointestinal disease, especially the elderly, should be informed of all unusual abdominal symptoms.

Such serious dermatological reactions as exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, in some cases fatal, against the background of NSAIDs, including diclofenac, were very rare. The greatest risk and frequency of severe dermatological reactions were observed in the first month of treatment with diclofenac. When developing in patients receiving diclofenac, the first signs of skin rashes, lesions of mucous membranes or other symptoms of hypersensitivity, the drug should be

canceled.

In rare cases, patients who are taking NSAIDs for the first time, including diclofenac, allergic reactions may occur, including anaphylactic / anaphylactoid reactions.

The anti-inflammatory effect of diclofenac and other NSAIDs may make it difficult to diagnose infectious processes.

Do not assign diclofenac together with other NSAIDs, including selective inhibitors of COX 2, due to the lack of data on increasing the effectiveness of joint therapy, and also because of the potential increase in adverse events. Since in the period of diclofenac, as well as other NSAIDs,there may be an increase in the activity of one or more liver enzymes, with prolonged therapy with the drug, as a precautionary measure, shows control of liver function, a clinical blood test, a feces analysis for occult blood. With the preservation and progression of violations of the hepatic function or the appearance of signs of liver disease, or other symptoms (eg, eosinophilia, rash, etc.), the drug should be withdrawn. It should be borne in mind that hepatitis against the background of diclofenac can develop without prodromal phenomena. On the background of therapy with NSAIDs, including diclofenac, fluid retention and edema were noted, therefore, care should be taken to monitor renal function in patients with hypertension, cardiac or renal dysfunction, elderly patients, patients receiving diuretics or other drugs that affect renal function, and patients with a significant decrease in the volume of circulating blood plasma of any etiology, for example, in the period before and after massive surgical interventions.After discontinuation of therapy with the drug, normalization of renal function to normal values is usually noted.

Diclofenac, as well as other NSAIDs, can temporarily inhibit platelet aggregation. Therefore, patients with hemostasis disorders should carefully monitor the relevant laboratory indicators.

With prolonged use of diclofenac, it is recommended to conduct regular clinical analysis of peripheral blood.

Exacerbation of bronchial asthma, Quincke's edema and urticaria are most often observed in patients with bronchial asthma, seasonal allergic rhinitis, nasal polyps, chronic obstructive pulmonary disease or chronic infectious diseases of the respiratory tract (especially associated with allergic rhinitis-like symptoms). In this group of patients, as well as in patients with allergies to other drugs (rash, itching or urticaria), special care should be taken when prescribing diclofenac (readiness for resuscitation).

To reduce the risk of developing adverse events, a minimally effective dose of diclofenac should be used with the minimum possible short course.Long-term diclofenac therapy and high-dose therapy may lead to an increased risk of developing serious cardiovascular thrombotic complications (including, myocardial infarction and stroke).

Effect on the ability to drive transp. cf. and fur:Patients who experience visual disturbances, dizziness, drowsiness, vertigo, or other abnormalities from the central nervous system against the background of diclofenac use should not drive vehicles and work with mechanisms.

Form release / dosage:

Solution for intramuscular injection 25 mg / ml.

Packaging:

To 3 ml in ampoules with a capacity of 5 ml of colorless neutral glass with a color fracture ring or with a colored dot and a notch or without a break ring, a colored dot and a notch. One, two or three color rings and / or a two-dimensional bar code, and / or alphanumeric coding or without additional color rings, a two-dimensional bar code, and alphanumeric coding can additionally be applied to the ampoules.

5 ampoules per contour cell packaging made of polyvinyl chloride film and aluminum foil lacquered or

film polymer or without foil and without film.Or 5 ampoules are placed in a prefabricated form (tray) made of cardboard with cells for laying ampoules.

One or two contour squares or cardboard trays, together with an instruction for use and a scarifier or knife with an ampoule, or without a scarifier and a knife ampoule, are placed in a cardboard box (bundle)

Storage conditions:In the dark place at a temperature of no higher than 25 0 C. Do not freeze. Keep out of the reach of children.

Shelf life:3 years. Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002813

Date of registration:13.01.2015

Date of cancellation:2020-01-13

The owner of the registration certificate:ATOLL, LLC ATOLL, LLC Russia

Manufacturer: & nbsp

OZON PHARM, LLC Russia

Information update date: & nbsp05.02.2016

Illustrated instructions

Instructions

Diclofenac (Diclofenac)